A Phase 2 Double-Blind Clinical Trial to Examine the Comparative Effects on Osteoarthritic Knee Pain of CGS-200-1 (1% Capsaicin Topical Liquid), CGS-200-5 (5% Capsaicin Topical Liquid), and CGS-200-0 (Vehicle, No Capsaicin)
Phase: PHASE2
Conditions: Osteoarthritis, Knee, Pain
Sponsor: Propella Therapeutics

 
 
A Phase 2 Double-Blind Clinical Trial to Examine the Comparative Effects on Osteoarthritic Knee Pain of 
CGS-200-1 (1% Capsaicin Topical Liquid), CGS-200-5 (5% Capsaicin Topical Liquid), and CGS-200-0 
(Vehicle, No Capsaicin) – Protocol  
  
Protocol Number:  VZU00025 
Protocol Date: 1-AUGUST-2018 
NCT03528369 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
FINAL / Version 5.0 1-AUGUST-2018 
Page 1 
Protocol Title: 
A Phase 2 Double-Blind Clinical Trial to Examine the Comparative Effects 
on Osteoarthritic Knee Pain of CGS-200-1 (1% Capsaicin Topical Liquid), 
CGS-200-5 (5% Capsaicin Topical Liquid), and CGS-200-0 (Vehicle, No 
Capsaicin)  
Protocol Number:  VZU00025 
 
Version No./Date:  5.0 / 1-AUGUST-2018 
 
Study Drug: 
CGS-200-5 (Capsaicin 5% Topical Liquid); 
CGS-200-1 (Capsaicin 1% Topical Liquid); and, 
CGS-200-0 (Investigational Drug Product Vehicle, 0% Capsaicin) 
  
IND #: 
138684 
 
Sponsor: 
Vizuri Health Sciences LLC  
12500 Fair Lakes Circle  
Suite 450 
Fairfax, VA 22033  
Phone: 301-728-0178 
Medical Monitor 
William S. Aronstein, Ph.D., M.D., F.A.C.P. 
Vice President, Medical Affairs 
CTI Clinical Trial & Consulting Services 
100 E. RiverCenter Blvd 
Covington, KY 41011 
Phone: 1-800-873-5695 
 
 
 
 
 
 
 
 
 
 
 
Confidential and Proprietary 
 
This protocol is a confidential communication document of Vizuri Health Sciences LLC. The recipient of this 
document agrees not to disclose the information contained herein to others without prior written authorization of 
Vizuri Health Sciences LLC. except that this document may be disclosed to appropriate Institutional Review 
Boards/Independent Ethics Committees or duly authorized representatives of Regulatory authorities such as the United 
States (U.S.) Food and Drug Administration, European Medicines Agency, or other cognizant authorities worldwide 
under the condition that they maintain confidentiality. 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
FINAL / Version 5.0 1-AUGUST-2018 
Page 2 
Investigator Agreement 
I confirm that I have read and understood this protocol and agree to conduct this study as outlined 
in the protocol and other information supplied to me. I agree to conduct this study in compliance 
with Good Clinical Practice (GCP) standards as defined by the International Conference on 
Harmonization (ICH) Guideline for Good Clinical Practice, the ethical principles of the 
Declaration of Helsinki, all applicable national, state and local regulations, as well as the 
requirements of the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and any other institutional requirements. 
Principal Investigator: 
Signature 
Date 
Name (please type or print) 
Institution 
Address 
 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
FINAL / Version 5.0 1-AUGUST-2018 
Page 3 
STUDY SYNOPSIS 
Sponsor: 
Vizuri Health Sciences LLC  
12500 Fair Lakes Circle  
Suite 450 
Fairfax, VA 22033 
Protocol Title: 
A Phase 2 Double-Blind Clinical Trial to Examine the Comparative 
Effects on Osteoarthritic Knee Pain of CGS-200-1 (1% Capsaicin 
Topical Liquid), CGS-200-5 (5% Capsaicin Topical Liquid), and 
CGS-200-0 (Vehicle, No Capsaicin)  
Protocol Number: 
VZU00025 
Study Phase: 
Phase 2 
Study Endpoints: 
  
The Primary Efficacy endpoint of this study will be to examine the 
extent of reduction in the WOMAC pain score, relative to baseline, 
provided by once daily, one-hour application of Vehicle 
(CGS-200-0), CGS-200-1, and CGS-200-5 at the following 
assessment times: 
 
Baseline: < 30 minutes prior to first daily application 
Day 35  31 Days (+/- 3 days) after fourth daily application 
 
and based thereon to determine whether the responses for treatment 
with CGS-200-1 and CGS-200-05 are significantly different from 
Vehicle (CGS-200-0) and from each other at the primary endpoint 
time.  
 
The Primary Safety endpoints will be: 
 
(1) The application of the study drug does not produce skin 
reactions (erythema, scaling, pruritus, or other) to a degree 
that is clinically of concern. Scoring of erythema and scaling 
at the application sites and of pruritus will be assessed per the 
scoring systems in Appendix F. 
 
(2) No SAE’s either possibly, probably, or definitely associated 
with study treatments. 
 
(3) Safety labs (hematology, serum chemistry and urinalysis) do 
not produce other than minimal – mild toxicities (Grade 1 or 
Grade 2). Scoring of clinical, hematological and urinalysis out 
of range findings for toxicity grading will be per Appendix B. 
 
 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
STUDY SYNOPSIS (continued) 
FINAL / Version 5.0 1-AUGUST-2018 
Page 4 
 
Secondary Efficacy endpoints will be: 
 
(1) 
To examine the extent of reduction in the WOMAC pain score, 
relative to baseline, provided by once daily, one-hour 
application of Vehicle (CGS-200-0), CGS-200-1 and 
CGS-200-5 at the following assessment times: 
 
Baseline: < 30 minutes prior to first daily application 
Day 5   24 hrs (+/- 3) after last of the 4 daily applications 
Day 19  15 days (+/- 3) after last of the 4 daily applications 
Day 64  60 days (+/- 3) after the last of 4 daily applications 
Day 94  90 days (+/- 3) after the last of 4 daily applications  
 
(2) 
Day 5, 19, 35, 64, and 94 WOMAC scores on the stiffness and 
function subscales as well as total WOMAC score (including 
the WOMAC pain score).  
 
 
Secondary Safety endpoints will be:  
 
(1) The distribution by study arms of specific Adverse Events 
(AEs) (e.g., local application site reactions, and other AEs 
(inclusive of findings for hematology and serum chemistry)).  
(2) Evaluate the amount of concomitant pain medications used 
overtime 
 
Tolerability endpoints (which are secondary in nature) will be: 
 
(1) The application of study drug does not produce burning-
stinging pain (“BSP”) at the application site to a degree that is 
not acceptable to the subject. BSP at the application site, this 
will be assessed using a 0 – 10 NRS scale without guideposts. 
“Acceptability” of BSP will be queried per subject at the end 
of each application period. 
 
(2) The application of the study drug does not produce pruritus 
during application or in the 24 hrs post-application to a degree 
that is not acceptable to the subject or, if bothersome to the 
subject, cannot be managed by application of ice or a cold pack 
or compress 
 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
STUDY SYNOPSIS (continued) 
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Study Duration 
13-14 weeks for each subject, excluding screening. 
Study Design: 
This is a multi-center, randomized, double-blind clinical trial in subjects 
with OA according to the 1986 American College of Rheumatology 
(ACR) criteria. There will be with three study arms: 
 
Arm 1  CGS-200-0 (Investigational Drug Product Vehicle) 
Arm 2  CGS-200-1 (1% Capsaicin in CGS-200 vehicle) 
Arm 3  CGS-200-5 (5% Capsaicin in CGS-200 vehicle) 
 
Each Arm will enroll 40 evaluable subjects, for a total of 120 evaluable 
subjects in this study. Subjects that give Informed Consent to participate 
and who are deemed after screening to be eligible to participate will be 
randomized to one of the three study Arms. 
 
Subjects will receive the Arm-appropriate treatment as a topical 
application over the frontal aspect of the knee(s) once daily on four 
consecutive days. The applications will be at the clinic but by the 
subject under supervision of clinic personnel. Wearing gloves 
supplied by the clinic staff, the subject will apply the study drug on 
and around the knee covering a 10cm by 10cm area. The application 
will be left in place for 60 (up to 65) minutes and then washed off at 
the clinic by clinic personnel. The amount of Investigational Drug 
Product to be applied is estimated to be approximately 0.13 mL based 
on experience in prior studies. Even though both knee(s) will receive 
application of study test materials, with regard to reduction in 
WOMAC pain and VAS pain score associated with study treatments, 
only one knee will be indicated as the “Study Knee”. This will be the 
knee with the highest WOMAC pain score at baseline. If both knees 
have equal WOMAC pain scores at baseline, then the right knee will 
be considered the “Study Knee” with regard to WOMAC pain and 
VAS pain score reduction.  
 
The Investigators, all site staff, study subjects and Clinical Research 
Organization (CRO) personnel (except for the Medical Monitor 
providing safety oversight) directly involved in the study will remain 
blinded to the treatment assignment throughout the trial.  
 
Estimated No. of 
Subjects: 
Total 120 evaluable subjects: 40 subjects will be allocated to each 
study Arm. An allowance of up to 10 subjects per Arm is to be 
provided for dropouts whose withdrawal is not due to lack of study 
drug tolerability).  
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
STUDY SYNOPSIS (continued) 
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Inclusion/Exclusion 
Criteria: 
Inclusion Criteria 
The subject must meet all of the following: 
1. Able to comprehend the informed consent form (ICF) and provide 
Informed Consent, and capable of complying with all study 
procedures; 
2. Male or female, 35 years of age to 75 years; 
3. OA of at least one knee according to 1986 ACR Classification 
Criteria; 
4. OA of at least one knee must be confirmed by tibiofemoral joint 
radiographs obtained within the past 6 months; 
5. Rheumatoid factor (RF) negative and Erythrocyte sedimentation rate 
(ESR) <40 mm/hr; 
6. Chronic knee pain in at least one knee for > 3 months; 
7. WOMAC pain score of > 250 (using VAS WOMAC format) at 
screening, and at baseline, in at least one knee; 
8. Knee pain score of > 5 on the NRS pain scale at  screening, and at 
baseline, in at least one knee; 
9. Knee pain is not potentially due to acute trauma unrelated to OA 
(no acute traumatic knee injury in medical history); 
10. No burning-stinging pain, unrelated to subject’s knee pain, at 
intended site of application; 
11. Knee pain must be greater than pain in any other part of subject’s 
body; 
12. ACR global functional status I, II, or III (excluding IV); 
13. If female, subject must be past childbearing age or otherwise must 
test negative for pregnancy. Males and females must agree to use 
effective birth control for at least 30 days after last dose of study 
drug. 
 
Exclusion Criteria 
 
The subject must not have any of the following: 
1. Spontaneously improving or rapidly deteriorating OA of the knee; 
2. Rheumatoid or psoriatic arthritis, or a form of arthritis (e.g. gout, 
pseudogout), Paget’s disease of bone, or any other disease affecting 
the joints that are inconsistent with a diagnosis of idiopathic OA; 
3. Use of topical, oral, or injectable steroids for 1 month prior to 
screening, or intraarticular visco-supplementation within 3 months 
prior to screening; 
4. Used any capsaicin-containing product on or in the vicinity of the 
knee within 4 weeks prior to screening; 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
STUDY SYNOPSIS (continued) 
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5. Used topically applied products (including emollients or 
moisturizers) on or in the vicinity of the knees or shaved the knees 
within 2 days prior to the first application of study drug; or an open 
wound near the knee; cutaneous erythema or edema; any 
inflammatory skin lesions such as eczema or psoriasis; cutaneous 
infections; or any other compromise of the skin; 
6. A history of sensitivity to topical substances inclusive of OTC 
topical analgesics; 
7. Labile or poorly controlled hypertension; 
8. Significant cardiovascular, renal, or other diseases or conditions, or 
laboratory or other test abnormalities that, in the opinion of the 
Investigator, would contraindicate participation in the trial; 
9. A psychiatric disorder or significant anxiety or depression that 
could interfere with the subject’s compliance with study procedures 
or completion of the study; 
10. Requires daytime use of medications or substances (alcohol, 
benzodiazepines, barbiturates, muscle relaxants, tranquilizers, 
hypnotics) that could diminish their cognitive ability to comply 
with study procedures; 
11. A history of drug or alcohol abuse within one year prior to 
screening; 
12. Requires or anticipates any surgical procedure within 3 months 
prior to screening, has had surgery on the affected joint within 
6 months prior to screening, has a prosthesis  in either knee , or 
would require surgery while participating in the trial; 
13. Pregnant or nursing; 
14. Treated with an investigational drug, device or therapy within 
30 days prior to screening. 
15. Body mass index greater than 45 kg/m2 
16. Skin on or near knee is broken or damaged or if there is an open 
wound on or near the knee. 
 
Investigational 
Product and Mode of 
Administration: 
CGS-200-1 and CGS-200-5 are topical analgesic liquids intended for 
application to intact, non-irritated skin in adults with musculo-skeletal 
pain inclusive of OA of the hands, wrists, elbows, or knees for the 
relief of pain, reduction of stiffness, and increased functional activity. 
CGS-200-1 is a multi-component formulation in which the active 
ingredient for the intended therapeutic effect is 1% capsaicin (wt/wt). 
CGS-200-5 is a multi-component formulation in which the active 
ingredient for the intended therapeutic effect is 5% capsaicin (wt/wt). 
Placebo for this study is the vehicle (designated CGS-200-0) which 
has no capsaicin. 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
STUDY SYNOPSIS (continued) 
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Page 8 
Study Monitoring 
This study will be monitored by CRO personnel. 
 
An electronic case report form (eCRF) will be used for this study 
Statistical Analysis 
Primary Efficacy Endpoint 
The group mean LMS difference between each Active Treatment Arm 
and the Vehicle Arm for the WOMAC pain score at Day 35 will be 
tested for significance of difference at a significance value of p < 0.05.  
 
Secondary Efficacy Endpoints 
The group mean LMS difference between each Active Treatment Arm 
and the Vehicle Arm for the WOMAC stiffness, function and total 
score at Days 5, 19, 35, 64, and 94 will be tested for significance of 
difference at a significance value of p < 0.05. 
 
Also, the group mean reduction in OA knee pain score on a 100 mm 
VAS scale for each active treatment arm will be compared to the 
vehicle arm and tested for significance of difference at a significance 
value of p < 0.05. 
 
For dose-response estimation:  
 
The group mean LMS difference between the 5% and the 1% Active 
Treatment Arms for the WOMAC pain, stiffness, function and total 
score at Day 35 will be tested for significance of difference at a 
significance value of p < 0.05. 
 
Primary Safety Endpoint 
This will be analyzed using descriptive statistics in tabular form. 
 
Secondary Safety Endpoint 
This will be analyzed using descriptive statistics in tabular form. 
 
Tolerability Endpoint 
This will be analyzed using descriptive statistics in tabular form. 
 
Other 
Sponsor may elect to conduct appropriate post-hoc analyses. 
 
 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
FINAL / Version 5.0 1-AUGUST-2018 
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SIGNATURE PAGE 
Product name:  
CGS-200-1 (Capsaicin 1% Topical Liquid) 
CGS-200-5 (Capsaicin 5% Topical Liquid) 
CGS-200-0 (Vehicle, 0% Capsaicin, placebo) 
 
Protocol Number: 
VZU00025 
 
The signatures of the representatives below constitute their approval of this protocol and provide the 
necessary assurances that this study will be conducted according to all stipulations stated in the protocol, 
including all statements as to confidentiality. It is also agreed that the study will not be initiated without the 
approval of an appropriate Institutional Review Board or Ethics Review Committee.  
 
Internal personnel (Vizuri Health Sciences LLC):  
 
 
 
 
 
John Todhunter, PhD 
Chief Scientific Officer 
Head of Regulatory Affairs 
Signature  
 
Date 
 
 
 
 
 
 
 
 
 
 
  
Margaret Fleming 
Independent Clinical Operations Consultant 
Signature  
 
Date 
 
 
 
 
 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
STUDY SYNOPSIS (continued) 
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Page 10 
TABLE OF CONTENTS
Page 
 
LIST OF TABLES....................................................................................................................................................... 13 
LIST OF FIGURES ..................................................................................................................................................... 14 
LIST OF APPENDICES ............................................................................................................................................. 15 
1.0 
INTRODUCTION ................................................................................................................................ 18 
1.1 
BACKGROUND AND RATIONALE .................................................................................................. 18 
1.2 
NONCLINICAL TOXICOLOGY SUMMARY .................................................................................... 23 
1.3 
PREVIOUS CLINICAL EXPERIENCE ............................................................................................... 27 
1.4 
SUMMARY OF SAFETY DATA ......................................................................................................... 32 
1.4.1 
Possible Risks ............................................................................................................... 35 
2.0 
STUDY OBJECTIVES ........................................................................................................................ 36 
2.1 
PRIMARY ENDPOINTS ...................................................................................................................... 36 
2.2 
SECONDARY ENDPOINTS ................................................................................................................ 37 
3.0 
STUDY DESIGN .................................................................................................................................. 39 
3.1 
OVERALL STUDY DESIGN ............................................................................................................... 39 
3.2 
DOSE LIMITING TOXICITY .............................................................................................................. 39 
4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................................................... 41 
4.1 
INCLUSION/ EXCLUSION CRITERIA: ............................................................................................. 41 
4.1.1 
Inclusion Criteria: ......................................................................................................... 41 
4.1.2 
Exclusion Criteria: ........................................................................................................ 42 
4.2 
REPLACEMENT OF SUBJECTS ......................................................................................................... 43 
5.0 
STUDY TREATMENT........................................................................................................................ 44 
5.1 
CGS-200-1, CGS-200-5, AND CGS-200-0 (VEHICLE) ...................................................................... 44 
5.1.1 
Formulation ................................................................................................................... 44 
5.1.2 
Packaging, Labeling and Storage .................................................................................. 45 
5.1.3 
Rationale for Dose Selection ......................................................................................... 45 
5.1.4 
Dosage and Administration ........................................................................................... 46 
5.1.5 
Reporting Product Defects ............................................................................................ 48 
5.2 
CONCURRENT MEDICATIONS ........................................................................................................ 48 
5.2.1 
Allowed Regimens ........................................................................................................ 48 
5.2.2 
Prohibited Medications ................................................................................................. 48 
5.3 
PROHIBITED PROCEDURES ............................................................................................................. 49 
6.0 
STUDY PROCEDURES ...................................................................................................................... 50 
6.1 
SCREENING VISIT .............................................................................................................................. 50 
6.2 
ON-TREATMENT EVALUATIONS: .................................................................................................. 51 
6.3 
FOLLOW-UP PERIOD EVALUATIONS ............................................................................................ 52 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
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6.4 
BIRTH CONTROL REQUIREMENTS ................................................................................................ 52 
6.5 
ASSESSMENTS AT TIME OF SAE, EARLY TERMINATION OR UNSCHEDULED VISIT ......... 53 
6.6 
STUDY BLOOD DRAW VOLUME ..................................................................................................... 54 
6.7 
RECOMMENDATIONS FOR MANAGEMENT OF POTENTIAL TOXICITIES ............................. 54 
6.7.1 
Allergic Reaction, Burning, or Pruritus ........................................................................ 54 
6.8 
CONCOMITANT MEDICATIONS/RESCUE MEDICATIONS ......................................................... 54 
6.9 
STOPPING CRITERIA ......................................................................................................................... 55 
6.9.1 
Criteria for Adverse Event Assessment ........................................................................ 55 
6.9.2 
General Criteria for Stopping Study Drug .................................................................... 55 
6.9.3 
Stopping Criteria ........................................................................................................... 55 
6.10 
WITHDRAWAL OF SUBJECTS FROM STUDY ............................................................................... 55 
7.0 
CLINICAL ACTIVITY ....................................................................................................................... 57 
8.0 
SAFETY ASSESSMENTS .................................................................................................................. 58 
8.1 
ADVERSE EVENTS ............................................................................................................................. 58 
8.1.1 
Definitions..................................................................................................................... 58 
8.1.2 
Reporting to the Sponsor ............................................................................................... 59 
8.1.3 
Investigator Evaluation of Adverse Events ................................................................... 59 
8.1.4 
Follow-up of Adverse Events........................................................................................ 62 
8.1.5 
Post Study SAEs ........................................................................................................... 62 
8.1.6 
Reporting to the Institutional Review Board/Independent Ethics Committee .............. 62 
8.2 
LABORATORY TESTS ........................................................................................................................ 63 
9.0 
DATA ANALYSIS METHODS .......................................................................................................... 64 
9.1 
DETERMINATION OF SAMPLE SIZE ............................................................................................... 64 
9.2 
RANDOMIZATION AND BLINDING ................................................................................................ 64 
9.3 
ANALYSIS SETS .................................................................................................................................. 64 
9.4 
SUBJECT ACCOUNTABILITY ........................................................................................................... 64 
9.5 
STATISTICAL METHODS .................................................................................................................. 65 
9.5.1 
Analysis of Demographic and Subject Characteristics ................................................. 65 
9.5.2 
Treatment Administration/Compliance ......................................................................... 65 
9.5.3 
Efficacy Analyses ......................................................................................................... 65 
9.5.4 
Tolerability Analyses .................................................................................................... 66 
9.5.5 
Safety Analyses ............................................................................................................. 67 
9.5.6 
Vital Signs ..................................................................................................................... 67 
9.5.7 
Interim Analyses ........................................................................................................... 68 
9.5.8 
Procedures for Missing, Unused and Spurious Data ..................................................... 68 
9.5.9 
Rules for Excluding Subjects from Analysis ................................................................ 69 
9.5.10 
Procedures for Reporting Deviations from Original Statistical Plan ............................ 69 
10.0 
CLINICAL STUDY ADMINISTRATION ........................................................................................ 70 
10.1 
INFORMED CONSENT........................................................................................................................ 70 
10.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE REVIEW AND 
APPROVAL ........................................................................................................................................... 70 

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Vizuri Health Sciences LLC. 
 
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10.3 
PROTOCOL COMPLIANCE ................................................................................................................ 71 
10.4 
PROTOCOL REVISIONS ..................................................................................................................... 71 
10.5 
DATA COLLECTION ........................................................................................................................... 71 
10.6 
DATA MANAGEMENT RESPONSIBILITIES ................................................................................... 72 
10.7 
STUDY MONITORING ........................................................................................................................ 73 
10.8 
DRUG ACCOUNTABILITY ................................................................................................................ 74 
10.9 
RETENTION OF RECORDS ................................................................................................................ 74 
10.10 
FINANCIAL DISCLOSURE ................................................................................................................. 75 
10.11 
PUBLICATION POLICY ...................................................................................................................... 75 
10.12 
STUDY OR STUDY SITE TERMINATION ........................................................................................ 75 
11.0 
REFERENCES ..................................................................................................................................... 77 
APPENDICES ............................................................................................................................................................ 79 
 

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Vizuri Health Sciences LLC. 
 
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LIST OF TABLES 
 
Page 
 
Table 1–1. 
Differences in Latin American and European Placebo Responses and Corresponding Latin 
American and European Responses to Active Treatment (Source: Study VZU00023) ...................... 22 
Table 1–2. 
Comparison of CGS-125-5 and CGS-200-5 Composition .................................................................. 23 
Table 1–3. 
Number of Subjects with BSP > 5 At Times After CGS-200-5 and CGS-200-10 Application in 
Study VZU00020 ................................................................................................................................ 27 
Table 6–1 
Screening Procedures .......................................................................................................................... 50 
Table 6–2 
On Treatment Evaluations ................................................................................................................... 51 
Table 6–3 
Follow-up Period Evaluations ............................................................................................................. 52 
 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
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LIST OF FIGURES 
 
Page 
 
Figure 1–1. 
Group Mean NRS Pain as Percent of Baseline .................................................................................... 30 
Figure 1–2. 
Group Mean WOMAC Pain as Percent of Baseline ............................................................................ 30 
Figure 1–3. 
U.S. Conducted OTC Study Vehicle (Placebo) Response Superimposed on Vehicle and 
CGS-200-5 responses in Dominican Republic Conducted Study VZU00023 .................................... 31 
 
 

CONFIDENTIAL 
Vizuri Health Sciences LLC. 
 
CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
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LIST OF APPENDICES 
 
 
Appendix A   Laboratory Tests 
Appendix B   Rheumatology Common Toxicity Criteria V2.0 
Appendix C   Schedule of Events 
Appendix D   Exploratory Assessment of Osteoarthritis Knee Pain 
Appendix E  
 VAS OA KNEE PAIN 
Appendix F  
 Assessment of Burning / Stinging Pain 
Appendix G   Assessment of Signs and Symptoms 
 
 
 

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CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
FINAL / Version 5.0 1-AUGUST-2018 
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LIST OF ABBREVIATIONS 
 
 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
ALK 
Alkaline phosphokinase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BP 
Blood pressure 
BPM 
Beats per minute 
BSP 
Burning stinging pain 
BUN 
Blood urea nitrogen 
C 
Celsius 
CBC 
Complete blood count 
CHO 
Chinese Hamster Ovary 
cm 
Centimeter 
Cmax 
Maximum concentration in serum 
CNS 
Central Nervous System 
CPK 
Creatine phosphokinase 
CRO 
Contract Research Organization 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
DR 
Dominican Republic 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ESR 
Erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
FSH 
Follicle-stimulating hormone 
FOB 
Functional Observation Battery 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
Hgb 
Hemoglobin 
HPLC 
High-performance liquid chromatography 
hr 
Hour 
HR 
Heart rate 
ICF  
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantification 
LSM 
Least Mean Squares 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
mg 
Milligram 

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LIST OF ABBREVIATIONS (continued) 
 
FINAL / Version 5.0 1-AUGUST-2018 
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min 
Minute 
mITT 
Modified Intent-to-Treat 
mL 
Milliliter 
µL 
Microliter 
mm 
Millimeter 
NRS 
Numeric Rating Scale 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OAKP 
Osteoarthritis knee pain 
OTC 
Over the counter 
PE 
Physical examination 
PI 
Principal Investigator 
RBC 
Red blood cell 
RCTC 
Rheumatology Common Toxicity Criteria 
RDC 
Remote data capture 
RF 
Rheumatoid factor 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAF 
Safety 
SF 
Synovial fluid 
SOP 
Standard Operating Procedure 
T 
Temperature 
TEAE 
Treatment-emergent adverse event 
TFM 
Tentative Final Monograph 
Tmax 
Time to maximum effect 
UA 
Urinalysis 
UCL 
Upper confidence limit 
ULN 
Upper limit of normal 
U.S. 
United States 
VAS 
Visual Analog Scale 
WBC 
White blood count 
WHO 
World Health Organization 
WOMAC  
Western Ontario and McMaster Universities Index of Osteoarthritis 
wt 
Weight 
 

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CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
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1.0 
INTRODUCTION 
1.1 
BACKGROUND AND RATIONALE 
The prevalence of arthritis in the general population is 21% overall, or approximately 
46.4 million adults in the United States (U.S.).[1] Most of individuals are likely to have 
osteoarthritis (OA), which is a very common disease. It is the third most common 
diagnosis made by primary care physicians in older patients and is the most common 
condition involving the knee. Significant knee pain affects about one quarter of the 
population that are 55 or older, and half of these individuals have radiographic evidence 
of OA and a quarter have some degree of disability. The risk of developing OA is 
related to advancing age, female sex, obesity, trauma, a family history and other factors. 
In 1986, the American College of Rheumatology (ACR) published classification 
criteria for OA of the knee.[2] Classification criteria are not diagnostic criteria, although 
they are often used as such by clinicians. The criteria are useful in clinical research, 
including clinical trials, to provide a uniform population for study. The classification 
criteria are shown in the table below. 
Clinical and laboratory 
Clinical and radiographic 
Clinical 
Knee pain  
 
+ 
At least 5 of 9: 
 
Age >50 years 
 
Stiffness <30 minutes 
 
Crepitus 
 
Bony tenderness 
 
Bony enlargement 
 
No palpable warmth 
 
ESR <40 mm/hr 
 
RF <1:40 
 
Synovial fluid signs of OA 
Knee pain  
 
+ 
At least 1 of 3: 
 
Age >50 years 
 
Stiffness <30 minutes 
 
Crepitus 
 
+ 
 
Osteophytes 
 
Knee pain  
 
+ 
At least 3 of 6: 
 
Age >50 years 
 
Stiffness <30 minutes 
 
Crepitus 
 
Bony tenderness 
 
Bony enlargement 
 
No palpable warmth 
 
 
ESR = Erythrocyte sedimentation rate; RF = rheumatoid factor; Synovial fluid (SF) signs of OA are clear, viscous 
fluid or SF white blood cell count <2,000/mm3 
The European League Against Rheumatism (EULAR) has developed guidelines for the 
diagnosis of OA.[3] During the development of the guidelines, they found that 3 
symptoms (persistent knee pain, morning stiffness, and decreased function) and 3 signs 
(crepitus, restricted movement, and bony enlargement) were most important in the 
diagnosis. The more symptoms and signs, the more certain is the diagnosis. While 
diagnostic guidelines are useful in patient care, it will be necessary to use classification 
criteria in this clinical trial. 

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CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
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FINAL / Version 5.0 1-AUGUST-2018 
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The pathogenesis of OA remains unclear; however, certain types of OA show familial 
aggregation, and excessive load on joints may play a role. In addition, over the years, 
there has been some consideration as to whether OA involves inflammation and 
whether it is a primary driver of the development of OA or whether trauma or other 
factors produce damage that results in secondary inflammation. 
Whatever the pathogenetic mechanisms may be, OA is a progressive disorder that 
results in disability. There is a great unmet medical need for more effective treatments 
for OA. Better treatment of the pain of OA has the potential for postponing disability 
and improving health-related quality of life 
Current standard of care for OA may include non-pharmacologic interventions such as 
exercise, weight loss, appropriate insoles, walking aids, patellar taping in a medial 
direction, thermal treatments, tai chi, psychosocial interventions and self-management 
programs.[4] Pharmacologic agents that can be used include acetaminophen, non-
steroidal anti-inflammatory drugs (NSAID) given orally or topically, tramadol, 
duloxetine, and intra-articular hyaluronate, corticosteroids, or injections. In addition, 
opioids may be considered in those who respond inadequately to initial interventions. 
In patients who have failed medical therapy or are not willing to undergo surgery, or 
for whom joint replacement surgery is contraindicated, opioid therapy is strongly 
recommended.  
Acetaminophen carries a risk of liver damage. The use of oral NSAIDs is associated 
with a potential for gastric and intestinal ulceration and high doses of NSAIDs have 
been associated with an elevated risk of cardiac problems. The intent of topical 
NSAIDs is to reduce the systemic levels of these drugs (thereby lowering the risk of 
gastro-intestinal damage) while providing for a therapeutically effective level in and 
around the affected area. However, these products – whether oral or topical – require 
regular daily use and administration more than once daily. The use of any opiate-
containing product poses a risk for addiction or diversion.  
There is therefore considerable unmet medical need for a treatment of OA knee pain 
(OAKP) that does not require regular daily use, does not carry the gastro-intestinal risks 
of NSAIDs or the liver risks of acetaminophen or the addiction / diversion risks of 
opiates, and can safely provide long lasting pain relief after a brief course of treatment.  

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CGS-200-1 and CGS-200-5 vs. CGS-200-0 Vehicle 
Protocol VZU00025 
 
 
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VZU00023 (in the DR) was approximately twice what was seen in VZU00022 (in the 
U.S.). 
This marked difference between the response to placebo (vehicle), using the same 
vehicle, in the U.S. study compared to the non-U.S. study, conducted in the Dominican 
Republic, appears to be consistent with the known higher rates of placebo response in 
studies conducted in Latin American countries[5], and which effect is within the well-
known influence of cultural differences in placebo responses [6]. The differences 
between placebo responses in the same studies conducted in Latin America and Europe 
and the corresponding differences for active treatment response are tabulated below 
(Table 1–1). The data in Table 1 suggest that on average, the placebo response in a 
study conducted in a Latin American culture country (such as the Dominican Republic) 
will be circa 2.6 times greater than in the same study conducted in European countries. 
This, by extension, suggests that the placebo response in a Latin American study may 
be similarly higher compared to the same study conducted in the U.S., the U.S. culture 
being typically more European than Latin American. Per Figure 1–3 once daily 
application of vehicle reduced group mean OA pain score to 60% of baseline by Day 
28 in the U.S. OTC study whereas the vehicle reduced group mean OA pain score to 
25% of baseline by Day 33 in the Dominican Republic study. Looking at these percent 
of baseline values in a different light, the absolute reduction of OA pain score 
associated with vehicle treatment was 40% for the U.S. study and 75% for the 
Dominican Republic study. The “absolute reduction” is 100% less the percentage of 
baseline at the assessment time (i.e., the degree of pain relief associated with a 
treatment). So, the placebo (vehicle) effect in the Dominican Republic study appears 
to be 1.9-times greater than the vehicle effect in the U.S. study. This is well within the 
range of differences reported by Xu et al. (2016).[5] 

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Table 1–1. 
Differences in Latin American and European Placebo Responses and 
Corresponding Latin American and European Responses to Active Treatment 
(Source: Study VZU00023) 
Study # 
LA Placebo 
EU Placebo 
LA/EU 
LA Active 
EU Active 
LA/EU 
Study 1 
61 
28 
2.18 
38 
45 
0.84 
Study 2 
66 
37 
1.78 
56 
46 
1.22 
Study 3 
58 
35 
1.66 
51 
55 
0.93 
Study 6 
68 
23 
2.96 
57 
57 
1.00 
Study 9 
42 
13 
3.23 
60 
52 
1.15 
Study 10 
53 
15 
3.53 
75 
50 
1.50 
Average 
2.56 
1.11 
S.D. 
0.79 
0.24 
% SD 
31% 
21% 
Data from Figure 1 in Xu et al., Arthritis Rheumatol., 68(suppl 10), Abstract # 2594 (2016)[5] 
It can be seen, also, from Table 1–1 that the difference in active treatment response in 
Latin America conducted studies and European conducted studies is slight. One can 
speculate that the large differences noted for placebo responses and the small 
differences noted for active treatment responses may be due to a cultural difference in 
the expectations of Latin American subjects compared European subjects. The Latin 
American may tend to believe more strongly that what the doctor or clinic is doing will 
help them, ergo the high placebo responses in Latin America; whereas, the European 
subjects may have lower expectations of obtaining relief, and a lower placebo response 
as a result. For active treatment, if the study treatment is actually beneficial, then the 
responses of European subjects and Latin American subjects would be similar, as is 
reported by Xu et al. (2016).[5] The role of cultural differences in expectations regarding 
treatment outcomes is well recognized and has been addressed by Bhugra and 
Ventriglio (2015).[6] 
In contrast to the magnitude of cultural effects on placebo response, the data presented 
by Xu et al. (2016) suggest that cultural differences in response to active treatment 
appear to be slight. [5] This suggests, in turn, that the pain relief efficacy data for active 
treatment (CGS-200-5) in study VZU00023 will hold up in the U.S. study planned 
under this protocol. Conversely, the large cultural differences in placebo responses, 
along with experience with vehicle response in a U.S. OTC product study, suggest that 
the vehicle response in the clinical study planned under this Investigational New Drug 
(IND) application will be much lower than was observed in study VZU00023 and likely 
similar to what was seen in the U. S. OTC product study. 

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1.2 
NONCLINICAL TOXICOLOGY SUMMARY 
Sponsor has conducted a number of non-clinical toxicology studies with high strength 
Capsaicin topical liquid. These studies have, for the most part, been conducted with a 
different formulation of high strength topical capsaicin than that which will be 
investigated under Protocol VZU00025. This alternate formulation is termed CGS-125 
and contains additional OTC Monograph topical analgesic agents. Table 1–2 below 
shows the difference between CGS-125 with 5% Capsaicin and CGS-200-5.  
Table 1–2. 
Comparison of CGS-125-5 and CGS-200-5 Composition  
Component 
CGS-125-5 
CGS-200-5 
Capsaicin 
5% 
5% 
Distilled Water 
 
44.55% 
Dehydrated Alcohol 
 
20% 
Polysorbate 80 
 
10% 
Diethylene Glycol Methyl Ether  
 
10% 
Propylene Glycol 
 
10% 
Na Hyaluronate SLMW (~20K Daltons) 
 
0.30% 
Na Hyaluronate (~1,000K Daltons) 
 
0.15% 
Methyl Salicylate 
50% 
 
Menthol 
15% 
 
Camphor 
11% 
 
Phenol 
1.50% 
 
Dehydrated Alcohol 
17.5% 
 
 
The CGS-125 formulation contains a number of OTC Monograph topical analgesics. 
These are known to have pharmacological activity and present the potential that the 
CGS-125 formulation could have more potential for toxicities than CGS-200, which 
contains none of these ingredients.  
Both formulations contain similar levels of dehydrated alcohol (i.e., ethanol), so they 
are comparable in this regard, CGS-200 has, otherwise, only one compound that has 
known pharmacological activity (capsaicin) and it is at the same level as in CGS-125-5. 
The excipients in CGS-200 are all of low toxicity potential.  
 
 

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The non-clinical toxicity studies that have been conducted on CGS-125, which include 
one in which CGS-125 and CGS-200 were compared directly for tolerability on 
application to rats, are listed following with an outcome summary for each. 
Central Nervous System (CNS) Safety Pharmacology 
A Functional Observation Battery (FOB) Neurological Assessment in the Male 
Sprague Dawley Rat Following a Single Dermal Application (Study # 1015-2201 / 
CiTox Labs, Montreal, Canada) 
CGS-125 (at 5%, 10% and 20% Capsaicin) tested at maximum practical 
dose. Single dermal application of 200 µL volume over 50 cm2 area for 2 hrs 
then removal with PEG 300. No suggestion of neurological deficits or 
effects. 
Respiratory Safety Pharmacology 
A Respiratory Safety Pharmacology Study in Conscious Male Sprague Dawley Rat 
Following a Single Dermal Application (Study # 1015-2211 / CiTox Labs, 
Montreal, Canada) 
CGS-125 (at 5%, 10% and 20% Capsaicin) tested at maximum practical 
dose. Single dermal application of 200 µL volume over 50 cm2 area for 2 hrs 
then removal with PEG 300. No suggestion of respiratory deficits or effects. 
Cardio-Vascular Safety Pharmacology 
A Cardiovascular Function Safety Pharmacology Study in Conscious Telemetered 
Male Beagle Dog Following a Dermal Application (Study # 1015-2292 / CiTox 
Labs, Montreal, Canada) 
CGS-125 (at 5%, 10% and 20% Capsaicin) tested at maximum practical 
dose. Single dermal application of 200 µL volume over 50 cm2 area for 2 hrs 
then removal with PEG 300. No suggestion of cardio-vascular deficits or 
effects. 

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Tolerability on Application, Rabbit 
Dermal Tolerance of Topical Capsaicin Formulations in Rabbits (Study # 2007-
6987 / Charles River Laboratories, Horsham, PA) 
CGS-125 (at 5% and 20% Capsaicin) tested at maximum practical dose. 
Single dermal application of 800 µL volume over 200 cm2 area for 2 hrs 
then removal with PEG 300. Vehicle, 5% and 20% well tolerated. No 
suggestion of safety issues observed. 
Tolerability on Application, Dog 
A Single Dermal Application Pilot Tolerability Study in Beagle Dogs  
(Study # 2015-2182 / Charles River Laboratories, Horsham, PA) 
CGS-125 (at 5%, 10% and 20% Capsaicin) tested at maximum practical 
dose. Single dermal application of 1600 µL volume over 400 cm2 area for 
2 hrs then removal with PEG 300. Vehicle, 5%, 10% and 20% well 
tolerated. No suggestion of safety issues observed. 
Tolerability on Application, Rat 
Single Dose Dermal Tolerance Study of Two Capsaicin Formulations  
(Study # 2007-3449 / Charles River Laboratories, Horsham, PA) 
Capsaicin in CGS-125 (at 0% and 20% Capsaicin) and in CGS-200 (at 2%, 
5% and 10% Capsaicin) tested at maximum practical dose.  
Both formulation tested at maximum practical dose. Single dermal 
application of 200 µL volume over 50 cm2 area for 2 hrs then removal with 
PEG 300.  
CGS-125 Outcome: Vehicle and 20% well tolerated. No suggestion of 
safety issues observed. 
CGS-200 Outcome: Both 2% and 5% well tolerated. 10% elicited strong 
aversion reaction in rats. No suggestion of safety issues. (Note: In non-U.S. 
clinical studies application of CGS-200-10% once daily for 1 hour on 4 
consecutive days has been well tolerated.) 

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Repeat Dose Toxicology in Rats 
A Seven Day Repeat Dose Dermal Toxicity Study of CGS-125 in Rats with a Four 
Week Recovery Period (Study # 2008-0727 / Charles River Laboratories, Horsham, 
PA) 
CGS-125 (at 5%, 10% and 20% Capsaicin) tested at maximum practical 
dose. Seven (7) consecutive daily dermal applications of 200 µL volume 
over 50 cm2 area for 2 hrs then removal with PEG 300. Vehicle, 5%, 10% 
and 20% well tolerated. No systemic or local toxicities elicited (on gross 
and histopathology examinations and assessments, hematology, urinalysis, 
or blood chemistries). No suggestion of safety issues. 
Repeat Dose Toxicology in Rabbits 
A Seven Day Repeat Dose Dermal Toxicity Study of CGS-125 in Rabbits with a Four 
Week Recovery Period (Study # 2008-0728 / Charles River Laboratories, Horsham, 
PA) 
CGS-125 (at 5%, 10% and 20% Capsaicin) tested at maximum practical 
dose. Seven (7) consecutive daily dermal applications of 800 µL volume 
over 200 cm2 area for 2 hrs then removal with PEG 300. Vehicle, 5%, 10% 
and 20% well tolerated. No systemic or local toxicities elicited (on gross 
and histopathology examinations and assessments, hematology, urinalysis, 
or blood chemistries). No suggestion of safety issues. 
Mutagenicity 
Bacterial Reverse Mutation Assay (Study # AE58RS.502-ICH.BTL / BioReliance, 
Rockville, MD) 
Capsaicin in CGS-125 tested in vitro against S. typhimurium TA98, TA100, 
TA1535, TA1537; E. coli WP2 uvrA at up to 5000 µg/plate. No evidence 
of mutagenic activity. 
 
 

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Clastogenic Potential 
In 
Vitro 
Mammalian 
Chromosomal 
Aberration 
Assay 
in 
CHO 
Cells  
(Study # AE58RS.331-CH.BTL / BioReliance, Rockville, MD) 
Capsaicin in CGS-125 tested in vitro against Chinese Hamster Ovary cells 
(CHO) at up to 30 µg/mL No evidence of clastogenic activity 
1.3 
PREVIOUS CLINICAL EXPERIENCE 
Study VZU00020 
This was a clinical study comparing the single dose tolerability of 5% and 10% 
capsaicin in CGS-125 and in CGS-200 (VZU00020) demonstrated that CGS-200 with 
5% and 10% capsaicin produced a mean burning- stinging pain (“BSP”) score of not 
more than 2.5 on a 0 – 10 NRS scale. In this same study the number of subjects 
reporting an NRS BSP score of 5 or greater (on the 0 – 10 scale) is as tabulated in  
Table 1–3 below: 
Table 1–3. 
Number of Subjects with BSP > 5 At Times After CGS-200-5 and 
CGS-200-10 Application in Study VZU00020 
% Caps 
15 Min Post 
30 Min Post 
60 Min Post 
90 Min Post 
5% 
2/15 
2/15 
3/15 
3/15 
10% 
3/15 
1/15 
3/15 
2/15 
 
Study VZU00021 
This was a study in which CGS-125 formulation of 5% and 10% capsaicin and CGS-
200 formulations of 5% and 10% were applied once daily for 1 hour on each of four 
sequential days to subjects with confirmed knee OA and a baseline NRS OA knee pain 
score of 5 or greater. OA knee pain was assessed daily on Days 1 (before the first 
application) and then on Days 2, 3 and 4 (prior to the daily application) and again on 
Days 5, 19 and 33. Burning-stinging pain at the application site was evaluated on a 
0 – 10 NRS scale. Erythema, scaling and pruritus were also assessed and scored at each 
protocol assessment time.  
In VZU00021, both CGS-200-05 and CGS-200-10 gave a high level of pain control 
with 85% or greater of subjects experiencing a reduction from baseline NRS of 50% or 

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greater and this pain relief lasted for at least 29 days after the last application of the 
investigational drug product. The degree and duration of pain relief was similar for 
CGS-125-05 but appeared to be less over the first 4 days for CGS-125-10: 
 
Drug 
Criterion: 
> 50% NRS 
Reduction 
Day 1 
1st Appl. 
Day 2 
2nd Appl. 
Day 3 
3rd Appl. 
Day 4 
4th Appl. 
Day 5 
Day 19 
Day 33 
Percent on Subject Knees Meeting the Criterion 
CGS-200-05 
0% 
42% 
85% 
88% 
100% 
81% 
92% 
CGS-200-10 
0% 
45% 
97% 
97% 
100% 
79% 
86% 
CGS-125-05 
0% 
60% 
80% 
80% 
90% 
100% 
100% 
CGS-125-10 
0% 
0% 
57% 
57% 
100% 
100% 
100% 
 
Both formulations at either strength were well tolerated and reduced OAKP by 
75% or more compared to baseline. Analgesic effect persisted to Day 33 (last 
follow up day). No serious adverse events (SAEs), no adverse events (AEs) 
resulting in subject discontinuation or subject requested withdrawal, only AEs that 
were possibly, probably or definitely treatment related were: (a) local at the 
application site and Rheumatology Common Toxicity Criteria (RCTC) toxicity 
grades were generally 1 (mild) and at highest 2 (moderate) and were mostly BSP 
with less frequent erythema, pruritus, and scaling (latter only for CGS-125-10); and 
(b) coughing / sneezing during or following application (RCTC Grade 1, mild) 
which was observed in a higher proportion of CGS-125 subjects (40% - 60%) than 
in CGS-200 subjects (20% - 27%). Comparison of Day 33 (study exit) values for 
serum chemistry and hematology with values at screening showed no remarkable 
changes in any subjects and no differences for any subject, comparing Day 33 to 
Screening, that were atypical of the normal variations in serum chemistry and 
hematology values in individuals for blood sampling at different time points. In 
summary, no suggestion of systemic toxicities related to treatment was observed. 
In Study VZU00021 neither vehicle or a true placebo was used as the study was 
designed to compare the CGS-200 formulation with the CGS-125 formulation in terms 
of tolerability and efficacy for a 4-day, once daily for 1-hour treatment regimen.  

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Study VZU00023 
This was a vehicle-controlled study of safety, tolerability and efficacy of CGS-200 
5% capsacian in subjects with OA of the knee. Single daily application for four 
consecutive days with 93 days (13 weeks) follow up. 
CGS-200-5 was well tolerated and reduced OAKP at 13 weeks by 93% compared 
to baseline. No SAEs, no AEs resulting in subject discontinuation or subject 
requested withdrawal, only AEs that were possibly, probably or definitely 
treatment related were: (a) local at the application site and RCTC toxicity grades 
were generally 1 (mild) and at highest 2 (moderate) and were mostly BSP (in 100% 
of subjects) with less frequent erythema (72% of subjects), and pruritus (56% or 
subjects) ; and (b) coughing / sneezing during or following application (RCTC 
Grade 1, mild) which was observed in 20% of subjects. No suggestion of systemic 
toxicities related to treatment was observed. 
In this study, Vehicle control had an unexpectedly high placebo effect, with 
reduction of OAKP scores by around 83% at 13 weeks. Unusually high placebo 
effects are known from the literature to occur in studies in Latin American 
countries such as the Dominican Republic.[5] No SAEs, no AEs resulting on subject 
discontinuation or subject requested withdrawal, only AEs that were possibly, 
probably or definitely treatment related were: (a) local at the application site and 
RCTC toxicity grades were generally 1 (mild) and at highest 2 (moderate) and were 
mostly BSP (in 35% of subjects) with less frequent erythema (15% of subjects), 
and pruritus (31% or subjects) ; and (b) coughing / sneezing during or following 
application (RCTC Grade 1, mild) which was observed in 3.8% of subjects. In this 
study, serum chemistries, hematology and urinalysis data were collected at 
screening but not at a later time point. However, as a reference point, no remarkable 
differences for serum chemistry and hematology were observed between screening 
values and vales at one month after study start in Study VZU00021. It was, 
therefore, concluded that in Study VZU00023 no remarkable differences in serum 
chemistry and hematology values between screening and one to three months after 
study start would be observed. No suggestion of systemic toxicities related to 
treatment was observed in Study VZU00023.  

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CGS-200 specific efficacy data from Study VZU00023 are summarized in the 
following figures: 
Figure 1–1. 
Group Mean NRS Pain as Percent of Baseline 
 
Figure 1–2. 
Group Mean WOMAC Pain as Percent of Baseline 
 
 
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
60%
65%
70%
75%
80%
85%
90%
95%
100%
105%
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95100
% Reduction
Study Day
VZU0023: Mean % NRS Pain Reduction to D93
Active
PLACEBO
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0
20
40
60
80
100
WOMAC Pain Mean % of Baseline
Study Day
WOMAC Pain Mean % of Day 1
WOMAC Pain - ACTIVE
WOMAC Pain PLACEBO

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It can be noted that for the NRS pain scores (Figure 1–1) the difference between 
placebo (vehicle) response and active treatment response is less than the difference 
between placebo (vehicle) response and active treatment response as assessed by the 
Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) pain 
subscale. Additionally, the placebo (vehicle) response is higher than expected based on 
data from a U.S. clinical study of Sponsor’s OTC Tentative Final Monograph (TFM) 
capsaicin product (0.025% capsaicin topical liquid). The placebo response in that study 
was in the range of only a 60% reduction in OA knee pain scores relative to baseline 
(using a 100 mm VAS scale for pain assessment). This is illustrated in Figure 1–3, next 
page, which superimposes the U.S. vehicle response data onto the VZU00023 response 
data through Day 33. In the U.S. OTC study the final assessment time was at Day 28 
and the vehicle was applied daily for 7 consecutive days either once daily or twice daily 
(with an application interval time of approximately 12 hrs). The vehicle response data 
shown in Figure 1–3 are for the once daily application of vehicle so as to be comparable 
to the once daily application of vehicle in study VZU00023. In the U.S. study, twice 
daily application of vehicle produced an approximately 55% reduction of group mean 
pain score relative to baseline.  
Figure 1–3. 
U.S. Conducted OTC Study Vehicle (Placebo) Response 
Superimposed on Vehicle and CGS-200-5 responses in Dominican 
Republic Conducted Study VZU00023 
 
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
55%
60%
65%
70%
75%
80%
85%
90%
95%
100%
105%
0
5
10
15
20
25
30
35
% Reduction
Study Day
VZU0023: Mean % NRS Pain Reduction to D33
Active
PLACEBO
OTC Placebo

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This marked difference between the response to placebo (vehicle), using the same 
vehicle, in the U.S. study compared to the non-U.S. study, conducted in the Dominican 
Republic, appears to be consistent with the known higher rates of placebo response in 
studies conducted in Latin American countries [5], and which effect is within the well-
known influence of cultural differences in placebo responses.[6] The differences 
between placebo responses in the same studies conducted in Latin America and Europe 
and the corresponding differences for active treatment response reported in Xu et al. 
(2016) suggest that on average, the placebo response in a study conducted in a Latin 
American culture country (such as the Dominican Republic) will be circa 2.6 times 
greater than in the same study conducted in European countries. [5] This, by extension, 
suggests that the placebo response in a Latin American study may be similarly higher 
compared to the same study conducted in the U.S., the U.S. culture being typically 
more European than Latin American. Per Figure 1–3 once daily application of vehicle 
reduced group mean OA pain score to 60% of baseline by Day 28 in the U.S. OTC 
study whereas the vehicle reduced group mean OA pain score to 25% of baseline by 
Day 33 in the Dominican Republic study. Looking at these percent of baseline values 
in a different light, the absolute reduction of OA pain score associated with vehicle 
treatment was 40% for the U.S. study and 75% for the Dominican Republic study. The 
“absolute reduction” is 100% less the percentage of baseline at the assessment time 
(i.e., the degree of pain relief associated with a treatment). So, the placebo (vehicle) 
effect in the Dominican Republic study appears to be 1.9-times greater than the vehicle 
effect in the U.S. study. This is well within the range of differences reported by Xu et 
al. (2016).[5] 
1.4 
SUMMARY OF SAFETY DATA 
There have been three clinical trials conducted with CGS-200-5 and CGS-200-10 
(VZU00020, VZU00021, and VZU00023). These have been conducted in the 
Dominican Republic with regulatory approval by CONABIOS and the local IRBs 
(Ethics Committees) for the study centers. With respect to the investigational drug 
product vehicle (CGS-200-0): One trial has been conducted in the Dominican Republic 
(VZU00023) and one trial was conducted in the U.S. (VZU00022). The U.S. study was 
for Sponsor’s OTC TFM product that contains 0.25% capsaicin in CGS-200 vehicle. 
To date: 

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• 
No SAEs have occurred 
• 
AE’s that are possibly, probably or definitely associated with study treatment 
have been limited to mild-moderate and expected reactions at the site of 
application and which will resolve within a few days of occurrence. 
• 
No suggestion of systemic toxicities has been observed 
Hematology and serum chemistries were assessed for subjects in Study VZU00021 at 
screening and then again at Day 33 (last study assessment day and planned exit day). 
These are not tabulated here as for very study subject there were no remarkable changes 
or differences which were outside what is typical for hematology and serum chemistry 
assessments taken on the same person but at different times.  
The amounts of capsaicin to be applied in this study and the likely systemic uptake of 
capsaicin by subjects in this study are quite small and further support that the topical 
applications of capsaicin to the subject’s knees in the planned study will be safe for the 
subjects. For the initial investigation planned under this IND capsaicin will be applied 
in two strengths: 1% capsaicin (CGS-200-1) and 5% capsaicin (CGS-200-5). Also, the 
vehicle will be applied as a placebo control. The ingredients in CGS-200-1 and 
CGS-200-5 are as indicted in the tables that follow. 
CGS-200 Formulations at 1% and 5% Capsaicin Content 
Ingredient 
CGS-200-5         
% w/w 
CGS-200-1      
% w/w 
Capsaicin 
5 
1 
Dehydrated Alcohol 
20 
20 
Polysorbate 80 
10 
8 
Diethylene Glycol Methyl Ether 
10 
10 
Propylene Glycol 
10 
10 
Na Hyaluronate (~1,000K Daltons) 
0.15 
0.16 
Na Hyaluronate SLMW (~20K Daltons) 
0.30 
0.32 
Distilled Water 
44.55 
50.52 
Totals 
100.00 
100.00 
 
The amount of CGS-200 applied to the knee per application is an approximate 
maximum of 0.15 gram per knee. If two knees receive application, then the total amount 
of CGS-200 applied per application is approximately 0.30 gram and this is applied to 
an area of approximately 200 cm2 (ca. 100 cm2 per knee). Note that both knees will 
receive study drug application but only one knee will be the study knee on which 

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assessments are performed. Using CGS-200-5 as the maximum capsaicin strength 
product for investigations under this IND, the amounts of each component applied per 
application are provided in the table below. 
Components Application Amounts for 
CGS-200 at 5% Capsaicin Content 
(knee(s) treated: 0.3 g CGS-200 Total) 
Ingredient 
CGS-200-5 % w/w 
Per Application 
Capsaicin 
5 
15 mg 
Dehydrated Alcohol 
20 
60 mg 
Polysorbate 80 
10 
30 mg 
Diethylene Glycol Methyl Ether 
10 
30 mg 
Propylene Glycol 
10 
30 mg 
Na Hyaluronate (~1,000K Daltons) 
0.15 
0.45 mg 
Na Hyaluronate SLMW (~20K Daltons) 
0.30 
0.90 mg 
Distilled Water 
44.55 
133.65 mg 
Totals 
100.00 
300.00 mg 
 
These are all trivially small amounts for each of the components by the topical route.  
For the capsaicin, the total maximum amount applied, 15 mg, would be a topical dosage 
of 0.21 mg/kg for a 70 kg person. As an application per cm2 of surface area it would be 
0.075 mg/cm2.  
One can compare the above 0.075 mg/cm2 (75 µg/cm2) with published data on 
capsaicin uptake from the 8% Qutenza patch (Babbar et al., 2009 [full copy in the 
Literature Appendix to Module 2]).[7] Babbar et al. (2009) report that areas of 
1,000 cm2 were treated with patches containing capsaicin at 640 µg capsaicin/cm2. 
Treatment duration was generally for 60 minutes (same as intended for the protocol 
under this present IND) but in some cases, was for up to 90 minutes. The total amount 
of capsaicin applied and the unit dosage rate (µg/cm2) reported by Babbar et al. (2009) 
and estimate for the initial clinical investigation planned under this IND and the ratio 
for comparing the Babbar et al. (2009) values to those estimated for the planned 
investigation are presented in the table below. 
Dose Index 
Babbar et al., 2009 
Protocol VZU00025 
Ratio: 
Babbar et al., 2009 / 
VZU00025 
mg Total 
640 mg 
15 mg 
43 
µg/cm2 
640 µg/cm2 
75 µg/cm2 
8.5 
mg/kg 
9.1 mg/kg 
0.21 mg/kg 
43 

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Babbar et al. (2009) reported that the lower limit of quantification (LLOQ) for their 
serum capsaicin assay was 0.5 ng/mL, which can be considered a sensitive high-
performance liquid chromatography (HPLC) method.[7] They also report that the 
percentage of subjects that had serum levels below the LLOQ was, in four different 
studies, respectively: 89%, 99%, 99.5%, and 94%. The median serum Cmax for all 
subjects in all studies was reported to be circa 2 ng/mL with a time to maximum effect 
(Tmax) of circa 1.5 hrs and with serum levels dropping to below LLOQ for all subjects 
by 4 – 5 hrs after patch removal.  
Given that the unit surface area application rate for capsaicin in Protocol VZU00025 
will be only about 12% of that used in the studies reported by Babbar et al., (2009) it 
suggests that there would be no subjects in Protocol VZU00025 who would have 
capsaicin serum levels above an LLOQ of 0.5 ng/mL.[7]  
In Non-Clinical studies (summarized above), no suggestions of potential systemic or 
site of application toxicities have been reported.  
1.4.1 
Possible Risks 
All safety data obtained in this trial will be carefully evaluated and used to inform the 
design of any future clinical trials. The potential risks of study participation include 
those associated with exposure to capsaicin and possible allergic reactions to capsaicin 
or one of the other components of the investigational products. Effects of topical 
exposure to capsaicin include erythema, edema, papules, scaling, pruritus, stinging and 
burning pain. These manifestations may also occur in unintended locations through 
transfer of the investigational products from the treatment area to other sites on the 
skin, mucous membranes, and ocular surfaces. Inhalation of fumes or aerosolization of 
the investigational products may cause irritation of airways with symptoms such as 
coughing. A temporary rise in blood pressure (hypertension) or difficulty sleeping 
could occur if pain from stinging and burning is severe. All subjects will receive a full 
explanation of potential risks and will sign an informed consent form prior to study 
participation. 
 
 

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2.0 
STUDY OBJECTIVES 
The objectives of the present study are the following: 
• 
To develop pain relief dose-response data for OAKP, compared to Vehicle, for 
the following concentrations of Capsaicin in CGS-200 vehicle: 1% and 5% using 
the WOMAC pain subscale (VAS formatted) as the primary pain index for relief 
of OAKP.  
• 
To confirm, in a U.S. based population, the high safety profile for CGS-200-5 
that was reported in Studies VZU00021 and VZU00023 in a Dominican Republic 
population. 
• 
To develop data for relief of signs and symptoms of osteoarthritis using the 
WOMAC subscales for pain, stiffness and function and total WOMAC score. 
• 
To develop OAKP relief data using the 100 mm VAS scale. 
2.1 
PRIMARY ENDPOINTS 
The Primary Efficacy endpoint of this study will be to examine the extent of reduction 
in the WOMAC pain score, relative to baseline, provided by once daily, one-hour 
application of Vehicle (CGS-200-0), CGS-200-1 and CGS-200-5 at the following 
assessment times: 
Baseline: < 30 minutes prior to first daily application 
Day 35  31 Days (+/- 3 days) after fourth daily application 
and based thereon to determine whether the responses for treatment with CGS-200-0, 
CGS-200-1, and CGS-200-05 are significantly different from Vehicle and from each 
other at the primary endpoint time.  
The Primary Safety Endpoints will be: 
(1) The application of the study drug does not produce skin reactions (erythema, 
scaling, pruritus, or other) to a degree that is clinically of concern. Scoring of 

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erythema and scaling at the application sites and of pruritus will be assessed per 
the scoring systems in Appendix F. 
(2) 
No SAE’s either possibly, probably or definitely associated with study 
treatments. 
(3) 
Safety labs (hematology, serum chemistry and urinalysis) do not produce other 
than minimal – mild toxicities (Grade 1 or Grade 2). Scoring of clinical, 
hematological and urinalysis out of range findings for toxicity grading will be 
per Appendix B. 
2.2 
SECONDARY ENDPOINTS  
Secondary Efficacy endpoints will be: 
(1) 
The extent of reduction in the WOMAC pain score, relative to baseline, 
provided by once daily, one-hour application of Vehicle (CGS-200-0), CGS-
200-1, and CGS-200-5 at the following assessment times: 
Baseline: < 30 minutes prior to first daily application 
Day 5  24 hrs (+/- 3) after last of the 4 daily applications 
Day 19  15 days (+/- 3) after last of the 4 daily applications 
Day 64  60 days (+/- 3) after the last of 4 daily applications 
Day 94  90 days (+/- 3) after the last of 4 daily applications 
(2) 
Day 5, 19, 35, 64, and 94 WOMAC scores on the stiffness and function 
subscales as well as total WOMAC score (including the WOMAC pain score).  
Secondary Safety endpoints will be:  
(1) 
The distribution by study arms of specific AEs (i.e.: local application site 
reactions), and other AEs (inclusive of findings for hematology, serum 
chemistry and urinalysis).  
(2) 
Evaluate the amount of concomitant pain medications used overtime 
 
 

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Tolerability endpoints (which are secondary in nature) will be: 
(1) 
The application of study drug does not produce burning-stinging pain (“BSP”) 
at the application site to a degree that is not acceptable to the subject. BSP at 
the application site, this will be assessed using a 0 – 10 NRS scale without 
guideposts. “Acceptability” of BSP will be queried per subject at the end of 
each application period. 
(2) 
The application of the study drug does not produce pruritus during application 
or in the 24 hrs post-application to a degree that is not acceptable to the subject 
or, if bothersome to the subject, cannot be managed by application of ice or a 
cold pack or compress. 
 
 

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3.0 
STUDY DESIGN 
3.1 
OVERALL STUDY DESIGN 
This is a multi-center, randomized, double-blind clinical trial to examine the 
comparative effects on OAKP of CGS-200-1 (1% Capsaicin content) (N=40), 
CGS-200-5 (5% Capsaicin content) (N=40), and CGS-200 Vehicle (no Capsaicin) 
(N=40) in subjects with OA of the knees according to the 1986 ACR criteria. Assigned 
doses will be applied at the clinic for 60 minutes on each of four consecutive days. 
Subjects will be randomized to one of the three Arms in this study: CGS-200-1 or 
CGS-200-5 or CGS-200-0 (Vehicle). All subjects will receive 4 consecutive days of 
treatment and will then be followed up until the Day 94 visit. 
Subjects will receive the study arm appropriate treatment as a topical application over 
the frontal aspect of the knee(s) once daily on four consecutive days. The applications 
will be at the clinic but by the subject wearing gloves under supervision of clinic 
personnel. The application will be left in place for 60 minutes and then washed off at 
the clinic by clinic personnel. The amount of Investigational Drug Product to be applied 
is estimated to be approximately 0.13 mL based on experience in prior studies. Even 
though both knee(s) will receive application of study test materials, with regard to 
reduction in WOMAC pain and  VAS pain score associated with study treatments, only 
one knee will be indicated as the “Study Knee”. This will be the knee with the highest  
WOMAC pain score at baseline. If both knees have equal WOMAC pain scores at 
baseline, then the right knee will be considered the “Study Knee” with regard to 
WOMAC pain and VAS pain score reduction.  
Data will be collected from Day 1 through Day 5 and then again on Days 19, 35, 64, 
and 94 for efficacy, tolerability, and safety measures. The Investigators, all site staff 
and Clinical Research Organization (CRO) personnel (except the Medical Monitor 
providing safety oversight) directly involved in the study will remain blinded to the 
treatment assignment throughout the trial.  
3.2 
DOSE LIMITING TOXICITY 
AEs and SAEs will be assessed according to the Rheumatology Common Toxicity 
Criteria (RCTC) v2.0[8] (Appendix B). 

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Dose limiting toxicity (DLT) stopping rules for the study drug are based mainly on 
Grade 2 events related to the study drug, with the following exceptions: 
1. Cutaneous CGS-200-1 (Capsaicin 1% Topical Liquid) and CGS-200-5 (Capsaicin 
5% Topical Liquid) have the potential for being associated with Grade 2 
administration site reactions such as erythema, pain and edema, and the DLT 
threshold has been set at Grade 3.  
2. The cut-point of Grade 3 to define a DLT and stop further administration of study 
drug was selected for the safety of subjects since the RCTC only require permanent 
discontinuation of drugs that attain a Grade 4. 
A DLT will be defined as any toxicity occurring within 14 days of treatment with the 
investigational product, and meeting the following criteria: 
• 
> Grade 3 AE including:  
− 
Allergic / Immunologic: immune reactions, rhinitis; 
− 
Cardiac: hypertension, hypotension; 
− 
Dermatologic: reaction at site of study drug administration; 
− 
Neuropsychiatric: inability to concentrate, insomnia (in absence of pain), 
peripheral sensory neuropathy. 
• 
Any other ≥ Grade 2 AE (excluding AEs captured above and pre-existing OA-
related conditions). 
 
 

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4.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
INCLUSION/ EXCLUSION CRITERIA: 
Subjects entering the study must meet all inclusion and exclusion criteria. 
4.1.1 
Inclusion Criteria: 
The subject must meet all of the following: 
1. 
Able to comprehend the informed consent form (ICF) and provide Informed 
Consent, and capable of complying with all study procedures; 
2. 
Male or female, 35 years of age to 75 years; 
3. 
OA of the at least one knee according to 1986 ACR Classification Criteria; 
4. 
OA of at least one knee must be confirmed by tibiofemoral joint radiographs 
obtained within the past 6 months; 
5. 
RF negative and ESR <40 mm/hr; 
6. 
Chronic knee pain in at least one knee for > 3 months; 
7. 
WOMAC pain score of > 250 (using VAS WOMAC format) at screening, and 
at baseline, in at least one knee; 
8. 
Knee pain score of > 5 on the NRS pain scale at screening, and at baseline, in at 
least one knee; 
9. 
Knee pain is not potentially due to acute trauma unrelated to OA (no acute 
traumatic knee injury in medical history); 
10. 
No burning-stinging pain, unrelated to subject’s knee pain, at intended site of 
application; 
11. 
Knee pain must be greater than pain in any other part of subject’s body; 
12. 
ACR global functional status I, II, or III (excluding IV); 

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13. 
If female, subject must be past childbearing age or otherwise must test negative 
for pregnancy. Males and females must agree to use effective birth control for 
at least 30 days after last dose of study drug. 
4.1.2 
Exclusion Criteria: 
The subject must not have any of the following: 
1. 
Spontaneously improving or rapidly deteriorating OA of the knee; 
2. 
Rheumatoid or psoriatic arthritis, or a form of arthritis (e.g. gout, pseudogout), 
Paget’s disease of bone, or any other disease affecting the joints that are 
inconsistent with a diagnosis of idiopathic OA; 
3. 
Use of topical, oral, or injectable steroids for 1 month prior to screening, or 
intraarticular-visco-supplementation within 3 months prior to screening; 
4. 
Used any capsaicin-containing product on or in the vicinity of the knee within 
4 weeks prior to screening; 
5. 
Used topically applied products (including emollients or moisturizers) on or in 
the vicinity of the knees or shaved the knees within 2 days prior to the first 
application of study drug; or an open wound near the knee; cutaneous erythema 
or edema; any inflammatory skin lesions such as eczema or psoriasis; cutaneous 
infections; or any other compromise of the skin; 
6. 
A history of sensitivity to topical substances inclusive of OTC topical 
analgesics; 
7. 
Significant cardiovascular, renal, or other diseases or conditions, or laboratory 
or other test abnormalities that, in the opinion of the Investigator, would 
contraindicate participation in the trial; 
8. 
Labile or poorly controlled hypertension;  
9. 
A psychiatric disorder or significant anxiety or depression that could interfere 
with the subject’s compliance with study procedures or completion of the study; 

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10. 
Requires daytime use of medications or substances (alcohol, benzodiazepines, 
barbiturates, muscle relaxants, tranquilizers, hypnotics) that could diminish 
their cognitive ability to comply with study procedures; 
11. 
A history of drug or alcohol abuse within one year prior to screening; 
12. 
Requires or anticipates any surgical procedure within 3 months prior to 
screening, has had surgery on the affected joint within 6 months prior to 
screening, has a prosthesis in either knee, or would require surgery while 
participating in the trial; 
13. 
Pregnant or nursing; 
14. 
Treated with an investigational drug, device or therapy within 30 days prior to 
screening. 
15. 
Body mass index greater than 45 kg/m2 
16. 
Skin on or near knee is broken or damaged or if there is an open wound on or 
near the knee. 
4.2 
REPLACEMENT OF SUBJECTS 
Subjects that do not receive 4 complete consecutive daily doses and/or drop out before 
completing the Day 35 visit may be replaced if the reason for dropping out is other than 
lack of drug product tolerability. A dose will be considered complete when at least 80% 
has been delivered on any study drug administration day; dosing will be considered 
complete overall when a total of at least 80%, in the aggregate, has been delivered 
across all study treatment days. Subjects that drop out or who cannot be followed up 
from after the Day 5 visit until the Day 35 visit may be replaced. Up to 10 subjects per 
arm may be replaced. 
 
 

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5.0 
STUDY TREATMENT 
5.1 
CGS-200-1, CGS-200-5, AND CGS-200-0 (VEHICLE) 
5.1.1 
Formulation 
CGS-200-1 and CGS-200-5 are topical analgesic liquids intended for application to 
intact, non-irritated skin in adults with musculoskeletal pain, including pain of OA of 
the hands, wrists, elbows, or knees for the relief of pain, reduction of stiffness, and 
increased functional activity. 
CGS-200-1 is a multi-component formulation in which the active ingredient for the 
intended therapeutic effect is capsaicin at a level of 1% for this study. 
CGS-200-5 is a multi-component formulation in which the active ingredient for the 
intended therapeutic effect is capsaicin at a level of up to 5% for this study.  
CGS-200-0 (Vehicle) contains all of the ingredients in CGS-200-1 and CGS-200-5 
except for capsaicin. 
The composition of study test materials is provided in the table below. 
Ingredient 
CGS-200-5 
% w/w 
CGS-200-1 
% w/w 
CGS-200-0 
Vehicle 
% w/w 
Capsaicin 
5 
1 
0 
Dehydrated Alcohol 
20 
20 
22.5 
Polysorbate 80 
10 
8 
7 
Diethylene Glycol Methyl Ether  
10 
10 
10 
Propylene Glycol 
10 
10 
10 
Na Hyaluronate (~1,000K Daltons) 
0.15 
0.16 
0.17 
Na Hyaluronate SLMW (~20K Daltons) 
0.30 
0.32 
0.33 
Distilled Water 
44.55 
50.52 
50 
 
 
 
 
Totals 
100.00 
100.00 
100.00 
 
CGS-200-1, CGS-200-5, and CGS-200-0 Vehicle will be stored at room temperature 
(15 - 30C) in a limited access location, protected from excessive light and heat. 
Storage conditions must also comply with the site’s institutional procedures and all 
applicable regulatory requirements. 

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Under clinic supervisions, each dose will be applied by the subject (who will be 
wearing gloves provided by the clinic) to the knee(s) over a 10 x 10 cm area on Days 
1, 2, 3, and 4 and at each application, will be washed off by clinic personnel after 
60 minutes (± 5 min). 
5.1.2 
Packaging, Labeling and Storage 
The vial label will contain the following information at a minimum: 
• 
Blinded code number 
• 
Volume (single dose vial; fill volume is up to 0.35mL) 
• 
Storage instructions 
• 
Manufacture Date 
• 
Investigational drug statement 
• 
Name of manufacturer 
• 
Name of sponsor 
Study drug inventory/accountability forms will be monitored during the study and 
reconciled by the study monitor at the end of the study. All used and unused 
investigational study drug must be accounted for on a study drug accountability form 
provided to the investigator by the site monitor.  
5.1.3 
Rationale for Dose Selection 
In a previous clinical investigation with CGS-200 5% and 10% capsaicin 
(Study VZU00021), both strengths gave essentially the same degree of pain relief and 
over essentially the same time course to maximum effect and lasting at least 29 days 
after cessation of treatment. Both strengths were well tolerated. Based on this, the 
choice of CGS-200-05 as the high dose Arm in this study is seen as rational. For the 
low dose Arm, CGS-200-1 was selected on the basis of being a reduction of 5-fold 
from the 5% dose, which degree of reduction is likely to give a lower response than the 
5% dose based on modeling of analgesic responses from 7 days of QD and BID doses 

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of 0.25% capsaicin in CGS-200 observed in a clinical study of Sponsor’s marketed 
OTC Monograph capsaicin topical product.  
5.1.4 
Dosage and Administration 
The study medication is for external use only and will be administered at the clinic by 
the subject under the supervision of trained site personnel. Wearing gloves, supplied 
by the clinic staff, a single dose of the assigned treatment will be topically applied to 
each knee on each of four dosing days. Both knees will be treated for all subjects, if 
possible, however only one knee will be the study knee on which assessments are 
performed. The first application of medication will be at Visit 2 on Day 1 (initiated at 
Time 0). Dosing on each of the three subsequent treatment days should be performed 
at the same time of day ±2 hours in relation to the start time of the initial dose on Day 1.  
With the knee relaxed, in a straight and horizontal position, treatment will begin by 
identifying a 10 cm by 10 cm area where the upper boundary is 1 cm above the patella, 
the center is aligned with the midline of the patella, and the line bisecting the 10 cm by 
10 cm square has 5 cm on either side medially and laterally to the midline of the patella. 
Each application of the study medication will consist of a single pass of the roller ball 
over the knee so as to completely cover the designated treatment area. The treatment 
will be applied continuously beginning at the upper left corner of the square and 
moving the rollerball horizontally to the upper right corner and moving back and forth 
in a continuous pattern in a downward progression until the entire square is covered. 
This should result in moistening the skin providing a thin film of medication 
(approximately 0.13 mL [or 0.13 gram] of drug product applied to 100 cm2 of knee 
surface, which represents 1.3 mg of solution per cm2). Areas that were already 
moistened should not be recoated. The study medication should not be applied to a knee 
if the subject is still experiencing stinging, burning, pruritus, erythema, or scaling from 
a prior application to that knee. In the case of a dose that is skipped, the subject should 
return as scheduled for their next visit at which time they may receive the next 
scheduled application of study medication if their symptoms have subsided. The 
treatment period will not be extended beyond 4 days.  
During the application process, care must be taken not to contaminate the outside of 
the bottle, other body surfaces, or equipment or other surfaces in the room. Any 
suspected contamination should be dealt with by washing off the formulation as soon 
as possible. 

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The subject’s knees will remain uncovered for 60 minutes (up to 65 minutes) after 
dosing to allow for assessments and proper absorption of the study medication. The 
subject must avoid touching the knee area during this time. The knees will then be 
cleansed by trained personnel according to specific procedures designed to remove any 
remaining residual formulation from the surface of the skin. After the area is cleansed, 
the subject may cover their knees, but should avoid doing so if possible. It is 
recommended that the subject wear shorts or a skirt during the treatment period rather 
than long pants. During the four days of treatment, subjects should also avoid exposing 
the knees to any form of heat (hot water, vigorous exercise, direct sunlight, etc.). If a 
subject experiences intolerable pain or severe irritation from the study medication, they 
may apply cold water, ice, or a cold pack or cold compress to their knee. If the subject 
continues to have unbearable pain, they should contact the study site for help with pain 
management. In the event of an allergic reaction or medical emergency, the Medical 
Monitor must be contacted immediately. 
Treatment assignment for all subjects enrolled in this study will be double-blind; the 
subjects and all site personnel and CRO personnel (except for the medical monitor 
providing safety oversight) involved in this study will not know the treatment given to 
any subject. Every effort should be made to maintain the study blind.  
Subjects will be monitored closely during and after application of treatment for any 
signs of acute adverse reactions. If an allergic reaction occurs, suggested guidelines are 
as follows: 
• 
Grade 3 or higher adverse reaction: 
− 
If treatment is ongoing, it must be immediately and permanently 
discontinued, the study drug should be washed off, and the subject should 
be treated symptomatically as clinically indicated. 
− 
The subject will be followed for safety as clinically indicated until the 
toxicity resolves, and in the opinion of the investigator, no further follow-
up regarding the toxicity is needed. Complete documentation of the event is 
required.  

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• 
Grade 2 adverse reaction: 
− 
If treatment is ongoing, it must be immediately interrupted and the subject 
should be treated symptomatically as clinically indicated. 
− 
Once the subject has recovered to baseline and, if in the opinion of the 
investigator the benefit/risk is favorable, consideration can be given to 
restarting the treatment the next day after pre-medicating with an 
H2-receptor antagonist and acetaminophen. 
• 
Grade 1 adverse reaction: 
− 
If treatment is ongoing, it may continue, but the subject should continue to 
be monitored carefully to ensure that ongoing signs and symptoms do not 
progress and worsen warranting intervention as described above. 
5.1.5 
Reporting Product Defects 
Any defects with the investigational products must be reported immediately by the site 
to the Medical Monitor and Vizuri Health Sciences with further notification to the site 
monitor.  
5.2 
CONCURRENT MEDICATIONS 
5.2.1 
Allowed Regimens 
Subjects may continue their baseline medication(s) as long as the medications are not 
prohibited as outlined in Section 5.2.2. If for any reason deemed necessary by the 
investigator, a subject requires additional medication(s) or change of dose, the 
medication(s), dosage change, route of administration, start and stop dates, and the 
indication for which it was given must be recorded in the source documents and 
electronic case report form (eCRF). 
5.2.2 
Prohibited Medications 
Subjects should not receive any of the following medications through Day 94 and for 
the additional times specified below: 

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• 
Topical, oral or injectable steroids for 1 month prior to screening, or 
intra-articular-visco-supplementation within 3 months prior to screening; 
• 
Any capsaicin-containing product on or in the vicinity of the knee within 4 weeks 
prior to screening; 
• 
Topically applied products (including emollients or moisturizers) on or in the 
vicinity of the knees within 2 days prior to the first application of study drug; 
• 
Topical or any other therapy on the knees that, in the Investigator’s opinion, might 
affect the study evaluation of signs/symptoms; 
• 
Daytime use of medications or substances (alcohol, benzodiazepines, 
barbiturates, muscle relaxants, tranquilizers, hypnotics) that could diminish 
cognitive ability to comply with study procedures; 
• 
Investigational drug, device or therapy within 30 days prior to screening. 
5.3 
PROHIBITED PROCEDURES 
Subjects should not undergo any of the following procedures through Day 94 and for 
the additional times specified below: 
• 
Anticipates any surgical procedure within 3 months of screening; 
• 
Had surgery on the affected joint within 6 months prior to screening; 
• 
Prosthesis at the index joint. 
• 
Subjects should not shave their knees within 2 days before Day 1 and through 
Day 5. 
 
 

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6.0 
STUDY PROCEDURES 
6.1 
SCREENING VISIT 
Written informed consent must be obtained before any screening procedures are 
performed that are not considered part of normal patient care. Screening for many 
subjects will be completed in 2 visits.  During the first visit, all screening activities with 
the exception of obtaining laboratory work should be completed. Prior  to this  second 
visit in which laboratory work will be collected, subjects must begin fasting (except 
water) for chemistry assessment beginning at midnight prior to the blood draw visit. If 
a subject presents for the first screening visit and has fasted on his/her own since 
midnight the blood draw may be taken at the first screening visit and a second screening 
visit will not be required.  Table 6–1 shows all the procedures to be conducted at the 
Screening Visit. Subjects should plan to be in the clinic a minimum 1.5 hours (up to 2 
to 3 hours) each visit.  
Table 6–1 
Screening Procedures 
Assessment 
Within 28 days of Study Day 1 
Clinic Visit 
X 
Informed Consent 
X 
Inclusion / Exclusion 
X 
Demographics 
X 
Medical & Medication History 
X 
Physical Exam 
X 
Heights & Weight 
X 
Vital Signsa 
X 
Knee X-raysb 
X 
12-lead electrocardiogram (ECG)c 
X 
Clinical Laboratory Testsd 
X 
Serum Pregnancy or Follicle-stimulating hormone (FSH) Teste 
X 
Application Site Pain, Erythema, Edema, Scaling, Pruritus Assessmentf 
X 
Exploratory Assessment of OA Knee Paing 
X 
WOMAC 
X 
Assessment of Concomitant Medicationsh 
X 
a 
Vital signs include temperature, blood pressure, heart rate and respiratory rate. 
b 
Knee-X-rays of both knees must be obtained unless films/images performed within 6 months before screening. Copies of 
film and results will be requested. 
c 
Standalone 12-lead ECG. 
d 
Clinical Laboratory Tests (Appendix A): 
 
Hematology: complete blood count (CBC) including red blood cells (RBC), hemoglobin, hematocrit, MCV, MCH, MCHC, 
white blood cells (WBC), differential white cell count, platelet count. 
ESR 
Chemistry: Blood Urea Nitrogen (BUN), creatinine, uric acid, bilirubin (total), sodium, potassium, calcium, magnesium, 
phosphorous (inorganic), chloride, bicarbonate, alkaline phosphatase (ALK), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), creatine phosphokinase 
(CPK), albumin, total protein, and glucose 
Immunoglobulin M (IgM) RF 
Urinalysis: pH, protein, glucose, ketones, bilirubin, blood, urobilinogen, specific gravity, leucocytes. Clinically significant 
abnormal dipstick results will require microscopic analysis. 

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e 
Serum pregnancy test for premenopausal women; FSH test to confirm postmenopausal status (females only) for up to 
2 years after cessation of menses 
f 
Application site pain will be assessed on the NRS (0-10); application site erythema/edema will be assessed using modified 
categorical Draize test (0-3).[9] Scaling and pruritus will also be scored on a similar categorical scale (0-3). Scoring for 
application site pain (not related to knee pain) and for erythema, edema, scaling and pruritus. (Appendix F and G). 
g 
Exploratory assessment of OA knee pain (average daily pain and daily worst pain) (Appendix F).  
h 
Document all medications taken within 90 days of the Screening visit. 
 
6.2 
ON-TREATMENT EVALUATIONS: 
Table 6–2 shows all procedures to be conducted during Study Days 1 to 4 when study 
drug is applied in the Clinic. 
Table 6–2 
On Treatment Evaluations 
Assessment 
Treatment Days 
TIMEFRAME 
1 
2 
3 
4 
Clinic Visit 
X 
X 
X 
X 
Randomization 
X 
 
 
 
Vital Signsa 
X 
X 
X 
X 
Urine Pregnancy Testb 
X 
 
 
 
Application Site Pain, Erythema, Edema, Scaling, Pruritus Assessmentc 
X 
X 
X 
X 
VAS OA Knee Pain Assessmentd 
X 
X 
X 
X 
WOMACe 
X 
 
 
 
Exploratory Assessment of OA Knee Painf 
X 
 
 
 
Drug Administration 
X 
X 
X 
X 
Assessment of Concomitant Medications 
X 
X 
X 
X 
AE Assessments 
X 
X 
X 
X 
a 
Vital signs include temperature, blood pressure, heart rate and respiratory rate pre-dose on Days 1-4 and at 90 minutes (± 5 
min) after applying study drug to knees. 
b 
Urine pregnancy test at baseline on Day 1 for premenopausal women. 
c 
Application site pain will be assessed on NRS (0-10); application site erythema/edema will be assessed using modified 
categorical Draize test (0-3). Scaling and pruritus will also be scored on a similar categorical scale (0-3). Scoring for 
application site pain (not related to knee pain) will be performed on drug administration Days 1-4 (pre-application 
[30 min], and at 15 (± 5 min), 30 (± 5 min), 60 (± 5 min) and 90 minutes (± 5 min) after application) and on Days 5, 20, 
and 35. Application site skin reactions (erythema, edema, scaling, pruritus) will be assessed on drug administration Days 1-4 
(pre-application [ 30 min], and at 15 (± 5 min), 30 (± 5 min), 60 (± 5 min) and 90 minutes (± 5 min) after application). ( 
Appendix E and Appendix F). 
d 
OA knee pain to be scored on 100mm VAS scale pre-treatment ( 30 min) on Days 1-4. 
e 
WOMAC Pain, Stiffness, and Physical Function will be performed on Day 1 prior to drug administration ( 30 min). 
f  
Exploratory assessment of OA knee pain (average daily pain and daily worst pain) (pre-application [<30 min]) (Appendix 
F). 
 
“BASELINE” is defined in this study as the WOMAC scores (pain, stiffness, function) and the 
VAS OA knee pain score recorded within 30 minutes of the first application of study drug. 
 
 
 
 

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6.3 
FOLLOW-UP PERIOD EVALUATIONS 
Table 6–3 shows all procedures to be conducted during the Follow-up Period (Clinic 
Days 5, 19, 35, 64 and 94).  
Table 6–3 
Follow-up Period Evaluations 
Assessment 
Follow-up Period Days 
TIMEFRAME 
5 
(24hrs post 
Day 4 [4 
hrs]) 
19±3 
(Post-
Treat 
Wk 3) 
35±3 
(Post-
Treat 
Wk 5) 
64 (+ 3), 
(Post-Treat 
Wk 9) 
94 (+ 3) 
(Post-Treat 
Wk 13) 
Unscheduled, 
Early 
Termination, 
SAEe 
Clinic Visit 
X 
X 
X 
X 
X 
X 
Vital Signsa 
X 
 
 
 
X 
X 
Physical Exam 
 
 
 
 
 
X 
Clinical Laboratory Tests 
X 
 
X 
 
X 
X 
Application Site Pain, Erythema, 
Edema, Scaling, Pruritus 
Assessmentb 
X 
X 
X 
X 
X 
X 
VAS OA Knee Painc 
X 
X 
X 
X 
X 
X 
WOMACd 
X 
X 
X 
X 
X 
X 
Assessment of Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
AE Assessments 
X 
X 
X 
X 
X 
X 
Study Exit 
 
 
 
 
X 
 
a 
Vital signs include temperature, blood pressure, heart rate and respiratory rate. 
b 
Application site pain will be assessed on NRS (0-10); application site erythema/edema will be assessed using modified 
categorical Draize test (0-3). Scaling and pruritus will also be scored on a similar categorical scale (0-3). Scoring for 
application site pain (not related to knee pain) will be performed on Days 5 (24 hrs [+/- 4 hrs]), 19 (+/- 3 days), 
35 (+/- 3 days), 64 (+/- 3 days) and 94 (+/- 3 days). Application site skin reactions (erythema, edema, scaling, pruritus) will 
be assessed on Days 5 (24 hrs [+/- 4 hrs]), 19 (+/- 3 days), 35 (+/- 3 days), 64 (+/- 3 days) and 94 (+/- 3 days). 
(Appendix E and Appendix F). 
c 
VAS OA knee pain will be performed on Days 5 (24 hrs [+/- 4 hrs]), 19 (+/- 3 days), 35 (+/- 3 days), 64 (+/- 3 days) and 94 
(+/- 3 days).  
d 
WOMAC Pain, Stiffness, and Physical Function will be performed on Days 5 (24 hrs [+/- 4 hrs]), 19 (+/- 3 days), 35 (+/- 3 
days), 64 (+/- 3 days) and 94 (+/- 3 days). 
e 
Refer to Section 6.5 for assessments to be completed at time of SAE, early termination or unscheduled visit. 
 
 
6.4 
BIRTH CONTROL REQUIREMENTS 
Female subjects of childbearing potential must agree to use a highly effective method 
of birth control (defined as those, alone or in combination, which result in a low 
failure rate, i.e., less than 1 percent per year, when used consistently and correctly) 
for at least 30 days after last dose of study drug. 
Male subjects must agree to use a highly effective method of birth control (defined as 
those, alone or in combination, which result in a low failure rate, i.e., less than 
1 percent per year, when used consistently and correctly) for at least 30 days after 
last dose of study drug. 

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The acceptable methods of birth control are: 
• 
Implanted, injected, or oral contraceptives 
• 
Intrauterine devices 
• 
Barrier methods (male condom, female condom, diaphragm) 
• 
Sexual abstinence (when this is the preferred and usual lifestyle of the subject) 
• 
Male subjects who have had a vasectomy 
• 
Female subjects who have had a hysterectomy, tubal ligation, or bilateral 
salpingectomy or women of postmenopausal status 
In addition, male subjects must not donate sperm during the study and for 30 days after 
the last dose of study drug.  
6.5 
ASSESSMENTS AT TIME OF SAE, EARLY TERMINATION OR 
UNSCHEDULED VISIT 
Additional activities may be performed at the Investigator’s discretion at the onset of 
an SAE, when subjects are prematurely taken off study, and/or for an unscheduled visit. 
• 
Assess vital signs (BP, HR, RR, and T) 
• 
Perform abbreviated symptom-driven physical exam (PE) 
• 
Application site pain will be assessed on numerical pain rating scale (0-10); 
application site edema will be assessed using categorical Draize test (0-3). 
Scoring for application site pain (not related to knee pain) and for erythema and 
edema will be performed at Early Termination and at Unscheduled Visits. 
• 
VAS OA knee pain and WOMAC will be performed at Early Termination and at 
Unscheduled Visits. 
• 
Collect blood: 
For local laboratory analysis: 

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− 
CBC with automated differential and platelets, and serum chemistry 
• 
Document AEs and concomitant medications 
6.6 
STUDY BLOOD DRAW VOLUME 
The total blood volume to be collected during the study is approximately 60 ml (two 
ounces). 
6.7 
RECOMMENDATIONS 
FOR 
MANAGEMENT 
OF 
POTENTIAL 
TOXICITIES 
6.7.1 
Allergic Reaction, Burning, or Pruritus 
In the case of any life-threatening event occurring during the treatment, the study drug 
must be immediately and permanently discontinued. While corticosteroids are strongly 
discouraged, they may be used if they are necessary for the safety of the subject. 
• 
Rash/pruritus/urticaria 
− 
If subject develops rash, pruritus, or urticaria, interrupt treatment if it is 
ongoing and promptly assess subject for any other associated 
signs/symptoms (e.g., hypotension, fever, respiratory distress). 
• 
Consider treating with H2 receptor antagonists as clinically indicated. 
If rash / pruritus / urticaria is isolated and resolves either 
spontaneously or with intervention, treatment with the study drug may 
be restarted.  
6.8 
CONCOMITANT MEDICATIONS/RESCUE MEDICATIONS 
Subjects may continue their baseline medication(s) as long as the medications are not 
among the prohibited medications listed in Section 5.2.2. The daily dose of each 
medication should be maintained throughout the study since any changes to this 
background regimen may have an effect on the assessment. Subjects are allowed to 
increase dosage of NSAIDs or use analgesics to treat minor pain throughout the study, 
provided all concomitant medications are back to baseline dosages within 24 hours of 
a clinical assessment visit.  

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If for any reason deemed necessary by the investigator, such as in the event of a 
substantial disease flare which cannot be treated with increased drugs (NSAIDs) or 
narcotic, a rescue medication can be initiated at any time that is in the best interests of 
the subject. Rescue medication should be carefully considered by the principal 
investigator (PI) since there may be an effect on the results of the study. All changes 
and start and stop dates, and the indication for which it was given must be recorded in 
the source documents and eCRF. Routine changes (dose, route, etc.) to the background 
treatments should not be performed. 
6.9 
STOPPING CRITERIA 
6.9.1 
Criteria for Adverse Event Assessment 
All AEs will be graded according to the RCTC v.2.0 (Appendix B). Please refer to 
Section 8.0, Safety Assessments for additional information. 
6.9.2 
General Criteria for Stopping Study Drug 
The study drug will be permanently discontinued for any subject who meets a DLT 
criterion as outlined in Section 3.2.  
6.9.3 
Stopping Criteria 
Any ≥ Grade 3 event considered related to the study drug and occurring during 
administration of the study drug will result in its permanent discontinuation for that 
subject. The Medical Monitor should be notified immediately and the subject should 
be followed for safety as clinically indicated until the toxicity resolves and in the 
opinion of the investigator, no further follow-up regarding the toxicity is needed. 
6.10 
WITHDRAWAL OF SUBJECTS FROM STUDY 
Subjects will be free to withdraw from treatment or from the study at any time for any 
reason, or they may be withdrawn/removed, if necessary (see reasons for withdrawal 
below). It is understood by all concerned that an excessive rate of withdrawals can 
render the study uninterpretable; therefore, unnecessary withdrawal of subjects should 
be avoided. 

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Subjects will be removed from treatment for the following reasons: 
• 
Unacceptable acute toxicities defined as: 
− 
Occurrence of a DLT 
Subjects will be removed from the study for the following reasons: 
• 
Withdrawal of consent 
• 
Non-compliance/Lost to follow-up 
• 
Pregnancy 
If treatment with study drug is interrupted and permanently stopped, subjects should 
remain on study and will be followed for scheduled safety and study assessments 
through Day 35. If the subject goes onto other treatment, this should be noted in the 
source documents and the concomitant medications eCRF. 
 
 

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7.0 
CLINICAL ACTIVITY 
Evidence of clinical activity will be assessed by the VAS OA knee pain scores recorded 
at pre-dose (< 30 min) on Days 1 2, 3, 4, and on Days 5, 19, 35, 64, and 94.  
The WOMAC instrument will we be used to evaluate the effectiveness of CGS-200-1 
and CGS-200-5 in the management of signs and symptoms of OA of the knee in 
addition to just management of OA knee pain on Days 5, 19, 35, 64, and 94. 
 
 

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8.0 
SAFETY ASSESSMENTS 
8.1 
ADVERSE EVENTS 
8.1.1 
Definitions 
The AE monitoring period begins with the start of study drug administration on Day 1 
and continues through Day 94. 
ADVERSE EVENT EXPERIENCE (AE) – any unfavorable or unintended sign, 
symptom, or disease that is temporally associated with the use of an investigational 
drug but is not necessarily caused by the investigational drug. This includes worsening 
(e.g.; increase in frequency or severity) of pre-existing conditions. 
SERIOUS ADVERSE EVENT (SAE) – an AE resulting in any of the following 
outcomes: 
• 
Death 
• 
Life-threatening (immediate risk of death) 
• 
Inpatient hospitalization 
• 
Prolongation of existing hospitalization 
• 
Persistent or significant disability or incapacity 
• 
Congenital anomaly/birth defect 
• 
Medically important* 
*Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in a subject’s 
hospitalization, or the development of drug dependency or drug abuse. 
UNEXPECTED ADVERSE EVENT – any adverse event, the specificity or severity of 
which is not consistent with the current Investigator Brochure (IB). Expected means 
that the event has previously been observed with the study drug and is identified and/or 

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described in the current IB. It does not mean that the event is expected with the 
underlying disease(s) or concomitant medications. 
8.1.2 
Reporting to the Sponsor 
All AEs that are identified from the start of study drug administration and through 
Day 94 will be documented in the source documents and the AE eCRF. All data fields 
on the AE eCRF should be completed. 
SAE must also be documented on the SAE Worksheet and sent to the sponsor/designee 
within 24 hours of site personnel becoming aware of an SAE. The SAE Worksheet 
should be completed as much as possible but should not be held until all information is 
available. Additional information, follow-up information, and corrections should be 
provided on subsequent SAE Worksheets that are clearly identified as follow-up (#1, 
#2, etc.) reports. SAE Worksheets should be sent by Email with Telephone Notification 
to the Drug Safety Department at: 
 
 
Telephone #: 1-513-619-4771 
 
 
Email:  
CTIsafety@CTIfacts.com 
 
 
Drug Safety personnel will be available to answer questions and assist site personnel 
in documenting SAEs and completing the SAE worksheet. 
8.1.3 
Investigator Evaluation of Adverse Events 
The determination of seriousness, severity and causality must be made by the physician 
investigator who is qualified to review AE information, provide a medical evaluation 
of AEs, and classify AEs based upon medical judgment. The investigator will evaluate 
all AEs with respect to seriousness (criteria listed above), severity, and causality 
(relationship to study drug) according to the guidelines listed below.  
Severity will be graded using the RCTC, v2.0. The RCTC is provided in Appendix B. 
In the event that an AE does not have a RCTC code, the following severity 
classifications will be used: 

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SEVERITY 
Grade 1: Mild  
 
Causing no limitation of usual activities 
Grade 2: Moderate 
 
Causing some limitation of usual activities 
Grade 3: Severe 
 
Causing inability to carry out usual activities 
Grade 4: Life Threatening* Potentially life threatening or disabling 
* Note – a severity assessment of Life Threatening is not necessarily the same as Life 
Threatening as a “Serious” criteria. The latter means that the event is an immediate 
threat to life as opposed to a potential threat to life. 
8.1.3.1 
Assessment of Seriousness 
Event seriousness will be determined according to the protocol definition of SAE in 
Section 8.1.1. 
8.1.3.2 
Assessment of Severity 
Event severity will be assigned according to the RCTC, v2.0. 
8.1.3.3 
Assessment of Causality 
The investigator is required to provide an assessment of causality or relationship of 
AEs to the study drug based on 1) temporal relationship of the event to the 
administration of study drug; 2) whether an alternative etiology has been identified; 
and 3) biological plausibility. The causality assessment categories that will be used for 
this study are described below. 
Note: If a causality assessment is not provided, a possible relationship will be assumed 
for regulatory reporting purposes. 
 
 

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Causality assessments that are considered Not Related to study drug: 
None: 
The event is related to an etiology other than the study drug (the alternative 
etiology must be documented in the subject’s medical record). 
Unlikely: A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or underlying disease 
provide plausible explanations. The event is unlikely to be related to the 
study drug and likely to be related to factors other than study drug. 
Causality assessments that are considered Related to study drug: 
Possible: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administrations of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear. 
Probable: A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge 
information is not required to fulfill this definition. 
Definite: A clinical event, including laboratory test abnormality, occurring in a 
plausible time relationship to drug administration, and 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. 
Note – ICH guidelines (3/95) clarify “reasonable causal relationship” to mean, 
“that there are facts (evidence) or arguments to suggest a causal relationship.” 

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8.1.4 
Follow-up of Adverse Events 
Adverse events will be captured from start of study drug treatment through Day 94. 
AEs are followed until final outcome is known or until the end of the study Day 94. 
AEs that are not resolved as of Day 94 are recorded on the AE eCRF as ongoing and 
in the outcome field as Not Recovered/Not Resolved. 
SAEs that have not resolved by Day 94 are followed until final outcome is known. If it 
is not possible to obtain a final outcome for a SAE (e.g., the subject is lost to follow-up), 
the reason a final outcome could not be obtained will be documented by the 
investigator. 
Pregnancy: 
All reports of pregnancy, or partner pregnancy, occurring after treatment with study 
drug and up to Day 94 must be reported via the Pregnancy Report form to Safety as per 
Section 8.1.2. Pregnancy itself is not an AE or SAE. However, any events arising 
during the pregnancy will be assessed and reported accordingly as an AE or SAE. A 
spontaneous abortion is always considered to be an SAE and shall be reported on the 
SAE Worksheet. Furthermore, any SAE occurring as a result of a post-study pregnancy 
and considered reasonably related to the investigational product by the investigator will 
be reported to Safety. All reported pregnancy cases will be followed up until outcome. 
8.1.5 
Post Study SAEs 
SAEs that occur after the Day 94 visit that are assessed by the investigator to be 
possibly, probably, or definitely related to study drug must be reported to Safety on a 
SAE Worksheet, as described in Section 8.1.2. Post study SAEs will not be documented 
on the AE eCRF. 
8.1.6 
Reporting to the Institutional Review Board/Independent Ethics Committee 
All SAEs that are considered unexpected and related to the investigational drug will be 
reported by Vizuri Health Sciences/designee as 15-Day (Expedited) reports to the 
regulatory authority AND to all participating investigators. Each investigator must 
notify the IRB/IEC responsible for reviewing the study at their site of all 15-Day 
Reports. Expected and unrelated SAEs will be reported periodically. 

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8.2 
LABORATORY TESTS 
Clinical laboratory tests (Appendix A) will be performed at Screening to determine 
eligibility and on Days 5 and 94 as outlined in Section 6.0. 
All female subjects who are biologically capable of having children will have a serum 
pregnancy test at screening and urine pregnancy test prior to dosing on Day 1. The 
results of the pregnancy tests must be confirmed to be negative before administration 
of study drug. FSH testing will be performed on postmenopausal women for up to 
2 years after cessation of menses to confirm postmenopausal status. 
 
 

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9.0 
DATA ANALYSIS METHODS 
9.1 
DETERMINATION OF SAMPLE SIZE 
A sample size analysis has been performed and suggests that a sample size of 
40 evaluable subjects per each of the three study arms will appropriately power this 
study.  
9.2 
RANDOMIZATION AND BLINDING 
Treatment assignment for all subjects enrolled in this study will be double-blind; the 
subjects and all site personnel and CRO personnel (with the exception of the Medical 
Monitor providing safety oversight) involved in this study will not know the treatment 
given to any subject. Every effort should be made to maintain the study blind.  
9.3 
ANALYSIS SETS 
The following three analysis sets will be defined for this study:  
The intent-to-treat (ITT) set will be defined as all randomized subjects, whether or not 
they receive study drug.  
The modified ITT (mITT) set will be defined as the subset of the ITT subjects that 
receive at least one dose of study medication and have at least one evaluable 
post-dosing efficacy endpoint. The mITT set will be defined based on randomized 
treatment rather than treatment actually received. All efficacy analyses will be carried 
out using the mITT set. 
The safety (SAF) set will be based on the ITT subjects, but will be based on the 
treatment actually received rather than randomized treatment. All safety analyses will 
be carried out using the SAF set. 
9.4 
SUBJECT ACCOUNTABILITY 
All subjects who meet the inclusion criteria for the study, sign the informed consent 
form, and are enrolled and exposed to the study medication will be accounted for in the 

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analyses. Subjects who are deemed ‘screen failures’ will not be accounted for in the 
data presentation of response or safety.  
9.5 
STATISTICAL METHODS 
9.5.1 
Analysis of Demographic and Subject Characteristics 
Subject demographic characteristics including age, gender, race, weight, and height 
will be summarized by treatment group. Subject baseline disease characteristics that 
are relevant to the evaluation of the treatment will be summarized by treatment group. 
9.5.2 
Treatment Administration/Compliance 
The Investigators will be responsible for the storage, dispensing, inventory, and 
accountability of all clinical supplies. An accurate, timely record of the disposition of 
all clinical supplies must be maintained. Subjects may be withdrawn from the study by 
the Sponsor for non-compliance with the protocol.  
9.5.3 
Efficacy Analyses 
Primary Efficacy Endpoint 
The group mean LMS difference between each Active Treatment Arm and the Vehicle 
Arm for the WOMAC pain score at Day 35 will be tested for significance of difference 
at a significance value of p < 0.05.  
Secondary Efficacy Endpoints 
The group mean LMS difference between each Active Treatment Arm and the Vehicle 
Arm for the WOMAC stiffness, function and total score at Day 35 will be tested for 
significance of difference at a significance value of p < 0.05 
Also, the group mean reduction in OA knee pain score on a 100 mm VAS scale for 
each active treatment arm will be compared to the vehicle arm and tested for 
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For dose-response estimation:  
The group mean LMS difference between the 5% and the 1% Active Treatment 
Arms for the WOMAC pain, stiffness, function and total score at Day 35 will be 
tested for significance of difference at a significance value of p < 0.05 
Efficacy analyses will be carried out on the mITT set. 
9.5.3.1 
Clinical Response 
Clinical response will be measured by reduction of WOMAC pain score. In order for a 
subject to be considered to have successfully obtained a clinical response, the following 
criteria must be met: 
WOMAC pain score reduced to 50% or less of baseline at any of the stated 
assessment times. 
The durability of clinical response up to Day 94 will be evaluated by a tabulation of 
clinical response at a Days 19, 35, 64, and the Day 94 visit by treatment group. Subjects 
who have successfully met the above criteria (reduction of a least 50% in NRS pain 
score) at the Day 5 visit and who remain at least at this reduction of pain score or lower 
at the Day 35 visit will be considered to have a durable clinical response. Subjects who 
at the Day 35 visit have less reduction in WOMAC in OAKP score than they did at the 
Day 5 assessment will be considered to have failed to achieve a durable clinical 
response.  
9.5.3.2 
Exploratory Analyses 
Post hoc tests may be performed to test for differences in the efficacy endpoints 
between the CGS-200-0 (Vehicle), CGS-200-1 and CGS-200-5 treatment groups for 
exploratory purposes. 
9.5.4 
Tolerability Analyses 
The primary tolerability endpoint will be tolerability of the formulations on each of 
Days 1, 2, 3, and 4. On each of these days, subjects will report an NRS score for 
burning / stinging at the application site pre-treatment and during treatment, and a 

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pre-treatment and during treatment pruritus score. Pre-treatment and during treatment 
erythema and scaling scores will be recorded by clinic staff assigned to the study. This 
will be done at 0, 15, 30, 60, and 90 minutes after application to capture time points 
during treatment and after washing the application site. The score for each of the above 
tolerability variables will be entered as a value at each assessment time. For each 
subject an “area under the curve” (AUC) calculation will be performed in 90 minute 
intervals for each score value. The AUC’s for tolerability variables combined will be 
compared between the CGS-200-5 and CGS-200-0 treatment groups. 
9.5.5 
Safety Analyses 
9.5.5.1 
Adverse Events 
The incidence of all reported AEs and treatment-emergent AEs (TEAE) will be 
tabulated. A TEAE is defined as an event that first occurs or worsens in intensity after 
the administration of study drug. AEs will be classified by system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). The 
severity of the AE will be graded using the RCTC v2.0 whenever possible. For AEs 
that are not included in the RCTC v2.0, the grading categories (mild, moderate, severe, 
and life-threatening) will be used and equated to the respective RCTC grade (Grades 
1, 2, 3, and 4). For incidence reporting, if a subject reports more than one AE that is 
coded to the same system organ class or preferred term, the subject will be counted 
only once for that specific system organ class or preferred term.  
An overview of AEs, which includes subject incidence of TEAEs, treatment-related 
AEs, severity of AEs, SAEs, deaths, and AEs leading to discontinuation, will be 
presented. For AEs presented by severity, the worst severity during the study will be 
presented for each subject. The subject incidence of TEAEs will be summarized by 
system organ class and preferred term. The subject incidence of treatment-related AEs 
and RCTC v2.0 toxicity grade will be summarized by preferred term. 
9.5.6 
Vital Signs 
Descriptive summaries of the vital signs (both raw and change from baseline values) 
including blood pressure, heart rate, respiratory rate, and body temperature will be 
prepared for each dose group. Descriptive statistics for quantitative variables will 
include sample size, mean, standard deviation, standard error, median, minimum, and 

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maximum. The 95% confidence interval of the mean will be constructed if it is 
appropriate (when there is more than 1 subject in a cohort). 
Vital sign values will be classified as low, normal or high based on the cut-off points 
defined below, and the data will be summarized by presenting shift tables from baseline 
to each post-baseline visit. For Baseline vital sign measurements: 
Measurement 
Lower 
Upper 
Unit 
Temperature 
<35.0 
>38.0 
C  
Systolic Blood Pressure (BP) 
<110 
>135 
mmHg 
Diastolic BP 
<65 
>85 
mmHg 
Heart Rate 
<50 
>110 
beats/min 
Respiratory Rate 
<12 
>20 
breaths/min 
 
For Post-baseline vital sign measurements: 
Measurement (unit) 
Low 
High 
Systolic Blood Pressure 
(mm Hg) 
> 20 point decrease from baseline  
> 20 point increase from baseline  
Diastolic Blood 
Pressure (mm Hg) 
>20 points decrease from baseline 
> 20 point increase from baseline 
Pulse (beats per minute 
(bpm)) 
< 50 and decrease from baseline ≥ 
15 
> 100 and increase from baseline ≥ 
15 
Temperature (C) 
<35 
>38 
Respiratory Rate 
(breaths per min) 
<12 
>20 
9.5.7 
Interim Analyses 
Interim analyses will be performed at Days 19, 35, and 64 per 9.5.3 and 9.5.3.1 above, 
9.5.8 
Procedures for Missing, Unused and Spurious Data 
Missing values will not be substituted by estimated values but treated as missing in the 
statistical evaluation. All data from all subjects dosed in the study will be included in 
all listings, plots, summary tables, and statistical analyses when appropriate. 

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9.5.9 
Rules for Excluding Subjects from Analysis 
All dosed subjects will be included in the analyses of safety. The sponsor will make 
any decisions regarding whether any subjects or any individual values belonging to a 
subject will be excluded from the efficacy evaluations when the protocol violation is 
considered to have a negative impact on the scientific aspects and interpretation of the 
study results. If the subject has received any study drug, all available safety data will 
be used. The reason(s) for any exclusion will be described in the report. 
9.5.10 
Procedures for Reporting Deviations from Original Statistical Plan 
Any deviations from the statistical analysis outlined in this protocol will be described, 
and reasons for the deviations listed, in the final Clinical Study Report. 
 
 

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10.0 
CLINICAL STUDY ADMINISTRATION 
10.1 
INFORMED CONSENT 
A copy of the proposed informed consent document must be submitted to the sponsor 
for review and comment prior to submission to the reviewing Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC). The consent form must be 
approved by the IRB/IEC and contain all elements required by national, state, local and 
institutional regulations or requirements.  
The study will be completely explained to each prospective study subject. Each subject 
found to be eligible for the study must voluntarily provide written informed consent 
(including consent for the use and disclosure of research-related health information), 
using the IRB/IEC-approved consent form, prior to his or her enrollment in the study 
(i.e., before any protocol-dictated procedures that are not part of normal patient care 
are performed). 
10.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
REVIEW AND APPROVAL 
The investigator shall assure that an IRB/IEC, constituted in accordance with the 
International Conference on Harmonization (ICH) Guideline for Good Clinical 
Practice (GCP), will provide initial and continuing review of the study. 
The investigator should provide the sponsor with a list of IRB/IEC members or IRB 
assurance number. Any documents that the IRB/IEC may need to fulfill its 
responsibilities, such as protocol amendments, and information concerning subject 
recruitment, payment or compensation procedures, or information from the sponsor 
will be submitted to the IRB/IEC. The IRB/IEC’s written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the 
investigator and the sponsor/designee, before the study is initiated. The investigator 
will transmit the IRB/IEC’s unconditional approval statement to the sponsor/designee 
before study drug supplies are shipped to the site. This approval must refer to the study 
by exact protocol title and number and should identify the documents reviewed and the 
date of review. 

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The Principal Investigator must inform the IRB/IEC of: 
• 
Changes in informed consent 
• 
Revisions of other documents originally submitted for review 
• 
Serious and/or unexpected adverse events occurring during the study  
• 
New information that may adversely affect the safety of subjects or the conduct 
of the study 
• 
Annual update and/or request for re-approval 
• 
Study completion 
10.3 
PROTOCOL COMPLIANCE 
Except for a change that is intended to eliminate an apparent immediate hazard to a 
study subject, the protocol shall be conducted as described. Any such change must be 
reported immediately to the sponsor and to the IRB/IEC. 
10.4 
PROTOCOL REVISIONS 
Protocol amendments will be prepared and approved by the sponsor. All protocol 
amendments will be signed by the investigator and submitted to the IRB/IEC for review 
prior to implementation. Documentation of IRB/IEC approval must be forwarded to 
the sponsor. If an amendment significantly alters the study design, increases potential 
risk to the subject or otherwise affects statements in the informed consent form, the 
informed consent form must be revised accordingly and submitted to the IRB/IEC for 
review and approval. The approved consent form must be used to obtain informed 
consent from new subjects prior to enrollment and must be used to obtain informed 
consent from subjects already enrolled if they are affected by the amendment. 
10.5 
DATA COLLECTION 
All data collected for each study subject will be entered in the eCRF developed in the 
Clinical Database and approved by the Sponsor. The database will be 21 CFR Part 11-
compliant. The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. The investigator is responsible for maintaining the accuracy, 
completeness, legibility, and timeliness of the data reported. All source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of data. 

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Data reported in the eCRF derived from source documents should be consistent with 
the source documents. 
The primary source document for this study will be the subject’s medical record. Data 
for the efficacy and tolerability variables will be recorded on a Data Sheet to be 
provided by Sponsor or designee and made part of the subject’s medical record. The 
Data Sheet will be similar to a paper CRF and will serve as a “hard copy” source 
document in case the eCRF becomes damaged or otherwise compromised. If the 
investigator(s) maintain separate research records, both the medical record and the 
research records will be considered the source documents for the purposes of auditing 
the study. 
The anonymity of subjects must be maintained. Subjects will be identified by their 
initials and an assigned subject number on eCRFs and other documents submitted to 
the sponsor. Documents that identify the subject beyond initials and subject number 
will not be submitted to the sponsor (e.g.; the signed informed consent document) and 
must be maintained in strict confidence by the investigator, except to the extent 
necessary to allow auditing by the regulatory authorities, study monitor, or sponsor 
representatives. 
Data recorded on source documents will be entered into eCRFs. The investigator must 
promptly review the completed eCRFs for each subject. A study monitor representing 
the sponsor will review the source documents against the eCRF on a regular basis 
through the study period as per the Study Monitoring Plan.  
Each eCRF will be electronically signed and dated by the Investigator. 
10.6 
DATA MANAGEMENT RESPONSIBILITIES 
For data coding, the following medical dictionaries will be used: 
• 
AEs and concomitant diseases: MedDRA; 
• 
Concomitant medication: World Health Organization (WHO) – Drug 
Visual and computerized methods of data validation will be applied in order to ensure 
accurate, consistent and reliable data for the subsequent statistical analysis. These 

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procedures aim to detect out-of-range values, contradictory data, abnormal evolutions 
over time, and possible undetected protocol violations (eligibility criteria, time and 
medication compliance, etc.).  
Data Management and the study monitor will generate electronic queries for resolution 
by the site. 
The database will be locked in order to protect write access after the following 
preconditions are fulfilled: 
• 
All data are entered in the database 
• 
All data queries are resolved 
• 
All necessary quality checks, in accordance with appropriate Standard Operating 
Procedures (SOPs), have been performed 
• 
Decisions have been made and agreed as to the identities of all protocol violators 
• 
All eCRFs have been source verified by the study monitor in the remote data 
capture (RDC) 
• 
All eCRFs have been approved by the Investigator in the RDC system 
• 
Written authorization from Vizuri Health Sciences is obtained. 
Upon completion of the study and resolution of all outstanding queries, Data 
Management will lock the database and generate the SAS datasets necessary for data 
analysis and reporting.  
The Data Management group will use the Clinical Database for storing and managing 
all data generated by this trial. 
10.7 
STUDY MONITORING 
The study sponsor, Vizuri Health Sciences, or its designee, will monitor the study. 
Study monitors representing the sponsor will visit study sites routinely throughout the 
trial. The sponsor/designee will review eCRFs and compare them with source 

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documents to verify accurate and complete collection of data and confirm that the study 
is being conducted according to the protocol. Auditors representing the sponsor may 
also similarly evaluate the study and its monitors. For these purposes, the investigator 
will make eCRFs and source documents available when requested. 
In addition, the study may be evaluated by representatives of the regulatory authorities, 
who will also be allowed access to study documents. The investigators should promptly 
notify Vizuri Health Sciences or its designee of any audits they have scheduled with 
any regulatory authority. 
The sponsor will promptly notify all investigators of all SAEs requiring expedited 
reporting that are considered unexpected and associated with the study drug. The 
investigator must also report these AEs to the IRB/IEC responsible for reviewing the 
study. SAEs that are expected and unrelated to the study drug will be reported 
periodically. 
If Vizuri Health Sciences, its designee, the investigator, the IRB/IEC or regulatory 
authority discover conditions arising during the study that indicate that the study should 
be halted or that the study center should be terminated, this action may be taken after 
appropriate consultation between Vizuri Health Sciences and the investigator. 
10.8 
DRUG ACCOUNTABILITY 
Upon receipt, the investigator is responsible for taking an inventory of the study drug. 
A record of this inventory must be kept and usage must be documented on study drug 
inventory forms provided by the Sponsor. 
10.9 
RETENTION OF RECORDS 
The investigator shall retain records and source documents pertaining to the study, 
including any films, tracings, computer discs or tapes. They will be retained for the 
longer of the maximum period required by the country and institution in which the 
study is conducted, or the period specified by the sponsor at the time the study is 
completed, terminated or discontinued. 

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If the investigator leaves the institution, the records shall be transferred to an 
appropriate designee who accepts the responsibility for the record retention. Notice of 
such transfer shall be documented in writing and provided to the sponsor. 
10.10 
FINANCIAL DISCLOSURE 
The investigator will provide Vizuri Health Sciences sufficient and accurate 
information on financial interests (proprietary or equity interests, payments exclusive 
of clinical trial costs) to allow complete disclosure to regulatory authorities. The 
investigator shall promptly update this information if any relevant changes occur during 
the course of the investigation and for a period of one year following study completion. 
10.11 
PUBLICATION POLICY 
Upon completion of the study, investigators are encouraged to publish the results in 
recognized scientific journals and at seminars or conferences. For multi-center trials, 
no investigator will be authorized to publish study results from an individual center 
until the earlier of the multi-center trial results are published or 12 months after the end 
or termination of the multi-center trial at all sites. 
A copy of all manuscripts and abstracts related to the study must be submitted to the 
sponsor for review and comment at least 30 days prior to submission for publication or 
for presentation at a scientific meeting. Proposed abstracts and publications will be 
reviewed promptly. The sponsor may delay publication for up to 90 days to allow the 
filing of a patent application or for other important reasons. The sponsor also reserves 
the right to delete from such materials any part or parts deemed to be confidential or 
proprietary. 
10.12 
STUDY OR STUDY SITE TERMINATION 
If Vizuri Health Sciences, the investigator or regulatory authority discover conditions 
arising during the study that indicate that the study should be halted or that the study 
center should be terminated, this action may be taken after appropriate consultation 
between Vizuri Health Sciences and the investigator. Conditions that may warrant 
termination of the study include, but are not limited to, the following: 

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• 
The discovery of an unexpected, serious, or unacceptable risk to the subjects 
enrolled in the study 
• 
A decision by the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
The study site may warrant termination under the following conditions: 
• 
Failure of the investigator to enroll subjects into the study at an acceptable rate 
• 
Failure of the investigator to comply with pertinent regulatory authority 
regulations 
• 
Submission of knowingly false information from the research facility to Vizuri 
Health Sciences, study monitor, or the regulatory authority 
• 
Insufficient adherence to protocol requirements 

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11.0 
REFERENCES 
1. 
Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, et al. 
Estimates of the prevalence of arthritis and other rheumatic conditions in the 
United States. Part I. Arthritis Rheum 2008;58(1):15-25. 
2. 
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, et al. 
Development of criteria for the classification and reporting of osteoarthritis. 
Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria 
Committee of the American Rheumatism Association. Arthritis Rheum 
1986;29(8):1039-1049. 
3. 
Zhang W, Doherty M, Peat G, Bierma-Zeinstra MA, Arden NK, Bresnihan B, 
et al. EULAR evidence-based recommendations for the diagnosis of knee 
osteoarthritis. Ann Rheum Dis 2010;69(3):483-489. 
4. 
Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, 
et al. American College of Rheumatology 2012 recommendations for the use of 
nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, 
hip, and knee. Arthritis Care Res (Hoboken) 2012;64(4):465-474. 
5. 
Xu X, Dong B, Hsu C-H, Hu C, Lei C, Song J, et al. Physician/site staff 
assessments contribute to high placebo respnse in rheumatoid arthritis clinical 
trials [abstract 2594]. Arthritis Rheumatol 2016;68(suppl 10) 2016 ACR/ARHP 
Annual Meeting. 
6. 
Bhugra D, Ventriglio A. Do cultures influence placebo response? Acta 
Psychiatr Scand 2015;132(4):227-230. 
7. 
Babbar S, Marier JF, Mouksassi MS, Beliveau M, Vanhove GF, Chanda S, et al. 
Pharmacokinetic analysis of capsaicin after topical administration of a 
high-concentration capsaicin patch to patients with peripheral neuropathic pain. 
Ther Drug Monit 2009;31(4):502-510. 

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8. 
Woodworth T, Furst DE, Alten R, Bingham CO, 3rd, Yocum D, Sloan V, et al. 
Standardizing assessment and reporting of adverse effects in rheumatology 
clinical trials II: the Rheumatology Common Toxicity Criteria v.2.0. J 
Rheumatol 2007;34(6):1401-1414. 
9. 
Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and 
toxicity of substances applied topically to the skin and mucous membranes. 
Division of Pharmacology Food and Drug Administration, Federal Security 
Agency 1944. 
 
 

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APPENDICES

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APPENDIX A 
 
 
LABORATORY TESTS

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APPENDIX A: LABORATORY TESTS 
Chemistry 
Urinalysis 
Glucose 
pH 
Sodium 
Protein 
Potassium 
Glucose 
Chloride 
Ketones 
Bicarbonate 
Bilirubin 
Blood Urea Nitrogen (BUN) 
Blood 
Creatinine 
Urobilinogen 
Calcium 
Specific gravity 
Magnesium 
Leucocytes 
Phosphorous – inorganic 
 
Lactate Dehydrogenase (LDH) 
 
Total Protein 
ACR OA criteria exclusions 
Albumin 
IgM-RF 
Alkaline Phosphatase (ALK) 
ESR 
Total Bilirubin 
 
Alanine Transaminase (ALT) 
Uric Acid 
Aspartate Transaminase (AST) 
 
Gamma-Glutamyl Transferase (GGT) 
 
Creatine Phosphokinase (CPK) 
Pregnancy 
 
Serum & Urine Pregnancy (βHCG) 
CBC with Automated Differential 
 
White Blood Cell Count (WBC) 
Follicle-stimulating Hormone (FSH) 
Red Blood Cell Count (RBC) 
 
Hemoglobin (Hgb) 
 
Platelet Count 
 
Automated 
White 
Blood 
Cell 
Differential 
 
Neutrophils (% & absolute) 
 
Lymphocytes (% & absolute) 
 
Red Cell Indices 
 
Hematocrit 
 
MCV 
 
MCH 
 
MCHC 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B 
 
 
RHEUMATOLOGY COMMON TOXICITY CRITERIA V2.0

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APPENDIX B: RHEUMATOLOGY COMMON TOXICITY CRITERIA V2.0 
Rheumatology Common Toxicity Criteria v.2.0 
Based on Woodworth TG, et al., 2007.[8] Standardizing assessment of adverse effects in rheumatology clinical trials II. Status of OMERACT Drug Safety Working Group May 
2006: OMERACT 8. Standardizing Assessment and Reporting of Adverse Effects in Rheumatology Clinical Trials: Enabling Description of Comparative Safety Profiles for 
Antirheumatic Therapies 
 
1-Mild 
Asymptomatic, or  
transient 
Short duration (<1 week)  
No change in life style  
No medication or OTC 
2- Moderate 
Symptomatic 
Duration (1-2 weeks)  
Alter lifestyle occasionally 
Meds relieve. (may be 
prescription), 
Study drug continued 
3- Severe 
Prolonged symptoms, reversible, 
major functional impairment 
Prescription meds/ partial relief 
May be hospitalized <24hr 
Temporary study drug 
discontinuation, or/and dose 
reduced 
4- Includes Life Threatening  
At risk of death  
Substantial disability, especially if 
permanent.  
Multiple meds 
 
Hospitalized >24 hr 
 
Study drug discontinued 
A. ALLERGIC/IMMUNOLOGIC 
A1. Allergic 
reaction/hypersensitivity 
(includes drug fever) 
Transient rash: drug fever 
<38°C: transient, asymptomatic 
bronchospasm 
Generalized urticaria 
responsive to meds; or drug 
fever > 38°C, or reversible 
bronchospasm 
Symptomatic bronchospasm 
requiring meds; symptomatic 
urticaria persisting with meds, 
allergy related 
oedema/angiodema 
Anaphylaxis, 
laryngeal/pharyngeal oedema, 
requiring resuscitation 
A2. Autoimmune reaction 
Serologic or other  
evidence of autoimmune 
reaction, but patient 
asymptomatic: all organ 
function normal and no 
treatment is required (e.g. 
vitiligo)  
Evidence of autoimmune 
reaction involving a non-
essential organ or functions, 
requiring treatment other than 
immunosuppressive drugs (e.g. 
hypothyroidism) 
Reversible autoimmune reaction 
involving function of a major 
organ or toxicity requiring short 
term immunosuppressive 
treatment (e.g. transient colitis or 
anaemia) 
Causes major organ dysfunction, 
or progressive, not reversible, or 
requires long term administration 
of high dose immunosuppressive 
therapy 
A3. Rhinitis 
(includes sneezing, 
nasal stuffiness, post 
nasal discharge) 
Transient, non-prescription 
meds relieve 
 
Prescription med. Required, 
slow 
 
Corticosteroids or other 
prescription med. With persistent 
disabling symptoms such as 
impaired exercise tolerance 
N/A 
 
A4. Serum sickness 
Transient, non-prescription 
meds relieve 
Symptomatic, slow response to 
meds (e.g. oral corticosteroids) 
 
Prolonged; symptoms only 
partially relieved by meds; 
parenteral corticosteroids 
required 
Major organ dysfunction, requires 
long-term high-dose 
immunosuppressive therapy 
 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
A. ALLERGIC/IMMUNOLOGIC (CONT) 
A5. Vasculitis 
Localized, not requiring 
treatment; or rapid response to 
meds; cutaneous 
Symptomatic, slow response to 
meds (e.g. oral corticosteroids) 
Generalized, parenteral 
corticosteroids required or/and 
short duration hospitalisation 
Prolonged, hospitalization, 
ischemic changes, amputation 
B. CARDIAC 
B1. Arrhythmia 
Transient, asymptomatic 
Transient, but symptomatic or 
recurrent, responds to meds 
Recurrent/persistent; 
maintenance prescription 
Unstable, hospitalization required; 
parenteral meds 
B2. Cardiac function   
Decreased 
Asymptomatic decline in resting 
ejection fraction by  
> 10%, but < 20% of baseline 
value 
Asymptomatic decline of 
resting ejection fraction ≥20% 
of baseline value 
CHF responsive to treatment 
Severe or refractory CHF 
B3. Edema 
Asymptomatic (e.g. 1 + 
feet/calves), self-limited, no 
therapy required 
Symptomatic (e.g. 2 + 
feet/calves), requires therapy 
Symptoms limiting function (e.g. 
3 + feet/calves, 2 + thighs), 
partial relief with treatment, 
prolonged 
Anasarca; no response to 
treatment 
 
 
B4. Hypertension  
(new onset or worsening) 
Asymptomatic, transient 
increase by > 20 mm Hg 
(diastolic) or to > 150/100 if 
previously normal, no therapy 
required 
Recurrent or persistent increase 
> 150/100 or by > 10 mm Hg 
(diastolic), requiring and 
responding readily to treatment 
Symptomatic increase >150/100, 
> 20 mmHg, persistent, requiring 
multi-agent therapy, difficult to 
control 
Hypertensive crisis 
B5. Hypotension  
(without underlying diagnosis) 
Transient, intermittent, 
asymptomatic, orthostatic 
decrease in blood pressure > 20 
mm Hg 
Symptomatic, without 
interference with function, 
recurrent or persistent > 20 mm 
Hg decrease, responds to 
treatment 
Syncope or symptomatic, 
interferes with function, 
requiring therapy and sustained 
medical attention, dose 
adjustment or drug 
discontinuation 
 
 
 
 
 
 
 
 
Shock 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
B. CARDIAC (CONT) 
B6. Myocardial ischaemia 
Transient chest pain/ECG 
changes; rapid relief with nitro 
Recurring chest pain, transient 
ECG ST-T changes; treatment 
relieves 
Angina with infarction, no or 
minimal functional compromise, 
reduce dose or discontinue study 
drug 
Acute myocardial infarction,  
arrhythmia and CHF 
B7. Pericarditis/ pericardial 
effusion 
Rub heard, asymptomatic 
Detectable effusion by 
echocardiogram, symptomatic 
NSAID required 
Detectable on chest X-ray, 
dyspnoea; or pericardiocentesis; 
requires corticosteroids 
Pulsus alternates with low cardiac 
output; requires surgery 
B8. Phlebitis/thrombosis/ 
Embolism 
(excludes injection sites) 
Asymptomatic, superficial, 
transient, local, or no treatment 
required 
Symptomatic, recurrent, deep 
vein thrombosis, no 
anticoagulant therapy required 
Deep vein thrombosis requiring 
anticoagulant therapy 
Pulmonary embolism 
C. GENERAL (constitutional) 
C1. Fatigue/malaise (asthenia) 
Increase over baseline;  
most usual daily functions 
maintained,  
short term 
Limits daily function 
intermittently over time 
Interferes with basic ADL, 
persistent 
Unable to care for self, bed or 
wheelchair bound > 50% of day 
debilitating, hospitalisation 
C2. Fever (pyrexia) 
(note: fever due to drug allergy 
should be coded as allergy) 
Transient, few 
symptoms 37.7-38.5°C 
Symptomatic, recurrent 38.6- 
39.9°C. Relieved by meds 
≥ 40°C; ≤24h, persistent 
symptoms; partial response to 
meds. 
≥ 40°C, debilitating, > 24h, 
hospitalization; no relief with 
meds 
C3. Headache 
Transient or intermittent,  
no meds or relieved with OTC 
Persistent, recurring, non-  
narcotic analgesics relieve 
Prolonged with limited response 
to narcotic medicine 
Intractable, debilitating, requires 
parenteral meds. 
C4. Insomnia 
Difficulty sleeping, short term, 
not interfering with function 
Difficulty sleeping 
Interfering with function, use of 
prescription med. 
Prolonged symptoms, with 
limited response to narcotic 
meds. 
Debilitating, hospitalization; no 
relief with meds 
C5. Rigors, chills 
Asymptomatic, transient,  
no meds, or non-  
narcotic meds relieve 
Symptomatic, narcotic meds 
relieve. 
Prolonged symptoms, with 
limited response to narcotic 
meds. 
Debilitating, hospitalization; no 
relief with meds 
C6. Sweating  
(diaphoresis) 
Episodic, transient 
Frequent, short term 
Frequent, drenching, disabling 
Dehydration, requiring IV 
fluids/hospitalization 24 hr 
C7. Weight gain 
5-9.9% 
10-19.9% 
20-30% 
NA 
C8. Weight loss 
5-9.9% 
10-19.9% 
20-30% 
NA 
 
 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
D. DERMATALOGIC 
 
 
 
 
D1. Alopecia 
Subjective, transient 
Objective, fully reversible 
Patchy, wig used, partly 
reversible 
Complete, or irreversible even if 
patchy 
D2. Bullous eruption 
Localised, asymptomatic 
Localised, symptomatic, 
requiring treatment 
Generalized, responsive to 
treatment; reversible 
Prolonged, generalized, or 
requiring hospitalization for 
treatment 
D3. Dry skin 
Asymptomatic, controlled with 
emollients 
Symptoms eventually (1-2 wks 
controlled with emollient 
Generalized, interfering with 
ADL >2 wks, persistent pruritus, 
partially responsive to treatment 
Disabling for extended period, 
unresponsive to ancillary therapy 
and requiring study drug 
discontinuation for relief 
D4. Injection site reaction 
Local erythema, pain, pruritus, < 
few days 
Erythema, pain, oedema, may 
include superficial phlebitis, 1-
2 wks 
Prolonged induration, superficial 
ulceration; includes thrombosis 
Major ulceration necrosis 
requiring surgery 
D5. Petechiae (without 
vasculitis) 
Few, transient asymptomatic 
Dependent areas, persistent up 
to 2 wks 
Generalized, responsive to 
treatment; reversible 
Prolonged, irreversible, disabling 
 
D6. Photosensitivity 
Transient erythema 
Painful erythema and oedema 
requiring topical treatment 
Blistering or desquamation, 
requires systematic 
corticosteroids 
Generalized exfoliation or 
hospitalisation 
D7. Pruritus 
Localised, asymptomatic,  
transient, local treatment 
Intense, or generalized, relieved 
by systematic medication 
Intense or generalized; poorly 
controlled despite treatment 
Disabling, irreversible 
 
 
D8. Rash  
(not bullous) 
Erythema, scattered 
macular/papular eruption; 
pruritus transient; TOC or no 
meds 
Diffuse macular/86papular 
eruption or erythema with 
pruritus; dry desquamation; 
treatment required 
Generalized, moist 
desquamation, requires systemic 
corticosteroids; responsive to 
treatment; reversible 
Exfoliative or ulcerating; or 
requires hospitalization; or 
parenteral corticosteroids 
D9. Induration/Fibrosis/ 
Thickening 
(not sclerodermal) 
Localized, high density on 
palpation, reversible, no effect 
on ADL and not disfiguring 
Local areas < 50% body 
surface, not disfiguring, 
transient interference with 
ADL, reversible 
 
 
 
Generalized, disfiguring, 
interferes with ADL, reversible 
Disabling, irreversible, systemic 
symptoms 
 
 
 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
E. EAR/NOSE/THROAT 
 
 
 
 
E1. Hearing loss 
Transient, 
intermittent, 
no  
interference with function 
Symptomatic, 
treatment 
required, reversible 
Interferes with function; 
incomplete response to treatment 
Irreversible deafness 
E2. Sense of smell 
Slightly altered 
Markedly altered 
Complete loss, reversible 
Complete loss, without recovery 
E3. Stomatitis 
Asymptomatic 
Painful, multiple, can eat 
Interferes with nutrition, slowly 
reversible 
Requires enteral support; residual 
dysfunction 
E4. 
Taste 
disturbance 
(dysgeusia) 
Transiently altered; metallic 
Persistently 
altered; 
limited 
effect on eating 
Disabling, effect on nutrition 
NA 
E5. Tinnitus 
Intermittent, 
transient, 
no  
interference with function 
Requires treatment, reversible 
Disabling, or associated with 
hearing loss 
Irreversible deafness 
 
E6. Voice changes 
(includes hoarseness, loss of 
voice, laryngitis 
Intermittent hoarseness, able to 
vocalise 
Persistent hoarseness, able to 
vocalize 
Whispered speech, slow return 
of ability to vocalise 
Unable to vocalize for extended 
period 
E7. Xerostomia 
(dry mouth) 
Transient dryness 
Relief with meds 
Interferes with nutrition, slowly 
reversible 
Extended duration 
interference 
with nutrition, requires parenteral 
nutrition 
F. EYE/OPHTHALMOLOGIC 
F1. Cataract 
Asymptomatic, no change in 
vision, non-progressive 
Symptomatic, partial visual loss, 
progressive 
Symptoms impairing function, 
vision loss requiring treatment, 
including surgery 
NA 
F2. Conjunctivitis 
Asymptomatic, transient, rapid 
response to treatment 
Symptomatic, 
responds 
to 
treatment, 
changes 
not 
interfering with function 
Symptoms prolonged, partial 
response to treatment, interferes 
with function 
NA 
F3. Lacrimation increased 
(tearing, watery eyes) 
Symptoms 
not 
requiring 
treatment, transient 
Symptomatic, 
treatment 
required, reversible 
Unresponsive to treatment with 
major effect on function 
NA 
F4. Retinopathy 
Asymptomatic, non- progressive, 
no treatment 
Reversible change in vision; 
readily responsive to treatment 
Disabling 
change 
in 
vision 
ophthalmological 
findings 
reversible, sight improves over 
time 
Loss of sight 
 
 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
F. EYE/OPHTHALMOLOGIC (CONT) 
F5. Vision changes  
(e.g. blurred, photophobia, night 
blindness, vitreous floaters) 
Asymptomatic, transient, no 
treatment required 
Symptomatic, vision changes 
not interfering with function, 
reversible 
Symptomatic, vision changes 
interfering with function 
Loss of sight 
F6. Xerophthalmia  
(dry eyes) 
Mild scratchiness 
Symptomatic without 
interfering with function, 
requires artificial tears 
 
 
Interferes with vision/function, 
corneal ulceration 
 
 
 
 
 
Loss of sight 
G. GASTROINTESTINAL 
G1. Anorexia 
Adequate food intake, minimal 
weight loss 
Symptoms requiring oral 
nutritional supplementation 
Prolonged, requiring iv support 
Requires hospitalization for 
nutritional support 
G2. Constipation 
Asymptomatic, transient, 
responds to stool softener, OTC 
laxatives 
Symptomatic, requiring 
prescription laxatives, 
reversible 
Obstipation requiring medical 
intervention 
Bowel obstruction. Surgery 
required. 
G3. Diarrhea 
Transient, increase of 2-3 
stools/day over pre-treatment (no 
blood or mucus), OTC agents 
relieve 
Symptomatic, increase 4-6 
stools/day, nocturnal stools, 
cramping, requires treatment 
with prescription meds. 
Increase > 6 stools/day, 
associated with disabling 
symptoms, e.g. incontinence, 
severe cramping, partial 
response to treatment. 
Prolonged, dehydration, 
unresponsive to treatment, requires 
hospitalization. 
G4. Dyspepsia  
(heartburn) 
Transient, intermittent, responds 
to OTC antacids,  
H-2 blockers 
Prolonged, recurrent, requires 
prescription meds, relieved by 
meds 
Persistent despite treatment, 
interferes with function, 
associated with GI bleeding 
NA 
G5. GI bleed  
(gastritis, gastric or duodenal 
ulcer diagnosed-define 
aetiology) 
Asymptomatic, endoscopic 
finding, haemocult + stools, no 
transfusion, responds rapidly to 
treatment 
Symptomatic, transfusion ≤2 
units needed; responds to 
treatment 
Haematemesis, transfusion 3-4 
units, prolonged interference 
with function 
Recurrent, transfusion > 4 units, 
perforation, requiring surgery, 
hospitalisation 
G6. Haematochezia  
(rectal bleeding) 
Haemorrhodial, 
asymptomatic, no transfusion 
Symptomatic, transfusion ≤2 
units, reversible 
Recurrent, transfusion > 3-4 
units 
> 4 units, hypotension, requiring 
hospitalisation 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life 
Threatening  
G. GASTROINTESTINAL (CONT) 
G7. Hepatitis 
Laboratory abnormalities,  
asymptomatic, reversible 
Symptomatic laboratory 
abnormalities, not 
interfering with function, 
slowly reversible 
Laboratory abnormalities 
persistent >2 wks, symptoms 
interfere with function 
Progressive, hepato-renal, 
anasarca, pre-coma or coma 
G8. Nausea, or nausea/vomiting 
(use diagnostic term) 
Transient, intermittent, minimal 
interference with intake, rapid 
response to meds. 
Persistent, recurrent, 
requires prescription meds, 
intake maintained 
Prolonged, interferes with 
daily function and nutritional 
intake, periodic iv fluids 
Hypotensive, 
hospitalization, parenteral 
nutrition, unresponsive to 
out-patient management 
G9. Pancreatitis 
Amylase elevation, 
intermittent nausea/vomiting, 
transient, responds rapidly to 
treatment 
Amylase elevation with 
abdominal pain, nausea, 
occasional vomiting, 
responsive to treatment 
Severe, persistent abdominal 
pain with pancreatic enzyme 
elevation, incomplete or slow 
response to treatment 
Complicated by shock, 
haemorrhage (acute 
circulatory failure) 
G10. Proctitis 
Perianal pruritus, haemorrhoids 
(new onset), transient, or 
intermittent, relieved by OTC 
meds 
Tenesmus or ulcerations, 
anal fissure, responsive to 
treatment, minimal 
interference with function 
Unresponsive to treatment, 
marked interference with 
function 
Mucosal necrosis with 
haemorrhage, infection, 
surgery required 
H. MUSCULOSKELETAL 
 
 
 
 
H1. Avascular necrosis 
Asymptomatic MRI changes, 
non-progressive 
MRI changes and 
symptoms responsive to 
rest and analgesia 
MRI changes, symptoms 
requiring surgical intervention 
Wheelchair bound; surgical 
repair not possible 
H2. Arthralgia 
Intermittent transient symptoms, 
no meds or relieved by OTC 
meds 
Persistent or recurrent 
symptoms, resolve with 
meds, little effect on 
function 
Severe symptoms despite 
meds impairs function 
Debilitating, hospitalization 
required for treatment 
H3. Leg cramps 
Transient, intermittent, does not 
interfere with function 
Recurrent symptoms, 
minimally interferes with 
function or sleep, responds 
to meds 
Persistent, prolonged 
interference with function or 
sleep, partial or no response to 
meds 
NA 
H4. Myalgia 
Occasional; does not interfere 
with function 
Frequent, requires meds 
(non- narcotic); minor 
effects on function 
Major change in 
function/lifestyle, narcotic 
pain meds 
Debilitating, profound 
weakness, requires 
wheelchair, unresponsive to 
meds 
 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
I. NEUROPSYCHIATRIC 
I1. Anxiety or Depression 
(mood alteration) 
Symptomatic, does not interfere 
with function; no meds 
Frequent symptoms, responds 
to meds; interferes with ADL 
at times 
Persistent, prolonged 
symptoms, partial or no 
response to meds, limits daily 
function 
Suicidal ideation or danger to self 
I2. Cerebrovascular ischaemia 
 
NA 
Single transient ischaemic 
event, responsive to treatment 
Recurrent transient ischaemic 
events 
Cerebrovascular vascular accident 
with permanent disability 
I3. Cognitive disturbance 
Subjective symptoms, transient, 
intermittent, not interfering with 
function 
Objective symptoms, 
persisting, interferes with daily 
function occasionally 
Persistent, or worsening 
objective symptoms; interferes 
with routine daily routine 
Debilitating/disabling and permanent; 
toxic psychosis 
 
 
I4. Depressed consciousness 
(somnolence) 
Observed, transient, 
intermittent, not interfering with 
function 
 
Somnolence or sedation, 
interfering with function 
Persistent, progressive, 
obtundation, stupor 
Coma 
I5. Inability to concentrate 
Subjective symptoms, does not 
interfere with function 
Objective findings, interferes 
with function 
Persistent, prolonged objective 
findings or organic cause 
NA 
I6. Insomnia 
(in absence of pain) 
Occasional difficulty sleeping, 
transient intermittent, not 
interfering with function 
Recurrent difficulty sleeping; 
requires meds for relief; 
occasional interference with 
function 
Persistent or worsening 
difficulty sleeping; severely 
interferes with routine daily 
function 
NA 
I7. Libido decreased 
Decrease in interest 
Loss of interest; influences 
relationship 
Persistent, prolonged 
interfering with relationship 
NA 
I8. Peripheral motor neuropathy 
Subjective or transient loss of 
deep tendon reflexes; function 
maintained 
Objective weakness, 
persistent, no significant 
impairment of daily function 
Objective weakness with 
substantial impairment of 
function 
Paralysis 
I9. Peripheral sensory 
neuropathy 
(sensory disturbance) 
Subjective symptoms without 
objective findings, transient, not 
interfering with function 
 
Objective sensory loss, 
persistent, not interfering with 
function 
Prolonged sensory loss or 
paraesthesias interfering with 
function 
NA 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
I. NEUROPSYCHIATRIC (CONT) 
I10 Seizure 
NA 
Recurrence of old seizures, 
controlled with adjustment of 
medication 
Recurrence/exacerbation with 
partial response to medication 
Recurrence not controlled, 
requiring hospitalization; new 
seizures 
I11 Vertigo 
(dizziness) 
Subjective symptoms, transient, 
intermittent, no treatment 
Objective findings, recurrent, 
meds relieve, occasionally 
interfering with function 
Persistent, prolonged, 
interfering with daily function; 
partial response to medication 
Debilitating without response to 
medication, hospitalisation 
J. PULMONARY 
J1. Asthma 
Occasional wheeze, no 
interference with activities 
Wheezing, requires oral meds, 
occasional interference with 
function 
Debilitating, requires nasal 02 
Requires ventilator assistance 
J2. Cough 
Transient, intermittent, 
occasional OTC meds relieve 
Persistent, requires narcotic or 
other prescription meds for 
relief 
Recurrent, persistent coughing 
spasms without consistent relief 
by meds, interferes with 
function 
Interferes with oxygenation; 
debilitating 
J3. Dyspnea 
Subjective, transient, no  
interference with function 
Symptomatic, intermittent or 
recurring, interferes with 
exertional activities 
Symptomatic during daily 
routine activities, interferes with 
function, treatment with 
intermittent nasal 02 relieves 
Symptomatic at rest, debilitating, 
requires constant nasal 02 
J4. Pleuritic pain  
(pleurisy) 
Transient, intermittent 
symptoms, no treatment or OTC 
meds relieve 
Persistent symptoms, requires 
prescription meds for relief 
Prolonged symptoms, interferes 
with function, requires frequent 
narcotic pain relief 
 
 
Debilitation, requiring 
hospitalisation 
J5. Pneumonitis (pulmonary 
infiltrates) 
Asymptomatic radiographic 
changes, transient, no treatment 
required 
Symptomatic, persistent, 
requiring corticosteroids 
Symptomatic, requiring 
treatment including 02 
Debilitating, not reversible; or  
requiring assisted ventilation 
J6. Pulmonary function 
decreased 
(FVC or carbon monoxide 
diffusion capacity — 
DLCO) 
76-90% of pre-treatment value 
51-75% of pre-treatment value 
26-50% of pre-treatment value 
≤25% of pre-treatment value 

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LABORATORY DATA 
K. HAEMATOLOGY 
 
1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
K1. Hgb (g/dl) decrease from 
pre-treatment 
1.0-1.4 
1.5-2.0 
2.1-2.9, or Hgb<8.0, >7.0 
≥ 3.0; or Hgb < 7.0 
K2. Leukopenia (total 
WBC) X 1000 
3.0-3.9 
2.0-2.9 
1.0-1.9 
< 1.0 
K3. Neutropenia 
(X 1000) 
1.5-1.9 
1.0-1.4 
0.5-0.9 
< 0.5 
K4. Lymphopenia 
(X 1000) 
1.5-1.9 
1.0-1.4 
0.5-0.9 
< 0.5 
K5. Platelets 
(X 1000) 
75-LLN 
50-74.9 
20-49.9; platelet transfusion 
required 
< 20; recurrent platelet 
transfusions 
L. CHEMISTRY 
L1. Hypercalcaemia 
(mg/dl) 
  
1.1 X ULN — 11.5 
11.6 — 12.5 
12.6 — 13.5; or symptoms 
present 
> 13.5; or associated coma 
 
L2. Hyperglycemia 
(mg/dl) Fasting 
140 — 160 
161 — 250 
251 — 500 
 
> 500, or associated with 
ketoacidosis 
L3. Hyperkalaemia  
(mg/dl) 
5.5 – 5.9 
6.0 – 6.4 
6.5 – 7.0 or any ECG change 
> 7.0 or any arrhythmia 
L4. Hypocalcaemia  
(mg/dl) 
 
0.9 X LLN – 7.8 
 
7.7 – 7.0 
 
 
 
 
6.9 - 6.5; or associated with 
symptoms 
< 6.5 or occurrence of tetany  
 
L5. Hypoglycemia  
(mg/dI) 
 
55 – 64 (no symptoms) 
 
40 – 54 (or symptoms present)  
30 – 39 (symptoms impair 
function)  
 
30 or coma 
 
L6. Hyponatraemia-  
(mg/dI) 
 
- 
125 – 129 
 
120 – 124 
 
< 120 
 
 

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1- Mild 
2- Moderate 
3- Severe 
4- Includes Life Threatening  
L. CHEMISTRY (CONT) 
L7. Hypokalaemia-  
(mg/dI) 
 
- 
3.0 – 3.4 
2.0 -4.0 X ULN 
2.5 – 2.9 
4.0 X ULN with weakness but 
without life-threatening signs 
or symptoms 
< 2.5 
> 4.0 X ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening 
L8. CPK (also if 
polymyositis-disease 
1.2 – 1.9 X ULN 
2.0 – 4.0 X ULN 
> 4.0 X ULN with weakness 
but without life-threatening 
signs or symptoms 
> 4.0 X ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening 
L9. Serum uric acid 
1.2 – 1.6 X ULN 
1.7 – 2.9 X ULN 
3.0 – 5.0 X ULN or gout 
NA 
L10. Creatinine (mg/d1) 
1.1-1.3 XULN 
1.3 – 1.8 X ULN 
1. – 3.0 X ULN 
> 3.0 X ULN 
L11. SGOT (AST) 
1.2 – 1.5 X ULN 
1.6 – 3.0 X ULN 
3.1 – 8.0 X ULN 
> 8.0 X ULN 
L12. SGPT (ALT) 
1.2 – 1.5 X ULN 
1.6 – 3.0 X ULN 
3.1 – 8.0 ULN 
> 8 X ULN 
L13. Alkaline 
Phosphatase 
1.1 – 2.0 X ULN 
2.1 – 3.0 X ULN 
3.1 – 5.0 X ULN 
 
> 5.0 X ULN 
 
L14. T. bilirubin 
1.1-1.4 XULN 
1.5 – 1.9 X ULN 
2.0 – 3.0 X ULN 
> 3.0 X ULN 
L15. LDH 
1.3 – 2.4 X ULN 
2.5 – 5.0 X ULN 
5.1 – 10 X ULN 
> 10 XULN 
M. URINALYSIS 
M1. Haematuria 
Micro only 
Gross, no clots 
Clots, transfusion < 2 units 
Transfusion required 
M2. Proteinuria (per 24 h) 
300 – 500 mg (tr/1+) 
501 – 1999 mg (2+) 
2 – 5.0 g (3+) nephritic 
syndrome 
5.0 g (4+) anasarca 
M3. WBC in Urine 
NA 
NA 
Indicating acute interstitial 
nephritis 
Associated with acute renal 
failure 
M4. Uric acid crystals 
Present without symptoms 
NA 
With stones or symptoms of 
stones (eg renal colic) 
Causing renal outflow 
obstruction and hospitalization 
 

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APPENDIX C 
 
 
SCHEDULE OF EVENTS

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APPENDIX C: SCHEDULE OF EVENTS 
Assessment 
SCR 
Treatment Days 
 
Follow-up Period Days 
TIMEFRAME 
Within 28  
days of Day 1 D1 
D2 
D3 
D4 
D5 
(Post Treat 
Day 1) 
D19± 3d  
(Post Treat 
Week 2) 
D35± 3d  
(Post Treat 
Week 4) 
 
D64± 3d  
(Post Treat 
Week 8) 
 
D94± 3d  
(Post Treat 
Week 12) 
Unscheduled, 
Early 
Termination, 
SAEl 
Clinic visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion 
x 
 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
 
Medical & Medication History 
x 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
 
 
Physical exam 
x 
 
 
 
 
 
 
 
 
 
x 
Height and Weighta  
x 
 
 
 
 
 
 
 
 
 
 
Vital Signsb 
x 
x 
x 
x 
x 
x 
 
 
 
x 
x 
Knee X-raysc  
x 
 
 
 
 
 
 
 
 
 
 
12-lead ECGd  
x 
 
 
 
 
 
 
 
 
 
 
Clinical lab testse  
x 
 
 
 
 
x 
 
x 
 
x 
x 
Pregnancy or FSH Testf  
x 
x 
 
 
 
 
 
 
 
 
 
Application Site Pain, Erythema, Scaling, 
Pruritus Assessmentg  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Exploratory Assessment of OA Knee Painh  
x 
x 
 
 
 
 
 
 
 
 
 
VAS OA Knee Pain Assessmenti 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
WOMACj  
x 
x 
 
 
 
x 
x 
x 
x 
x 
x 
Drug administration 
 
x 
x 
x 
x 
 
 
 
 
 
 
Assess. Of Concomitant Medicationsk  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
AE Assessments 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Exit 
 
 
 
 
 
 
 
 
 
x 
 
 

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Schedule of Events (Continued)  
a. 
Height and weight obtained at Screening. 
b. Vital signs include temperature, blood pressure, heart rate and respiratory rate. Performed at Screening, on Days 1-4 at pre-dose and at 90 minutes (± 5 min) after applying study 
drug to knees, and at Follow-up on Day 5 and 94. 
c. 
Knee X-rays of both knees must be obtained unless films/images performed within 6 months before screening. Copies of film and results will be requested. 
d. Standalone 12-lead ECG performed at Screening. 
e. 
Clinical laboratory tests include (Appendix A): 
Hematology: full blood count including RBC, hemoglobin, hematocrit, MCV, MCH, MCHC, WBC, differential white cell count, platelet count (Screening, Day 5, Day 35 and 
Day 94); 
Erythrocyte sedimentation rate (Screening only); 
Chemistry: BUN, creatinine, uric acid, bilirubin (total), sodium, potassium, calcium, magnesium, phosphorous (inorganic), chloride, bicarbonate, ALK, AST (SGOT), ALT 
(SGPT), LDH, GGT, CPK, albumin, total protein, and glucose (Screening, Day 5, Day 35 and Day 94); 
IgM RF (Screening only); 
Urinalysis: pH, protein, glucose, ketones, bilirubin, blood, urobilinogen, specific gravity, leucocytes (Screening, Day 5, Day 35 and Day 94). Clinically significant abnormal dipstick 
results will require microscopic analysis. 
f. 
Serum pregnancy test at Screening and urine pregnancy test at baseline on Day 1 for premenopausal women; FSH (follicle stimulating hormone) test at Screening to confirm 
postmenopausal status (females only) for up to 2 years after cessation of menses. 
g. Application site pain will be assessed on NRS (0-10); application site erythema/edema will be assessed using modified categorical Draize test (0-3). Scaling and pruritus will 
also be scored on a similar categorical scale (0-3). Scoring for application site pain (not related to knee pain) will be performed on drug administration Days 1-4 (pre-application 
[ 30 min], and at 15 (± 5 min), 30 (± 5 min), 60 (± 5 min) and 90 minutes (± 5 min) after application) and on Days 5, 19, 35, 64 and 94. Application site skin reactions (erythema, 
edema, scaling, pruritus) will be assessed on drug administration Days 1-4 at pre-application ( 30 min), and at 15 (± 5 min), 30 (± 5 min), 60 (± 5 min) and 90 minutes (± 5 min) 
after application), and on Days 5 (24 hrs [+/- 4 hrs]), 19 (+/- 3 days), 35 (+/- 3 days), 64 (+/- 3 days) and 94 (+/- 3 days). (Appendix E and Appendix F) 
h. Exploratory assessment of OA knee pain (average daily pain and daily worst pain) at Screening and Day 1 (pre-application [<30 min]) (Appendix D). 
i. 
OA Knee pain to be scored on 100 mm VAS scale (Appendix G) pre-treatment ( 30 min) on Days 1, 2, 3 and 4 and also on clinic visits at Days 5 (24 hrs [+/- 4 hrs]), 
19 (+/- 3 days), 35 (+/- 3 days), 64 (+/- 3 days) and 94 (+/- 3 days).  
j. 
WOMAC Pain, Stiffness, and Physical Function will be performed at Screening and on Day 1 prior to drug administration ( 30 min) and on Days 5 (24 hrs [+/- 4 hrs]), 19 (+/- 
3 days), 35 (+/- 3 days), 64 (+/- 3 days) and 94 (+/- 3 days). 
k. Document all medications taken within 90 days of the Screening Visit through Day 94. 
l. 
Refer to Section 6.5 for assessments to be completed at time of SAE, early termination or unscheduled visit. 

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APPENDIX D 
 
 
EXPLORATORY ASSESSMENT OF OSTEOARTHRITIS KNEE PAIN 

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APPENDIX D: EXPLORATORY ASSESSMENT OF OSTEOARTHRITIS KNEE PAIN 
Obtained at Screening and pre-dose on Day 1. 
 
On a scale from 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, how 
would you rate your AVERAGE DAILY PAIN 
0 
1 
2 
3 
4 
5 
6 
7  
8 
9 
10  
No  
 
 
 
 
 
 
 
 
 
Worst Pain 
 
Pain 
 
 
 
 
 
 
 
 
 
Imaginable 
 
On the same scale, how would you rate your DAILY WORST PAIN 
0 
1 
2 
3 
4 
5 
6 
7  
8 
9 
10  
No  
 
 
 
 
 
 
 
 
 
Worst Pain 
 
Pain 
 
 
 
 
 
 
 
 
 
Imaginable 
 
 
 
 
 
 
 

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APPENDIX E 
 
 
VAS OA KNEE PAIN 

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APPENDIX E: VAS OA Knee Pain 
Obtained on Days 1-4: Pre-application (< 30 min), and on Days 5, 19, 35, 64 and 94.  
 
VAS Pain Scale (100 mm) 
On the line below make a mark that represents your present level of pain for your RIGHT knee 
 
no pain  
 
 
 
 
 
 
 
 
 
 
  worst  
 pain imaginable 
On the line below make a mark that represents your present level of pain for your LEFT knee 
 
no pain  
 
 
 
 
 
 
 
 
 
 
  worst  
 pain imaginable 
 
 
 
 

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APPENDIX F 
 
 
ASSESSMENT OF BURNING / STINGING PAIN 

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APPENDIX F: ASSESSMENT OF BURNING / STINGING PAIN 
Obtained on Days 1-4: Pre-application (< 30 min), and at 15 (+ 5 min), 30 (+ 5 min), 60 (+ 5 min), 
and 90 minutes (+ 5 min) after application, and on Days 5, 19, 35, 64 and 94.  
Assessment of Burning / Stinging Pain 
The question below refers to BURNING OR STINGING PAIN that you may be feeling right now 
affecting the skin in the area around your knees. 
On a scale from 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, how 
would you rate your pain RIGHT NOW in your RIGHT KNEE? (Please circle the number) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No               
 
 
 
 
 
 
 
 
Worst Pain 
Pain                 
 
 
 
 
 
 
 
Imaginable 
 
 
On a scale from 0 to 10, with 0 being no pain at all and 10 being the worst pain imaginable, how 
would you rate your pain RIGHT NOW in your LEFT KNEE? (Please circle the number) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No                
 
 
 
 
 
 
 
 
Worst Pain 
Pain                 
 
 
 
 
 
 
 
Imaginable 

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APPENDIX G 
 
 
ASSESSMENT OF SIGNS AND SYMPTOMS

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APPENDIX G: ASSESSMENT OF SIGNS AND SYMPTOMS 
Obtained on Days 1 – 4: Pre-application (< 30 min), and at 15 (± 5 min), 30 (± 5 min), 60 (± 5 min), 
and 90 minutes (± 5 min) after application, and on Days 5, 19, 35, 64 and 94. 
Assessment of Signs and Symptoms 
Right Knee 
Left Knee 
Scaling (Circle Response): 
Scaling (Circle Response): 
0 =  None: no evidence of scaling 
0 =  None: no evidence of scaling 
1 =  Mild: mainly fine scales predominate 
1 =  Mild: mainly fine scales predominate 
2 =  Moderate: somewhat coarser scales 
2 =  Moderate: somewhat coarser scales 
3 =  Severe: coarse, thick scales; rough 
surface 
3 =  Severe: coarse, thick scales; rough surface 
 
 
Erythema (Circle Response): 
Erythema (Circle Response): 
0 =  None: no evidence of redness 
0 =  None: no evidence of redness 
1 =  Mild: barely perceptible redness 
1 =  Mild: barely perceptible redness 
2 =  Moderate: obvious redness, possible 
presence of edema 
2 =  Moderate: obvious redness, possible 
presence of edema 
3 =  Severe: bright red, possible edema 
3 =  Severe: bright red, possible edema 
 
 
Pruritus (Circle Response): 
Pruritus (Circle Response): 
0 =  None: no itching 
0 =  None: no itching 
1 =  Mild: occasional, slight itching 
1 =  Mild: occasional, slight itching 
2 =  Moderate: frequent or constant itching; 
does not disturb sleep 
2 =  Moderate: frequent or constant itching; 
does not disturb sleep 
3 =  Severe: bothersome itching; disturbs 
sleep 
3 =  Severe: bothersome itching; disturbs sleep