A 4-week, Randomized, Double-blind, Multicenter, Placebo-controlled Phase 2 Study to Evaluate the Efficacy and Safety of HP-5000 in Subjects With Osteoarthritis (OA) of the Knee
Phase: PHASE2
Conditions: Osteoarthritis of the Knee
Sponsor: Noven Pharmaceuticals, Inc.

Clinical Study Protocol 
 
 
Protocol Title:  
A 4-Week, Randomized, Double-Blind, 
Multicenter, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of HP-
5000 in Subjects with Osteoarthritis (OA) of 
the Knee 
Date of Protocol:    
31-Oct-2016 
NCT Number:  
NCT03277066 

Noven Pharmaceuticals, Inc. 
16.1 Study Information 
Clinical Study Report HP-5000-US-05  
AD-MW-36.04 18-Jun-2019 
CONFIDENTIAL 
16.1.1 
Protocol and Protocol Amendments 
Final Amendment #2.0, dated 12-Jan-2018 
Final Amendment #1.0, dated 22-May-2017 
Final Protocol, Version 1.0, dated 31-Oct-2016 
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(WOMAC) pain score of 
 at the Baseline Visit (V2). 
6.
If female:
a.
Subject is not breastfeeding or pregnant as confirmed by a negative
pregnancy test at or within 48 hours of the Screening Visit.  Women of child-
bearing potential must use an acceptable method of contraception (including
oral contraceptives, hormone implant, intrauterine device, and spermicide
with barrier method, or male sexual partner[s] surgically sterile).
b.
Subject could not become pregnant because she is surgically sterile
(hysterectomy or tubal ligation), confirmed to be postmenopausal (having
amenorrhea for ≥12 months), or has had a hysterectomy with or without
bilateral oophorectomy at least 6 months prior to the Screening Visit.
7.
Able to swallow and tolerate rescue medication, APAP (moderately sized tablets).
8.
Be reliable, willing, and able to cooperate with all study procedures including the
following:
a.
Accurately fill out the eDiary on a daily basis.
b.
Return for study visits on the required dates.
c.
Accurately and reliably report symptoms (including treatment-emergent signs
and symptoms).
d.
Use the patch as required by protocol.
Exclusion criteria: 
1.
Body mass index (BMI) > 40.
2.
The non-target knee pain severity score is 
 at Screening
and Baseline (Day 0).
3.
Any subject who disobeyed the restriction of prohibited therapies (i.e., use rescue
medication) during Screening prior to the start of the Washout Period and 2 days
prior to the Baseline Visit (V2).
4.
Secondary OA of the knee (rheumatoid arthritis, gout, psoriasis, syphilitic
neuropathy, ochronosis, metabolic or other primary bone disease or acute trauma).
5.
Clinically significant elevation of serum creatinine (176.8 μmol/L), aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) (3 x upper limit of
normal [ULN]) at the Screening Visit.
6.
Known allergy or hypersensitivity to the use of diclofenac, 
, 
, ethanol, acetylsalicylic acid (aspirin [ASA]), or any other
NSAID.
7.
Severe uncontrolled cardiac, renal, hepatic or other systemic disease.
8.
A documented gastroduodenal ulcer (upper GI series or endoscopy) or any GI
bleeding (except hemorrhoidal) within 6 months prior to Screening Visit.
9.
Documented history of alcohol or drug abuse within 1 year prior to study entry or
positive alcohol/drug screen findings at Screening or Baseline.
10. Presence of chondrocalcinosis on X-ray if associated with a history of pseudogout
or inflammatory flare-ups.
11. MAJOR SURGERY:  Previous damage or surgery to the target knee at any time
(i.e., damage/reconstruction of the anterior or posterior cruciate ligaments).
12. MINOR SURGERY on the target knee defined as anything other than major
surgery (as defined above) within 1 year before study enrollment.
13. Treatment with oral or intra-muscular corticosteroids within 90 days of Screening
Visit, treatment of the target knee with topical or intra-articular corticosteroids
within 90 days of Screening Visit, or topical or intra-articular corticosteroid
treatment of any other joint within 30 days of Screening (see Section 9.10.2).
14. Any subject who had received intra-articular viscosupplementation (e.g.,
Synvisc®) in the target knee 90 days prior to Screening Visit.
15. Any subject who had used opioids 7 days prior to the Screening Visit.
16. Any subject who had previous exposure to HP-5000.
17. Any subject whose participation would conflict with contraindications, warnings
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Safety endpoints:  
• 
Adverse events, AEs leading to discontinuation from the study drug, SAEs, 
and deaths. 
• 
Change from Baseline in clinical laboratory results (including fasting glucose 
and total lipids [8 to 10 hours of fasting is required for these laboratory 
testing]), ECG results, body weight, and vital signs. 
• 
Dermal safety: adhesion, irritation, discomfort, and adhesive residue. 
Pharmacokinetic endpoint: 
• 
Plasma concentrations of diclofenac (for both HP-5000
 and HP-5000
on Day 14 and 28 (or at the Early Termination Visit). 
STATISTICAL 
METHODS 
This section presents a summary of the planned statistical analyses.  A Statistical 
Analysis Plan (SAP) that describes the details of the analyses to be conducted will be 
written prior to database lock.  Unless otherwise indicated, all testing of statistical 
significance will be 2-sided.  A difference resulting in a P value of <0.05 will be 
considered statistically significant. 
 
For analyses involving study site, if the number of subjects per site is small, sites may 
be pooled for analysis, or omitted from statistical models.   The final determination 
will be made prior to database lock. 
 
Summary statistics will be provided for the variables described below.  For continuous 
variables, these statistics will typically include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum.  For categorical variables, these 
statistics will typically include the number and percentage of subjects in each 
category. 
 
Analysis Populations  
• 
Intent-to-Treat (ITT):  Will include all randomized subjects.  Regardless of 
any protocol deviations, analyses performed on the ITT set will be based on 
the randomized treatment assignment and all available data. 
 
• 
Full Analysis Set (FAS):  Will include all randomized subjects who have had 
at least 1 patch of Double-blind study drug applied and who have a Baseline 
WOMAC pain score and at least 1 post-baseline assessment of the primary 
efficacy measure (WOMAC pain score).  Evaluable subjects will be defined 
as those who meet the FAS definition.  The FAS will be used as the primary 
set for analysis of efficacy endpoints based on randomized treatment 
assignment. 
 
• 
Safety Analysis Set (SAF):  Will include all subjects who have had at least 1 
patch of double-blind study medication applied and who have at least 1 post-
dose safety measurement during the Double-blind Treatment Phase.  In the 
unlikely event that errors may have occurred in treatment arm assignments, 
then analyses using the SAF will be based on treatment actually received.  
The SAF will be used for both the analysis of dermal evaluations and safety 
endpoints. 
 
• 
Pharmacokinetic Analysis Set (PAS):  Will include all subjects who have 
received at least 1 dose of study drug during the Double-blind Treatment 
Phase and have at least 1 blood sample for pharmacokinetic (PK) assessment.  
Subjects may be excluded from the PAS set if they significantly violate 
inclusion or exclusion criteria, significantly violate the protocol in a way that 
may influence the PK analysis, if any unexpected error occurs during the 
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study that may influence the PK analysis (e.g., early detachment of 
transdermal systems, apparent sample switching, etc.) or if their data are 
unavailable or incomplete.  The PAS will be used for the analysis with 
model-based approach.  Excluded cases will be documented together with the 
reason for exclusion. 
 
Primary Efficacy Analysis:  The primary efficacy endpoint of this study is the 
change from Baseline to Week 4 in the WOMAC pain score; the primary analysis set 
is the FAS.  The comparisons of interest are: 
• 
HP-5000
 versus placebo 
• 
HP-5000
 versus placebo 
 
The estimand in the primary analysis for efficacy for each dose is the difference 
between treatments groups (HP-5000 dose group vs. placebo) in the change from 
Baseline to Week 4 in WOMAC pain score in all subjects as randomized, under the 
assumption that all randomized subjects remain on their randomized treatment 
throughout the study.  WOMAC scores obtained more than 24 hours after 
discontinuation of double-blind study drug will be excluded as a-priori defined 
outliers. 
 
The primary efficacy variable, the change from Baseline to Week 4 in the WOMAC 
pain score will be analyzed using a mixed model repeated measures (MMRM) 
analysis.  The MMRM model will include change from Baseline in WOMAC pain 
score as the repeated dependent variable, with treatment (HP-5000
, 
HP-5000
, and placebo), treatment-by-visit interaction, and the Baseline 
WOMAC pain score as covariates.  An unstructured covariance matrix will be 
assumed.  If the unstructured covariance matrix fails to converge, a series of other 
covariance structures will be tested for use.  The MMRM model may be repeated on 
additional analysis sets as a sensitivity analysis.  If the normality assumption is 
violated, analysis of covariance (ANCOVA) on rank-transformed data will be used as 
utility analysis and additional supportive analyses may be performed. 
 
Other sensitivity analyses may be performed on the primary endpoint to assess the 
robustness of the results based on the model used for primary analysis.  These analyses 
may include multiple imputation and pattern-mixture models for handling of missing 
data.  Details will be provided in the SAP.  The analyses will be performed according 
to the National Academy of Sciences (2010) guidelines. 
 
Analysis of Secondary Efficacy Endpoints:  Other secondary efficacy endpoints will 
be analyzed using the change in mean as appropriate. 
• 
WOMAC LK3.1 OA Index (pain) – change between Baseline and Week 1, 
and Week 2. 
• 
WOMAC LK3.1 OA Index (stiffness) between Baseline and Week 1, Week 2 
and Week 4. 
• 
WOMAC LK3.1 OA Index (physical function) between Baseline and Week 
1, Week 2 and Week 4. 
• 
WOMAC LK3.1 OA Index (composite score) between Baseline and Week 1, 
Week 2 and Week 4. 
• 
Patient Global Assessment between Baseline and Week 4. 
• 
Patient Global Impression of Change between Week 1 and Week 4. 
• 
Pain intensity assessed on an 11-point NRS between Baseline, Week 1, Week 
2, and Week 4. 
• 
Use of rescue medication between Baseline and Week 1, Week 2 and Week 
4. 
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Additional categorical response analyses may be performed; additional details will be 
provided in the SAP.  Additional categorical response analyses may be performed; 
additional details will be provided in the SAP. 
 
Analysis of Safety and Dermal Assessments:  All safety summaries will be 
descriptive; statistical significance tests may be performed on safety data that will be 
described in the SAP.  Safety variables include AEs, clinical laboratory values, vital 
signs, ECG readings, physical examination results, and dermal safety results.  No 
formal inferential analyses will be conducted for safety variables, unless otherwise 
noted. 
 
Analysis of PK: 
Plasma concentrations of diclofenac (for both HP-5000
 and HP-5000
 
will be evaluated and summarized as descriptive statistics by treatment. 
SAMPLE SIZE 
DETERMINATION 
Assuming an effect size of 
 
 
 
 on the change in WOMAC pain score from Baseline to Week 4 
between active HP-5000
 and HP-5000
 treatments vs. placebo, the 
probability for detecting the clinically meaningful effect size 
 or higher will be 
approximately 67% having 75 evaluable subjects per each active arm and 150 
evaluable subjects in the placebo arm.  Having 3 treatment arms, the total number of 
subjects randomized in the study and included in the primary analysis set should be 
approximately 300.  A sufficient number of subjects will be screened to randomize the 
proposed sample size. 
STUDY TREATMENT 
DURATION 
The maximum treatment duration for each subject is 4 weeks.  The total duration of 
study participation for each subject is approximately 9 weeks. 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES .....................................................................................................................2 
2. 
SYNOPSIS .................................................................................................................................................3 
Analysis of PK: .................................................................................................................................9 
3. 
TABLE OF CONTENTS .........................................................................................................................10 
4. 
LIST OF ABBREVIATIONS...................................................................................................................15 
5. 
INTRODUCTION ....................................................................................................................................16 
5.1. Background and Rationale ..............................................................................................................16 
5.2. Clinical Experience .........................................................................................................................17 
5.3. Summary of Potential Risks and Benefits .......................................................................................19 
6. 
OBJECTIVES ...........................................................................................................................................20 
6.1. Primary Objectives ..........................................................................................................................20 
6.2. Secondary Objectives ......................................................................................................................20 
7. 
STUDY DESIGN .....................................................................................................................................21 
7.1. Overall Study Design and Plan - Description .................................................................................21 
7.2. Discussion of Study Design ............................................................................................................25 
7.3. Study Sites .......................................................................................................................................25 
8. 
SUBJECT POPULATION .......................................................................................................................26 
8.1. Selection of Study Population .........................................................................................................26 
8.2. Study Entry Criteria ........................................................................................................................26 
8.2.1 Inclusion Criteria .................................................................................................................26 
8.2.2 Exclusion Criteria ................................................................................................................27 
8.2.3 Premature Subject Withdrawal ............................................................................................29 
8.3. Subject Replacement Criteria ..........................................................................................................30 
9. 
TREATMENTS ........................................................................................................................................31 
9.1. Identification of Investigational Product .........................................................................................31 
9.1.1 Labeling ...............................................................................................................................31 
9.1.2 Packaging ............................................................................................................................31 
9.2. Treatments Administered ................................................................................................................32 
9.3. Dispensing and Storage ...................................................................................................................32 
9.4. Method of Assigning Subjects to Treatment Groups ......................................................................32 
9.5. Blinding and Unblinding Treatment Assignment ...........................................................................33 
9.6. Selection of Doses and Administration in the Study ......................................................................34 
9.7. Dose Adjustment Criteria ................................................................................................................34 
9.8. Drug Accountability ........................................................................................................................34 
9.9. Treatment Compliance ....................................................................................................................35 
9.10. Permitted and Prohibited Therapies ................................................................................................37 
9.10.1 Permitted Therapies .............................................................................................................37 
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9.10.2 Prohibited Therapies ............................................................................................................37 
9.11. Treatment after End of Study ..........................................................................................................38 
10. STUDY PROCEDURES ..........................................................................................................................39 
10.1. Study Periods and Visits .................................................................................................................39 
10.1.1 Screening/Washout Period ..................................................................................................39 
10.1.1.1 Screening Period (Visit 1) .......................................................................................39 
10.1.1.2 Washout Period .......................................................................................................40 
10.1.2 Baseline Visit (Visit 2, Day 0) ............................................................................................40 
10.1.3 Double-blind Treatment Phase ............................................................................................41 
10.1.4 Follow-up Visit ....................................................................................................................43 
10.1.5 Early Termination Visit (if applicable) ...............................................................................43 
10.1.6 Overall Study Schedule .......................................................................................................44 
10.2. Assessments ....................................................................................................................................44 
10.2.1 Efficacy ...............................................................................................................................44 
10.2.1.1 Western Ontario and McMaster Universities Osteoarthritis Index .........................44 
10.2.1.2 Patient Global Assessment ......................................................................................46 
10.2.1.3 Patient Global Impression of Change .....................................................................46 
10.2.1.4 Numeric Rating Scale .............................................................................................46 
10.2.1.5 Use of Rescue Medication ......................................................................................47 
10.2.2 Safety ...................................................................................................................................47 
10.2.2.1 Laboratory Safety Assessments ..............................................................................47 
10.2.2.2 Clinical Examinations .............................................................................................49 
10.2.2.3 Adverse Events........................................................................................................49 
10.2.2.4 Evaluations of Patch and Dermal Assessment ........................................................50 
10.2.3 Pharmacokinetic Assessments .............................................................................................52 
11. ADVERSE EVENTS................................................................................................................................53 
11.1. Definitions .......................................................................................................................................53 
11.1.1 Adverse Events ....................................................................................................................53 
11.1.2 Unexpected Adverse Event .................................................................................................54 
11.1.3 Serious Adverse Events .......................................................................................................54 
11.2. Management of Adverse Events .....................................................................................................55 
11.2.1 Collection ............................................................................................................................55 
11.2.2 Any clinically relevant observations made during the visit will also be 
considered AEs.Evaluation .................................................................................................55 
11.2.2.1 Severity of Adverse Events .....................................................................................55 
11.2.2.2 Seriousness ..............................................................................................................56 
11.2.2.3 Action Taken ...........................................................................................................56 
11.2.2.4 Outcome at the Time of Last Observation ..............................................................56 
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11.2.2.5 Adverse Event Relationship to Investigational Product..........................................56 
11.2.3 Documentation ....................................................................................................................57 
11.2.4 Treatment of Adverse Events ..............................................................................................57 
11.2.5 Follow-up ............................................................................................................................58 
11.2.6 Reporting of Adverse Events ..............................................................................................58 
11.2.6.1 Serious Adverse Events...........................................................................................58 
11.2.6.2 Nonserious Adverse Events ....................................................................................60 
11.2.7 Adverse Events of Special Interest ......................................................................................60 
11.2.8 Pregnancy Reporting ...........................................................................................................61 
12. DATA SAFETY MONITORING BOARD .............................................................................................63 
13. STATISTICAL METHODS .....................................................................................................................64 
13.1. Study Endpoints ..............................................................................................................................64 
13.1.1 Primary Efficacy Endpoint ..................................................................................................64 
13.1.2 Secondary Efficacy Endpoints ............................................................................................64 
13.1.3 Safety Endpoints ..................................................................................................................64 
13.1.4 Pharmacokinetics Endpoint .................................................................................................64 
13.2. Sample Size Determination .............................................................................................................64 
13.3. Analysis Populations .......................................................................................................................65 
13.4. Statistical Analyses .........................................................................................................................66 
13.4.1 Study Subjects and Demographics ......................................................................................66 
13.4.1.1 Disposition and Withdrawals ..................................................................................66 
13.4.1.2 Protocol Deviations .................................................................................................66 
13.4.1.3 Demographics and Other Baseline Characteristics .................................................66 
13.4.2 Exposure and Compliance ...................................................................................................67 
13.4.3 Efficacy Analyses ................................................................................................................67 
13.4.3.1 Primary Analysis .....................................................................................................67 
13.4.3.2 Analyses for Secondary Endpoint ...........................................................................68 
13.4.4 Safety and Tolerability Analyses ........................................................................................68 
13.4.4.1 Adverse Events........................................................................................................68 
13.4.4.2 Concomitant Medications .......................................................................................69 
13.4.4.3 Clinical Laboratory Evaluations .............................................................................69 
13.4.4.4 Vital Signs and Body Weight ..................................................................................69 
13.4.4.5 Electrocardiograms .................................................................................................69 
13.4.4.6 Physical Examination Findings ...............................................................................70 
13.4.4.7 Dermal Safety..........................................................................................................70 
13.4.5 Pharmacokinetic Analyses ..................................................................................................70 
13.4.6 Interim Analysis ..................................................................................................................70 
13.5. Database ..........................................................................................................................................70 
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14. STUDY CONDUCT .................................................................................................................................71 
14.1. Sponsor and Investigator Responsibilities ......................................................................................71 
14.1.1 Sponsor Responsibilities .....................................................................................................71 
14.1.2 Investigator Responsibilities ...............................................................................................71 
14.1.3 Site Initiation .......................................................................................................................72 
14.2. Screen Failures ................................................................................................................................72 
14.3. Study Documents ............................................................................................................................72 
14.3.1 Investigator’s Regulatory Documents .................................................................................73 
14.3.2 Case Report Forms ..............................................................................................................73 
14.3.3 Source Documents ...............................................................................................................73 
14.4. Data Quality Control .......................................................................................................................74 
14.4.1 Monitoring Procedures ........................................................................................................74 
14.4.2 Data Management ................................................................................................................75 
14.4.3 Quality Assurance/Audit .....................................................................................................75 
14.5. Premature Termination of the Study ...............................................................................................76 
14.5.1 Record Retention .................................................................................................................76 
14.5.2 Sample Retention ................................................................................................................77 
14.6. Amendments to the Protocol ...........................................................................................................77 
14.7. Clinical Study Report ......................................................................................................................77 
14.8. Use of Information and Publication ................................................................................................77 
14.9. Subject Insurance and Indemnity ....................................................................................................78 
14.10. 
Data Protection ....................................................................................................................78 
15. ETHICAL AND LEGAL CONSIDERATIONS ......................................................................................79 
15.1. Ethical Conduct of the study ...........................................................................................................79 
15.2. Subject Information and Informed Consent ....................................................................................79 
15.3. Approval by Institutional Review Board ........................................................................................79 
15.4. Subject Insurance and Finance ........................................................................................................80 
16. REFERENCES .........................................................................................................................................81 
17. ATTACHMENTS .....................................................................................................................................82 
17.1. Schedule of Events ..........................................................................................................................83 
17.2. Investigator’s Agreement ................................................................................................................86 
18. APPENDICES ..........................................................................................................................................87 
18.1. Western Ontario and McMaster Universities Osteoarthritis (WOMAC) LK3.1 Index ..................87 
18.2. Patient Global Assessment Scale (PGA).........................................................................................88 
18.3. Patient Global Impression of Change Scale ....................................................................................88 
18.4. 11-Point Numeric Rating Scale (NRS) ...........................................................................................88 
18.4.1 Regulations ..........................................................................................................................89 
18.4.2 Good Clinical Practice Guidelines ......................................................................................89 
 
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LIST OF FIGURES 
Figure 1 
Study Design ..................................................................................................................... 24 
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4. LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APAP 
acetaminophen  
ASA 
acetyl salicylic acid 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CRA 
clinical research associate 
CRO 
contract research organization  
 
 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
institutional review board 
ITT 
intent-to-treat 
IVRS 
interactive voice response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OTC 
over the counter 
PK 
Pharmacokinetics 
PAS 
pharmacokinetic analysis set 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
standard deviation 
TDDS 
transdermal drug delivery system  
ULN 
upper limit of normal 
WOMAC 
West Ontario and McMasters Universities Osteoarthritis Index 
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5. INTRODUCTION 
5.1. Background and Rationale 
An estimated 52.5 million adults (22.7% of the population)1 in the United States (US) have 
doctor-diagnosed osteoarthritis (OA); 22.7 million (9.8% of all adults) have arthritis and 
arthritis-attributable activity limitations.  Based on these data, it is projected that 78 million 
(26%) adults aged 18 years or older will have doctor-diagnosed arthritis by the year 2040.2  
Patients with arthritis are encouraged to be active, since it has been shown that exercise and 
activity help to decrease pain associated with OA, improve function, and delay disability.  
However activity and exercise are often limited by the pain associated with arthritis, and this 
pain may become part of a cycle of inactivity and weight gain that tends to perpetuate the 
stiffness and disability associated with OA.  Additionally, oral medications used over time may 
cause gastrointestinal (GI) distress and interfere with the blood-clotting cycle.  Opioid 
medications often lose their effectiveness with chronic use and require increasing dosages; 
patients may also become dependent on their opioid pain reliever, thereby introducing additional 
health problems into the equation.  There is an unmet need for a safe, reliable, and effective pain 
medication without the risk and lack of efficacy associated with those currently available. 
 
Diclofenac sodium is from the phenylacetic acid class of nonsteroidal anti-inflammatory drug 
(NSAIDs) developed by Ciba Geigy Co., Ltd., Switzerland, in 1965.  In the US, diclofenac 
sodium is available in various dose forms, including tablet, eye drop, extended-release tablet, gel, 
patch, capsule, and solution.  The mechanism of action of NSAIDs is not completely understood 
but may be related to prostaglandin synthetase (cyclooxygenase [COX]-1 and COX-2) inhibition. 
 
Noven Pharmaceuticals, Inc. has started the development of a formulation of diclofenac sodium 
for topical administration via a transdermal patch system, the HP-5000 for the treatment of pain 
of OA of the knee(s).  The topical HP 5000 patch will provide patients with OA with another 
treatment option that may have potential benefits compared with the existing formulations, as 
follows: 
• Transfer of drug into the treatment target area resulting in lower systemic and GI 
exposure when compared to orally administered diclofenac sodium and a possible 
reduction of systemic side effects including GI ulcers/lesions and adverse reactions such 
as nausea, vomiting, dyspepsia, and stomach pain. 
• Improvement of compliance with 
 compared with existing topical 
formulations and use by patients who have difficulty swallowing oral preparations. 
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5.2. Clinical Experience 
To date, the HP-5000 development program includes 
 
.  These studies have been completed 
 
evaluating the PK and tolerability in 
healthy volunteers.  The lead formulations for this 
program, HP 5000 
 and HP 5000 
, both of which contain 
 
diclofenac sodium 
 with a patch size of 
, were selected based on the diclofenac 
pharmacokinetic profile and patch performance characteristics, such as irritation and adhesion on 
the mobile knee joint application site. 
 
It should be noted that the HP 5000 
 formulation is also being developed 
 by Noven’s 
parent company, 
 for different 
 indications 
(i.e., 
 and 
 and is referred to as the 
 (also known as 
.  Study 
 has been included in the development program to provide 
additional safety data.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Further details about HP-5000 are found in the Investigator’s Brochure. 
5.3. Summary of Potential Risks and Benefits 
The potential benefits of study participation are that subjects with OA (1) may experience a 
reduction in pain and inflammation as a result of treatment with the HP-5000 patch and (2) will 
understand that they are contributing to the scientific knowledge that may lead to expansion of 
the treatment options for subjects with OA. 
 
The potential risks of study participation include those associated with exposure to the HP-5000 
patch and the risks of medical evaluation, including venipuncture. 
 
A summary of the pharmaceutical properties and known potential risks of the HP-5000 patch is 
provided in the current version of the investigator’s brochure.3  The investigator must become 
familiar with all sections of the HP-5000 patch IB. 
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6. OBJECTIVES 
6.1. Primary Objectives 
• To evaluate the efficacy of HP-5000 in subjects with osteoarthritis of the knee compared 
to placebo. 
6.2. Secondary Objectives 
The secondary objectives of this study are: 
• To evaluate the skin irritation, discomfort, adhesion, and adhesive residue following 
administration of HP-5000. 
• To evaluate the safety and tolerability of HP-5000. 
• To determine the plasma concentrations of diclofenac following administration of HP-
5000. 
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7. STUDY DESIGN 
7.1. Overall Study Design and Plan - Description 
This is a 4-week, randomized, double-blind, multicenter, placebo-controlled phase 2 study to 
evaluate the efficacy, safety and tolerability of HP-5000 compared with that of placebo in the 
treatment of OA.  The study will run for approximately 9 weeks comprised of up to a maximum 
of 28-day Screening Phase that will include a Washout Period of up to a maximum of 14 days, a 
4-week Double-blind Treatment Phase, and a 1-week Follow-up Safety Period.  Subjects will be 
randomly assigned to receive 
 one of the following 3 treatments in a 1:1:2 ratio:  HP-5000
, HP-5000
 or placebo patch, respectively.  The placebo patch will be 
identical in appearance to the 2 HP-5000 active patches.  The total number of subjects 
randomized in the study and included in the primary analysis will be approximately 300. 
 
The duration of double-blind treatment is expected to be 4 weeks and the total duration of the 
study for each individual subject will be approximately 9 weeks. 
 
• Screening/Washout Period: Visit 1 (up to 28 Days): This is the period between 
Screening Visit (V1) and Baseline Visit (V2): After signing the informed consent, the 
Screening Phase will begin.  Subjects whose preliminary entry criteria have been met on 
Visit 1 will be contacted by the site via telephone starting from Day -25 and will be 
instructed to begin the Washout Period for 7 to a maximum of 14 days (or at least 5 half-
lives, whichever is longer) prior to start the Baseline Visit (V2).   
 
During Visit 1, subjects will receive instruction on how to use the patient eDiary.  The 
first pain score will be performed at the site at the Screening Visit (V1).  If eligible, 
subjects will have to record pain severity of their target knee score on the patient eDiary 
every day at home before the start of the Washout and during the Washout Period using 
the 11-point NRS Scale.  Subjects may start rescue medication usage as needed from the 
start of the Washout Period (i.e., Day -25).    Subjects will record rescue medication 
usage in their eDiary starting from the Washout Period.   
 
 
 
  If 
determined to be eligible, the subject will continue to record his/her pain score daily of 
the target knee during the Washout Period.  The mean pain score, using the 11-point NRS 
scale, of at least the last 2 consecutive days immediately prior to the Baseline Visit 
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(Day 0) will be calculated for subjects to be considered eligible for study participation 
and be randomized for study treatment (See Section 8.2.1).  During the Washout Period, 
rescue medication (acetaminophen [APAP]) will be permitted (a maximum of 2 g/day) 
except within 2 calendar days prior to the Baseline Visit (i.e., rescue medication is 
prohibited from Day-2 until clinic visit on Day 0). 
•
Baseline Visit: Visit 2 (Day 0):  Subjects will be re-evaluated according to the inclusion
and exclusion criteria and the mean patient eDiary pain score will be calculated.  Subjects
who continue to meet all of the inclusion criteria, none of the exclusion criteria, who have
completed the patient eDiary for at least 2 daily NRS scores of the last 3 consecutive
days immediately prior to the Baseline Visit, and whose mean pain score is at least 5 at
Baseline (V2) for those subjects who had a mean pain score of 2 to < 3 at the start of the
Washout Period or has increased by at least 2 worsening scores for those who had a mean
pain score of 3 to 6 at the start of the Washout Period and, will be randomized to receive
one of 2 active formulations of HP-5000 or placebo (see Section 8.2.1).
•
Double-blind Treatment Phase:  On Day 1 of the Double-blind Treatment Phase,
subjects will start applying their assigned patch for 4 consecutive weeks (from
approximately Week 5 through 8):  Subjects will be randomized to receive either
HP-5000
 HP-5000
 or placebo patch.  Dose modifications will
NOT be permitted.  Subjects who cannot tolerate their designated study drug dose will be
withdrawn from the study.
•
Follow-up Period: Visit 6 (Week 9):  After the 4-week of the Double-blind Treatment
Phase, the study center will conduct a follow-up phone call for safety monitoring or
based on the investigator’s judgment, a subject may return to the study center for the
safety Follow-up Visit.
Note: All subjects will be contacted by phone between clinical visits to assess AEs, general well-
being, provide visit reminders, and reinforce eDiary record and treatment compliance.  Dose 
modifications will NOT be permitted and study procedures will be reinforced. 
At each clinical study visit, subjects will undergo efficacy and safety evaluations including 
dermal safety assessments.  Efficacy evaluations will include the change from Baseline values in 
the Western Ontario and McMaster Universities (WOMAC) LK3.1 OA index for pain, stiffness, 
physical function, and composite score, the Patient Global Assessment (PGA), the Patient Global 
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Impression of Change (PGIC), and pain intensity assessed on an 11-point NRS and the subjects’ 
use of rescue medication. 
 
Note: NRS will be performed at home. WOMAC, PGA, and PGIC will be performed at the site 
during each clinic visit. 
 
Safety evaluation will include collection of AEs, physical examination findings, vital sign 
measurements, electrocardiogram (ECGs), clinical laboratory test results, body weight, and 
dermal safety assessments.  All AEs observed by the study personnel or reported by the subject 
during the study (from the time of study drug administration through the post treatment visit) 
will be documented. 
 
Safety dermal characteristics will be assessed using a 5-point numerical scale of adhesion, 
Berger and Bowman scale of Irritation, 5-point numerical scale of Discomfort, and 5-point 
numerical scale of Adhesive Residue.4  In addition, subjects will record at home the 
 patch 
application and removal times in eDiaries along with any incidence of patch detachment and any 
dermal safety experience. 
 
Plasma pharmacokinetic sampling will be performed as scheduled.  Plasma concentrations of 
diclofenac will be assessed by venous blood sampling on Day 14 and 28 (or at the Early 
Termination Visit).  Study center personnel will also assess study drug and eDiary compliance. 
 
Figure 1 presents a schematic view of the study design. 
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7.2. Discussion of Study Design 
The double-blind, placebo-controlled study uses 3 patches 
 HP-5000 
and placebo) of identical appearance to ensure blinding.  The total duration of study drug 
exposure will be 4 weeks.  The follow-up safety evaluation will be performed one week after the 
last study dose. 
 
The use of rescue medication is prohibited within 2 calendar days prior to the Baseline Visit 
(Day 0) and within 1 calendar day prior to each clinic visit during the Double-blind Treatment 
Phase, thus ensuring the integrity of the assessments. 
7.3. Study Sites 
The study will take place at approximately 
 sites in the US.  Each site is anticipated to screen a 
sufficient number of subjects to be able to randomize an aggregate number of approximately 
300 subjects. 
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8. SUBJECT POPULATION 
8.1. Selection of Study Population  
The study will enroll up to 300 subjects in a 1:1:2 ratio (HP-5000
 HP-5000
 
Placebo) with osteoarthritis pain of the knee.  The pain should have been stable over the previous 
six months prior to Screening (Visit 1). 
 
A screening log of potential study candidates and/or an enrollment log of enrolled subjects must 
be maintained at each study site. 
8.2. Study Entry Criteria 
All subjects being considered for participation in this clinical study must meet all the inclusion 
criteria and none of the exclusion criteria. 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. Provide written informed consent, prior to entering the study or undergoing any study 
procedures. 
2. Male or female aged 40 to 85 years with a clinical diagnosis of OA of the target knee 
according to the American College of Rheumatology (ACR) criteria, including: 
a. Symptoms for at least 6 months prior to Screening. 
b. Knee pain in the target knee for 30 days of the preceding month (periarticular knee 
pain due to OA and not due to any other conditions such as bursitis, tendonitis, etc...). 
c. The pain in the target knee required the use of nonsteroidal anti-inflammatory drugs 
(NSAIDs) either over the counter (OTC) per recommendation of a physician or 
prescribed. 
d. On stable pain therapy (i.e., at least 3 days per week for the previous month) with an 
oral or topical NSAID prescribed or recommended by a clinician for 30 days prior to 
the Screening Visit. 
3. Has an X-ray of the target knee, taken no more than 1 year before Baseline, showing 
evidence of OA with Kellgren-Lawrence grade 1 to 3 disease. 
4. Has mild to moderate pain in the designated/target study knee: 
 
 
 
 
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5. Has a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 
score of 
 at the Baseline Visit (V2). 
6. If female: 
a. Subject is not breastfeeding or pregnant as confirmed by a negative pregnancy test at 
or within 48 hours of the Screening Visit.  Women of child-bearing potential must use 
an acceptable method of contraception (including oral contraceptives, hormone 
implant, intrauterine device, and spermicide with barrier method, or male sexual 
partner[s] surgically sterile). 
b. Subject could not become pregnant because she is surgically sterile (hysterectomy or 
tubal ligation), confirmed to be postmenopausal (having amenorrhea for ≥12 months), 
or has had a hysterectomy with or without bilateral oophorectomy at least 6 months 
prior to the Screening Visit. 
7. Able to swallow and tolerate rescue medication, APAP (moderately sized tablets). 
8. Be reliable, willing, and able to cooperate with all study procedures including the 
following: 
a. Accurately fill out the eDiary on a daily basis. 
b. Return for study visits on the required dates. 
c. Accurately and reliably report symptoms (including treatment-emergent signs and 
symptoms). 
d. Use the patch as required by protocol. 
 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if the he or she meets any of the following criteria: 
1. Body mass index (BMI) > 40. 
2. The non-target knee pain severity score is 
 at Screening and 
Baseline (Day 0). 
3. Any subject who disobeyed the restriction of prohibited therapies (i.e., use rescue 
medication) during Screening prior to the start of the Washout Period and 2 days prior to 
the Baseline Visit (V2). 
4. Secondary OA of the knee (rheumatoid arthritis, gout, psoriasis, syphilitic neuropathy, 
ochronosis, metabolic or other primary bone disease or acute trauma). 
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5. Clinically significant elevation of serum creatinine (176.8 μmol/L), aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) (3 x upper limit of normal 
[ULN]) at the Screening Visit. 
6. Known allergy or hypersensitivity to the use of diclofenac, 
 
 
 
 ethanol, acetylsalicylic acid (aspirin [ASA]), or any other NSAID. . 
7. Severe uncontrolled cardiac, renal, hepatic or other systemic disease. 
8. A documented gastroduodenal ulcer (upper GI series or endoscopy) or any GI bleeding 
(except hemorrhoidal) within 6 months prior to Screening Visit. 
9. Documented history of alcohol or drug abuse within 1 year prior to study entry or 
positive alcohol/drug screen findings at Screening or Baseline. 
10. Presence of chondrocalcinosis on X-ray if associated with a history of pseudogout or 
inflammatory flare-ups. 
11. MAJOR SURGERY:  Previous damage or surgery to the target knee at any time (i.e., 
damage/reconstruction of the anterior or posterior cruciate ligaments). 
12. MINOR SURGERY on the target knee defined as anything other than major surgery (as 
defined above) within 1 year before study enrollment. 
13. Treatment with oral or intra-muscular corticosteroids within 90 days of Screening Visit, 
treatment of the target knee with topical or intra-articular corticosteroids within 90 days 
of Screening Visit, or topical or intra-articular corticosteroid treatment of any other joint 
within 30 days of Screening (see Section 9.10.2). 
14. Any subject who had received intra-articular viscosupplementation (e.g., Synvisc®) in the 
target knee 90 days prior to Screening Visit. 
15. Any subject who had used opioids 7 days prior to the Screening Visit. 
16. Any subject who had previous exposure to HP-5000. 
17. Any subject whose participation would conflict with contraindications, warnings or 
precautions as stated in the prescribing information for oral or topical diclofenac (e.g., 
any subject taking ACE inhibitors, cyclosporine, diuretics, lithium, or methotrexate – 
refer Section 3.1.5 of the Investigator Brochure (IB) for prescribing information). 
18. Use of another investigational drug within 30 days prior to study entry. 
19. Any subject with resolved, ongoing, or pending litigation or disability related to any 
health-related cause. 
20. Any subject with fibromyalgia. 
21. Any other painful or disabling conditions affecting the knee or leg. 
22. Any skin abnormality present at the potential patch application site that is likely to be 
aggravated by the study drug (i.e., infection, rash, excessive fragility or dryness, any cut 
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or abrasion), presence of tattoo, excessive hair or open sores, or scar tissue.  Presence of 
significant skin disorder such as atrophy, psoriasis, or vitiligo. 
23. Any subject expecting to have knee replacement surgery within 6 months. 
24. Any subject with a psychiatric condition in the investigator’s opinion may interfere with 
subject’s participation in the study. 
25. The subject is an employee, or family member of an employee, of the study center, the 
contract research organization (CRO) or the sponsor involved in this study. 
8.2.3 Premature Subject Withdrawal 
In accordance with the Declaration of Helsinki (48th WMA General Assembly, Somerset West, 
Republic of South Africa, October 1996), subjects have the right to withdraw participation from 
the study at any time for any reason.  Every reasonable attempt should be made by the 
investigator to keep subjects in the study; however, subjects must be withdrawn from the study if 
they withdraw consent to participate.  Investigators must make at least 3 attempts to contact 
subjects who fail to attend scheduled visits by telephone or any other means. 
 
The investigator also has the right to remove subjects from the study for the following reasons: 
• Adverse events:  If the reason for removal of a subject from the study is an AE, the 
principal specific event and any related test results will be recorded on the electronic case 
report form (eCRF).  If a subject withdraws because of an AE plus another reason, the 
withdrawal will be considered due to the AE and the eCRF will be completed to reflect 
this reason for withdrawal.  A narrative description will be required for all early 
withdrawals due to AEs. 
• The request of the subject, his/her representative, investigator or sponsor, whether for 
administrative or other reasons. 
• Noncompliance with study drug or non-compliance with subject eDiary completion, 
protocol violation, or unreliable behavior. 
• Pregnancy.  If the subject becomes pregnant during the clinical study, the study drug 
should be stopped immediately and the subject will be withdrawn from the study and 
followed until delivery. 
 
If a subject is withdrawn early from the study, the following procedures will be performed: 
• The date of the last dose of study drug and all observations collected up to the time of 
termination will be recorded on the Early Withdrawal eCRF page along with the reason 
for termination.  All Early Withdrawal procedures should be completed and recorded on 
the Early Withdrawal eCRF page.  If withdrawal occurs at a regular scheduled visit, the 
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Early Withdrawal eCRF page should be used instead of the regular visit eCRF page to 
record any information related to the visit. 
• In order to enable the most complete recording of any subject who withdraws early from 
the study, it is important to evaluate these subjects at the study center as soon as possible.  
Subjects who are withdrawing early should undergo an Early Withdrawal/Termination 
Visit and a Follow-up Safety Visit must be scheduled. 
 
Subjects may be withdrawn if continuing in the study is not in the subject’s best interest; their 
condition worsens during the study, or for safety reasons, as determined by the investigator.  
Subjects may also be withdrawn due to lack of compliance with the protocol or if the subject is 
unwilling to continue participation in the study. 
8.3. Subject Replacement Criteria 
Subjects who withdraw after randomization and the application of the first treatment patch will 
not be replaced. 
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9. TREATMENTS 
9.1. Identification of Investigational Product 
The following is a description of study drug: 
• HP-5000
 
Each patch contains 
 diclofenac sodium. 
• HP-5000
 
Each patch contains 
 diclofenac sodium.  
 
One patch 
 will be applied 
 to alternate sides of the target knee 
(inner and outer knee).  Detailed application instructions for subjects will be provided in a 
separate manual. 
 
HP-5000 will be supplied as 
 
 
9.1.1 Labeling 
Labels will be computer-generated for all investigational products (IPs) with the following 
information (other information may also be included as needed): 
• Blinded packaged lot number 
• Protocol number 
• Subject number (record at the time of dispensing) 
• Directions for use 
• Package contents (quantity) 
• Storage instructions 
• Caution: “New Drug – Limited by United States Law to Investigational Use” and “Keep 
out of reach of children” 
• Sponsor name and address 
9.1.2 Packaging 
In the Double-blind Treatment Phase HP-5000
 HP-5000
 and placebo patches will 
be packaged so as to be blinded to the investigator, the study clinic personnel, and the subjects. 
 
Sites and subjects will be instructed to save all empty packaging or packaging containing unused 
patches for final disposition by the sponsor or its designee. 
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The Drug Dispensing Log must be available for monitoring, auditing, or inspection.  Section 9.8 
details the accountability of clinical supplies through the use of a Drug Dispensing Log. 
9.2. Treatments Administered 
HP-5000 will be administered 
 for a maximum of 28 ± 2 days. 
The treatment arms for this study are the following: 
Treatment Arm 
 Treatment 
HP-5000
  
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
HP-5000
 
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
Placebo 
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
Patch Application 
A separate guidance for patch application will be provided to subjects for applying, securing, and 
removing the patch. 
9.3. Dispensing and Storage 
Study drug supplied by 
 is to be used exclusively in the 
clinical study according to the instructions of this protocol.  The investigator is responsible for 
dispensing study drug according to the dosage scheme and for ensuring proper storage of study 
drug. 
 
The investigator must confirm the receipt of study drug with his/her signature.  A copy of this 
receipt must be kept by the investigator, and another copy will be stored at Noven 
Pharmaceuticals, Inc. (hereafter referred to as “Noven”), and/or 
  Until study 
drug is dispensed to the subjects, it must be stored at 25°C and in a dry place in a securely locked 
area that is not generally accessible. 
 
All study drug supplies must be stored in a secure locked area with access limited to the 
investigator or those persons authorized by the investigator to dispense the study drug to 
subjects.  Study drug should be stored as per the label. 
9.4. Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who will meet study entry criteria will be 
randomly assigned in a 1:1:2 ratios to receive HP-5000
 HP-5000
 or placebo 
patches, respectively.  The randomization numbers will be assigned sequentially through a 
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central interactive voice response system (IVRS) as subjects who met eligibility criteria are 
enrolled into the study.  The study center will not be a blocking factor in the randomization 
schedule.  At designated visits, subjects will be given a kit containing sufficient study drug to last 
until the next scheduled study visit. 
 
The randomization schedule will be prepared by 
 before the start of the study.  
No one involved in the clinical conduct will have access to the randomization schedule before 
official unblinding of treatment assignment.  No subject will be randomized into this study more 
than once. 
9.5. Blinding and Unblinding Treatment Assignment 
To protect the blind, placebo patches will be identical in appearance to the HP-5000
 and 
HP-5000-
 patches. 
 
All subjects, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to study drug treatment assignment with the exception of a 
prespecified unblinded statistician/programmer from 
 who will have 
access to the randomization code.  The unblinded study personnel will not participate in study 
procedures or data analysis prior to unblinding of the study data to all study related personnel.  If 
an interim analysis is to be conducted, then unblinded personnel who are not otherwise involved 
in the study will prepare the data for review. 
 
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in 
the conduct of the clinical study.  Treatment unblinding is discouraged if knowledge of the 
treatment assignment will not materially change the planned management of a medical 
emergency.  Unblinding will be permitted in a medical emergency that requires immediate 
knowledge of the subject’s treatment assignment. 
 
In the case of a medical emergency, to appropriately treat the subject, study drug will need to be 
unblinded.  The investigator may break the randomization code for an individual subject.  
However, the investigator should make every effort to discuss the unblinding of the subject with 
the medical monitor prior to unblinding whenever possible. 
 
If the investigator is not able to discuss treatment unblinding in advance, then he/she must notify 
the medical monitor immediately of the blind breaking incident without revealing the subject’s 
treatment assignment. 
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In all such cases, the AE necessitating the emergency blind break will be handled as an SAE in 
accordance with the procedures indicated above.  Any broken code will be clearly justified, 
explained by a comment on the appropriate eCRF page along with the date and reason for study 
discontinuation; and captured on the SAE Form. 
 
The investigator or designee must record the date and reason for unblinding or study 
discontinuation on the appropriate eCRF for that subject.  In all cases that are not emergencies, 
the investigator must discuss the event with the medical monitor prior to unblinding the subject’s 
treatment assignment. 
 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study.  Thus, the overall study blind will not be compromised.  If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study.  The investigator will make this decision after consultation with the medical monitor. 
9.6. Selection of Doses and Administration in the Study 
The dose of diclofenac 
 in a patch size of 
 applied 
 and rotated between 
 on the knee (inner and outer knee) is based on the following considerations: 
• 
 
 
• Dose that targets diclofenac exposure after HP-5000 patch application that is similar to 
that of registered topical diclofenac products and considerably lower than that of oral 
diclofenac tablets. 
• The data from previous studies investigating irritation and PK support the proposed dose 
of 
 and a patch size of 
 applied 
 and rotated between 
 on 
the knee for the lead formulations (HP-5000
 and HP-5000
. 
9.7. Dose Adjustment Criteria 
Dose adjustment is NOT allowed in this study. 
9.8. Drug Accountability 
The investigator (or pharmacist, as appropriate) must maintain adequate records of the receipt 
and conditions of all study drugs, dispensing, return, or other disposition of study drug including 
the date, quantity dispensed to each subject, batch or code number, identification of subjects 
(subject number [and initials]) who received study drug and any reasons for departure from the 
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protocol-dispensing regimen.  Receipt of study drug must also be confirmed within IVRS.  The 
drug accountability records, along with used and unused packaging must be available for 
monitoring, auditing, or inspection.  Each site must keep accurate records of drug received at 
site, dispensed to the subjects. 
 
The investigator will not supply study drug to any person except those named as sub-
investigators (on the Form FDA 1572), designated study personnel, and subjects in this study.  
The investigator will not dispense study drug from any study sites to other than those listed (on 
the Form FDA 1572). 
 
Study drug may not be relabeled or reassigned for use by other subjects.  If any of study drugs is 
not dispensed, lost, stolen, unusable, or is received in a damaged container, this information must 
be documented and reported to Noven and appropriate regulatory agencies, as required. 
 
At the completion of the study, a final reconciliation of all study drugs (used and unused) must 
performed by the site and only unused patches must be returned to the sponsor (or designated 
location).  The unused study drug must be left in the original packaging and returned to the 
sponsor (or designee) for destruction. 
9.9. Treatment Compliance 
Treatment compliance with study drug regimens will be assessed by study personnel via the 
counts of returned unused patches, patch application, removal and by questioning the subject, if 
necessary, at every post-randomization visit.  Treatment compliance will also be calculated as 
the number of patches applied divided by the prescribed number of patches over a given period, 
expressed as a percentage. 
 
At Visits 3 through 5 or any Early Termination Visit, the study drug (patches) from the previous 
Double-blind Treatment Phase will be returned to the investigator.  The study drug will be 
inventoried and noncompliance defined assuming less than 80% or more than 120% of study 
drug during any evaluation period (visit to visit).  If the subject is noncompliant, the Medical 
Advisor should be contacted to discuss the subject’s eligibility to continue in the study. 
 
The subject must be counseled if compliance is not satisfactory (used 6 or less patches per 
week).  If a subject has been noncompliant on two consecutive visits, the subject may be 
withdrawn early from the study for non-compliance. 
 
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For each 28-day study drug administration period, subjects will be asked to record their daily 
intake/use of rescue medication/study drug in the eDiary.  Deviations from the planned doses 
(overdose, missed dose or timing) will be recorded on the subjects’ eCRF.  These eDiaries will 
be reviewed by study personnel at each study visit and will be collected as source documents.  
Information from that subject eDiary will be transcribed on the appropriate eCRF pages for 
documentation of subject compliance with study drug.  Compliance will include the following: 
 
1. Telephone Follow-up: A telephone follow-up call will be performed between Screening 
(Visit 1) and Baseline (Visit 2), before the start of the Washout Period and another one 
during the Follow-up Period. 
 
2. Patient Education: At all clinical study visits, the investigator will explain the 
importance of the following: 
 
a. applying study medication 
 to the target knee after 
showering/bathing;  
b. recording patient eDiary information every day; 
c. accurately reporting pain; 
d. accurately reporting rescue medication use; 
e. understanding when to return for next visit and the importance of returning on 
schedule; and 
f. adhering to the overall research plan. 
 
During Screening (Visit 1), the investigator will provide the subject with an introduction to 
the various questionnaires including the 
 that will be used during the 
entire study and the patient eDiary. 
 
3. Patient eDiary :  The subject eDiary will be used by the subject to record required 
assessments including the time of patch application/removal, the NRS scores, the use of 
rescue medication, and questionnaires about adhesion, skin irritation, discomfort and 
adhesive residue. 
 
4. Rescue Medication:  If needed, subjects will be allowed to take up to a maximum of 2 
grams (4 tablets) of oral acetaminophen per day as rescue medication for pain of the 
target and/or the non-target knee except within 2 calendar days prior to Baseline Visit 
(V2) and within 1 calendar  day for all subsequent visits (V3, V4 and V5).  Information 
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regarding the use of rescue medication, such as the number of tablets, will be recorded on 
the appropriate concomitant medication eCRF. 
9.10. Permitted and Prohibited Therapies 
Prior to the Double-blind Treatment Phase, subjects will discontinue all prescription and  OTC 
analgesic medications for 7 days to 14 days (or at least 5 half-lives, whichever is longer); 
however, rescue medication (acetaminophen [APAP]) is permitted during the Washout Period, if 
required.  A maximum of 2 g/day of APAP will be allowed as a rescue treatment of both target 
and non-target knee pain except within the 2 calendar days prior to the Baseline Visit (i.e., rescue 
medication is prohibited from Day -2 until clinic visit on Day 0) and within the 1 calendar day 
prior to each clinic visit (e.g., rescue medication is prohibited from Day 6 until clinic visit on 
Day 7 if the subject will visit the study site on Day 7).  APAP will be provided by the Sponsor.  
Subjects are NOT allowed to apply study treatment drug (HP-5000/Placebo) on the non-target 
knee at any time during the Double-blind Treatment Phase. 
 
All concomitant medications used prior or during treatment (including OTC medications and 
herbal supplements) will be recorded in the source document and on the appropriate eCRF page.  
9.10.1 Permitted Therapies 
Glucosamine, chondroitin, and antidepressants (used for any indication other than pain) will be 
allowed if used as stable therapy for at least 90 days prior to Screening Visit.  However, if used 
for less than 90 days, these drugs will be considered prohibited concomitant medications and will 
require a Washout Period.  Other concomitant medications for treatment of ongoing medical 
conditions are allowed, but should be limited to those medications considered necessary in the 
opinion of the investigator. 
9.10.2  Prohibited Therapies 
Any NSAIDs (selective or nonselective), any opioids, APAP (>2 g/day), ASA (>81 mg/day), 
corticosteroids (a stable dose by inhalation for seasonal allergies and/or topical use for 
dermatologic allergies are allowed), anticonvulsants (i.e., pregabalin and gabapentin etc...), 
muscle relaxants, other oral analgesics (prescription and/or OTC), antidepressants prescribed for 
the control of chronic pain syndromes, antihistamine with a sedative effect, sedatives for 
insomnia, topical products on the knee including methyl salicylate, camphor, menthol, 
methylsulfonylmethane, 
 or capsaicin, any intra-articular treatments for the knee, any 
nonpharmaceutical therapy or device to relieve knee pain (including physiotherapy, massage 
therapy, hot wax therapy etc.) are not allowed to be taken during the study. 
 
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Subjects will be allowed to continue stable ASA therapy not for OA pain (up to 81 mg/day). 
9.11. Treatment after End of Study 
After completing the study, each subject will be referred to their primary care physician and 
treated according to standard clinical practice. 
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10. STUDY PROCEDURES 
Subjects must provide written informed consent before any study-related procedures are 
initiated, including the cessation of prohibited concomitant therapy. 
 
For the timing of assessments and procedures throughout the study, refer to the schedule of 
events (see Section 17.1).  Throughout the study, every reasonable effort should be made by 
study personnel to follow the timing of assessments and procedures in the schedule of events for 
each subject.  If a subject misses a clinical study visit for any reason, the visit should be 
rescheduled as soon as possible. 
10.1. Study Periods and Visits 
10.1.1 Screening/Washout Period 
10.1.1.1 Screening Period (Visit 1) 
Screening/Washout Period should be up to 28 days prior to the Baseline Visit.  The subject must 
be screened before entering the Washout Period of the study.  The following procedures will be 
performed at Screening Visit (V1): 
1. Obtain written informed consent and assign a screening number. 
2. Assess inclusion/exclusion criteria. 
3. Collect demographic information and record medical history, including prior and current 
therapies (e.g., prescription and nonprescription medications). 
4. Perform a complete physical examination, which will include assessment of the head, 
eyes, ears, nose, and throat, cardiovascular, respiratory, gastrointestinal/abdominal, 
musculoskeletal, dermatological, neurological, and psychiatric/psychological body 
systems. Weight (kg), height (cm), and vital signs will be measured. 
5. Perform urine drug, alcohol and pregnancy tests. 
6. Identify the target knee.  The subject will be instructed to refer to this specific (target) 
knee throughout his/her participation in the study when responding to study efficacy 
assessment. 
7. Instruct the subject on how to use NRS and WOMAC before performing first 
assessments. 
8. Administer the WOMAC questionnaire.  
9. Perform NRS evaluation for the target knee and the non-target knee pain. 
10. Review of X-ray of the target knee and perform 12-lead ECG and laboratory tests to 
determine subject’s eligibility.  If subject does NOT have any X-ray done within the past 
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year, a mandatory new X-ray to confirm the disease will have to be performed prior to 
starting the Washout Period. 
11. Instruct the subject on how to use of an eDiary. 
12. Dispense rescue medication. 
13. Dispense an eDiary. 
10.1.1.2 Washout Period 
Subjects whose eligibility has been preliminarily confirmed at Screening will be asked to 
washout of current medications for at least 7 days to a maximum of 14 days (or at least 5 half-
lives, whichever is longer).  During this period, the following will take place: 
 
Before the start of the Washout Period (i.e., 3 days after Visit 1), the following will take 
place: 
1. Before the start of the Washout Period, eDiary NRS 11-point pain scores will be 
reviewed by the investigator or the study coordinator via telephone.  A record of this 
review will be recorded in the source documents and eCRF pages. 
2. An NRS assessment for the target knee pain will be performed.  
 
 
  
 
During the Washout Period, the following will take place: 
1. Subjects will be instructed by the site to stop taking all prescription and physician 
recommended OTC analgesic medications, but will be informed that rescue medication 
(i.e., acetaminophen) may be used (a maximum of 2 g/day) as needed except within 2 
calendar days prior to the Baseline Visit (V2). 
2. Review subject’s use of rescue medication. 
3. Review subject’s use of prior/concomitant medications. 
4. Subject will be instructed to continue assessing and recording in the eDiary his/her pain 
of the target knee daily at home using the NRS 11-point pain scale during the Washout 
Period. 
10.1.2 Baseline Visit (Visit 2, Day 0) 
The following will take place during the Baseline Visit (Visit 2, Day 0): 
1. Confirm subject’s continued eligibility relative to inclusion/exclusion criteria. 
2. Assign a subject ID number and randomly assign the subject to a treatment group using 
IVRS. 
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3. Obtain vital sign measurements, including weight. 
4. Administer the WOMAC questionnaire. 
5. Perform Patient’s Global Assessment (PGA). 
6. Perform an NRS 11-point pain assessment for the target knee and non-target knee pain. 
7. Review subject’s use of rescue medication. 
8. Perform a 12-lead ECG. 
9. Obtain blood and urine samples for laboratory testing. 
10. Perform a urine drug, alcohol and pregnancy tests. 
11. Review the subject’s eDiary. 
12. Perform Baseline dermal safety assessment (irritation only). 
13. Review subject’s use of prior/concomitant medications. 
14. Dispense rescue medication and perform rescue medication accountability/reconciliation. 
15. Dispense the Double-blind study drug and instruct subjects on proper patch application.  
Subjects should apply the patch at home the next day after showering/bathing. 
16. Subjects will be instructed not to bathe or shower while wearing the study drug; a bath or 
a shower may be taken in the morning or in the evening before any patch is applied 
. 
17. Subject will be instructed to report to the site and record on the eDiary patch detachment 
and incidences of irritation, discomfort, and adhesive residue and not to participate in 
strenuous activities or other activities that cause heavy perspiration during the double-
blind treatment phase. 
10.1.3 Double-blind Treatment Phase 
During the 4-week Double-blind Treatment Phase, the following will take place: 
 
At home, subjects are required to conduct the following: 
1. Apply study medication on the target knee (inner or outer by 
 rotation) after 
showering/bathing. 
2. Perform and complete  the following assessments in an eDiary daily: 
a. Perform and record scoring of the pain of the target knee using the NRS 11- point 
pain scale.   
b. Record the time of patch application and removal. 
c. Record the time of complete patch detachment (if applicable).  
d. Record the number of tablets of rescue medication used.  
e. Record any issues with adhesion, skin irritation, discomfort and adhesive residue. 
 
Note: Do NOT apply study medication on non-target knee at all times. 
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In clinic visits, investigators (or site personnel as appropriate) conduct the following: 
Visit 3: 
1. Obtain vital sign measurements. 
2. Administer the WOMAC questionnaire. 
3. Perform Patient Global Assessment. 
4. Perform Patient Global Impression of Change (PGIC). 
5. Perform daily NRS 11-point pain assessments for the target knee pain only. 
6. Review subject’s use of rescue medication/concomitant medication. 
7. Perform a urine pregnancy test. 
8. Re-instruct the subject concerning the patch application and removal method if the 
subject has a problem with patch application and/or patch adhesion. 
9. Dispense study medication and rescue medication and perform drug accountability/ 
reconciliation of both. 
10. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
11. Review AEs. 
12. Review the subjects’ eDiary entries. 
 
Visit 4: 
1. Obtain vital sign measurements. 
2. Review the subjects’ eDiary entries.  
3. Administer the WOMAC questionnaire.  
4. Perform Patient Global Assessment. 
5. Perform Patient Global Impression of Change. 
6. Perform daily NRS 11-point pain assessments for the target knee pain only. 
7. Review subject’s use of rescue medication/concomitant medication. 
8. Perform a urine pregnancy test. 
9. Re-instruct the subject concerning the patch application method if the subject has a 
problem with patch application and/or patch adhesion. 
10. Dispense study medication and rescue medication and perform drug accountability/ 
reconciliation. 
11. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
12. Review AEs. 
13. Review the subjects’ eDiary entries. 
14. Obtain pharmacokinetic blood sample. 
 
Visit 5 
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1. Obtain vital sign measurements. 
2. Collect and review the subjects’ eDiary entries. 
3. Administer the WOMAC questionnaire. 
4. Perform Patient Global Assessment. 
5. Perform Patient Global Impression of Change. 
6. Perform daily NRS 11-point pain assessments for the target knee pain only. 
7. Review subject’s use of rescue medication/concomitant medication. 
8. Perform a urine pregnancy test. 
9. Perform drug accountability/reconciliation. 
10. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
11. Review AEs. 
12. Obtain blood and urine samples for laboratory testing. 
13. Obtain subject’s weight. 
14. Obtain pharmacokinetic blood sample. 
15. Perform a 12-lead ECG. 
16. Perform physical examination. 
 
During the time interval between visits, the site coordinator may regularly contact (via 
telephone) the subjects to ensure that the subject’s scheduled dose is administered and daily 
NRS pain scores are recorded correctly.  The subjects will be informed by the site personnel 
that they may contact the site if problems/questions arise. 
 
Note: After Visit 5, subjects may resume their standard of care treatment. 
10.1.4 Follow-up Visit  
A follow-up phone Visit will take place approximately 7 days after the end-of-treatment (EOT) 
visit (or Early Termination Visit), and will include the following assessment and procedures: 
1. Review subject’s use of concomitant medications. 
2. Review AEs. 
10.1.5 Early Termination Visit (if applicable) 
Subjects who are discontinued for any reason after Baseline (Visit 2) must complete the Early 
Withdrawal Visit.  If the subject comes for an Unscheduled Visit and a decision to withdraw the 
subject is made, then the Early Withdrawal Visit procedures will be performed and the Early 
Withdrawal Visit eCRF will be completed (and not the Unscheduled Visit eCRF).  During this 
visit the following assessments and procedures will be performed: 
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1. Collect and review the subject’s eDiary entries. 
2. Perform physical examination. 
3. Obtain vital sign measurements including weight. 
4. Administer the WOMAC questionnaire.  
5. Perform Patient’s Global Assessment. 
6. Perform Patient’s Global Impression of Change. 
7. Perform a NRS 11-point pain assessment for the target knee pain only. 
8. Review subject’s use of rescue and concomitant medications. 
9. Perform a 12-lead ECG. 
10. Obtain blood and urine samples for laboratory testing. 
11. Perform a urine pregnancy test. 
12. Perform drug accountability/reconciliation. 
13. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
14. Review AEs. 
15. Obtain pharmacokinetic blood sample. 
10.1.6 Overall Study Schedule 
The planned sequence and approximate duration of the study periods will be as follows: 
1. Screening/Washout Period:  Up to 28 days (the Washout Period will occur the last 7 to 14 
days of the Screening Phase). 
2. Double-blind Treatment Phase:  4 weeks 
3. Follow-up Period:  1 week 
The maximum treatment duration for each subject is 4 weeks.  The study duration for each 
subject is approximately 9 weeks. 
10.2. Assessments 
10.2.1 Efficacy 
10.2.1.1 Western Ontario and McMaster Universities Osteoarthritis Index 
The Western Ontario and McMaster Universities Osteoarthritis Index Likert (LK) version 3.1 is 
the most recent version of this instrument for the assessment of hip and knee OA.  The WOMAC 
Osteoarthritis Index is widely used to measure pain, stiffness, and physical function in subjects 
with OA pain.  It is considered to be a reliable and valid instrument for this indication.5,6,7   
 
The WOMAC Pain scale evaluates the following 5 items: 
1. Walking 
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2. Stair climbing 
3. Noctural 
4. Rest 
5. Weight bearing 
 
Each item is rated on a scale of 0 to 4, with 0 being no difficulty and 4 being extreme difficulty. 
 
The WOMAC Stiffness scale assesses 2 items: 
1. Morning stiffness, and 
2. Stiffness occurring later in the day. 
Each item is rated on a scale of 0 to 4, with 0 being no difficulty and 4 being extreme difficulty. 
 
The WOMAC Physical Function assesses the following 17 categories using the 0 to 4 scale 
described previously: 
1. Descending stairs 
2. Ascending stairs 
3. Rising from sitting 
4. Standing 
5. Bending to floor 
6. Walking on a flat surface 
7. Getting in/getting out of car 
8. Going shopping 
9. Putting on socks 
10. Lying in bed 
11. Taking off socks 
12. Rising from bed 
13. Getting in/out of bath 
14. Sitting 
15. Getting on/off toilet 
16. Heavy domestic duties 
17. Light domestic duties 
 
The WOMAC Composite score is most commonly calculated by summing the items for all 3 
subscales.  Higher scores on the WOMAC indicate worse pain, stiffness, and functional 
limitations.  The total score is calculated as follows: Total score= __/96= __% 
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10.2.1.2 Patient Global Assessment 
The PGA is a self-administered instrument that measures the subject’s overall impression of their 
OA pain in their target knee on a 5-point scale where 0 = “Very Good” and 4 = “Very Poor”. 
Subjects will be asked the complete the following statement: 
“How would you rate your osteoarthritis condition over the last 24 hours?” 
The response options include the following: 
 
Very Good 
0 
 
Good 
1 
 
Moderate 
2 
 
Poor 
3 
 
Very Poor 
4 
10.2.1.3 Patient Global Impression of Change 
The Patient Global Impression of Change is a self-administered instrument that measures change 
in subjects’ overall improvement with treatment on a scale where 1 = “very much improved” and 
7 = “very much worse.”  Subjects will be asked the following question:  “How would you rate 
your overall improvement with treatment during the clinical trial?”  The response options include 
the following: 
 
Very Much Improved 
1 
 
Much Improved 
2 
 
Minimally Improved 
3 
 
No Change 
4 
 
Minimally Worse 
5 
 
Much Worse 
6 
 
Very Much Worse 
7 
10.2.1.4 Numeric Rating Scale 
The NRS is an 11-point scale from 0 to 10. On this scale, 0 = no pain and 10 = the worst pain 
imaginable.  NRS 11-point scale will be assessed in two ways.  One is the average pain condition 
over the last 24 hours, and the other is the worst painful condition over the last 24 hours.  
 
The subject will rate his or her target knee pain intensity using the following question:  “On a 
scale from 0 to 10, where “zero” represents “no pain” and “10” represents “the worst possible 
pain,” how would you rate the pain that you have been feeling in your knee over the last 24 
hours?” 
Note: 
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1. The NRS pain score for assessment is an average of the NRS pain scores reported for 
pain over the last 24 hours for the last 3 days prior to each clinic or phone visit except for 
Screening and Baseline Visits. 
2. The NRS pain assessment must be performed daily by the subject at home between 
Screening (V1) and the start of the Washout Period.  
 
 
 
3. The subject will continue assessing and recording the NRS pain score daily at home 
during the Washout Period.  
  
 
  
10.2.1.5 Use of Rescue Medication 
For the 4-week Double-blind Treatment Phase, subjects will be asked to record their daily 
intake/use of rescue medication in the eDiary.  Rescue medication will be limited as follows: 
2 gram/day APAP may be used Except and within 1 calendar day prior to other clinic visits. 
10.2.2 Safety 
Safety assessments will include the evaluation of laboratory assessments, vital signs, 12-lead 
ECGs, physical examinations, dermal safety assessments and AEs. 
10.2.2.1 Laboratory Safety Assessments 
10.2.2.1.1 Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the timepoints specified in the 
schedule of events (see Section 17.1). 
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Hematology: 
 
 
 
 
Hemoglobin, hematocrit, red blood cell (RBC) count, RBC 
indices, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, platelet count (or estimate), white 
blood cell count including differential. 
 
Serum chemistry: 
Albumin, total bilirubin, direct bilirubin, total protein, calcium, 
alkaline 
phosphatase, 
alanine 
aminotransferase, 
aspartate 
aminotransferase, blood urea nitrogen, creatinine, fasting glucose 
and total lipids [8 to 10 hours after fasting is required for these 
laboratory testing], cholesterol, triglycerides, high density 
lipoprotein, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid. 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones, leukocyte 
esterase, nitrite, total bilirubin, urobilinogen. 
Pregnancy test (urine): 
For women of childbearing potential only. 
Urine drug screen: 
Amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
methamphetamine, 
methadone, 
phencyclidine, 
and 
tetrahydrocannabinol. 
Alcohol test (urine): 
Ethanol. 
A central laboratory will be used to process all hematology, clinical chemistry, urinalysis 
samples.  Urine drug screens and alcohol tests pregnancy tests will be conducted at the study 
sites.  Details on sampling, handling, and storage of samples will be given in a separate 
laboratory manual. 
 
Note:  Female subjects (of childbearing potential) will undergo a urine pregnancy test at 
Screening (Visit 1) and at every subsequent visit. 
10.2.2.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products.  Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens 
in both the clinic and laboratory settings.  Refer to current recommendations of the appropriate 
authorities. 
 
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In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples.  Procedures and regulations for the packaging and 
shipping of biological samples are outlined in the HP-5000-US-05 laboratory manual.  The 
investigator is responsible for ensuring that all study samples that are to be transported to another 
location are appropriately packed and shipped according to the applicable regulations. 
10.2.2.2 Clinical Examinations 
10.2.2.2.1 Vital Signs and Weight 
Vital signs, including heart rate, respiratory rate, temperature and supine blood pressure will be 
measured at designated timepoints.  Blood pressure will be measured with the subject in the 
supine position only.  The supine blood pressure should be measured after the subject has been 
lying down for five minutes.  Weight (kg) will also be measured. 
10.2.2.2.2 Electrocardiogram 
The 12-lead ECG will be a complete, standardized recording and will be performed at designated 
timepoints after the subject has been in a supine position for at least 5 minutes before the 12-lead 
ECG is obtained.  All ECG recordings will be identified with the subject number, initials, date, 
and time of the recording and will be attached to the subject’s eCRF. 
10.2.2.2.3 Physical Examination 
The following physical examination will be performed at designated timepoints before potential 
exposure to study drug and at the completion of exposure. 
• General Appearance 
• Abdomen 
• Head/ Face 
• Skin, Hair, and Nails 
• Eyes/ Fundoscopy 
• Musculoskeletal: Extremities, Spine 
• Ears/Hearing 
• Vascular/Circulatory 
• Nose 
• Lymphatic 
• Mouth, Teeth and Throat 
• Psychiatric/Behavior 
• Neck & Thyroid 
• Brief neurologic 
• Chest/Lungs 
 
 
10.2.2.3 Adverse Events 
The definitions and management of and special considerations for AEs are provided in 
Section 11. 
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10.2.2.4 Evaluations of Patch and Dermal Assessment 
Patch Adhesion  
Patch adhesion will be assessed in two ways (in-clinic and at-home).  At each clinic visit, patch 
adhesion will be assessed by the investigator or a designee using the following 5-point numerical 
scale: 
• 
0 = ≥90% adhered (essentially no lift off the skin). 
• 
1 = ≥75% to <90% adhered (some edges only lifting off of the skin). 
• 
2 = ≥50% to <75% adhered (less than half of the system lifting off of the skin). 
• 
3 = <50% adhered but not detached (more than half the system lifting off of the skin 
without falling off). 
• 
4 = patch detached (patch completely off the skin). 
 
During the Double-blind Treatment Phase at home, subjects will only report on any incidence of 
patch detachment in the eDiary. 
 
Irritation 
At each clinic visit, the application site where the previous patch was applied will be examined 
for signs of skin irritation.  All subjects will be evaluated by a trained investigator or designee 
using the Berger and Bowman scale (Berger and Bowman 1982) as described below. 
 
Half grades will not be assigned if reactions fall between the unit grades, rather, the more severe 
of the 2 grades will be assigned. 
 
Dermal Response 
• 
0 = no evidence of irritation 
• 
1 = minimal erythema, barely perceptible 
• 
2 = definite erythema, readily visible; minimal edema or minimal papular response 
• 
3 = erythema and papules 
• 
4 = definite edema 
• 
5 = erythema, edema, and papules 
• 
6 = vesicular eruption 
• 
7 = strong reaction spreading beyond the application site 
 
Other Effects  
• 
A = slightly glazed appearance 
• 
B = marked glazed appearance 
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• 
C = glazing with peeling and cracking 
• 
F = glazing with fissures 
• 
G = film of dried serous exudates covering all or part of the patch site 
• 
H = small petechial erosions and/or scabs 
• 
N = no other observations 
 
Dermal response score will be rated on a 0 to 7 scale, whereby 0 is rated as “No evidence of 
irritation” and 7 is rated as “Strong reaction spreading beyond test (application) site.” 
 
Other effects will be scored via a letter scale and a corresponding numeric scale, whereby N (0) 
is rated as “No effects” and H (3) is rated as “Small petechial erosions and/or scabs.” 
 
During the Double-blind Treatment Phase at home, subjects will complete a questionnaire about 
skin irritation in the eDiary. 
 
Discomfort 
Discomfort will be assessed by the investigator or a designee using a predefined discomfort 
rating scale.  The evaluator will ask the subject, “Are you experiencing any discomfort related to 
the patch?”  If the answer is no, the overall level of discomfort will be rated as 0.  If the answer is 
yes, the evaluator will then ask the subject to rate the discomfort as mild, moderate, or severe. 
Any discomfort mentioned should be recorded and rated as follows: 
• 
0 = No discomfort 
• 
1 = Mild discomfort 
• 
2 = Moderate but tolerable discomfort 
• 
3 = Severe, intolerable discomfort 
• 
4 = Patch not present 
 
During the Double-blind Treatment Phase at home, subjects will complete a questionnaire about 
discomfort in the eDiary. 
 
Adhesive Residue  
At each clinic visit, the amount of adhesive residue remaining at the application site where the 
previous patch was applied will be examined by the investigator or a designee and scored 
according to the scale below: 
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• 
0 = None 
• 
1 = Light 
• 
2 = Medium 
• 
3 = Heavy 
• 
4 = Patch not present 
 
During the Double-blind Treatment Phase at home, subjects will complete a questionnaire about 
adhesive residue in the eDiary. 
10.2.3 Pharmacokinetic Assessments 
Blood samples for the determination of plasma diclofenac concentrations will be collected at 
specified visits after the application of the study drug as per the Schedule of Events in Section 
17.1.  A volume of approximately 4 mL of blood will be collected at Visit 4 (Day 14) and Visit 5 
(Day 28); or at the Early Termination Visit, if applicable.  The LC/MS/MS validation method 
will be used to analyze the plasma sample to determine the diclofenac concentrations and blood 
sampling times will be recorded. 
 
The total blood volume collected will be approximately 40 mL (inclusive of pharmacokinetic 
and clinical safety laboratory collections). 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product.  An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
 
Pre-existing diseases or conditions will NOT be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition during the Double-
blind Treatment Phase (Worsening of a pre-existing condition is considered an AE.). 
 
Events occurring in subjects treated with placebo will also be considered AEs.  However, AEs 
reported during treatment-free periods before study drug has been administered are not 
considered AEs; these events are captured on the eCRF as updates to the subject’s medical 
history. 
 
• All AEs encountered during the clinical study will be reported on the eCRF. All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from 
after the start of the study drug.  AEs in clinical investigation subjects include any change 
in the subject’s condition.  This includes symptoms, physical findings, or clinical 
syndromes. 
• An abnormal laboratory value may be considered an AE if the identified laboratory 
abnormality leads to any type of intervention whether prescribed in the protocol or not.  It 
is up to the investigator to determine whether an abnormal laboratory value constitutes an 
AE.  If an abnormal laboratory value is caused by a disease process, the disease process 
and not the laboratory abnormality should be listed as the AE (e.g., if new onset viral 
hepatitis is causing elevated ALT, hepatitis and not the elevated ALT should be listed as 
the AE). 
• Examples of laboratory abnormalities, which should be considered as AEs include those 
which result in withdrawal of the study treatment, withholding study treatment pending 
some investigational outcome, reduction of dose of the study treatment, or additional 
concomitant treatment.  All laboratory abnormalities considered to constitute an AE 
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should be reported on the appropriate AE page of the eCRF.  Laboratory abnormalities do 
not need to be listed as separate AEs if they are considered to be part of a clinical 
syndrome that is being reported as an AE.  It is the responsibility of the investigator to 
review all laboratory findings in all subjects.  Abnormal values should be commented 
upon as to clinical relevance or importance on the eCRF or the laboratory report as 
appropriate.  Medical and scientific judgment should be exercised in deciding whether an 
isolated laboratory abnormality should be classified as an AE. 
• Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
11.1.2 Unexpected Adverse Event 
An expected AE is one for which the nature or severity is consistent with the known AE profile 
of the product.  For a study drug, the known information is contained in the IB which includes 
the HP-5000 Developmental Core Safety Information. 
 
An unexpected adverse event is one for which the specificity or severity is not consistent with 
the current IB and Developmental Core Safety Information. 
 
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected events. 
11.1.3 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening.  
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE:  An elective hospital admission to treat a condition present before exposure to the test 
drug, or a hospital admission for a diagnostic evaluation of an AE, does NOT qualify the 
condition or event as an SAE. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly. 
NOTE:  A congenital anomaly in an infant born to a mother who was exposed to study drug 
during pregnancy is an SAE.  However, a newly diagnosed pregnancy in a subject that has 
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received a study drug is NOT considered an SAE unless it is suspected that study drug 
interacted with a contraceptive method and led to the pregnancy. 
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, development of drug dependency, or drug abuse. 
11.2. Management of Adverse Events 
Adverse events will be collected from the time of first dose administration through the Follow-up 
Visit or Early Termination Visit, whichever occurs first. 
 
Subjects who complete the Double-blind Treatment Phase or terminate early will continue to be 
monitored for AEs for 30 days from last day for study treatment, unless they withdraw consent 
or are lost to follow-up. 
11.2.1 Collection 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously.  At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation.  The investigator will 
then monitor and/or ask about or evaluate AEs using non-leading questions, such as: 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
11.2.2 Any clinically relevant observations made during the visit will also be considered 
AEs.Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention.  The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention.  The event 
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interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
 
It is important to distinguish between severe AEs and SAEs.  Severity is a classification of 
intensity whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.3. 
11.2.2.3 Action Taken 
Action taken may consist of: 
Drug 
withdrawn 
An indication that a medication schedule was modified through termination of 
a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as follows: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
 
NOTE:  Only select fatal as an outcome when the AE results in death.  If more than 1 AE is 
possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE.  Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to study drug.  The 
categories for classifying the investigator’s opinion of the relationship are listed below. 
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Not related 
An AE with sufficient evidence to accept that there is no causal relationship to 
study drug administration (e.g., no temporal relationship to drug 
administration, because the drug was administered after onset of event; 
investigation shows that the drug was not administered; another cause was 
proven). 
Unlikely related An AE, including laboratory test abnormality, with a temporal relationship to 
study drug administration that makes a causal relationship improbable, and in 
which other drugs, events or underlying disease provide plausible 
explanations. 
Possibly related An AE with a reasonable time sequence to administration of the study drug, 
but which could also be explained by concurrent disease or other drugs or 
events. Information on drug withdrawal may be lacking or unclear. 
Definitely 
Related 
An AE occurring in a plausible time relationship to study drug administration, 
and which cannot be explained by a concurrent disease or other drugs or 
events.  The response to withdrawal of the drug (dechallenge) is clinically 
reasonable. 
11.2.3 Documentation 
All AEs occurring within the period of observation for the study must be documented in the 
eCRF with the following information; where appropriate (The period of observation for the study 
is described in Section 11.2): 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to study drug 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care.  If such treatment constitutes a deviation from the protocol, the subject should be 
withdrawn from the study and the reason and date of withdrawal must be documented in the 
eCRF.  The decision about whether the subject may continue in the study will be made by the 
sponsor after consultation with the investigator and/or medical monitor. 
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If AEs occur in a subject that is not tolerable, the investigator must decide whether to withdraw 
the subject from the study and/or treat the subject.  Special procedures may be recommended for 
the specific study drug, such as the collection of a serum sample for determining blood 
concentrations of study drug, or treatment regimens, as appropriate. 
 
It is NOT necessary to unblind a subject’s treatment assignment in most circumstances, even if 
an SAE has occurred. If unblinding is necessary, see Section 9.5 for a description of the 
unblinding procedures. 
11.2.5 Follow-up  
ALL ongoing SAEs at the time of discontinuation will be followed (up to a maximum of 30 days 
after the last dose of study medication) to a satisfactory resolution, or until it becomes stable, or 
until it can be explained by another known causes (i.e., concurrent condition or medication) and 
clinical judgment indicates that further evaluation is not warranted.  All ongoing AEs at the time 
of discontinuation will be followed for up to 7 days.  All findings relevant to the final outcome of 
an AE must be reported in the subject’s medical record and recorded on the eCRF page. 
11.2.6 Reporting of Adverse Events 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to 
 within 24 hours 
of first becoming aware of the event by completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the 
source documents and eCRF, and sending the SAE form to the sponsor by one of the following 
methods: 
  
All SAEs, irrespective of relationship to study treatment, must be reported as soon as 
possible but no later than 1 business day by Fax to: 
 
Email: 
 
 
 
The “Clinical Trial Serious Adverse Event Report Form (SAE form)” must be used for 
reporting. 
It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality.  All SAEs must be 
followed to resolution, or if resolution is unlikely, to stabilization.  Any follow-up information 
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received on serious adverse events should be forwarded within one business day of its receipt.  If 
the follow-up information changes the investigator’s assessment of causality, this should also be 
noted on the follow-up SAE form. 
 
SAEs, regardless of causality assessment, must be collected through the Termination Visit and 
for 30 days following study drug discontinuation, whichever is longer. 
 
Any SAE judged by the investigator to be related to the study treatment should be reported to the 
sponsor regardless of the length of time that has passed since study completion. 
 
The written report should be submitted on the SAE form provided for this purpose.  At the time 
of first notification, the investigator or designee should provide the following information, if 
available: 
• Protocol number 
• Reporter (study site and investigator) 
• Subject’s study number 
• Subject’s year of birth 
• Subject’s gender 
• Date of first dose of study drug 
• Date of last dose of study drug, if applicable 
• Adverse event term 
• Date of occurrence of the event 
• A brief description of the event, outcome to date, and any actions taken 
• The seriousness criteria that were met 
• Concomitant medication at onset of the event 
• Relevant medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to study drug (“Is there a reasonable 
possibility that the study drug caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the subject’s treatment 
assignment 
 
The investigator must fax/mail a written SAE Report Form that describes the SAE to the 
recipients of the initial information, who will forward the information to the sponsor. 
 
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Preliminary SAE reports and/or any missing or additional relevant information concerning the 
SAE should be provided to the recipients of the initial information as soon as possible on a 
follow-up SAE Report Form, together with the following information (adverse event, date of 
occurrence, subject ID, study ID, study drug, and site number) including copies of hospital case 
reports, autopsy reports and other documents requested by the sponsor; this will allow the 
follow-up information to be linked to the initial SAE report. 
 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his/her health authorities, institutional review board 
(IRB), principal and coordinating investigators, study investigators, and institutions. 
11.2.6.2 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF page and reported by 
 to Noven.  
11.2.7 Adverse Events of Special Interest 
The overall systemic safety profile of diclofenac is well known and established as reflected in the 
Investigator’s Brochure (IB) including Developmental Core Safety Information, which are in 
part based on the current label of the 
  In patients taking 
 
 
 
 
 
 
  
 
The overall safety of HP-5000 patches at doses ranging from 
 
 
  The HP-5000 patches used in the clinical 
studies 
 
  Some of the commonly reported 
AEs across the 
  The remaining commonly reported AEs are 
either known adverse reactions to other commercially available dose forms that contain 
diclofenac (application site pruritus, back pain, and myalgia with diclofenac containing solutions 
or patches) or consistent with events of application site skin reactions commonly reported as AEs 
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with other topical medications that contain diclofenac 
 
 
11.2.8  Pregnancy Reporting 
All females of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation.  Females should be instructed to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected. 
 
Male study participants will be instructed to practice birth control measures to prevent a partner’s 
pregnancy during the subject’s study participation and for 90 days following the last dose 
administration. 
 
Pregnancy testing will be conducted prior to administration of study drug on every female of 
childbearing potential.  A female who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
 
A female who becomes pregnant during study drug treatment will be immediately withdrawn 
from the study.  Any female who becomes pregnant during treatment and within 30 days of 
discontinuing study drug will be followed by the investigator until birth or termination of 
pregnancy.  Any pregnancy for which the estimated date of conception occurred prior to the 
Termination Visit of the study and for 30 days following study drug discontinuation, whichever 
is longer, must be reported. 
 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
 
An induced abortion or a spontaneous abortion is considered to be a SAE and should be reported 
in the same timeframe and in the same manner as all other SAEs (see Section 11.2.6.1). 
 
The investigator must report the pregnancy to 
 Pharmacovigilance using the 
Pregnancy Data Collection Form via the same fax number and/or email address as for SAE 
reporting.  The investigator should contact the designated individuals who receive SAE 
notification and record information related to the pregnancy on an Exposure in Utero form 
provided by the sponsor or its designee. 
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Pregnancies must be reported as soon as possible, but no later than 1 business day, by Fax 
to: 
 
 
 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy. 
 
All Pregnancies must be followed to outcome. The outcome of the pregnancy must be 
reported as soon as possible but not later than one business day. 
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12. DATA SAFETY MONITORING BOARD 
There will be no Data Safety Monitoring Board for this study. 
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13. STATISTICAL METHODS 
13.1. Study Endpoints 
13.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in WOMAC LK3.1 OA pain score from Baseline 
and Week 4. 
13.1.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
• WOMAC LK3.1 OA Index (pain) – change between Baseline and Week 1, and Week 2  
• WOMAC LK3.1 OA Index (stiffness) between Baseline and Week 1, Week 2, and Week 
4 
• WOMAC LK3.1 OA Index (physical function) between Baseline and Week 1, Week 2, 
and Week 4 
• WOMAC LK3.1 OA Index (composite score) between Baseline and Week 1, Week 2, 
and Week 4 
• Patient Global Assessment between Baseline and Week 4 
• Patient Global Impression of Change between Week 1 and Week 4 
• Pain intensity assessed on an 11-point NRS between Baseline and Week 1, Week 2, and 
Week 4 
• Use of rescue medication between Baseline and Week 1, Week 2, and Week 4 
13.1.3 Safety Endpoints 
• Adverse events, AEs leading to discontinuation from the study drug, SAEs, and deaths. 
• Change from Baseline in clinical laboratory results (including fasting glucose and total 
lipids [8 to 10 hours after fasting is required for these laboratory testing]), ECG results, 
body weight, and vital signs. 
• Dermal safety: adhesion, irritation, discomfort, and adhesive residue. 
13.1.4 Pharmacokinetics Endpoint 
Plasma concentrations of diclofenac (for both HP-5000
 and HP-5000
 on Day 14 
and 28 (or at the Early Termination Visit). 
13.2. Sample Size Determination 
Assuming an effect size of 
 
 on the 
change in WOMAC pain score from Baseline to Week 4 between active HP-5000
 and HP-
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5000
 treatments and placebo, the probability for detecting the clinically meaningful 
effect size 
 or higher will be approximately 67% having 75 evaluable subjects per each 
active arm and 150 evaluable subjects in the placebo arm.  Having 3 treatment arms, the total 
number of subjects randomized in the study and included in the primary analysis set should be 
approximately 300.  A sufficient number of subjects will be screened to randomize the proposed 
sample size. 
13.3. Analysis Populations 
The following 4 analysis populations are planned for this study: 
• Intent-to-Treat (ITT):  Includes all consented and randomized subjects.  Regardless of 
any protocol deviations, analyses performed on the ITT set will be based on the 
randomized treatment assignment and all available data. 
• Full Analysis Set (FAS):  Includes all randomized subjects who have had at least 1 patch 
of double-blind study drug applied and who have a Baseline WOMAC pain score and at 
least 1 post-baseline assessment of the primary efficacy measure (WOMAC pain score).  
Evaluable subjects will be defined as those who meet the FAS definition.  The FAS will 
be used as the primary set for analysis of efficacy endpoints based on randomized 
treatment assignment. 
• Safety Analysis Set (SAF):  Includes all subjects who have had at least 1 patch of 
Double-blind study drug applied and who have at least 1 post-dose safety measurement 
during the Double-blind Treatment Phase.  In the unlikely event that errors may have 
occurred in treatment arm assignments, then analyses using the SAF will be based on 
treatment actually received.  The SAF will be used for the analysis of dermal evaluations 
and safety endpoints. 
• Pharmacokinetic Analysis Set (PAS):  Includes all subjects who have received at least 
1 dose of study drug during the Double-blind Treatment Phase and have at least 1 blood 
sample for PK assessment.  Subjects may be excluded from the PAS set if they 
significantly violate inclusion or exclusion criteria, significantly violate the protocol in a 
way that may influence the PK analysis, if any unexpected error occurs during the study 
that may influence the PK analysis (e.g., early detachment of transdermal systems, 
apparent sample switching, etc.) or if their data are unavailable or incomplete.  The PAS 
will be used for the analysis with model-based approach.  Excluded cases will be 
documented together with the reason for exclusion. 
 
Inclusion in the analysis populations will be determined prior to database lock. 
 
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If a subject is randomized incorrectly or is administered the incorrect study drug, analyses of the 
ITT population will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment. 
13.4. Statistical Analyses 
This section presents a summary of the planned statistical analyses.  A Statistical Analysis Plan 
(SAP) that describes the details of the analyses to be conducted will be written prior to database 
lock.  Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a 
difference resulting in a P value of <0.05 will be considered statistically significant.  For 
analyses involving study site, if the number of subjects per site is small, sites may be pooled for 
analysis, or omitted from statistical models.  The final determination will be made prior to 
database lock. 
 
Summary statistics will be provided for the variables described below.  For continuous variables, 
these statistical analyses will typically include the number of subjects, mean, standard deviation 
(SD), median, minimum, and maximum.  For categorical variables, these statistics will typically 
include the number and percentage of subjects in each category. 
13.4.1 Study Subjects and Demographics 
13.4.1.1 Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal will be tabulated overall and by treatment group.  The number of subjects and 
patches in each analysis population will be reported. 
13.4.1.2 Protocol Deviations 
A by-subject listing of all protocol deviations and violations will be reported in Clinical Study 
Report. 
13.4.1.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for all analysis populations.  Demographic variables will 
include age, gender, height, and weight.  Information on race and ethnicity will be collected for 
any eventual analysis of differences in response to study drug, in accordance with local 
regulatory requirements.  Baseline subject characteristics will include medical history, physical 
examination findings, and previous OA treatment modalities. 
 
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Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and preferred terms. 
13.4.2 Exposure and Compliance 
Investigational product administration will be summarized in terms of the number of patches 
applied and removed, the number of patches removed earlier along with the summary of reasons 
for early removal.  For each subject mean in terms of duration of exposure will be calculated.  
Descriptive statistics for these quantities, including the mean, median, SD, minimum, maximum, 
and quartiles, will be provided by treatment group. 
13.4.3 Efficacy Analyses 
Efficacy variables will be summarized and analyzed using the FAS population as primary, unless 
otherwise specified. 
13.4.3.1 Primary Analysis 
The primary efficacy endpoint of this study is the change from Baseline to Week 4 in the 
WOMAC pain score; the primary analysis set is the FAS.  The comparisons of interest are: 
• HP-5000
 versus placebo 
• HP-5000
 versus placebo 
 
The estimand in the primary analysis for efficacy for each dose is the difference between 
treatments groups (HP-5000 dose group vs. placebo) in the change from Baseline to Week 4 in 
WOMAC pain score in all subjects as randomized, under the assumption that all randomized 
patients remain on their randomized treatment throughout the study.  WOMAC scores obtained 
more than 24 hours after discontinuation of study drug will be excluded as a-priori defined 
outliers. 
 
The primary efficacy variable, the change from Baseline to Week 4 in the WOMAC pain score 
will be analyzed using a mixed model repeated measures (MMRM) analysis.  The MMRM 
model will include change from Baseline in WOMAC pain score as the repeated dependent 
variable, with treatment (HP-5000
, HP-5000
 and placebo), visit, treatment-by-visit 
interaction, and the Baseline WOMAC pain score as covariates.  An unstructured covariance 
matrix will be assumed.  If the unstructured covariance matrix fails to converge, a series of other 
covariance structures will be tested for use. 
 
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The MMRM model may be repeated on additional analysis sets as a sensitivity analysis.  If the 
normality assumption is violated, analysis of covariance (ANCOVA) on rank-transformed data 
will be used as utility analysis and additional supportive analyses may be performed. 
 
Other sensitivity analyses may be performed on the primary endpoint to assess the robustness of 
the results based on the model used for primary analysis.  These analyses may include multiple 
imputation and pattern-mixture models for handling of missing data.  Details will be provided in 
the SAP.  The analyses will be performed according to the National Academy of Sciences (2010) 
guidelines.8 
13.4.3.2 Analyses for Secondary Endpoint 
The secondary endpoints will use the change in mean for analysis (as applicable): 
 
Additional categorical response analyses may be performed; additional details will be provided 
in the SAP. 
13.4.4 Safety and Tolerability Analyses 
All safety summaries will be descriptive; statistical significance tests may be performed on 
safety data that will be described in the SAP. 
 
Safety analyses will be conducted using data from the safety population (as defined in 
Section 13.3).  Safety variables include AEs, clinical laboratory values, body weight, vital signs, 
ECG readings, physical examination results, and dermal safety results.  No formal inferential 
analyses will be conducted for safety variables, unless otherwise noted. 
13.4.4.1 Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), 
Version 19. 
 
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with study drug through 
the Follow-up Visit or Early Termination Visit, whichever occurs first.  The number and 
percentage of subjects with AEs will be displayed for each treatment group by system 
organ class and preferred term.  Summaries of AEs by severity and relationship to study 
drug will also be provided.  Serious adverse events and AEs resulting in discontinuation 
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of study drug will be summarized separately in a similar manner.  Subject listings of AEs, 
SAEs, and AEs causing discontinuation of study drug will be produced. 
13.4.4.2 Concomitant Medications 
Prior and concomitant therapies will be summarized for the Safety population.  All prior and 
concomitant medications recorded in the eCRF will be coded to generic term and all matching 
Anatomic Therapeutic Classification (ATC) codes using the current version (2017) of WHO 
Drug.  Summaries will be prepared using the coded generic term.  All prior and concomitant 
medications recorded in the eCRF will be listed. 
13.4.4.3 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from Baseline values will be presented for clinical laboratory values for each 
treatment group at each time point. 
 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from Baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by study visit.  Pre- and post-treatment values will 
also be presented with an analysis of mean changes from Baseline. 
 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges.  Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
13.4.4.4 Vital Signs and Body Weight 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for body weight, body-mass index, systolic blood 
pressure, diastolic blood pressure, heart rate, and respiratory rate. 
 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges, will be tabulated showing change from Baseline (shift tables) for each parameter by 
treatment group and by study visit.  Pre- and post-treatment values may also be presented with an 
analysis of mean changes from Baseline. 
13.4.4.5 Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point.  
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Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (both correction methods), and 
HR for each treatment group at each time point. 
13.4.4.6 Physical Examination Findings 
The abnormal findings in the complete physical examination will be captured and analyzed as 
adverse events. 
13.4.4.7 Dermal Safety 
The number and percentage of subjects with findings related to dermal safety including adhesion, 
irritation, discomfort, and adhesive residue will be summarized.  A by-subject listing of 
individual dermal safety findings will also be provided. 
13.4.5 Pharmacokinetic Analyses 
Plasma concentrations of diclofenac (for both HP-5000
 and HP-5000
 will be 
evaluated and summarized as descriptive statistics by treatment. 
13.4.6 Interim Analysis 
No interim analyses are planned. 
13.5. Database 
The final database will be compliant with FDA Data Standard catalog from Electronic Common 
Technical Document / eCTD (May, 2015) and Providing Regulatory Submissions in Electronic 
Format - Standardized Study Data (July 2016). 
 
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14. STUDY CONDUCT 
The study will be conducted in accordance with all applicable regulatory requirements, including 
ICH GCP guidelines, subject privacy requirements, and the ethical principles that are outlined in 
the Declaration of Helsinki. 
 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles (see 
Section 15).  The sponsor reserves the right to withdraw a subject from the study (see 
Section 8.2.3), to terminate participation of a study site at any time, and/or to discontinue the 
study. 
 
Noven agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (see Section 17.2), the investigator indicates that he/she 
has carefully read the protocol, fully understands the requirements, and agrees to conduct the 
study in accordance with the procedures and requirements described in this protocol. 
 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including the April 1996 International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Guidance for Industry E6 Good Clinical Practice (GCP), and in agreement with the 2013 version 
of the Declaration of Helsinki.  While delegation of certain aspects of the study to sub-
investigators and study coordinators is appropriate, the investigator will remain personally 
accountable for closely overseeing the study and for ensuring compliance with the protocol and 
all applicable regulations and guidelines.  The investigator is responsible for maintaining a list of 
all persons that have been delegated study-related responsibilities (e.g., sub-investigators and 
study coordinators) and their specific study-related duties. 
 
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Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, study drugs, and their 
specific duties within the context of the study.  Investigators are responsible for providing Noven 
with documentation of the qualifications, GCP training, and research experience for themselves 
and their staff as required by the sponsor and the relevant governing authorities. 
 
To ensure compliance with the guidelines, the study may be audited by an independent person.  
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after the initiation visit has 
been conducted.  The investigator and the full study site staff must be available at this visit.  All 
staff must have an initiation visit before they conduct any study specific procedures. 
 
The study site will not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed consent form (ICF). 
2. All required regulatory documents have been submitted to and approved by the sponsor 
or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
 
Following the initiation visit, the study will be monitored as per clinical monitoring plan, or 
additional visit may occur when deemed necessary, while subjects are actively randomized into 
the study. 
14.2. Screen Failures 
Subjects who fail any of the inclusion and/or exclusion criteria may not be rescreened for the 
study.  In certain cases, and case-by-case basis, a subject may be rescreened once and permitted 
into the study following consultation with the Sponsor and Medical Monitor who must make an 
assessment that the subject is eligible to participate in the study. 
14.3. Study Documents 
All documentation and material provided by Noven or 
 for this study are to be 
retained in a secure location and treated as confidential material. 
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14.3.1 Investigator’s Regulatory Documents 
The regulatory documents are listed in the HP-5000-US-05 Study Manual.  All required 
regulatory documents must be received from the investigator and reviewed and approved by 
Noven or its designee before the study site can initiate the study and before Noven will authorize 
shipment of study drug to the study site.  Copies of the investigator’s regulatory documents must 
be retained at the study site in a secure location.  Additional documents, including a copy of the 
protocol and applicable amendments, the HP-5000 topical patch IB, eCRF completion 
guidelines, copies of regulatory references, copies of IRB correspondence, and study drug 
accountability records should also be retained as part of the investigator’s regulatory documents.  
It is the investigator’s responsibility to ensure that copies of all required regulatory documents 
are organized, current, and available for inspection. 
14.3.2 Case Report Forms 
By signing the Investigator’s Agreement (see Section 17.2), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign 
an ICF. 
 
Case report forms are considered confidential property of Noven and should be handled and 
stored accordingly.  The sponsor or its designee will provide the necessary training on the use of 
the specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit in a neat, legible manner to ensure accurate interpretation of data.  All 
requested information must be entered in the electronic data capture (EDC) system according to 
the completion guidelines provided by the sponsor or its designee.  The eCRFs must be signed 
by the investigator or a sub-investigator.  These signatures serve to attest that the information 
contained in the eCRF is accurate and true. 
14.3.3 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation.  Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records.  All source documents must be 
accessible for verification by the site monitor, auditor, and IRB for inspections and by the 
regulatory authority(ies).  Direct access to source documents must be guaranteed by the 
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investigator, sub-investigator, or study coordinator, who must provide support at all times for 
these activities.  Subject confidentiality will be protected at all times. 
 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory, to the sponsor or its designee.  A paper copy of the laboratory results 
will be provided to the study site and should be retained with each subject’s source data. 
14.4. Data Quality Control 
Noven and its designees will perform quality control checks on this clinical study. 
14.4.1 Monitoring Procedures 
Noven and/or its designee will monitor the study to ensure study is conducted in accordance with 
the protocol, GCP, and applicable regulations and guidelines.  The assigned clinical research 
associates (CRAs) will visit the investigator and study site at periodic intervals and maintain 
periodic communication.  It will be the CRA's responsibility to inspect the eCRFs at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
consistency and accuracy of the data being entered.  The investigator agrees to allow the CRAs 
and other authorized Noven personnel access.  The CRAs will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff.  While on site, the 
CRAs will review: 
• regulatory documents, directly comparing entries in the EDC system with the source 
documents 
• consenting procedures 
• laboratory test reports 
• other patient records and study documents 
• AE procedures, storage and accountability of study drug and study materials 
 
The CRA will ask for clarification and/or correction of any noted inconsistencies.  Procedures 
for correcting eCRF are described in the study manual.  As representatives of the sponsor, CRAs 
are responsible for notifying project management of any noted protocol deviations. 
 
By signing the Investigator’s Agreement (see Section 17.2), the investigator agrees: 
• to meet with the CRAs during study site visits; 
• to ensure that study staff is available to the CRAs as needed; 
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• to provide the CRAs access to all study documentation, to the clinical supplies 
dispensing and storage area; and 
• to assist the monitors in their activities, if requested 
Further, the investigator agrees to allow Noven or designee auditors or inspectors from 
regulatory agencies to review records, and to assist the inspectors in their duties, if requested. 
14.4.2 Data Management 
Noven or designee will be responsible for activities associated with the data management of this 
study.  The standard procedures for handling and processing records will be followed per GCP 
and 
 standard operating procedures.  A comprehensive data management plan 
will be developed including a data management overview, description of database contents, 
annotated eCRF, pre-entry review list, self-evident correction conventions, query contacts, and 
consistency checks. 
 
Study site personnel will be responsible for providing resolutions to all data queries.  The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data.  Procedures for soliciting and documenting resolution to data 
queries are described in the study manual. 
14.4.3 Quality Assurance/Audit 
Study sites, study database and study documentation may be subject to quality assurance audits 
during the course of the study by Noven or its designee.  Audits may be undertaken to check 
compliance with GCP guidelines, and can include: 
• site audits 
• TMF audits 
• database audits 
• document audits (e.g., protocol and/or CSR) 
 
Noven or its designee may conduct additional audits on a selection of study sites, which will 
require access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities clinical 
inspection according to GCP guidelines.  The investigator should agree to cooperate with the 
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auditor during the visit and will be available to supply the auditor with eCRFs or other study files 
necessary to conduct that audit or inspection.  Any findings will be strictly confidential. 
 
If a regulatory authority informs the investigator that it intends to conduct a clinical inspection, 
the investigator shall notify Noven immediately. 
14.5. Premature Termination of the Study  
The study may be prematurely terminated at Noven’s discretion at any time and for any reason.  
If the study is terminated or suspended, Noven will promptly inform the investigators/sites and 
the regulatory authority(ies) of the termination or suspension and the reason(s) for the 
termination or suspension.  The ethics committee will also be promptly informed and provided 
with the reason(s) for the termination or suspension by Noven or by the investigator/institution, 
as specified by the applicable regulatory requirement(s). 
 
Study Site Closure: 
At the end of the study, all study sites will be closed.  Noven may terminate participation of a 
study site at any time.  Examples of conditions that may require premature termination of a study 
site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.5.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until: 
• At least 2 years after the last marketing authorization for the study drug has been 
approved or the sponsor has discontinued its research with study drug, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
study drug 
 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or if needed by the sponsor. 
 
At the end of such period, the investigator shall notify the sponsor in writing of her/his intent to 
destroy all such material.  The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense.  
The final database will be archived by Noven according to the regulatory requirements. 
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14.5.2 Sample Retention 
Samples may be used for purposes related to this research.  The samples will be stored until the 
sponsor has determined that specimens are no longer needed and the decision has been made that 
none of the samples needs to be reanalyzed.  In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 
14.6. Amendments to the Protocol 
Modifications of the signed protocol are only possible by approved protocol amendments and 
with the agreement of all responsible persons.  The procedure for approval of a protocol 
amendment is identical to that for approval of the protocol.  The ethics committee must be 
informed of all protocol amendments and should be asked for its opinion as to whether a full re-
evaluation of the ethical aspects of the study is necessary by the committee.  This should be fully 
documented. 
 
The investigator must not implement any deviation from or change to the protocol without 
discussion with and agreement by Noven and prior review and documented approval/favorable 
opinion of the amendment from the relevant ethics committee, except where it is necessary to 
eliminate an immediate hazard to study subjects or where the change(s) involves only logistical 
or administrative aspects of the study (e.g., change in monitor(s), change of telephone number(s), 
etc.). 
 
Protocol amendments will be submitted to the appropriate authority(ies) as required by the 
applicable regulatory requirement(s). 
14.7. Clinical Study Report 
A final integrated clinical/statistical report will be prepared that is compliant with the ICH 
Harmonised Tripartite Guideline: Structure and content of clinical study reports. 
14.8. Use of Information and Publication 
All information concerning study drug, Noven’s operations, patent applications, formulae, 
manufacturing processes, basic scientific data, and formulation information supplied by Noven 
or its designee to the investigator and not previously published, is considered confidential and 
remains the sole property of Noven.  Case report forms also remain the property of Noven.  The 
investigator agrees to use this information for purposes of study execution through finalization. 
 
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The information developed in this study will be used by Noven in connection with the continued 
development of study drug and thus may be disclosed as required to other clinical investigators 
or government regulatory agencies. 
 
The information generated by this study is the property of Noven.  Publication or other public 
presentation of study drug data resulting from this study requires prior review and written 
approval of Noven.  Abstracts, manuscripts, and presentation materials should be provided to 
Noven for review at least 30 days prior to the relevant submission deadline. 
 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until Noven has reviewed and commented on such a 
presentation or manuscript for publication. 
14.9. Subject Insurance and Indemnity 
Noven will provide the insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study.  The terms of insurance will be kept in the 
study files. 
14.10. 
Data Protection 
Personal and sensitive personal data will be treated as confidential.  The results of the study will 
be made available for review by authorized representatives of Noven and/or submitted to one or 
more sponsor offices worldwide, the ethics committee, and regulatory authorities. 
 
Prior to the subject’s enrollment in the study, the subject’s consent is required for the data to be 
used for these purposes and to gain direct access to their medical records for data verification 
purposes. 
 
The subject must be assured that their identity will be protected.  To facilitate this, a unique 
identification code will be assigned by the investigator to each study subject.  This will be used 
instead of the subject’s name and cross-referenced with the subject’s date of birth when reporting 
AEs and /or other study-related data. 
 
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15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Ethical Conduct of the study 
The guidelines of the World Medical Association Declaration of Helsinki in its revised edition 
(64th General Assembly, Fortaleza, Brazil, October 2013), the April 1996 ICH guidelines (E6) 
of GCP (including archiving of essential study documents), as well as the demands of national 
drug and data protection laws and other applicable regulatory requirements, will be strictly 
followed.  Approval will be obtained from the appropriate regulatory authorities of participating 
country(ies) before sites are initiated. 
15.2. Subject Information and Informed Consent 
The investigator is responsible for ensuring that no subject is subject to any study-related 
examination or activity before that subject has given informed consent.  The subject must give 
written consent after the receipt of detailed information.  The verbal explanation will cover all 
the elements specified in the written information provided for the subject. 
 
The investigator will inform the subject of the aims, methods, anticipated benefits, and potential 
hazards of the study, including any discomfort it may entail.  The subject must be given every 
opportunity to clarify any points he/she does not understand and, if necessary, ask for more 
information.  At the end of the interview, the subject may be given time to reflect if this is 
required, or if the subject requests more time.  Subjects and/or legal guardian will be required to 
sign and date the informed consent form.  After completion, informed consent forms will be kept 
and archived by the investigator in the investigator's study file. 
 
It should be emphasized that the subject is at liberty to withdraw their consent to participate at 
any time, without penalty or loss of benefits to which the subject is otherwise entitled.  Subjects 
who refuse to give, or withdraw, written informed consent may not be included or continued in 
this study, but this will not impact on their subsequent care. 
15.3. Approval by Institutional Review Board  
For Investigational New Drug (IND) studies, the minimum standards of conduct and 
requirements for informed consent are defined in the FDA regulations.  Prior to initiation of the 
study at each study site, the protocol, the informed consent form(s), the subject information 
sheet(s), details of the subject recruitment procedures, and any other relevant study 
documentation will be submitted to the responsible local and/or national IRB and approved. 
 
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Written notification of approval is to be provided by the investigator to the sponsor’s monitor 
before shipment of investigational drug supplies, and will include the date of the committee’s 
approval and the chairperson’s signature.  This written approval must consist of a completed 
Noven form, IRB Approval Form, or written documentation from the IRB containing the same 
information. 
 
Protocol amendments must also be reviewed and approved by the IRB.  Written approval from 
the IRB, or a designee, must be received by Noven before implementation.  This written 
approval will consist of a completed IRB approval form or written documentation from the IRB 
containing the same information. 
 
The investigator will report promptly to the IRB any new information that may adversely affect 
the safety of subjects or the conduct of the study.  Similarly, the investigator will submit written 
summaries of the study status to the IRB annually, or more frequently if requested by the IRB.  
Upon completion of the study, the investigator will provide the IRB with a brief report of the 
outcome of the study, if required. 
15.4. Subject Insurance and Finance  
Noven will provide the insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study.  Details on finance and insurance will be 
provided in a separate agreement between the investigator and the sponsor. 
 
 
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16. REFERENCES
 
 
1  Barbour KE, Helmick CG, Theis KA, Murphy LB, Hootman JM, Brady TJ, Cheng YJ. 
Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United 
States, 2010-2012. MMWR 2013;62 (44):869-873. 
2  Centers for Disease Control and Prevention.  
https://www.cdc.gov/arthritis/data_statistics/index. htm. Accessed 24 June 2016. 
3  Investigational Brochure, Diclofenac Sodium Transdermal Drug Delivery System, HP-5000 
Transdermal Patch. Noven Pharmaceuticals, Inc. 
 
Edition No. 03, September 9, 2014. 
4  Berger, R.S., and .J.P. Bowman.  “A Reappraisal of the 21 -day Cumulative Irritation Test in 
Man." Toxicol. - (It. 6’ Ocz~lw Toxicol., 1982; l(2); 109- 115. 
5  Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW.  Validation study of 
WOMAC: a health status instrument for measuring clinically important patient relevant 
outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J 
Rheumatol. 1988;15:1833-1840. 
6  Bellamy N. Pain assessment in osteoarthritis:  experience with the WOMAC osteoarthritis 
index. Semin Arthritis Rheum. 1989;18:14-17. 
7  Chan AT, Manson JE, Albert CM, et al.  Nonsteroidal anti-inflammatory drugs, 
acetaminophen, and the risk of cardiovascular events. Circulation. 2006;113(12):1578-1587. 
8  National Research Council (US) Panel on Handling Missing Data in Clinical Trials.  The 
prevention and treatment of missing data in clinical trials. Washington (DC):  National 
Academies Press (US); 2010. 
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17. ATTACHMENTS
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17.1. Schedule of Events 
Phase 
Screening 
Double-blind Treatment 
Follow-
up 
End of 
Treatment 
Period 
 
Washout 
Baseline 
 
 
 
 
 
 
 
 
Week 
-1 
 
 
1 
2 
3 
4 
5 
 
Clinic visit 
1 
 
2 
 
3 
 
4 
 
5 
 
 
Phone visit 
 
1 
 
 
 
 
 
 
 
2 
 
Study Day 
-28 to -14k 
-25 to -1k 
0 
1 to 6 
7 
8 to 13 
14 
15 to 27 
28 
35 
 
Visit Window (Days) 
 
 
 
 
±2 
 
±2 
 
±2 
±2 
 
Assessments/Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
 
X 
 
 
 
 
 
 
 
 
Randomization (IVRS)a 
 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
X 
Vital signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
X 
 
X 
WOMAC Painc 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient Global Assessment 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient Global Impression 
of Change 
 
 
 
 
X 
 
X 
 
X 
 
X 
Pain Intensity 11-Point 
NRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense Rescue 
Medication 
X 
 
X 
 
X 
 
X 
 
 
 
 
Use of Rescue Medicationd 
 
X 
Xd 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECGe 
X 
 
X 
 
 
 
 
 
X 
 
X 
Clinical Laboratory 
(Hematology,  biochemistry 
& urinalysis)f 
Xf 
 
Xf 
 
 
 
 
 
X 
 
X 
Fasting Glucose & Lipidsg 
X 
 
X 
 
 
 
 
 
X 
 
X 
Urine Pregnancy Test 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Drug  Screen 
X 
 
X 
 
 
 
 
 
 
 
 
Alcohol Test 
X 
 
X 
 
 
 
 
 
 
 
 
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Phase 
Screening 
Double-blind Treatment 
Follow-
up 
End of 
Treatment 
Period 
 
Washout 
Baseline 
 
 
 
 
 
 
 
 
Week 
-1 
 
 
1 
2 
3 
4 
5 
 
Clinic visit 
1 
 
2 
 
3 
 
4 
 
5 
 
 
Phone visit 
 
1 
 
 
 
 
 
 
 
2 
 
Study Day 
-28 to -14k 
-25 to -1k 
0 
1 to 6 
7 
8 to 13 
14 
15 to 27 
28 
35 
 
Visit Window (Days) 
 
 
 
 
±2 
 
±2 
 
±2 
±2 
 
Assessments/Procedures 
 
 
 
 
 
 
 
 
 
 
 
PK Blood Sample 
 
 
 
 
 
 
X 
 
X 
 
X 
Subject eDiaryh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study Medication 
Applicationi 
 
 
 
Xh 
X 
X 
X 
X 
 
 
 
Dermal Evaluationsj 
 
 
X 
Xl 
X 
Xl 
X 
Xl 
X 
 
X 
Prior/Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsm 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X-Rayn 
X 
 
 
 
 
 
 
 
 
 
 
Drug Accountability 
 
 
Xo 
 
X 
 
X 
 
X 
 
X 
 
Abbreviations: AE = adverse event; ET = early termination; ECG = electrocardiogram; ID = identification; I/E = inclusion/exclusion; IVRS = interactive voice 
response system; NRS = numeric rating scale; PK = pharmacokinetic; WOMAC = Western Ontario and McMaster Universities Arthritis Index. 
 
a. 
Subjects will be randomized to HP-5000
, HP-5000-
, or placebo in a 1:1:2 ratio. 
b. Vital signs, including heart rate, respiratory rate, and a supine blood pressure will be measured after the subject has been in a supine position for 5 minutes. 
c. 
WOMAC Total Pain Score will include WOMAC pain intensity, WOMAC stiffness, and WOMAC physical function. 
d. Rescue medication may be used during the Washout Period except within 2 calendar days prior to Visit 2 and within 1 day prior to each subsequent visit. 
e. 
A standard 12-lead electrocardiogram (ECG) will be performed after the subject has been supine for at least 5 minutes. 
f. 
Clinical laboratory testing includes hematology, biochemistry, and urinalysis. Results from laboratory testing done at Screening Visit will be used for 
confirmation of subject eligibility at Baseline Visit. 
g.  Fasting glucose and lipids should be performed after 8 to 10 hours of fasting.  Subject must be instructed to fast for 8 to 10 hours (no food or drink, except 
for water) before coming for the Baseline assessments, if not done at Screening. 
h 
Subjects will be instructed on how to use of the electronic diary (eDiary) at the Screening Visit.  For each 28-day administration period, subjects will be 
asked to record their NRS score, their intake/use of study drug and rescue medication in the eDiary. 
i. 
Study treatment will be applied on Day 1 of the Double-blind Treatment Phase.  Instructions for application and removal of study drug patches will be 
provided to the subject at the Baseline Visit (V2). 
j. 
Dermal evaluations will assess skin adhesion, irritation, discomfort, and adhesive residue. 
k.   Screening/Washout Period should be up to 28 days.  Washout Period can be initiated 3 days after Screening Visit. 
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l.    During the Double-blind Treatment Phase, subjects will report the incidence of patch detachment by answering Yes or No and will perform dermal 
assessments daily at home. 
m.   AEs will be collected starting from the first administered dose. 
n. Historical X-rays done within one year prior to the Screening Visit are acceptable.  If subject does NOT have any X-Ray done within the past year, a 
mandatory new X-Ray to confirm the disease will have to be performed prior to starting the Washout Period. 
o. Only for rescue medication. 
 
Note:  
 should be administered at the Screening and Baseline Visits after the subject has been consented and 
passed all the eligibility criteria defined in the protocol first.
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17.2. Investigator’s Agreement 
PROTOCOL 
NUMBER: 
HP-5000-US-05 
PROTOCOL TITLE: 
A 4-week, Randomized, Double-blind, Multicenter, Placebo-controlled 
Phase 2 Study to Evaluate the Efficacy and Safety of HP-5000 in 
Subjects with Osteoarthritis (OA) of the Knee 
 
FINAL PROTOCOL: 
 
Amendment #2: 12 January 2018 
I have read this protocol and agree to conduct this clinical study as outlined herein. I will ensure 
that all sub-investigators and other study staff members have read and understand all aspects of 
this protocol. I agree to cooperate fully with Noven during the study. I will adhere to all FDA, 
ICH, and other applicable regulations and guidelines regarding clinical trials on an IP during and 
after study completion. 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
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18. APPENDICES 
18.1. Western Ontario and McMaster Universities Osteoarthritis (WOMAC) LK3.1 Index  
This is an example of the WOMAC index. The actual index will be provided in the eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
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18.2. Patient Global Assessment Scale (PGA) 
This is a sample questionnaire.  The actual questionnaire will be provided in the study reference 
manual.  
The subject will provide their overall impression of the status of their OA in the target knee on a 
5-point scale where 0 = “Very Good” and 4 = “Very Poor.” 
Subjects will be asked to complete the following statement:  “How would you rate your 
osteoarthritis condition over the last 24 hours?” The response options include the following: 
1. Very Good 
2. Good 
3. Moderate 
4. Poor 
5. Very Poor 
18.3. Patient Global Impression of Change Scale  
This is an example of the Patient Global Impression of Change (PGIC) scale. The actual 
instrument will be included in the study reference manual. 
The Patient Global Impression of Change is a self-administered instrument that measures change 
in subjects’ overall improvement with treatment on a scale where 1 = “very much improved” and 
7 = “very much worse.” Subjects will be asked the following question: “How would you rate 
your overall improvement with treatment during the clinical trial?” The response options include 
the following: 
 
Very Much Improved 
1 
 
Much Improved 
2 
 
Minimally Improved 
3 
 
No Change 
4 
 
Minimally Worse 
5 
 
Much Worse 
6 
 
Very Much Worse 
7 
 
18.4. 11-Point Numeric Rating Scale (NRS) 
This is a sample of the Numerical Rating Scale. Please use the rating scale provided in the study 
reference manual. 
 
Instructions:  Show the pain scale to the subject and explain that on the 0 to 10 pain rating scale, 
0 means no pain and 10 means the worst possible pain. A value in the middle of the scale 
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(around 5) would be moderate pain; a value of 2 or 3 would be mild pain and a value of 7 or 
higher is considered severe pain. 
Ask the subject the following question: “On a scale of 0 – 10, with 0 being ‘no pain’ and 10 
being the ‘worst possible pain’, how would you rate your pain over the last 24 hours?” 
The intent of the question is to gain an understanding of the intensity of the subject’s target knee 
pain at over the last 24 hours. 
 
 
No Pain 
Worst Possible Pain 
 
Adapted from: Farrar JT, Young JP, La Moreaux L, Werth JL, and Poole MR: Clinical importance 
of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94 
(2001) 149–158Regulations and Good Clinical Practice Guidelines. 
18.4.1 Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
18.4.2 Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
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(hysterectomy or tubal ligation), confirmed to be postmenopausal (having 
amenorrhea for ≥12 months), or has had a hysterectomy with or without 
bilateral oophorectomy at least 6 months prior to the Screening Visit. 
7. Able to swallow and tolerate rescue medication with APAP (moderately sized 
tablets). 
8. Be reliable, willing, and able to cooperate with all study procedures including the 
following: 
a. 
Accurately fill out the diary on a daily basis. 
b. Return for study visits on the required dates. 
c. 
Accurately and reliably report symptoms (including treatment-emergent signs 
and symptoms). 
d. Use the patch as required by protocol. 
 
Exclusion criteria:  
1. Body mass index (BMI) > 40 
2. The non-target knee pain severity score is 
 at Screening 
or Baseline (Day 0) Visit. 
3. Any subject who disobeyed the restriction of prohibited therapies (e.g., rescue 
medication) during Screening/Washout Period. 
4. Secondary OA of the knee (rheumatoid arthritis, gout, psoriasis, syphilitic 
neuropathy, ochronosis, metabolic or other primary bone disease or acute trauma). 
5. Clinically significant elevation of serum creatinine (176.8 μmol/L), aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) (3 x upper limit of 
normal [ULN]). 
6. Known allergy or hypersensitivity to the use of diclofenac, 
 
 
, ethanol, acetylsalicylic acid (aspirin [ASA]), or any other 
NSAID. 
7. Severe, uncontrolled cardiac, renal, hepatic or other systemic disease. 
8. A documented (upper gastrointestinal [GI] series or endoscopy) gastroduodenal 
ulcer or any GI bleeding (except hemorrhoidal) within 6 months prior to 
Screening Visit. 
9. Documented history of alcohol or drug abuse within 1 year prior to study entry or 
positive alcohol/drug screen findings at Screening or Baseline. 
10. Presence of chondrocalcinosis on X-ray if associated with a history of pseudogout 
or inflammatory flare-ups. 
11. MAJOR SURGERY:  Previous damage or surgery to the target knee at any time 
(i.e., damage/reconstruction of the anterior or posterior cruciate ligaments). 
12. MINOR SURGERY on the target knee defined as anything other than major 
surgery (as defined above) for less than 1 year before study enrollment. 
13. Current treatment with oral, topical, intra-articular, or intra-muscular 
corticosteroids on the target knee within 90 days of Screening Visit or into any 
other joint within 30 days of screening. 
14. Any subject who had received intra-articular viscosupplementation (e.g., 
Synvisc®) in the target knee 90 days prior to Screening Visit. 
15. Any subject who had used opioids 7 days prior to the Screening Visit. 
16. Any subject who had previous exposure to HP-5000. 
17. Any subject whose participation would conflict with contraindications, warnings 
or precautions as stated in the prescribing information for oral or topical 
diclofenac (e.g., any subject taking ACE inhibitors, cyclosporine, diuretics, 
lithium, or methotrexate – refer to Investigator Brochure for prescribing 
information). 
18. Use of another investigational drug within 30 days prior to study entry. 
19. Any subject with resolved, ongoing, or pending litigation or disability related to 
any health-related cause. 
20. Any subject with fibromyalgia. 
21. Any painful or disabling conditions affecting the knees or legs. 
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significance will be 2-sided, and a difference resulting in a P value of <0.05 will be 
considered statistically significant. 
 
For analyses involving study site, if the number of subjects per site is small, sites may 
be pooled for analysis, or omitted from statistical models.  The final determination will 
be made prior to database lock. 
 
Summary statistics will be provided for the variables described below.  For continuous 
variables, these statistics will typically include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum.  For categorical variables, these 
statistics will typically include the number and percentage of subjects in each 
category. 
 
Analysis Populations  
 
Intent-to-Treat (ITT):  Will include all consented and randomized subjects.  
Regardless of any protocol deviations, analyses performed on the ITT set will 
be based on the randomized treatment assignment and all available data. 
 
 
Full Analysis Set (FAS):  Will include all randomized subjects who have had 
at least 1 patch of double-blind study drug applied and who have a Baseline 
WOMAC pain score and at least 1 post-baseline assessment of the primary 
efficacy measure (WOMAC pain score).  Evaluable subjects will be defined 
as those who meet the FAS definition.  The FAS will be used as the primary 
set for analysis of efficacy endpoints based on randomized treatment 
assignment. 
 
 
Safety Analysis Set (SAF):  Will include all subjects who have had at least 1 
patch of double-blind study medication applied and who have at least 1 post-
dose safety measurement during the double-blind Treatment Phase.  In the 
unlikely event that errors may have occurred in treatment arm assignments, 
then analyses using the SAF will be based on treatment actually received.  
The SAF will be used for the analysis of dermal evaluations and safety 
endpoints. 
 
 
Pharmacokinetic Analysis Set (PAS):  Will include all subjects who have 
received at least 1 dose of study drug during the double-blind treatment phase 
and have at least 1 blood sample for pharmacokinetic (PK) assessment.  
Subjects may be excluded from the PAS set if they significantly violate 
inclusion or exclusion criteria, significantly violate the protocol in a way that 
may influence the PK analysis, if any unexpected error occurs during the 
study that may influence the PK analysis (e.g., early detachment of 
transdermal systems, apparent sample switching, etc.) or if their data are 
unavailable or incomplete.  The PAS will be used for the analysis with 
model-based approach.  Excluded cases will be documented together with the 
reason for exclusion. 
 
Primary Efficacy Analysis:  The primary efficacy endpoint of this study is the 
change from Baseline to Week 4 in the WOMAC pain score; the primary analysis set 
is the FAS.  The comparisons of interest are: 
 
HP-5000
 versus placebo 
 
HP-5000
 versus placebo 
 
The estimand in the primary analysis for efficacy for each dose is the difference 
between treatments groups (HP-5000 dose group vs. placebo) in the change from 
Baseline to Week 4 in WOMAC pain score in all subjects as randomized, under the 
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approximately 300.  A sufficient number of subjects will be screened to randomize the 
proposed sample size. 
STUDY TREATMENT 
DURATION 
The maximum treatment duration for each subject is 4 weeks.  The total duration of 
study participation for each subject is approximately 9 weeks. 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES .....................................................................................................................2 
2. 
SYNOPSIS .................................................................................................................................................3 
Analysis of PK: .................................................................................................................................8 
3. 
TABLE OF CONTENTS .........................................................................................................................10 
4. 
LIST OF ABBREVIATIONS...................................................................................................................15 
5. 
INTRODUCTION ....................................................................................................................................16 
5.1. Background and Rationale ..............................................................................................................16 
5.2. Clinical Experience .........................................................................................................................17 
5.3. Summary of Potential Risks and Benefits .......................................................................................19 
6. 
OBJECTIVES ...........................................................................................................................................20 
6.1. Primary Objectives ..........................................................................................................................20 
6.2. Secondary Objectives ......................................................................................................................20 
7. 
STUDY DESIGN .....................................................................................................................................21 
7.1. Overall Study Design and Plan - Description .................................................................................21 
7.2. Discussion of Study Design ............................................................................................................25 
7.3. Study Sites .......................................................................................................................................25 
8. 
SUBJECT POPULATION .......................................................................................................................26 
8.1. Selection of Study Population .........................................................................................................26 
8.2. Study Entry Criteria ........................................................................................................................26 
8.2.1 Inclusion Criteria .................................................................................................................26 
8.2.2 Exclusion Criteria ................................................................................................................27 
8.2.3 Premature Subject Withdrawal ............................................................................................29 
8.3. Subject Replacement Criteria ..........................................................................................................30 
9. 
TREATMENTS ........................................................................................................................................31 
9.1. Identification of Investigational Product .........................................................................................31 
9.1.1 Labeling ...............................................................................................................................31 
9.1.2 Packaging ............................................................................................................................31 
9.2. Treatments Administered ................................................................................................................32 
9.3. Dispensing and Storage ...................................................................................................................32 
9.4. Method of Assigning Subjects to Treatment Groups ......................................................................32 
9.5. Blinding and Unblinding Treatment Assignment ...........................................................................33 
9.6. Selection of Doses and Administration in the Study ......................................................................34 
9.7. Dose Adjustment Criteria ................................................................................................................34 
9.8. Drug Accountability ........................................................................................................................34 
9.9. Treatment Compliance ....................................................................................................................35 
9.10. Permitted and Prohibited Therapies ................................................................................................37 
9.10.1 Permitted Therapies .............................................................................................................37 
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9.10.2 Prohibited Therapies ............................................................................................................37 
9.11. Treatment after End of Study ..........................................................................................................38 
10. STUDY PROCEDURES ..........................................................................................................................39 
10.1. Study Periods and Visits .................................................................................................................39 
10.1.1 Screening/Washout Period ..................................................................................................39 
10.1.1.1 Screening Period .....................................................................................................39 
10.1.1.2 Washout Period .......................................................................................................40 
10.1.2 Baseline Visit (Day 0) .........................................................................................................40 
10.1.3 Double-blind Treatment Phase ............................................................................................41 
10.1.4 Follow-up Visit ....................................................................................................................43 
10.1.5 Early Termination Visit (if applicable) ...............................................................................43 
10.1.6 Overall Study Schedule .......................................................................................................43 
10.2. Assessments ....................................................................................................................................44 
10.2.1 Efficacy ...............................................................................................................................44 
10.2.1.1 Western Ontario and McMaster Universities Osteoarthritis Index .........................44 
10.2.1.2 Patient Global Assessment ......................................................................................45 
10.2.1.3 Patient Global Impression of Change .....................................................................45 
10.2.1.4 Numeric Rating Scale .............................................................................................46 
10.2.1.5 Use of Rescue Medication ......................................................................................46 
10.2.2 Safety ...................................................................................................................................46 
10.2.2.1 Laboratory Safety Assessments ..............................................................................47 
10.2.2.2 Clinical Examinations .............................................................................................48 
10.2.2.3 Adverse Events........................................................................................................49 
10.2.2.4 Evaluations of Patch and Dermal Assessment ........................................................49 
10.2.3 Pharmacokinetic Assessments .............................................................................................51 
11. ADVERSE EVENTS................................................................................................................................52 
11.1. Definitions .......................................................................................................................................52 
11.1.1 Adverse Events ....................................................................................................................52 
11.1.2 Unexpected Adverse Event .................................................................................................53 
11.1.3 Serious Adverse Events .......................................................................................................53 
11.2. Management of Adverse Events .....................................................................................................54 
11.2.1 Collection ............................................................................................................................54 
11.2.2 Evaluation ............................................................................................................................54 
11.2.2.1 Severity of Adverse Events .....................................................................................54 
11.2.2.2 Seriousness ..............................................................................................................55 
11.2.2.3 Action Taken ...........................................................................................................55 
11.2.2.4 Outcome at the Time of Last Observation ..............................................................55 
11.2.2.5 Adverse Event Relationship to Investigational Product..........................................55 
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11.2.3 Documentation ....................................................................................................................56 
11.2.4 Treatment of Adverse Events ..............................................................................................56 
11.2.5 Follow-up ............................................................................................................................57 
11.2.6 Reporting of Adverse Events ..............................................................................................57 
11.2.6.1 Serious Adverse Events...........................................................................................57 
11.2.6.2 Nonserious Adverse Events ....................................................................................59 
11.2.7 Adverse Events of Special Interest ......................................................................................59 
11.2.8 Pregnancy Reporting ...........................................................................................................60 
12. DATA SAFETY MONITORING BOARD .............................................................................................62 
13. STATISTICAL METHODS .....................................................................................................................63 
13.1. Study Endpoints ..............................................................................................................................63 
13.1.1 Primary Efficacy Endpoint ..................................................................................................63 
13.1.2 Secondary Efficacy Endpoints ............................................................................................63 
13.1.3 Safety Endpoints ..................................................................................................................63 
13.1.4 Pharmacokinetics Endpoint .................................................................................................63 
13.2. Sample Size Determination .............................................................................................................63 
13.3. Analysis Populations .......................................................................................................................64 
13.4. Statistical Analyses .........................................................................................................................65 
13.4.1 Study Subjects and Demographics ......................................................................................65 
13.4.1.1 Disposition and Withdrawals ..................................................................................65 
13.4.1.2 Protocol Deviations .................................................................................................65 
13.4.1.3 Demographics and Other Baseline Characteristics .................................................65 
13.4.2 Exposure and Compliance ...................................................................................................66 
13.4.3 Efficacy Analyses ................................................................................................................66 
13.4.3.1 Primary Analysis .....................................................................................................66 
13.4.3.2 Analyses for Secondary Endpoint ...........................................................................67 
13.4.4 Safety and Tolerability Analyses ........................................................................................67 
13.4.4.1 Adverse Events........................................................................................................67 
13.4.4.2 Concomitant Medications .......................................................................................68 
13.4.4.3 Clinical Laboratory Evaluations .............................................................................68 
13.4.4.4 Vital Signs and Body Weight ..................................................................................68 
13.4.4.5 Electrocardiograms .................................................................................................69 
13.4.4.6 Physical Examination Findings ...............................................................................69 
13.4.4.7 Dermal Safety..........................................................................................................69 
13.4.5 Pharmacokinetic Analyses ..................................................................................................69 
13.4.6 Interim Analysis ..................................................................................................................69 
13.5. Database ..........................................................................................................................................69 
14. STUDY CONDUCT .................................................................................................................................70 
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14.1. Sponsor and Investigator Responsibilities ......................................................................................70 
14.1.1 Sponsor Responsibilities .....................................................................................................70 
14.1.2 Investigator Responsibilities ...............................................................................................70 
14.1.3 Site Initiation .......................................................................................................................71 
14.2. Screen Failures ................................................................................................................................71 
14.3. Study Documents ............................................................................................................................71 
14.3.1 Investigator’s Regulatory Documents .................................................................................72 
14.3.2 Case Report Forms ..............................................................................................................72 
14.3.3 Source Documents ...............................................................................................................72 
14.4. Data Quality Control .......................................................................................................................73 
14.4.1 Monitoring Procedures ........................................................................................................73 
14.4.2 Data Management ................................................................................................................74 
14.4.3 Quality Assurance/Audit .....................................................................................................74 
14.5. Premature Termination of the Study ...............................................................................................75 
14.5.1 Record Retention .................................................................................................................75 
14.5.2 Sample Retention ................................................................................................................76 
14.6. Amendments to the Protocol ...........................................................................................................76 
14.7. Clinical Study Report ......................................................................................................................76 
14.8. Use of Information and Publication ................................................................................................76 
14.9. Subject Insurance and Indemnity ....................................................................................................77 
14.10. 
Data Protection ....................................................................................................................77 
15. ETHICAL AND LEGAL CONSIDERATIONS ......................................................................................78 
15.1. Ethical Conduct of the study ...........................................................................................................78 
15.2. Subject Information and Informed Consent ....................................................................................78 
15.3. Approval by Institutional Review Board ........................................................................................78 
15.4. Subject Insurance and Finance ........................................................................................................79 
16. REFERENCES .........................................................................................................................................80 
17. ATTACHMENTS .....................................................................................................................................81 
17.1. Schedule of Events ..........................................................................................................................82 
17.2. Investigator’s Agreement ................................................................................................................84 
18. APPENDICES ..........................................................................................................................................85 
18.1. Western Ontario and McMaster Universities Osteoarthritis (WOMAC) LK3.1 Index ..................85 
18.2. Patient Global Assessment Scale (PGA).........................................................................................86 
18.3. Patient Global Impression of Change Scale ....................................................................................86 
18.4. 11-Point Numeric Rating Scale (NRS) ...........................................................................................86 
18.4.1 Regulations ..........................................................................................................................87 
18.4.2 Good Clinical Practice Guidelines ......................................................................................87 
 
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LIST OF FIGURES 
Figure 1 
Study Design ..................................................................................................................... 24 
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4. LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APAP 
acetaminophen  
ASA 
acetyl salicylic acid 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CRA 
clinical research associate 
CRO 
contract research organization  
 
 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
institutional review board 
ITT 
intent-to-treat 
IVRS 
interactive voice response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OTC 
over the counter 
PK 
Pharmacokinetics 
PAS 
pharmacokinetic analysis set 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
standard deviation 
TDDS 
transdermal drug delivery system  
ULN 
upper limit of normal 
WOMAC 
West Ontario and McMasters Universities Osteoarthritis Index 
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5. INTRODUCTION 
5.1. Background and Rationale 
An estimated 52.5 million adults (22.7% of the population)1 in the United States (US) have 
doctor-diagnosed osteoarthritis (OA); 22.7 million (9.8% of all adults) have arthritis and 
arthritis-attributable activity limitations.  Based on these data, it is projected that 78 million 
(26%) adults aged 18 years or older will have doctor-diagnosed arthritis by the year 2040.2  
Patients with arthritis are encouraged to be active, since it has been shown that exercise and 
activity help to decrease pain associated with OA, improve function, and delay disability.  
However activity and exercise are often limited by the pain associated with arthritis, and this 
pain may become part of a cycle of inactivity and weight gain that tends to perpetuate the 
stiffness and disability associated with OA.  Additionally, oral medications used over time may 
cause gastrointestinal (GI) distress and interfere with the blood-clotting cycle.  Opioid 
medications often lose their effectiveness with chronic use and require increasing dosages; 
patients may also become dependent on their opioid pain reliever, thereby introducing additional 
health problems into the equation.  There is an unmet need for a safe, reliable, and effective pain 
medication without the risk and lack of efficacy associated with those currently available. 
 
Diclofenac sodium is from the phenylacetic acid class of nonsteroidal anti-inflammatory drug 
(NSAIDs) developed by Ciba Geigy Co., Ltd., Switzerland, in 1965.  In the US, diclofenac 
sodium is available in various dose forms, including tablet, eye drop, extended-release tablet, gel, 
patch, capsule, and solution.  The mechanism of action of NSAIDs is not completely understood 
but may be related to prostaglandin synthetase (cyclooxygenase [COX]-1 and COX-2) inhibition. 
 
Noven Pharmaceuticals, Inc. has started the development of a formulation of diclofenac sodium 
for topical administration via a transdermal patch system, the HP-5000 for the treatment of pain 
of OA of the knee(s).  The topical HP 5000 patch will provide patients with OA with another 
treatment option that may have potential benefits compared with the existing formulations, as 
follows: 
 Transfer of drug into the treatment target area resulting in lower systemic and GI 
exposure when compared to orally administered diclofenac sodium and a possible 
reduction of systemic side effects including GI ulcers/lesions and adverse reactions such 
as nausea, vomiting, dyspepsia, and stomach pain. 
 Improvement of compliance with 
 compared with existing topical 
formulations and use by patients who have difficulty swallowing oral preparations. 
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5.2. Clinical Experience 
To date, the HP-5000 development program includes 
 
  These studies have been completed 
with various formulations of the diclofenac transdermal drug delivery system (TDDS), 
evaluating the PK and tolerability in 104 healthy volunteers.  The lead formulations for this 
program, HP 5000 
 and HP 5000 
 both of which contain 
 
diclofenac sodium 
 with a patch size of 
 
 were selected based on the diclofenac 
pharmacokinetic profile and patch performance characteristics, such as irritation and adhesion on 
the mobile knee joint application site. 
 
It should be noted that the HP 5000 
formulation is also being developed 
 by Noven’s 
parent company, 
 for different 
 indications 
(i.e., 
 and 
 and is referred to as the 
 (also known as 
.  Study 
 has been included in the development program to provide 
additional safety data.  
 
 
 
The phase 1 studies performed on healthy volunteers are as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. OBJECTIVES 
6.1. Primary Objectives 
 To evaluate efficacy of HP-5000 in subjects with osteoarthritis of the knee compared to 
placebo. 
 To evaluate the safety and tolerability of HP-5000 compared to placebo. 
6.2. Secondary Objectives 
The secondary objectives of this study are: 
 To evaluate skin irritation, discomfort, adhesion, and adhesive residue following 
administration of HP-5000. 
 To determine the plasma concentrations of diclofenac following administration of HP-
5000. 
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7. STUDY DESIGN 
7.1. Overall Study Design and Plan - Description 
This is a 4-week, randomized, double-blind, multicenter, placebo-controlled phase 2 study to 
evaluate the efficacy, safety and tolerability of HP-5000 compared with that of placebo in the 
treatment of OA.  The study will run for approximately 9 weeks comprised of up to a maximum 
of 28-day Screening Phase that will include a Washout Period of up to a maximum 14 days, a 4-
week Treatment Phase, and a 1-week Follow-up Period.  Subjects will be randomly assigned to 
receive 
 one of the following 3 treatments in a 1:1:2 ratio:  HP-5000
 
 HP-5000-
 
 or placebo patch, respectively.  The placebo patch will be identical in appearance 
to the 2 HP-5000 active patches.  The total number of subjects randomized in the study and 
included in the primary analysis will be approximately 300. 
 
The duration of double-blind treatment is expected to be 4 weeks and the total time in the study 
will be approximately 9 weeks. 
 
 Screening/Washout Period: Visit 1 (up to 28 Days): Screening and start of baseline 
diary (BL): After signing the informed consent, the Screening Phase will begin.  Subjects 
whose preliminary entry criteria have been met will be contacted by the site via telephone 
starting from Day -25 and will be instructed to begin the Washout Period for 7 to a 
maximum of 14 days prior to start the Baseline Visit.  Subjects will receive instruction on 
how to use of the patient diary.  Subjects should complete the patient diary every day 
during the Washout Period and record pain severity of their target knee and rescue 
medication usage from the day of Screening Visit to the day of the Baseline Visit.  The 
mean score of the last 3 consecutive days immediately prior to the Baseline Visit will be 
calculated for subjects to be considered eligible for study participation.  During the 
Washout Period, rescue medication (acetaminophen [APAP]) will be permitted (a 
maximum of 2 g/day) except within 2 calendar days prior to the Baseline Visit (i.e., 
rescue medication is prohibited from Day-2 until clinic visit on Day 0). 
 
 Baseline Visit: Visit 2 (0 Day):  Subjects will be reevaluated according to the inclusion 
and exclusion criteria and the average patient diary pain score will be calculated.  Those 
subjects who continue to meet all of the inclusion criteria, none of the exclusion criteria, 
who have completed the patient diary for at least 3 consecutive days immediately prior to 
Baseline Visit, and whose average pain score is at least 5 will be randomized to receive 
one of 2 formulation of HP-5000 or placebo. 
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 Double-blind Treatment Phase:  On Day 1 of the Treatment Phase, subjects will start 
applying their assigned patch for 4 Weeks (from Week 5 through 8):  Subjects will be 
randomized to receive either HP-5000
 patch, HP-5000
 patch, or placebo 
patch.  Dose modifications will NOT be permitted.  Subjects who cannot tolerate their 
designated study drug dose will be withdrawn from the study. 
 
 Follow-up Period: Visit 6 (Week 9):  After the 4-week Treatment Phase, the study 
center will conduct a follow-up phone call for safety monitoring or based on the 
investigator’s judgment, a subject may return to the study center for the safety Follow-up 
Visit. 
 
All subjects will be contacted by phone between visits to assess AEs, general well-being, provide 
visit reminders, and reinforce diary record and treatment compliance.  Dose modifications will 
NOT be permitted and study procedures will be reinforced. 
 
At each study visit, subjects will undergo efficacy and safety evaluations.  Efficacy evaluations 
will include the change from baseline values in the Western Ontario and McMaster Universities 
(WOMAC) LK3.1 OA index for pain, stiffness, physical function, and composite score, the 
Patient Global Assessment, the Patient Global Impression of Change, and pain intensity assessed 
on an 11-point NRS and the subjects’ use of rescue medication. 
 
Safety evaluation will include collection of AEs, physical examination findings, vital sign 
measurements, electrocardiogram (ECGs), clinical laboratory test results, and body weight.  All 
AEs observed by the study personnel or reported by the subject during the study (from the time 
of study drug administration through the post treatment visit) will be documented. 
 
Dermal characteristics will be assessed by 5-point numerical scale of adhesion, Berger and 
Bowman scale of Irritation, 5-point numerical scale of Discomfort, and 5-point numerical scale 
of Adhesive Residue.4  In addition, subjects will record the 
 patch application and removal 
times in electronic diaries along with any incidence of patch detachment. 
 
Plasma pharmacokinetic sampling will be performed as scheduled.  Plasma concentrations of 
diclofenac will be assessed by venous blood sampling on Day 14 and 28 (or at the Early 
Termination Visit).  Study center personnel will also assess study drug and diary compliance. 
 
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Figure 1 presents a schematic view of the study design. 
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7.2. Discussion of Study Design 
The double-blind, placebo-controlled study uses 3 patches 
 HP-5000 and 
placebo) of identical appearance to ensure blinding.  The total duration of study drug exposure 
will be approximately 4 weeks.  The safety evaluation will be performed one week after the last 
dose. 
 
The use of rescue medication is prohibited within 2 calendar days prior to the Baseline Visit and 
within 1 calendar day prior to clinic visits during the Treatment Phase, thus ensuring the integrity 
of the assessments. 
7.3. Study Sites 
The study will take place at approximately 
 sites in the US.  Each site is anticipated to screen a 
sufficient number of subjects to be able to randomize an aggregate number of approximately 
300 subjects. 
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8. SUBJECT POPULATION 
8.1. Selection of Study Population  
The study will enroll up to 300 subjects in a 1:1:2 ratio (HP-5000
 HP-5000
 
Placebo) with osteoarthritis of the knee.  The pain should have been stable over the previous six 
months prior to Screening (Visit 1). 
 
A screening log of potential study candidates and/or an enrollment log of enrolled subjects must 
be maintained at each study site. 
8.2. Study Entry Criteria 
All subjects being considered for participation in this study must meet all the inclusion criteria 
and none of the exclusion criteria. 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if he or she meets all of the following criteria: 
1. Provide written informed consent, prior to entering the study or undergoing any study 
procedures. 
2. Male or female aged 40 to 85 years with a clinical diagnosis of OA of the target knee 
according to the American College of Rheumatology (ACR) criteria, including: 
a. Symptoms for at least 6 months prior to screening. 
b. Knee pain in the target knee for 30 days of the preceding month (periarticular knee 
pain due to OA and not due to other conditions such as bursitis, tendonitis, etc.). 
c. The pain in the target knee required the use of prescription nonsteroidal anti-
inflammatory drugs (NSAIDs) and/or prescribed over the counter (OTC) medication. 
d. On stable pain therapy (i.e., at least 3 days per week for the previous month) with an 
oral or topical NSAID prescribed by a clinician for 30 days prior to the Screening 
Visit. 
3. Has an X-ray of the target knee, taken no more than 1 year before Baseline, showing 
evidence of OA with Kellgren-Lawrence grade 1 to 3 disease. 
4. Has at least moderate pain in the designated study knee: 
 
 
 
 
 
 
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5. Has a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain 
score of 
 at the Baseline Visit. 
6. If female: 
a. Subject is not breastfeeding or pregnant as confirmed by a negative pregnancy test at 
or within 48 hours of the Screening Visit.  Women of child-bearing potential must use 
an acceptable method of contraception (including oral contraceptives, hormone 
implant, intrauterine device, and spermicide with barrier method, or male sexual 
partner[s] surgically sterile). 
b. Subject could not become pregnant because she is surgically sterile (hysterectomy or 
tubal ligation), confirmed to be postmenopausal (having amenorrhea for ≥12 months), 
or has had a hysterectomy with or without bilateral oophorectomy at least 6 months 
prior to the Screening Visit. 
7. Able to swallow and tolerate rescue medication with APAP (moderately sized tablets). 
8. Be reliable, willing, and able to cooperate with all study procedures including the 
following: 
a. Accurately fill out the diary on a daily basis. 
b. Return for study visits on the required dates. 
c. Accurately and reliably report symptoms (including treatment-emergent signs and 
symptoms). 
d. Use the patch as required by protocol. 
 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if the he or she meets any of the following criteria: 
1. Body mass index (BMI) > 40. 
2. The non-target knee pain severity score is 
 at Screening and 
Baseline (Day 0). 
3. Any subject who disobeyed the restriction of prohibited therapies (e.g., rescue 
medication) during Screening/Washout Period. 
4. Secondary OA of the knee (rheumatoid arthritis, gout, psoriasis, syphilitic neuropathy, 
ochronosis, metabolic or other primary bone disease or acute trauma). 
5. Clinically significant elevation of serum creatinine (176.8 μmol/L), aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) (3 x upper limit of normal 
[ULN]) at the Screening Visit. 
6. Known allergy or hypersensitivity to the use of diclofenac, 
, 
 
 
 ethanol, acetylsalicylic acid (aspirin [ASA]), or any other NSAID. 
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7. Severe, uncontrolled cardiac, renal, hepatic or other systemic disease. 
8. A documented (upper GI series or endoscopy) gastroduodenal ulcer or any GI bleeding 
(except hemorrhoidal) within 6 months prior to Screening Visit. 
9. Documented history of alcohol or drug abuse within 1 year prior to study entry or 
positive alcohol/drug screen findings at Screening or Baseline. 
10. Presence of chondrocalcinosis on X-ray if associated with a history of pseudogout or 
inflammatory flare-ups. 
11. MAJOR SURGERY:  Previous damage or surgery to the target knee at any time (i.e., 
damage/reconstruction of the anterior or posterior cruciate ligaments). 
12. MINOR SURGERY on the target knee defined as anything other than major surgery (as 
defined above) for less than 1 year before study enrollment. 
13. Current treatment with oral, topical, intra-articular, or intra-muscular corticosteroids on 
the target knee within 90 days of Screening Visit or into any other joint within 30 days of 
screening. 
14. Any subject who had received intra-articular viscosupplementation (e.g., Synvisc®) in the 
target knee 90 days prior to Screening Visit. 
15. Any subject who had used opioids 7 days prior to the Screening Visit. 
16. Any subject who had previous exposure to HP-5000. 
17. Any subject whose participation would conflict with contraindications, warnings or 
precautions as stated in the prescribing information for oral or topical diclofenac (e.g., 
any subject taking ACE inhibitors, cyclosporine, diuretics, lithium, or methotrexate – 
refer to Investigator Brochure for prescribing information). 
18. Use of another investigational drug within 30 days prior to study entry. 
19. Any subject with resolved, ongoing, or pending litigation or disability related to any 
health-related cause. 
20. Any subject with fibromyalgia. 
21. Any painful or disabling conditions affecting the knee or leg. 
22. Any skin abnormality present at the potential patch application site that is likely to be 
aggravated by the study drug (i.e., infection, rash, excessive fragility or dryness, any cut 
or abrasion), presence of tattoo, excessive hair or open sores, or scar tissue.  Presence of 
significant skin disorder such as atrophy, psoriasis, or vitiligo. 
23. Any subject expecting to have knee replacement surgery within 6 months. 
24. Any subject with a psychiatric condition in the investigator’s opinion may interfere with 
participation in the study. 
25. The subject is an employee, or family member of an employee, of the study center, the 
contract research organization (CRO) or the sponsor involved in this study. 
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8.2.3 Premature Subject Withdrawal 
In accordance with the Declaration of Helsinki (48th WMA General Assembly, Somerset West, 
Republic of South Africa, October 1996), subjects have the right to withdraw participation from 
the study at any time for any reason.  Every reasonable attempt should be made by the 
investigator to keep subjects in the study; however, subjects must be withdrawn from the study if 
they withdraw consent to participate.  Investigators must make at least 3 attempts to contact 
subjects who fail to attend scheduled visits by telephone or other means. 
 
The investigator also has the right to remove subjects from the study.  Subjects may be removed 
from the study for the following reasons: 
 Adverse events:  If the reason for removal of a subject from the study is an AE, the 
principal specific event and any related test results will be recorded on the electronic case 
report form (eCRF).  If a subject withdraws because of an AE plus another reason, the 
withdrawal will be considered due to the AE and the eCRF will be completed to reflect 
this reason for withdrawal.  A narrative description will be required for all early 
withdrawals due to AEs. 
 The request of the subject, his/her representative, investigator or sponsor, whether for 
administrative or other reasons. 
 Noncompliance with study drug or non-compliance with subject diary completion, 
protocol violation, or unreliable behavior. 
 Pregnancy.  If the subject becomes pregnant during the clinical study, the study drug 
should be stopped immediately and the subject withdrawn from the study. 
 
If a subject is withdrawn early from the study, the following will be performed: 
 The date of the last dose of study drug and all observations collected up to the time of 
termination will be recorded on the Early Withdrawal eCRF page along with the reason 
for termination.  All Early Withdrawal procedures should be completed and recorded on 
the Early Withdrawal eCRF page.  If withdrawal occurs at a regularly scheduled visit, the 
Early Withdrawal eCRF page should be used instead of the regular visit eCRF page to 
record any information related to the visit. 
 In order to enable the most complete recording of any subject who withdraws early from 
the study, it is important to evaluate these subjects at the study center as soon as possible.  
Subjects who are withdrawing early should undergo an Early Withdrawal Visit and a 
Follow-Up Visit must be scheduled. 
 
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Subjects may be withdrawn if continuing in the study is not in the subject’s best interest; their 
condition worsens during the study, or for safety reasons, as determined by the investigator.  
Subjects may also be withdrawn due to lack of compliance with the protocol or if the subject is 
unwilling to continue participation in the study. 
8.3. Subject Replacement Criteria 
Subjects who withdraw after randomization and the application of the first treatment patch will 
not be replaced. 
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The Drug Dispensing Log must be available for monitoring, auditing, or inspection.  Section 9.8 
details the accountability of clinical supplies through the use of a Drug Dispensing Log. 
9.2. Treatments Administered 
HP-5000 will be administered 
 for a maximum of 28 ± 2 days. 
The treatment arms for this study are the following: 
Treatment Arm 
 Treatment 
HP-5000
  
One patch applied 
to alternate side of the target knee (inner 
or outer). 
HP-5000
 
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
Placebo 
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
Patch Application 
A separate guidance for patch application will be provided to subjects for applying, securing, and 
removing the patch. 
9.3. Dispensing and Storage 
Study drug supplied by 
 is to be used exclusively in the 
clinical study according to the instructions of this protocol.  The investigator is responsible for 
dispensing study drug according to the dosage scheme and for ensuring proper storage of study 
drug. 
The investigator must confirm the receipt of study drug with his/her signature.  A copy of this 
receipt must be kept by the investigator, and another copy will be stored at Noven 
Pharmaceuticals, Inc. (hereafter referred to as “Noven”), and/or 
  Until study 
drug is dispensed to the subjects, it must be stored at 25°C and in a dry place in a securely locked 
area that is not generally accessible. 
All study drug supplies must be stored in a secure locked area with access limited to the 
investigator or those persons authorized by the investigator to dispense the study drug to 
subjects.  Study drug should be stored as per the label. 
9.4. Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly 
assigned in a 1:1:2 ratios to receive HP-5000
HP-5000
 or placebo patches.  The 
randomization numbers will be assigned sequentially through a central interactive voice response 
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system (IVRS) as subjects who met eligibility criteria are enrolled into the study.  The study 
center will not be a blocking factor in the randomization schedule.  At designated visits, subjects 
will be given a kit containing sufficient study drug to last until the next scheduled study visit. 
 
The randomization schedule will be prepared by 
 before the start of the study.  
No one involved in the clinical conduct will have access to the randomization schedule before 
official unblinding of treatment assignment.  No subject will be randomized into this study more 
than once. 
9.5. Blinding and Unblinding Treatment Assignment 
To protect the blind, placebo patches will be identical in appearance to the HP-5000
 and 
HP-5000
 patches. 
 
All subjects, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment with the exception of a prespecified 
unblinded statistician/programmer from 
 who will have access to the 
randomization code.  The unblinded study personnel will not participate in study procedures or 
data analysis prior to unblinding of the study data to all study related personnel.  If an interim 
analysis is to be conducted, then unblinded personnel who are not otherwise involved in the 
study will prepare the data for review. 
 
Study personnel will endeavor to safeguard the integrity of the study blind to minimize bias in 
the conduct of the study.  Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency.  
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. 
 
In the case of a medical emergency, to appropriately treat the subject, study drug will need to be 
unblinded.  The investigator may break the randomization code for an individual subject.  
However, the investigator should make every effort to discuss the unblinding of the subject with 
the medical monitor prior to unblinding whenever possible. 
 
If the investigator is not able to discuss treatment unblinding in advance, then he/she must notify 
the medical monitor immediately of the blind breaking incident without revealing the subject’s 
treatment assignment. 
 
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In all such cases, the AE necessitating the emergency blind break will be handled as an SAE in 
accordance with the procedures indicated above.  Any broken code will be clearly justified, 
explained by a comment on the appropriate eCRF page along with the date and reason for study 
discontinuation; and captured on the SAE Form. 
 
The investigator or designee must record the date and reason for unblinding or study 
discontinuation on the appropriate eCRF for that subject.  In all cases that are not emergencies, 
the investigator must discuss the event with the medical monitor prior to unblinding the subject’s 
treatment assignment. 
 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding the treatment assignments for the 
remaining subjects in the study.  Thus, the overall study blind will not be compromised.  If a 
subject’s treatment assignment is unblinded, he/she may or may not be asked to withdraw from 
the study.  The investigator will make this decision after consultation with the medical monitor. 
9.6. Selection of Doses and Administration in the Study 
The dose of diclofenac 
 in a patch size of 
 
 applied 
 and rotated between 
 on the knee (inner and outer knee) is based on the following considerations: 
 
 
 
 Dose that targets diclofenac exposure after HP-5000 patch application that is similar to 
that of registered topical diclofenac products and considerably lower than that of oral 
diclofenac tablets. 
 
The data from previous studies investigating irritation and PK support the proposed dose of 
 and a patch size of 
 
 applied 
 and rotated between 
 on the knee 
for the lead formulations (HP-5000
 and HP-5000
 
9.7. Dose Adjustment Criteria 
Dose adjustment is NOT allowed in this study. 
9.8. Drug Accountability 
The investigator (or pharmacist, as appropriate) must maintain adequate records of the receipt 
and conditions of all study drugs, dispensing, return, or other disposition of study drug including 
the date, quantity dispensed to each subject, batch or code number, identification of subjects 
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(subject number [and initials]) who received study drug and any reasons for departure from the 
protocol-dispensing regimen.  Receipt of study drug must also be confirmed within IVRS.  The 
drug accountability records, along with used and unused packaging must be available for 
monitoring, auditing, or inspection.  Each site must keep accurate records of drug received at 
site, dispensed to the subjects. 
 
The investigator will not supply study drug to any person except those named as sub-
investigators (on the Form FDA 1572), designated study personnel, and subjects in this study.  
The investigator will not dispense study drug from any study sites other than those listed (on the 
Form FDA 1572). 
 
Study drug may not be relabeled or reassigned for use by other subjects.  If any of study drugs is 
either not dispensed, lost, stolen, unusable, or is received in a damaged container, this 
information must be documented and reported to Noven and appropriate regulatory agencies, as 
required. 
 
At the completion of the study, a final reconciliation of all study drugs (used and unused) must 
performed and returned to the sponsor (or designated location).  The unused study drug must be 
left in the original packaging and returned to the sponsor (or designee) for destruction. 
9.9. Treatment Compliance 
Treatment compliance with study drug regimens will be assessed by study personnel via the 
counts of returned unused patches, patch application, removal and by questioning the subject, if 
necessary, at every post-randomization visit.  Treatment compliance will also be calculated as 
the number of patches applied divided by the prescribed number of patches over a given period, 
expressed as a percentage. 
 
At Visits 3 through 5 or any Early Termination Visit, the study drug (patches) from the previous 
Treatment Phase will be returned to the investigator.  The study drug will be inventoried and 
noncompliance defined asusing less than 80% or more than 120% of study drug during any 
evaluation period (visit to visit).  If the subject is noncompliant, the Medical Advisor should be 
contacted to discuss the subject’s eligibility to continue in the study. 
 
The subject must be counseled if compliance is not satisfactory (used 6 or less patches per 
week).  If a subject has been noncompliant on two consecutive visits, the subject may be 
withdrawn early from the study for non-compliance. 
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For each 28-day study drug administration period, subjects will be asked to record their daily 
intake/use of rescue medication/study drug in the diary.  Deviations from the planned doses 
(overdose, missed dose or timing) will be recorded on the subjects’ eCRF.  These diaries will be 
reviewed by study personnel at each visit and will be collected as source documents.  
Information from that subject diary will be transcribed on the appropriate eCRF pages for 
documentation of subject compliance with study drug.  Compliance will include the following: 
 
1. Telephone follow-up: A telephone follow-up call will be performed between Screening 
(Visit 1) and Baseline (Visit 2), before the start of the Washout Period and another one 
during the Follow-up Period. 
 
2. Patient Education: At all study visits, the investigator will explain the importance of the 
following: 
 
a. applying study medication 
 to the target knee after 
showering/bathing;  
b. recording patient diary information every day; 
c. accurately reporting pain; 
d. accurately reporting rescue medication use; 
e. understanding when to return for next visit and the importance of returning on 
schedule; and 
f. adhering to the overall research plan. 
 
During Screening (Visit 1), the investigator will provide the subject with an introduction to 
the various questionnaires that will be used during the study and the patient diary. 
 
3. Patient Dairy (e-Diary):  The patient diary will be used by the subject to record required 
assessments including the time of patch application/removal, the NRS scores, the use of 
rescue medication, and questionnaires about adhesion, skin irritation, discomfort and 
adhesive residue. 
 
4. Rescue Medication:  If needed, patients will be allowed to take up to 2 grams of 
acetaminophen per day as rescue medication for pain of the target and/or the non-target 
knee.  Information regarding the use of rescue medication will be recorded on the 
appropriate concomitant medication eCRF. 
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9.10. Permitted and Prohibited Therapies 
Prior to the double-blind treatment period, subjects will stop taking all prescription and 
prescribed OTC analgesic medications for at least 7 days; however, rescue medication 
(acetaminophen [APAP]) is permitted during the Washout Period if required.  A maximum of 
2 g/day of APAP will be allowed for rescue treatment of both target and non-target knee pain 
except within the 2 calendar days prior to the Baseline Visit (i.e., rescue medication is prohibited 
from Day -2 until clinic visit on Day 0) and within the 1 calendar day prior to each clinic visit 
(e.g., rescue medication is prohibited from Day 6 until clinic visit on Day 7 if the subject will 
visit the study site on Day 7).  APAP will be provided by the Sponsor.  Subjects are NOT 
allowed to apply study treatment drug (HP-5000/Placebo) on the non-target knee at any time 
during the study period. 
 
All concomitant medications used (including OTC medications and herbal supplements) will be 
recorded in the source document and on the appropriate eCRF page. 
9.10.1 Permitted Therapies 
Glucosamine, chondroitin, and antidepressants (for indication of depression) will be allowed if 
used as stable therapy for at least 90 days prior to Screening Visit.  Other concomitant 
medications for treatment of ongoing medical conditions are allowed, but should be limited to 
those medications considered necessary in the opinion of the investigator. 
9.10.2  Prohibited Therapies 
Any NSAIDs (selective or nonselective), any opioids, APAP (>2 g/day), ASA (>81 mg/day), 
corticosteroids (a stable does by inhalation for seasonal allergies and/or topical use for 
dermatologic allergies are allowed), anticonvulsants (i.e., pregabalin and gabapentin etc.), 
muscle relaxants, other oral analgesics (prescription and/or OTC), antidepressants prescribed for 
the control of chronic pain syndromes, antihistamine with a sedative effect, sedatives for 
insomnia, topical products on the knee including methyl salicylate, camphor, menthol, 
methylsulfonylmethane, 
 or capsaicin, any intra-articular treatments for the knee, any 
nonpharmaceutical therapy or device to relieve knee pain (including physiotherapy, massage 
therapy, hot wax therapy etc.) may not be taken during the study. 
 
Note:  Glucosamine, chondroitin, and antidepressants (for the indication of depression) will be 
allowed if used as stable therapy for 90 days prior to Screening Visit.  However, if in use for 
fewer than 90 days, these drugs will be considered as prohibited concomitant medications and 
will require a Washout Period. 
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Subjects will be allowed to continue stable ASA therapy not for OA pain (up to 81 mg/day). 
9.11. Treatment after End of Study 
After completing the study, each subject will be referred to their primary care physician and 
treated according to standard clinical practice. 
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10. STUDY PROCEDURES 
Subjects must provide written informed consent before any study-related procedures are 
initiated, including the cessation of prohibited concomitant therapy. 
 
For the timing of assessments and procedures throughout the study, refer to the schedule of 
events (see Section 17.1).  Throughout the study, every reasonable effort should be made by 
study personnel to follow the timing of assessments and procedures in the schedule of events for 
each subject.  If a subject misses a study visit for any reason, the visit should be rescheduled as 
soon as possible. 
10.1. Study Periods and Visits 
10.1.1 Screening/Washout Period 
10.1.1.1 Screening Period 
Screening/Washout Period should be up to 28 days prior to the Baseline Visit.  The subject must 
be screened before entering the Washout Period of the study.  The following procedures will be 
performed at Screening Visit: 
1. Obtain written informed consent and assign a screening number. 
2. Assess inclusion/exclusion criteria. 
3. Collect demographic information and record medical history, including prior and current 
therapies (e.g., prescription and nonprescription medications). 
4. Perform a complete physical examination, which will include assessment of the head, 
eyes, ears, nose, and throat, cardiovascular, respiratory, gastrointestinal/abdominal, 
musculoskeletal, dermatological, neurological, and psychiatric/psychological body 
systems. Weight (kg), height (cm), and vital signs will be measured. 
5. Perform urine drug, alcohol and pregnancy tests. 
6. Identify the target knee.  The subject will be instructed to refer to this specific (target) 
knee throughout his/her participation in the study when responding to study efficacy 
assessment. 
7. Instruct the subject how to use NRS and WOMAC before performing first assessments. 
8. Administer the WOMAC questionnaire and calculate the composite score. 
9. Perform NRS evaluation for the target knee and the non-target knee pain. 
10. Review of x-ray of the target knee and perform 12-lead ECG and laboratory tests to 
determine subject’s eligibility.  If subject does NOT have any X-ray done within the past 
year, a mandatory new X-ray to confirm the disease will have to be performed prior to 
starting the Washout Period. 
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11. Instruct the subject on how to use of an electronic diary (eDiary). 
12. Dispense rescue medication. 
13. Dispense an eDairy. 
10.1.1.2 Washout Period 
Subjects whose eligibility has been preliminarily confirmed at screening will be asked to 
washout of current medications for at least 7 days (up to a maximum of 14 days).  During this 
period, the following will take place: 
1. Electronic diary NRS pain scores before the start of the Washout Period will be reviewed 
by the investigator or the study coordinator.  A record of this review will be recorded in 
the source documents and eCRF pages. 
2. Subjects will stop taking all prescription and OTC analgesic medications, but will be 
informed that rescue medication (i.e., acetaminophen) may be used (a maximum of 
2 g/day) except within 2 calendar days prior to the Baseline Visit. 
3. Perform an NRS assessment for the target knee pain and calculate the mean score for the 
least 3 days before the Baseline Visit. 
4. Review subject’s use of rescue medication. 
5. Review subject’s use of prior/concomitants medications. 
6. Dispense and review electronic diary (eDairy). 
10.1.2 Baseline Visit (Day 0) 
The following will take place during the Baseline Visit (Day 0): 
1. Confirm subject’s continued eligibility relative to inclusion/exclusion criteria. 
2. Assign a subject ID number and randomly assign the subject to a treatment group using 
IVRS. 
3. Obtain vital sign measurements, including weight. 
4. Administer the WOMAC questionnaire and calculate the composite score. 
5. Perform Patient’s Global Assessment. 
6. Perform an NRS 11-point pain assessment for the target knee and non-target knee pain. 
7. Review subject’s use of rescue medication. 
8. Perform a 12-lead ECG. 
9. Obtain blood and urine samples for laboratory testing. 
10. Perform a urine drug, alcohol and pregnancy tests. 
11. Review and dispense the subject’s diary. 
12. Perform baseline dermal safety assessment (irritation only). 
13. Review subject’s use of prior/concomitants medications. 
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14. Dispense rescue medication and perform rescue medication accountability/reconciliation. 
15. Dispense the double-blind study medication and instruct subjects on proper patch 
application.  Subjects should apply the patch at home after showering/bathing 
 
16. Subjects will be instructed not to bathe or shower while wearing the study medication; a 
bath or a shower may be taken in the morning/in the evening before any patch is applied. 
17. Subject will be instructed to report patch detachment and incidences of irritation, 
discomfort, and adhesive residue and not to participate in strenuous activities or other 
activities that cause heavy perspiration during the double-blind treatment phase. 
10.1.3 Double-blind Treatment Phase 
During the 4-week double-blind treatment phase, the following will take place: 
 
At home, subjects are required to conduct the following: 
1. Apply study medication on the target knee (inner or outer by 
 rotation) after 
showering/bathing. 
2. Complete daily assessments in an e-Diary, which include the time of patch application 
and removal, the NRS pain score, the use of rescue medication, adhesion, skin irritation, 
discomfort and adhesive residue. 
 
In clinic visits, investigators (or site personnel as appropriate) conduct the following: 
Visit 3: 
1. Obtain vital sign measurements. 
2. Administer the WOMAC questionnaire and calculate the composite score. 
3. Perform Patient Global Assessment. 
4. Perform Patient Global Impression of Change. 
5. Perform daily NRS 11-point pain assessments for the target knee pain. 
6. Review subject’s use of rescue medication/concomitant medication. 
7. Perform a urine pregnancy test. 
8. Re-instruct the subject concerning the patch application method if the subject has a 
problem with patch application and/or patch adhesion. 
9. Dispense study medication/rescue medication and perform drug accountability/ 
reconciliation. 
10. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
11. Review AEs. 
12. Review the subjects’ diary entries. 
 
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Visit 4: 
1. Obtain vital sign measurements. 
2. Administer the WOMAC questionnaire and calculate the composite score. 
3. Perform Patient Global Assessment. 
4. Perform Patient Global Impression of Change. 
5. Perform daily NRS 11-point pain assessments for the target knee pain. 
6. Review subject’s use of rescue medication/concomitant medication. 
7. Perform a urine pregnancy test. 
8. Re-instruct the subject concerning the patch application method if the subject has a 
problem with patch application and/or patch adhesion. 
9. Dispense study medication/rescue medication and perform drug accountability/ 
reconciliation. 
10. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
11. Review AEs. 
12. Review the subjects’ diary entries. 
13. Obtain pharmacokinetic blood sample. 
 
Visit 5 
1. Obtain vital sign measurements. 
2. Administer the WOMAC questionnaire and calculate the composite score. 
3. Perform Patient Global Assessment. 
4. Perform Patient Global Impression of Change. 
5. Perform daily NRS 11-point pain assessments for the target knee pain. 
6. Review subject’s use of rescue medication/concomitant medication. 
7. Perform a urine pregnancy test. 
8. Perform drug accountability/ reconciliation. 
9. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
10. Review AEs. 
11. Review the subjects’ diary entries. 
12. Obtain blood and urine samples for laboratory testing. 
13. Obtain subject’s weight. 
14. Obtain pharmacokinetic blood sample. 
15. Perform a 12-lead ECG. 
16. Perform physical examination. 
 
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During the time interval between visits, the site coordinator may regularly contact (by 
telephone) the subjects to ensure that the subject’s scheduled dose is administered and daily 
NRS pain scores are recorded correctly.  The subjects will be informed that they may contact 
the site if problems/questions arise. 
10.1.4 Follow-up Visit  
A follow-up phone Visit will take place approximately 7 days after the end-of-treatment (EOT) 
visit (or Early Termination Visit), and will include the following assessment and procedures: 
1. Review subject’s use of concomitant medications. 
2. Review AEs. 
10.1.5 Early Termination Visit (if applicable) 
Subjects who are discontinued for any reason after Baseline (Visit 2) must complete the Early 
Withdrawal Visit.  If the subject comes for an Unscheduled Visit and a decision to withdraw the 
subject is made, then the Early Withdrawal Visit procedures will be performed and the Early 
Withdrawal Visit eCRF will be completed (and not the Unscheduled Visit eCRF).  During this 
visit the following assessments and procedures will be performed: 
1. Perform physical examination. 
2. Obtain vital sign measurements including weight. 
3. Administer the WOMAC questionnaire and calculate the composite score. 
4. Perform Patient’s Global Assessment. 
5. Perform Patient’s Global Impression of Change. 
6. Perform a NRS 11-point pain assessment for the target knee pain. 
7. Review subject’s use of rescue and concomitant medications. 
8. Perform a 12-lead ECG. 
9. Obtain blood and urine samples for laboratory testing. 
10. Perform a urine pregnancy test. 
11. Collect and review the subject’s diary entries. 
12. Perform drug accountability. 
13. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
14. Review AEs. 
15. Obtain pharmacokinetic blood sample. 
10.1.6 Overall Study Schedule 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening/Washout Period:  Up to 28 days (the Washout Period will occur the last 7 to 14 
days of the Screening Phase). 
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2. Double-blind Treatment Phase:  4 weeks
3. Follow-up Period:  1 week
The maximum treatment duration for each subject is approximately 4 weeks.  The maximum 
study duration for each subject is approximately 9 weeks. 
10.2. Assessments 
10.2.1 Efficacy 
10.2.1.1 Western Ontario and McMaster Universities Osteoarthritis Index 
The Western Ontario and McMaster Universities Osteoarthritis Index Likert (LK) version 3.1 is 
the most recent version of this instrument for the assessment of hip and knee OA.  The WOMAC 
Osteoarthritis Index is widely used to measure pain, stiffness, and physical function in subjects 
with OA pain.  It is considered to be a reliable and valid instrument.5,6,7  
The WOMAC Pain scale evaluates the following 5 items: 
Each item is rated on a scale of 0 to 4, with 0 being no difficulty and 4 being extreme difficulty. 
The WOMAC Stiffness scale assesses 2 items: 
Each item is rated on a scale of 0 to 4, with 0 being no difficulty and 4 being extreme difficulty. 
The WOMAC Physical Function assesses the following categories using the 0 to 4 scale 
described previously: 
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The WOMAC Composite score is most commonly calculated by summing the items for all 3 
subscales.  Higher scores on the WOMAC indicate worse pain, stiffness, and functional 
limitations.  The total score is calculated as follows: Total score= __/96= __% 
10.2.1.2 Patient Global Assessment 
The PGA is a self-administered instrument that measures the subject’s overall impression of their 
OA pain in their target knee on a 5-point scale where 0 = “Very Good” and 4 = “Very Poor”. 
Subjects will be asked the complete the following statement: 
“How would you rate your osteoarthritis condition over the last 24 hours?” 
The response options include the following: 
 
Very Good 
0 
 
Good 
1 
 
Moderate 
2 
 
Poor 
3 
 
Very Poor 
4 
10.2.1.3 Patient Global Impression of Change 
The Patient Global Impression of Change is a self-administered instrument that measures change 
in subjects’ overall improvement with treatment on a scale where 1 = “very much improved” and 
7 = “very much worse.”  Subjects will be asked the following question:  “How would you rate 
your overall improvement with treatment during the clinical trial?”  The response options include 
the following: 
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Very Much Improved 
1 
Much Improved 
2 
Minimally Improved 
3 
No Change 
4 
Minimally Worse 
5 
Much Worse 
6 
Very Much Worse 
7 
10.2.1.4 Numeric Rating Scale 
The NRS is an 11-point scale from 0 to 10. On this scale, 0 = no pain and 10 = the worst pain 
imaginable.  NRS will be assessed in two ways.  One is the average pain condition over the last 
24 hours, and the other is the worst painful condition over the last 24 hours. 
The subject will rate his or her target knee pain intensity using the following question:  “On a 
scale from 0 to 10, where “zero” represents “no pain” and “10” represents “the worst possible 
pain,” how would you rate the pain that you have been feeling in your knee over the last 24 
hours?” 
Note: 
1. The NRS pain score for assessment is an average of the NRS pain scores reported for
pain over the last 24 hours for the last 3 days prior to each clinic or phone visit except
Screening Visit.
2. The NRS pain scores in at least 2 of the last 3 days prior to washout start (Phone Visit 1)
and Baseline (Visit 2) is required.
10.2.1.5 Use of Rescue Medication 
For the 4-week double-blind treatment phase, subjects will be asked to record their daily 
intake/use of rescue medication in the diary.  Rescue medication will be limited as follows: 
2 gram/day APAP may be used except and within 1 calendar day prior to other visits. 
10.2.2 Safety 
Safety assessments will include the evaluation of laboratory assessments, vital signs, 12-lead 
ECGs, physical examinations, and AEs. 
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10.2.2.1 Laboratory Safety Assessments 
10.2.2.1.1 Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
schedule of events (see Section 17.1). 
Hematology: 
Hemoglobin, hematocrit, red blood cell (RBC) count, RBC 
indices, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, platelet count (or estimate), white 
blood cell count including differential. 
Serum chemistry: 
Albumin, total bilirubin, direct bilirubin, total protein, calcium, 
alkaline 
phosphatase, 
alanine 
aminotransferase, 
aspartate 
aminotransferase, blood urea nitrogen, creatinine, fasting glucose, 
cholesterol, triglycerides, high density lipoprotein, sodium, 
potassium, chloride, bicarbonate, lactate dehydrogenase, uric 
acid. 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones, leukocyte 
esterase, nitrite, total bilirubin, urobilinogen. 
Pregnancy test (urine): 
For women of childbearing potential only. 
Urine drug screen: 
Amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
methamphetamine, 
methadone, 
phencyclidine, 
and 
tetrahydrocannabinol. 
Alcohol test (urine): 
Ethanol. 
A central laboratory will be used to process all hematology, clinical chemistry, urinalysis 
samples.  Urine drug screens and alcohol tests pregnancy tests will be conducted at the study 
sites.  Details on sampling, handling, and storage of samples will be given in a separate 
laboratory manual. 
 
Note:  Female patients (of childbearing potential) will undergo a urine pregnancy test at 
Screening (Visit 1) and a urine pregnancy test at every subsequent visit. 
10.2.2.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products.  Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens 
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in both the clinic and laboratory settings.  Refer to current recommendations of the appropriate 
authorities. 
 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples.  Procedures and regulations for the packaging and 
shipping of biological samples are outlined in the HP-5000-US-05 laboratory manual.  The 
investigator is responsible for ensuring that all study samples that are to be transported to another 
location are appropriately packed and shipped according to the applicable regulations. 
10.2.2.2 Clinical Examinations 
10.2.2.2.1 Vital Signs and Weight 
Vital signs, including heart rate, respiratory rate, temperature and supine blood pressure will be 
measured at designated timepoints.  Blood pressure will be measured with the subject in the 
supine position only.  The supine blood pressure should be measured after the subject has been 
lying down for five minutes.  Weight (kg) will also be measured. 
10.2.2.2.2 Electrocardiogram 
The 12-lead ECG will be a complete, standardized recording and will be performed at designated 
timepoints after the subject has been supine position for at least 5 minutes before the 12-lead 
ECG is obtained.  All ECG recordings will be identified with the subject number, initials, date, 
and time of the recording and will be attached to the subject’s eCRF. 
10.2.2.2.3 Physical Examination 
The following physical examination will be performed at designated timepoints before potential 
exposure to study drug and at the completion of exposure. 
 General Appearance 
 Abdomen 
 Head/ Face 
 Skin, Hair, and Nails 
 Eyes/ Fundoscopy 
 Musculoskeletal: Extremities, Spine 
 Ears/Hearing 
 Vascular/Circulatory 
 Nose 
 Lymphatic 
 Mouth, Teeth and Throat 
 Psychiatric/Behavior 
 Neck & Thyroid 
 Brief neurologic 
 Chest/Lungs 
 
 
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10.2.2.3 Adverse Events 
The definitions and management of and special considerations for AEs are provided in 
Section 11. 
10.2.2.4 Evaluations of Patch and Dermal Assessment 
Patch Adhesion  
Patch adhesion will be assessed in two ways (in-clinic and at-home).  At each clinic visit, patch 
adhesion will be assessed by the investigator or a designee using the following 5-point numerical 
scale: 
• 
0 = ≥90% adhered (essentially no lift off the skin). 
• 
1 = ≥75% to <90% adhered (some edges only lifting off of the skin). 
• 
2 = ≥50% to <75% adhered (less than half of the system lifting off of the skin). 
• 
3 = <50% adhered but not detached (more than half the system lifting off of the skin 
without falling off). 
• 
4 = patch detached (patch completely off the skin). 
During the Treatment Phase at home, subjects will report on any incidence of patch detachment 
in the diary. 
 
Irritation 
At each clinic visit, the application site where the previous patch was applied will be examined 
for signs of skin irritation.  All subjects will be evaluated by a trained investigator or designee 
using the Berger and Bowman scale (Berger and Bowman 1982) as described below. 
 
Half grades will not be assigned if reactions fall between the unit grades, rather, the more severe 
of the 2 grades will be assigned. 
 
Dermal Response 
• 
0 = no evidence of irritation 
• 
1 = minimal erythema, barely perceptible 
• 
2 = definite erythema, readily visible; minimal edema or minimal papular response 
• 
3 = erythema and papules 
• 
4 = definite edema 
• 
5 = erythema, edema, and papules 
• 
6 = vesicular eruption 
• 
7 = strong reaction spreading beyond the application site 
 
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Other Effects  
• 
A = slightly glazed appearance 
• 
B = marked glazed appearance 
• 
C = glazing with peeling and cracking 
• 
F = glazing with fissures 
• 
G = film of dried serous exudates covering all or part of the patch site 
• 
H = small petechial erosions and/or scabs 
• 
N = no other observations 
 
Dermal response score will be rated on a 0 to 7 scale, whereby 0 is rated as “No evidence of 
irritation” and 7 is rated as “Strong reaction spreading beyond test (application) site.” 
 
Other effects will be scored via a letter scale and a corresponding numeric scale, whereby N (0) 
is rated as “No effects” and H (3) is rated as “Small petechial erosions and/or scabs.” 
 
During the treatment phase at home, subjects will complete a questionnaire about skin irritation 
in the diary. 
 
Discomfort 
Discomfort will be assessed by the investigator or a designee using a predefined discomfort 
rating scale.  The evaluator will ask the subject, “Are you experiencing any discomfort related to 
the patch?”  If the answer is no, the overall level of discomfort will be rated as 0.  If the answer is 
yes, the evaluator will then ask the subject to rate the discomfort as mild, moderate, or severe. 
Any discomfort mentioned should be recorded and rated as follows: 
• 
0 = No discomfort 
• 
1 = Mild discomfort 
• 
2 = Moderate but tolerable discomfort 
• 
3 = Severe, intolerable discomfort 
• 
4 = Patch not present 
During the Treatment Phase at home, subjects will complete a questionnaire about discomfort in 
the diary. 
 
Adhesive Residue  
At each clinic visit, the amount of adhesive residue remaining at the application site where the 
previous patch was applied will be examined by the investigator or a designee and scored 
according to the scale below: 
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• 
0 = None 
• 
1 = Light 
• 
2 = Medium 
• 
3 = Heavy 
• 
4 = Patch not present 
During the treatment phase at home, subjects will complete a questionnaire about adhesive 
residue in the diary. 
10.2.3 Pharmacokinetic Assessments 
Blood samples for the determination of plasma diclofenac concentrations will be collected at 
specified visits after the application of the study drug as per the Schedule of Events in attachment 
17.1.  A volume of approximately 4 mL of blood will be collected at Visit 4 (Day 14) and Visit 5 
(Day 28); or at the Early Termination Visit, if applicable.  The LC/MS/MS validation method 
will be used to analyze the plasma sample to determine the diclofenac concentrations and blood 
sampling times will be recorded. 
 
The total blood volume collected will be approximately 40 mL (inclusive of pharmacokinetic 
and clinical safety laboratory collections). 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product.  An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
 
Pre-existing diseases or conditions will NOT be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition during the Treatment 
Phase (Worsening of a pre-existing condition is considered an AE.). 
 
Events occurring in subjects treated with placebo are also considered AEs.  However, AEs 
reported during treatment-free periods before study drug has been administered are not 
considered AEs; these events are captured on the eCRF as updates to the subject’s medical 
history. 
 
 All AEs encountered during the clinical study will be reported on the eCRF. All AEs, 
regardless of relationship to study drug or procedure, should be collected beginning from 
after the start of the study drug.  AEs in clinical investigation subjects include any change 
in the subject’s condition.  This includes symptoms, physical findings, or clinical 
syndromes. 
 An abnormal laboratory value may be considered an AE if the identified laboratory 
abnormality leads to any type of intervention whether prescribed in the protocol or not.  It 
is up to the investigator to determine whether an abnormal laboratory value constitutes an 
AE.  If an abnormal laboratory value is caused by a disease process, the disease process 
and not the laboratory abnormality should be listed as the AE (e.g., if new onset viral 
hepatitis is causing elevated ALT, hepatitis and not the elevated ALT should be listed as 
the AE). 
 Examples of laboratory abnormalities, which should be considered as AEs include those 
which result in withdrawal of the study treatment, withholding study treatment pending 
some investigational outcome, reduction of dose of the study treatment, or additional 
concomitant treatment.  All laboratory abnormalities considered to constitute an AE 
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should be reported on the appropriate AE page of the eCRF.  Laboratory abnormalities do 
not need to be listed as separate AEs if they are considered to be part of a clinical 
syndrome that is being reported as an AE.  It is the responsibility of the investigator to 
review all laboratory findings in all subjects.  Abnormal values should be commented 
upon as to clinical relevance or importance on the eCRF or the laboratory report as 
appropriate.  Medical and scientific judgment should be exercised in deciding whether an 
isolated laboratory abnormality should be classified as an AE. 
 Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 
11.1.2 Unexpected Adverse Event 
An expected AE is one for which the nature or severity is consistent with the known AE profile 
of the product.  For a study drug, the known information is contained in the IB which includes 
the HP-5000 Developmental Core Safety Information. 
 
An unexpected adverse event is one for which the specificity or severity is not consistent with 
the current IB and Developmental Core Safety Information. 
 
Furthermore, reports that add significant information on specificity or severity of a known, 
already documented adverse reaction constitute unexpected events. 
11.1.3 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 results in death 
 is life-threatening.  
NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE:  An elective hospital admission to treat a condition present before exposure to the test 
drug, or a hospital admission for a diagnostic evaluation of an AE, does NOT qualify the 
condition or event as an SAE. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly. 
NOTE:  A congenital anomaly in an infant born to a mother who was exposed to study drug 
during pregnancy is an SAE.  However, a newly diagnosed pregnancy in a subject that has 
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received a study drug is NOT considered an SAE unless it is suspected that study drug 
interacted with a contraceptive method and led to the pregnancy. 
 is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, development of drug dependency, or drug abuse. 
11.2. Management of Adverse Events 
Adverse events will be collected from the time of first dose administration through the Follow-up 
Visit or Early Termination Visit, whichever occurs first. 
 
Subjects who complete the Treatment Phase or terminate early will continue to be monitored for 
AEs for 30 days from last day for study treatment, unless they withdraw consent or are lost to 
follow-up. 
11.2.1 Collection 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously.  At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation.  The investigator will 
then monitor and/or ask about or evaluate AEs using non-leading questions, such as: 
 “How are you feeling?” 
 “Have you experienced any issues since your last visit?” 
 “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
 
11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention.  The event does not generally interfere with usual activities of 
daily living. 
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Moderate 
Usually alleviated with additional specific therapeutic intervention.  The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
 
It is important to distinguish between severe AEs and SAEs.  Severity is a classification of 
intensity whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.3. 
11.2.2.3 Action Taken 
Action taken may consist of: 
Drug 
withdrawn 
An indication that a medication schedule was modified through termination of 
a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as follows: 
 Recovered/resolved 
 Recovered/resolved with sequelae 
 Recovering/resolving 
 Not recovered/not resolved 
 Fatal* 
 Unknown 
Note:  Only select fatal as an outcome when the AE results in death.  If more than 1 AE is 
possibly related to the subject’s death, the outcome of death should be indicated for each such 
AE.  Although “fatal” is usually an event outcome, events such as sudden death or unexplained 
death should be reported as SAEs. 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to study drug.  The 
categories for classifying the investigator’s opinion of the relationship are listed below. 
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Not related 
An AE with sufficient evidence to accept that there is no causal relationship to 
study drug administration (e.g., no temporal relationship to drug 
administration, because the drug was administered after onset of event; 
investigation shows that the drug was not administered; another cause was 
proven). 
Unlikely related An AE, including laboratory test abnormality, with a temporal relationship to 
study drug administration that makes a causal relationship improbable, and in 
which other drugs, events or underlying disease provide plausible 
explanations. 
Possibly related An AE with a reasonable time sequence to administration of the study drug, 
but which could also be explained by concurrent disease or other drugs or 
events. Information on drug withdrawal may be lacking or unclear. 
Definitely 
Related 
An AE occurring in a plausible time relationship to study drug administration, 
and which cannot be explained by a concurrent disease or other drugs or 
events.  The response to withdrawal of the drug (dechallenge) is clinically 
reasonable. 
11.2.3 Documentation 
All AEs occurring within the period of observation for the study must be documented in the 
eCRF with the following information; where appropriate (The period of observation for the study 
is described in Section 11.2): 
 AE name or term 
 When the AE first occurred (start date and time) 
 When the AE stopped (stop date and time or an indication of “ongoing”) 
 Severity of the AE 
 Seriousness (hospitalization, death, etc.) 
 Actions taken 
 Outcome 
 Investigator opinion regarding the AE relationship to study drug 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care.  If such treatment constitutes a deviation from the protocol, the subject should be 
withdrawn from the study and the reason and date of withdrawal must be documented in the 
eCRF.  The decision about whether the subject may continue in the study will be made by the 
sponsor after consultation with the investigator and/or medical monitor. 
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If AEs occur in a subject that is not tolerable, the investigator must decide whether to withdraw 
the subject from the study and/or treat the subject.  Special procedures may be recommended for 
the specific study drug, such as the collection of a serum sample for determining blood 
concentrations of study drug, or treatment regimens, as appropriate. 
 
It is NOT necessary to unblind a subject’s treatment assignment in most circumstances, even if 
an SAE has occurred. If unblinding is necessary, see Section 9.5 for a description of the 
unblinding procedures. 
11.2.5 Follow-up  
ALL ongoing SAEs at the time of discontinuation will be followed (up to a maximum of 30 days 
after the last dose of study medication) to a satisfactory resolution, or until it becomes stable, or 
until it can be explained by another known causes (i.e., concurrent condition or medication) and 
clinical judgment indicates that further evaluation is not warranted.  All ongoing AEs at the time 
of discontinuation will be followed for up to 7 days.  All findings relevant to the final outcome of 
an AE must be reported in the subject’s medical record and recorded on the eCRF page. 
11.2.6 Reporting of Adverse Events 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to 
 within 24 hours 
of first becoming aware of the event by completing, signing and dating the Serious Adverse 
Event Report Form, verifying the accuracy of the information recorded in the form with the 
source documents and eCRF, and sending the SAE form to the sponsor by one of the following 
methods: 
  
All SAEs, irrespective of relationship to study treatment, must be reported as soon as 
possible but no later than 1 business day by Fax to: 
 
Email: 
 
 
 
The “Clinical Trial Serious Adverse Event Report Form (SAE form)” must be used for 
reporting. 
 
 
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It is very important that the SAE report form be filled out as completely as possible at the time of 
the initial report.  This includes the investigator’s assessment of causality.  All SAEs must be 
followed to resolution, or if resolution is unlikely, to stabilization.  Any follow-up information 
received on serious adverse events should be forwarded within one business day of its receipt.  If 
the follow-up information changes the investigator’s assessment of causality, this should also be 
noted on the follow-up SAE form. 
 
SAEs, regardless of causality assessment, must be collected through the Termination Visit and 
for 30 days following study drug discontinuation, whichever is longer. 
 
Any SAE judged by the investigator to be related to the study treatment should be reported to the 
sponsor regardless of the length of time that has passed since study completion. 
 
The written report should be submitted on the SAE form provided for this purpose.  At the time 
of first notification, the investigator or designee should provide the following information, if 
available: 
 Protocol number 
 Reporter (study site and investigator) 
 Subject’s study number 
 Subject’s year of birth 
 Subject’s gender 
 Date of first dose of study drug 
 Date of last dose of study drug, if applicable 
 Adverse event term 
 Date of occurrence of the event 
 A brief description of the event, outcome to date, and any actions taken 
 The seriousness criteria that were met 
 Concomitant medication at onset of the event 
 Relevant medical history information 
 Relevant laboratory test findings 
 Investigator’s opinion of the relationship to study drug (“Is there a reasonable 
possibility that the study drug caused the SAE? Yes or No?”) 
 Whether and when the investigator was unblinded as to the subject’s treatment 
assignment 
 
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The investigator must fax/mail a written SAE Report Form that describes the SAE to the 
recipients of the initial information, who will forward the information to the sponsor. 
 
Preliminary SAE reports and/or any missing or additional relevant information concerning the 
SAE should be provided to the recipients of the initial information as soon as possible on a 
follow-up SAE Report Form, together with the following information (adverse event, date of 
occurrence, subject ID, study ID, study drug, and site number) including copies of hospital case 
reports, autopsy reports and other documents requested by the sponsor; this will allow the 
follow-up information to be linked to the initial SAE report. 
 
The investigator is required to comply with applicable regulations (including local laws and 
guidances) regarding the notification of his/her health authorities, institutional review board 
(IRB), principal and coordinating investigators, study investigators, and institutions. 
11.2.6.2 Nonserious Adverse Events 
Nonserious AEs will be recorded in the eCRF page and reported by 
 to Noven. 
Special Considerations. 
11.2.7 Adverse Events of Special Interest 
The overall systemic safety profile of diclofenac is well known and established as reflected in the 
Investigator’s Brochure (IB) including Developmental Core Safety Information, which are in 
part based on the current label of the 
  In patients taking 
 
 
 
 
 
 
  
 
The overall safety of HP-5000 patches at doses ranging from 
 
 
 
 
.  The HP-5000 patches used in the clinical 
studies 
 
  Some of the commonly reported 
AEs across the 
 remaining commonly reported AEs are 
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either known adverse reactions to other commercially available dose forms that contain 
diclofenac (application site pruritus, back pain, and myalgia with diclofenac containing solutions 
or patches) or consistent with events of application site skin reactions commonly reported as AEs 
with other topical medications that contain diclofenac 
 
 
11.2.8  Pregnancy Reporting 
All females of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
study participation.  Females should be instructed to contact the investigator or study staff 
immediately if pregnancy occurs or is suspected. 
 
Male study participants will be instructed to practice birth control measures to prevent a partner’s 
pregnancy during the subject’s study participation and for 90 days following the last dose 
administration. 
 
Pregnancy testing will be conducted prior to administration of study drug on every female of 
childbearing potential.  A female who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a screening failure. 
 
A female who becomes pregnant during study drug treatment will be immediately withdrawn 
from the study.  Any female who becomes pregnant during treatment and within 30 days of 
discontinuing study drug will be followed by the investigator until birth or termination of 
pregnancy.  Any pregnancy for which the estimated date of conception occurred prior to the 
Termination Visit of the study and for 30 days following study drug discontinuation, whichever 
is longer, must be reported. 
 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
 
An induced abortion or a spontaneous abortion is considered to be a SAE and should be reported 
in the same timeframe and in the same manner as all other SAEs (see Section 11.2.6.1). 
 
The investigator must report the pregnancy to 
 Pharmacovigilance using the 
Pregnancy Data Collection Form via the same fax number and/or email address as for SAE 
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reporting.  The investigator should contact the designated individuals who receive SAE 
notification and record information related to the pregnancy on an Exposure in Utero form 
provided by the sponsor or its designee. 
 
Pregnancies must be reported as soon as possible, but no later than 1 business day, by Fax 
to: 
Email: 
 
 
 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy. 
 
All Pregnancies must be followed to outcome. The outcome of the pregnancy must be 
reported as soon as possible but not later than one business day. 
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12. DATA SAFETY MONITORING BOARD 
There will be no Data Safety Monitoring Board for this study. 
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13. STATISTICAL METHODS 
13.1. Study Endpoints 
13.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in WOMAC LK3.1 OA pain score from Baseline 
and Week 4. 
13.1.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
 WOMAC LK3.1 OA Index (pain) – change between Baseline and Week 1, and Week 2 
 WOMAC LK3.1 OA Index (stiffness) 
 WOMAC LK3.1 OA Index (physical function) 
 WOMAC LK3.1 OA Index (composite score) 
 Patient Global Assessment 
 Patient Global Impression of Change 
 Pain intensity assessed on an 11-point NRS 
 Use of rescue medication 
13.1.3 Safety Endpoints 
 Adverse events, AEs leading to discontinuation from the study drug, SAEs, and deaths. 
 Change from baseline in clinical laboratory results (including fasting glucose and lipids), 
ECG results, body weight, and vital signs. 
 Dermal safety: adhesion, irritation, discomfort, and adhesive residue. 
13.1.4 Pharmacokinetics Endpoint 
Plasma concentrations of diclofenac (for both HP-5000
 and HP-5000
 on Day 14 
and 28 (or at the Early Termination Visit). 
13.2. Sample Size Determination 
Assuming an effect size of 
 
 on the 
change in WOMAC pain score from baseline to Week 4 between active HP-5000
 and HP-
5000-
 treatments and placebo, the probability for detecting the clinically meaningful 
effect size 
 or higher will be approximately 67% having 75 evaluable subjects per each 
active arm and 150 evaluable subjects in the placebo arm.  Having 3 treatment arms, the total 
number of subjects randomized in the study and included in the primary analysis set should be 
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approximately 300.  A sufficient number of subjects will be screened to randomize the proposed 
sample size. 
13.3. Analysis Populations 
The following 4 analysis populations are planned for this study: 
 Intent-to-Treat (ITT):  Includes all consented and randomized subjects. Regardless of any 
protocol deviations, analyses performed on the ITT set will be based on the randomized 
treatment assignment and all available data. 
 Full Analysis Set (FAS):  Includes all randomized subjects who have had at least 1 patch 
of double-blind study drug applied and who have a Baseline WOMAC pain score and at 
least 1 post-Baseline assessment of the primary efficacy measure (WOMAC pain score).  
Evaluable subjects will be defined as those who meet the FAS definition.  The FAS will 
be used as the primary set for analysis of efficacy endpoints based on randomized 
treatment assignment. 
 Safety Analysis Set (SAF):  Includes all subjects who have had at least 1 patch of 
double-blind study drug applied and who have at least 1 post-dose safety measurement 
during the double-blind treatment phase.  I n the unlikely event that errors may have 
occurred in treatment arm assignments, then analyses using the SAF will be based on 
treatment actually received.  The SAF will be used for the analysis of dermal evaluations 
and safety endpoints. 
 Pharmacokinetic Analysis Set (PAS):  Includes all subjects who have received at least 
1 dose of study drug during the double-blind treatment phase and have at least 1 blood 
sample for PK assessment.  Subjects may be excluded from the PAS set if they 
significantly violate inclusion or exclusion criteria, significantly violate the protocol in a 
way that may influence the PK analysis, if any unexpected error occurs during the study 
that may influence the PK analysis (e.g., early detachment of transdermal systems, 
apparent sample switching, etc.) or if their data are unavailable or incomplete.  The PAS 
will be used for the analysis with model-based approach. Excluded cases will be 
documented together with the reason for exclusion. 
 
Inclusion in the analysis populations will be determined prior to database lock. 
 
If a subject is randomized incorrectly or is administered the incorrect study drug, analyses of the 
ITT population will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment. 
 
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13.4. Statistical Analyses 
This section presents a summary of the planned statistical analyses.  A SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  Unless otherwise 
indicated, all testing of statistical significance will be 2-sided, and a difference resulting in a P 
value of <0.05 will be considered statistically significant.  For analyses involving study site, if 
the number of subjects per site is small, sites may be pooled for analysis, or omitted from 
statistical models. The final determination will be made prior to database lock. 
 
Summary statistics will be provided for the variables described below.  For continuous variables, 
these statistics will typically include the number of subjects, mean, standard deviation (SD), 
median, minimum, and maximum.  For categorical variables, these statistics will typically 
include the number and percentage of subjects in each category. 
13.4.1 Study Subjects and Demographics 
13.4.1.1 Disposition and Withdrawals 
The numbers of subjects randomized, completing, and withdrawing, along with reasons for 
withdrawal will be tabulated overall and by treatment group.  The number of subjects and 
patches in each analysis population will be reported. 
13.4.1.2 Protocol Deviations 
A by-subject listing of all protocol deviations and violations will be reported in Clinical Study 
Report. 
13.4.1.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for all analysis populations.  Demographic variables will 
include age, gender, height, and weight.  Information on race and ethnicity will be collected for 
any eventual analysis of differences in response to study drug, in accordance with local 
regulatory requirements.  Baseline subject characteristics will include medical history, physical 
examination findings, and previous OA treatment modalities. 
 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization Drug 
Dictionary (WHO-DD) Anatomical Therapeutic Chemical (ATC) classes and preferred terms. 
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13.4.2 Exposure and Compliance 
Investigational product administration will be summarized in terms of the number of patches 
applied and removed, the number of patches removed earlier along with the summary of reasons 
for early removal.  For each subject mean in terms of duration of exposure will be calculated.  
Descriptive statistics for these quantities, including the mean, median, SD, minimum, maximum, 
and quartiles, will be provided by treatment group. 
13.4.3 Efficacy Analyses 
Efficacy variables will be summarized and analyzed using the FAS population as primary, unless 
otherwise specified. 
13.4.3.1 Primary Analysis 
The primary efficacy endpoint of this study is the change from Baseline to Week 4 in the 
WOMAC pain score; the primary analysis set is the FAS.  The comparisons of interest are: 
 HP-5000
 versus placebo 
 HP-5000
 versus placebo 
 
The estimand in the primary analysis for efficacy for each dose is the difference between 
treatments groups (HP-5000 dose group vs. placebo) in the change from Baseline to Week 4 in 
WOMAC pain score in all subjects as randomized, under the assumption that all randomized 
patients remain on their randomized treatment throughout the study.  WOMAC scores obtained 
more than 24 hours after discontinuation of study drug will be excluded as a-priori defined 
outliers. 
 
The primary efficacy variable, the change from Baseline to Week 4 in the WOMAC pain score 
will be analyzed using a mixed model repeated measures (MMRM) analysis.  The MMRM 
model will include change from baseline in WOMAC pain score as the repeated dependent 
variable, with treatment (HP-5000
 HP-5000-
 and placebo), visit, treatment-by-visit 
interaction, and the baseline WOMAC pain score as covariates.  An unstructured covariance 
matrix will be assumed.  If the unstructured covariance matrix fails to converge, a series of other 
covariance structures will be tested for use. 
 
The MMRM model may be repeated on additional analysis sets as a sensitivity analysis.  If the 
normality assumption is violated, analysis of covariance (ANCOVA) on rank-transformed data 
will be used as utility analysis and additional supportive analyses may be performed. 
 
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Other sensitivity analyses may be performed on the primary endpoint to assess the robustness of 
the results based on the model used for primary analysis.  These analyses may include multiple 
imputation and pattern-mixture models for handling of missing data.  Details will be provided in 
the SAP.  The analyses will be performed according to the National Academy of Sciences (2010) 
guidelines.8 
13.4.3.2 Analyses for Secondary Endpoint 
The following secondary endpoints will use the change in mean for analysis (as applicable): 
 WOMAC LK3.1 OA Index (pain) – change between Baseline and Week 1, and Week 2 
 WOMAC LK3.1 OA Index (stiffness) 
 WOMAC LK3.1 OA Index (physical function) 
 WOMAC LK3.1 OA Index (composite score) 
 Patient Global Assessment 
 Patient Global Impression of Change 
 Pain intensity assessed on an 11-point NRS 
 Use of rescue medication 
 
Additional categorical response analyses may be performed; additional details will be provided 
in the SAP. 
13.4.4 Safety and Tolerability Analyses 
All safety summaries will be descriptive; statistical significance tests may be performed on 
safety data that will be described in the SAP. 
 
Safety analyses will be conducted using data from the safety population (as defined in 
Section 13.3).  Safety variables include AEs, clinical laboratory values, body weight, vital signs, 
ECG readings, physical examination results, and dermal safety results.  No formal inferential 
analyses will be conducted for safety variables, unless otherwise noted. 
13.4.4.1 Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), 
Version 19. 
Treatment-emergent AEs are defined as: 
 AEs with onset at the time of or following the start of treatment with study drug through 
the Follow-up Visit or Early Termination Visit, whichever occurs first.  The number and 
percentage of subjects with AEs will be displayed for each treatment group by system 
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organ class and preferred term.  Summaries of AEs by severity and relationship to study 
drug will also be provided.  Serious adverse events and AEs resulting in discontinuation 
of study drug will be summarized separately in a similar manner.  Subject listings of AEs, 
SAEs, and AEs causing discontinuation of study drug will be produced. 
13.4.4.2 Concomitant Medications 
Prior and concomitant therapies will be summarized for the Safety population.  All prior and 
concomitant medications recorded in the eCRF will be coded to generic term and all matching 
Anatomic Therapeutic Classification (ATC) codes using the current version (2017) of WHO 
Drug.  Summaries will be prepared using the coded generic term.  All prior and concomitant 
medications recorded in the eCRF will be listed. 
13.4.4.3 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each 
treatment group at each time point. 
 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by study visit.  Pre- and post-treatment values will 
also be presented with an analysis of mean changes from baseline. 
 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges.  Any out-of-range values that are identified by the 
investigator as being clinically significant will also be shown in a data listing. 
13.4.4.4 Vital Signs and Body Weight 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for body weight, body-mass index, systolic blood 
pressure, diastolic blood pressure, heart rate, and respiratory rate. 
 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges, will be tabulated showing change from baseline (shift tables) for each parameter by 
treatment group and by study visit.  Pre- and post-treatment values may also be presented with an 
analysis of mean changes from baseline. 
 
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13.4.4.5 Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point.  
 
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (both correction methods), and 
HR for each treatment group at each time point. 
13.4.4.6 Physical Examination Findings 
The abnormal findings in the complete physical examination will be captured and analyzed as 
adverse events. 
13.4.4.7 Dermal Safety 
The number and percentage of subjects with findings related to dermal safety including adhesion, 
irritation, discomfort, and adhesive residue will be summarized.  A by-subject listing of 
individual dermal safety findings will also be provided. 
13.4.5 Pharmacokinetic Analyses 
Plasma concentrations of diclofenac (for both HP-5000
 and HP-5000
 will be 
evaluated and summarized as descriptive statistics by treatment. 
13.4.6 Interim Analysis 
No interim analyses are planned. 
13.5. Database 
The final database will be compliant with FDA Data Standard catalog from Electronic Common 
Technical Document / eCTD (May, 2015) and Providing Regulatory Submissions in Electronic 
Format - Standardized Study Data (July 2016). 
 
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14. STUDY CONDUCT 
The study will be conducted in accordance with all applicable regulatory requirements, including 
ICH GCP guidelines, subject privacy requirements, and the ethical principles that are outlined in 
the Declaration of Helsinki. 
 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles (see 
Section 15).  The sponsor reserves the right to withdraw a subject from the study (see 
Section 8.2.3), to terminate participation of a study site at any time, and/or to discontinue the 
study. 
 
Noven agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (see Section 17.2), the investigator indicates that he/she 
has carefully read the protocol, fully understands the requirements, and agrees to conduct the 
study in accordance with the procedures and requirements described in this protocol. 
 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including the April 1996 International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Guidance for Industry E6 Good Clinical Practice (GCP), and in agreement with the 2013 version 
of the Declaration of Helsinki.  While delegation of certain aspects of the study to sub-
investigators and study coordinators is appropriate, the investigator will remain personally 
accountable for closely overseeing the study and for ensuring compliance with the protocol and 
all applicable regulations and guidelines.  The investigator is responsible for maintaining a list of 
all persons that have been delegated study-related responsibilities (e.g., sub-investigators and 
study coordinators) and their specific study-related duties. 
 
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Investigators should ensure that all persons who have been delegated study-related 
responsibilities are adequately qualified and informed about the protocol, study drugs, and their 
specific duties within the context of the study.  Investigators are responsible for providing Noven 
with documentation of the qualifications, GCP training, and research experience for themselves 
and their staff as required by the sponsor and the relevant governing authorities. 
 
To ensure compliance with the guidelines, the study may be audited by an independent person.  
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.1.3 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after the initiation visit has 
been conducted.  The investigator and the full study site staff must be available at this visit.  All 
staff must have an initiation visit before they conduct any study specific procedures. 
 
The study site will not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the 
appropriate informed consent form (ICF). 
2. All required regulatory documents have been submitted to and approved by the sponsor 
or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
 
Following the initiation visit, the study will be monitored as per clinical monitoring plan, or 
additional visit may occur when deemed necessary, while subjects are actively randomized into 
the study. 
14.2. Screen Failures 
Subjects who fail any of the inclusion and/or exclusion criteria may not be rescreened for the 
study.  In certain cases, and case-by-case basis, a subject may be rescreened once and permitted 
into the study following consultation with the Sponsor and Medical Monitor who must make an 
assessment that the subject is eligible to participate in the study. 
14.3. Study Documents 
All documentation and material provided by Noven or 
 for this study are to be 
retained in a secure location and treated as confidential material. 
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14.3.1 Investigator’s Regulatory Documents 
The regulatory documents are listed in the HP-5000-US-05 Study Manual.  All required 
regulatory documents must be received from the investigator and reviewed and approved by 
Noven or its designee before the study site can initiate the study and before Noven will authorize 
shipment of study drug to the study site.  Copies of the investigator’s regulatory documents must 
be retained at the study site in a secure location.  Additional documents, including a copy of the 
protocol and applicable amendments, the HP-5000 topical patch IB, eCRF completion 
guidelines, copies of regulatory references, copies of IRB correspondence, and study drug 
accountability records should also be retained as part of the investigator’s regulatory documents.  
It is the investigator’s responsibility to ensure that copies of all required regulatory documents 
are organized, current, and available for inspection. 
14.3.2 Case Report Forms 
By signing the Investigator’s Agreement (see Section 17.2), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign 
an ICF. 
 
Case report forms are considered confidential property of Noven and should be handled and 
stored accordingly.  The sponsor or its designee will provide the necessary training on the use of 
the specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit in a neat, legible manner to ensure accurate interpretation of data.  All 
requested information must be entered in the electronic data capture (EDC) system according to 
the completion guidelines provided by the sponsor or its designee.  The eCRFs must be signed 
by the investigator or a sub-investigator.  These signatures serve to attest that the information 
contained in the eCRF is accurate and true. 
14.3.3 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation.  Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records.  All source documents must be 
accessible for verification by the site monitor, auditor, and IRB for inspections and by the 
regulatory authority(ies).  Direct access to source documents must be guaranteed by the 
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investigator, sub-investigator, or study coordinator, who must provide support at all times for 
these activities.  Subject confidentiality will be protected at all times. 
 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory, to the sponsor or its designee.  A paper copy of the laboratory results 
will be provided to the study site and should be retained with each subject’s source data. 
14.4. Data Quality Control 
Noven and its designees will perform quality control checks on this clinical study. 
14.4.1 Monitoring Procedures 
Noven and/or its designee will monitor the study to ensure study is conducted in accordance with 
the protocol, GCP, and applicable regulations and guidelines.  The assigned clinical research 
associates (CRAs) will visit the investigator and study site at periodic intervals and maintain 
periodic communication.  It will be the CRA's responsibility to inspect the eCRFs at regular 
intervals throughout the study, to verify the adherence to the protocol and the completeness, 
consistency and accuracy of the data being entered.  The investigator agrees to allow the CRAs 
and other authorized Noven personnel access.  The CRAs will maintain current personal 
knowledge of the study through observation, review of study records and source documentation, 
and discussion of the conduct of the study with the investigator and staff.  While on site, the 
CRAs will review: 
 regulatory documents, directly comparing entries in the EDC system with the source 
documents 
 consenting procedures 
 laboratory test reports 
 other patient records and study documents 
 AE procedures, storage and accountability of study drug and study materials 
 
The CRA will ask for clarification and/or correction of any noted inconsistencies.  Procedures 
for correcting eCRF are described in the study manual.  As representatives of the sponsor, CRAs 
are responsible for notifying project management of any noted protocol deviations. 
 
By signing the Investigator’s Agreement (see Section 17.2), the investigator agrees: 
 to meet with the CRAs during study site visits; 
 to ensure that study staff is available to the CRAs as needed; 
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 to provide the CRAs access to all study documentation, to the clinical supplies 
dispensing and storage area; and 
 to assist the monitors in their activities, if requested 
Further, the investigator agrees to allow Noven or designee auditors or inspectors from 
regulatory agencies to review records, and to assist the inspectors in their duties, if requested. 
14.4.2 Data Management 
Noven or designee will be responsible for activities associated with the data management of this 
study.  The standard procedures for handling and processing records will be followed per GCP 
and 
 
 standard operating procedures.  A comprehensive data management plan 
will be developed including a data management overview, description of database contents, 
annotated eCRF, pre-entry review list, self-evident correction conventions, query contacts, and 
consistency checks. 
 
Study site personnel will be responsible for providing resolutions to all data queries.  The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data.  Procedures for soliciting and documenting resolution to data 
queries are described in the study manual. 
14.4.3 Quality Assurance/Audit 
Study sites, study database and study documentation may be subject to quality assurance audits 
during the course of the study by Noven or its designee.  Audits may be undertaken to check 
compliance with GCP guidelines, and can include: 
 site audits 
 TMF audits 
 database audits 
 document audits (e.g., protocol and/or CSR) 
 
Noven or its designee may conduct additional audits on a selection of study sites, which will 
require access to subject notes, study documentation, and facilities or laboratories used for the 
study. 
 
The study site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IRB or regulatory authorities clinical 
inspection according to GCP guidelines.  The investigator should agree to cooperate with the 
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auditor during the visit and will be available to supply the auditor with eCRFs or other study files 
necessary to conduct that audit or inspection.  Any findings will be strictly confidential. 
 
If a regulatory authority informs the investigator that it intends to conduct a clinical inspection, 
the investigator shall notify Noven immediately. 
14.5. Premature Termination of the Study  
The study may be prematurely terminated at Noven’s discretion at any time and for any reason.  
If the study is terminated or suspended, Noven will promptly inform the investigators/sites and 
the regulatory authority(ies) of the termination or suspension and the reason(s) for the 
termination or suspension.  The ethics committee will also be promptly informed and provided 
with the reason(s) for the termination or suspension by Noven or by the investigator/institution, 
as specified by the applicable regulatory requirement(s). 
 
Study Site Closure: 
At the end of the study, all study sites will be closed.  Noven may terminate participation of a 
study site at any time.  Examples of conditions that may require premature termination of a study 
site include, but are not limited to, the following: 
 Noncompliance with the protocol and/or applicable regulations and guidelines 
 Inadequate subject enrollment 
14.5.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until: 
 At least 2 years after the last marketing authorization for the study drug has been 
approved or the sponsor has discontinued its research with study drug, or 
 At least 2 years have elapsed since the formal discontinuation of clinical development of 
study drug 
 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or if needed by the sponsor. 
 
At the end of such period, the investigator shall notify the sponsor in writing of her/his intent to 
destroy all such material.  The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense.  
The final database will be archived by Noven according to the regulatory requirements. 
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14.5.2 Sample Retention 
Samples may be used for purposes related to this research.  The samples will be stored until the 
sponsor has determined that specimens are no longer needed and the decision has been made that 
none of the samples needs to be reanalyzed.  In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 
14.6. Amendments to the Protocol 
Modifications of the signed protocol are only possible by approved protocol amendments and 
with the agreement of all responsible persons.  The procedure for approval of a protocol 
amendment is identical to that for approval of the protocol.  The ethics committee must be 
informed of all protocol amendments and should be asked for its opinion as to whether a full re-
evaluation of the ethical aspects of the study is necessary by the committee.  This should be fully 
documented. 
 
The investigator must not implement any deviation from or change to the protocol without 
discussion with and agreement by Noven and prior review and documented approval/favorable 
opinion of the amendment from the relevant ethics committee, except where it is necessary to 
eliminate an immediate hazard to study subjects or where the change(s) involves only logistical 
or administrative aspects of the study (e.g., change in monitor(s), change of telephone number(s), 
etc). 
 
Protocol amendments will be submitted to the appropriate authority(ies) as required by the 
applicable regulatory requirement(s). 
14.7. Clinical Study Report 
A final integrated clinical/statistical report will be prepared that is compliant with the ICH 
Harmonised Tripartite Guideline: Structure and content of clinical study reports. 
14.8. Use of Information and Publication 
All information concerning study drug, Noven’s operations, patent applications, formulae, 
manufacturing processes, basic scientific data, and formulation information supplied by Noven 
or its designee to the investigator and not previously published, is considered confidential and 
remains the sole property of Noven.  Case report forms also remain the property of Noven.  The 
investigator agrees to use this information for purposes of study execution through finalization. 
 
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The information developed in this study will be used by Noven in connection with the continued 
development of study drug and thus may be disclosed as required to other clinical investigators 
or government regulatory agencies. 
 
The information generated by this study is the property of Noven.  Publication or other public 
presentation of study drug data resulting from this study requires prior review and written 
approval of Noven.  Abstracts, manuscripts, and presentation materials should be provided to 
Noven for review at least 30 days prior to the relevant submission deadline. 
 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until Noven has reviewed and commented on such a 
presentation or manuscript for publication. 
14.9. Subject Insurance and Indemnity 
Noven will provide the insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study.  The terms of insurance will be kept in the 
study files. 
14.10. 
Data Protection 
Personal and sensitive personal data will be treated as confidential.  The results of the study will 
be made available for review by authorized representatives of Noven and/or submitted to one or 
more sponsor offices worldwide, the ethics committee, and regulatory authorities. 
 
Prior to the subject’s enrollment in the study, the subject’s consent is required for the data to be 
used for these purposes and to gain direct access to their medical records for data verification 
purposes. 
 
The subject must be assured that their identity will be protected.  To facilitate this, a unique 
identification code will be assigned by the investigator to each study subject.  This will be used 
instead of the subject’s name and cross-referenced with the subject’s date of birth when reporting 
AEs and /or other study-related data. 
 
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15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Ethical Conduct of the study 
The guidelines of the World Medical Association Declaration of Helsinki in its revised edition 
(64th General Assembly, Fortaleza, Brazil, October 2013), the April 1996 ICH guidelines (E6) 
of GCP (including archiving of essential study documents), as well as the demands of national 
drug and data protection laws and other applicable regulatory requirements, will be strictly 
followed.  Approval will be obtained from the appropriate regulatory authorities of participating 
country(ies) before sites are initiated. 
15.2. Subject Information and Informed Consent 
The investigator is responsible for ensuring that no subject is subject to any study-related 
examination or activity before that subject has given informed consent.  The subject must give 
written consent after the receipt of detailed information.  The verbal explanation will cover all 
the elements specified in the written information provided for the subject. 
 
The investigator will inform the subject of the aims, methods, anticipated benefits, and potential 
hazards of the study, including any discomfort it may entail.  The subject must be given every 
opportunity to clarify any points he/she does not understand and, if necessary, ask for more 
information.  At the end of the interview, the subject may be given time to reflect if this is 
required, or if the subject requests more time.  Subjects and/or legal guardian will be required to 
sign and date the informed consent form.  After completion, informed consent forms will be kept 
and archived by the investigator in the investigator's study file. 
 
It should be emphasized that the subject is at liberty to withdraw their consent to participate at 
any time, without penalty or loss of benefits to which the subject is otherwise entitled.  Subjects 
who refuse to give, or withdraw, written informed consent may not be included or continued in 
this study, but this will not impact on their subsequent care. 
15.3. Approval by Institutional Review Board  
For Investigational New Drug (IND) studies, the minimum standards of conduct and 
requirements for informed consent are defined in the FDA regulations.  Prior to initiation of the 
study at each study site, the protocol, the informed consent form(s), the subject information 
sheet(s), details of the subject recruitment procedures, and any other relevant study 
documentation will be submitted to the responsible local and/or national IRB and approved. 
 
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Written notification of approval is to be provided by the investigator to the sponsor’s monitor 
before shipment of investigational drug supplies, and will include the date of the committee’s 
approval and the chairperson’s signature.  This written approval must consist of a completed 
Noven form, IRB Approval Form, or written documentation from the IRB containing the same 
information. 
 
Protocol amendments must also be reviewed and approved by the IRB.  Written approval from 
the IRB, or a designee, must be received by Noven before implementation.  This written 
approval will consist of a completed IRB approval form or written documentation from the IRB 
containing the same information. 
 
The investigator will report promptly to the IRB any new information that may adversely affect 
the safety of subjects or the conduct of the study.  Similarly, the investigator will submit written 
summaries of the study status to the IRB annually, or more frequently if requested by the IRB.  
Upon completion of the study, the investigator will provide the IRB with a brief report of the 
outcome of the study, if required. 
15.4. Subject Insurance and Finance  
Noven will provide the insurance in accordance with local guidelines and requirements as a 
minimum for the subjects participating in this study.  Details on finance and insurance will be 
provided in a separate agreement between the investigator and the sponsor. 
 
 
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16. REFERENCES
 
 
1  Barbour KE, Helmick CG, Theis KA, Murphy LB, Hootman JM, Brady TJ, Cheng YJ. 
Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United 
States, 2010-2012. MMWR 2013;62 (44):869-873. 
2  Centers for Disease Control and Prevention.  
https://www.cdc.gov/arthritis/data_statistics/index. htm. Accessed 24 June 2016. 
3  Investigational Brochure, Diclofenac Sodium Transdermal Drug Delivery System, HP-5000 
Transdermal Patch. Noven Pharmaceuticals, Inc. 
. 
Edition No. 03, September 9, 2014. 
4  Berger, R.S., and .J.P. Bowman.  “A Reappraisal of the 21 -day Cumulative Irritation Test in 
Man." Toxicol. - (It. 6’ Ocz~lw Toxicol., 1982; l(2); 109- 115. 
5  Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW.  Validation study of 
WOMAC: a health status instrument for measuring clinically important patient relevant 
outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J 
Rheumatol. 1988;15:1833-1840. 
6  Bellamy N. Pain assessment in osteoarthritis:  experience with the WOMAC osteoarthritis 
index. Semin Arthritis Rheum. 1989;18:14-17. 
7  Chan AT, Manson JE, Albert CM, et al.  Nonsteroidal anti-inflammatory drugs, 
acetaminophen, and the risk of cardiovascular events. Circulation. 2006;113(12):1578-1587. 
8  National Research Council (US) Panel on Handling Missing Data in Clinical Trials.  The 
prevention and treatment of missing data in clinical trials. Washington (DC):  National 
Academies Press (US); 2010. 
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17. ATTACHMENTS
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17.1. Schedule of Events 
Phase 
Screening 
Double-blind Treatment 
Follow-
up 
End of 
Treatment 
Period 
 
Washout 
Baseline 
 
 
 
 
 
 
 
 
Week 
-1 
 
 
 
1 
 
2 
 
4 
5 
 
Clinic visit 
1 
 
2 
 
3 
 
4 
 
5 
 
 
Phone visit 
 
1 
 
 
 
 
 
 
 
2 
 
Study Day 
-28 to -14j 
-25 to -1j 
0 
1 to 6 
7 
8 to 13 
14 
15 to 27 
28 
35 
 
Visit Window (Days) 
 
 
 
 
±2 
 
±2 
 
±2 
 
 
Assessments/Procedures
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
 
X 
 
 
 
 
 
 
 
 
Randomization (IVRS)a 
 
 
X 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
X 
 
X 
Vital signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
X 
 
X 
WOMAC Painc 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient Global 
Assessment 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient Global 
Impression of Change 
 
 
 
 
X 
 
X 
 
X 
 
X 
Pain Intensity 11-Point 
NRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense Rescue 
Medication 
X 
 
X 
 
X 
 
X 
 
 
 
 
Use of Rescue 
Medicationd 
 
X 
Xd 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECGe 
X 
 
X 
 
 
 
 
 
X 
 
X 
Clinical Laboratoryf 
Xf 
 
X 
 
 
 
 
 
X 
 
X 
Urine Pregnancy Test 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Drug  Screen 
X 
 
X 
 
 
 
 
 
 
 
 
Alcohol Test 
X 
 
X 
 
 
 
 
 
 
 
 
PK Blood Sample 
 
 
 
 
 
 
X 
 
X 
 
X 
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Subject Diaryg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study Medication 
Applicationh 
 
 
 
Xh 
X 
X 
X 
X 
 
 
 
Dermal Evaluationsi 
 
 
X 
Xk 
X 
Xk 
X 
Xk 
X 
 
X 
Prior/Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Eventsl 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X-Raym 
X 
 
 
 
 
 
 
 
 
 
 
Drug Accountability 
 
 
Xn 
 
X 
 
X 
 
X 
 
X 
 
Abbreviations: AE = adverse event; ET = early termination; ECG = electrocardiogram; ID = identification; I/E = inclusion/exclusion; IVRS = interactive voice 
response system; NRS = numeric rating scale; PK = pharmacokinetic; WOMAC = Western Ontario and McMaster Universities Arthritis Index. 
 
a. 
Subjects will be randomized to HP-5000
 HP-5000
 or placebo in a 1:1:2 ratio. 
b. 
Vital signs, including heart rate, respiratory rate, and sitting blood pressure will be measured after the subject has been in a sitting position for 5 minutes. 
c. 
WOMAC Pain will include WOMAC pain intensity, WOMAC stiffness, and WOMAC physical function. 
d. 
Rescue medication may be used during the Washout Period except within 2 calendar days prior to Visit 2. 
e. 
A standard 12-lead electrocardiogram (ECG) will be performed after the subject has been supine for at least 5 minutes. 
f. 
Clinical laboratory testing includes hematology, biochemistry, and urinalysis. Results from laboratory testing done at Screening Visit will used for 
confirmation of subject eligibility at Baseline Visit. 
g.  Subjects will be instructed in the use in the use of the electronic diary at the Screening Visit. For each 28-day administration period, subjects will be asked to 
record their daily intake/use of study drug in the electronic diary. 
h. 
Study treatment will applied on Day 1 of the Treatment Phase. Instructions for application and removal of study drug patches will be provided to the subject 
on Baseline Visit. 
i. 
Dermal evaluations will assess skin adhesion, irritation, discomfort, and adhesive residue. 
j.   Screening/Washout Period should be up to 28 days. Washout Period will be initiated 3 days after Screening Visit. 
k.    During the treatment period at home, subjects will report the incidence of patch detachment by answering Yes or No. 
l.    AEs will be collected after the first dosing. 
m. Historical X-rays done within one year prior to the Screening Visit are acceptable. If subject does NOT have any X-Ray done within the past year, a 
mandatory new X-Ray to confirm the disease will have to be performed prior to starting the Washout Period. 
n. 
Only for rescue medication. 
 
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17.2. Investigator’s Agreement 
PROTOCOL 
NUMBER: 
HP-5000-US-05 
PROTOCOL TITLE: 
A 4-week, Randomized, Double-blind, Multicenter, Placebo-controlled 
Phase 2 Study to Evaluate the Efficacy and Safety of HP-5000 in 
Subjects with Osteoarthritis (OA) of the Knee 
FINAL PROTOCOL: 
Amendment #1: 22 May 2017 
I have read this protocol and agree to conduct this clinical study as outlined herein. I will ensure 
that all sub-investigators and other study staff members have read and understand all aspects of 
this protocol. I agree to cooperate fully with Noven during the study. I will adhere to all FDA, 
ICH, and other applicable regulations and guidelines regarding clinical trials on an IP during and 
after study completion. 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
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18. APPENDICES 
18.1. Western Ontario and McMaster Universities Osteoarthritis (WOMAC) LK3.1 Index  
This is an example of the WOMAC index. The actual index will be provided in the eCRF. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
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18.2. Patient Global Assessment Scale (PGA) 
This is a sample questionnaire.  The actual questionnaire will be provided in the study reference 
manual.  
The subject will provide their overall impression of the status of their OA in the target knee on a 
5-point scale where 0 = “Very Good” and 4 = “Very Poor.” 
Subjects will be asked to complete the following statement:  “How would you rate your 
osteoarthritis condition over the last 24 hours?” The response options include the following: 
1. Very Good 
2. Good 
3. Moderate 
4. Poor 
5. Very Poor 
18.3. Patient Global Impression of Change Scale  
This is an example of the Patient Global Impression of Change (PGIC) scale. The actual 
instrument will be included in the study reference manual. 
The Patient Global Impression of Change is a self-administered instrument that measures change 
in subjects’ overall improvement with treatment on a scale where 1 = “very much improved” and 
7 = “very much worse.” Subjects will be asked the following question: “How would you rate 
your overall improvement with treatment during the clinical trial?” The response options include 
the following: 
 
Very Much Improved 
1 
 
Much Improved 
2 
 
Minimally Improved 
3 
 
No Change 
4 
 
Minimally Worse 
5 
 
Much Worse 
6 
 
Very Much Worse 
7 
 
18.4. 11-Point Numeric Rating Scale (NRS) 
This is a sample of the Numerical Rating Scale. Please use the rating scale provided in the study 
reference manual. 
 
Instructions:  Show the pain scale to the subject and explain that on the 0 to 10 pain rating scale, 
0 means no pain and 10 means the worst possible pain. A value in the middle of the scale 
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(around 5) would be moderate pain; a value of 2 or 3 would be mild pain and a value of 7 or 
higher is considered severe pain. 
Ask the subject the following question: “On a scale of 0 – 10, with 0 being ‘no pain’ and 10 
being the ‘worst possible pain’, how would you rate your pain over the last 24 hours?” 
The intent of the question is to gain an understanding of the intensity of the patient’s target knee 
pain at over the last 24 hours. 
 
 
No Pain 
Worst Possible Pain 
 
Adapted from: Farrar JT, Young JP, La Moreaux L, Werth JL, and Poole MR: Clinical importance 
of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94 
(2001) 149–158Regulations and Good Clinical Practice Guidelines. 
18.4.1 Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
 FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
 FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
 FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
18.4.2 Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
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7. Signed informed consent form  
8. Able to swallow and tolerate rescue medication with APAP (moderately sized 
tablets) 
Exclusion criteria:   
1. Body mass index (BMI) > 40 
2. At Screening and Baseline (Day 0), the non-target knee pain severity score is 
 
  
3. Any subject who disobeyed the restriction of prohibited therapies (eg, rescue 
medication) during Screening/Washout period. 
4. Secondary OA of the knee (rheumatoid arthritis, gout, psoriasis, syphilitic 
neuropathy, ochronosis, metabolic or other primary bone disease or acute trauma)  
5. Clinically significant elevation of serum creatinine (176.8 μmol/L), aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) (3 x upper limit of 
normal [ULN])  
6. Known allergy or hypersensitivity to the use of diclofenac, 
, 
 
, ethanol, acetylsalicylic acid (aspirin [ASA]), or any other 
NSAID  
7. Severe, uncontrolled cardiac, renal, hepatic or other systemic disease  
8. A documented (upper GI series or endoscopy) gastroduodenal ulcer or any GI 
bleeding (except hemorrhoidal) within 6 months prior to screening visit  
9. Documented history of alcohol or drug abuse within 1 year prior to study entry 
or positive alcohol/drug screen findings at screening or baseline 
10. Presence of chondrocalcinosis on X-ray if associated with a history of pseudogout 
or inflammatory flare-ups  
11. MAJOR SURGERY: Previous damage or surgery to the knee at any time (ie, 
damage/reconstruction of the anterior or posterior cruciate ligaments)  
12. MINOR SURGERY on the target knee defined as anything other than major 
surgery as defined above less than 1 year before enrolment  
13. Current treatment with oral, topical, intra-articular, or intra-muscular 
corticosteroids on the target knee within 90 days of screening visit or into any 
other joint within 30 days of screening 
14. Any subject who had received intra-articular viscosupplementation (eg, 
Synvisc®) in the target knee 90 days prior to screening visit  
15. Any subject who had used opioids 7 days prior to the screening visit.  
16. Any subject who had previous exposure to HP-5000 
17. Use of another investigational drug within 30 days prior to study entry  
18. Any subject with resolved, ongoing, or pending litigation or disability related to 
any health-related cause  
19. Any subject with fibromyalgia  
20. Any painful or disabling conditions affecting the knee or leg  
21. Any skin abnormality present at the potential patch application site that is likely 
to be aggravated by the study drug (ie, infection, rash, excessive fragility or 
dryness, any cut or abrasion), presence of tattoo, excessive hair or open sores, or 
scar tissue. Presence of significant skin disorder such as atrophy, psoriasis, or 
vitiligo 
22. Any subject expecting to have knee replacement surgery within 6 months 
23. Any subject with a psychiatric condition which in opinion of the investigator, 
may interfere with participation in the study 
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For analyses involving study site, if the number of subjects per site is small, sites may 
be pooled for analysis, or omitted from statistical models. The final determination will 
be made prior to database lock.  
Summary statistics will be provided for the variables described below. For continuous 
variables, these statistics will typically include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum. For categorical variables, these 
statistics will typically include the number and percentage of subjects in each 
category. 
Analysis Populations  
 
Intent-to-Treat (ITT): includes all consented and randomized subjects. 
Regardless of any protocol deviations, analyses performed on the ITT set will be 
based on the randomized treatment assignment and all available data. 
 
Full Analysis Set (FAS): includes all randomized subjects who have had at least 
1 patch of double-blind study medication applied and who have a Baseline 
WOMAC pain score and at least 1 post-baseline assessment of the primary 
efficacy measure (WOMAC pain score). Evaluable subjects will be defined as 
those who meet the FAS definition. The FAS will be used as the primary set for 
analysis of efficacy endpoints based on randomized treatment assignment. 
 
Safety Analysis Set (SAF): includes all subjects who have had at least 1 patch of 
double-blind study medication applied and who have at least 1 post-dose safety 
measurement during the double-blind treatment period. In the unlikely event that 
errors may have occurred in treatment arm assignments, then analyses using the 
SAF will be based on treatment actually received. The SAF will be used for the 
analysis of dermal evaluations and safety endpoints. 
 
Pharmacokinetic Analysis Set (PAS): includes all subjects who have received at 
least 1 dose of study medication during the double blind treatment period and 
have at least 1 blood sample for pharmacokinetic (PK) assessment. Subjects may 
be excluded from the PAS set if they significantly violate inclusion or exclusion 
criteria, significantly violate the protocol in a way that may influence the PK 
analysis, if any unexpected error occurs during the study that may influence the 
PK analysis (eg, early detachment of transdermal systems, apparent sample 
switching, etc.) or if their data are unavailable or incomplete. The PAS will be 
used for the analysis with model-based approach. Excluded cases will be 
documented together with the reason for exclusion. 
Primary Efficacy Analysis: The primary efficacy endpoint of this trial is the change 
from Baseline to Week 4 in the WOMAC pain score; the primary analysis set is the 
FAS. The comparisons of interest are: 
 
HP-5000
 versus placebo 
 
HP-5000
 versus placebo 
The primary efficacy variable, the change from baseline to Week 4 in the WOMAC 
pain score will be analyzed using a mixed model repeated measures (MMRM) 
analysis. The MMRM model will include change from baseline in WOMAC pain 
score as the repeated dependent variable, with treatment (HP-5000
 
HP-5000
 and placebo), visit, treatment-by-visit interaction, and the baseline 
WOMAC pain score as covariates. An unstructured covariance matrix will be 
assumed. If the unstructured covariance matrix fails to converge, a series of other 
covariance structures will be tested for use. The MMRM model may be repeated on 
additional analysis sets as a sensitivity analysis. If the normality assumption is 
violated, analysis of covariance (ANCOVA) on rank-transformed data will be used as 
utility analysis and additional supportive analyses may be performed. 
Other sensitivity analyses may be performed on the primary endpoint to assess the 
robustness of the results based on the model used for primary analysis. This analyses 
may include multiple imputation and pattern-mixture models for handling of missing 
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data. Details will be provided in the SAP. The analyses will be performed according 
to the National Academy of Sciences (2010) guidelines. 
Analysis of Secondary Efficacy Endpoints: Other secondary efficacy endpoints will 
be analyzed using the change in mean as appropriate. 
 
WOMAC LK3.1 OA Index (pain) – change between Baseline and Week 1 and 2 
 
WOMAC LK3.1 OA Index (stiffness) 
 
WOMAC LK3.1 OA Index (physical function) 
 
WOMAC LK3.1 OA Index (composite score) 
 
Patient Global Assessment 
 
Patient Global Impression of Change 
 
Pain intensity assessed on an 11-point NRS 
 
Use of rescue medication 
Additional categorical response analyses may be performed; additional details will be 
provided in the SAP. Additional categorical response analyses may be performed; 
additional details will be provided in the SAP. 
Analysis of Safety: All safety summaries will be descriptive; statistical significance 
tests may be performed on safety data that will be described in the SAP. Safety 
variables include treatment-emergent AEs, clinical laboratory values, vital signs, ECG 
readings, physical examination results, and dermal safety results. No formal 
inferential analyses will be conducted for safety variables, unless otherwise noted. 
Analysis of PK: Plasma concentrations of diclofenac (for both HP-5000
 and 
HP-5000
 will be evaluated and summarized as descriptive statistics by 
treatment. 
SAMPLE SIZE 
DETERMINATION 
Assuming an effect size of 
 
 
on the change in WOMAC pain score from baseline to Week 4 between active HP-
5000
 and HP-5000
 treatments and placebo, the probability for detecting 
the clinically meaningful effect size 
or higher will be approximately 67% having 
75 evaluable subjects per each active arm and 150 evaluable subjects in the placebo 
arm. Having 3 treatment arms, the total number of subjects randomized in the trial 
and included in the primary analysis set should be approximately 300. A sufficient 
number of subjects will be screened to randomize the proposed sample size. 
STUDY TREATMENT 
DURATION 
The maximum treatment duration for each subject is 4 weeks. The total duration of 
study participation for each subject is approximately 7 weeks. 
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3. TABLE OF CONTENTS 
1. 
APPROVAL SIGNATURES ...................................................................................................2 
2. 
SYNOPSIS ...............................................................................................................................3 
3. 
TABLE OF CONTENTS .........................................................................................................9 
4. 
LIST OF ABBREVIATIONS.................................................................................................13 
5. 
INTRODUCTION ..................................................................................................................15 
5.1. Background and Rationale ............................................................................................15 
5.2. Clinical Experience .......................................................................................................15 
5.3. Summary of Potential Risks and Benefits .....................................................................17 
6. 
OBJECTIVES .........................................................................................................................18 
6.1. Primary Objective .........................................................................................................18 
6.2. Secondary Objectives ....................................................................................................18 
7. 
STUDY DESIGN ...................................................................................................................19 
7.1. Overall Study Design and Plan .....................................................................................19 
7.2. Discussion of Study Design ..........................................................................................21 
7.3. Study Sites .....................................................................................................................21 
8. 
SUBJECT POPULATION .....................................................................................................22 
8.1. Selection of Study Population .......................................................................................22 
8.2. Study Entry Criteria ......................................................................................................22 
8.2.1 Inclusion Criteria ...............................................................................................22 
8.2.2 Exclusion Criteria ..............................................................................................23 
8.3. Premature Subject Withdrawal .....................................................................................24 
8.4. Subject Replacement Criteria ........................................................................................24 
9. 
TREATMENTS ......................................................................................................................25 
9.1. Identification of Investigational Product .......................................................................25 
9.1.1 Labeling .............................................................................................................25 
9.1.2 Packaging ..........................................................................................................25 
9.2. Treatments Administered ..............................................................................................26 
9.3. Dispensing and Storage .................................................................................................26 
9.4. Method of Assigning Subjects to Treatment Groups ....................................................26 
9.5. Blinding and Unblinding Treatment Assignment .........................................................27 
9.6. Selection of Doses and Administration in the Study ....................................................27 
9.7. Dose Adjustment Criteria ..............................................................................................27 
9.8. Drug Accountability ......................................................................................................28 
9.9. Treatment Compliance ..................................................................................................28 
9.10. Permitted and Prohibited Therapies ..............................................................................28 
9.10.1 Permitted Therapies ...........................................................................................28 
9.10.2 Prohibited Therapies ..........................................................................................29 
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9.11. Treatment after End of Study ........................................................................................29 
10. STUDY PROCEDURES ........................................................................................................30 
10.1. Study Periods and Visits ...............................................................................................30 
10.1.1 Screening and Washout .....................................................................................30 
10.1.1.1 Screening ...............................................................................................30 
10.1.1.2 Washout Period .....................................................................................30 
10.1.2 Baseline Visit (Day 0) .......................................................................................31 
10.1.3 Double-blind Treatment Period .........................................................................31 
10.1.4 Follow-up Visit ..................................................................................................32 
10.1.5 Early Termination Visit (if applicable) .............................................................32 
10.1.6 Overall Study Schedule .....................................................................................33 
10.2. Assessments ..................................................................................................................33 
10.2.1 Efficacy .............................................................................................................33 
10.2.1.1 Western Ontario and McMaster Universities Osteoarthritis Index .......33 
10.2.1.2 Patient Global Assessment ....................................................................34 
10.2.1.3 Patient Global Impression of Change ...................................................34 
10.2.1.4 Numeric Rating Scale ...........................................................................35 
10.2.1.5 Use of Rescue Medication ....................................................................35 
10.2.2 Safety .................................................................................................................35 
10.2.2.1 Laboratory Safety Assessments ............................................................35 
10.2.2.2 Clinical Examinations ...........................................................................36 
10.2.2.3 Adverse Events......................................................................................37 
10.2.2.4 Evaluations of Patch and Dermal Assessment ......................................37 
10.2.3 Pharmacokinetic Assessments ...........................................................................39 
11. ADVERSE EVENTS..............................................................................................................40 
11.1. Definitions .....................................................................................................................40 
11.1.1 Adverse Events ..................................................................................................40 
11.1.2 Unexpected Adverse Event ...............................................................................40 
11.1.3 Serious Adverse Events .....................................................................................40 
11.1.4 Significant Adverse Events ...............................................................................41 
11.2. Management of Adverse Events ...................................................................................41 
11.2.1 Collection ..........................................................................................................41 
11.2.2 Evaluation ..........................................................................................................41 
11.2.2.1 Severity of Adverse Events ...................................................................41 
11.2.2.2 Seriousness ............................................................................................42 
11.2.2.3 Action Taken .........................................................................................42 
11.2.2.4 Outcome at the Time of Last Observation ............................................42 
11.2.2.5 Adverse Event Relationship to Investigational Product........................42 
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11.2.3 Documentation ..................................................................................................43 
11.2.4 Treatment of Adverse Events ............................................................................43 
11.2.5 Follow-up ..........................................................................................................43 
11.2.6 Notification ........................................................................................................44 
11.2.6.1 Serious Adverse Events.........................................................................44 
11.2.6.2 Nonserious Adverse Events ..................................................................45 
11.2.7 Adverse Events of Special Interest ....................................................................45 
11.2.8 Pregnancy ..........................................................................................................45 
12. DATA SAFETY MONITORING BOARD ...........................................................................47 
13. STATISTICAL METHODS ...................................................................................................48 
13.1. Study Endpoints ............................................................................................................48 
13.1.1 Primary Efficacy Endpoint ................................................................................48 
13.1.2 Secondary Efficacy Endpoints ..........................................................................48 
13.1.3 Safety Endpoints ................................................................................................48 
13.1.4 Pharmacokinetics Endpoint ...............................................................................48 
13.2. Sample Size Determination ...........................................................................................48 
13.3. Analysis Populations .....................................................................................................49 
13.4. Statistical Analyses .......................................................................................................49 
13.4.1 Study Subjects and Demographics ....................................................................50 
13.4.1.1 Disposition and Withdrawals ................................................................50 
13.4.1.2 Protocol Deviations ...............................................................................50 
13.4.1.3 Demographics and Other Baseline Characteristics ...............................50 
13.4.2 Exposure and Compliance .................................................................................50 
13.4.3 Efficacy Analyses ..............................................................................................50 
13.4.3.1 Primary Analysis ...................................................................................50 
13.4.3.2 Analyses for Secondary Endpoint .........................................................51 
13.4.4 Safety and Tolerability Analyses ......................................................................51 
13.4.5 Pharmacokinetic Analyses ................................................................................51 
13.4.5.1 Adverse Events......................................................................................51 
13.4.5.2 Clinical Laboratory Evaluations ...........................................................52 
13.4.5.3 Vital Signs .............................................................................................52 
13.4.5.4 Electrocardiograms ...............................................................................52 
13.4.5.5 Physical Examination Findings .............................................................52 
13.4.5.6 Dermal Safety........................................................................................52 
13.4.6 Interim Analysis ................................................................................................52 
14. STUDY CONDUCT ...............................................................................................................53 
14.1. Sponsor and Investigator Responsibilities ....................................................................53 
14.1.1 Sponsor Responsibilities ...................................................................................53 
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14.1.2 Investigator Responsibilities .............................................................................53 
14.2. Site Initiation .................................................................................................................54 
14.3. Screen Failures ..............................................................................................................54 
14.4. Study Documents ..........................................................................................................54 
14.4.1 Investigator’s Regulatory Documents ...............................................................54 
14.4.2 Case Report Forms ............................................................................................54 
14.4.3 Source Documents .............................................................................................55 
14.5. Data Quality Control .....................................................................................................55 
14.5.1 Monitoring Procedures ......................................................................................55 
14.5.2 Data Management ..............................................................................................55 
14.5.3 Quality Assurance/Audit ...................................................................................56 
14.6. Study Termination .........................................................................................................56 
14.6.1 Record Retention ...............................................................................................56 
14.6.2 Sample Retention ..............................................................................................57 
14.7. Changes to the Protocol ................................................................................................57 
14.8. Use of Information and Publication ..............................................................................57 
15. ETHICAL AND LEGAL CONSIDERATIONS ....................................................................58 
15.1. Declaration of Helsinki and Good Clinical Practice .....................................................58 
15.2. Subject Information and Informed Consent ..................................................................58 
15.3. Approval by Institutional Review Board ......................................................................58 
15.4. Finance and Insurance ...................................................................................................58 
16. REFERENCES .......................................................................................................................59 
17. ATTACHMENTS ...................................................................................................................60 
17.1. Schedule of Events ........................................................................................................61 
17.2. Investigator’s Agreement ..............................................................................................63 
18. APPENDICES ........................................................................................................................64 
18.1. Western Ontario and McMaster Universities Osteoarthritis (WOMAC) LK3.1 Index 65 
18.2. Patient Global Assessment Scale (PGA).......................................................................66 
18.3. Patient Global Impression of Change Scale ..................................................................67 
18.4. 11-Point Numeric Rating Scale (NRS) .........................................................................68 
18.5. Regulations and Good Clinical Practice Guidelines .....................................................69 
18.5.1 Regulations ........................................................................................................69 
18.5.2 Good Clinical Practice Guidelines ....................................................................69 
 
LIST OF FIGURES 
Figure 1 
Study Design .....................................................................................................20 
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4. LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
APAP 
acetaminophen  
ASA 
acetyl salicylic acid 
AST 
aspartate aminotransferase 
BMI 
body mass index 
CRA 
clinical research associate 
CRO 
contract research organization  
 
 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent-to-treat 
IVRS 
interactive voice response system 
LD 
low dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OTC 
over the counter 
PK 
Pharmacokinetics 
PAS 
pharmacokinetic analysis set 
SAE 
serious adverse event 
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SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOP 
standard operation procedure 
TEAE 
treatment-emergent adverse event 
TDDS 
transdermal drug delivery system  
ULN 
upper limit of normal 
WOMAC 
West Ontario and McMasters Universities Osteoarthritis Index 
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6. OBJECTIVES 
6.1. Primary Objective 
 To evaluate efficacy of HP-5000 compared to placebo 
 To evaluate the safety of HP-5000 compared to placebo 
 
6.2. Secondary Objectives 
 Secondary objectives include the following:To assess the skin irritation, discomfort, 
adhesion, and adhesive residue of HP-5000  
 To assess the plasma concentrations of diclofenac following administration of HP-5000 
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7.
STUDY DESIGN
7.1. Overall Study Design and Plan 
This 4-week, randomized, double-blind, multicenter, placebo-controlled study is designed to 
compare the safety and efficacy of HP-5000 with that of placebo in the treatment of OA. Subjects 
will be randomly assigned to receive 1 of the following 3 treatments in a 1:1:2 ratio: HP-5000
 
patch, HP-5000
 patch, or placebo  patch 
 The placebo patch will be identical in 
appearance to the 2 HP-5000 active patches. The total number of subjects randomized in the trial 
and included in the primary analysis will be approximately 300. The duration of double-blind 
treatment is expected to be 4 weeks and the total time in the study will be approximately 7 weeks. 
Efficacy will be assessed by the change from baseline values in the Western Ontario and McMaster 
Universities (WOMAC) LK3.1 OA index for pain. Efficacy assessments will also include the use 
of the WOMAC LK3.1 OA index for stiffness, physical function, and composite score, the Patient 
Global Assessment, the Patient Global Impression of Change, pain intensity assessed on an 
11-point NRS and the subjects’ use of rescue medication.
Safety will be assessed by evaluating adverse events (AEs), physical examination findings, vital 
sign measurements, electrocardiogram (ECGs),  clinical laboratory test results, and body weight. 
All AEs observed by the study personnel or reported by the subject during the study (from the time 
of study drug administration through the posttreatment visit) will be documented. 
Dermal characteristics will be assessed by 5-point numerical scale of adhesion, Berger and 
Bowman scale of Irritation, 5-point numerical scale of Discomfort, and 5-point numerical scale of 
Adhesive Residue.4 In addition, subjects will record the 
 patch application and removal times 
in electronic diaries along with any incidence of patch detachment. 
Plasma concentrations of diclofenac will be assessed by venous blood sampling on Day 14 and 28 
(or at the early termination visit). 
Figure 1 presents a schematic view of the study design. 
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7.2. Discussion of Study Design 
The double-blind, placebo-controlled study uses 3 patches (2 formulations of HP-5000 and 
placebo) of identical appearance to ensure blinding.  
The use of rescue medication is prohibited within 2 calendar days prior to the baseline visit and 
within 1 calender day prior to clinic visits during the treatment period, thus ensuring the integrity 
of the assessments. 
7.3. Study Sites 
The study will take place at approximately 
 sites in the US. Each site is anticipated to screen a 
sufficient number of subjects to be able to randomize an aggregate number of approximately 
300 subjects.  
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or has had a hysterectomy with or without bilateral oophorectomy at least 6 months 
prior to the screening visit  
7. Signed informed consent form  
8. Able to swallow and tolerate rescue medication with APAP (moderately sized tablets) 
 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if the he or she meets any of the following criteria: 
1. Body mass index (BMI) > 40 
2. At Screening and Baseline (Day 0), the non-target knee pain severity score is 
 
  
3. Any subject who disobeyed the restriction of prohibited therapies (eg, rescue medication) 
during Screening/Washout period. 
4. Secondary OA of the knee (rheumatoid arthritis, gout, psoriasis, syphilitic neuropathy, 
ochronosis, metabolic or other primary bone disease or acute trauma)  
5. Clinically significant elevation of serum creatinine (176.8 μmol/L), aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) (3 x upper limit of normal [ULN])  
6. Known allergy or hypersensitivity to the use of diclofenac, 
 
 
 
ethanol, acetylsalicylic acid (aspirin [ASA]), or any other NSAID  
7. Severe, uncontrolled cardiac, renal, hepatic or other systemic disease  
8. A documented (upper GI series or endoscopy) gastroduodenal ulcer or any GI bleeding (except 
hemorrhoidal) within 6 months prior to screening visit  
9. Documented history of alcohol or drug abuse within 1 year prior to study entry or positive 
alcohol/drug screen findings at screening or baseline 
10. Presence of chondrocalcinosis on X-ray if associated with a history of pseudogout or 
inflammatory flare-ups  
11. MAJOR SURGERY: Previous damage or surgery to the knee at any time (ie, 
damage/reconstruction of the anterior or posterior cruciate ligaments)  
12. MINOR SURGERY on the target knee defined as anything other than major surgery as defined 
above less than 1 year before enrolment  
13. Current treatment with oral, topical, intra-articular, or intra-muscular corticosteroids on the 
target knee within 90 days of screening visit or into any other joint within 30 days of screening 
14. Any subject who had received intra-articular viscosupplementation (eg, Synvisc®) in the target 
knee 90 days prior to screening visit  
15. Any subject who had used opioids 7 days prior to the screening visit.  
16. Any subject who had previous exposure to HP-5000 
17. Use of another investigational drug within 30 days prior to study entry  
18. Any subject with resolved, ongoing, or pending litigation or disability related to any health-
related cause  
19. Any subject with fibromyalgia  
20. Any painful or disabling conditions affecting the knee or leg  
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21. Any skin abnormality present at the potential patch application site that is likely to be 
aggravated by the study drug (ie, infection, rash, excessive fragility or dryness, any cut or 
abrasion), presence of tattoo, excessive hair or open sores, or scar tissue. Presence of 
significant skin disorder such as atrophy, psoriasis, or vitiligo 
22. Any subject expecting to have knee replacement surgery within 6 months 
23. Any subject with a psychiatric condition which in opinion of the investigator, may interfere 
with participation in the study 
24. The subject is an employee, or family member of an employee, of the study center, the contract 
research organization (CRO) or the sponsor involved in this study.. 
8.3. Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. Every reasonable attempt should be made by the 
investigator to keep subjects in the study; however, subjects must be withdrawn from the study if 
they withdraw consent to participate. Investigators must attempt to contact subjects who fail to 
attend scheduled visits by telephone or other means.  
Subjects may be withdrawn if continuing in the study is not in the subject’s best interest, their 
condition worsens during the study, or for safety reasons, as determined by the investigator. 
Subjects may also be withdrawn due to lack of compliance with the protocol or if the subject is 
unwilling to continue participation in the trial. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that are to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4. Subject Replacement Criteria 
Subjects who withdraw after randomization and the application of the first treatment patch will 
not be replaced. 
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9.2. Treatments Administered 
HP-5000 will be administered 
 for a maximum of 28 days. 
The treatment arms for this study are the following: 
Treatment Arm 
 Treatment 
HP-5000
  
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
HP-5000
 
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
Placebo 
One patch applied 
 to alternate side of the target knee (inner 
or outer). 
Patch Application 
An example of the guidance information to be provided to subjects for applying, securing, and 
removing the patch will be provided separately.  
9.3. Dispensing and Storage 
The IP supplied by 
 is to be used exclusively in the clinical 
study according to the instructions of this protocol. The investigator is responsible for dispensing 
the IP according to the dosage scheme and for ensuring proper storage of the IP. 
The investigator must confirm the receipt of the IP with his/her signature. A copy of this receipt 
must be kept by the investigator, and another copy will be stored at Noven Pharmaceuticals, Inc. 
(hereafter referred to as “Noven”), and/or 
 Until the IP is dispensed to the 
subjects, it must be stored at 25°C and in a dry place in a securely locked area that is not generally 
accessible. 
The key to the storage area is to be kept by the investigator or designee responsible for the IP. The 
storage area will be accessible only to those persons authorized by the investigator to dispense the 
IP. 
9.4. Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly 
assigned in a 1:1:2 ratio to HP-5000
 HP-5000
 or placebo patches. The 
randomization schedule will be computer generated using a permuted block algorithm and will 
randomly allocate IP to randomization numbers. The randomization numbers will be assigned 
sequentially through a central interactive voice response system (IVRS) as subjects are entered 
into the study. The study center will not be a blocking factor in the randomization schedule. 
The randomization schedule will be prepared by Premier Research before the start of the study. 
No one involved in the clinical conduct will have access to the randomization schedule before 
official unblinding of treatment assignment. No subject will be randomized into this study more 
than once. 
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9.8. Drug Accountability 
The investigator must maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the IP including the date, quantity, batch or code number, and identification of 
subjects (subject number [and initials]) who received the IP. The investigator will not supply the 
IP to any person except those named as subinvestigators (on the Form FDA 1572), designated 
study personnel, and subjects in this study. The investigator will not dispense the IP from any study 
sites other than those listed (on the Form FDA 1572). The IPs may not be relabeled or reassigned 
for use by other subjects. If any of the IP is not dispensed, is lost, stolen, unusable, or is received 
in a damaged container, this information must be documented and reported to Noven and 
appropriate regulatory agencies, as required. 
Upon completion of the study, the IP must be left in the original packaging and returned to the 
sponsor or designee for destruction or return. 
9.9. Treatment Compliance 
Treatment compliance with IP regimens will be assessed by study personnel via the counts of 
returned unused patches and by questioning the subject, if necessary, at every post-randomization 
visit. A subject who is not compliant (used 6 or less patches per week) will be counseled at each 
visit on the importance of taking the IP as instructed. A subject who is deemed noncompliant on 
2 consecutive visits may be withdrawn from the study. 
For each 28-day administration period, subjects will be asked to record their daily intake/use of 
rescue medication/IP in the diary. Deviations from the planned doses (missed dose or timing) will 
be recorded on the subjects’ eCRF. These diaries will be reviewed by study personnel at each visit 
and will be collected as source documents. Information from that subject diary will be transcribed 
on the appropriate eCRF pages for documentation of subject compliance with IP. 
9.10. Permitted and Prohibited Therapies 
Some designated therapies are prohibited during the study. Prior to the double-blind treatment 
period, subjects will stop taking all prescription and over-the-counter (OTC) analgesic medications 
for at least 7 days; however, rescue medication (acetaminophen [APAP]) is permitted during the 
wash-out if required. A maximum of 2 g/day of APAP will be allowed for rescue treatment of both 
target and non-target knee pain except within the 2 calendar days prior to the baseline visit (ie, 
rescue medication is prohibited from Day -2 until clinic visit on Day 0) and within the 1 calendar 
day prior to each clinic visit (eg, rescue medication is prohibited from Day 6 until clinic visit on 
Day 7 if the subject will visit the study site on Day 7). APAP will be prepared by the Sponsor. 
Subjects are not allowed to apply HP-5000 on the non-target knee at any time in the study period.  
All concomitant medications used (including OTC medications and herbal supplements) will be 
recorded in the source document and on the appropriate eCRF.  
9.10.1 Permitted Therapies 
Glucosamine, chondroitin, and antidepressants (for indication of depression) will be allowed if 
used as stable therapy for 90 days prior to screening visit. Other concomitant medications for 
treatment of ongoing medical conditions are allowed, but should be limited to those medications 
considered necessary in the opinion of the investigator.  
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9.10.2 Prohibited Therapies 
Any NSAIDs (selective or nonselective), any opioids, APAP (>2 g/day), ASA (>81 mg/day), 
corticosteroids (a stable does by inhalation for seasonal allergies and/or topical use for 
dermatologic allergies are allowed), anticonvulsants (ie, pregabalin and gabapentine), muscle 
relaxants, other oral analgesics (prescribed or OTC), antidepressants prescribed for the control of 
chronic pain syndromes, antihistamine with a sedative effect, sedatives for insomnia, topical 
products on the knee including methyl salicylate, camphor, menthol, methylsulfonylmethane, 
 or capsaicin, any intra-articular treatments for the knee, any nonpharmaceutical therapy or 
device to relieve knee pain (including physiotherapy, massage therapy, hot wax therapy etc.) may 
not be taken during the study. 
Glucosamine, chondroitin, and antidepressants (for the indication of depression) will be allowed 
if used as stable therapy for 90 days prior to screening visit. However, if in use for fewer than 
90 days, these drugs will be considered as prohibited concomitant medications and will require 
washout. 
Subjects will be allowed to continue stable ASA therapy not for OA pain (up to 81 mg/day). 
9.11. Treatment after End of Study 
After completing the study, each subject will be referred to their primary care physician and treated 
according to standard clinical practice. 
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10. STUDY PROCEDURES 
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of events 
(Section 17.1). Throughout the study, every reasonable effort should be made by study personnel 
to follow the timing of assessments and procedures in the schedule of events for each subject. If a 
subject misses a study visit for any reason, the visit should be rescheduled as soon as possible. 
10.1. Study Periods and Visits 
10.1.1 Screening and Washout 
10.1.1.1 Screening 
Screening/Washout period should be at least 10 days up to 17 days prior to the baseline visit. The 
subject must be screened before entering the washout period of the study. The following 
procedures will be performed at screening: 
1. Obtain written informed consent and assign a screening number. 
2. Assess inclusion/exclusion criteria. 
3. Collect demographic information and record medical history, including current therapies (eg, 
prescription and nonprescription medications). 
4. Perform a physical examination including weight, height, and vital signs. 
5. Perform urine drug, alcohol and pregnancy tests. 
6. Identify the target knee.  The subject will be instructed to refer to this specific (target) knee 
throughout his/her participation in the study when responding to study efficacy assessment.  
7. Instruct the subject how to use NRS and WOMAC before performing first assessments 
8. Perform WOMAC pain intensity, stiffness and physical function assessments 
9. Calculate WOMAC composite score 
10. Perform NRS evaluation for the target knee and the non-target knee pain, review of x-ray of 
the target knee, 12-lead ECG, and laboratory tests to determine eligibility. 
11. Instruct the subject in the use of an electronic diary 
12. Dispense rescue medication. 
13. Dispense electronic diary. 
10.1.1.2 Washout Period 
Three days after the screening visit, subjects whose eligibility has been preliminarily confirmed at 
screening will be asked to wash out of current medications for at least 7 days (up to 14 days). 
During this period, the following will take place: 
1. Electronic diary NRS pain scores before the Washout Period will be reviewed by the 
investigator or the study coordinator. A record of this review will be recorded in the source 
documents and eCRFs. 
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2. Subjects will stop taking all prescription and OTC analgesic medications, but will be informed 
that rescue medication may be used (a maximum of 2 g/day) except within 2 calendar days 
prior to the baseline visit. 
3. Perform an NRS assessment for the target knee pain. 
4. Review subject’s use of rescue medication. 
10.1.2 Baseline Visit (Day 0) 
The following will take place during the baseline visit (Day 0): 
1. Review subject’s continued eligibility relative to inclusion/exclusion criteria. 
2. Randomly assign the subject to a treatment group using IVRS and assign a subject ID number. 
3. Obtain vital sign measurements, including weight. 
4. Perform WOMAC pain intensity, stiffness and physical function assessments. 
5. Calculate WOMAC composite score 
6. Perform Patient’s Global Assessment. 
7. Perform an NRS 11-point pain assessment for the target knee and non-target knee pain. 
8. Review subject’s use of rescue medication. 
9. Perform a 12-lead ECG. 
10. Obtain blood and urine samples for laboratory testing. 
11. Perform a urine pregnancy test. 
12. Review the subject’s diary entries. 
13. Perform baseline dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
14. Review subject’s use of prior medications. 
15. Dispense rescue medication and perform rescue medication accountability/ reconciliation  
16. Dispense double-blind study medication and instruct subjects on proper patch application.  
Subjects should apply the first day of study medication to the target knee in the presence of 
site staff, unless the subject intends to shower/bathe later in the day. For this scenario, the first 
patch should be applied at home after showering/bathing. 
17. Subjects will be instructed not to bathe or shower while wearing the study medication; a bath 
or a shower may be taken in the morning/in the evening before the first patch is applied. 
18. Subjects will also be instructed not to participate in strenuous activities or other activities that 
cause heavy perspiration during the double-blind treatment period. 
10.1.3 Double-blind Treatment Period 
During the 4-week double-blind treatment period, the following will take place: 
1. Obtain vital sign measurements (during clinic Visits 3, 4, and 5, only). 
2. Perform WOMAC pain intensity, stiffness and physical function assessments (during clinic 
Visits 3, 4, and 5, only). 
3. Calculate WOMAC composite score (during clinic Visits 3, 4, and 5, only). 
4. Perform Patient Global Assessment (during clinic Visits 3, 4, and 5) 
5. Perform Patient Global Impression of Change (during clinic Visits 3, 4, and 5). 
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6. Perform daily NRS 11-point pain assessments for the target knee pain. 
7. Review subject’s use of rescue medication  
8. Perform a urine pregnancy test (during clinic Visits 3, 4, and 5) 
9. Re-instruct the subject concerning the patch application method if the subject has a problem 
with patch application and/or patch adhesion 
10. Dispense study medication/rescue medication and perform drug accountability/ reconciliation  
11. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
12. Review subject’s use of concomitant medications  
13. Review AEs  
14. Review the subjects’ diary entries 
15. Obtain blood samples for laboratory testing (clinic Visit 5). 
16. Obtain subject’s weight (clinic Visit 5). 
17. Obtain pharmacokinetic blood sample (clinic Visit 4 and 5). 
18. Perform a 12-lead ECG (clinic Visit 5). 
19. Perform physical examination (clinic Visit 5). 
20. During the time interval between visits, the site coordinator may regularly contact (by 
telephone) the subjects to ensure that the subject’s scheduled dose is administered and daily 
NRS pain scores are recorded correctly. The subjects will be informed that they may contact 
the site if problems/questions arise.  
10.1.4 Follow-up Visit  
This visit will take place approximately 7 days after the end-of-treatment visit (or early termination 
visit), and will include the following assessment and procedures: 
1. Collect and review the subjects’ electronic diaries. 
2. Review subject’s use of concomitant medications. 
3. Review AEs. 
10.1.5 Early Termination Visit (if applicable) 
If this visit is required, the following assessment and procedures will be performed:  
1. Perform physical examination. 
2. Obtain vital sign measurements. 
3. Obtain subject’s weight. 
4. Perform WOMAC pain intensity, stiffness and physical function assessment. 
5. Calculate WOMAC composite score 
6. Perform Patient’s Global Assessment.  
7. Perform Patient’s Global Impression of Changes 
8. Perform a NRS 11-point pain assessment for the target knee pain. 
9. Review subject’s use of rescue medication. 
10. Perform a 12-lead ECG. 
11. Obtain blood samples for laboratory testing. 
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12. Collect and review the subject’s diary entries. 
13. Perform drug accountability. 
14. Perform dermal safety assessment (irritation, discomfort, adhesion, adhesive residue). 
15. Review subject’s use of concomitant medications. 
16. Review AEs. 
17. Obtain pharmacokinetic blood sample. 
10.1.6 Overall Study Schedule 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening and Washout Periods: 10 to 17 days 
2. Double-blind Treatment Period: 4 weeks  
3. Follow up Period: 1 week  
The maximum treatment duration for each subject is approximately 4 weeks. The maximum study 
duration for each subject is approximately 7 weeks. 
10.2. Assessments 
10.2.1 Efficacy 
10.2.1.1  Western Ontario and McMaster Universities Osteoarthritis Index 
The Western Ontario and McMaster Universities Osteoarthritis Index Likert (LK) version 3.1 is 
the most recent version of this instrument for the assessment of hip and knee OA. The WOMAC 
Osteoarthritis Index is a widely used, self-administered assessment used to measure pain, stiffness, 
and physical function in subjects with OA. It is considered to be a reliable and valid instrument.5,6,7   
The WOMAC Pain scale evaluates the following 5 items:  
1. Walking 
2. Stair climbing 
3. Noctural 
4. Rest 
5. Weight bearing 
Each item is rated on a scale of 0 to 4, with 0 being no difficulty and 4 being extreme difficulty.  
The WOMAC Stiffness scale assesses 2 items: morning stiffness and stiffness occurring later in 
the day. Each item is rated on a scale of 0 to 4, with 0 being no difficulty and 4 being extreme 
difficulty. 
The WOMAC Physical Function assesses the following the following categories using the 0 to 4 
scale described previously: 
1. Descending stairs  
2. Ascending stairs 
3. Rising from sitting 
4. Standing 
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5. Bending to floor 
6. Walking on a flat surface 
7. Getting in/getting out of car 
8. Going shopping 
9. Putting on socks 
10. Lying in bed 
11. Taking off socks 
12. Rising from bed 
13. Getting in/out of bath 
14. Sitting 
15. Getting on/off toilet 
16. Heavy domestic duties 
17. Light domenstic duties 
The Womac Composite score is most commonly calculated by summing the items for all 3 
subscales. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. 
The total score is calculated as follows: Total score= __/96= __% 
10.2.1.2 Patient Global Assessment 
The PGA is a self-administered instrument that measures the subject’s overall impression of their 
OA in their target knee on a 5-point scale where 0 = “Very Good” and 4 = “Very Poor”.   
Subjects will be asked the complete the following statement: “How would you rate your 
osteoarthritis condition over the last 24 hours?”  The response options include the following: 
 
Very Good 
0 
 
Good 
1 
 
Moderate 
2 
 
Poor 
3 
 
Very Poor 
4 
10.2.1.3 Patient Global Impression of Change 
The Patient Global Impression of Change is a self-administered instrument that measures change 
in subjects’ overall improvement with treatment on a scale where 1 = “very much improved” and 
7 = “very much worse.” Subjects will be asked the following question: “How would you rate your 
overall improvement with treatment during the clinical trial?” The response options include the 
following: 
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Very Much Improved 
1 
 
Much Improved 
2 
 
Minimally Improved 
3 
 
No Change 
4 
 
Minimally Worse 
5 
 
Much Worse 
6 
 
Very Much Worse 
7 
10.2.1.4 Numeric Rating Scale 
The NRS is an 11-point scale from 0 to 10. On this scale, 0 = no pain and 10 = the worst pain 
imaginable. NRS will be assessed in two ways. One is the average pain condition over the last 
24 hours, and the other is the worst painful condition over the last 24 hours.  
Pain intensity in the target knee will be assessed using an 11-point NRS.The subject will rate his 
or her target knee pain intensity using the following question: “On a scale from 0 to 10, where 
“zero” represents “no pain” and “10” represents “the worst possible pain,” how would you rate the 
pain that you have been feeling in your knee over the last 24 hours?” 
Note: 
1. The NRS pain score for assessment is an average of the NRS pain scores reported for pain 
over the last 24 hours for the last 3 days prior to each clinic or phone visit except Screening 
Visit. 
2. The NRS pain scores in at least 2 of the last 3 days prior to wash-out start (Phone Visit 1) 
and Baseline (Visit 2) are required. 
10.2.1.5 Use of Rescue Medication 
For the 4-week double-blind treatment period, subjects will be asked to record their daily 
intake/use of rescue medication in the diary. Rescue medication will be limited as follows: 
2 gram/day APAP may be used except within 2 calendar days prior to the baseline visit and within 
1 calendar day prior to other visits.  
10.2.2 Safety 
Safety assessments will include the evaluation of laboratory assessments, vital signs, 12-lead 
ECGs, physical examinations, and AEs. 
10.2.2.1 Laboratory Safety Assessments 
10.2.2.1.1 Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
schedule of events (Section 17.1). 
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Hematology: 
hemoglobin, hematocrit, red blood cell (RBC) count, RBC indices, mean 
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 
platelet count (or estimate), white blood cell count including differential 
Serum chemistry: 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, 
creatinine, glucose, sodium, potassium, chloride, bicarbonate, lactate 
dehydrogenase, uric acid 
Coagulation panel: prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis: 
pH, specific gravity, blood, glucose, protein, ketones 
Pregnancy test 
(urine): 
for women of childbearing potential only 
Urine drug screen: 
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, and tetrahydrocannabinol. 
Blood and urine samples for hematology, serum chemistry, and urinalysis will be sent to a central 
laboratory for analysis. Urine drug screens and pregnancy tests will be conducted at the study sites. 
10.2.2.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist regarding the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 
of biological samples are outlined in the HP-5000-US-05 laboratory manual. The investigator is 
responsible for ensuring that all study samples that are to be transported to another location are 
appropriately packed and shipped according to the applicable regulations.  
10.2.2.2 Clinical Examinations 
10.2.2.2.1 Vital Signs 
Vital signs, including heart rate, respiratory rate, and sitting blood pressure will be measured at 
designated timepoints after the subject has been in a sitting position for 5 minutes. Temperature 
will also be measured. 
10.2.2.2.2  Electrocardiogram 
A standard 12-lead ECG will be performed at designated timepoints after the subject has been 
supine for at least 5 minutes. All ECG recordings will be identified with the subject number, 
initials, date, and time of the recording and will be attached to the subject’s eCRF. 
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10.2.2.2.3 Physical Examination 
The following physical examination will be performed at designated timepoints before potential 
exposure to the IP and at the completion of exposure. 
 General Appearance 
 Abdomen 
 Head/ Face 
 Skin, Hair, and Nails 
 Eyes/ Fundoscopy 
 Musculoskeletal: Extremities, Spine 
 Ears/Hearing 
 Vascular/Circulatory 
 Nose 
 Lymphatic 
 Mouth, Teeth and Throat 
 Psychiatric/Behavior 
 Neck & Thyroid 
 Brief neurologic 
 Chest/Lungs 
 
10.2.2.3 Adverse Events 
The definitions and management of and special considerations for AEs are provided in Section 11. 
10.2.2.4 Evaluations of Patch and Dermal Assessment 
Patch Adhesion  
Patch adhesion will be assessed in two ways. In the clinic, patch adhesion will be assessed by the 
investigator or a designee using a predefined patch adhesion scale with scores on a 5-point 
numerical scale, by reference to the Abbreviated New Drug Application draft guidance of June 
2016, at each clinic visit. The following information will be included in the full protocol that will 
be submitted with the IND:  
• 
0 = ≥90% adhered (essentially no lift off the skin)  
• 
1 = ≥75% to <90% adhered (some edges only lifting off of the skin)  
• 
2 = ≥50% to <75% adhered (less than half of the system lifting off of the skin)  
• 
3 = <50% adhered but not detached (more than half the system lifting off of the skin without 
falling off)  
• 
4 = patch detached (patch completely off the skin)  
During the treatment period at home, subjects will report the incidence of patch detachment by 
answering Yes or No. 
Irritation 
application site where the previous patch was applied will be examined for signs of skin irritation 
at each clinic visit. All subjects will be evaluated by a trained investigator or designee using the 
Berger and Bowman scale (Berger and Bowman 1982) as described below.  
Half grades will not be assigned if reactions fall between the unit grades, rather, the more severe 
of the 2 grades will be assigned. Findings will be graded using the following 2 scales, which will 
be included in the full protocol that will be submitted with the IND:  
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Dermal Response  
• 
0 = no evidence of irritation  
• 
1 = minimal erythema, barely perceptible  
• 
2 = definite erythema, readily visible; minimal edema or minimal papular response  
• 
3 = erythema and papules  
• 
4 = definite edema  
• 
5 = erythema, edema, and papules  
• 
6 = vesicular eruption  
• 
7 = strong reaction spreading beyond the application site  
Other Effects  
• 
A = slightly glazed appearance  
• 
B = marked glazed appearance  
• 
C = glazing with peeling and cracking  
• 
F = glazing with fissures  
• 
G = film of dried serous exudates covering all or part of the patch site  
• 
H = small petechial erosions and/or scabs  
• 
N = no other observations  
Dermal response score will be rated on a 0 to 7 scale, whereby 0 is rated as “No evidence of 
irritation” and 7 is rated as “Strong reaction spreading beyond test (application) site.” 
Other effects will be scored via a letter scale and a corresponding numeric scale, whereby N(0) is 
rated as “No effects” and H(3) is rated as “Small petechial erosions and/or scabs.” 
Discomfort  
Discomfort will be assessed by the investigator or a designee using a predefined discomfort rating 
scale. The evaluator will ask the subject, “Are you experiencing any discomfort related to the 
patch?” If the answer is no, the overall level of discomfort will be rated as 0. If the answer is yes, 
the evaluator will then ask the subject to rate the discomfort as mild, moderate, or severe. Any 
discomfort mentioned should be recorded and rated as follows:  
• 
0 = No discomfort  
• 
1 = Mild discomfort  
• 
2 = Moderate but tolerable discomfort  
• 
3 = Severe, intolerable discomfort  
• 
4 = Patch not present  
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Adhesive Residue  
The amount of adhesive residue remaining at the application site where the previous patch was 
applied will be examined by the investigator or a designee at each clinic visit and scored according 
to the scale below:  
• 
0 = None  
• 
1 = Light  
• 
2 = Medium  
• 
3 = Heavy 
• 
4 = Patch not present 
10.2.3 Pharmacokinetic Assessments 
Blood samples for plasma concentrations of diclofenac will be obtained on Day 14 and 28 or at 
the early termination visit. 
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11. ADVERSE EVENTS 
11.1. Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product. An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 
Events occurring in subjects treated with placebo are also considered AEs. However, AEs reported 
during treatment-free periods before IP has been administered are not considered AEs; these events 
are captured on the eCRF as updates to the subject’s medical history. 
11.1.2 Unexpected Adverse Event 
An expected AE is one for which the nature or severity is consistent with the known AE profile of 
the product. For an IP, the known information is contained in the IB which includes the HP-5000 
Develepmental Core Safety Information.  
An unexpected adverse event is one for which the specificity or severity is not consistent with the 
current IB and Develepmental Core Safety Information.  
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events.  
11.1.3 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 results in death 
 is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
 requires 
inpatient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
NOTE: An elective hospital admission to treat a condition present before exposure to the 
test drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP interacted with a 
contraceptive method and led to the pregnancy.  
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 is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, development of drug dependency, or drug abuse 
11.1.4 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of test drug, dose reduction, or significant additional concomitant therapy. 
11.2. Management of Adverse Events 
Adverse events will be collected from the time of first dose administration through the Follow-up 
Visit or Early Termination Visit, whichever occurs first. 
Subjects who terminate early will continue to be monitored for 30 days from last treatment for 
AEs, unless they withdraw consent or are lost to follow-up. 
11.2.1 Collection 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
 “How are you feeling?” 
 “Have you experienced any issues since your last visit?” 
 “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
11.2.2 Evaluation 
11.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
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It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.3. 
11.2.2.3 Action Taken 
Action taken may consist of 
Dose increased 
An indication that a medication schedule was modified by addition; either by 
changing the frequency, strength or amount. 
Dose not 
changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by subtraction, either 
by changing the frequency, strength or amount. 
Drug 
interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug 
withdrawn 
An indication that a medication schedule was modified through termination 
of a prescribed regimen of medication. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
11.2.2.4 Outcome at the Time of Last Observation 
The outcome at the time of last observation will be classified as follows: 
 Recovered/resolved 
 Recovered/resolved with sequelae 
 Recovering/resolving 
 Not recovered/not resolved 
 Fatal* 
 Unknown 
*Only select fatal as an outcome when the AE results in death. If more than 1 AE is possibly 
related to the subject’s death, the outcome of death should be indicated for each such AE. 
[Although “fatal” is usually an event outcome, events such as sudden death or unexplained death 
should be reported as SAEs.] 
11.2.2.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are listed below. 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (eg, no temporal relationship to drug administration, 
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because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven.) 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship improbable, and in which 
other drugs, events or underlying disease provide plausible explanations. 
Possibly related An AE with a reasonable time sequence to administration of the IP, but which 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 
Definitely 
Related 
An AE occurring in a plausible time relationship to IP administration, and 
which cannot be explained by a concurrent disease or other drugs or events. 
The response to withdrawal of the drug (dechallenge) is clinically reasonable. 
11.2.3 Documentation 
All AEs occurring within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2.) 
 AE name or term 
 When the AE first occurred (start date and time) 
 When the AE stopped (stop date and time or an indication of “ongoing”) 
 Severity of the AE 
 Seriousness (hospitalization, death, etc.) 
 Actions taken 
 Outcome 
 Investigator opinion regarding the AE relationship to the IP 
11.2.4 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. If such treatment constitutes a deviation from the protocol, the subject should be withdrawn 
from the study and the reason must be documented in the eCRF. The decision about whether the 
subject may continue in the study will be made by the sponsor after consultation with the 
investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
For doubleblinded studies like HP-5000-US-05, it is not necessary to unblind a subject’s treatment 
assignment in most circumstances, even if an SAE has occurred. If unblinding is necessary, see 
Section 9.5 for a description of the unblinding procedures. 
11.2.5 Follow-up 
Any AE will be followed (up to a maximum of 30 days after the last dose of study medication) to 
a satisfactory resolution, until it becomes stable, or until it can be explained by another known 
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causes (ie, concurrent condition or medication) and clinical judgment indicates that further 
evaluation is not warranted. All findings relevant to the final outcome of an AE must be reported 
in the subject’s medical record and recorded on the eCRF page.  
11.2.6 Notification 
11.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs promptly to 
 within 24 hours 
of first becoming aware of the event by completing, signing and dating the Serious Adverse Event 
Report Form, verifying the accuracy of the information recorded in the form with the source 
documents and eCRF, and sending the SAE form to the sponsor by one of the following methods:  
Email: 
 
Fax number: 
 
The written report should be submitted on the SAE form provided for this purpose. At the time of 
first notification, the investigator or designee should provide the following information, if 
available: 
 Protocol number 
 Reporter (study site and investigator) 
 Subject’s study number 
 Subject’s year of birth 
 Subject’s gender 
 Date of first dose of IP 
 Date of last dose of IP, if applicable 
 Adverse event term 
 Date of occurrence of the event 
 A brief description of the event, outcome to date, and any actions taken 
 The seriousness criteria that were met 
 Concomitant medication at onset of the event 
 Relevant medical history information 
 Relevant laboratory test findings 
 Investigator’s opinion of the relationship to IP. (“Is there a reasonable possibility that the IP 
caused the SAE? Yes or No?”) 
 Whether and when the investigator was unblinded as to the subject’s treatment assignment  
The investigator must fax/mail a written SAE Report Form that describes the SAE to the recipients 
of the initial information, who will forward the information to the sponsor.  
Any missing or additional relevant information concerning the SAE should be provided to the 
recipients of the initial information as soon as possible on a follow-up SAE Report Form, together 
with the following information (adverse event, date of occurrence, subject ID, study ID, IP, and 
site number); this will allow the follow-up information to be linked to the initial SAE report.  
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using the Pregnancy Data Collection Form via the same fax number and/or email address as for 
SAE reporting. The investigator should contact the designated individuals who receive SAE 
notification and record information related to the pregnancy on an Exposure in Utero form 
provided by the sponsor or its designee. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy. The investigator is also responsible for following the pregnancy until delivery or 
termination. These findings must be reported on the Exposure in Utero form and forwarded to the 
designated individuals. The event meets the SAE criterion only if it results in a spontaneous 
abortion or a congenital anomaly.  
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12. DATA SAFETY MONITORING BOARD 
There will be no Data Safety Monitoring Board for this study. 
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13.3. Analysis Populations 
The following 4 analysis populations are planned for this study:  
 Intent-to-Treat (ITT): includes all consented and randomized subjects. Regardless of any 
protocol deviations, analyses performed on the ITT set will be based on the randomized 
treatment assignment and all available data. 
 Full Analysis Set (FAS): includes all randomized subjects who have had at least 1 patch of 
double-blind study medication applied and who have a Baseline WOMAC pain score and 
at least 1 post-Baseline assessment of the primary efficacy measure (WOMAC pain score). 
Evaluable subjects will be defined as those who meet the FAS definition. The FAS will be 
used as the primary set for analysis of efficacy endpoints based on randomized treatment 
assignment. 
 Safety Analysis Set (SAF): includes all subjects who have had at least 1 patch of 
double-blind study medication applied and who have at least 1 post-dose safety 
measurement during the double-blind treatment period. In the unlikely event that errors 
may have occurred in treatment arm assignments, then analyses using the SAF will be 
based on treatment actually received. The SAF will be used for the analysis of dermal 
evaluations and safety endpoints. 
 Pharmacokinetic Analysis Set (PAS): includes all subjects who have received at least 
1 dose of study medication during the double blind treatment period and have at least 
1 blood sample for PK assessment. Subjects may be excluded from the PAS set if they 
significantly violate inclusion or exclusion criteria, significantly violate the protocol in a 
way that may influence the PK analysis, if any unexpected error occurs during the study 
that may influence the PK analysis (eg, early detachment of transdermal systems, apparent 
sample switching, etc.) or if their data are unavailable or incomplete. The PAS will be used 
for the analysis with model-based approach. Excluded cases will be documented together 
with the reason for exclusion. 
Inclusion in the analysis populations will be determined prior to database lock. 
If a subject is randomized incorrectly or is administered the incorrect IP, analyses of the 
ITT population will be based on the assigned treatment whereas all other analyses will be based 
on the actual treatment. 
13.4. Statistical Analyses 
This section presents a summary of the planned statistical analyses. A SAP that describes the 
details of the analyses to be conducted will be written prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of <0.05 will be considered statistically significant.  
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for analysis, or omitted from statistical models. The final determination will be made prior to 
database lock.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of subjects, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of subjects in each category. 
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Other sensitivity analyses may be performed on the primary endpoint to assess the robustness of 
the results based on the model used for primary analysis. This analyses may include multiple 
imputation and pattern-mixture models for handling of missing data. Details will be provided in 
the Statistical Analysis Plan (SAP). The analyses will be performed according to the National 
Academy of Sciences (2010) guidelines.8 
13.4.3.2  Analyses for Secondary Endpoint 
The following secondary endpoints will use the change in mean for analysis (as applicable):  
 WOMAC LK3.1 OA Index (pain) – change between Baseline and Week 1 and 2 
 WOMAC LK3.1 OA Index (stiffness) 
 WOMAC LK3.1 OA Index (physical function) 
 WOMAC LK3.1 OA Index (composite score) 
 Patient Global Assessment 
 Patient Global Impression of Change 
 Pain intensity assessed on an 11-point NRS 
 Use of rescue medication 
Additional categorical response analyses may be performed; additional details will be provided in 
the SAP. 
13.4.4 Safety and Tolerability Analyses 
All safety summaries will be descriptive; statistical significance tests may be performed on safety 
data that will be described in the SAP. 
Safety analyses will be conducted using data from the safety population (as defined in 
Section 13.3). Safety variables include treatment-emergent AEs, clinical laboratory values, vital 
signs, ECG readings, physical examination results, and dermal safety results. No formal inferential 
analyses will be conducted for safety variables, unless otherwise noted. 
13.4.5 Pharmacokinetic Analyses 
Plasma concentrations of diclofenac (for both HP-5000
 and HP-5000
 will be 
evaluated and summarized as descriptive statistics by treatment. 
13.4.5.1 Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), Version 19.  
Treatment-emergent AEs are defined as: 
 AEs with onset at the time of or following the start of treatment with IP through the follow-up 
visit or early termination visit, whichever occurs first.  The number and percentage of subjects 
with AEs will be displayed for each treatment group by system organ class and preferred term. 
Summaries of AEs by severity and relationship to IP will also be provided. Serious adverse 
events and AEs resulting in discontinuation of IP will be summarized separately in a similar 
manner. Subject listings of AEs, SAEs, and AEs causing discontinuation of IP will be 
produced. 
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13.4.5.2 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from baseline values will be presented for clinical laboratory values for each treatment 
group at each time point. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges will be tabulated showing change from baseline (shift tables) for each clinical 
laboratory analyte by treatment group and by study visit. Pre- and post-treatment values will also 
be presented with an analysis of mean changes from baseline.  
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with corresponding normal ranges. Any out-of-range values that are identified by the investigator 
as being clinically significant will also be shown in a data listing. 
13.4.5.3 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline will be calculated for systolic blood pressure, diastolic blood pressure, heart 
rate, and respiratory rate. 
The number of subjects with vital signs values categorized as below, within, or above normal 
ranges, will be tabulated showing change from baseline (shift tables) for each parameter by 
treatment group and by study visit. Pre- and post-treatment values may also be presented with an 
analysis of mean changes from baseline. 
13.4.5.4 Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized for each treatment group at each time point.  
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (both correction methods), and 
HR for each treatment group at each time point. 
13.4.5.5 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed for each treatment group. 
13.4.5.6 Dermal Safety 
The number and percentage of subjects with findings related to dermal safety including adhesion, 
irritation, discomfort, and adhesive residue will be summarized. A by-subject listing of individual 
dermal safety findings will also be provided. 
13.4.6 Interim Analysis 
No interim analyses are planned.  
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14. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1. Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15). The sponsor reserves the right to withdraw a subject from the study (Section 8.3), to 
terminate participation of a study site at any time (Section 14.6), and/or to discontinue the study 
(Section 14.6 for US studies). 
Noven agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.2), the investigator indicates that he/she has 
carefully read the protocol, fully understands the requirements, and agrees to conduct the study in 
accordance with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including the April 1996 International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
Guidance for Industry E6 Good Clinical Practise (GCP), and in agreement with the 2013 version 
of the Declaration of Helsinki. While delegation of certain aspects of the study to subinvestigators 
and study coordinators is appropriate, the investigator will remain personally accountable for 
closely overseeing the study and for ensuring compliance with the protocol and all applicable 
regulations and guidelines. The investigator is responsible for maintaining a list of all persons that 
have been delegated study-related responsibilities (eg, subinvestigators and study coordinators) 
and their specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related responsibilities 
are adequately qualified and informed about the protocol, IPs, and their specific duties within the 
context of the study. Investigators are responsible for providing Noven with documentation of the 
qualifications, GCP training, and research experience for themselves and their staff as required by 
the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
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14.2. Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB approval for the protocol and the appropriate 
ICF. 
2. All regulatory documents have been submitted to and approved by the sponsor or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation meeting. 
14.3. Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may not be rescreened for the study.  
14.4. Study Documents 
All documentation and material provided by Noven or 
 for this study are to be 
retained in a secure location and treated as confidential material. 
14.4.1 Investigator’s Regulatory Documents 
The regulatory documents are listed in the HP-5000-US-05 Study Manual. 
The regulatory documents must be received from the investigator and reviewed and approved by 
Noven or its designee before the study site can initiate the study and before Noven will authorize 
shipment of IP to the study site. Copies of the investigator’s regulatory documents must be retained 
at the study site in a secure location. Additional documents, including a copy of the protocol and 
applicable amendments, the HP-5000 topical patch IB, eCRF completion guidelines, copies of 
regulatory references, copies of IRB correspondence, and IP accountability records should also be 
retained as part of the investigator’s regulatory documents. It is the investigator’s responsibility to 
ensure that copies of all required regulatory documents are organized, current, and available for 
inspection. 
14.4.2 Case Report Forms 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
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14.4.3 Source Documents 
Information recorded in the EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data. 
14.5. Data Quality Control 
Noven and its designees will perform quality control checks on this clinical study. 
14.5.1 Monitoring Procedures 
Noven and/or its designee will conduct site visits to monitor the study and ensure compliance with 
the protocol, GCP, and applicable regulations and guidelines. The assigned clinical research 
associates (CRAs) will visit the investigator and study site at periodic intervals and maintain 
periodic communication. The investigator agrees to allow the CRAs and other authorized Noven 
personnel access. The CRAs will maintain current personal knowledge of the study through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigator and staff. While on site, the CRAs will review 
 regulatory documents, directly comparing entries in the EDC system with the source 
documents 
 consenting procedures 
 AE procedures 
 storage and accountability of IP and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF are described in the study manual. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to meet with the 
CRAs during study site visits; to ensure that study staff is available to the CRAs as needed; to 
provide the CRAs access to all study documentation, to the clinical supplies dispensing and storage 
area; and to assist the monitors in their activities, if requested. Further, the investigator agrees to 
allow Noven or designee auditors or inspectors from regulatory agencies to review records, and to 
assist the inspectors in their duties, if requested.  
14.5.2 Data Management 
Noven or designee will be responsible for activities associated with the data management of this 
study. The standard procedures for handling and processing records will be followed per GCP and 
 standard operating procedures. A comprehensive data management plan will 
be developed including a data management overview, description of database contents, annotated 
eCRF, pre-entry review list, self-evident correction conventions, query contacts, and consistency 
checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
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corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the study manual. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Noven or its designee. Audits may be undertaken to check 
compliance with GCP guidelines, and can include: 
 site audits 
 TMF audits 
 database audits 
 document audits (eg, protocol and/or CSR) 
Noven or its designee may conduct additional audits on a selection of study sites, requiring access 
to subject notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with eCRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Noven immediately. 
14.6. Study Termination 
The study may be terminated at Noven’s discretion at any time and for any reason. 
Study Site Closure: 
At the end of the study, all study sites will be closed. Noven may terminate participation of a study 
site at any time. Examples of conditions that may require premature termination of a study site 
include, but are not limited to, the following: 
 Noncompliance with the protocol and/or applicable regulations and guidelines 
 Inadequate subject enrollment 
14.6.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until 
 At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
 At least 2 years have elapsed since the formal discontinuation of clinical development of the 
IP 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of her/his intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
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14.6.2 Sample Retention 
Samples may be used for purposes related to this research. The samples will be stored until the 
sponsor has determined that specimens are no longer needed and the decision has been made that 
none of the samples needs to be reanalyzed. In addition, identifiable samples can be destroyed at 
any time at the request of the subject. 
14.7. Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Noven. The protocol amendment must be signed by the 
investigator and approved by the IRB before it may be implemented. Protocol amendments will 
be filed with the appropriate regulatory agency having jurisdiction over the conduct of the study. 
14.8. Use of Information and Publication 
All information concerning IP, Noven’s operations, patent applications, formulae, manufacturing 
processes, basic scientific data, and formulation information supplied by Noven or its designee to 
the investigator and not previously published, is considered confidential and remains the sole 
property of Noven. Case report forms also remain the property of Noven. The investigator agrees 
to use this information for purposes of study execution through finalization.  
The information developed in this study will be used by Noven in connection with the continued 
development of IP and thus may be disclosed as required to other clinical investigators or 
government regulatory agencies. 
The information generated by this study is the property of Noven. Publication or other public 
presentation of IP data resulting from this study requires prior review and written approval of 
Noven. Abstracts, manuscripts, and presentation materials should be provided to  
Noven for review at least 30 days prior to the relevant submission deadline.  
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until Noven has reviewed and commented on such a 
presentation or manuscript for publication. 
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15. ETHICAL AND LEGAL CONSIDERATIONS 
15.1. Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry E6 
GCP (including archiving of essential study documents), the 2013 version of the Declaration of 
Helsinki, and the applicable regulations of the country in which the study is conducted. 
15.2. Subject Information and Informed Consent 
A properly constituted, valid IRB must review and approve the protocol, the investigator’s 
informed consent document, and related subject information and recruitment materials before the 
start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
15.3. Approval by Institutional Review Board  
For Investigational New Drug (IND) studies, the minimum standards of conduct and requirements 
for informed consent are defined in the FDA regulations. 
A valid IRB must review and approve this protocol before study initiation. Written notification of 
approval is to be provided by the investigator to the sponsor’s monitor before shipment of 
investigational drug supplies, and will include the date of the committee’s approval and the 
chairperson’s signature. This written approval must consist of a completed Noven form, IRB 
Approval Form, or written documentation from the IRB containing the same information. 
Until written approval by the IRB has been received by the investigator, no subject may undergo 
any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB. Written approval from the 
IRB, or a designee, must be received by Noven before implementation. This written approval will 
consist of a completed IRB approval form or written documentation from the IRB containing the 
same information. 
15.4. Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 
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16. REFERENCES 
1  Barbour KE, Helmick CG, Theis KA, Murphy LB, Hootman JM, Brady TJ, Cheng YJ. 
Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United 
States, 2010-2012. MMWR 2013;62 (44):869-873. 
2  Centers for Disease Control and Prevention. 
https://www.cdc.gov/arthritis/data_statistics/index. htm. Accessed 24 June 2016. 
3  Investigational Brochure, Diclofenac Sodium Transdermal Drug Delivery System, HP-5000 
Transdermal Patch. Noven Pharmaceuticals, Inc. 
 
Edition No. 03, September 9, 2014. 
4  Berger, R.S., and .J.P. Bowman, 1982, “A Reappraisal of the 21 -day Cumulative Irritation 
Test in Man,” ./. Toxicol. - (It. 6’ Ocz~lw Toxicol., l(2); 109- 1 15. 
5  Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of 
WOMAC: a health status instrument for measuring clinically important patient relevant 
outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J 
Rheumatol. 1988;15:1833-1840. 
6  Bellamy N. Pain assessment in osteoarthritis: experience with the WOMAC osteoarthritis 
index. Semin Arthritis Rheum. 1989;18:14-17. 
7  Chan AT, Manson JE, Albert CM, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, 
and the risk of cardiovascular events. Circulation. 2006;113(12):1578-1587. 
8  National Research Council (US) Panel on Handling Missing Data in Clinical Trials. The 
prevention and treatment of missing data in clinical trials. Washington (DC): National 
Academies Press (US); 2010. 
 
 
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17. ATTACHMENTS
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17.1. Schedule of Events 
Assessment 
Screening 
Visit 
Wash-out 
Period 
Baseline 
Visit 
Double-blind Treatment Period 
Follow 
up 
ET 
Week 
-1 
 
 
 
1 
 
2 
 
4 
5 
 
Clinic visit 
1 
 
2 
 
3 
 
4 
 
5 
 
Phone visit 
 
1 
 
 
 
 
 
 
 
2 
Study Day -17 to -10i -14~-7 to -1i 
0 
1 to 6 
7 
8 to 13 
14 
15 to 27 
28 
35 
Visit Window (Days) 
 
 
 
 
±2 
 
±2 
 
±2 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Subject ID card 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
 
X 
 
 
 
 
 
 
 
 
Randomization (IVRS)a 
 
 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
X 
 
X 
Vital signsb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
X 
 
X 
WOMAC pain intensity 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
WOMAC stiffness 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
WOMAC physical function 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient Global Assessment 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Patient Global Impression of Change 
 
 
 
 
X 
 
X 
 
X 
 
X 
Pain intensity 11-point NRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Dispense rescue medication 
X 
 
X 
 
X 
 
X 
 
 
 
 
Use of rescue medicationc 
 
X 
Xc 
X 
X 
X 
X 
X 
X 
 
X 
12-lead ECGd 
X 
 
X 
 
 
 
 
 
X 
 
X 
Clinical laboratorye  
X 
 
X 
 
 
 
 
 
X 
 
X 
Urine pregnancy test  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
PK blood sample 
 
 
 
 
 
 
X 
 
X 
 
X 
Subject diaryf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Apply study medicationg 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Drug accountability 
 
 
Xl 
 
X 
 
X 
 
X 
 
X 
Dermal evaluationsh 
 
 
X 
Xj 
X 
Xj 
X 
Xj 
X 
 
X 
Prior/Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEsk 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Abbreviations: AE = adverse event; ET = early termination; ECG = electrocardiogram; ID = identification; I/E = inclusion/exclusion; IVRS = interactive voice 
response system; NRS = numeric rating scale; PK = pharmacokinetic; WOMAC = Western Ontario and McMaster Universities Arthritis Index 
a. 
Subjects will be randomized either HP-5000
 HP-5000
 or placebo in a 1:1:2 ratio. 
b. Vital signs, including heart rate, respiratory rate, and sitting blood pressure will be measured after the subject has been in a sitting position for 5 minutes 
c. 
Rescue medication may be used during the Washout Period except within 2 calendar days prior to Visit 2. 
d. A standard 12-lead electrocardiogram (ECG) will be performed after the subject has been supine for at least 5 minutes 
e. 
Clinical laboratory testing includes hematology, biochemistry, and urinalysis. 
f.  Subjects will be instructed in the use in the use of the electronic diary at the screening visit.For each 28-day administration period, subjects will be asked to 
record their daily intake/use of IP in the electronic diary. 
g. Instructions for application and removal of study drug patches will be provided to the subject 
h. Dermal evaluations will assess skin adhesion, irritation, discomfort, and adhesive residue. 
i.     Screening/Washout period should be 10 to 17 days. Washout period will be initiated 3 days after Screening Visit. 
j.    During the treatment period at home, subjects will report the incidence of patch detachement by answering Yes or No. 
k.    AEs will be collected after the first dosing. 
l.    Rescue medication only. 
 
 
 
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17.2. Investigator’s Agreement 
PROTOCOL 
NUMBER: 
HP-5000-US-05 
PROTOCOL TITLE: 
A 4-week, Randomized, Double-blind, Multicenter, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of HP-5000 in Subjects with 
Osteoarthritis (OA) of the Knee 
FINAL PROTOCOL: 31 Oct 2016 
I have read this protocol and agree to conduct this clinical trial as outlined herein. I will ensure 
that all subinvestigators and other study staff members have read and understand all aspects of this 
protocol. I agree to cooperate fully with Noven during the study. I will adhere to all FDA, ICH, 
and other applicable regulations and guidelines regarding clinical trials on an IP during and after 
study completion. 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
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18. APPENDICES 
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18.1. Western Ontario and McMaster Universities Osteoarthritis (WOMAC) LK3.1 Index  
This is an example of the WOMAC index. The actual index will be provided in the eCRF.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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18.2. Patient Global Assessment Scale (PGA) 
This is a sample questionnaire. The actual questionnaire will be provided in the study reference 
manual.  
The subject will provide their overall impression of the status of their OA in the target knee on a 
5-point scale where 0 = “Very Good” and 4 = “Very Poor.”  
Subjects will be asked to complete the following statement: “How would you rate your 
osteoarthritis condition over the last 24 hours?” The response options include the following: 
1. Very Good 
2. Good 
3. Moderate 
4. Poor 
5. Very Poor 
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18.3. Patient Global Impression of Change Scale  
This is an example of the Patient Global Impression of Change (PGIC) scale. The actual 
instrument will be included in the study reference manual.  
The Patient Global Impression of Change is a self-administered instrument that measures change 
in subjects’ overall improvement with treatment on a scale where 1 = “very much improved” and 
7 = “very much worse.” Subjects will be asked the following question: “How would you rate your 
overall improvement with treatment during the clinical trial?” The response options include the 
following: 
 
Very Much Improved 
1 
 
Much Improved 
2 
 
Minimally Improved 
3 
 
No Change 
4 
 
Minimally Worse 
5 
 
Much Worse 
6 
 
Very Much Worse 
7 
 
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18.4. 11-Point Numeric Rating Scale (NRS) 
This is a sample of the Numerical Rating Scale. Please use the rating scale provided in the study 
reference manual. 
Instructions: Show the pain scale to the subject and explain that on the 0 to 10 pain rating scale, 
0 means no pain and 10 means the worst possible pain. A value in the middle of the scale (around 
5) would be moderate pain; a value of 2 or 3 would be mild pain, and a value of 7 or higher is 
considered severe pain. 
Ask the subject the following question: “On a scale of 0 – 10, with 0 being ‘no pain’ and 10 being 
the ‘worst possible pain’, how would you rate your pain over the last 24 hours?” 
The intent of the question is to gain an understanding of the intensity of the patient’s target knee 
pain at over the last 24 hours. 
 
 
 
 
 
No Pain 
Worst Possible Pain 
 
Adapted from: Farrar JT, Young JP, La Moreaux L, Werth JL, and Poole MR: Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 94 
(2001) 149–158 
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18.5. Regulations and Good Clinical Practice Guidelines 
18.5.1 Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
 FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
 FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
 FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
18.5.2 Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
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