Clinical trial NCT05968482
Conditions: Healthy
Sponsor: Amzell
Start date: 2023-07-11; Completion date: 2024-12-02
Enrollment: 74 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The goal of this clinical trial is to compare drug exposure from two different products (AMZ001 and Diclofenac Sodium 1% Gel) in healthy participants on Day 7 after repeated topical administrations for 7 days.

Participants will receive, in a crossover design, three different treatments

* AMZ001 Low dose
* AMZ001 High dose
* Diclofenac Sodium 1% Gel

Safety and tolerability of AMZ001 will be also investigated.

Detailed description:
On their both knees, participants will apply once daily either low dose of AMZ001 or high dose of AMZ001 for 7 consecutive days. Participants will also apply Diclofenac Sodium 1% Gel as per label information on each knee.

Intensive pharmacokinetic assessment (blood samplings) will be performed on the first day of application (Day 1) as well as on the last day of application (Day 7).

Each participant will receive each of the three treatments in a randomized manner. Between each treatment, participant will not receive any of the three tested therapies between 3 weeks before receiving the next therapy. (washout period)

Participants will stay on the clinical unit only during each period of treatment but not during washout period.

Arms: arm 1: AMZ001 applied once daily for 7 consecutive days arm 2: AMZ001 applied once daily for 7 consecutive days arm 3: Reference product applied four-times daily for 7 consecutive days
Interventions: intervention 1: Diclofenac Sodium Gel
Intervention descriptions: intervention 1: Topical application on both knees

Protocol documents:
Prot_000.pdf: 
Amzell B.V. 
Protocol No. AMZ001-008 
      Date: 23-March-2023 
Confidential 
CLINICAL STUDY PROTOCOL 
A Phase 1, Single-Center, Randomized, Open-Label, Bioavailability and Safety Three 
Period Crossover Multiple-Dose Study Comparing Two Dose Levels (6 mL [5.5 g] and 8 
mL [7.4 g]) of AMZ001 (Diclofenac Sodium Gel 3.06%) and One Dose Level (32 g) of 
Voltaren Arthritis Pain Gel (Diclofenac Sodium Gel 1%) in Healthy Subjects 
Protocol No. AMZ001-008 
IND Number: 
116375 
Study Product: 
AMZ001 
Indication: 
Relief of the pain associated with arthritis 
Phase: 
1 
Name and Address of Sponsor: 
Amzell B.V. 
Siriusdreef 31 
2132 WT Hoofddorp 
The Netherlands 
Telephone:  +31.235.560.460 
Fax:  +31.235.560.461 
Name and Address of Principal 
Investigator & Contract 
Research Organization: 
Jonathan S. Dosik, M.D. 
TKL Research, Inc. 
One Promenade Blvd, Suite 1101/1201 
Fair Lawn, NJ 07410 
Telephone number: (201) 587-0500 
Good Clinical Practice (GCP) 
Statement: 
This study will be performed in compliance with ICH GCP 
guidelines. 
The information in this document is confidential and is proprietary to Amzell B.V. It is 
understood that information in this document shall not be disclosed to any third party, in any 
form, without prior written consent of an authorized officer of Amzell B.V. 


Amzell B.V. 
 
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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
SYNOPSIS 
TITLE OF STUDY:  A Phase 1, Single-Center, Randomized, Open-Label, Bioavailability and 
Safety Three Period Crossover Multiple-Dose Study Comparing Two Dose Levels (6 mL [5.5 g] 
and 8 mL [7.4 g]) of AMZ001 (Diclofenac Sodium Gel 3.06%) and One Dose Level (32 g) of 
Voltaren Arthritis Pain Gel (Diclofenac Sodium Gel 1%) in Healthy Subjects 
STUDY SITE(S):  1 site in the U.S. 
PLANNED STUDY PERIOD:  Approximately 18 weeks (study 
participation for a subject) 
CLINICAL PHASE: 1 
OBJECTIVES: 
The primary objective of the study is to compare the bioavailability of two dose levels (6 mL 
[5.5 g] and 8 mL [7.4 g]) of AMZ001 (diclofenac sodium gel 3.06%) applied once daily as 3 mL 
and 4 mL per knee on both knees, respectively, and one dose level of Voltaren Arthritis Pain Gel 
(32 g, diclofenac sodium gel 1%) applied four times daily as 4 g per knee on both knees after 
repeated topical administrations in healthy subjects for 7 days. 
The secondary objectives of the study are to:  
- 
Determine the pharmacokinetic (PK) profile of the two dose levels (6 mL [5.5 g] and 8 
mL [7.4 g]) of AMZ001 (diclofenac sodium gel 3.06%) and one dose level (32 g) of 
Voltaren Arthritis Pain Gel (diclofenac sodium gel 1%). 
- 
Assess the safety and tolerability of the two different doses of AMZ001 (diclofenac 
sodium gel 3.06%) and Voltaren Arthritis Pain Gel (diclofenac sodium gel 1%). 
DESIGN: 
This is a randomized, open-label, three period crossover, multiple-dose study to investigate the 
bioavailability, safety, and tolerability of two dose levels (6 mL [5.5 g] and 8 mL [7.4 g]) of 
AMZ001 applied once daily as 3 mL and 4 mL per knee on both knees, respectively, and one 
dose level of Voltaren Arthritis Pain Gel (32 g) applied four times daily as 4 g per knee on both 
knees after repeated dosing in healthy subjects for 7 days. 
Before inclusion into the study, all subjects will undergo a physical examination, including vital 
signs, and blood samples will be collected for laboratory assessments (hematology, clinical 
chemistry, and urinalysis).  
Subjects will be randomized to one of six dosing sequences: 
 
Period 1  
(Sequence 1) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 2) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 3) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 4) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 


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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
(Sequence 5) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 6) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
 
Period 2  
(Sequence 1) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 2) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 3) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 4) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 5) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 6) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
 
Period 3  
(Sequence 1) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 2) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 3) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 4) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 5) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 6) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
 
Note: Between Periods 1 and 2 and Periods 2 and 3, there will be a 21-day (+7-day) washout, 
and the subjects will not be confined to the study site. 
The gel will be administered to the knee by subject under the supervision of designated clinical 
site staff member for consistency in application and to ensure the correct amount is applied to 
each knee at the specified dose and frequency for 7 consecutive days.  The subject will then spread 
the gel directly to the pre-defined treatment area of approximately 400 cm2 (6 mL AMZ001 and 
32 g Voltaren Arthritis Pain Gel) and 500 cm2 (8 mL AMZ001) for each subject knee as per 
detailed application instructions.  Subjects will be confined at the study site only for the duration 
of each treatment period (Days -1 to Day 8) of the study. Subjects are permitted to shower ≥ 1-
hour pre-dose and after 3-hours or greater post-dose. Blood samples for PK analyses will be 
collected prior to (within 1 hour) application and at 2 (±15 min), 4 (±15 min), 6 (±15 min), 8 (±15 
min), 10 (±15 min), 12 (±15 min), 14 (±15 min), 16 (±15 min), 18 (±15 min), 20 (±15 min), 24 
(±30 min) hours after application on Days 1 and 7. One blood sample will be collected on Days 
3, 4, 5, and 6 prior (within 1 hour) to the first daily application of gel to measure the trough level 
of each study drug.  
At the end of Period 3, there will be three additional PK blood samples taken respectively at 3 
weeks (21 days), 4 weeks (28 days), and 5 weeks (35 days) after the last application to compare 
elimination phase of AMZ001 vs. Voltaren Arthritis Pain Gel and to further describe the 


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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
elimination phase of the AMZ001 product. During this follow-up period, subjects will not be 
confined to the study site. 
If a sampling time point and application time fall at the same time, the blood sample should be 
taken immediately prior to application. 
NUMBER OF SUBJECTS (PLANNED):  A sufficient number of subjects will be screened and 
approximately 75 subjects will be randomized to give 60 evaluable subjects across six dosing 
sequences. 
CRITERIA FOR INCLUSION/EXCLUSION: 
Inclusion criteria: 
1. Healthy male or female subjects 18-65 years of age (e.g., in general good physical health, 
as judged by the Investigator and no clinically relevant abnormalities identified by a 
detailed medical history, full physical examination, including blood pressure and pulse 
rate measurement, 12-lead ECG or clinical laboratory tests) 
2. Has a body mass index (BMI) between 18.0 and 35.0 kg/m2 at Screening. 
3. In the case of females of child-bearing potential ([FCBP) unless surgically sterilized 
[hysterectomy, bilateral oophorectomy, bilateral tubal ligation] or are postmenopausal for 
at least 12 months), are using two acceptable forms of birth control (hormonal 
contraceptives i.e., oral/implant/injectable/transdermal; intrauterine device (IUD) and/or 
barrier methods [female condom, male condom, diaphragm, cervical cap, spermicide]; 
note: 2 barrier methods are two acceptable forms of birth control)).  Abstinence or 
partner’s vasectomies are acceptable if the female subject agrees to implement two 
acceptable forms of birth control if her lifestyle/partner changes. 
4. Females of child-bearing potential have a negative serum pregnancy test (SPT) at 
Screening and negative urine pregnancy test (UPT) on Day -1 of each period and at end 
of treatment (EOT) visit (Period 3, Day 8) 
5. Are free of any systemic or dermatologic disorder and chronic or acute infections, which, 
in the opinion of the Principal Investigator (PI), will interfere with the study results or 
increase the risk of adverse events (AEs) 
6. Read, understand, and provide signed informed consent before any assessment is 
performed. 
 
Exclusion criteria: 
The presence of any of the following excludes a subject from study enrollment: 
1. Subject has any visible skin disease, skin lesions, wounds, or a significant amount of 
hair at the application site (knee)  
2. Use of an investigational medicinal product (IMP) within 30 days or 5 half-lives (if 
known), whichever is longer, of enrollment or during the study. 


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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
3. Treated with systemic or local diclofenac within 30 days of enrollment or during the 
study (except for study IMP) 
4. Known hypersensitivity to diclofenac, any excipients (ethanol, propylene glycol, 
diethylene glycol monoethyl ether, myristyl alcohol, hydroxypropyl cellulose, and 
water), aspirin, Xarelto, coumadin, or other non-steroidal anti-inflammatory drugs 
(NSAIDs), including Cyclooxygenase-2 (COX-2) inhibitors. 
5. Any history of drug hypersensitivity, asthma, urticaria, or other significant allergic 
diathesis. Subjects with uncomplicated seasonal allergic rhinitis can be accepted only if 
the expected allergy season is clearly outside enrollment / treatment periods. 
6. Females who are pregnant and/or lactating 
7. Of child-bearing potential but not willing to use adequate contraception for the duration 
of the study 
8. Subject is a current smoker and unable to abstain from smoking during the treatment 
periods. 
9. Use of any topical medication, cosmetics, cream, ointments, lotions on the treatment site 
1 week prior to enrollment through EOT visit. 
10. Use of any medication (including over-the-counter medication, dietary supplements, and 
herbal remedies) within 2 weeks before first scheduled study drug administration or 
within less than 5 times the elimination half-life of the respective drug (whichever is 
longer) or is anticipated to require concomitant medication during the 2-week period or 
at any time throughout the study. Consumption of any drug metabolizing enzyme (e.g., 
cytochrome P450 3A4 (CYP3A4) or other cytochrome P450 enzymes) inducing or 
inhibiting beverages or food (e.g., broccoli, Brussel sprouts, grapefruit, grapefruit juice, 
star fruit) within 3 days prior to and during each treatment period. 
Allowed treatments are: 
• Systemic contraceptives and hormone replacement therapy, as long as female subject 
is on stable treatment for at least 3 months and continues treatment throughout the 
study. 
• Occasional use of acetaminophen 500 mg (up to 1000 mg daily) 
• Single intake of other drugs only if judged by the investigator to have no clinical 
relevance and will not confound the interpretation of the study results. 
11. Subject has a known or suspected malignancy, excluding basal cell cancer unless it is 
associated with the treatment area. 
12. Subject has a positive blood screen for human immunodeficiency virus (HIV), hepatitis 
B surface antigen (HBsAg), hepatitis C antibody (Anti-HCV) 
13. Subject has any acute or chronic condition or is using medications, which, in the 
investigator’s opinion, would make it unsafe for the subject to participate in this study, 


Amzell B.V. 
 
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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
including clinically significant abnormal laboratory values, vital signs, physical 
examination findings prior to randomization or during study participation. 
14. History or current evidence of renal disease or impaired renal function at screening as 
indicated by abnormal levels of serum creatinine (> 1.43 mg/dL) or BUN (≥ 35 mg/dL) 
or the presence of clinical. significant abnormal urinary constituents (e.g., albuminuria)  
15. History or current evidence of ongoing hepatic disease or impaired hepatic function at 
screening. A subject will be excluded if more than one of the following lab value 
deviations are found: 1) AST (≥ 1.5 ULN), ALT (≥ 1.5 ULN), 2) GGT (≥ 1.5 ULN), 
ALP (≥ 1.5 ULN), 3) total bilirubin (> 2.00 mg/dL) or creatine kinase (≥ 3 ULN). A 
single deviation from the above values is acceptable and will not exclude the candidate, 
unless specifically advised by the Investigator. 
16. Subject has clinically relevant chronic or acute infectious illnesses or febrile infections 
within 2 weeks prior to the first scheduled study drug administration 
17. Subject has gastrointestinal bleeding issues, e.g., Gastroesophageal Reflux Disease 
(GERD), Peptic Ulcer Disease (PUD) 
18. Subject has a hospital admission or major surgery within 30 days prior to randomization. 
19. Subject has a donation or blood collection of more than 1 unit (approximately 450 mL) 
of blood (or blood products) or acute loss of blood during the 30 days prior to 
randomization. 
20. Subject has a history of alcohol abuse, prescription drug abuse, or illicit drug use within 
6 months prior to Screening. 
21. Subject meets eligibility criteria, but study is filled 
22. Subject who is an investigational site staff member directly involved in the conduct of 
the study and his/her family members, site staff member otherwise supervised by the 
Investigator, or subject who is a Amzell B.V. employee directly involved in the conduct 
of the study 
INVESTIGATIONAL PRODUCT: AMZ001 is provided in dispensing package. Each 
dispenser contains diclofenac sodium 3.06% in a gel base. AMZ001 is delivered in aliquots of 
either 1 mL (0.92 g containing 28.2 mg of diclofenac sodium) or 1.5 mL (1.38 g containing 42.2 
mg of diclofenac sodium) per pump actuation. Voltaren Arthritis Pain Gel is provided in tubes 
containing 100 g of the topical gel in each tube. Each tube contains diclofenac sodium in a gel 
base (10 mg of diclofenac sodium per gram of gel or 1%). 
DURATION OF STUDY: The study duration is approximately 18 weeks for each subject, 
inclusive of screening period. 
 
 
 


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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
ENDPOINTS: 
Primary endpoint: 
• Compare the exposure to diclofenac, as measured by plasma concentration, area under the 
curve from time zero to 24 hours (AUC0-24), and maximum (peak) plasma drug 
concentration (Cmax) at steady state between two different dose levels of AMZ001 and one 
dose level of Voltaren Arthritis Pain Gel in healthy subjects on Day 7. 
Secondary endpoint(s):   
• The PK parameters Cmax, minimum plasma drug concentration (Cmin), time to reach 
maximum (peak) plasma concentration following drug administration (Tmax), time to 
reach minimum plasma concentration following drug administration (Tmin), terminal 
disposition rate constant (λz), the time it takes for the plasma drug concentration to 
decrease by half (T½), average plasma drug concentration (Cav) and peak-to-trough 
fluctuation (PTF) of the two different dose levels of AMZ001 and one dose of Voltaren 
Arthritis Pain Gel will be calculated. The PK parameters for Day 1 will also be calculated 
and considered as secondary endpoints. 
Safety endpoint(s): 
• Adverse Events (AEs); including serious, treatment emergent, adverse drug reactions 
(ADRs) 
• Local and systemic tolerability 
STATISTICAL METHODS: 
Below is a summary of the statistical analysis methods. For more details on each analysis, please 
refer to Section 9. 
Sample Size: Based on the assumption (averaging historical data and 000084 result), intra-subject 
coefficient of variation (CV) was 61%. A total of sixty (60) evaluable subjects will achieve 80% 
power using 95% confidence interval (CI), to account for multiplicity. The true ratio that was 
used in the sample size calculation was 1.05. Enough healthy adults will be screened to randomize 
approximately seventy-five (75) subjects to ensure sixty (60) evaluable subjects, assuming a 20% 
dropout and non-evaluable rate. All subjects will receive all 3 treatments over the course of the 3 
study periods. Subjects will be randomized to one of the 6 possible sequences of 3 treatments, as 
specified in the design section above, to provide adequate information about the PK parameters 
and safety for the purposes of this study. 
Statistical analysis: Descriptive statistics will be used to summarize the baseline demographic 
information. 
Safety analysis: Descriptive statistics will be used to summarize AEs, laboratory data, physical 
examinations, and vital signs. 


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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
Pharmacokinetic (PK) Analysis: PK analysis will be performed using SAS® system. 
PK parameters area under the plasma concentration-time curve from time zero to time t (AUC0-τ) 
and Cmax will be compared across treatment groups using an analysis of variance (ANOVA) 
model. The ratio of the PK parameters will be estimated along with 90% confidence limits to 
assess comparable bioavailability.  


Amzell B.V.
Protocol No. AMZ001-008
Date: 23-March-2023
Page 9
TKL Study No. P1980822
Status: Final v1.0
SIGNATURE PAGE
AMZO01 (Diclofenac Sodium Gel 3.06%)
Sponsor Protocol Number:
TKL ProtocolNumber:
AMZ001-008
P1980822
The signatures of the following representatives constitute their approval of this protocol and
provide the necessary assurances that this study will be conducted according to all stipulations
stated in the protocol,
inclding
all statements as to confidentiality.
It is also agreed that the study
will not be initiated without the approval of an appropriate Institutional Review Board ([RB).
Approved by the following:
-DocuSigned by:
VarioCamara, Pl)
SigaALAlameDariaCanara,PhO
Amzell B.V.:
3/24/2023
Dario Carrara, PhD
ChiefExecutive Officer
SigrfngReason:
lapprovethisdocument
ISigning
Time: 3/24/2023 | 5:42:16 AM PDT
Darioa5AFA,EBAAE11653475DA86
Date
-DocuSigned by:
TKL Research,Ine:
John C. Lyssikatos
Vice President, Clinical Operations
Joln lysakates
3/23/2023
. STgnerName.JonnLyssIkatos
SigisatuReason:
I approve this document
Date
SR23|11:11:41 AMPOT
E369CB9BDODO1704104
Johng
ohn 2D5
Michael Tuley Plu)
Signing Reason: I approve this document
-BEQA074St9443499E30D520D1EBB3FD
Irina krauss, N, MSN
-DocuSigned by
3/23/2023
Michael Tuley, PhD
Vice President, Data Sciences and
Quality Assurance
BigniFName:
MichaelTuley,PhD
MiciauigTak49B|
12:08:29PMPDT
Date
3/23/2023
Irina Krause, RN, MSN
Director,
Phase 1
Operations
nSName:
Irina Krause, RN, MSN
hmgReason:
l approve
this
document
Date
rinaKraise,
RNROMBN27 PMEDT
OD9920D912154147852ACDECEE722A44
Confidential


Amzell B.V.
Protocol No. AMZ001-008
Date: 23-March-2023
Page 10
TKL Study No. P1980822
Status: Final vl.0
SIGNATURE PAGE FOR INVESTIGATOR
AMZO01 (Diclofenac Sodium Gel 3.06%)
Sponsor Protocol Number:
TKL ProtocolNumber:
AMZ001-008
P1980822
I have read this protocol. I approve this document and I agree that it contains all necessary details
for carrying out the study as described. I will conduct this study in accordance with the design and
specific provision of this protocol and will make a reasonable effort to complete the study within
the time designated. I will provide copies of this protocol and access to all information furnished
by Amzell B.V. to study personnel under my supervision. I will discuss this material with them to
ensure they are fully informed about the study product and study procedures. I will let them know
that this information is confidential and proprietary to Amzell B.V. and that it may not be further
disclosed to third parties. I understand that the study may be terminated or enrollment suspended
at any time by Amzell B.V., with or without cause, or by me if it becomesnecessary to protect the
best interests of the study patients.
I agree to conduct this study in full accordance with Food and Drug Administration Regulations,
Institutional Review Board Regulations, and International Council for Harmonisation Guidelines
for Good ClinicalPractices.
-DocuSigned by:
uateau S.Doik, M)
StyTer tName. Joratrar S.Dustk,MO
3/23/2023
Jonathan S. Dosik, M.D.
Principal Investigator
Signstae
Reason:lapprovethisdocument
JonathanS.Dos
2127 AMPDT
Date
4283CE4B43F94F898680A25E3220B712
Confidential


Amzell B.V. 
 
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Protocol No. AMZ001-008 
 
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Date: 23-March-2023 
 
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Confidential 
TABLE OF CONTENTS 
SYNOPSIS .......................................................................................................................................2 
SIGNATURE PAGE .......................................................................................................................9 
SIGNATURE PAGE FOR INVESTIGATOR ..............................................................................10 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................15 
LIST OF FIGURES .......................................................................................................................15 
LIST OF ABBREVIATIONS ........................................................................................................16 
 
INTRODUCTION ..................................................................................................................18 
1.1 
Scientific Justification for Conducting the Study ............................................................18 
1.2 
Benefit / Risk Aspects ......................................................................................................20 
 
STUDY OBJECTIVES AND ENDPOINTS ..........................................................................20 
2.1 
Objectives .........................................................................................................................20 
 Primary Objectives .....................................................................................................20 
 Secondary Objectives .................................................................................................21 
2.2 
Endpoints ..........................................................................................................................21 
 Primary Endpoint .......................................................................................................21 
 Secondary Endpoint(s) ...............................................................................................21 
 Safety Endpoint(s) .....................................................................................................21 
 
INVESTIGATIONAL PLAN .................................................................................................21 
3.1 
Overall Study Design .......................................................................................................21 
 Study Design ..............................................................................................................21 
 Application Instructions .............................................................................................24 
 Study Schedule ...........................................................................................................24 
3.2 
Planned Number of Study Sites and Subjects ..................................................................24 
3.3 
Interim Analysis ...............................................................................................................24 
3.4 
Data Monitoring Committee ............................................................................................24 
3.5 
Discussion of Overall Study Design and Choice of Control Groups ...............................25 
 Study Design ..............................................................................................................25 
 Selection of Endpoints ...............................................................................................25 
 Blinding ......................................................................................................................25 


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 Selection of Doses in the Study .................................................................................25 
 Selection and Timing of Dose for Each Subject ........................................................25 
 
SELECTION OF STUDY POPULATION ............................................................................26 
4.1 
Study Population ..............................................................................................................26 
 Inclusion Criteria .......................................................................................................26 
 Exclusion Criteria ......................................................................................................26 
4.2 
Method of Assigning Subjects to Treatment Groups .......................................................28 
 Recruitment ................................................................................................................28 
 Randomization ...........................................................................................................29 
4.3 
Restrictions .......................................................................................................................29 
 Prior and Concomitant Therapies ..............................................................................29 
 Other Restrictions ......................................................................................................29 
4.4 
Withdrawal Criteria ..........................................................................................................29 
4.5 
Subject Replacement ........................................................................................................30 
 
TREATMENTS ......................................................................................................................30 
5.1 
Treatments Administered .................................................................................................30 
 Investigational Medicinal Product (IMP) ..................................................................30 
5.2 
Medicinal Product(s) ........................................................................................................31 
 Characteristics and Source of Supply ........................................................................31 
 Packaging and Labeling .............................................................................................31 
 Conditions for Storage and Use .................................................................................32 
5.3 
Treatment Compliance .....................................................................................................32 
 Dispensing and Accountability ..................................................................................32 
 Assessment of Compliance ........................................................................................32 
5.4 
Prior and Concomitant Therapy .......................................................................................32 
5.5 
Return and Destruction of Medicinal Products ................................................................32 
 
STUDY PROCEDURES ........................................................................................................33 
6.1 
Study Flow Chart .............................................................................................................33 
6.2 
Study Procedures ..............................................................................................................35 
 Screening (Days -30 to -2) .........................................................................................35 


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 Day -1 .........................................................................................................................36 
 Days 1, 7, and 8 ..........................................................................................................36 
 
STUDY ASSESSMENTS ......................................................................................................38 
7.1 
Assessments Related to the Primary Endpoint .................................................................38 
 Pharmacokinetics .......................................................................................................38 
7.2 
Other Assessments ...........................................................................................................38 
 Vital Signs ..................................................................................................................38 
 Laboratory Parameters ...............................................................................................38 
 Physical examination .................................................................................................39 
 12-Lead Electrocardiogram (ECG) ............................................................................39 
 Administration Site Reactions ...................................................................................40 
7.3 
Handling of Biological Samples ......................................................................................40 
7.4 
Laboratory Values ............................................................................................................40 
 
ADVERSE EVENTS..............................................................................................................40 
8.1 
Adverse Event (AE) Definition ........................................................................................40 
8.2 
Collection and Recording of Adverse Events ..................................................................41 
 Collection of Adverse Events ....................................................................................41 
 Recording of Adverse Events ....................................................................................41 
8.3 
Pregnancy and Pregnancy Outcome .................................................................................44 
8.4 
Serious Adverse Events ....................................................................................................45 
 Serious Adverse Event (SAE) Definition ..................................................................45 
 Collection, Recording and Reporting of Serious Adverse Events .............................46 
8.5 
Follow-up of Adverse Events and Serious Adverse Events .............................................47 
 Follow-up of Adverse Events with Onset during the Study ......................................47 
 
STATISTICAL METHODS ...................................................................................................48 
9.1 
Determination of Sample Size..........................................................................................48 
9.2 
Subject Disposition ..........................................................................................................48 
9.3 
Protocol Deviations ..........................................................................................................48 
9.4 
Statistical Analysis Sets (or Populations).........................................................................48 
 Safety Population .......................................................................................................48 


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 Pharmacokinetic (PK) Population ..............................................................................49 
 PK Analysis Set .........................................................................................................49 
9.5 
Study Population ..............................................................................................................49 
 Demographics and other Baseline Characteristics .....................................................49 
 Medical History, Concomitant Medication and Physical Examination .....................49 
9.6 
Treatment Compliance .....................................................................................................49 
9.7 
Endpoint Assessments ......................................................................................................49 
 General Considerations ..............................................................................................49 
 Pharmacokinetics (PK) ..............................................................................................50 
 Primary Endpoint .......................................................................................................50 
 Secondary Endpoint(s) ...............................................................................................50 
 Safety Endpoint(s) .....................................................................................................50 
 Adverse Events (AEs) ................................................................................................50 
9.8 
Interim Analyses ..............................................................................................................52 
9.9 
Exclusion of Data from Analysis .....................................................................................52 
9.10 Handling of Dropouts and Missing Data..........................................................................52 
 DATA HANDLING AND RECORD KEEPING ..................................................................52 
10.1 Recording of Data ............................................................................................................52 
10.2 Data Management ............................................................................................................52 
10.3 Retention of Documents ...................................................................................................53 
10.4 Confidentiality of Subject Data ........................................................................................53 
10.5 Clinical Monitoring Plan (CMP) ......................................................................................54 
10.6 Audit Procedures ..............................................................................................................55 
10.7 Investigational Medicinal Product (IMP) .........................................................................55 
10.8 Laboratory Samples and Analysis ....................................................................................56 
 CHANGES IN CONDUCT OF THE STUDY .......................................................................56 
11.1 Protocol Amendments ......................................................................................................56 
11.2 Deviations from the Protocol ...........................................................................................57 
11.3 Premature Study Termination ..........................................................................................57 
 REPORTING AND PUBLICATION .....................................................................................57 


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12.1 Clinical Study Report .......................................................................................................57 
12.2 Confidentiality and Ownership of Study Data .................................................................57 
12.3 Publication Policy ............................................................................................................57 
 ETHICAL AND REGULATORY ASPECTS .......................................................................57 
13.1 Institutional Review Board (IRB) ....................................................................................57 
13.2 Ethical Conduct of the Study ...........................................................................................58 
13.3 Subject Information and Consent .....................................................................................58 
 ARCHIVING ..........................................................................................................................59 
14.1 Trial Master File ...............................................................................................................59 
 REFERENCES .......................................................................................................................60 
 
LIST OF TABLES 
Table 1 - Study Flow Chart for Periods 1, 2 and 33 .......................................................................34 
Table 2 - PK Outpatient Visits .......................................................................................................35 
Table 3 - Safety Laboratory Parameters ........................................................................................39 
 
LIST OF FIGURES 
Figure 1: 
Study Design: Three Treatments, Three Period Crossover Design ...........................23 
 
 
 


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LIST OF ABBREVIATIONS 
ACR 
American College of Rheumatology 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANOVA 
Analysis of Variance 
Anti-HCV 
Hepatitis C antibody 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the curve for 0-24 hours 
AUCτ 
Area under the plasma concentration-time curve from time zero to time t 
BUN 
Blood urea nitrogen 
Cav 
Average plasma drug concentration 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIPT 
Cumulative Irritant Patch Test 
Cmax 
Maximum (peak) plasma drug concentration 
Cmin 
Minimum plasma drug concentration 
CMP 
Clinical Monitoring Plan 
COV 
Closeout Visit 
COX 
Cyclooxygenase 
CRO 
Contract Research Organization 
Ctrough 
Concentration of drug reached immediately before the next dose 
CV 
Cardiovascular 
DDC 
Direct data capture 
DDE 
Direct data entry 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
Electronic data capture 
eICF 
Electronic informed consent form 
EOT 
End of treatment 
ET 
Early termination 
FCBP 
Females of child-bearing potential 
FDA 
Food and Drug Administration 
g 
Gram 
GI 
Gastrointestinal 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GMP 
Good Manufacturing Practice 
HBsAg 
Hepatitis B surface antigen 


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HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product (refers to both AMZ001 and Voltaren 
Arthritis Pain Gel) 
IMV 
Interim Monitoring Visit 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
λz 
Terminal disposition rate constant 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/dL 
Milligram per deciliter 
mL 
Milliliter 
N 
Total number of subjects/observations 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
pg 
Picograms per milliliter 
QD 
Once daily 
 
QID 
Four times a day 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PKAS 
Pharmacokinetic analysis set  
PTF 
Peak-to-trough fluctuation  
RIPT 
Repeat Insult Patch Test 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SDV 
Source data verification 
SIV 
Site Initiation Visit 
SMP 
Safety Management Plan 
SOC 
System organ class 
SOP 
Standard Operating Procedure 
SPT 
Serum pregnancy test 
T1/2 
The time it takes for the plasma drug concentration to decrease by half 
TEAE 
Treatment emergent adverse event 
TKL 
TKL Research, Inc. 
Tmax 
Time to reach maximum (peak) plasma concentration following drug 
administration 
Tmin 
Time to reach minimum plasma concentration following drug administration 
ULN 
Upper limit normal 
UPT 
Urine pregnancy test 


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INTRODUCTION 
Diclofenac is widely employed in the treatment of pain and inflammation. It is a member of the 
aniline phenylacetate class of acidic non-steroidal anti-inflammatory drugs (NSAIDs). The 
combination of the lipid solubility of the phenylacetate moiety along with its solubility in alkaline 
and other salts equips diclofenac with highly favorable physicochemical properties for penetrating 
through membranes (Rainsford et al., 2008). 
Osteoarthritis (OA) is a chronic disease characterized by the breakdown and eventual loss of the 
cartilage of one or more joints. Cartilage is a protein substance that functions as a protective 
cushion between the adjoining bones. This degenerative joint disease increases with age, is more 
prevalent when there is physical stress on the joint (for example, athletes such as hockey players 
suffer from knee and hip joint pain and inflammation, others may suffer from OA due to obesity), 
and is the leading cause of chronic musculoskeletal pain and disability in elderly populations 
(Zhang and Jordan, 2010). This progressive, complex, multifactorial, disease affects up to 50% of 
the adult population over the age of 65 and pain is the most significant symptom. In addition to 
pain, stiffness, and limitations of functional activities of daily living are experienced, including 
rising from a chair, walking, balancing and using stairs. OA commonly affects the hands, feet, 
spine, and large weight-bearing joints, such as the hips and knees (Song et al., 2006; Johnson and 
Hunter, 2014; Allen and Golightly, 2015). 
There are two distinct types of OA.  Primary (idiopathic) OA is defined as a degenerative disorder 
of aging.  Secondary OA is associated with an apparent cause for the breakdown of cartilage, such 
as injury or overuse, heredity, obesity, other diseases (e.g., hemochromatosis, acromegaly) and 
types of arthritis (e.g., rheumatoid arthritis). 
AMZ001 (diclofenac sodium 3.06%) - formerly FE999312 (diclofenac sodium 3%), is being 
developed for the relief of pain symptoms as a result of OA of the knee. The formulation was 
designed for rapid absorption through the skin after application to target sites. 
The aim of this study is to evaluate the bioavailability, safety, and tolerability of two dose levels 
(6 mL [5.5 g] and 8 mL [7.4 g]) of AMZ001, applied once daily, in comparison with one dose 
level (32 g) of Voltaren Arthritis Pain Gel, applied four times daily, after repeated dosing in healthy 
subjects for 7 days. 
1.1 
Scientific Justification for Conducting the Study 
Non-steroidal anti-inflammatory drugs (NSAIDs) are often employed for symptomatic relief of 
mild-to moderate pain associated with OA. Traditional orally ingested NSAIDs have a high 
incidence of gastrointestinal (GI) and cardiovascular (CV) adverse effects (FitzGerald and 
Patrono, 2001; García Rodríguez et al., 2008). The acidic molecules in NSAIDs directly irritate 
the gastric mucosa and the inhibition of the COX-1 and COX-2 isoenzymes decreases the levels 
of protective prostaglandins. Common GI adverse drug reactions (ADRs) include dyspepsia, 
diarrhea, nausea/vomiting, and gastric ulceration/bleeding (Sostres et al., 2013; Laine, 2003). A 
previous study demonstrated that NSAIDs with a long half-life and/or slow-release formulation 


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are associated with coincident inhibition of COX-1 and COX-2 isozymes which result in an 
increased risk of upper GI bleeding and perforation (Massó González et al., 2010). 
The dose-dependent risk of orally administered NSAIDs has triggered the development of different 
formulations, including topically applied formulations. The transcutaneous administration of 
NSAIDs offers advantages over systemically administered medications, including a lower total 
systemic daily dose for patients to ameliorate pain symptoms, site-specific delivery, and the 
circumvention of first-pass hepatic metabolism. In patients with chronic OA, the American 
College of Rheumatology (ACR) and the Osteoarthritis Research Society International (OARSI) 
generally recommend oral treatments (acetaminophen, NSAIDs) and topical NSAIDs equally, 
favoring topical therapy for patients who have pre-existing GI risk, exhibit multiple co-
morbidities, or are 75 years of age and older (Hochberg et al., 2012; Nelson et al., 2014; Whelton, 
1999). The concern for GI, hepatic, and renal toxicity is appropriate in such situations. 
Topical NSAIDs are useful for the local treatment of acute and chronic musculoskeletal conditions 
(Gøtzsche, 2007; Derry et al., 2015; Persson et al., 2016). These formulations penetrate the skin 
and permeate to tissues or joints, providing site-specific delivery of the drug to target areas and 
high local concentrations to exert a therapeutic effect. Topical formulations effectively lead to 
lower circulating levels of these drugs, thus minimizing the risk of harmful effects, and 
simultaneously provides symptom control comparable with oral counterparts (Klinge and Sawyer, 
2013). 
In a pharmacokinetic (PK) study, subjects treated with diclofenac sodium 0.1% gel had only 1 to 
3% of systemic exposure to diclofenac compared with the recommended 75 mg daily dose of oral 
diclofenac sodium, despite the fact that the subjects had a first-degree sunburn (Magnette et al., 
2004). A similar observation was made by Kienzler and colleagues comparing the systemic 
bioavailability and pharmacodynamics of topical diclofenac sodium 1% gel with oral diclofenac 
sodium in healthy subjects. Systemic exposure with the topical preparation was 5- to 17-fold lower 
than with oral diclofenac. Topical diclofenac did not inhibit platelet aggregation and was devoid 
of GI AE compared with oral diclofenac (Kienzler et al., 2010).  
 
In a randomized, double-blind, vehicle-controlled trial of 492 adult patients, topical treatment with 
diclofenac sodium 1% gel achieved statistically and clinically significant improvements of pain 
over a three-month treatment period (Barthel et al., 2009). Equivalence studies between topical 
diclofenac gel or solution was shown to be as effective as oral diclofenac or ibuprofen in patients 
with OA of the hand or knee, but with fewer systemic AE (Zacher et al., 2001; Roth and Fuller, 
2011).  
 
Overall, the data demonstrate that topical diclofenac is superior to placebo and comparable to oral 
diclofenac in the treatment of patients with knee OA, with a lower incidence of GI complaints 
compared to oral therapy. Topical agents may offer a safe, well-tolerated and effective alternative 
to systemic therapies in the treatment of patients with chronic, localized musculoskeletal injuries 
(Galer, 2011).  


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Amzell B.V. is introducing a novel transdermal hydroalcoholic gel formulation with diclofenac 
sodium as the active ingredient (AMZ001). This formulation is designed for rapid and efficient 
diclofenac absorption compared with other topical diclofenac products. To date, four Phase 1 
studies have been completed: a 21-Day, randomized, controlled study to evaluate the skin irritation 
potential of AMZ001 (diclofenac sodium 3.06%), using a Cumulative Irritant Patch Test (CIPT) 
design, in 43 healthy subjects, 34 of whom completed the trial (AMZ001-001); a randomized, 
controlled study to evaluate the sensitizing potential of AMZ001 using a Repeat Insult Patch Test 
(RIPT) design in 200 healthy subjects (AMZ001-002), two PK studies (000084 and 
AMZ001-005 [a Phase 1 PK and safety study of AMZ001 (diclofenac sodium gel 3.06%) in 
comparison with Voltaren® (diclofenac sodium gel 1%)] in healthy subjects. 
Amzell B.V. has focused the development on once-a-day therapy. The aim of this additional PK 
study (AMZ001-008) is to characterize the rate and extent to which diclofenac is absorbed from 
two different doses of AMZ001 applied once-daily. The two doses have been selected from the 
outcomes of the previous Phase 1 PK and safety study (AMZ001-005) in an attempt to provide 
comparable systemic diclofenac exposure as Voltaren Arthritis Pain Gel. 
1.2 
Benefit / Risk Aspects 
Given the well-known safety profile of diclofenac, the risks related to treatment with topical 
diclofenac gel at the proposed dose are regarded as low. However, due to the alcohol content of 
the product, frequent applications to the skin may cause application site reactions including 
pruritus, erythema, dryness, and urticaria.  There is also a risk of infection at site of puncture for 
blood draws. 
The excipients used for the formulation of AMZ001 are well known and have been used in 
previously conducted studies as well as in already Food and Drug Administration (FDA)-approved 
topical products, such as Elestrin and Anturol.  Overall, the risks posed to the subjects participating 
in the study are deemed low and ethically justifiable, and medical surveillance is considered 
adequate to ensure safety of the subjects. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objectives 
The primary objective of the study is to compare the bioavailability of two dose levels (6 mL 
[5.5 g] and 8 mL [7.4 g]) of AMZ001 (diclofenac sodium gel 3.06%) applied once daily as 3 mL 
and 4 mL per knee on both knees and one dose level of Voltaren Arthritis Pain Gel (32 g, diclofenac 
sodium gel 1%) applied four times daily as 4 g per knee on both knees after repeated topical 
administrations in healthy subjects for 7 days. 


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Secondary Objectives 
- 
Determine the PK profile of the two dose levels (6 mL [5.5 g] and 8 mL [7.4 g]) of 
AMZ001 (diclofenac sodium gel 3.06%) and one dose level (32 g) of Voltaren Arthritis 
Pain Gel (diclofenac sodium gel 1%). 
- 
Assess the safety and tolerability of the two different dose levels of AMZ001 (diclofenac 
sodium gel 3.06%) and one dose level of Voltaren Arthritis Pain Gel (diclofenac sodium 
gel 1%). 
2.2 
Endpoints 
Primary Endpoint 
•
Compare the exposure to diclofenac, as measured by plasma concentration, area under the
curve from time zero to 24 hours (AUC0-24), and maximum (peak) plasma drug
concentration (Cmax) at steady state between two different dose levels of AMZ001 and one
dose level of Voltaren Arthritis Pain Gel in healthy subjects on Day 7.
Secondary Endpoint(s) 
•
The PK parameters Cmax, minimum plasma drug concentration (Cmin), time to reach
maximum (peak) plasma concentration following drug administration (Tmax), time to reach
minimum plasma concentration following drug administration (Tmin), terminal disposition
rate constant (λz), the time it takes for the plasma drug concentration to decrease by half
(T½), average plasma concentration (Cav) and peak-to-trough fluctuation (PTF) of the two
different dose levels of AMZ001 and one dose level of Voltaren Arthritis Pain Gel will be
calculated.  The PK parameters for Day 1 will also be calculated and considered as
secondary endpoints.
Safety Endpoint(s) 
•
Adverse Events (AEs); including serious, treatment emergent, ADRs
•
Local systemic tolerability
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
See Figure 1 for the treatment schedule (Three Treatments, Three Period Crossover Design). 
Study Design 
This is a randomized, open-label, three period crossover, multiple-dose study to investigate the 
bioavailability, safety, and tolerability of two dose levels (6 mL [5.5 g] and 8 mL [7.4 g]) of 
AMZ001 applied once daily on both knees and one dose level of Voltaren Arthritis Pain Gel (32 
g) applied four-times daily on both knees after repeated dosing in healthy subjects for 7 days.


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Before inclusion into the study, all subjects will undergo a physical examination, including vital 
signs, and blood samples will be collected for laboratory assessments (hematology, clinical 
chemistry, and urinalysis).  
Subjects will be randomized to one of six dosing sequences, see Figure 1 for an overall summary 
of the study design: 
Period 1  
(Sequence 1) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 2) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 3) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 4) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 5) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 6) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
 
Period 2  
(Sequence 1) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 2) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 3) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 4) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 5) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 6) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
 
Period 3  
(Sequence 1) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 2) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
(Sequence 3) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 4) Voltaren Arthritis Pain Gel – 32 g daily: 4 g on each knee 4 times daily 
(Sequence 5) AMZ001 – 8 mL (7.4 g) daily: 4 doses of 1 mL on each knee QD 
(Sequence 6) AMZ001 – 6 mL (5.5 g) daily: 2 doses of 1.5 mL on each knee QD 
 
Note: Between Periods 1 and 2 and Periods 2 and 3, there will be a 21-day (+ 7-day) washout, and 
the subjects will not be confined to the study site. 


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Figure 1: 
Study Design: Three Treatments, Three Period Crossover Design   
 
 


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The gel will be administered to the knee by subject under supervision of designated clinical site 
staff member for consistency in application and to ensure the correct amount is applied to each 
knee at the specified dose and frequency for 7 consecutive days.  The subject will then spread the 
gel directly to the pre-defined treatment area of approximately 400 cm2 (6 mL AMZ001 and 32 g 
Voltaren Arthritis Pain Gel) and 500 cm2 (8 mL AMZ001) for each subject’s knee as per detailed 
application instructions.   
Subjects will be confined at the study site only for the duration of each treatment period (Days -1 
to Day 8) of the study. Subjects are permitted to shower ≥ 1-hour pre-dose and after 3-hours or 
greater post-dose. Blood samples for PK analyses will be collected prior to (within 1 hour) 
application and at 2 (±15 min), 4 (±15 min), 6 (±15 min), 8 (±15 min), 10 (±15 min), 12 (±15 min), 
14 (±15 min), 16 (±15 min), 18 (±15 min), 20 (±15 min), and 24 (±30 min) hours after initial 
application on Days 1 and 7. One blood sample will be collected on Days 3, 4, 5, and 6 prior to 
(within 1 hour) the first application of gel to measure the trough level of each study drug.  
At the end of Period 3, there will be three additional PK blood samples taken respectively at 3 
weeks (21 days), 4 weeks (28 days), and 5 weeks (35 days) after the last application to compare 
elimination phase of AMZ001 vs. Voltaren Arthritis Pain Gel and to further describe the 
elimination phase of the AMZ001 product. During this follow-up period, subjects will not be 
confined to the study site. 
If a sampling time point and application time fall at the same time, the blood sample should be 
taken immediately prior to application. 
 Application Instructions 
The specified Investigational Medicinal Product (IMP) will be administered by subject under 
supervision of designated clinical site staff member for consistency in application and to ensure 
the correct amount is applied to each knee at the specified dose and frequency for 7 consecutive 
days, as per the AMZ001 and Voltaren Application Instructions.   
 Study Schedule 
The study duration is approximately 18 weeks for each subject. 
3.2 
Planned Number of Study Sites and Subjects 
The study will be conducted at 1 site in the U.S. A sufficient number of subjects will be screened 
and approximately 75 subjects will be randomized to give 60 evaluable subjects across the six 
dosing sequences. 
3.3 
Interim Analysis 
Not applicable. 
3.4 
Data Monitoring Committee  
No Data Monitoring Committee is planned. 


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3.5 
Discussion of Overall Study Design and Choice of Control Groups 
 Study Design 
A randomized, open-label, three period crossover, multiple-dose design will evaluate the PKs and 
compare the bioavailability of two different dose levels of AMZ001 and one dose level of Voltaren 
Arthritis Pain Gel.   
Note: Between Periods 1 and 2, Periods 2 and3, there will be a 21-day (+7-day) washout. At the 
end of Period 3 there will be a 35-day follow-up period, during which time there will be 3 
scheduled PK follow-up outpatient visits (see Table 2). 
Safety and tolerability will also be assessed. 
 Selection of Endpoints 
The PK parameter levels (AUC0-24 and Cmax) of AMZ001 will be used to compare the 
bioavailability of diclofenac sodium gel 3.06% to the marketed Voltaren Arthritis Pain Gel 
product. 
 Blinding 
The clinical conduct of this study will be open-label.  The bioanalytical lab will not be provided 
with the randomization schedule and therefore will be blinded to the treatments administered.  
 Selection of Doses in the Study 
Higher concentration and absorption characteristics of the AMZ001 formulation will provide a 
delivery of diclofenac that allows for application once daily (QD) compared to dosing four times 
a day (QID) recommended for the reference product, Voltaren Arthritis Pain Gel. Comparative 
efficacy trials support the proposal of QD dosing for AMZ001 (Bihlet et al. 2020). Using already 
conducted PK studies, PK modelling and simulation have been conducted to estimate appropriate 
doses that should provide same exposure as Voltaren Arthritis Pain Gel. Two doses have been 
selected: 6mL and 8mL of AMZ001.  Overall, the objective is to identify one dose of the AMZ001 
formulation. 
See Section 3.1.1 for doses selected.  
 Selection and Timing of Dose for Each Subject 
 On-Site Application during PK Sampling 
The IMP should be applied at the specified times: 
• AMZ001 will be administered to the knee by the subject under supervision of designated 
clinical site staff member QD in the morning. 
• Voltaren Arthritis Pain Gel will be applied QID, approximately every 4-5 hours while 
subjects are awake (e.g., 7:00 am, 12:00 pm, 5:00 pm, and 10:00 pm) 


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Each application time is subject to a ±30-minute window based on Day 1 dosing times. 
If a sampling time point and application time fall at the same time, the blood sample should be 
taken immediately prior to application. 
 
SELECTION OF STUDY POPULATION 
4.1 
Study Population 
Every effort will be made to enroll approximately equivalent numbers of male and female subjects. 
 Inclusion Criteria 
1. Healthy male or female subjects 18-65 years of age (e.g., in general good physical health, 
as judged by the Investigator and no clinically relevant abnormalities identified by a 
detailed medical history, full physical examination, including blood pressure and pulse rate 
measurement, 12-lead ECG or clinical laboratory tests) 
2. Has a body mass index (BMI) between 18.0 and 35.0 kg/m2 at Screening 
3. In the case of females of child-bearing potential ([FCBP] unless surgically sterilized 
[hysterectomy, bilateral oophorectomy, bilateral tubal ligation] or are postmenopausal for 
at least 12 months), are using two acceptable forms of birth control (hormonal 
contraceptives i.e., oral/implant/injectable/transdermal; intrauterine device (IUD) and/or 
barrier methods [female condom, male condom, diaphragm, cervical cap, spermicide]; 
note: 2 barrier methods are two acceptable forms of birth control)).  Abstinence or partner’s 
vasectomies are acceptable if the female subject agrees to implement two acceptable forms 
of birth control if her lifestyle/partner changes. 
4. Females of child-bearing potential have a negative serum pregnancy test (SPT) at 
Screening and negative urine pregnancy test (UPT) on Day -1 of each period and at end of 
treatment (EOT) visit (Period 3, Day 8) 
5. Are free of any systemic or dermatologic disorder and chronic or acute infections, which, 
in the opinion of the Principal Investigator (PI), will interfere with the study results or 
increase the risk of adverse events (AEs) 
6. Read, understand, and provide signed informed consent before any assessment is 
performed. 
 
 Exclusion Criteria 
The presence of any of the following excludes a subject from study enrollment: 
1. Subject has any visible skin disease, skin lesions, wounds, or a significant amount of hair 
at the application site (knee).  
2. Use of an investigational medicinal product (IMP) within 30 days or 5 half-lives (if 
known), whichever is longer, of enrollment or during the study 


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3. Treated with systemic or local diclofenac within 30 days of enrollment or during the 
study (except for study IMP) 
4. Known hypersensitivity to diclofenac, any excipients (ethanol, propylene glycol, 
diethylene glycol monoethyl ether, myristyl alcohol, hydroxypropyl cellulose, and water), 
aspirin, Xarelto, coumadin, or other NSAIDs, including Cyclooxygenase-2 (COX-2) 
inhibitors 
5. Any history of drug hypersensitivity, asthma, urticaria, or other significant allergic 
diathesis. Subjects with uncomplicated seasonal allergic rhinitis can be accepted only if 
expected allergy season is clearly outside enrolment/ treatment periods. 
6. Females who are pregnant and/or lactating 
7. Of child-bearing potential but not willing to use adequate contraception for the duration 
of the study 
8. Subject is a current smoker and unable to abstain from smoking during the treatment 
periods. 
9. Use of any topical medication, cosmetics, cream, ointments, lotions on the treatment site 
1 week prior to enrollment through EOT visit. 
10. Use of any medication (including over-the-counter medication, dietary supplements, and 
herbal remedies) within 2 weeks before first scheduled study drug administration or 
within less than 5 times the elimination half-life of the respective drug (whichever is 
longer) or is anticipated to require concomitant medication during the 2-week period or at 
any time throughout the study. Consumption of any drug metabolizing enzyme (e.g., 
cytochrome P450 3A4 (CYP3A4) or other cytochrome P450 enzymes) inducing or 
inhibiting beverages or food (e.g., broccoli, Brussels sprouts, grapefruit, grapefruit juice, 
star fruit) within 3 days prior to and during each treatment period. 
Allowed treatments are: 
• Systemic contraceptives and hormone replacement therapy, as long as female subject 
is on stable treatment for at least 3 months and continues treatment throughout the 
study. 
• Occasional use of acetaminophen 500 mg (up to 1000 mg daily) 
• Single intake of other drugs only if judged by the investigator to have no clinical 
relevance and will not confound the interpretation of the study results. 
11. Subject has a known or suspected malignancy, excluding basal cell cancer unless it is 
associated with the treatment area. 
12. Subject has a positive blood screen for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), hepatitis C antibody (Anti-HCV) 
13. Subject has any acute or chronic condition or is using medications, which, in the 
investigator’s opinion, would make it unsafe for the subject to participate in this study, 


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including clinically significant abnormal laboratory values, vital signs, physical 
examination findings prior to randomization or during study participation. 
14. History or current evidence of renal disease or impaired renal function at screening as 
indicated by abnormal levels of serum creatinine (> 1.43 mg/dL) or BUN (≥ 35 mg/dL) 
or the presence of clinically significant abnormal urinary constituents (e.g., albuminuria)  
15. History or current evidence of ongoing hepatic disease or impaired hepatic function at 
screening. A subject will be excluded if more than one of the following lab value 
deviations are found: 1) AST (≥ 1.5 ULN), ALT (≥ 1.5 ULN), 2) GGT (≥ 1.5 ULN), ALP 
(≥ 1.5 ULN), 3) total bilirubin (> 2.00 mg/dL) or creatine kinase (≥ 3 ULN). A single 
deviation from the above values is acceptable and will not exclude the candidate, unless 
specifically advised by the Investigator. 
16. Subject has clinically relevant chronic or acute infectious illnesses or febrile infections 
within 2 weeks prior to the first scheduled study drug administration 
17. Subject has gastrointestinal bleeding issues, e.g., Gastroesophageal Reflux Disease 
(GERD), Peptic Ulcer Disease (PUD) 
18. Subject has a hospital admission or major surgery within 30 days prior to randomization. 
19. Subject has a donation or blood collection of more than 1 unit (approximately 450 mL) of 
blood (or blood products) or acute loss of blood during the 30 days prior to 
randomization. 
20. Subject has a history of alcohol abuse, prescription drug abuse, or illicit drug use within 6 
months prior to Screening. 
21. Subject meets eligibility criteria, but study is filled 
22. Subject who is an investigational site staff member directly involved in the conduct of the 
study and his/her family members, site staff member otherwise supervised by the 
Investigator, or subject who is a Amzell B.V. employee directly involved in the conduct of 
the study 
Reasons for permanent discontinuation from the study may include the following: 
1. Subject request 
2. Adverse events that the Investigator believes may compromise the safety of the subject or 
the interpretation of study results. 
4.2 
Method of Assigning Subjects to Treatment Groups 
 Recruitment 
The study site will recruit only healthy subjects. COVID-19 screening, testing, and prevention 
procedures will be followed as per local guidelines and study plan. 


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 Randomization 
The treatment given to individual subjects is determined by a randomization schedule. 
4.3 
Restrictions 
 Prior and Concomitant Therapies 
This study is being performed in normal healthy subjects. No planned consumption of concomitant 
medications, dietary supplements, and herbal remedies (other than hormonal contraceptives and 
occasional use of acetaminophen) will be allowed 2 weeks prior to start of the study and throughout 
study completion. 
 Other Restrictions 
• Subjects will be advised to avoid exposing the pre-defined application area to direct 
sunlight during the treatment periods. 
• Subjects should avoid gel contact with the eyes, nose, and mouth; if gel contact occurs, 
rinse the affected area thoroughly with water.  
• Subjects will be advised to wash their hands thoroughly after rubbing the gel into their 
knees, after each full IMP administration. 
• No smoking throughout the treatment period of the study (permitted during washout 
periods and follow-up)  
• No consumption of alcohol containing products throughout treatment period (permitted 
during washout periods and follow-up) 
• No consumption of caffeine/theophylline (xanthine) – containing products (e.g., coffee, 
green tea, black tea, coco-cola, cocoa) throughout treatment period (permitted during 
washout periods and follow-up) 
• Acceptance of standardized food and beverages throughout each treatment period 
• No performance of highly strenuous physical exercise (body building, high 
performance sports) from 72 hours prior to start of the study and throughout the study 
until completion 
• No consumption of food or beverages that have an influence on IMP pharmacokinetics 
such as, star fruit, grapefruit or grapefruit containing food or beverages from 3 days 
prior to and during each treatment period (permitted during washout periods and 
follow-up) 
4.4 
Withdrawal Criteria 
The following medical and other reasons justify a premature termination (by subject or 
Investigator) of any of the IMPs: 
 Withdrawal of informed consent, 


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 Serious adverse event (SAE)/AE, 
 Allergic reaction to the study materials, 
 Subject’s request, 
 Occurrence of one of the safety criteria for exclusion after treatment has been instituted, 
 Subject is lost to follow-up, and/or 
 Investigator’s judgment. 
The subjects have the right to withdraw from the study at any time for any reason, without the need 
to justify their decision. However, the Investigator should record the reason for the subject’s 
withdrawal, if possible. The Investigator also has the right to withdraw subjects if the Investigator 
considers that the study treatment may compromise the safety of the subject or the subjects’ non-
compliance may impact the interpretation of the study results.  
For any discontinuation, the Investigator will perform the follow-up examinations, obtain all the 
required details, and document the date of the premature termination and the main reason in the 
electronic Case Report Form (eCRF). 
Data obtained after the subject has withdrawn his/her consent cannot be entered into the database.  
This also applies to biological samples drawn prior to the withdrawal of the consent but not 
analyzed at the time of the withdrawal, unless the subject consents to the use of these data. 
4.5 
Subject Replacement 
Subjects that are withdrawn during the study after the first administration of IMP will be replaced 
so there are 60 evaluable subjects across the six dosing sequences. 
 
TREATMENTS 
5.1 
Treatments Administered 
 Investigational Medicinal Product (IMP) 
Both AMZ001 and Voltaren Arthritis Pain Gel will be referred to as study IMPs. 
 AMZ001 
AMZ001 is provided in dispensing package containing 3.06% diclofenac sodium in a gel base.  
AMZ001 is delivered in aliquots of either 1 mL (0.92 g containing 28.2 mg of diclofenac sodium) 
or 1.5 mL (1.38 g containing 42.2 mg of diclofenac sodium) per pump actuation. For the purpose 
of this study, AMZ001 will be administered using the dispensers measuring 1 mL/actuation (for 
the 8 mL (7.4 g) daily dose) or 1.5mL/actuation (for the 6 mL (5.5 g) daily dose). 
A detailed application instruction will be provided to the dedicated clinical site staff member and 
subjects. 
 Voltaren Arthritis Pain Gel 
Voltaren Arthritis Pain Gel is provided in tubes containing 100 g of the topical gel in each tube. 
Each tube contains diclofenac sodium in a gel base (10 mg of diclofenac sodium per gram of gel 


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or 1%). A detailed application instruction will be provided to the dedicated site study member and 
subjects. 
5.2 
Medicinal Product(s) 
 Characteristics and Source of Supply 
AMZ001 is manufactured according to the principles of Good Manufacturing Practice (GMP) and 
is a 3.06% diclofenac sodium topical gel administered from a dispensing package measuring either 
1 mL per actuation or 1.5 mL per actuation. The amount of gel contained in each delivery dispenser 
is sufficient to cover the duration of the 7-day treatment period. 
Voltaren Arthritis Pain Gel is sourced within the US from GlaxoSmithKline plc and is a 1% 
diclofenac sodium topical gel administered from 100g tubes. 
 Packaging and Labeling 
 Investigational Medicinal Product (IMP) 
Labelling of the AMZ001 dispensing package will be performed under the responsibility of TKL 
Research, Inc. (TKL) in accordance with GMP and Good Clinical Practice (GCP) guidelines, as 
well as any national regulatory requirements.  Each IMP dispenser will be labeled with study 
specific labels. The verbiage on the labels will be in accordance with US federal regulation 21 
CFR § 312.6: 
• The immediate package of an investigational new drug intended for human use shall bear 
a label with the statement “Caution: New Drug – Limited by Federal (or US) law to 
investigational use”. 
• The label or labelling of an investigational new drug shall not bear any statement that is 
false or misleading in any particular and shall not represent that the investigational new 
drug is safe or effective for the purposes for which it is being investigated. 
The dispensing packages are packaged in boxes according to their administration volume.  
The dispenser label will have a pre-printed protocol number and a dedicated space for filling in 
the subject number. The site will record the subject number on the dispenser label, and batch/lot 
number in the pharmacy records prior to use.  The dispenser will also be weighed to assure 
compliance. 
Each Voltaren Arthritis Pain Gel tube will be labelled. The label will contain a dedicated space for 
filling in the subject number and protocol information by clinical site staff prior to dispensing to 
subjects. The tube label will have a pre-printed protocol number and a dedicated space for filling 
in the subject number. The site will record the subject number on the tube label and batch/lot 
number in the pharmacy records prior to use. The tube(s) will also be weighed to assure 
compliance. 
The study site will, under the responsibility of the Investigator, complete and return the Drug 
Delivery Note (packing slip) to Amzell B.V. verifying the receipt of the drug. 


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 Conditions for Storage and Use 
The Investigator will ensure that both IMPs will be stored in appropriate conditions at room 
temperature – AMZ001: STORE UPRIGHT 20-25°C (68-77°F) with a permitted excursion of 15-
30°C (59o-86oF); Voltaren Arthritis Pain Gel: 20-25°C (68-77°F) with a permitted excursion of 
15-30°C (59o-86oF); in a secure location with controlled access.  The temperature in the storage 
area shall be monitored daily on-site when the office is open, and the values shall be documented 
in a temperature log.  Storage and/or transit temperature deviations must be reported to Amzell 
B.V. without delay. All affected IMP will be quarantined on-site until a determination of 
acceptability is completed, and approved for use by Amzell B.V. 
5.3 
Treatment Compliance 
 Dispensing and Accountability 
All handling of medicinal products will be done by trained and authorized personnel at the site. 
The IMP will only be applied to subjects who meet the eligibility criteria and are allocated as 
applicable in the study. 
The study site will document the dates and quantities (IMPs to be weighed before and after dose 
application) of IMP applied to each subject and will maintain the batch/lot numbers of the IMP.  
Subject numbers will be marked on each delivery dispenser (AMZ001) and tube (Arthritis Pain 
Gel) by the study site and recorded. The monitor will verify the drug accountability during the 
study and document any discrepancies. Used dispensing packages and tubes will be saved for drug 
accountability. 
 Assessment of Compliance 
Compliance will be assessed by weighing the dispensing package or tube before and after use daily 
on-site. 
5.4 
Prior and Concomitant Therapy 
Any prior or concomitant medication will be recorded in the electronic Case Report Form (eCRF) 
with the main reason for its use. 
5.5 
Return and Destruction of Medicinal Products 
IMP samples assigned as reserve (retention) IMP samples will be maintained at study site until the 
end of the required retention period, as per US federal regulations 21 CFR § 320.38 and 320.63.  
Reserve IMP samples will be randomly selected and set aside prior to the beginning of the study 
enrollment. 
When drug accountability has been finalized, verified by the monitor, and signed off by the 
Investigator, all used and unused IMP (except for the reserve IMP samples retained on site, as per 
US federal regulations 21 CFR § 320.38 and 320.63) will be sent by study site for destruction in 
accordance with national requirements. 


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STUDY PROCEDURES 
6.1 
Study Flow Chart 
This same flow chart will be used for all 3 periods; all dosing sequences have the same procedures. 
 
Note: Between Periods 1 and 2 and Periods 2 and 3, there will be a 21-day (+ 7 day) washout 
  
 


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Table 1 - Study Flow Chart for Periods 1, 2 and 33 
Procedures (Days) 
-30 to -2 
Day 
-12 
1 
2 
3 
4 
5 
6 
7 
8E 
 
Screening1 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Treatment Assessments 
 
 
Informed consent 
 XA 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
Sample Collection 
 
 
Clinical chemistry, 
hematology, and urinalysis 
X 
 
 
 
 
 
 
 
 
X 
HIV and HBsAg, Anti-HCV 
X 
 
 
 
 
 
 
 
 
 
Blood samples for PK 
 
 
XBG 
XH 
XF 
XF 
XF 
XF 
XBG 
X 
SPT (FCBP) 
X 
 
 
 
 
 
 
 
 
 
UPT (FCBP) 
 
X 
 
 
 
 
 
 
 
XI 
 
Investigational Medicinal Product (IMP) 
 
 
Weigh IMP 
 
 
XC 
XC 
XC 
XC 
XC 
XC 
XC 
 
IMP application 
 
 
XD 
XD 
XD 
XD 
XD 
XD 
XD 
 
 
Other Assessments/Procedures 
 
 
Vital signs 
X 
X 
 
 
 
 
 
 
 
X 
Physical examination 
X 
X 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
Baseline Treatment area 
assessment 
X 
X 
 
 
 
 
 
 
 
 
Assessment of skin reaction 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Admit / Discharge 
 
X 
 
 
 
 
 
 
 
X 
1Note, only 1 screening will be done before Period 1.  
2Day -1 will be repeated after each washout period and before starting Periods 2 and 3 of treatment. 3Use Table 2 
at the completion of Period 3. 
 
A. Subject must sign informed consent prior to any study procedures 
B. 
On Day 1 and Day 7, Pre-dose (within 1 hour pre-dose) and 2 (±15 min), 4 (±15 min), 6 (±15 min), 8 (±15 min), 10 (±15 min), 
12 (±15 min), 14 (±15 min), 16 (±15 min), 18 (±15 min), 20 (±15 min), and 24 (±30 min) hours (on Days 2 and 8) post initial 
application  
C. 
Before and after dosing 
D. As specified for the assigned treatment regimen 
E. 
If a subject prematurely withdraws from the study at any time, all attempts should be made to complete the following:  reason 
for withdrawal; assessment of skin reaction; weigh IMP container; physical examination; vital signs; clinical laboratory safety 
tests; AEs and concomitant medication. 
F. 
Collect PK blood sample prior to morning dosing (within 1 hour pre-dose). 
G. On Day 1 and 7, if Voltaren Arthritis Pain Gel applications overlap with PK collections, blood samples will be obtained prior 
to each Gel application. 
H. Day 2 pre-dose will be the same collection as 24 hours post application on Day 1. 
I. 
Only conducted on Day 8 of Period 3 (EOT visit) or Early Termination (ET) visit.    
 


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At the end of Period 3, there will be three additional PK blood samples taken respectively at 3 
weeks (21 days), 4 weeks (28 days), and 5 weeks (35 days) after the last application to compare 
elimination phase of AMZ001 vs. Voltaren Arthritis Pain Gel and to further describe the 
elimination phase of the AMZ001 product. During this follow-up period, subjects will not be 
confined to the study site. Subjects will be reminded on the restrictions to be followed as part of 
concomitant medications prior to being discharged on Day 8 of this 3rd period. 
Table 2 - PK Outpatient Visits 
PK Outpatient Visits (Post Period 3) 
3 Weeks (21 days) 
±2 days 
 
4 Weeks (28 days) 
±2 days 
 
5 Weeks (35 days) 
±2 days 
Sample Collection 
Blood samples for PK 
X 
 
X 
 
X 
Other Assessments/Procedures 
Adverse events 
X 
 
X 
 
X 
Concomitant medication 
X 
 
X 
 
X 
6.2 
Study Procedures 
All subjects must provide written informed consent prior to any study procedures.   
 Screening (Days -30 to -2) 
The following procedures will be performed or reviewed at this visit: 
• Informed consent 
• Medical history 
• Demographics 
• Inclusion/Exclusion criteria  
• Treatment area assessment 
• Physical examination 
• Vital signs 
• Clinical laboratory safety tests (clinical chemistry, hematology, and urinalysis) 
• HIV, HBsAg and Anti-HCV 
• SPT (for FCBP) 
• 12-lead ECG 
• Concomitant medication 


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 Day -1 
Day -1 will be repeated after each washout period and before starting Periods 2 and 3 of 
treatment. 
The following procedures will be performed or reviewed: 
• Inclusion/Exclusion criteria 
• Vital signs 
• Physical exam 
• UPT (for FCBP) 
• Baseline treatment area assessment 
• AEs 
• Concomitant medication 
• Subjects will then be admitted into the study site 
 Days 1, 7, and 8  
Subjects in each dosing sequence (1-6) will begin treatment at this visit and 24-hour PK samples 
will be collected. 
The following procedures will be performed or reviewed: 
• Assessment of treatment area prior to Randomization (Period 1, Day 1 only) 
• Inclusion/Exclusion criteria 
• Randomization (Period 1, Day 1 only) 
• Weigh Voltaren Arthritis Pain Gel container or AMZ001 dispenser – before and after 
dosing (Day 1 and Day 7) 
• IMP application according to respective treatment period and dosing sequence (Day 1 and 
Day 7) 
• Vital signs (Day 8) 
• AEs 
• Concomitant medication 


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• Assessment of skin reaction prior to the first application on Day 7 and on Day 8 
(approximately 24 hours after the first application on Day 7) 
• Physical examination (Day 8) 
• Blood samples for PK on Day 1 and Day 7: Pre-dose (within 1 hour pre-dose) and at 2 
(±15 min), 4 (±15 min), 6 (±15 min), 8 (±15 min), 10 (±15 min), 12 (±15 min), 14 (±15 
min), 16 (±15 min), 18 (±15 min), 20 (±15 min), and on Day 8 approximately 24 (±30 
min) post initial application on Day 7. Day 2 pre-dose will be the same collection as 24 
hours post application on Day 1. 
• UPT (for FCBP) (Day 8) 
• Clinical chemistry, hematology, and urinalysis (Day 8) 
• Then discharged from the study site (Day 8) 
 Day 2, 3, 4, 5, and 6 
Subjects in each dosing sequence (1-6) will continue treatment and one PK sample will be 
collected prior to dosing. 
The following procedures will be performed: 
• Weigh Voltaren Arthritis Pain Gel container or AMZ001 dispenser – before and after 
dosing 
• Assessment of skin reaction prior to the first application of the day 
• IMP application according to respective treatment period and dosing sequence (Day 2, 3, 
4, 5 and 6) 
• AEs 
• PK blood sample – within 1 hour pre-dose in the morning.  The Day 2 pre-dose will be the 
same collection as 24 hours post application on Day 1. 
• Concomitant medication 
Note: Between Periods 1 and 2 and Periods 2 and 3, there will be a 21-day (+ 7-day) washout, and 
the subjects will not be confined to the study site. 
At the end of Period 3, there will be three additional PK blood samples taken respectively at 3 
weeks (21 days), 4 weeks (28 days), and 5 weeks (35 days) (see Table 2) after the last application 
to compare elimination phase of AMZ001 vs. Voltaren Arthritis Pain Gel and to further describe 
the elimination phase of the AMZ001 product. 


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STUDY ASSESSMENTS 
Laboratories will provide Laboratory Manuals that will cover all blood and urine tests and describe 
sampling and shipment procedures including contact details, storage conditions, equipment, 
volume, analytical method, reference ranges, etc. The laboratory manuals will be provided to the 
clinical investigational unit before the start of the study. 
7.1 
Assessments Related to the Primary Endpoint 
 Pharmacokinetics 
Blood samples for measurement of plasma concentration of diclofenac will be collected on the 1st 
and 7th day of treatment (Days 1 and 7). Samples will be collected pre-dose (within 1 hour) and 2 
(±15 min), 4 (±15 min), 6 (±15 min), 8 (±15 min), 10 (±15 min), 12 (±15 min), 14 (±15 min), 16 
(±15 min), 18 (±15 min), 20 (±15 min), and 24 (±30 min) hours post initial application (Day 8). 
One blood sample will be collected on the 3rd, 4th, 5th, and 6th day of treatment (Days 3, 4, 5, 
and 6). These samples will be collected within 1 hour prior to dosing in the morning. At the end 
of Period 3, there will be three additional PK blood samples taken respectively at 3 weeks (21 
days), 4 weeks (28 days), and 5 weeks (35 days) after the last application of IMP (see Table 2). 
Specific instructions on sample handling will be described in the laboratory manual provided by 
the bioanalytical laboratory.  Samples will be split into two aliquots:  one aliquot for analysis (with 
sufficient material to allow for a repeat analysis at the bioanalytical laboratory) and one aliquot 
remaining at the clinical site to serve as a backup sample. Samples will be shipped frozen to the 
bioanalytical laboratory for analysis. A validated liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) method with an LLOQ of 50 pg/mL for the analysis of diclofenac will 
be employed for sample analysis, as described in a sample analysis plan. 
7.2 
Other Assessments 
 Vital Signs 
Vital signs comprising systolic and diastolic arterial blood pressure, pulse and body temperature 
will be assessed at screening, Day -1, and Day 8 visits. Systolic and diastolic blood pressure will 
be measured after the subject has been in seated or supine position for at least 1 minute. All 
recordings will be performed using standard equipment. 
Clinically significant abnormal findings will be reported as adverse events (AEs). 
 Laboratory Parameters 
 Clinical Safety Laboratory Tests 
Blood samples for clinical chemistry, hematology and urinalysis will be collected at screening and 
on Day 8. Laboratory safety evaluations will be performed according to Table 3 below. The clinical 
chemistry, hematology and urinalysis will be performed by a diagnostic laboratory. 
Clinically significant abnormal findings will be reported as AEs. 


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Table 3 - Safety Laboratory Parameters 
Clinical Chemistry 
Hematology 
Urinalysis 
Alanine 
aminotransferase 
Hematocrit 
Protein 
Alkaline phosphatase 
Hemoglobin 
Glucose 
Aspartate 
aminotransferase 
Platelet count 
Bilirubin 
Calcium 
Red blood cell count 
pH 
Cholesterol 
Reticulocytes 
Nitrite 
Creatinine 
White blood cell 
count with differential  
Ketone 
Gamma-glutamyl 
transferase 
Monocytes, large 
unclassified cells 
Urobilinogen 
Glucose 
 
Blood 
Potassium 
 
Leukocytes 
Sodium 
 
 
Total bilirubin 
 
 
Triglycerides 
 
 
Urea (blood urea 
nitrogen) 
 
 
SPT (screening only) 
 
 
Serology: HIV, 
HBsAG, and HCV 
test (screening only) 
 
 
 Physical examination 
Physical examination will be performed at the screening, Day -1, and Day 8. Clinically significant 
abnormal findings at follow-up will be reported as AEs. 
A full physical examination will include an evaluation of the head, eyes, ears, nose, throat, neck, 
heart, chest, lungs, abdomen, extremities, skin, and any other notable conditions.  
 12-Lead Electrocardiogram (ECG) 
A standard bedside 12-lead ECG will be recorded using the study site’s own ECG equipment and 
will be evaluated by the Investigator.   


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 Administration Site Reactions 
The skin at the application site will be examined by the Investigator or designee (see Section 6.2 
for when examinations will take place). The skin tolerability will be documented in the eCRF 
according to the terminology of the International Contact Dermatitis Research Group: 
0 no reaction (negative documentation) 
1 doubtful reaction 
2 mild erythema 
3 strong erythema 
4 very strong erythema and edema 
These administration site reactions will be recorded in an eCRF page dedicated to dermal findings. 
Mild, strong, and very strong erythema and edema (skin tolerability score ≥2) will be reported as 
AEs. 
7.3 
Handling of Biological Samples 
A detailed description of all sample collections and shipment procedures will be included in a 
separate laboratory manual. 
7.4 
Laboratory Values 
The Investigator will review the laboratory test results, evaluate, and document whether the results 
are non-clinically or clinically significant. 
 
ADVERSE EVENTS 
8.1 
Adverse Event (AE) Definition 
An AE is any untoward medical occurrence in a subject participating in a clinical study. It includes: 
• Any unfavorable and unintended sign, symptom or disease temporally associated with the 
use of the IMP, whether or not considered to be caused by the IMP. 
• AEs commonly observed, and AEs anticipated based on the pharmacological effect of the 
IMP. 
• Any laboratory abnormality, vital sign or finding from physical or other examinations 
assessed as clinically significant by the Investigator [Note:  findings from assessments and 
examinations done during screening are not AEs but are recorded as medical history.] 
• Accidental injuries, reasons for any change in medication (drug and/or dose), reasons for 
any medical, nursing or pharmacy consultation, or reasons for admission to hospital or 
surgical procedures. 


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• Overdoses and medication errors with and without clinical consequences. 
All pre-treatment events will be captured as medical history. 
A treatment emergent AE (TEAE) is defined as any AE occurring after start of IMP administration 
and within the time of residual drug effect (5 days), or a pre-treatment AE or pre-existing medical 
condition that worsens in intensity after treatment with the IMP and within the time of residual 
drug effect. 
A post-treatment AE is defined as any AE occurring after the first dose of study drug and until the 
last study visit (end-of-study visit) or until 3 weeks post dose (whichever is longer). 
8.2 
Collection and Recording of Adverse Events 
 Collection of Adverse Events 
The Investigator must monitor the health of the subject throughout the study from the time of 
enrolment until the last study visit. 
The sources of AEs cover: 
• The subject’s response to questions about his or her health (a standard non-leading question 
such as “How have you been feeling since your last visit?” is asked at each visit). 
• Symptoms spontaneously reported by the subject. 
• Investigations and examinations where the findings are assessed by the Investigator to be 
clinically significant changes or abnormalities. 
• Other information relating to the subject’s health becoming known to the Investigator (e.g., 
hospitalization). 
 Recording of Adverse Events 
The Investigator must record all AEs in the AE Log provided in each subject’s eCRF with 
information about: 
• AE 
• Date and time of onset (time can be omitted, if applicable) 
• Intensity 
• Causal relationship to IMP 
• Action taken with IMP. 
• Other action taken. 


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• Date and time of outcome (time can be omitted, if applicable) 
• Outcome 
• Seriousness 
Each of the items in the AE Log is described in detail in the following sections. 
Adverse Event 
Adverse events should be recorded as diagnoses, if available. If not, separate signs and symptoms 
should be recorded. One diagnosis/symptom should be entered per record. 
If a subject suffers from the same AE more than once and the subject recovers in between the 
events, the AEs should be recorded separately. If an AE changes in intensity, a worst-case approach 
should be used when recording the event, i.e., the highest intensity and the longest duration of the 
event. Exception:  If a symptom or diagnosis with onset before the first IMP administration (i.e., 
a pre-treatment event) increases in intensity, this must be recorded as AE. The initial symptom or 
diagnosis should be recorded as medical history. While AE should be reported with date/time of 
onset when the intensity increased. 
Note: A procedure is not an AE; the reason for conducting the procedure is. Hospitalization is not 
an AE; the reason for hospitalization is. Death is not an AE, but the cause of death is (an exception 
is sudden death of unknown cause, which is an AE). 
Date and Time of Onset 
The date of onset is the date when the first sign(s) or symptom(s) were first noted. If the AE is an 
abnormal clinically significant laboratory test or outcome of an examination, the onset date is the 
date the sample was taken, or the examination was performed.  
Intensity 
The intensity of an AE must be classified using the following 3-point scale: 
Mild: 
Awareness of signs or symptoms, but no disruption of usual activity. 
Moderate: 
Event sufficient to affect usual activity (disturbing). 
Severe: 
Inability to work or perform usual activities (unacceptable). 
 
 
 
 


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Causal Relationship to IMP 
The possibility of whether the IMP caused the AE must be classified as one of the following: 
Reasonable possibility:   
There is evidence or argument to suggest a causal relationship between the IMP and the AE. The 
AE may occur as part of the pharmacological action of the IMP or may be unpredictable in its 
occurrence.  
Examples:   
• adverse events that are uncommon but are known to be strongly associated with IMP 
exposure. 
• adverse events that are not commonly associated with IMP exposure, but the event occurs 
in association with other factors strongly suggesting causation, such as a strong temporal 
association or the event recurs on rechallenge. 
No reasonable possibility: 
• There is no reasonable evidence or argument to suggest a causal relationship between the 
IMP and the AE. 
Examples: 
• known consequences of the underlying disease or condition under investigation. 
• adverse events common in the study population, which are also anticipated to occur with 
some frequency during the course of the study, regardless of IMP exposure. 
Action Taken with IMP 
The action taken with the IMP in response to an AE must be classified as one of the following: 
• No change (medication schedule maintained or no action taken) 
• Withdrawn 
• Interrupted 
 
 
 
 


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Other Action Taken 
Adverse events requiring therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the subject. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment for an emergency situation. 
If medication is administered to treat the AE, this medication should be entered in the eCRF. 
Date and Time of Outcome 
The date and time (time can be omitted, if applicable) the subject recovered or died. If outcome is 
“Not recovered” or “Recovering” no date of outcome can be recorded. 
Outcome 
The outcome of an AE must be classified as one of the following: 
• Recovered (fully recovered or the condition has returned to the level observed at initiation 
of study treatment) 
• Recovered with sequelae (resulted in persistent or significant disability/incapacity) 
• Recovering 
• Not recovered 
• Fatal 
8.3 
Pregnancy and Pregnancy Outcome 
If a pregnancy occurs in female subjects, the IMP should be immediately stopped, and the subject 
must be withdrawn from the study (as pregnancy is an exclusion criteria). TKL will inform Amzell 
B.V. including information about contact details for the follow-up on the course and outcome of 
the pregnancy. The pregnancy must be followed-up at least until the birth of the infant and one 
month after the birth of the infant. In general, the follow-up will include the course, duration, and 
the outcome of the pregnancy as well as neonatal health. If a pregnancy results in an abnormal 
outcome (birth defect/congenital anomaly) TKL will report this as a serious AE to Amzell B.V. 


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8.4 
Serious Adverse Events 
 Serious Adverse Event (SAE) Definition 
An event is defined a 
serious adverse event if it: 
Guidance 
results in death 
Any event resulting in a fatal outcome must be fully documented 
and reported, including deaths occurring within four weeks after 
the treatment ends and irrespective of the causal relationship to 
the IMP. The death of a subject enrolled in a study is per se not 
an event, but an outcome. 
is life-threatening 
The term life-threatening refers to an AE in which the subject 
was at immediate risk of death at the time of the event. It does 
not refer to an event, which may have caused death if it were 
more severe. 
requires in-patient 
hospitalization or 
prolongation of existing 
hospitalization 
The term hospitalization means that the subject was admitted to 
hospital, or that existing hospitalization was extended as a result 
of an event. Hospitalization describes a period of at least 24 
hours. An overnight stay for observation, stay at emergency 
room or treatment on an out-patient basis do not constitute a 
hospitalization. However, medical judgment must always be 
exercised and when in doubt the case should be considered 
serious (i.e., if the case fulfills the criterion for a medically 
important event). Hospitalizations for administrative or social 
purposes do not constitute an SAE. Hospital admissions and/or 
surgical operations planned before study inclusion are not 
considered AEs, if the illness or disease existed before the 
subject was enrolled in the study, provided that the condition did 
not deteriorate during the study. 
results in persistent or 
significant 
disability/incapacity 
Disability/incapacity means a substantial disruption of a 
person’s ability to conduct normal life functions. In doubt, the 
decision should be left to medical judgment by the Investigator. 
is a congenital 
anomaly/birth defect 
Congenital anomaly/birth defect observed in any offspring of the 
subject conceived during treatment with the IMP. 


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An event is defined a 
serious adverse event if it: 
Guidance 
is an important medical 
event 
Important medical events are 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 
important medical events include AEs that suggest a significant 
hazard, 
contraindication 
or 
precaution, 
occurrence 
of 
malignancy or development of drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding 
whether events qualify as medically important. 
Important medical events include any suspected transmission of 
an infectious agent via a medicinal product. Any organism virus 
or infectious particle (e.g., prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent. A transmission of 
an infectious agent may be suspected from clinical symptoms or 
laboratory findings indicating an infection in a subject exposed 
to a medicinal product. 
Collection, Recording and Reporting of Serious Adverse Events 
SAE Reporting by the Investigator 
All SAEs must be reported immediately as soon as it becomes known to the Investigator and not 
later than within 24 hours of their knowledge of the occurrence of an SAE. 
TKL Pharmacovigilance Group 
Allyson Hudson 
TKL Research, Inc. 
Tel: (201) 587-0500, ext. 2522 
Cell: (973) 897-7152 
Fax: (201) 296-6660 
pharmacovigilance@tklresearch.com 
The Investigator will complete the eCRF SAE report Form with the fullest possible details within 
3 calendar days of the Investigator’s knowledge of the SAE. 
Additional information relevant to the SAE such as hospital records, results from investigations, 
e.g., laboratory parameters (that are not already uploaded in the eCRF), invasive procedures, scans
and x-rays, and autopsy results can be faxed or scanned and e-mailed to TKL using the contact 
details in the section above. In any case this information must be supplied by the Investigator upon 


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request from TKL. On any copies provided, such details such as subject’s name, address, and 
hospital ID number should be redacted, and the subject number provided, instead. 
The Investigator will supply TKL and the institutional review board (IRB) with any additional 
requested information such as results of post-mortem examinations and hospital records. 
Completion of the Demographics, AE Log, Medical History Log and Concomitant Medication 
Log are mandatory for initial reports and for follow-up reports if any relevant changes have been 
made since the initial report.  
Expedited Reporting 
TKL will report all SAEs to Amzell B.V. as per the protocol-specific SAE flow procedures. 
Any AEs that are serious, unexpected, and with a reasonable possible causality to the IMP, as 
judged by either the Investigator or Amzell B.V., will be reported to regulatory authorities in US 
and to IRB within the stipulated timelines. Full details on the reporting procedures, responsibilities, 
and personnel are presented in the Safety Management Plan (SMP). 
The expectedness is assessed by Amzell B.V. 
SAEs will be considered reportable regardless of whether or not the IMP was used in accordance 
with the provisions in the protocol. 
8.5 
Follow-up of Adverse Events and Serious Adverse Events 
Follow-up of Adverse Events with Onset during the Study 
During the study, the Investigator must follow-up on each AE until it is resolved or until the 
medical condition of the subject is stable. 
After the subject’s last visit, the Investigator must follow-up on any AEs that occurred during the 
study classified as serious or considered to have a reasonable possible causality to the IMP with 
the outcome “Not recovered” until resolved or until the medical condition of the subject is stable. 
All such relevant follow-up information must be reported to Amzell B.V. If the event is a chronic 
condition, the Investigator and Amzell B.V. may agree that further follow-up is not required.  
Collection of SAEs with Onset after Last Visit 
If an Investigator becomes aware of a SAE after the subject’s last visit and assesses the SAE to 
have a reasonable possible causality to the IMP, the case will have to be reported to Amzell B.V., 
regardless how long after the end of the study this takes place. Such reports will be considered for 
expedited reporting and managed as such. 


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STATISTICAL METHODS 
Additional details of the proposed statistical analysis methods will be documented in the Statistical 
Analysis Plan (SAP), which will be written following finalization of the protocol and prior to study 
unblinding/analysis (as appropriate). This section is a summary of the planned statistical analyses 
of the most important endpoints including primary and key secondary endpoints. The SAP creation 
and statistical analysis will be performed by Lead Statistician (Guidance for Industry 
Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs-General Considerations, 
March 2014). 
All concentration and PK data will be listed. This includes any data for subjects who are not 
included in the analysis (e.g., subjects withdrawn from the study due to AEs). 
9.1 
Determination of Sample Size 
Based on the assumption (averaging historical data and Phase 1 Study 000084 study results), intra-
subject coefficient of variation (CV) was 61%. A total of sixty (60) evaluable subjects will achieve 
80% power using 95% confidence interval (CI), to account for multiplicity. The true ratio that was 
used in the sample size calculation was 1.05. Enough healthy adults will be screened to randomize 
approximately seventy-five (75) subjects to ensure sixty (60) evaluable subjects, assuming a 20% 
dropout and non-evaluable rate. All subjects will receive all 3 treatments over the course of the 3 
study periods. Subjects will be randomized to one of the 6 possible sequences of 3 treatments, as 
specified in the design in Figure 1, to provide adequate information about the PK parameters and 
safety for the purposes of this study. 
9.2 
Subject Disposition 
All healthy subjects screened and enrolled will be followed to completion. All subjects should be 
included in the analysis unless prespecified in the protocol e.g., PK parameters can be derived or 
major deviations that impact PK as described below. The subjects screened but not found eligible 
will be included in the study report but not study analysis. 
9.3 
Protocol Deviations 
Major protocol violations, such as significant non-compliance or other serious unforeseen 
violations deemed to invalidate the data collected for the purpose of the study will lead to exclusion 
of the data from analysis.  In case of minor protocol violations, data will not be excluded from the 
data analysis.  The rating of protocol violations as either ‘minor’ or ‘major’ will be decided on the 
basis of a review of the data before declaration of the ‘clean file’ and lock of database. 
9.4 
Statistical Analysis Sets (or Populations) 
Safety Population 
The safety population will include randomized subjects who received at least one dose of AMZ001 
or Voltaren Arthritis Pain Gel. The randomized population will be used for safety analysis, 


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presentation of compliance and all baseline characteristics (demographics, medical history, prior 
and concomitant medication, and physical examination). 
 Pharmacokinetic (PK) Population 
The PK population is defined as all randomized subjects who have at least one post-dose PK value, 
and who have no major protocol deviations concerning PKs. 
 PK Analysis Set 
Two pharmacokinetic analysis sets (PKAS1 and PKAS2) will be considered for this clinical trial. 
PKAS1 includes all subjects of the PK population, for which the relevant PK parameters (at least 
area under the plasma concentration-time curve from time zero to time to [AUC0-t] or Cmax) can be 
derived for the reference treatment along with at least one of AMZ001 test products, 6 mL or 8 
mL, regardless of baseline diclofenac concentration of the individual Cmax in the relevant periods. 
This analysis set will be used in PK summaries and the primary analysis and the secondary PK 
analysis. 
PKAS2 includes all subjects of the PK population, for which the relevant PK parameters (at least 
AUC0-t or Cmax) can be derived for the reference treatment along with at least one of AMZ001 test 
products, 6 mL or 8 mL, and with baseline concentration ≤ 5% of the individual Cmax in the relevant 
periods. This analysis set will be used for sensitivity analysis (and perform same analysis as 
PKAS1). 
9.5 
Study Population 
 Demographics and other Baseline Characteristics 
Descriptive statistics from the randomized population will be used to summarize the baseline 
demographic information.  For continuous variables, data will be presented by descriptive statistics 
(e.g., number, mean, median, standard deviation, medians, and range).  For categorical variables, 
these data will be presented as counts and percentages.  
Missing values will not be imputed. 
 Medical History, Concomitant Medication and Physical Examination 
Medical history and concomitant medication will be presented in by-subject listings for the 
randomized population. 
9.6 
Treatment Compliance 
Treatment compliance will be presented from the safety population. 
9.7 
Endpoint Assessments 
 General Considerations 
Descriptive statistics will be used to summarize these study data.  For continuous variables, data 
will be presented by descriptive statistics (e.g., number, mean, median, standard deviation, 


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medians, and range). For categorical variables, these data will be presented as counts and 
percentages.  
Missing values will not be imputed. 
 Pharmacokinetics (PK) 
PK analysis will be performed using the SAS® system. PK parameters assessed at Day 1 and Day 
7 will include AUC0-τ, Cmax, Cmin, Cav, PTF, Tmax, Tmin, λz, and T½, and will be presented in listings 
for individual subjects and summarized in tables and figures.  
PK parameters AUC0-τ and Cmax will be compared across treatment groups using an analysis of 
variance (ANOVA) model. The ratio of the PK parameters will be estimated along with 90% 
confidence limits to assess comparable bioavailability.  
Please refer to the SAP for detailed analysis method. 
 Primary Endpoint 
Compare the exposure to diclofenac sodium, as measured by plasma concentration, AUC0-24 and 
Cmax at steady state between two different dose levels of AMZ001 and one dose level of Voltaren 
Arthritis Pain Gel in healthy subjects on Day 7. 
 Secondary Endpoint(s) 
The PK parameters Cmax, Cmin, Tmax, Tmin, λz, T½, Cav and PTF of the two different dose levels of 
AMZ001 and the one dose level of Voltaren Arthritis Pain Gel will be calculated. The PK 
parameters for Day 1 will also be calculated and considered as secondary endpoints.  
 Safety Endpoint(s) 
Adverse events (AEs) including serious, treatment emergent, adverse drug reactions (ADRs) 
Local and systemic tolerability 
 Vital signs 
Vital signs (blood pressure, pulse rate, and body temperature) will be summarized. 
 Clinical chemistry, hematology and urinalysis 
Change from baseline of clinical chemistry, hematology and urinalysis parameters will be 
summarized. 
 Adverse Events (AEs) 
A SMP is created to specifically identify how safety of the subjects will be monitored and follow-
up will be performed for the study.  The SMP is summarized below. 
AEs will be coded according to the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and grouped by system organ class (SOC). All data will be listed by subject. 


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Only TEAEs will be presented in summary tables. Separate data listing will be provided for AEs 
that are defined as pre-treatment or post-treatment emergent. 
 Overview of Treatment Emergent Adverse Events (TEAEs) 
A TEAE summary table will be presented including for each treatment the number of subjects 
reporting an AE, the percentage of subjects with an AE, and the number of events reported, for the 
following categories:   
• All AEs 
• Severe adverse events  
• SAEs 
• ADRs 
• AEs leading to subject withdrawal.  
• Death 
AEs classified as a reasonable possibility are categorized as related to the IMP and are defined as 
ADRs. 
 Incidence of TEAEs 
Summary tables will be prepared for the incidence of TEAEs per treatment by MedDRA SOC and 
preferred term, presenting number of subjects reporting an AE, the percentage of subjects (%) with 
an AE, and the number of events reported.  Summary tables will be prepared for: 
• All TEAEs 
• AEs by causality 
• AEs by intensity 
• ADRs by intensity 
Missing values will be treated as missing except for causality, intensity, seriousness, and outcome 
of an AE, at which occurrence a “worst case” approach will be taken.  Thus, if causality is missing 
the AE will be regarded as related to the IMP, if the intensity is missing the intensity of the AE 
will be regarded as severe, if seriousness is missing the AE will be regarded as an SAE, and if the 
outcome is missing and no date of outcome is present the outcome is regarded as “not recovered”. 
 Serious adverse events and other significant adverse events 
Separate listings will be provided for SAEs and other significant AEs. 
 


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 Application site reactions 
Assessments of application site reactions will be summarized by dose over the assessment time. 
 Physical examination 
Physical examination will be listed by subject. 
9.8 
Interim Analyses 
No interim analyses are planned. 
9.9 
Exclusion of Data from Analysis 
Refer to Statistical Analysis Plan for details. 
9.10 
Handling of Dropouts and Missing Data 
Refer to Statistical Analysis Plan for details. 
 
DATA HANDLING AND RECORD KEEPING 
10.1 
Recording of Data 
Data will be recorded via electronic data capture (EDC) and e-source direct data capture (DDC). 
Electronic Case Report Forms (eCRFs), which will be designed to identify each subject by 
randomization number and, where appropriate, subject's initials, the product being evaluated, study 
visit parameters to be measured or collected and the results observed. All entries to the eCRFs 
must be made as instructed by Amzell B.V. at study initiation.  
The PI must sign the designated page(s) of the eCRFs, thereby stating that he/she takes 
responsibility for the accuracy of the data in the entire eCRF.  All records will be kept in 
conformance to applicable national laws and regulations. 
The copy of signed electronic informed consent form (eICF) will be included in each subject’s 
file.  When the study treatment is completed, the eICF will be kept in the appropriate file folder; 
otherwise, a note indicating where the records can be located will be made. 
In addition to the eCRFs, individual subject e-source DDC files will be maintained.  These 
documents may include the visit dates, the clinical study number, the name or initials of the subject, 
medical history or previous physical examinations, demographic and medical information, 
including laboratory data, skin assessments, concomitant medications/treatments, etc., any AEs 
encountered, and other notes, as appropriate. 
10.2 Data Management 
Data will be double-keyed and validated using ClinPlus (DZS Software Solutions), which directly 
generates SAS® data sets, Clinical Data Interchange Standards Consortium (CDISC) format. After 
resolution of double-key discrepancies and a combination of manual and automated data review 


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procedures, the final data sets will be subject to a Quality Assurance audit. SAS® programs for 
data analysis and presentation will be applied to secure validated data sets. 
10.3 
Retention of Documents 
Essential documents, as listed below, must be retained in a secure place by the Investigator for a 
minimum of 5 years from completion of the study, or as long as needed to comply with national 
and international regulations (generally 2 years after discontinuing clinical development or after 
the last marketing approval). Amzell B.V. will notify the Investigator(s)/institution(s) when the 
study-related records are no longer required. The Investigator agrees to adhere to the document 
retention procedures by signing the protocol.  
Essential documents include: 
• The study protocol and any amendments, 
• IRB approvals for the study protocol and all amendments, 
• All e-source documents and laboratory records, 
• eCRF originals or copies, 
• Subjects' eICFs (with study number and title of study), 
• FDA Financial Disclosure Forms 
• Site Delegation of Duties Log 
• IP Accountability Documentation 
• FDA form 1572 (as required) 
• Any other pertinent study document (i.e., correspondence, study report[s]). 
All study related documents will be stored at either the study site at 1201 Promenade Blvd, Fair 
Lawn, NJ 07410 in a secured room accessible only to TKL employees, or at a specified offsite 
location that provides a secure environment with burglar/fire alarm systems, camera detection, and 
controlled temperature and humidity. Originals or copies of the eCRFs, source documents, 
correspondence, IRB documents, study reports, etc., will be available for the Sponsor's review on 
the premises of TKL. Amzell B.V. must be informed of the offsite location at the time the 
documents are transferred to long-term storage. 
No study site document may be destroyed without prior written agreement between the 
Investigator and Amzell B.V.  Should TKL choose to assign the study documents to another party 
or move them to another location, Amzell B.V. must be notified. 
10.4 
Confidentiality of Subject Data 
The Investigator will preserve the confidentiality of the subjects' data. eCRFs and other documents 
submitted to Amzell B.V. will reference subjects only by an anonymized subject ID, which 
uniquely identifies the subject in the context of the study. The Investigator will maintain 


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documents not meant for submission to the sponsor, e.g., the confidential subject identification 
code and the signed informed consent forms, in strict confidence. All data are subject to 
monitoring, audits and inspection. If, as an exception, it is necessary for safety or regulatory 
reasons to identify the subject, both Amzell B.V. and the Investigator are bound to keep this 
information confidential. 
10.5 
Clinical Monitoring Plan (CMP) 
The CMP identifies the monitoring schedule and the rationale for the frequency and type of 
monitoring visits.  Since this study is using Direct Data Entry (DDE), in addition to agreed-upon 
source data verification (SDV), on-site monitoring visits will be limited to assuring that the site 
understands and is following the protocol, is adequately monitoring subject safety, and is managing 
the drug supply. The CMP also provides details on the use of risk-based monitoring and source 
document verification.  If the monitor is not allowed access to any e-source records during source 
document verification, certified printouts provided by the site can be used. In addition to on-site 
monitoring, monitors will perform remote monitoring, electronically reviewing data in near real-
time. 
Communication 
Timeframe 
Site initiation visit (SIV) 
The site must have a SIV (if SSV not performed). 
First monitoring visit   
See CMP. 
Interim monitoring visits 
(IMV) 
As specified in the CMP 
Closeout visit (COV) 
The site must have a COV. 
Site Update and Monitoring 
Calls 
Monitors will contact the site as needed via email or telephone, 
based on review of site activity and the quality of data entry and 
DDC. 
Teleconferences between 
the site and Contract 
Research Organization 
(CRO) 
Monitors will schedule teleconferences as appropriate to discuss 
the overall study status and to discuss study-wide related issues.   


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Communication 
Timeframe 
Initiation, Monitoring and 
Closeout Visit Reports 
Interim monitoring visits can be performed on-site or online.  On-
site visits are preceded by a confirmation letter sent to the site.  
The confirmation letter must outline the date, time and purpose 
of the monitoring visit 
Monitors will route all online, Initiation, Monitoring and COV 
Reports for signature to their supervisor(s).  The TKL Project 
Manager will review the report and enter comments if needed. 
Following the completion of an on-site monitoring visit report, 
the monitor provides feedback to the site, identifying any 
outstanding issues from the visit. 
Study updates, Protocol 
Amendments, etc. 
Will be forwarded to site during study. 
Adverse Events (AE) and 
Serious Adverse Events 
(SAE) 
The primary method for reporting the event consists of entering 
data into the AE and SAE forms and completing the MedWatch 
FDA Form 3500A. 
 
10.6 
Audit Procedures 
In addition to the routine monitoring procedures, the study site will be audited in depth for study 
Quality Assurance by Amzell B.V., an external auditor on behalf of the Sponsor, and maybe by a 
regulatory authority. This audit may include a review of all source documents, drug records, 
reserve sample retention records and original eCRFs at the study unit used in the study. Subject 
confidentiality will be maintained at all times and consent for this will be obtained before entry of 
the subject into the clinical study.  If an inspection is requested by a regulatory authority, the 
Investigator must immediately inform Amzell B.V. that this request has been made. 
10.7 
Investigational Medicinal Product (IMP)  
Monitors will verify that the Investigator maintains accurate and adequate records including dates 
of treatment, duration of treatment, and appropriate follow-up. Monitors will perform IMP and 
reserve sample accountability and verify storage conditions of the IMP and reserve samples (secure 
location, temperature logs, etc.) in accordance with manufacturers’ instructions.  Monitors will 
verify that the site has an adequate supply for ongoing and new subjects.  
During the course of the study, the monitor is responsible for assuring the accountability and 
reconciliation of the IMP. To assist with this, the monitor will review or perform the following, as 
appropriate: 


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• IMP Receipt and return of delivery note(s) 
• Reserve Sample Request/Log 
• All used and unused IMP (except for the reserve IMP samples retained on site) will be sent 
by the study site for destruction in accordance with national requirements: 
o Certificate of destruction to be provided to Amzell once done. 
10.8 
Laboratory Samples and Analysis 
Laboratory samples, both for clinical safety and PK analysis, will be processed through a local 
laboratory (LabCorp for safety analysis and Sannova for PK analysis) and the results will be sent 
to TKL.  
Specific details for PK laboratory sample processing are described in the Sannova Sample Analysis 
Plan. Specific details for clinical laboratory sample handling (clinical chemistry, hematology, 
serology and urinalysis samples) are detailed in the LabCorp Laboratory Manual. 
 
 CHANGES IN CONDUCT OF THE STUDY 
11.1 
Protocol Amendments 
Any changes or additions to this clinical study protocol require a written protocol amendment that 
must be approved by Amzell B.V. and the Investigator before implementation. Amendments 
significantly affecting the safety of subjects, the scope of the investigation or the scientific quality 
of the study, require additional approval by the appropriate IRB for the study site. A copy of the 
written approval of the IRB, which becomes part of the protocol, must be given to the Sponsor. 
Examples of amendments requiring such approval are: 
1. An increase in study product dosage or duration of product exposure of subjects, 
2. A significant change in the study design, 
3. An increase in the number of invasive procedures to which subjects are exposed, and 
4. Addition or deletion of a test procedure for safety monitoring. 
These requirements for approval should in no way prevent any immediate action from being taken 
by the Investigator or Amzell B.V. in the interests of preserving the safety of all subjects included 
in the trial. If an immediate change to the protocol is felt to be necessary by the Investigator and 
is implemented by him/her for safety reasons, Amzell B.V. should be notified immediately and 
the IRB at the center should be informed within 10 working days. 
Amendments affecting only administrative aspects of the study do not require formal protocol 
amendments or IRB approval, but the IRB of each center must be kept informed of such 
administrative changes.  Examples of administrative changes not requiring formal protocol 
amendments and IRB approval that can be treated as administrative amendments include: 


Amzell B.V. 
 
Page 57 
Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
1. 
Changes in the staff used to monitor studies (e.g., Amzell B.V. staff versus TKL), 
and 
2. 
Minor changes in the packaging or labeling of the IP. 
11.2 
Deviations from the Protocol 
Deviations from the planned study conduct are not permitted; any deviations and changes in study 
conduct must be reported to Amzell B.V., the IRB, and noted in the final clinical study report.  
11.3 
Premature Study Termination 
Both Amzell B.V. and the Investigator (after consultation with Amzell B.V.) reserve the right to 
terminate or suspend the study at any time.  Should this be necessary, the procedures will be 
arranged on an individual study basis after review and consultation by both parties. It is the 
responsibility of the Investigator to notify the IRB of the termination/suspension and the reason(s). 
In terminating the study, Amzell B.V. and the Investigator will ensure that adequate consideration 
is given to the protection of the subjects’ interests. 
 
REPORTING AND PUBLICATION 
12.1 
Clinical Study Report 
The data and information collected during this study will be reported in a Clinical Study Report 
prepared by the TKL.  
12.2 
Confidentiality and Ownership of Study Data 
Any confidential information relating to the IMP or the Study, including any data and results from 
the study will be the exclusive property of Amzell B.V.  The Investigator and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging to 
Amzell B.V. 
12.3 
Publication Policy 
No presentation or publication of data from this study can be initiated without the explicit written 
consent and in direct collaboration with Amzell B.V. 
 
ETHICAL AND REGULATORY ASPECTS 
13.1 
Institutional Review Board (IRB) 
Before implementing this study, the protocol, the proposed ICF and other information to subjects, 
must be reviewed by a properly constituted IRB. A signed and dated statement that the protocol 
and informed consent have been approved by the IRB must be given to TKL and Amzell B.V. 
before study initiation. The name and occupation of the chairman and the members of the IRB 
must also be supplied to TKL and Amzell B.V. This committee must also approve any amendments 
to the protocol, other than administrative ones, and a signed and dated statement of approval must 
be sent to Amzell B.V. prior to initiation of the amendment procedures. 


Amzell B.V. 
 
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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
13.2 
Ethical Conduct of the Study 
This study must be carried out in compliance with the protocol and in accordance with TKL’s 
standard operating procedures (SOPs).  These are designed to ensure adherence to good clinical 
practice (GCP) guidelines, as described in:  
 International Conference on Harmonisation (ICH) Tripartite Guidelines for GCP 1996.  
Directive 91/507/, The Rules Governing Medicinal Products in the European 
Community. 
 United States 21 Code of Federal Regulations dealing with clinical studies (including 
parts 50 and 56 concerning informed consent and IRB. 
 Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964 
and amendments).   
The Investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of GCP that it conforms to. 
13.3 
Subject Information and Consent 
The Investigator or designee must explain to each subject (or legally authorized representative) the 
nature of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits involved, and any discomfort it may entail.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, and 
that withdrawal of consent will not affect his/her subsequent medical treatment or relationship with 
the treating physician. 
This informed consent should be given by means of a standard written statement, written in non-
technical language.  The subject should read and consider the statement before signing and dating 
it, and he/she should be given a copy of the signed document.  If written consent is not possible, 
oral consent (assent) can be obtained, if witnessed by a signed statement from one or more people 
not involved in the study, mentioning why the subject was unable to sign the form. 
No subject can enter the study before a dated informed consent has been obtained from 
him/her, or his/her legally authorized representative. 
The ICF is considered to be part of the protocol and must be submitted by the Investigator with it 
for IRB approval. TKL will supply a proposed ICF to be approved by Amzell B.V. TKL’s ICF 
contains all elements (information or statements), as per ICH E6(R2) section 4.8.10 and 21 CFR 
§ 50.25[c], and is presented in a non-technical language that is understandable to the subject. Any 
changes to the proposed consent form suggested by the Investigator must be agreed to by TKL and 
Amzell B.V. before submission to the IRB, and a copy of the approved version must be provided 
to Amzell B.V. after IRB approval. 


Amzell B.V. 
 
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Protocol No. AMZ001-008 
 
TKL Study No. P1980822 
Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
 
ARCHIVING 
14.1 
Trial Master File 
TKL will archive the trial master file in accordance with ICH-GCP, applicable regulatory 
requirements and TKL SOP. 


Amzell B.V. 
 
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Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
 
REFERENCES 
Rainsford KD, Kean WF, Ehrlich GE. Review of the pharmaceutical properties and clinical effects 
of the topical NSAID formulation, diclofenac epolamine. Curr Med Res Opin. 2008;24(10):2967-
92. 
Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin Geriatr Med. 2010;26(3):355-69. 
Song J, Chang RW, Dunlop D. Population impact of arthritis on disability in older adults. Arthritis 
Rheum. 2006;55:248-55. 
Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheum. 
2014;28(1):5-15. 
Allen KD, Golightly YM. Epidemiology of osteoarthritis: state of the evidence. Curr Opin 
Rheumatol. 2015;27(3):276-83. 
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 
2001;345:433–42. 
García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of 
myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general 
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Sostres C, Gargallo CJ, Lanas A. Nonsteroidal anti-inflammatory drugs and upper and lower 
gastrointestinal mucosal damage. Arthritis Res Ther. 2013;15(Suppl 3):S3 http://arthritisresearch.-
com/content/15/S3/S3. 
Laine L. Gastrointestinal effects of NSAIDs and coxibs. J Pain Symptom Manag. 2003;25(Suppl 
2):S32-S40. 
Massó González EL, Patrignani P, Tacconelli S, García Rodríguez LA. Variability of risk of upper 
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Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 
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Nelson AE, Allen KD, Golightly YM, Goode AP, Jordan JM. A systematic review of 
recommendations and guidelines for the management of osteoarthritis: The chronic osteoarthritis 


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management initiative of the U.S. bone and joint initiative. Semin Arthritis Rheum. 
2014;43(6):701-12. 
Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and 
clinical implications. Am J Med. 1999;106(5B):13S-24S. 
Gøtzsche PC. NSAIDs. BMJ Clinical Evidence. 2007;2007:1108. 
Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ. Topical NSAIDs for acute 
musculoskeletal pain in adults. Cochrane Data Syst Rev. 2015;6:CD007402. doi: 10.1002/ 
14651858.CD007402.pub3. 
Persson MSM, Fu Y, Bhattacharya A, et al. Relative efficacy of topical non-steroidal anti-
inflammatory drugs and capsaicin in osteoarthritis: protocol for an individual patient data meta-
analysis. Systematic Rev. 2016;5:165. doi: 10.1186/s13643-016-0348-8. 
Klinge SA, Sawyer GA. Effectiveness and safety of topical versus oral nonsteroidal anti-
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Magnette JL, Kienzler JL, Sallin D, Ménart C, Nollevaux F, Knops A. Diclofenac systemic 
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versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol. 2010;50(1):50-61. 
Barthel HR, Haselwood D, Longley S, Gold MS, Altman RD. Randomized controlled trial of 
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Date: 23-March-2023 
 
Status: Final v1.0 
 
 
Confidential 
Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs-
General Considerations, March 2014. 
 
 
 


 
 
Protocol Clarification Letter, v1.0 
 
 
AMZ001-008 
 
 
06-June-2023 
Page 1 of 3 
 
PROTOCOL CLARIFICATION LETTER (06-June-2023) 
 
 
A Phase 1, Single-Center, Randomized, Open-Label, Bioavailability and Safety 
Three Period Crossover Multiple-Dose Study Comparing Two Dose Levels (6 
mL [5.5 g] and 8 mL [7.4 g]) of AMZ001 (Diclofenac Sodium Gel 3.06%) and 
One Dose Level (32 g) of Voltaren Arthritis Pain Gel (Diclofenac Sodium Gel 
1%) in Healthy Subjects 
 
 
Amzell B.V. Protocol No. AMZ001-008 
TKL STUDY NO. P1980822 
Protocol Version: Final v1.0 
Protocol Date: 23-March-2023 
 
 
 
The purpose of this protocol clarification letter is to correct an error in Figure 1 of the protocol.   
 
 
 
 
 
Dario Carrara, PhD  
Chief Executive Officer 
Signature  
 
Date 
 
 
 
 
 
 
Irina Krause, RN, MSN 
Senior Director, Phase I Operations 
 
Signature  
 Date 
 
 
 
 
6/9/2023
6/6/2023


 
 
 
Protocol Clarification Letter, v1.0 
 
 
 
AMZ001-008 
 
 
 
06-June-2023 
Page 2 of 3 
1. To remove the subject numbers from Figure 1  
 
Figure 1: Study Design: Three Treatments, Three Period Crossover Design  
Current text:   
 
 


 
 
 
Protocol Clarification Letter, v1.0 
 
 
 
AMZ001-008 
 
 
 
06-June-2023 
Page 3 of 3 
Revised text:  
 
 
 

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