A Phase 1, Multiple-dose, Single-center, Randomized, Open-label, 2-period, 2-treatment Crossover Systemic Bioavailability Study of Diclofenac Comparing AMZ001 (Diclofenac Sodium Gel) Applied Once Daily on Each Knee Diclofenac Diethylammonium Gel 1.16% Applied 4 Times Daily on Each Knee in Healthy Subjects
Phase: PHASE1
Conditions: Healthy Volunteer
Sponsor: Amzell

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AMZ001-009 
 
2/101 
Protocol Final 2.0 / 10-OCT-2024 
Table of Contents 
 
Title Page ................................................................................................................................... 1 
Table of Contents ....................................................................................................................... 2 
List of Abbreviations ................................................................................................................. 8 
1.Protocol Summary ................................................................................................................ 13 
1.1. 
Synopsis .................................................................................................................... 13 
1.2. 
Schema ...................................................................................................................... 17 
1.3. 
Schedule of Activities ............................................................................................... 18 
2.Introduction ........................................................................................................................... 23 
2.1. 
Study Rationale ......................................................................................................... 23 
2.2. 
Background ............................................................................................................... 24 
2.3. 
Benefit/Risk Assessment ........................................................................................... 27 
2.3.1. 
Risk Assessment ................................................................................................ 27 
2.3.2. 
Warnings and Precautions.................................................................................. 30 
2.3.3. 
Benefit Assessment ............................................................................................ 31 
2.3.4. 
Overall Benefit Risk Conclusion ....................................................................... 31 
3.Objectives and Endpoints ..................................................................................................... 32 
4.Study Design ......................................................................................................................... 33 
4.1. 
Overall Design........................................................................................................... 33 
4.2. 
Scientific Rationale for Study Design ....................................................................... 34 
4.2.1. 
Sex and Age Distribution ................................................................................... 34 
4.3. 
Justification for Dose ................................................................................................ 35 
4.4. 
Start / End of Study Definition .................................................................................. 35 
5.Study Population ................................................................................................................... 36 
5.1. 
Inclusion Criteria ....................................................................................................... 36 
5.1.1. 
Inclusion Criteria to be Checked at Screening ................................................... 36 
5.1.2. 
Inclusion Criteria to be Re-checked upon Admission and Re-Admission (Day -1 of 
Periods 1 and 2) ............................................................................................................... 37 
5.2. 
Exclusion Criteria ...................................................................................................... 38 

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5.2.1. 
Exclusion Criteria to be Checked at Screening.................................................. 38 
5.2.2. 
Exclusion Criteria to be re-checked upon Admission and Re-Admission (Day -1 of 
Periods 1 and 2) ............................................................................................................... 41 
5.3. 
Lifestyle Considerations ............................................................................................ 42 
5.3.1. 
Meals and Dietary Restrictions .......................................................................... 42 
5.3.2. 
Caffeine, Alcohol, and Tobacco ........................................................................ 42 
5.3.3. 
Activity .............................................................................................................. 42 
5.3.4. 
Other Restrictions .............................................................................................. 42 
5.4. 
Screen Failures .......................................................................................................... 44 
5.5. 
Criteria for Temporarily Delaying Randomization ................................................... 44 
6.Study Interventions and Concomitant Therapy .................................................................... 45 
6.1. 
Study Interventions Administered ............................................................................. 45 
6.2. 
Preparation, Handling, Storage, and Accountability ................................................. 46 
6.3. 
Assignment to Study Intervention ............................................................................. 48 
6.4. 
Blinding, Masking ..................................................................................................... 48 
6.5. 
Study Intervention Compliance ................................................................................. 48 
6.6. 
Dose Modification ..................................................................................................... 48 
6.7. 
Continued Access to Study Intervention after the End of the Study ......................... 49 
6.8. 
Treatment of Overdose .............................................................................................. 49 
6.9. 
Prior and Concomitant Therapy ................................................................................ 50 
6.9.1. 
Rescue Medicine ................................................................................................ 51 
7.Discontinuation of Study Intervention and Subject Discontinuation/Withdrawal ............... 52 
7.1. 
Discontinuation of Study Intervention ...................................................................... 52 
7.1.1. 
Discontinuation Criteria for Individual Subjects ............................................... 52 
7.2. 
Subject Discontinuation / Withdrawal from the Study ............................................. 53 
7.2.1. 
Discontinuation / Withdrawal Criteria for Individual Subjects ......................... 53 
7.2.2. 
Replacement of Subjects .................................................................................... 54 
7.3. 
Further Stopping Rules.............................................................................................. 54 
7.3.1. 
Premature Discontinuation of the Complete Study ........................................... 54 
7.4. 
Lost to Follow-up ...................................................................................................... 55 

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8.Study Assessments and Procedures ...................................................................................... 56 
8.1. 
Administrative and Baseline Procedures .................................................................. 56 
8.1.1. 
Demographic ...................................................................................................... 56 
8.1.2. 
Body Weight and Height, BMI .......................................................................... 56 
8.1.3. 
Medical History ................................................................................................. 57 
8.1.4. 
Baseline Treatment Area Assessment ................................................................ 57 
8.1.5. 
Other Baseline Characteristics ........................................................................... 57 
8.2. 
Efficacy and/or Immunogenicity Assessments ......................................................... 57 
8.3. 
Safety Assessments ................................................................................................... 57 
8.3.1. 
Physical Examinations ....................................................................................... 57 
8.3.2. 
Vital Signs .......................................................................................................... 58 
8.3.3. 
Electrocardiograms ............................................................................................ 58 
8.3.4. 
Clinical Safety Laboratory Tests ....................................................................... 59 
8.3.5. 
Pregnancy Testing .............................................................................................. 59 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring .............................................. 59 
8.3.7. 
Other Assessments ............................................................................................. 60 
8.3.8. 
Local tolerability ................................................................................................ 60 
8.4. 
Adverse Events and Serious Adverse Events ............................................................ 60 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .............. 61 
8.4.2. 
Method of Detecting AEs and SAEs ................................................................. 61 
8.4.3. 
Follow-up of AEs and SAEs .............................................................................. 61 
8.4.4. 
Regulatory Reporting Requirements for SAEs .................................................. 61 
8.4.5. 
Pregnancy ........................................................................................................... 62 
8.4.6. 
Adverse Events of Special Interest .................................................................... 64 
8.5. 
Pharmacokinetics ...................................................................................................... 64 
8.5.1. 
Bioanalytical Methods ....................................................................................... 64 
8.5.2. 
Pharmacokinetic Evaluation .............................................................................. 65 
8.6. 
Pharmacodynamics.................................................................................................... 66 
8.7. 
Genetics ..................................................................................................................... 66 
8.8. 
Biomarkers ................................................................................................................ 66 

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8.9. 
Immunogenicity Assessments ................................................................................... 66 
8.10. 
Health Economics or Medical Resource Utilization and Health Economics ........ 66 
9.Statistical Considerations ...................................................................................................... 67 
9.1. 
Statistical Hypotheses ............................................................................................... 67 
9.2. 
Analysis Sets ............................................................................................................. 67 
9.3. 
Statistical Analyses ................................................................................................... 67 
9.3.1. 
Efficacy Analyses .............................................................................................. 67 
9.3.2. 
Safety Analyses .................................................................................................. 67 
9.3.3. 
Pharmacokinetic Analyses ................................................................................. 68 
9.3.4. 
Other Analyses ................................................................................................... 69 
9.4. 
Interim Analysis ........................................................................................................ 69 
9.5. 
Sample Size Determination ....................................................................................... 69 
9.6. 
Protocol Deviations ................................................................................................... 69 
9.7. 
Data Management ..................................................................................................... 70 
9.7.1. 
Database Lock .................................................................................................... 70 
9.7.2. 
Soft Lock ............................................................................................................ 70 
9.7.3. 
Data Review Meeting ........................................................................................ 70 
9.7.4. 
Hard Lock .......................................................................................................... 70 
9.7.5. 
SDTM and ADaM Conversion .......................................................................... 70 
10.Supporting Documentation and Operational Considerations ............................................. 71 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............... 71 
10.1.1. Regulatory and Ethical Considerations .............................................................. 71 
10.1.2. Financial Disclosure........................................................................................... 71 
10.1.3. Clinical Study Insurance and Subject Compensation ........................................ 72 
10.1.4. Informed Consent Process ................................................................................. 72 
10.1.5. Recruitment ........................................................................................................ 72 
10.1.6. Data Protection................................................................................................... 73 
10.1.7. Committees Structure......................................................................................... 73 
10.1.8. Dissemination of Clinical Study Data................................................................ 73 
10.1.9. Data Quality Assurance ..................................................................................... 74 

AMZ001-009 
 
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10.1.10. Source Documents ............................................................................................. 74 
10.1.11. Study and Site Closure ....................................................................................... 75 
10.1.12. Publication Policy .............................................................................................. 75 
10.1.13. Clinical Study Report ......................................................................................... 75 
10.2. 
Appendix 2: Clinical Laboratory Tests ................................................................. 76 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................................... 79 
10.3.1. Definitions.......................................................................................................... 79 
10.3.2. Definition of SAE .............................................................................................. 81 
10.3.3. Recording and Follow-Up of AE and/or SAE ................................................... 83 
10.3.4. Reporting of SAEs ............................................................................................. 88 
10.4. 
Appendix 4: Contraceptive Guidance.................................................................... 89 
10.4.1. Definitions.......................................................................................................... 89 
10.4.2. Contraception Guidance..................................................................................... 91 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ......... 92 
10.6. 
Appendix 6: Pharmacokinetic Parameters ............................................................. 95 
10.7. 
Appendix 7: Sponsor Signature Page .................................................................... 96 
10.8. 
Appendix 8: Principal Investigator Signature Page ............................................... 97 
11.References ........................................................................................................................... 98 
 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
List of Tables 
Table 1: 
Schedule of Activities for Periods 1 and 2 ................................................................. 19 
Table 2: 
Summary on nonclinical information ......................................................................... 26 
Table 3: 
Summary on key risks ................................................................................................ 29 
Table 4: 
Objectives and Endpoints ........................................................................................... 32 
Table 5: 
Restrictions ................................................................................................................. 43 
Table 6: 
Study Interventions ..................................................................................................... 45 
Table 7:  
Dermal response score ................................................................................................ 60 
Table 8: 
Pharmacokinetic Parameters for diclofenac in plasma ............................................... 65 
Table 9: 
Protocol-Required Safety Laboratory Assessments ................................................... 77 
 
List of Figures  
Figure 1: 
Overall Study Design .............................................................................................. 17 
 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
List of Abbreviations  
Abbreviations of PK parameters are provided in Section 10.6. 
ACR 
American College of Rheumatology 
ADaM 
Analysis Data Model 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
HBsAG 
Hepatitis B surface antigen 
ANOVA 
Analysis of variance 
anti-HCV 
Hepatitis C antibody 
AST 
Aspartate aminotransferase 
AxMP 
Auxiliary medicinal product 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte (German Federal 
Institute for Drugs and Medical Devices) 
BID 
“Bis in die”, i.e., 2 times daily 
BMI 
Body mass index 
BSA 
Body surface area 
BUN 
Blood urea nitrogen 
CA 
Competent authority 
CDISC 
Clinical data interchange standards consortium 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 

AMZ001-009 
 
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CIPT 
Cumulative irritant patch test 
CNS 
Central nervous system 
CoC 
Certificate of compliance 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus disease 2019 
C(P)K 
Creatine (phospho-)kinase 
(e)CRF 
(Electronic) case report form  
CRO 
Contract research organization 
CSR 
Clinical study report  
CTFG 
Clinical Trial Facilitation Group 
CTS 
Clinical trial supplies department  
CV 
Coefficient of variation 
DILI 
Drug-induced liver injury 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
ED 
Early discontinuation 
EM(E)A 
European Medicines Agency 
EOT 
End of trial 
eSource 
Electronic source 
EU 
European Union 
FDA 
Food and drug administration 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GLDH 
Glutamate dehydrogenase 
GLP  
Good Laboratory Practice  
HBsAG  
Hepatitis B virus surface antigen  
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
IB 
Investigator's Brochure 
ICF 
Informed consent form 
ICH 
International council on harmonization 
(I)EC 
(Independent) ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
ISR 
Incurred Samples 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LAM 
Lactational amenorrhea method 
LC-MS 
Liquid chromatography - mass spectrometry 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry 
LDH 
Lactate dehydrogenase 

AMZ001-009 
 
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(L)LOQ 
(Lower) limit of quantification 
LS 
Least square 
MedDRA 
Medical Dictionary for Regulatory Activities 
MS 
Mass spectrometry 
NIMP 
Non-investigational medicinal product 
NSAID 
Non-steroidal anti-inflammatory drug 
OA 
Osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
OECD 
Organization for Economic Cooperation and Development 
PD 
Pharmacodynamic(s) 
PhV 
Pharmacovigilance 
PK 
Pharmacokinetic(s) 
QD 
“Quaque die”, i.e., once daily 
QID 
“Quarter in die”, i.e., 4 times daily 
QRS 
Part of electrocardiographic wave representing ventricular depolarization 
RIPT 
Repeat insult patch test 
RNA 
Ribonucleic acid 
RSI 
Reference safety information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SAS 
Statistical analysis system 
SCR 
Screening 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
SDTM 
Study data tabulation model 
SmPC 
Summary of Product Characteristics 
SoA 
Schedule of activities 
SOC 
System organ class 
SOP  
Standard operating procedure  
SUSAR  
Suspected unexpected serious adverse reaction  
TEAE 
Treatment emergent adverse event 
TID 
“Ter in die”, i.e., 3 times daily 
TMF 
Trial master file 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WHO 
World Health Organization 
WOCBP 
Woman of child-bearing potential 
WONCBP 
Woman of non-childbearing potential 
WOP 
Wash-out period 
 

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AMZ001-009 
 
18/101 
Protocol Final 2.0 / 10-OCT-2024 
1.3. 
Schedule of Activities 
A schedule of activities (SoA) presenting the timepoints for the study-related measures / actions 
is provided in Table 1. 
• Whenever different assessments and procedures are to be performed at the same nominal time, 
the following sequence will be followed (except for screening and Day -1 evaluations): 
1. 12-lead ECG (at screening only) / Vital signs; 
2. Blood sampling ([PK and safety]) as close as possible to the nominal time; 
3. Other assessments and procedures; 
4. Assessment of local skin irritation at 30 minutes after application of the gel (first 
morning dose) in each study period (see Section 8.3.8). 
Any assessments / actions at the timepoint of dosing will be performed pre-dose, administration 
of the study intervention is the last action for the respective timepoint, unless indicated otherwise.  
Any meals or water intake will be served after the assessments / actions for a given timepoint are 
completed.  
Assessment time windows will be defined in a deviation manual. Any time deviations falling into 
the allowed time windows will not be considered a protocol deviation.

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AMZ001-009 
 
24/101 
Protocol Final 2.0 / 10-OCT-2024 
The dose of AMZ001 has been selected from the outcomes of the previous Phase 1 PK and safety 
studies, in an attempt to provide comparable systemic diclofenac exposure as Voltaren Emulgel 
1.16% Gel. 
In line with the current EMA guidance on topically applied products (EMA, 2010, EMA, 2018), 
the present study is conducted to provide evidence that the systemic diclofenac exposure for the 
test product, AMZ001, compared to the reference product, Voltaren Emulgel 1.16% Gel, is similar. 
2.2. 
Background 
Non-steroidal anti-inflammatory drugs (NSAIDs) are often employed for symptomatic relief of 
mild-to moderate pain associated with OA. Traditional orally ingested NSAIDs are responsible for 
an increase in incidence of gastrointestinal (GI) and cardiovascular adverse effects 
(FitzGerald et al.  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 
are associated with coincident inhibition of COX-1 and COX-2 isozymes which result in an 
increased risk of upper GI bleeding and perforation (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 et al., 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 

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AMZ001-009 
 
27/101 
Protocol Final 2.0 / 10-OCT-2024 
pain gel (diclofenac sodium gel 1%) in healthy subjects after multiple-dose topical 
administrations for 7 consecutive days in healthy subjects (AMZ001-008). 
In addition, one (1) 4-week Phase 2/3 efficacy study in 444 patients of 3 different countries (United 
States, Denmark, and Czech Republic) has been successfully completed: 
• A multicenter, placebo-controlled, double-blind, randomized trial of AMZ001 for the 
treatment of knee OA symptoms (NCT03691844). The trial also included a single-blind 
component, consisting of Voltaren. The aim of the trial was to evaluate the efficacy and 
safety and tolerability of once or twice daily application of AMZ001 during a 28-day period 
in subjects with radiographic and symptomatic knee OA in either one or both knees 
(AMZ001-006; Bihlet, 2020). 
Overall, the safety profile of the active ingredient diclofenac and the excipients used in AMZ001 
are well known. The clinical trials conducted with AMZ001, as listed above, confirmed the safety 
in the intended indication.  
More detailed information on the chemistry, pharmacology, efficacy, and safety of AMZ001 can 
be found in the current IB.  
2.3. 
Benefit/Risk Assessment 
2.3.1. 
Risk Assessment 
This study will be performed in healthy subjects who will not have medical or health benefits from 
administration of AMZ001 or Voltaren Emulgel 1.16% Gel. 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 study interventions, 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. During this clinical study, safety will be 
monitored on an ongoing basis. 
The excipients used for the formulation of AMZ001 are well known and have been used in 
previously conducted studies as well as in already EU-approved topical products, such as Testavan 
(SmPC Testavan, 2023). 
No Serious Adverse Reaction (SAR) was observed in the performed clinical trials with AMZ001. 
One (1) SAE “cerebrovascular accident” occurred in the CIPT study and was considered to be 
unlikely related to treatment, and the subject was discontinued from the study. No treatment related 
SAEs have been reported to date (see Section 7.10 of the IB). 
Relevant emerging safety data, e.g., serious adverse events (SAEs), suspected unexpected serious 
adverse reactions (SUSARs), and serious safety-related protocol deviations, which are affecting 
the benefit/risk assessment of the study will be communicated as soon as possible between the 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
Sponsor, the study site and investigators and study subjects (more details of the communication 
process are given in Section 8.4.4). Regular telephone conferences with the site will be held to 
discuss any upcoming relevant safety information during the conduct of the study. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of diclofenac can be found in the current IB of AMZ001, and the SmPC of Voltaren 
Emulgel 1.16% Gel (Name of marketed reference product in Germany: Voltaren Schmerzgel 
11,6 mg/g Gel). If IB/SmPC are updated during the study, the new version(s) will be made 
available to the investigators and filed in the study file. 
Key risks that subjects in the study might be exposed to may arise from study-related procedures 
as well as from the administration of study interventions, as outlined in the tabular summary below 
(see Table 3): 

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Protocol Final 2.0 / 10-OCT-2024 
in some people due to its content of propylene glycol. In addition, the medicine contains fragrance 
with benzyl benzoate, benzyl alcohol, citral, citronellol, coumarin, d-limonene, eugenol, farnesol, 
geraniol, and linalool, which may cause allergic reactions. 
Voltaren Emulgel should be applied only to intact, non-diseased skin and not to skin wounds or 
open injuries. It should not be allowed to come into contact with the eyes or mucous membranes 
and should not be ingested. Treatment should be discontinued if a skin rash develops after applying 
the product. Subjects should be warned against excessive exposure to sunlight in order to reduce 
the incidence of photosensitivity. Some possibility of gastro-intestinal bleeding in those with a 
significant history of this condition has been reported in isolated cases. Specific exclusion criteria 
and restrictions are in place to address these issues in this study (see Section 5.2 and Section 5.3.4). 
Diclofenac is contraindicated during the third trimester of pregnancy with reference to experience 
from treatment with NSAIDs with systemic uptake. Data from epidemiological studies suggest an 
increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a 
prostaglandin synthesis inhibitors in early pregnancy. The systemic concentration of diclofenac is 
lower after topical administration, compared to oral formulations. To address this issue, adequate 
contraceptive measures have been defined for female subjects of childbearing potential (see 
Sections 5.1 and 10.4). No increased risk of major congenital abnormalities was found in the 
offspring of 705 fathers using NSAIDs in a large cohort study. Males trying to conceive can 
continue to take NSAIDs, such as diclofenac (Hui, 2022). Therefore, no specific contraception 
measures are required for male subjects with a WOCBP female partner (see Section 5.1). 
2.3.3. 
Benefit Assessment 
Healthy subjects may expect no direct benefits from participating in this clinical study. However, 
thorough medical check-ups may be an advantage.  
2.3.4. 
Overall Benefit Risk Conclusion 
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. 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. 
Risk minimization measures routinely implemented in Phase 1 clinical studies are considered 
adequate, including exclusion criteria for laboratory parameters and observation of vital signs. 
Administration will be discontinued in case of events that unacceptably endanger the safety of the 
subjects (Section 7).  
This clinical study will start after the favorable opinion of the IEC and once permission of the CA 
has been obtained. All investigations will be conducted in compliance with the clinical study 
protocol, ICH GCP, and any additional applicable regulatory requirements. 

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AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
In both study periods, the total in-house period for each subject will be at least 9 days per period, 
with at least 8 overnight stays.  
Detailed information on study procedures is provided in the SoA for all study days (see 
Section 1.3). 
Further information on study interventions and application instructions is provided in Section 6.1. 
The duration of the study will be approximately 9 weeks per subject, depending on the length of 
the screening period (up to 21 days) and the length of the wash-out period (at least 21 days). For 
each subject, the study will end with the above-mentioned EOT. See Section 1.3 (SoA). 
The total duration of the study will be approximately 3 months.  
Planned sample size: A sufficient number of subjects will be screened and approximately 
34 subjects will be randomized to ensure that at least 26 subjects are available for evaluation. 
Minimum number of valid subjects with complete study interventions: 26 subjects. 
Interim analyses are not planned. 
4.2. 
Scientific Rationale for Study Design 
4.2.1. 
Sex and Age Distribution 
The envisaged indication for AMZ001 is relief of the pain associated with arthritis in males and 
females.  
Arthritis includes approximately 100 conditions that affect the joints and surrounding tissues.  In 
a recent evaluation, approximately 21.2% of U.S. adults aged ≥18 years had diagnosed arthritis. 
Nearly one half of adults with arthritis (48.3%) were aged ≥65 years, and 40.0% were aged 45 to 
64 years (Fallon, 2023). 
This Phase 1 study will primarily focus on the evaluation of PK parameters. In order to reduce 
variability not related to differences between products, the study will be performed in healthy male 
and female volunteers from 18 to 65 years of age. In line with the guideline on the investigation 
of bioequivalence (EMA, 2010), the model, in vivo healthy volunteers, is regarded as adequate to 
detect formulation differences and to allow extrapolation of the results to populations for which 
the reference medicinal product is approved (e.g., for the elderly). 
Adequate contraceptive methods will be applied in female subjects of child-bearing (see 
Sections 5.1 and 10.4). Possible differences between sexes will not be evaluated, as there are no 
gender differences in the pharmacokinetics of diclofenac (Voltaren Emulgel Product Monograph, 
2017).  

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AMZ001-009 
 
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5. 
Study Population 
No subject may be randomly assigned to study intervention unless adherence to all eligibility 
criteria as given in Sections 5.1 and 5.2 is established.  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Individuals who do not meet the eligibility criteria due to medical findings will be advised to 
consult a doctor as applicable. 
5.1. 
Inclusion Criteria 
A subject is eligible to be included in the clinical study only, if all of the following criteria apply: 
5.1.1. 
Inclusion Criteria to be Checked at Screening  
Age 
1. Age of 18 to 65 years inclusive, at the time of signing the informed consent. 
Weight 
2. Body mass index (BMI) within the range of 18.0-30.0 kg/m2 (inclusive) at screening. 
Sex and Contraceptive/ Barrier Requirements 
3.  Male and female. 
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a. Male Subjects: 
No specific contraception measures are required for male subjects with a WOCBP female partner. 
b. Female Subjects: 
• A female subject is eligible to participate if she is not pregnant or breastfeeding, and one of the 
following conditions applies: 
o Is a WONCBP as defined in Section 10.4. 
OR 
o Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described in Section 10.4 
without interruption, during trial participation and until 30 days after the last 
administration of study intervention and agrees not to donate eggs (ova, oocytes) for the 
purpose of reproduction during this period. The Investigator should evaluate the potential 

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Protocol Final 2.0 / 10-OCT-2024 
for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship 
to the first dose of study intervention. 
• A WOCBP must have a negative highly sensitive serum pregnancy test at screening. 
Additional requirements for pregnancy testing during and after study intervention are provided 
in Sections 5.1.2 and 8.3.5. 
• The Investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
Type of Subject and Disease Characteristics 
4. Subject is overtly healthy as determined by medical evaluation including medical history, full 
physical examination, vital signs, and ECG.  
5. Subject is free of any systemic or dermatologic disorder and chronic or acute infections, which, 
in the opinion of the Investigator, may interfere with the study results or increase the risk of 
adverse events. 
Drugs and Stimulants 
6. Subject is a non-smoker, former smoker or stable non-smoker (= 0 cigarettes, pipes, cigars, or 
others) for at least 3 months prior to screening. Subjects must also have abstained from use of 
other nicotine containing products (e.g., nicotine patch, chewing gum or e-cigarettes) for at 
least 3 months before screening. 
Informed Consent 
7. Capable of giving signed informed consent as described in Section 10.1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol prior 
to any clinical study specific procedure. 
5.1.2. 
Inclusion Criteria to be Re-checked upon Admission and Re-Admission (Day -1 
of Periods 1 and 2) 
Sex and Contraceptive/Barrier Requirements 
8. No changes in medical conditions or prior/concomitant therapy further to sex and 
contraceptive/barrier requirements compared to screening. 
9. A WOCBP must have a negative highly sensitive urine pregnancy test on Days -1, within 
24 hours before the first dose of study intervention of each study period, (see Section 8.3.5). 
o If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. In such cases, the subject must be excluded from participation 
if the serum pregnancy result is positive. 

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Protocol Final 2.0 / 10-OCT-2024 
Type of Subject and Disease Characteristics 
10. Subject is overtly healthy as determined by medical evaluation including check of changes in 
medical history compared to screening, abbreviated physical examination, and vital signs.  
11. No changes in type of subject and disease characteristics compared to screening.  
Drugs and Stimulants 
12. No changes in drugs and stimulants compared to screening. 
5.2. 
Exclusion Criteria  
Subjects are excluded from the study if any of the following criteria apply: 
5.2.1. 
Exclusion Criteria to be Checked at Screening  
Medical Conditions 
13. Any visible skin disease, skin lesions, wounds, or a significant amount of hair at the application 
sites (both knees). 
14. Any history or evidence of any clinically relevant cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrinologic, hematologic, immunologic, metabolic, genitourinary, 
pulmonary, neurologic, dermatologic, musculoskeletal, psychiatric and/or other major disease 
as determined by medical evaluation (including [abbreviated] physical examination) capable 
of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk 
when taking the study intervention; or interfering with the interpretation of data. 
15. Any known or suspected malignancy, excluding basal cell cancer unless it is associated with 
the treatment area. 
16. Any gastrointestinal bleeding issues, e.g., Gastroesophageal Reflux Disease, Peptic Ulcer 
Disease. 
17. Any hospital admission or major surgery within 30 days prior to randomization. 
18. History or current evidence of ongoing hepatic disease or impaired hepatic function at 
screening as indicated by diagnostic assessments. 
19. History or current evidence of renal disease or impaired renal function at screening as indicated 
by diagnostic assessments.  
20. Any clinically relevant history of allergic conditions requiring hospitalization or prolonged 
systemic treatment (including drug allergies, drug hypersensitivity, asthma, angioedema, 
urticaria, eczema, acute rhinitis precipitated by acetylsalicylic acid or other NSAIDs, allergies 
requiring therapy with corticosteroids or anaphylactic reactions), excluding allergic contact 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
sensitizations (e.g., nickel allergy). Subjects with uncomplicated seasonal allergic rhinitis can 
be accepted only if the expected allergy season is clearly outside enrolment/ treatment periods. 
21. Known or suspected hypersensitivity to diclofenac, or any components of the formulation used 
(i.e., diethylene glycol monoethyl ether, myristyl alcohol, ethyl alcohol, hydroxypropyl 
cellulose, diethylamine, carbomers, cetomacrogol, cocoyl capryloccaprate, isopropyl alcohol, 
propylene glycol, liquid paraffin, fragrance with benzyl benzoate, benzyl alcohol, 
citral, citronellol, coumarin, d-limonene, eugenol, farnesol, geraniol, linalool), aspirin, 
Xarelto, coumadin, or other non-steroidal anti-inflammatory drugs (NSAIDs), including 
Cyclooxygenase-2 (COX-2) inhibitors. 
22. Contraindications for the use of study interventions.  
23. Any clinically relevant chronic or acute infectious illnesses or febrile infections within 2 weeks 
prior to the first scheduled administration of study intervention. 
24. Evidence of COVID-19 signs or symptoms or confirmed COVID-19 infection within the last 
2 weeks prior to screening. 
Prior/Concomitant Therapy 
25. Treatment with systemic or local diclofenac within 30 days of enrollment or during the study 
(except for study interventions). 
26. Use of any concomitant medication or any drugs / medicines (including over-the-counter 
medication, dietary supplements, natural and herbal remedies) within 2 weeks before the first 
scheduled administration of study intervention or within less than 10 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.  
Occasional use of Paracetamol (acetaminophen) 500 mg is allowed (up to 1000 mg daily, 
medicinal products in their original packaging, approved and marketed in Germany).  
Oral, injectable, implantable, and topical contraceptives as outlines in Section 10.4 and 
hormone replacement therapy are permitted, as long as the female subject is on stable treatment 
for at least 3 months and continues treatment throughout the study.  
Single intake of other medication is only permitted, if it is judged by the Investigator to have 
no clinical relevance and if it is not expected to confound the interpretation of the study results. 
27. Use of any topical medication, cosmetics, cream, ointments, lotions on the treatment site 
2 weeks prior to enrollment through EOT visit, see Table 5 of the study protocol. 

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Protocol Final 2.0 / 10-OCT-2024 
Prior/Concurrent Clinical Study Experience 
28. Use of any investigational drug or participation in any clinical study within 30 days or  
10 half-life times (if known) of study drug administered in a previous trial, whichever is longer, 
prior to the expected date of first administration of study intervention. 
Diagnostic assessments 
29. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (anti-HCV) and 
anti-human immunodeficiency virus antibodies (anti-HIV 1 and 2 and HIV 1-p24 antigen) at 
screening;  
30. Positive screen for alcohol, drugs of abuse and cotinine test at screening. 
31. Supine systolic blood pressure >140 mmHg or <90 mmHg; diastolic blood pressure 
>90 mmHg or <50 mmHg and pulse rate <50 bpm or >90 bpm, and tympanic body 
temperature of <35.9 and >37.6°C at screening. 
32. 12-lead ECG with clinically relevant abnormality or showing a QTcF >450 ms for male and 
>470 ms for female subjects, PR >215 ms, or QRS >120 ms at screening. 
33. Elevations in alanine aminotransferase (ALT) ≥1.1 x ULN, aspartate aminotransferase (AST) 
≥1.2 x ULN, serum bilirubin ≥1.2 x ULN, creatinine ≥1.1 x ULN, blood urea nitrogen (BUN) 
≥35 mg/dL, or presence of clinically significant abnormal urinary constituents (e.g., 
albuminuria) at screening. 
34. Elevations in more than one of the following lab values: Gamma-glutamyl transferase (GGT) 
≥1.5 ULN; alkaline phosphatase (ALP) ≥1.5 ULN; creatine kinase (CK) ≥3 ULN at screening. 
A single deviation from the above values is acceptable and will not exclude the candidate, 
unless specifically advised by the Investigator. 
Other Exclusions 
35. Any use of drugs-of-abuse or alcohol abuse within 6 months prior to screening. 
Higher than low-risk alcohol consumption i.e., consumption of an average weekly alcohol 
intake of >14 units/week for men (daily dose of >24 g, weekly dose of >168 g) and 
>7 units/week for women (daily dose of >12 g, weekly dose of >84 g). One unit (12 g) 
corresponds to 0.3 L of beer/day or 0.12 L of wine/day or 1 glass (at 2 cL) of spirits/day. 
36. Excessive consumption of caffeine- or xanthine-containing food or beverages (>5 cups of 
coffee a day or equivalent) or inability to stop consuming from 48 hours prior to first planned 
administration of study intervention. 
37. Intake of specified food or beverages containing grapefruit, grapefruit juice, grapefruit hybrids, 
star fruit, Seville orange, tangelo, pomelos, exotic citrus fruits, as specified in Table 5 of the 
study protocol, within 14 days prior to (re-) admission and during both treatment periods. 

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Protocol Final 2.0 / 10-OCT-2024 
38. Regular consumption of poppy seed containing food prior to screening.  
39. Female subject who plans to become pregnant during the clinical study period and for 3 months 
after final study intervention administration. 
40. 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. 
41. Employee of the Sponsor, the Nuvisan Group, or other Contract Research Organization (CRO) 
involved in the clinical study. 
42. Legal incapacity or limited legal capacity, or incarceration. 
43. Inability to understand or communicate reliably with the Investigator or considered by the 
Investigator to be unable to or unlikely to co-operate with the protocol requirements, 
instructions, and study-related restrictions. 
44. Any other conditions or factors which in the opinion of the Investigator may interfere with 
study conduct. 
5.2.2. 
Exclusion Criteria to be re-checked upon Admission and Re-Admission (Day -1 
of Periods 1 and 2) 
Medical Conditions 
45. No changes in medical conditions compared to screening. 
Prior/Concomitant Therapy 
46. No changes in prior/concomitant therapy compared to screening. 
Prior/Concurrent Clinical Study Experience 
47. No changes in prior/concomitant study experience compared to screening. 
Diagnostic assessments 
48. Positive screen for alcohol, drugs of abuse, and cotinine test upon admission to each 
intervention period 
49. Supine systolic blood pressure >140 mmHg or <90 mmHg; diastolic blood pressure 
>90 mmHg or <50 mmHg and pulse rate <50 bpm or >90 bpm upon admission. 
Other Exclusions 
50. No clinically relevant changes in other exclusion criteria compared to screening. 

AMZ001-009 
 
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5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
• During the in-house stay(s), the subjects may only consume food and beverages provided by 
the study site. The diet provided (maximum of 4 meals per day) will consider the imposed 
restrictions. On Days 1 to 7 of both study periods, subjects will receive standardized meals, 
served at customary times. 
• Further dietary restrictions to be observed are displayed in Table 5. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
•  Restrictions on caffeine, alcohol, and tobacco are described in Table 5. 
5.3.3. 
Activity 
• Restrictions on activity are described in Table 5. 
5.3.4. 
Other Restrictions 
• Other restrictions are described in Table 5. 

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AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
Table 6 (continued):  Study Interventions 
Intervention 
Label 
AMZ001 
Voltaren Emulgel 
Sourcing 
The Sponsor will provide Nuvisan 
GmbH with the medication, which 
will be released by the Sponsor QP 
according to Good Manufacturing 
Practice Annex 13 for use in the 
study. CTS Nuvisan will create a 
CoC for the labelling activities 
performed. 
Nuvisan will source medication 
available on the local market.  
Packaging 
and Labelling 
Study intervention will be provided 
by the Sponsor in dispensing 
packages, measuring 1 mL per 
actuation. Each IMP dispenser will 
be labelled according to country 
requirement by Nuvisan. 
Study intervention will be used as 
unchanged product with market 
authorization 
AxMP=auxiliary medicinal product, NA=not applicable, NIMP=non-investigational medicinal product; 
IMP=investigational medicinal product. 
 
In each period, subjects will receive multiple topically applied doses of AMZ001 gel or 
Voltaren Emulgel 1,16% Gel from Day 1 to Day 7, as outlined in Table 6 and in line with the 
detailed administration instructions.  
Study interventions will be self-administered to both knees by the subject himself / herself under 
the supervision of a 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 spread the gel directly to the pre-defined treatment area of 
approximately 500 cm2 for AMZ001 and 400 cm2 for Voltaren Emulgel 1.16% Gel, for each 
subject knee as per detailed application instructions. Further information on restrictions is provided 
in Table 5. Further instructions for use will be provided in an IMP handling manual.  
AMZ001 IMP dispensers and Voltaren Emulgel 1.16% Gel tubes will be weighed throughout the 
study before and after each administration of study intervention, as outlined in the SoA 
(Section 1.3). 
6.2. 
Preparation, Handling, Storage, and Accountability 
1. The Sponsor will supply enough study intervention AMZ001 to Nuvisan Clinical Trial 
Supplies (CTS) Department. 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
2. Nuvisan will source the commercial reference product Voltaren Emulgel 1.16% Gel from the 
German market. 
3. Nuvisan CTS Department will document the receipt of the study intervention AMZ001 and 
must confirm appropriate conditions (e.g., temperature) have been maintained during transit 
for all study intervention received and any discrepancies are reported and resolved before use 
of the study intervention AMZ001. Nuvisan CTS Department will be responsible for transfer 
to the site. 
4. Study intervention AMZ001 will be packed and labelled study specifically by Nuvisan CTS 
Department before the clinical part of the study starts. QP release of clinical supplies will be 
performed by the Sponsor as per the German clinical study labelling requirements. 
5. Only subjects enrolled in the study may receive study intervention and only authorized site 
staff may supply, prepare, or supervise the administration of study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labelled storage conditions with access limited to 
the Investigator and authorized site staff. 
6. All study intervention administrations will be performed in accordance with the product 
specifications under supervision of site staff authorized by the Principal Investigator. 
7. The Investigator is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).  
8. The number of unused study intervention will be documented by Nuvisan CTS Department. 
According to the provisions of the Sponsor the unused study intervention will be destroyed 
once the final reconciliation has been completed and the authorization for destruction has 
been received from the Sponsor. 
9. Further guidance and information for the final disposition of unused study interventions are 
provided in the applicable manual. 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
6.3. 
Assignment to Study Intervention 
Subject 
identification and 
intervention 
assignment 
After informed consent procedure, every subject is given a 
screening number.  
Within the afternoon of Day -1 of Period 1 until pre-dose of Day 1 
of Period 1, before any Day 1 procedures, subjects will be assigned 
a unique 3-digit randomization number in ascending numerical 
order. The number encodes the subject’s assignment to one of the 
2 arms of the study, according to the randomization list provided by 
Nuvisan CTS Department. Each subject will be dispensed study 
intervention, labelled with their unique randomization number 
throughout the study. 
Replacement subjects of already randomized subjects prior to 
dosing will be assigned to the intervention as the original subject. 
Randomization number will be the number of the original subject 
plus 100. For example, the replacement for screening number 012 
will receive the random number 112. 
Only subjects who comply with all eligibility criteria can be included into the study. Subjects will 
be assigned to randomization numbers in accordance with Nuvisan standard operational 
procedures (SOPs). 
The Investigator will keep a record relating the subject identifiers (screening and random number) 
and the names of all subjects who have given their informed consent, to allow easy checking of 
data in subject files, when required. This record will also include the date of subject’s enrolment 
and completion, as well as subjects who could not be randomly assigned to study intervention for 
whatever reason. 
6.4. 
Blinding, Masking 
The study will be performed in a non-blinded design. 
6.5. 
Study Intervention Compliance 
The administration of the study intervention will be performed in the clinical unit by qualified 
clinical professionals of the Investigator’s team. Deviation(s) from the prescribed dosage regimen 
should be recorded in the case report form (CRF).  
6.6. 
Dose Modification 
No dose modifications are envisaged during this study. 

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AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
3. If requested by the responsible PhV expert (determined on a case-by-case basis), obtain a 
plasma sample for PK analysis within 1 day from the date of the last dose of study 
intervention. 
4. Document the quantity of the excess dose as well as the duration of the overdose in the CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the subject. 
6.9. 
Prior and Concomitant Therapy 
Any medication taken at or after the time of first study intervention, regardless of whether it had 
started prior to the study or not, is to be recorded as concomitant medication. Prior medications 
are defined as any medication taken which had been stopped prior to the first study intervention.  
Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and 
dietary or herbal supplements) within 2 weeks or 10 half-lives (whichever is longer) before the 
start of study intervention until completion of the EOT visit. Information on non-permitted prior 
or concomitant therapy including drugs and herbal remedies is provided in the list of exclusion 
criteria and meals and dietary restrictions. See Sections 5.2 and Table 5 for further details. 
In addition, subjects must abstain from using any topical medication, cosmetics, cream, ointments, 
lotions on the treatment site 2 weeks prior to enrollment through EOT visit, as indicated in the list 
of exclusion criteria (see Section 5.2 and Table 5). 
Except when necessary to treat an AE, subjects are not allowed to use those medications, starting 
from the specified timepoints until completion of the study. 
Paracetamol (acetaminophen) at doses of 500 mg ( 2 gram/day, if needed), is permitted for use 
any time during the study. Contraceptives as outlined in Section 10.4 are also permitted. Hormone 
replacement therapy is permitted, as long as the female subject is on stable treatment for at least 
3 months and continues treatment throughout the study (see Section 5.2).  
Single intake of other medication is only permitted, if it is judged by the Investigator to have no 
clinical relevance and if it is not expected to confound the interpretation of the study results. 
Other concomitant medication may be considered on a case-by-case basis to avoid immediate 
hazard to the subjects by the Investigator who may wish to consult with the Medical Monitor or 
Sponsor.  
For any concomitant therapy used, the name of the drug, the reason for use, dates of administration 
including start and end dates and dosage information including dose and frequency will be 
recorded in the CRF. In consultation with the Sponsor, a decision may be taken by the Investigator 
to withdraw a subject from the study when other concomitant medication is required or has been 
taken without consulting the Investigator. 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
6.9.1. 
Rescue Medicine 
Not applicable. 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
7. 
Discontinuation of Study Intervention and Subject 
Discontinuation/Withdrawal  
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a subject to permanently discontinue study intervention. 
If study intervention is permanently discontinued, the subject will remain in the study. Safety, and 
tolerability data as well as PK data will be collected to the furthest possible extent and the subject 
will be asked to participate in the early discontinuation visit.  
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
intervention and ED / EOT visit and for any further evaluations that need to be completed. 
7.1.1. 
Discontinuation Criteria for Individual Subjects 
The Investigator will withdraw a subject from receiving further study intervention in the following 
cases: 
• Occurrence of an AE of severe severity in case of causal relationship to study intervention. 
• Relevant signs or symptoms affecting subject safety. Any events that unacceptably endanger 
the safety of the subject. 
• If, in the Investigator's opinion, continuation of the study would be harmful to the subject’s 
well-being.  
• Hypersensitivity reactions classified as severe. 
• Impossibility to obtain blood samples in general.  
• Abnormal blood pressure including hypotension defined as systolic <70 mmHg and/or 
diastolic <40 mmHg, or hypertension defined as systolic >160 mmHg and/or diastolic 
>110 mmHg (evaluated with the subject in supine position for a minimum of 5 minutes and 
confirmed by 2 repeat measurements). In case of repeat abnormal findings, see above, this 
should lead to direct study withdrawal.  
• Creatinine >1.1xULN  
• Use of nonpermitted concomitant medications. However, any medications considered 
necessary for the subject’s wellbeing may be given at the discretion of the Investigator. 
• Occurrence of pregnancy. See Section 8.4.5 and Section 10.4.  
7.1.1.1. 
Liver Chemistry Stopping Criteria 
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a subject meets one of the following conditions or if the Investigator believes that it is in best 
interest of the subject: 

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Protocol Final 2.0 / 10-OCT-2024 
• Increase in ALT or AST ≥3xULN and/or total bilirubin >2xULN considered by the 
Investigator to be at least possibly related to the study intervention. ALT ≥3xULN and bilirubin 
≥2 x ULN (>35% direct bilirubin) has to be reported as SAE (refer to Section 10.5). 
7.2. 
Subject Discontinuation / Withdrawal from the Study 
7.2.1. 
Discontinuation / Withdrawal Criteria for Individual Subjects 
• A subject may withdraw from the study at any time at their own request without giving reasons. 
The subject will not suffer any disadvantage as a result. A subject may be withdrawn at any 
time at the discretion of the Investigator for safety, behavioral, compliance, or administrative 
reasons. This is expected to be uncommon.  
• At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See SoA in Section 1.3 for data to be collected at the time of study 
discontinuation and ED and for any further evaluations that need to be completed.  
• The subject will be permanently discontinued from both the study intervention and the study 
at that time. 
• If the subject withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
• If a subject withdraws from the study, they may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
• Subjects who discontinue may not re-enter the study.  
• Depending on the timepoint of discontinuation, a withdrawn subject is referred to as either 
“screening failure” or “dropout” as specified in Sections 5.4 and Section 7.2.2. 
The Investigator will withdraw a subject from the study in the following cases: 
• Request by the subject to discontinue (withdrawal of consent).  
• At the specific request of the Sponsor and in liaison with the Investigator (e.g., obvious non-
compliance). 
• Any clinically relevant symptom or sign which in the opinion of the Investigator and/or 
Sponsor warrants subject withdrawal. 
• Impossibility to obtain samples. 
• Positive results from pregnancy testing.  
• Protocol deviation judged as significant by the Investigator, including non-compliance to the 
required study considerations (e.g., food/diet requirements). 

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Protocol Final 2.0 / 10-OCT-2024 
• Depending on the timepoint of withdrawal, a withdrawn subject will be referred to as either 
“screening failure” or “dropout” as specified in Section 5.4 and Section 7.2.2. 
7.2.2. 
Replacement of Subjects  
A subject who discontinues the study prematurely for any reason is defined as a ‘dropout’ if the 
subject has already been randomly assigned to study intervention.  
Dropouts will be replaced only if the number of subjects completing the study becomes less than 
34 to ensure a total number of 26 evaluable subjects. For details regarding intervention assignment 
of replacement subjects, please refer to Section 6.3.  
The data obtained from dropouts will be used in the evaluation to the largest possible extent.  
7.3. 
Further Stopping Rules 
7.3.1. 
Premature Discontinuation of the Complete Study 
The Sponsor may discontinue the complete study at any time, for ethical or scientific reasons. The 
Principal Investigator is entitled to stop the study at any time due to medical reasons. In such a 
case, the Principal Investigator should consult the Sponsor at the earliest opportunity. 
The study may be terminated prematurely or temporarily halted if any unacceptable findings are 
identified. The occurrence of 1 of the following stopping criteria shall result in an immediate stop 
of dosing and a temporary halt of the study:  
• A serious adverse reaction (i.e., an SAE considered at least possibly related to the study 
intervention administration) in 1 subject.  
• AEs of at least moderate severity in ≥50 % of the subjects for which a causal relationship to 
the study intervention or study related procedures cannot be excluded. 
• Severe non-serious adverse reaction (i.e., severe non-serious AEs considered as, at least, 
possibly related to the study intervention administration) in 2 subjects, independent of within 
or not within the same system organ class. 
• Unacceptable risks, any relevant toxicity, or a negative change in the risk/benefit assessment 
is identified. This might include the occurrence of AEs which character, severity or frequency 
is new in comparison to the existing risk profile.  
• Any data derived from other clinical studies or toxicological studies become available which 
negatively influence the risk/benefit assessment. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 

AMZ001-009 
 
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Protocol Final 2.0 / 10-OCT-2024 
regulatory requirements. The Investigator shall promptly inform the subject and should assure 
appropriate subject therapy and/or follow-up. 
Further information on study and site closure is provided in Section 10.1.11. 
7.4. 
Lost to Follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether the subject wishes to and/or should continue in the study or not. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject (where possible, contact via email along with 
3 telephone calls and, if necessary, a certified letter to the subject’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the subject’s 
medical record. 
Should the subject continue to be unreachable, they will be considered to have withdrawn from 
the study.  

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Protocol Final 2.0 / 10-OCT-2024 
8. 
Study Assessments and Procedures 
• Prior to performing any study assessments, the Investigator will obtain written informed 
consent as specified in Section 10.1.4.  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Adherence to the 
study design requirements, including those specified in the SoA, is essential and required for 
study conduct.  
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study intervention. 
• All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
• In the event of a significant study-continuity issue (e.g., caused by a pandemic), alternate 
strategies for subject visits, assessments, medication distribution and monitoring may be 
implemented by the Sponsor or the Investigator, as per local health authority/ethics 
requirements. All procedures adapted to the situation must be submitted, if required as per local 
regulations, through a protocol amendment to the Regulatory Authority and IEC for approval 
prior to implementation of mitigation procedures. 
• The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
8.1. 
Administrative and Baseline Procedures 
8.1.1. 
Demographic 
For demographic assessment the following parameters will be recorded: age (incl. year of birth), 
sex, race / ethnicity. 
8.1.2. 
Body Weight and Height, BMI 
Body weight will be measured by a member of the Investigator’s team under the following 
conditions: 
• Subject in underwear and without shoes after having emptied their bladder 
• Electronic physician (column) scale with digital display, measurement units 0.1 kg 

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The subject’s height (without shoes) will be measured to calculate the BMI. The BMI will be 
calculated by data management directly in the electronic CRF. The study site might calculate in 
addition for eligibility check.  
8.1.3. 
Medical History 
Medical history findings (i.e., previous diagnoses, diseases, or surgeries) considered relevant to 
the study will be collected: 
Any relevant findings from the past that occurred prior to signing the informed consent form or 
started prior to signing the informed consent form, are still ongoing but resolve before start of first 
study intervention administration will be recorded in the Medical History section of the CRF. 
Occurrences after obtaining informed consent or presently occurring and worsening after signing 
the informed consent form will be recorded in the AE section of the CRF.  
8.1.4. 
Baseline Treatment Area Assessment 
A treatment area of approximately 500 cm2 for AMZ001 and  400 cm2 for Voltaren Emulgel 1.16% 
Gel will be pre-defined for each subject knee on Day -1 of each study period, as per detailed 
application instructions. 
A baseline treatment area assessment will be performed for each knee during screening, and on 
Days-1 of Period 1 and Period 2, as outlined in Section 8.3.8 for the assessment of local tolerability. 
8.1.5. 
Other Baseline Characteristics 
Information on smoking and alcohol consumption will be collected. 
8.2. 
Efficacy and/or Immunogenicity Assessments 
This section is not applicable as efficacy / effectiveness and/or immunogenicity is not assessed in 
this study. 
8.3. 
Safety Assessments 
The safety profile of the study interventions will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, ECGs, 
and clinical laboratory tests. 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). Additional 
assessments during the study will be conducted at the discretion of the Investigator. 
8.3.1. 
Physical Examinations 
• A comprehensive physical examination will be performed by a physician and will include at a 
minimum, assessment of the eyes, ears, nose, and throat as well as assessment of the cardiac, 

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peripheral vascular, pulmonary, musculoskeletal, neurologic, abdominal, lymphatic, and 
dermatologic system. 
• An abbreviated physical examination will be performed by a physician and will include, at a 
minimum, assessments of the skin, abdomen (liver and spleen), lungs, and cardiovascular 
system. 
• Investigators should pay special attention to clinical signs related to previous serious illnesses. 
• All pre-existing and relevant medical events must be recorded and described in the source 
documents. All efforts to attach support documentation (i.e., reports, results, etc.) must be 
done. 
8.3.2. 
Vital Signs 
• Vital signs will be measured after at least 5 minutes rest in a supine position and will include 
body temperature, pulse rate, and systolic and diastolic blood pressure at the timepoints 
specified in the SoA (Section 1.3). 
• Blood pressure and pulse should not be measured on the same arm where blood samples are 
taken from. 
• Body temperature will be measured auricularly with a calibrated device. 
• Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only in case of doubt or if an automated device is not available. 
• Further vital signs measurements during the clinical study are at the discretion of the 
Investigator. 
8.3.3. 
Electrocardiograms 
• The ECG is for screening purposes only. A single 12-lead ECGs will be obtained as outlined 
in the SoA (Section 1.3) during using an ECG machine that automatically calculates the heart 
rate and measures PR(Q), QRS, QT, and QTcF intervals.  
• Subjects should rest for at least 5 minutes in supine position before ECG collection is 
performed. 
• ECG results will be stored electronically, printed, and timely reviewed by the Investigator. The 
original printout will be stored with the subject’s source data. 
• The ECG should be interpreted (normal/abnormal) by the Investigator. For abnormal ECG, the 
clinical significance (yes/no) should be judged by the Investigator and the abnormality is to be 
specified. ECG recording will be repeated as appropriate. 

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8.3.4. 
Clinical Safety Laboratory Tests 
• Clinical laboratory assessments will be performed by Nuvisan GmbH. 
• All protocol-required laboratory assessments, as defined in Section 10.2, must be conducted in 
accordance with the laboratory manual and the SoA (Section 1.3). 
• Any abnormalities in any of the laboratory parameters will be judged by an Investigator 
individually in relation to the reference ranges. 
• The Investigator must review the laboratory results, document this review, and record any 
clinically significant changes occurring during the study after first dosing as an AE. The 
laboratory results must be retained with source documents.  
• All laboratory tests with values considered clinically significantly abnormal, with major 
deviation and/or possible pathological relevance during participation in the study should be 
repeated until the values return to normal or baseline or the absence of clinical relevance can 
be confirmed. If clinically significant values do not return to normal/baseline within a period 
judged reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
8.3.5. 
Pregnancy Testing 
• WOCBP subjects should only be included after a negative highly sensitive serum pregnancy 
test at screening and highly sensitive urine pregnancy test on Days -1 of each study period, 
within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed 
as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the 
subject must be excluded from participation if the serum pregnancy result is positive. 
• Additional urine pregnancy testing will be performed on Day 8 of Period 2 (EOT) and during 
the early discontinuation visit. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy 
is otherwise suspected during the time from ICF signature until follow-up visit/early 
discontinuation visit. 
8.3.6. 
Suicidal Ideation and Behavior Risk Monitoring 
Neither the test nor the reference product is considered a CNS-active drug. Therefore, there is no 
increased risk of suicidal ideation or behavior. 

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• The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up unresolved AEs. 
• The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
• All AEs and SAEs will be collected from the signing of the informed consent until EOT / early 
discontinuation visit at the timepoints specified in the SoA (Section 1.3). 
• All SAEs will be recorded and reported to the Sponsor or designee within the time frames 
indicated in Section 10.3.4.  
• Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, or death as outcome of an SAE, 
at any time after a subject has been discharged from the study, and they consider the event to 
be reasonably related to an IMP, or study participation, the Investigator must promptly notify 
the Sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
During the reporting period unfavorable changes in the subject’s condition will be recorded as AEs, 
regardless, if reported by the subjects or observed by the investigative team. Care will be taken not 
to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal 
questioning of the subject is the preferred method to inquire about AE occurrences (e.g., "How do 
you feel?” or “How have you been feeling since the last questioning?"). 
8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the subject is lost to follow-up (as defined in Section 7.4). Further 
information on follow-up procedures is given in Section 10.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a study 
intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the competent authority (CA) and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authorities, Independent Ethics Committees (IEC), and Investigators. 

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• The Sponsor is responsible for assessing whether an SAE is expected or not (see also 
Section 10.3). Section 7 of the current IB of AMZ001, and the SmPC of Voltaren Emulgel 
1.16% Gel will be used as reference safety information (RSI) for this clinical study. 
• Suspected unexpected serious adverse reactions (SUSARs) will be expedited by the Sponsor’s 
designee to IECs, CA, and Investigator following pertinent national legislation. 
• Within the EU, all relevant information about any SUSAR will be reported electronically and 
without delay to the EudraVigilance database. The reporting period for SUSARs is determined 
as follows:  
o Fatal or life-threatening SUSARs, as soon as possible, and in any event not later than 
7 days after the Sponsor became aware of the reaction 
o Non-fatal or non-life-threatening SUSARs, not later than 15 days after the Sponsor 
became aware of the reaction 
o SUSARs which were initially considered to be non-fatal or non-life-threatening, but 
which turn out to be fatal or life-threatening, as soon as possible and in any event not 
later than 7 days after the Sponsor became aware of the reaction being fatal or  
life-threatening. 
• To ensure timely reporting, the Sponsor may submit an initial incomplete report followed up 
by a complete report. 
• If Investigators become aware of an SAE with a suspected causal relationship to the 
study intervention and/or study procedure occurring after the end of the clinical trial, 
Investigators shall, without undue delay, report the SAE to the Sponsor. 
• Unexpected events which affect the benefit-risk balance of the clinical trial but are not 
SUSARs must be notified in the EU without undue delay, but no later than 15 days from the 
date the Sponsor became aware of this event. 
• An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then 
file it along with the IB and will notify the IEC, if appropriate according to local requirements. 
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
• Further information on SAE reporting is provided in Section 10.3.4. 
8.4.5. 
Pregnancy 
Females are only allowed to participate in this study, if they are women of non-childbearing 
potential or if they agree to use highly effective contraceptive measures (in combination with a 

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• Any poststudy pregnancy-related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as described in Section 8.4.4. While the 
Investigator is not obligated to actively seek this information in former pregnant study subjects, 
he may learn of an SAE through spontaneous reporting. 
• Any female subject who becomes pregnant while participating in the study will discontinue 
study intervention or be withdrawn from the study. 
8.4.6. 
Adverse Events of Special Interest 
No AEs of special interest have been defined for this study. 
8.5. 
Pharmacokinetics 
• Bioanalytical analyses will be performed at Nuvisan GmbH Bioanalytical Department.  
• Detailed information on sample collection, handling, storage, and shipment will be provided 
in a laboratory manual. 
• All sample handling procedures, including the date/time of each sample collection, the 
date/time of placement into frozen storage (at the end of the sample workup), and the date/time 
of transfer or shipment of the samples to the responsible analyst will be documented in detail. 
• Plasma samples will be collected for measurement of plasma concentrations of diclofenac as 
specified in the SoA (Section 1.3).  
• The actual date and time (24-hour clock time) of each sample will be recorded. In case the 
actual sampling time deviates from the scheduled sampling time, a comment must be given in 
the e-source. Samples collected within the time windows defined in the deviation manual (see 
Section 1.3), will not be considered a protocol deviation. Deviations will be considered when 
calculating the PK parameters.  
Samples will be used to evaluate the PK of study intervention. Samples collected for analyses 
of diclofenac plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. 
• Genetic analyses will not be performed on these plasma samples.  
8.5.1. 
Bioanalytical Methods 
• Bioanalytical analyses will be performed in accordance with the principles of Good Laboratory 
Practice (GLP), GCP, and ICH M10. The procedure for determination of concentrations of 
diclofenac in plasma samples will be described in the bioanalytical protocol.  
• Information relating to the responsible persons, specification of communication rules, handling 
of the informed consent and confidentiality of personal data, specification of the analytical 
method (matrix, calibration range, samples volume, etc.), sample storage, “Incurred Samples” 

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• For calculation of PK parameters, concentrations below the lower limit of quantification 
(LLOQ) will be treated as zero.  
• AUC will be regarded as unreliable if more than two consecutive results are missing or if the 
concentrations were quantifiable for fewer than 5 timepoints. Cmax and tmax will be regarded as 
unreliable if the maximum was observed preceding or following a sample with missing data. 
In case of multiple peaks, Cmax and tmax refer to the highest measured concentration even if 
there should be earlier peaks. In case of two or more samples with the same concentration (as 
supplied by the analyst), tmax refers to the earlier of these. 
• Unreliable parameters will be listed and flagged accordingly and set to missing for calculation 
of descriptive statistics and statistical analysis. If a PK parameter is unreliable for more than 
20% of the subjects, this parameter will additionally be evaluated as sensitivity analysis 
including the reliable cases. 
• More details will be provided in the SAP. 
8.6. 
Pharmacodynamics 
PD parameters are not evaluated in this study. 
8.7. 
Genetics 
Pharmacogenetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity Assessments 
Not applicable. 
8.10. 
Health Economics or Medical Resource Utilization and Health 
Economics 
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 

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• Safety data will be listed by subject. 
• AEs will be encoded using the MedDRA dictionary, latest version. Summary tables by 
intervention will be generated for TEAEs (as defined in Section 10.3.1), sorted by system 
organ class and preferred term, in which the number and percentages of subjects with 
treatment-emergent AEs and frequency of the events are reported. 
• Any AEs that continue but change in severity within a study intervention will be counted as 
one and only one AE considering the worst severity in frequency tables whereas a recurrent 
AE (e.g. a headache for a couple of hours each day) will be counted as several AEs. 
• AE occurring after administration of any study intervention will be counted towards the last 
intervention received before the onset, even if the event is not resolved at the beginning of the 
following intervention. An AE that worsens after a later intervention period will be counted 
towards both study interventions. 
• Laboratory values outside the normal ranges will be flagged. A listing of abnormal laboratory 
values and clinically relevant abnormal laboratory values will also be provided. 
• Descriptive statistics of vital signs and ECG data will be presented for each timepoint by 
intervention.  
• The ECG interpretation of the Investigator will be tabulated as the number and percentage of 
subjects with “normal”, “abnormal, not clinically significant”, or “abnormal, clinically 
significant” results by intervention and timepoint. 
• The skin irritation scores (i.e., the ‘dermal response score’, see Table 7) will be summarized 
by application site and treatment. Furthermore, the proportion of subjects with each irritation 
score will be presented by application site and treatment. 
9.3.3. 
Pharmacokinetic Analyses  
• All PK analyses will be performed on the PK Analysis Set, if not stated otherwise. 
• Concentration-time courses and PK parameters will be tabulated by intervention. 
• The following statistics will be calculated for each of the sampling timepoints: number of 
cases/ measurements (denoted as “n”), geometric mean and geometric coefficient of variation 
(CV, in %), arithmetic mean, standard deviation (SD) and CV (in %), minimum, median, 
maximum.  
• Individual and arithmetic mean plasma concentration versus time curves (using the actual 
sampling times for individual plots and the scheduled sampling times for mean plots) will be 
plotted by intervention using both linear and log-linear scale. 

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Further analysis for the primary PK parameter AUC0-24: 
• In order to achieve a better approximation to a normal distribution, the pharmacokinetic 
parameters AUC0-24 on Day 1 and Day 7 will be logarithmically transformed. Afterwards, they 
will be evaluated statistically using ANOVA with INTERVENTION, PERIOD, SEQUENCE 
and SUBJECT(SEQUENCE) as fixed effects. Least-squares (LS) means, LS intervention 
difference, and 90% confidence intervals (CI) for the intervention differences on the log-scale 
will be obtained for AUC0-24 on Day 1 and on Day 7. The results will be back-transformed to 
the original scale by exponentiation to provide geometric least-square means, point estimate 
of the geometric mean ratio (Test/Reference) and its corresponding 90% CI. 
• Only subjects that have a valid AUC0-24 in both periods will be included in the  
above-mentioned model. 
Further analysis for the secondary PK parameter Cmax: 
• The same ANOVA model as described for AUC0-24 above will be provided for the secondary 
parameter Cmax. 
9.3.4. 
Other Analyses  
Not applicable. 
9.4. 
Interim Analysis  
No formal interim analyses will be performed within Nuvisan Biostatistical Department.  
9.5. 
Sample Size Determination 
It is planned to assign 34 subjects to study intervention to have at least 26 evaluable subjects 
completing the study. If deemed necessary to meet the target number of 26 evaluable subjects, 
dropouts may be replaced (refer to Section 7.2.2).  
Based on the assumption (average CV of 3 historical studies), the intra-subject coefficient of 
variation (CV) was about 43%. A total of 26 evaluable subjects will achieve 80% power, that the 
90% confidence interval (CI) is included in the pre-defined acceptance range of 0.7-1.43, which is 
deemed to be appropriate. The true ratio that was used in the sample size calculation was 1.05. 
Enough healthy adults will be screened to randomize approximately 34 subjects to ensure 
26 evaluable subjects, assuming an approximate 20% dropout and non-evaluable rate. 
9.6. 
Protocol Deviations 
• A protocol deviation is any change, divergence, or departure from the study design, or 
procedures defined in the protocol. Protocol deviations will be identified prior to database lock. 

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• Important protocol deviations are a subset of protocol deviations that may significantly affect 
the completeness, accuracy and/or reliability of the study data or that may significantly affect 
a subject’s rights, safety, or well-being.  
• Protocol deviations will be pre-specified in a deviation manual, discussed on an ongoing basis 
and finally categorized as important/non-important during the DRM. A protocol deviation may 
also be declared as finding/event that leads to an exclusion of data or complete subjects from 
an Analysis Set (see Section 9.2). 
• Important protocol deviations will also be described in the CSR. 
9.7. 
Data Management 
Nuvisan will be responsible for clinical data management activities for this study. The full details 
of procedures for data handling will be documented in the Data Management Plan.  
Medical coding will be done using the latest version of the coding dictionaries for MedDRA for 
AEs and medical history to the primary SOC and WHO Drug Global Dictionary for concomitant 
medications. Coding will be performed by Data Management and needs to be approved by the 
Investigator and Sponsor. 
9.7.1. 
Database Lock 
Study database must be soft and hard locked to ensure their integrity for the generation of results, 
analysis and submissions. 
9.7.2. 
Soft Lock 
When validation (including external data reconciliation), SAE reconciliation and all coding 
activities, as well as medical review activities, QC activities have been completed and there are no 
further open issues or open queries the database will be soft locked. 
9.7.3. 
Data Review Meeting 
A DRM will be held for the study by the biostatistician to check the data status, discuss any open 
issues and provide proposals for resolution, as well as finally agree on the categorization of the 
protocol deviations and assignment of subjects to analysis sets.  
9.7.4. 
Hard Lock 
After finalization and approval of the DRM minutes, and after all actions resulting from the DRM 
minutes are completed, e.g., additional solving of queries, the database will be hard locked. Hard 
lock needs to be authorized by the study team. 
9.7.5. 
SDTM and ADaM Conversion 
The database and the electronic external data will be converted to CDISC / SDTM and ADaM. 

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10. 
Supporting Documentation and Operational Considerations 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
Before the start of the study, Nuvisan on behalf of the Sponsor will apply for approval for the 
performance of the study at the CA (German Federal Institute for Drugs and Medical Devices 
[BfArM]) and the IEC.  
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
• The protocol, modifications to the protocol (modifications), ICF, IB, and other relevant 
documents (e.g., advertisements) must be submitted to an IEC and reviewed and approved by 
the IEC before the study is initiated. 
• Any substantial modification to the protocol (substantial modification) will require CA and 
IEC approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects. 
• The Investigator will be responsible for the following: 
o Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
ICH guidelines, the IEC, European Regulation 536/2014, and all other applicable local 
regulations 
o Performing a benefit-risk assessment on an ongoing basis and informing the IEC about 
any changes. Moreover, making sure that any substantial modifications to the protocol 
(substantial modifications) will be submitted and approved prior to implementation 
10.1.2. 
Financial Disclosure 
• Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  
• Investigators are responsible for providing information on financial interests during the study 
and for 1 year after completion of the study. 

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10.1.3. 
Clinical Study Insurance and Subject Compensation 
• In accordance with local law, insurance coverage will be provided for all subjects participating 
in this study. 
• Subjects will be paid compensation for participation and will be reimbursed for travel-related 
costs. 
10.1.4. 
Informed Consent Process 
• The Investigators or their representative will explain the nature of the study to the subject and 
answer all questions regarding the study. 
• Subjects must be informed that their participation is voluntary. Subjects will be required to 
sign a statement of informed consent that meets the requirements of local regulations, 
ICH guidelines, and the IEC. 
• The written ICF must be signed and personally dated by the subject and by the Investigator 
who conducted the informed consent discussion.  
• Subjects should be informed of the possibility to withdraw consent without giving any reason 
and to require that all previously retained identifiable samples will be destroyed to prevent 
future analyses, according to national provisions. The information should include a statement 
that the consequence of the subject’s withdrawal of consent will be that no new information 
will be collected from the subject and added to existing data or database. 
• All subjects who sign the ICF will be assigned a screening number. 
• Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. Any revised ICF must receive the IEC approval / favorable opinion 
in advance of use. 
• One original of the signed and dated ICF will be provided to the subject. A second original 
will be retained in the Investigator site file. 
• The Investigator should maintain a log of all subjects who signed the ICF. 
• Subjects who are rescreened are required to sign a new ICF. 
10.1.5. 
Recruitment 
The study will be performed in adult subjects fully capable of giving informed consent. 
Detailed description of the recruitment strategy will be provided in country- and site-specific 
documentation, as applicable. 

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10.1.6. 
Data Protection 
Personal and sensitive personal data will be treated as confidential. Data protection and privacy 
regulations will be observed in capturing, forwarding, processing, and storing subject data.  
Authorized access only is assured by strict rules on Nuvisan firewall. Nuvisan uses strict rules to 
separate the networks within the company. User groups with various permission sets are 
maintained within Nuvisan network to ensure confidentiality of records. Connections to the 
Nuvisan network from the off-site access point have to use a virtual private network. The Nuvisan 
network is constantly being monitored for potential threats, viruses, and other security related 
issues by a separate security operation center. To prevent a security breach, all Nuvisan employees 
are trained on how to proceed in case of receiving suspicious email. 
• Subjects will be assigned a unique identifier. Any subject records or datasets that are 
transferred to the Sponsor will contain the identifier only; subject names or any information 
which would make the subject identifiable will not be transferred. Only the Investigator and 
the clinical team will be able to link the subjects’ trial data to the subjects via an identification 
list kept at the site. The subjects’ original medical data that are reviewed at the site during 
source data verification by the monitor, audits and during health authority inspections will be 
kept strictly confidential. 
• The subject must be informed that their personal study-related data will be used by the Sponsor 
in accordance with the EU General Data Protection Regulation. The level of disclosure must 
also be explained to the subject. 
• The subject must be informed that their medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor and by inspectors 
from regulatory authorities without violating the confidentiality of the subject to the extent 
permitted by law and regulations. 
• All personal data collected and processed for the purpose of this study should be managed by 
the Investigator and their staff with adequate precautions to ensure confidentiality of those 
data, as per national and/or local laws and regulations on personal data. 
• Measures are in place to mitigate the possible adverse effects of a data security breach and are 
in line with the EU General Data Protection Regulation and relevant national legislations. 
These measures are defined in the CRO’s SOPs regarding IT Security and Serious Breaches. 
10.1.7. 
Committees Structure 
Not applicable. 
10.1.8. 
Dissemination of Clinical Study Data 
This clinical study will be registered in a clinical study database (e.g., ClinicalTrials.gov) before 
enrolment of the first subject. All data and results and all intellectual property rights in the data 

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and results derived from the study will be the property of the Sponsor who may utilize them in 
various ways, such as for submission to government regulatory authorities or disclosure to other 
Investigators. 
10.1.9. 
Data Quality Assurance 
• All subject data relating to the study will be recorded and transmitted to the Sponsor or 
designee electronically. The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF. 
• The Investigator must permit study-related monitoring, audits, IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan.  
• Nuvisan GmbH is responsible for the data management of this study including quality checking 
of the data.  
• The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
10.1.10. 
Source Documents 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. 
• CRF data must be consistent with the source documents, or the discrepancies must be 
explained.  
• Definition of what constitutes source data can be found in the source data location form. 

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10.1.11. 
Study and Site Closure 
• The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  
• Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed. 
• The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
• Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
o Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines; 
o Inadequate recruitment of subjects by the Investigator; 
o Discontinuation of further study intervention development. 
10.1.12. 
Publication Policy 
• A summary of the results of the clinical trial according to Annex IV of the EU Clinical Trials 
Regulation (Regulation (EU) No 536/2014) will be uploaded to CTIS within 1 year and 
published within 30 months after the end of the clinical trial. 
• The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results.  
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.13. 
Clinical Study Report 
• After completion of the study, a clinical study report covering clinical and statistical aspects 
of the study will be prepared by Nuvisan GmbH in line with ICH E3 in consultation with the 
Sponsor. 
 
 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 9 will be performed by the local laboratory at the timepoints 
specified in the SoA (Section 1.3). 
• Details of all methodology and reference ranges will be provided in the TMF. 
• Investigators must document their review of each laboratory safety report. 
• The results of each test will be transferred electronically to the clinical database. 
• Protocol-specific requirements for inclusion or exclusion of subjects are detailed in Section 5 
of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the Investigator or required by local regulations. 
• Sampling for scheduled laboratory examinations will be done with subjects in a fasted state, 
i.e. an overnight fast (= nothing to eat or drink except water) of ≥10 h has to be adhered to. 

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Table 9: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology Platelet count 
 
White Blood Cell Count 
with Differential 
(absolute and %): 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Reticulocytes 
Hemoglobin 
Hematocrit 
Red blood cell count 
Clinical 
Chemistry 
Alanine 
aminotransferasea 
Calcium 
Glucose 
Alkaline phosphatase 
Cholesterol 
Magnesium 
Aspartate 
aminotransferase 
Creatinine 
Potassium 
Bilirubin (total)a,b 
Creatine phosphokinasec 
Sodium 
Blood urea nitrogen 
γ-Glutamyl-transferase 
Triglycerides 
Urinalysis 
• Specific gravity 
• pH, hemoglobin, urobilinogen, bilirubin, protein, glucose, ketones, nitrite, 
leukocyte esterase by dipstick 
• In case of positive results for protein, leukocyte esterase, hemoglobin or 
nitrite on the dip stick, flow cytometry count and classification will be 
performed.  
Other Tests 
• Urine drug screen:  
Amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, 
methamphetamines, methylenedioxymethamphetamine, methadone, 
opiates, tricyclic antidepressants, phencyclidine 
• Urine cotinine test 
• Serum (at screening only) and highly sensitive urine human chorionic 
gonadotropin (hCG) pregnancy test (female subjects only) 
• At screening only: 
o Thyroid stimulating hormone (TSH)d 
o Follicle Stimulating Hormone (FSH) (to confirm postmenopausal 
status, female subjects only) 

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Laboratory 
Assessments 
Parameters 
• Serology: 
Hepatitis B surface antigen [HBsAg], Hepatitis C antibody [anti-HCV], 
anti-human immunodeficiency virus antibodies (anti-HIV 1 + 2) and 
HIV p24 antigen combined 
Notes: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7 and Section 10.5. All events of ALT ≥3 × upper limit of normal (ULN) 
and bilirubin ≥2 × ULN (>35% direct bilirubin) which may indicate severe liver injury (possible Hy’s Law), must 
be reported as an SAE. 
b In case of increased bilirubin (total), the direct bilirubin will be determined. 
c If increased, creatine kinase (muscle-brain type) and Troponin I (if CK-MB/CK-total x 100 >6.0% or CK-MB 
>25 U/L) will be determined. 
d If TSH is out of range, additionally free triiodothyronine and free thyroxine will be determined. 
 
 

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require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 

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Stop and start date as well as the action with the study intervention due to medication errors, 
overdose, abuse, or misuse must be documented as follows: 
o Dose not changed  
o Drug interrupted 
o Drug withdrawn  
o Unknown 
o Not applicable 
If a medication error, overdose, abuse, and misuse is accompanied by an AE, as determined by 
the Investigator, the AE should be recorded on the CRF. 

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10.4. 
Appendix 4: Contraceptive Guidance  
10.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming postmenopausal unless permanently sterile (see 
below) 
• A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
o Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 
• Permanent sterilization methods (for the purpose of this study) include: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical records, 
medical examination, or medical history interview. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
 

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Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
1. Premenopausal female with permanent infertility due to one of the following (for the purpose 
of this study): 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the subject’s medical records, 
medical examination, or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
o A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH (>40 IU/L or mIU/mL) is required. 
o Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment. 

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10.4.2. 
Contraception Guidance 
• CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS)c 
Bilateral tubal occlusion 
Azoospermic partner (vasectomized or due to a to medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of 
the woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. Spermatogenesis cycle is approximately 90 days. 
Note: documentation of azoospermia for a male subject can come from the site personnel’s review of the 
subject’s medical records, medical examination, or medical history interview. 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently 
and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc 
− oral 
− intravaginal 
− transdermal 
− injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
Sexual abstinence 
 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the subject.) 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction). 

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Phase 1 liver chemistry stopping criteria are designed to assure subject safety and to evaluate 
liver event etiology. 
Phase 1 Liver Chemistry Stopping Criteria and Follow-Up Assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
 
ALT/AST-absolute 
 
ALT or AST ≥3 x ULN 
ALT or AST ≥3 x ULN AND total bilirubin  2 x ULN (for subjects 
with known Gilbert’s syndrome these criteria only apply if total 
bilirubin ≥2xULN, and direct bilirubin >2xULN and at least doubled 
from baseline value) OR international normalized ratio (INR) >1.5, 
report to the Sponsor in expedited manner and as an SAE if SAE 
criteria are met a,b. 
Suggested Actions, Monitoring, and Follow up Assessments 
Actions 
Follow Up Assessments 
• Immediately discontinue study intervention. 
• Report the event to the Sponsor within 
24 hours. 
• Complete the liver event eSource and 
complete an SAE data collection tool if the 
event also met the criteria for an SAEb 
• Perform liver follow-up assessments as 
described in the Follow Up Assessment 
column.  
• Do not restart/rechallenge subject with 
study intervention  
• Monitor the subject until liver chemistry test 
abnormalities resolve, stabilize, or return to 
baseline (see MONITORING). 
 
MONITORING: 
If ALT or AST 3 x ULN AND total bilirubin 
2 x ULN or INR >1.5: 
• Repeat liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total bilirubin, 
and INR) and perform liver event follow-up 
assessments within 24 hours. 
• Viral hepatitis serologyc 
• Obtain blood sample for PK analysis 
after the most recent dosed.  
• Obtain CPK, LDH, GGT, glutamate 
dehydrogenase (GLDH) and serum 
albumin. 
• Fractionate bilirubin if total bilirubin 
2 x ULN. 
• Obtain complete blood count with 
differential to assess eosinophilia. 
• Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE CRF.  
• Record use of concomitant medications 
(including acetaminophen, recreational 
drugs, herbal remedies, and other over-
the-counter medications) on the 
concomitant medications CRF. 
• Record alcohol use on the liver event 
alcohol intake CRF. 
 

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• Monitor subject twice weekly until liver 
chemistry test abnormalities resolve, 
stabilize, or return to baseline. 
• A specialist or hepatology consultation is 
recommended. 
 
If ALT or AST ≥3 x ULN AND total bilirubin 
<2 x ULN and INR ≤ 1.5: 
• Perform liver chemistry tests (include ALT, 
AST, alkaline phosphatase, total bilirubin, 
and INR) and liver chemistry follow-up 
assessments within 24 to 72 hours. 
• Monitor subjects weekly until liver chemistry 
abnormalities resolve, stabilize, or return to 
baseline. 
 
If ALT or AST ≥3 x ULN AND total 
bilirubin  2 x ULN or INR >1.5 obtain 
the following in addition to the assessments 
listed above: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) to 
evaluate liver disease; complete liver 
imaging CRF. 
• Liver biopsy may be considered and 
discussed with local specialist if 
available, for instance: 
o In subjects when serology raises the 
possibility of autoimmune hepatitis  
o In subjects when suspected DILI 
progresses or fails to resolve on 
withdrawal of study intervention 
o In subjects with acute or chronic 
atypical presentation  
• If liver biopsy is conducted, then 
complete liver biopsy CRF. 

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Notes: 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention if ALT or AST  3 x ULN and total bilirubin  2 x ULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable 
urinary bilirubin on dipstick which is indicative of direct bilirubin elevations suggesting liver injury.  
b All events of ALT or AST  3 x ULN and total bilirubin  2 x ULN (for subjects with known Gilbert’s 
syndrome these criteria only apply if total bilirubin ≥2xULN, and direct bilirubin >2xULN and at least doubled 
from baseline value) or ALT or AST  3 x ULN and INR >1.5 may indicate severe liver injury (possible 
‘Hy’s Law’) and must be reported to Sponsor in an expedited manner and as an SAE if SAE criteria met 
(excluding studies of hepatic impairment or cirrhosis). The INR stated threshold value will not apply to 
subjects receiving anticoagulants.  
c Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; 
cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile 
antibody or monospot testing); and hepatitis E IgM antibody. 
d PK sample may not be required for subjects known to be receiving placebo or non-comparator interventions. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to 
the PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the Laboratory Manual. 
 
 
 

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10.6. Appendix 6: Pharmacokinetic Parameters 
Symbol 
Definition 
AUC0-24 
The partial area under the concentration-time curve (AUC) from time zero 
(= dosing time) to 24 hours. In cases where the actual observation time is not 
equal to the scheduled observation time AUC0-24 will be calculated according 
to the following rules:  
• using the actual study time at scheduled 24 hours if the sample was 
taken earlier and within the allowed time window defined separately in 
a deviation manual 
• by interpolation if the sample was taken later than the scheduled 
24 hours 
• in all other cases, AUC0-24 will be set to missing 
Cave 
The average concentration on Day 7. Cave = AUC− /24. 
Cmax 
Maximum observed concentration.  
Cmin 
The minimum observed concentration on Day 7.  
PTF 
The peak trough fluctuation on Day 7. PTF = 100*(Cmax-Cmin)/Cave. 
Racc(AUC 0-24) 
Day 7 versus 
Day 1 
The accumulation ratio after repeated administration calculated as 
Racc(AUC −) = (AUC0-24 after multiple dose on Day 7) / (AUC0-24 on Day 1). 
Swing 
(Cmax - Cmin) / Cmin on Day 7 
tmax 
Time of observed maximal concentration (time to reach Cmax). 
tmin 
The time to reach the minimum observed concentration. 
 

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