Clinical trial NCT05279131
Conditions: Keratosis, Actinic
Sponsor: Almirall, S.A.
Start date: 2022-06-28; Completion date: 2022-12-28
Enrollment: 105 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the safety, tolerability and treatment effect of tirbanibulin ointment 1% when applied to a field of approximately 100 cm\^2 on the face or balding scalp.

Detailed description:

Arms: arm 1: Participants will apply tirbanibulin ointment 1% once daily for 5 days beginning Day 1. Participants will be evaluated for safety, tolerability, and the presence of Actinic Keratosis (AK) lesions in the treatment field (TF) until completion of the response assessment period at Day 57.
Interventions: intervention 1: Tirbanibulin ointment 1%
Intervention descriptions: intervention 1: Applied topically for 5 days over a field of approximately 100 cm\^2 on the face or balding scalp with AK.

Protocol documents:
Prot_000.pdf: 
Final Report M-14867-32
CONFIDENTIAL                                                     ALMIRALL
16
APPENDICES
16.1 STUDY INFORMATION
16.1.1 Protocol, Protocol Amendments and Clarification Letters
M-14867-32 Clinical Trial Protocol Version 1.0, 23-JAN-2022
M-14867-32 Clinical Trial Protocol Amendment Version 2.0, 21-MAR-2022
M-14867-32 Protocol Clarification Letter – Contraception, 08-AUG-2022
M-14867-32 Protocol Clarification Letter – Paper Diary, 03-JAN-2023
Final Version 1.0 


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ALMIRALL, S.A.
Clinical Trial Protocol M-14867-32
Clinical Trial Protocol Title:
A Phase 3, Multicenter, Open-label, Single-arm
Study to Evaluate the Safety and Tolerability of 
Tirbanibulin Ointment 1% Applied to a Field of 
Approximately 100 cm2 on the Face or Balding Scalp 
in Adult Patients with Actinic Keratosis
Investigational Medicinal 
Product(s):
Tirbanibulin ointment 1% (Klisyri®)
Indication:
Actinic keratosis (AK)
Development Phase:
Phase 3
Final Protocol Version Date:
Version 1.0, 23 January 2022
Amendment(s)
Number:
None
Date:
N/A
IND Number:
122464
Sponsor:
Almirall, S.A.
Ronda General Mitre, 151
08022 Barcelona, Spain
This document is confidential. It contains proprietary information of Almirall, S.A. 
that may not be used, divulged, published, or disclosed without the prior consent of 
Almirall, S.A.


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Protocol Amendment Summary of Changes
There have been no amendments to the trial protocol.


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Sponsor Signatures
Clinical Trial Protocol Title:
A Phase 3, Multicenter, Open-label, Single-arm 
Study to Evaluate the Safety and Tolerability of 
Tirbanibulin Ointment 1% Applied to a Field of 
Approximately 100 cm2 on the Face or Balding Scalp 
in Adult Patients with Actinic Keratosis
Trial Code:
M-14867-32
The individuals signing this clinical trial protocol declare that they have reviewed it for 
completeness, accuracy. They are responsible for the trial and agree to conduct it in adherence 
to the present document, any amendments, to International Council for Harmonisation (ICH)
Good Clinical Practices (GCP) guidelines, and to local regulatory requirements, wherever 
applicable.
Sponsor
Almirall, S.A.
Ronda General Mitre, 151
08022 Barcelona, Spain
Functional Role
Name
Signature
Date
This document was electronically signed in the eDMS R&D system.
Manifestation of the e-signatures are available at the end of this document which are the equivalent 
of handwritten signatures, in compliance with 21CFR Part 11
PPD
PPD
PPD
PPD
PPD
PPD


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Principal Investigator Signature
Clinical Trial Protocol Title:
A Phase 3, Multicenter, Open-label, Single-arm
Study to Evaluate the Safety and Tolerability of 
Tirbanibulin Ointment 1% Applied to a Field of 
Approximately 100 cm2 on the Face or Balding Scalp 
in Adult Patients with Actinic Keratosis
Trial Code:
M-14867-32
The individual signing this clinical trial protocol declares that he/she has reviewed it for 
completeness, accuracy. He/she is responsible for the trial and agrees to conduct it in adherence 
to the present document, any amendments, to International Council for Harmonisation (ICH) 
Good Clinical Practices (GCP) guidelines, and to local regulatory requirements, wherever 
applicable.
Principal Investigator
Role
Name
Signature
Date
Principal 
Investigator


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1
Protocol Synopsis
Title:
A Phase 3, Multicenter, Open-label, Single-arm Study to Evaluate the Safety and Tolerability 
of Tirbanibulin Ointment 1% Applied to a Field of Approximately 100 cm2 on the Face or 
Balding Scalp in Adult Patients with Actinic Keratosis
Investigators:
A Principal Investigator will be designated at each participating clinical trial center and a 
Coordinating Investigator will be nominated among the participating sites. The name, address, 
and affiliation of each Principal Investigator and the Coordinating Investigator will be detailed 
in the final clinical study report (CSR).
Trial Center(s):
The trial is planned to be conducted at approximately 20 centers in the United States (US).
Trial Duration:
The duration of the entire study from first patient, first visit to last patient, last visit is 
anticipated to be approximately 8 months.
Phase of Development:
This is a Phase 3 trial.
Rationale:
Tirbanibulin is an antiproliferative agent that causes cell cycle arrest and apoptosis. In two 
well-controlled Phase 3 clinical trials, tirbanibulin ointment 1% was demonstrated to be an 
effective and safe treatment for actinic keratosis (AK) of the face or balding scalp, when applied 
topically once daily for 5 consecutive days to a field of 25 cm2 containing 4 to 8 clinically 
typical, visible, and discrete AK lesions.
On the basis of the Phase 3 trial results, tirbanibulin ointment 1% was approved in the US and 
Europe for the topical treatment of AK on the face or scalp, over a field up to 25 cm2. However, 
AK often affects larger areas of ultraviolet (UV) light-damaged skin; thus, there is a need for a 
product to treat AK patients with affected fields larger than 25 cm2.
This study will assess the safety and tolerability of tirbanibulin ointment 1% administered 
under the same posology (once daily for 5 days) to a field of approximately 100 cm2 on the 
face or balding scalp containing 4 to 12 clinically typical, visible, and discrete AK lesions.
Objectives:
The primary objective is to evaluate the safety and tolerability of tirbanibulin ointment 1% 
when applied to a field of approximately 100 cm2 on the face or balding scalp.
Additionally, the treatment effect of tirbanibulin ointment 1% when applied to a field of 
approximately 100 cm2 on the face or balding scalp will be explored.


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Trial Design:
This is a Phase 3 multicenter, open-label, single-arm trial to evaluate safety and local 
tolerability of tirbanibulin ointment 1% administered topically for 5 days over a field of 
approximately 100 cm2 on the face or balding scalp in adult patients with AK.
The study consists of a 4-week (28-day) Screening Period, a 5-day Treatment Period, and a
Response Assessment Period of approximately 7 weeks (see Table 1, Schedule of 
Assessments):
x During the Treatment Period, patients will apply tirbanibulin ointment 1% once daily for 
5 days beginning on Day 1.
x All patients will be evaluated for safety, tolerability, and the presence of AK lesions in the 
treatment field (TF) until completion of the Response Assessment Period at Day 57.
Number of Patients:
Approximately 125 patients will be screened to initiate treatment in approximately 
100 patients.
Trial Population:
Male and female AK patients, aged 18 years or older, having 4 to 12 clinically typical, visible, 
and discrete AK lesions over a field of approximately 100 cm2 on the face or the balding scalp. 
A minimum of 50% of patients will be older than 65 years old and approximately two-thirds 
of the patients will be treated for AK lesions on the face and one-third on the scalp.
Test Investigational Medicinal Product, Dosage, and Mode of Administration:
Substance code/name:
Tirbanibulin
Administration route:
Topical
Strength:
1%
Dosage form:
Ointment
Tirbanibulin ointment 1% will be applied once daily for one 5-day treatment course. On Day 1, 
treatment application will occur at the investigational site in the morning under the supervision 
of clinical trial site staff. Between Days 2 and 5, the treatment will be self-administered once
daily at home.
Reference Investigational Medicinal Product, Dosage, and Mode of Administration:
Not applicable. No control arm will be included in this study.
Methodology:
Study visits and assessments will be performed in accordance with the Schedule of 
Assessments (Table 1).
Duration of Treatment:
The duration of each patient’s treatment is 5 days.


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Duration of Patients’ Participation in the Trial:
The total duration of each patient’s participation in the trial, including screening, treatment, 
and response assessment is estimated to be approximately 3 months.
Statistical Methods
Sample Size Calculation
With 100 patients and assuming an expected percentage of patients with at least one local 
tolerability sign of approximately 90%, the precision in the estimation of that percentage will 
be approximately 11%. The precision is defined as the width of the 95% confidence interval.
Furthermore, 100 patients will provide approximately 10% and 13% precision in the estimation 
of the percentage of patients with the local tolerability events of particular interest, specifically 
vesiculation/pustulation (assuming an expected percentage of 8%) and erosion/ulceration 
(assuming an expected percentage of 12%), respectively.
Endpoints
Safety Endpoints
x Local Tolerability Assessment:
o Local tolerability score by visit (0-3) for each individual sign (erythema, flaking/scaling, 
crusting, swelling, vesiculation/pustulation, and erosion/ulceration)
o Maximum local tolerability score post baseline through all the visits for each individual 
sign
o Time to maximum local tolerability score for each individual sign
o Local tolerability signs composite score (0-18) by visit, defined as the sum of the scores 
graded from 0 to 3 on all six individual tolerability sign categories
o Maximum local tolerability signs composite score post baseline through all the visits
o Time to maximum local tolerability composite score
o Pigmentation and scarring in the TF through all the visits
x Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events 
(TESAEs), adverse events of special interest (AESIs), clinical laboratory data, and other 
safety assessments (vital signs, physical examinations [PEs], electrocardiograms [ECGs])
Exploratory Endpoints
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count from total lesions in the TF at each visit
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count, for lesions that were already present at baseline, from total lesions in the TF at each
visit
x Absolute number and percent change of new lesions from total lesions in the TF at each visit


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Statistical Analysis
All analyses will be performed on the Safety population, defined as all patients who have 
received at least one dose of study treatment.
Safety Endpoints
Descriptive statistics will be provided for all safety endpoints.
Local tolerability signs composite score, and specific local tolerability scores will be analyzed 
by means of descriptive statistics and provided by visit. The maximum local tolerability scores
and maximum local tolerability composite score will be presented. The number and percentage 
of patients with hypo- or hyperpigmentation and scarring in the TF will be presented separately 
by visit as well as the number and percentage of patients with changes from baseline in 
pigmentation and scarring in the TF.
TEAEs and TESAEs recorded during the study will be presented, including the total number 
of events and the number and percentage of patients with events. Summaries of the number 
and percentage of patients with TEAEs (and number and percentage of events), study drug-
related TEAEs, TEAEs by severity, TESAEs, TESAEs with an outcome of death, and TEAEs 
leading to temporary or definite discontinuation of the study treatment will be provided. 
Specific tables describing AESIs will be also provided. The number and percentage of patients 
who experience one or more AESI will be tabulated by AESI.
For PEs, ECGs, vital signs, and clinical laboratory parameters, the number and percentage of 
patients with normal or abnormal results will be presented at scheduled visits. Descriptive 
statistics for continuous variables will be provided at scheduled visits together with a summary 
of changes from baseline for each parameter. Shift tables will be provided when appropriate.
Exploratory Endpoints
Descriptive statistics will be provided for exploratory endpoints overall and by subgroups:  age
(<65 and ≥65), gender (male/female), number of lesions at baseline (≤8 and >8), treatment 
location (face/scalp), history of skin cancer (yes/no), and Fitzpatrick skin type (I/II and 
III/IV/V/IV).
Interim Analysis
No interim analysis is planned for this trial.






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h All patients who have unresolved local tolerability signs, hypo- or hyper-pigmentation, scarring in the TF, or treatment-related AEs at Day 57 will return for additional follow-up every 7 to 28 
days until these have resolved, have returned to the baseline value, or are deemed stabilized by the Investigators.
i Measurement of vital signs will include blood pressure, heart rate, respiratory rate, and body temperature. Measurements of systolic and diastolic blood pressure will be performed after at least 
5 minutes of rest in a supine position and preferably on the same arm.
j Patients will complete a diary (Study App) to record daily dates and times of study treatment application. The diary (Study App) will be checked by the Investigator (or designee) at Visit 5.
k TF identification (face/scalp)
l Baseline photo is only required in case of any significant change from Screening is detected in the TF as per the Investigator judgement or if the quality of the image captured at Screening is 
not appropriate. If no photo is needed at baseline, then the screening photo will be considered the baseline assessment.
m Study drug will be applied by the subject at home before study Visit 3 on Day 5, which will take place at the clinical site.


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2
Table of Contents
Protocol Amendment Summary of Changes............................................................................2
Sponsor Signatures ...................................................................................................................3
Principal Investigator Signature ..............................................................................................4
1
Protocol Synopsis.................................................................................................5
2
Table of Contents ...............................................................................................12
Table of Tables........................................................................................................................15
3
List of Abbreviations..........................................................................................16
4
Sponsor, Investigator(s) and Trial Administrative Structure...........................18
4.1
Sponsor..........................................................................................................................18
4.2
Investigator(s)...............................................................................................................18
4.3
Administrative Structure.............................................................................................18
5
Introduction........................................................................................................18
5.1
Background Information.............................................................................................18
5.1.1
Indication......................................................................................................................................18
5.1.2
Unmet Medical Need....................................................................................................................19
5.1.3
Mechanism of Action....................................................................................................................19
5.1.5
Clinical Studies.............................................................................................................................20
5.2
Summary of the Known Potential Risks and Benefits..............................................21
5.3
Scientific Rationale for the Trial ................................................................................22
6
Objectives and Endpoints...................................................................................22
6.1
Objectives......................................................................................................................22
6.2
Endpoints......................................................................................................................22
6.2.1
Safety Endpoints...........................................................................................................................22
6.2.2
Exploratory Endpoints ..................................................................................................................23
7
Trial Design and Rationale................................................................................23
7.1
Trial Design ..................................................................................................................23
7.2
Trial Rationale..............................................................................................................23
7.2.1
Rationale for Trial Design ............................................................................................................23
7.2.2
Rationale for Trial Population ......................................................................................................24
7.2.3
Rationale for Trial Dose and Regimen .........................................................................................24
7.2.4
Rationale for Trial Assessments ...................................................................................................24
8
Selection of Trial Population and Withdrawal of Patients ..............................25
8.1
Number of Patients ......................................................................................................25
8.2
Inclusion Criteria .........................................................................................................25
8.3
Exclusion Criteria ........................................................................................................25
8.4
Treatment Discontinuation Criteria...........................................................................27
8.5
Trial Withdrawal Criteria...........................................................................................27
8.6
Screening Failures........................................................................................................28
CCI


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8.7
Patient Replacement Criteria......................................................................................28
8.8
Termination of the Trial..............................................................................................28
8.8.1
End of Trial Definition .................................................................................................................28
8.8.2
Completed Patient Definition .......................................................................................................28
8.8.3
Premature Trial Termination.........................................................................................................29
9
Treatments..........................................................................................................29
9.1
Identity of Trial Investigational Medicinal Products................................................29
9.2
Packaging and Labelling .............................................................................................30
9.3
Shipment, Storage, and Accountability......................................................................30
9.4
Treatment Administration ..........................................................................................30
9.5
Treatment Compliance................................................................................................31
9.6
Methods for Assigning Patients to Treatment Groups.............................................32
9.6.1
Patient Identification.....................................................................................................................32
9.6.2
Randomization..............................................................................................................................32
9.7
Blinding.........................................................................................................................32
9.8
Unblinding by the Investigator ...................................................................................32
9.9
Pre-trial, Concomitant, and Post-trial Medications/Therapy..................................32
9.9.1
Pre-trial Medications.....................................................................................................................32
9.9.2
Concomitant Medications.............................................................................................................33
9.9.3
Prohibited Concomitant Medications............................................................................................33
9.9.4
Post-trial Medications...................................................................................................................33
10
Trial Procedures and Assessments....................................................................33
10.1
General Conditions of the Trial..................................................................................33
10.2
Patient’s General Conditions During the Trial .........................................................34
10.3
Scheduled Activities and Trial Visits..........................................................................34
10.3.1
Screening Period...........................................................................................................................34
10.3.2
Response Assessment Period........................................................................................................36
10.3.3
Unscheduled and Repeated Tests..................................................................................................37
10.4
Lesion Assessments ......................................................................................................37
10.5
Safety and Tolerability Assessments ..........................................................................37
10.5.1
Adverse Events.............................................................................................................................37
10.5.2
Focused Dermatological Examination of the Treatment Field .....................................................38
10.5.3
Physical Examinations and Vital Signs ........................................................................................39
10.5.4
Electrocardiograms.......................................................................................................................40
10.5.5
Laboratory Testing........................................................................................................................40
10.6
Other .............................................................................................................................41
10.7
Adverse Events.............................................................................................................41
10.7.1
Definitions ....................................................................................................................................41
10.7.2
Reporting of Adverse Events........................................................................................................42
10.7.3
Recording of Adverse Events .......................................................................................................43
10.7.4
Reporting of Serious Adverse Events and Adverse Events of Special Interest ............................44
10.7.5
Follow-up of Adverse Events / Serious Adverse Events ..............................................................45
10.8
Pregnancies...................................................................................................................45
10.9
Unblinding for Safety Reasons....................................................................................46
11
Statistics..............................................................................................................46


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11.1
Sample Size Calculation ..............................................................................................46
11.2
Structure and Methodology of the Statistical Analysis.............................................46
11.3
Analysis Populations....................................................................................................46
11.4
Descriptive Statistics....................................................................................................47
11.5
Demographics and Baseline Characteristics..............................................................47
11.6
Study and Treatment Compliance..............................................................................47
11.7
Prior and Concomitant Medications ..........................................................................47
11.8
Statistical Methods.......................................................................................................47
11.8.1
Analysis of Safety Endpoints........................................................................................................47
11.8.2
Analysis of Exploratory Endpoints...............................................................................................48
11.9
Handling of Missing Data............................................................................................48
11.10
Multiplicity Strategy....................................................................................................48
11.11
Subgroup Analyses.......................................................................................................48
11.12
Interim Analysis ...........................................................................................................48
12
Data Handling, Processing, and Record Keeping ............................................48
12.1
Data Collection.............................................................................................................49
12.1.1
Identification of the Trial Data Sources........................................................................................49
12.1.2
Electronic Case Report Forms ......................................................................................................49
12.1.3
Patient Diary .................................................................................................................................51
12.2
Data Management and Quality Control ....................................................................51
12.3
Investigator and Trial Master Files............................................................................52
12.4
Documents and Record Keeping.................................................................................52
13
Quality Control and Quality Assurance............................................................53
13.1
Training of Staff...........................................................................................................53
13.2
Monitoring....................................................................................................................53
13.3
Inspections and Audits.................................................................................................53
14
Ethics..................................................................................................................54
14.1
Responsibilities.............................................................................................................54
14.2
Patient Information and Informed Consent..............................................................54
14.3
Institutional Review Board/Independent Ethics Committee....................................55
14.4
Patient Data Protection................................................................................................55
15
Financing and Insurance..................................................................................56
16
Publication Policy ..............................................................................................56
17
Other Practical Considerations .........................................................................57
17.1
Investigator’s Brochure...............................................................................................57
17.2
Final Clinical Trial Report..........................................................................................57
17.3
Protocol Amendments..................................................................................................57
17.4
Protocol Deviations ......................................................................................................57
18
References ..........................................................................................................57


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19
Appendices..........................................................................................................59
Appendix 1, Highly Effective Methods of Birth Control.......................................................60
Appendix 2, Patch Test for the Assessment of Contact Dermatitis.......................................61
Table of Tables
Table 1
Schedule of Assessments......................................................................................9
Table 2
Fitzpatrick Skin Type.........................................................................................35
Table 3
Local Tolerability Signs and Grading Scale.....................................................39
Table 4
Laboratory Testing Parameters.........................................................................40


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3
List of Abbreviations
AE
Adverse event
AESI
Adverse event of special interest
AK
Actinic keratosis
ALCOA
Attributable, legible, contemporaneous, original, and accurate
BCC
Basal cell carcinoma
CDISC
Clinical Data Interchange Standards Consortium
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease 2019
CRA
Clinical Research Associate
CRO
Clinical Research Organization
CROOP
Clinical Research Organization Oversight Plan
CSR
Clinical Study Report
DMP
Data Management Plan
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EoS
End of Study
ET
Early termination
eTMF
Electronic Trial Master File
FDA
Food & Drug Administration (United States)
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MUsT
Maximum usage trial
OTC
Over-the-counter
PDF
Portable document format
PE
Physical examination
PIS
Patient Information Sheet
PK
Pharmacokinetic
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SCC
Squamous cell carcinoma


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SOP
Standard Operating Procedure
TEAE
Treatment-emergent adverse event
TESAE
Treatment-emergent serious adverse event
TF
Treatment field
TMF
Trial Master File
US
United States
UV
Ultraviolet
WOCBP
Women of child-bearing potential


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4
Sponsor, 
Investigator(s) 
and 
Trial 
Administrative 
Structure
4.1
Sponsor
Almirall, S.A. (Legal entity)
General Mitre, 151
08022 Barcelona, Spain
Almirall Research and Development Centre:
Laureà Miró, 408-410
08980 Sant Feliu de Llobregat
Barcelona, Spain
4.2
Investigator(s)
A Principal Investigator will be designated at each participating clinical trial center and a 
Coordinating Investigator will be nominated among the participating sites.  The name, address, 
and affiliation of each Principal Investigator and the Coordinating Investigator will be detailed 
in the final clinical study report (CSR).
4.3
Administrative Structure
Medical Expert appointed by the Sponsor for this trial:
MD, PhD
Almirall Research and Development Centre
Laureà Miró, 408-410
08980 Sant Feliu de Llobregat
Barcelona, Spain
Telephone: 
Email: 
This study will be conducted by a Contract Research Organization (CRO) on behalf of the 
Sponsor; the Sponsor will maintain oversight of the CRO. Refer to the CRO Oversight Plan 
(CROOP) for details and see Section 10.7.4 for Serious Adverse Event (SAE) and Adverse 
Event of Special Interest (AESI) reporting.
5
Introduction
A summary on the indication, mechanism of action, and completed nonclinical and clinical 
studies is provided below. A detailed description of the chemistry, pharmacology, efficacy, and 
safety of tirbanibulin ointment 1% is provided in the Athenex KX2-391 (tirbanibulin) 
Investigator’s Brochure.
5.1
Background Information
5.1.1
Indication
Actinic keratosis (AK) is an ultra-violet (UV) light-induced pre-cancerous lesion of the skin 
that represents the initial clinical manifestation of intra-epidermal abnormal keratinocyte 
PPD
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proliferation (Röwert-Huber, 2007; Fernandez Figueras, 2017). Given the demonstrated 
potential for progression to invasive squamous cell carcinoma (SCC), dermatologists 
encourage and actively pursue treatment, as recommended in current national and international 
guidelines (Hofbauer, 2014; Werner, 2015; de Berker, 2017; Leitlinienprogramm Onkologie, 
2019).
Actinic keratosis presents as erythematous, scaly patches on the skin of sun-exposed areas and 
so particularly affecting the face, scalp, and extremities, either as a single lesion or multiple 
lesions and may present in as an entire field (“field cancerization”) with widespread actinic 
damage, such as in areas on the forehead or the back of the hand (Dodds, 2014; Figueras Nart, 
2018). Actinic keratosis is common in older, fair-skinned populations of European ancestry, 
and is more frequently observed in men (Flohil, 2013).
Precise estimates of AK prevalence are difficult, owing to its strong association with increased 
age. The prevalence of AK in the US has been reported to range from 11% to 26% (Salasche, 
2000). Recent studies in Europe suggest that AK prevalence there ranges from 33% to 49% for 
men and 14% to 28% for women (Eder, 2014, Tizek, 2019, Flohil, 2013, Ferrándiz, 2016,
Fargnoli, 2017, Dziunycz, 2018).
In some cases, AK represents a carcinoma in situ of the skin, and when left untreated, AK can 
progress to invasive SCC (Röwert-Huber, 2007; Werner, 2013; Fernandez Figueras, 2017).
Cutaneous SCC represents 20% to 50% of skin cancers (Que, 2018) and poses a significant 
threat due to its ability to metastasize to any organ in the body (Burton, 2016). Up to 65% of 
SCCs arise from pre-existing AK; however, the risk of progression to SCC of a single AK 
lesion per year has been reported to be very low, 0% to 0.075% in patients without a previous 
history of non-melanoma skin cancer (Marks, 1988), and up 0.53% per lesion in patients with 
a prior history of non-melanoma skin cancer (Werner, 2013; Green, 2017).
5.1.2
Unmet Medical Need
Tirbanibulin ointment 1% is approved in the US and Europe for the topical treatment of AK
on the face or scalp, over a field up to 25 cm2. However, AK often affects larger areas of UV 
light-damaged skin; thus, there is a need for a product to treat AK patients over fields larger 
than 25 cm2.
Although a limited number of AK field-directed therapies are currently available that target 
areas larger than 25 cm2, there remain unmet needs for patients with AK in terms of tolerability 
and treatment convenience/adherence. Topical therapies, such as 5-fluorouracil and 
imiquimod, frequently present safety and tolerability events during treatment that may lead to 
treatment discontinuation. While diclofenac sodium 3%, which is also used over larger fields, 
has a good safety and tolerability profile, it is administered over a longer treatment period (60 to
90 days) and drugs with shorter treatment durations are desirable, as they are associated with 
better adherence (Goldenberg, 2017). In a survey of 40 dermatologists in France, short 
treatment duration was the primary consideration in selecting a field-directed topical treatment
(Savary, 2019). Thus, there is a need in the current armamentarium for well-tolerated, short-
duration therapies targeted to areas larger than 25 cm2.
5.1.3
Mechanism of Action
Tirbanibulin has potent anti-proliferative and anti-tumor activities in vitro and in vivo by virtue 
of its ability to induce cell cycle arrest and apoptotic cell death by disrupting the cellular 


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microtubule network via direct binding to tubulins. Furthermore, it is associated with disruption 
of Src tyrosine kinase signaling.
5.1.4
Nonclinical Studies
5.1.5
Clinical Studies
The clinical development program on topical tirbanibulin includes 10 completed clinical trials 
that enrolled a total of 1338 subjects, 989 subjects who received tirbanibulin ointment 1% and 
349 subjects who received vehicle ointment. Of the 989 subjects treated with tirbanibulin 
ointment 1%, 597 were patients with AK and 392 were healthy adults.
Pharmacokinetics
Pharmacokinetic studies showed that tirbanibulin ointment 1% was minimally absorbed in 
patients with AK after topical application to 25 cm2 on the face or balding scalp once daily for 
5 consecutive days. Exposure (Cmax, AUC0-24) was higher when tirbanibulin ointment 1% was 
applied to the face versus the scalp. A proportional increase in systemic exposure (Cmax,
AUC0-24) was observed when tirbanibulin ointment 1% was applied to an area measuring 
100 cm2 on the face or balding scalp.
CCI


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Efficacy and Safety
The efficacy and safety studies included two Phase 3 double-blind, vehicle-controlled, 
randomized trials, KX01-AK-003 (N=351) and KX01-AK-004 (N=351), that were conducted 
in the US to evaluate the efficacy and safety of tirbanibulin ointment 1% compared to vehicle 
ointment in patients with AK on face or balding scalp. Tirbanibulin ointment 1% once daily 
for 5 days was effective in the treatment of AK on either the face or balding scalp, with 
statistically significantly higher rates of complete and partial clearance at Day 57 in the treated 
field as compared to control vehicle (complete clearance, 49% vs 9%, respectively). Treatment-
related adverse events (AEs) were few (16% vs 10%, respectively) and consisted of mostly 
transient mild to moderate application site pruritus and pain that required no treatment; there 
were no treatment-related SAEs. Signs assessing local tolerability were mostly mild to 
moderate erythema and flaking/scaling. Mean composite scores for local tolerability signs
peaked at Day 8 and were mostly resolved by Day 29.
The safety of treating larger AK fields (>25 cm2) was evaluated in a Phase 1, maximal usage 
trial (MUsT), in which tirbanibulin ointment 1% was applied to an area measuring 100 cm2 on
the face or balding scalp in 28 patients with AK. The most frequently reported treatment-related 
AEs were application site pruritus and application site pain. All AEs were mild or moderate in 
intensity; no severe AEs were reported. The most frequently reported local tolerability signs 
were erythema and flaking/scaling. Most local tolerability signs were mild or moderate, with
severe erythema and flaking/scaling reported in 14.3% of patients each. Local tolerability sign 
composite scores peaked around Day 7 to 8 and were mostly resolved by Day 29.
A detailed description of the completed clinical studies is provided in the Athenex KX2-391 
Ointment 1% (tirbanibulin) Investigator’s Brochure.
5.2
Summary of the Known Potential Risks and Benefits
Actinic keratosis is a UV light–induced pre-cancerous lesion of the skin that represents the 
initial clinical manifestation of intra-epidermal abnormal keratinocyte proliferation. Given the 
demonstrated potential for progression to SCC, dermatologists generally encourage and 
actively pursue treatment, with a goal of completely eliminating AK lesions, thereby reducing 
the risk of progression to invasive SCC.
Data from the two pivotal Phase 3 studies demonstrate that treatment with tirbanibulin ointment 
1% once-daily for 5 days is effective in the treatment of AK of the face or balding scalp.
In the pivotal studies, the safety profile of tirbanibulin ointment 1% showed a low rate of 
treatment-emergent AEs and no unexpected or unanticipated safety findings. The overall 
incidence of treatment-emergent AEs (TEAEs) was similar between the tirbanibulin ointment
1% and vehicle groups, and there were no treatment-related treatment-emergent serious AEs
(TESAEs) or discontinuations due to a TEAE. There were also no long-term safety concerns 
related to tirbanibulin ointment 1% in patients followed up to 1 year after Day 57.
The most frequently reported local tolerability signs were transient, mild to moderate erythema 
and flaking/scaling. Treatment-related AEs were mostly transient, mild to moderate 
application-site pruritus or pain, and most did not require treatment.


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The safety profile of tirbanibulin ointment 1% observed in the Phase 1 maximal-use trial
M-14687-01, in which study drug was applied to 100 cm2 on the face or balding scalp, was 
consistent with that observed in the pivotal studies.
Based on the available efficacy and safety data from the completed clinical and nonclinical 
studies, the benefit-risk assessment is positive and supports the evaluation of tirbanibulin 
ointment 1% in this Phase 3 study of patients with AK of the face or scalp.
Further information regarding the nonclinical and clinical characteristics, summaries of the 
known and potential risks, as well as reasonably expected adverse reactions of the product 
under investigation, is provided in the Athenex KX2-391 (tirbanibulin) Investigator’s 
Brochure.
5.3
Scientific Rationale for the Trial
Tirbanibulin is an antiproliferative agent that causes cell cycle arrest and apoptosis. In two 
well-controlled Phase 3 clinical trials, tirbanibulin ointment 1% was demonstrated to be an 
effective and safe treatment for AK of the face or balding scalp, when applied topically once 
daily for 5 consecutive days to a field of 25 cm2 containing 4 to 8 clinically typical, visible, 
and discrete AK lesions.
On the basis of the Phase 3 trial results, tirbanibulin ointment 1% was approved in the US and 
Europe for the topical treatment of AK on the face or scalp, over a field up to 25 cm2. However, 
AK often affects larger areas of UV light-damaged skin; thus, there is a need for a product to 
treat AK patients with affected fields larger than 25 cm2.
This study will assess the safety and tolerability of tirbanibulin ointment 1% administered 
under the same posology (once daily for 5 days) to a field of approximately 100 cm2 on the 
face or balding scalp containing 4 to 12 clinically typical, visible, and discrete AK lesions.
6
Objectives and Endpoints
6.1
Objectives
The primary objective of the trial is to evaluate the safety and tolerability of tirbanibulin 
ointment 1% when applied to a field of approximately 100 cm2 on the face or balding scalp.
Additionally, the treatment effect of tirbanibulin ointment 1% when applied to a field of 
approximately 100 cm2 on the face or balding scalp will be explored.
6.2
Endpoints
6.2.1
Safety Endpoints
Safety Endpoints
x Local Tolerability Assessment:
o Local tolerability score by visit (0-3) for each individual sign (erythema, flaking/scaling, 
crusting, swelling, vesiculation/pustulation, and erosion/ulceration)
o Maximum local tolerability score post baseline through all the visits for each individual 
sign
o Time to maximum local tolerability score for each individual sign


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o Local tolerability signs composite score (0-18) by visit, defined as the sum of the scores 
graded from 0 to 3 on all six individual tolerability sign categories
o Maximum local tolerability signs composite score post baseline through all the visits
o Time to maximum local tolerability composite score
o Pigmentation and scarring in the TF through all the visits
x TEAEs, TESAEs, adverse events of special interest (AESIs), clinical laboratory data, and 
other safety assessments (vital signs, physical examinations [PEs], electrocardiograms 
[ECGs])
6.2.2
Exploratory Endpoints
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count from total lesions in the TF at each visit
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count, for lesions that were already present at baseline, from total lesions in the TF at each 
visit
x Absolute number and percent change of new lesions from total lesions in the TF at each visit
7
Trial Design and Rationale
7.1
Trial Design
This is a Phase 3 multicenter, open-label, single-arm trial to evaluate safety and local 
tolerability of tirbanibulin ointment 1% administered topically for 5 days over a field of 
approximately 100 cm2 on the face or balding scalp in adult patients with AK.
The study consists of a 4-week (28-day) Screening Period, a 5-day Treatment Period, and a
Response Assessment Period of approximately 7 weeks (see Table 1, Schedule of 
Assessments):
x During the Treatment Period, patients will apply tirbanibulin ointment 1% once daily for 
5 days beginning on Day 1.
x All patients will be evaluated for safety, tolerability, and the presence of AK lesions in the 
TF until completion of the Response Assessment Period at Day 57.
7.2
Trial Rationale
7.2.1
Rationale for Trial Design
Since tirbanibulin ointment 1% is an approved product and there is no change in the 
formulation or posology, the main objective of this study is to evaluate the safety and 
tolerability of tirbanibulin ointment 1% applied over an extended field (100 cm2) in adult 
patients with AK on the face or balding scalp.
The duration of the study considers both safety and efficacy. From a local tolerability 
perspective, most of the local signs are expected to be resolved by Day 29. However, the study 
duration is extended up to Day 57, in order to assess the treatment effect as exploratory 
endpoints.


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In addition to the overall incidence of local tolerability events, the sample size considers
detection of local tolerability signs of particular interest, specifically, vesiculation/pustulation 
and erosion/ulceration (see Section 11.1). When severe, these local tolerability signs can lead 
to permanent local events such as dyspigmentation or scarring.
7.2.2
Rationale for Trial Population
The study will be conducted in male and female AK patients, aged 18 years or older, having 
4 to 12 clinically typical, non-hypertrophic, non-hyperkeratotic, visible, and discrete AK 
lesions over a field of approximately 100 cm2 on the face or the balding scalp.
Enrollment will be controlled such that the trial population is representative of the population 
expected to use the product in terms of age and treated area. A minimum of 50% of patients 
older than 65 years old will be included and approximately two-thirds of the patients will be 
treated for AK lesions on the face and one-third on the scalp.
7.2.3
Rationale for Trial Dose and Regimen
In this study patients will be treated with tirbanibulin ointment 1% daily for 5 consecutive days 
beginning on Day 1. Treatment will be applied to a field measuring approximately 100 cm2 on
the face or balding scalp. There are no changes in treatment duration or posology. Tirbanibulin 
ointment 1% has shown effectiveness in the treatment of AK lesions and the good safety and 
tolerability profile supports the field extension to a higher area to satisfy medical needs.
In a Phase 2 trial (KX01-AK-002), efficacy and safety results of 3 and 5-day treatment 
regimens over 25 cm2 were compared. The 5-day regimen showed substantial clinical activity 
and acceptable local tolerability. The 5-day treatment regimen showed a higher proportion of 
patients with 100% clearance at Day 57 compared with the 3-day regimen (43% vs 32%,
respectively), as well as a higher proportion of patients maintaining their treatment response at 
12 months (43% vs 30%, respectively). Patients in the 5-day regimen experienced slightly more 
mild/moderate erythema and flaking/scaling, but local signs were self-limited with both 
regimens and by Day 29 had essentially returned to baseline values. 
7.2.4
Rationale for Trial Assessments
In prior studies, mild to moderate erythema and flaking/scaling were the most frequently 
observed signs when assessing local tolerability. Local tolerability signs following treatment 
will be characterized and assessed throughout this study and reported separately from AEs.
Standard safety assessments will be performed throughout the study including the capture of 
AEs, SAEs, concomitant medications, laboratory testing for hematology, blood chemistry, and
urinalysis, PEs and vital signs measures, and ECGs.
Lesion counts in the TF will be performed at Screening, Day 1/Baseline (predose), and at every 
visit from Day 5 up to Day 57 to evaluate the treatment effect of tirbanibulin ointment 1%, 
when applied to an area measuring 100 cm2 on the face or balding scalp.


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8
Selection of Trial Population and Withdrawal of Patients
8.1
Number of Patients
Approximately 125 patients will be screened to initiate treatment in approximately 
100 patients.
8.2
Inclusion Criteria
All of the following criteria must be met for inclusion of a patient in the trial:
1. Male or female and ≥18 years old at the time of consent
2. Having a TF on the face or balding scalp (excluding lips, eyelids, and inside nostrils and 
ears) that
x measures approximately 100 cm2 (eg, mid face) and
x contains 4 to 12 clinically typical, visible, and discrete AK lesions within the TF
3. If a woman of childbearing potential (WOCBP), ie, fertile, defined as a female in the life 
period from menarche and until becoming post-menopausal (no menses for 12 months 
without an alternative medical cause) or permanently sterile (with hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy at least 3 months prior to Screening), she must:
x have a negative urine pregnancy test using a highly sensitive method at screening and on 
Day 1 prior to treatment administration
x be using highly effective methods of birth control (defined in Appendix 1) for at least 
30 days or 1 menstrual cycle, whichever is longer, prior to the study treatment and must 
agree to continue use during the study period and until at least 30 days or 1 menstrual 
period, whichever is longer, after the last dose of investigational product
x agree to have pregnancy tests while in the study and at the end of the study (according to 
the Schedule of Assessments in Table 1)
4. Willing to avoid excessive sunlight or UV light exposure, including the use of tanning beds, 
to the face or scalp during the study
5. Ability to understand the purpose and risks of the trial, willingness and ability to comply 
with the protocol, and provided written informed consent in accordance with institutional 
and regulatory guidelines
8.3
Exclusion Criteria
Patients will be excluded from trial enrollment if they meet any of the following criteria:
1. Presence in the TF of:
a) Clinically atypical and/or rapidly changing AK lesions in the TF
b) Hyperkeratotic or hypertrophic lesions, recalcitrant disease (had cryosurgery on 
2 previous occasions) and/or cutaneous horn
c) Confluent AK lesions (ie, non-discrete lesions defined as per inclusion criteria)
d) History of invasive SCC, Bowen’s disease, basal cell carcinoma (BCC), or other 
malignant tumors in the TF


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e) Any other dermatological disease that causes difficulty with examination
2. Location of the TF is:
x On any location other than the face or balding scalp
x Within 5 cm of an incompletely healed wound
x Within 5 cm of a suspected BCC or other neoplasia
x Periorbital, lips, or nostrils
3. Previous treatment with tirbanibulin ointment 1%.
4. Anticipated need for inpatient hospitalization or inpatient surgery from Day 1 to Day 57
5. Treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, photodynamic 
therapy, or other treatments for AK within the TF or within 2 cm of the TF, within 8 weeks 
prior to the Screening visit
6. Use of systemic retinoids (eg, isotretinoin, acitretin, bexarotene) within 6 months prior to 
the Screening visit
7. Use of the following therapies and/or medications within 4 weeks prior to the Screening 
visit:
x Cosmetic or therapeutic procedures (eg, use of liquid nitrogen, surgical excision, 
curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing) 
within the TF or within 2 cm of the selected TF
x Treatment with cytotoxic drugs (eg, cyclophosphamide, vinblastine, chlorambucil, 
methotrexate).
x Treatment with systemic medications that modulate and/or suppress the immune system 
(eg, cyclosporine, azathioprine, methotrexate, prednisone, alefacept, infliximab, 
interferons/interferon inducers).
x Therapy/treatment with UV-A or UV-B light.
8. Use of the following therapies and/or medications within 2 weeks prior to the Screening 
visit:
x Acid-containing therapeutic products (eg, salicylic acid or fruit acids, such as alpha and 
beta-hydroxyl acids and glycolic acids), topical retinoids, or light chemical peels within 
the TF or within 2 cm of the selected TF
x Topical steroids within the TF or within 2 cm of the selected TF
x Artificial tanners within the TF or within 5 cm of the selected TF
9. A history of sensitivity and/or allergy to any of the ingredients in the study medication
10. Patients with significant abnormalities on the medical history, PE findings, vital signs, 
ECG, clinical chemistry, hematology, and urinalysis results that in the judgment of the 
Investigator may interfere with the interpretation of the results.
11. A skin disease (eg, atopic dermatitis, psoriasis, seborrheic dermatitis, eczema) or condition 
(eg, scarring, open wounds) that, in the opinion of the Investigator, might interfere with the 
study conduct or evaluations, or which exposes the patient to unacceptable risk by study 
participation


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12. Significant uncontrolled or unstable medical diseases or conditions that, in the opinion of 
the Investigator, would expose the patient to unacceptable risk by study participation
13. Females who are pregnant or nursing or seeking to become pregnant
14. Participated in an investigational drug trial during which an investigational study 
medication was administered within 30 days or 5 half-lives of the investigational product, 
whichever is longer, before dosing in the current study
15. Patient who is employee or relative to employees at the research site or Almirall
8.4
Treatment Discontinuation Criteria
Any patient may discontinue from study treatment at any time during the trial at the discretion 
of the Investigator or at the request of the patient. For patients who discontinue treatment, 
efforts should be made to encourage the patient to remain in the trial and complete the trial-
related assessments. The main reason for such a premature treatment discontinuation must be 
documented in the electronic case report form (eCRF), as follows:
x Adverse event: If a patient experiences an AE, treatment discontinuation will be at the 
discretion of either the Investigator or the patient regardless of the causal relationship to the 
investigational medical product (IMP).
x Protocol deviation: Any protocol deviation detected should be corrected when possible and 
the patient should be allowed to continue. ONLY the following deviations should lead to 
treatment discontinuation: those which could affect patient's safety (eg, illness requiring 
treatment(s) which in the clinical judgement of the Investigator [or after discussion with the 
trial monitor] might invalidate the trial by interfering with the IMP) or which are due to 
patient unwillingness to comply with the trial activities or those violations of inclusion 
and/or exclusion criteria detected
x Lost to follow-up: Non-attendance. In these cases, every effort should be made by the 
Investigator to ascertain the reason and to assure patient’s attendance as soon as possible. 
Every effort (at least three documented attempts) should be made to contact the patient and 
documented in the medical records. If patient cannot be reached after that, a registered mail 
letter will be sent to the patient and documented in the medical records
x Patient's personal request: The patient is permitted to stop his/her treatment at any time 
during the trial without incurring any loss in his/her medical care. The Investigator should 
ensure that such discontinuation is not due to an AE or disease exacerbation, in which case 
the corresponding reason should be recorded
x Pregnancy
8.5
Trial Withdrawal Criteria
Any patient may withdraw from the trial at any time during the trial at the discretion of the 
Investigator or at the request of the patient. The main reason for such a premature study 
withdrawal must be documented in the eCRF, as follows:
x Adverse event: If a patient experiences an AE, study withdrawal will be at the discretion of 
either the Investigator or the patient regardless of the causal relationship to the IMP.
x Death


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x Protocol deviation: Any protocol deviation detected should be corrected when possible and 
the patient should be allowed to continue. ONLY the following deviations should lead to 
patient withdrawal: those which could affect patient's safety (eg, illness requiring 
treatment(s) which in the clinical judgement of the Investigator [or after discussion with the 
trial monitor might invalidate the trial by interfering with the IMP) or which are due to 
patient unwillingness to comply with the trial activities or those violations of inclusion 
and/or exclusion criteria detected
x Lost to follow-up: Non-attendance. In these cases, every effort should be made by the 
Investigator to ascertain the reason and to assure patient’s attendance as soon as possible. 
Every effort (at least three documented attempts) should be made to contact the patient and 
documented in the medical records. If patient cannot be reached after that, a registered mail 
letter will be sent to the patient and documented in the medical records
x Patient's personal request: The patient is permitted to stop his/her participation at any time 
during the trial without incurring any loss in his/her medical care. The Investigator should 
ensure that such withdrawal is not due to an AE or disease exacerbation, in which case the 
corresponding reason should be selected
x Trial terminated by Sponsor
8.6
Screening Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently treated in the study. A minimal set of screen failure information is required 
to be entered into the database to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from Competent Authorities. Minimal information includes 
demography, screen failure reason, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this trial (screen failures) will not 
be rescreened.
8.7
Patient Replacement Criteria 
Patients who withdraw from the trial at any time will not be replaced.
8.8
Termination of the Trial
8.8.1
End of Trial Definition
The “end of trial” is defined as the date of the last visit of the last patient, either at Day 57 or
earlier, if the last patient discontinues prematurely. The end of trial will be communicated to
the Competent Authorities and Institutional Review Boards (IRBs) / Independent Ethics 
Committees (IECs) according to local regulations.
8.8.2
Completed Patient Definition
Patients who complete all the phases of the study, including the last visit as described in the 
Schedule of Assessments (Table 1), will be considered to be completed patients.


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8.8.3
Premature Trial Termination
Almirall reserves the right to prematurely terminate (ie, suspend) the trial. 
Certain circumstances may require the premature termination of the trial including:
x The Investigator/Coordinating Investigator and the Sponsor feel that the type, number, 
and/or severity of AEs justify discontinuation of the trial.
x The Sponsor considers the applied doses of the trial drug to be no longer relevant.
x Data not known before becoming available and that raise concerns about the safety of the 
trial drug so that continuation would pose potential risks to the patient
If the trial is terminated or suspended, the Sponsor/CRO will promptly inform the Investigators. 
The IRBs/IECs should be promptly informed and provided the reason(s) for the termination or 
suspension by the Investigator, as specified by the applicable regulatory requirement(s).
The Investigator will inform the patients and will collect and keep all the data up to the date of 
discontinuation. Samples retrieved up to the date of trial termination will be analyzed as per 
protocol.
If the trial is prematurely terminated or suspended, trial results will be reported according to 
the requirements outlined in this protocol, as far as applicable.
The Clinical Data Interchange Standards Consortium (CDISC) criteria should be followed 
while recording the patient trial discontinuation reasons.
9
Treatments
9.1
Identity of Trial Investigational Medicinal Products
Investigational medicinal product manufacturing, labelling, packaging, and release will be 
done following Good Manufacturing Practice (GMP). 
Tirbanibulin is a white to off-white ointment containing tirbanibulin freebase active drug
substance. For a full product description, refer to the KX2-391 Ointment 1% (tirbanibulin) 
Investigator’s Brochure.
Test Investigational Medicinal Product
Substance Code/Name
Tirbanibulin
Route of Administration
Topical
Dosage Form
Ointment
Strength
1%
Reference Investigational Medicinal Product
This is single arm study; no reference IMP will be used.


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9.2
Packaging and Labelling
Study drug will be packed and labeled in accordance with local regulations by the Sponsor 
according to GMP conditions, including but not limited to the Sponsor contact details, protocol 
number, drug identification, storage conditions, and content of study drug. A sample label will 
be filed in the Investigator file.
On Day 1, patients will be dispensed a study kit containing 5 zipper bags each with a single-
dose packet containing 350 mg tirbanibulin ointment 1%.
Local regulatory requirements will be fulfilled for packaging and labelling (US 21 Code of 
Federal Regulations 312.6).
9.3
Shipment, Storage, and Accountability
Only participants enrolled in the trial may receive trial IMP and only authorized site staff may 
supply or administer trial IMP. All drug supplies must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff.
Tirbanibulin ointment 1% must be stored at 20°C to 25°C (68°F to 77°F) with excursions 
permitted to 15°C to 30°C (59°F to 86°F). Do not refrigerate or freeze tirbanibulin ointment 
1%. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medication received and ensure that any discrepancies 
are reported and resolved before use of the study medication. 
The Investigator, the trial staff, institution, or the head of the medical institution (where 
applicable) is responsible for clinical supplies accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). The Investigator will 
maintain accurate records of receipt of all study drugs, including dates of receipt. In addition, 
accurate records will be kept regarding when and how much study drug is dispensed and used 
by each patient in the study.
Reasons for departure from the expected dispensing regimen must also be recorded. At the 
completion of the study, to satisfy regulatory requirements regarding drug accountability, all 
study medication will be reconciled and retained or destroyed according to applicable 
regulations. Further guidance and information for the final disposition of unused 
investigational products are provided in the Study Reference or equivalent manual.
Empty packages and unused medication will be returned to Almirall or a designated depot, 
where the remaining medication will be destroyed according to regulatory requirements.
Retention drug samples will be kept by the Sponsor or designee, during the trial and until it is 
legally required after trial completion.
The Investigator and trial staff must adhere to Good Clinical Practice (GCP) guidelines, as well 
as local or regional requirements.
9.4
Treatment Administration
Treatment will begin on Day 1, following confirmation of patient eligibility and collection of 
all pre-dose samples and assessments.


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At Baseline (Day 1 pre-dose), the Investigator will confirm the TF on the face or balding scalp 
that was identified at Screening and the patients will receive instructions on how to apply the 
topical medication and how to care for the TF.
Patients will be provided with 5 single-dose packets containing tirbanibulin ointment 1%.
The first dose will be administered by the patient under the supervision of study personnel on 
Day 1 at the site. The patient will self-administer the remaining single-dose packets once daily 
at home for the next 4 consecutive days. The fifth dose should be applied by the patient at home 
before the Day 5 site visit.
Tirbanibulin ointment 1% will be applied to cover the treatment field of approximately 
100 cm2, corresponding to approximately 0.5% of the body surface area. Study medication 
should be applied each day at approximately the same time. The treatment field should not be 
wet, should be kept dry for approximately 8 hours after application, and should not be touched 
or covered with dressing. The ointment should not be applied near the eyes, mouth, or lips.
Patients will return the used medication packaging (all parts of each packet, including the torn 
opening part) and any unused study medication back to the clinical site at the next visit to check 
compliance and for drug reconciliation purposes. Further details will be given in the study 
manuals (see Section 9.5).
9.5
Treatment Compliance
Compliance with the study treatment will be assessed by site personnel on Day 5. Compliance 
will be assessed by counting the dispensed and returned used tirbanibulin ointment 1% single-
use packets. Patients will be instructed to return both the used and unused study treatment back 
to the clinical site. This information will be recorded in the eCRF.
Deviations from the prescribed dosage regimen should be also recorded in the eCRF.
Patients will record dates and times of study treatment application, including dates for study 
treatment delays in the electronic diary of the study mobile application (Study App).
The amount of study drug applied will be determined based on weight. The site will record the 
weight, as a whole, of the 5 packets each one in their respective closed zipper storage bags 
before and after dosing to quantify the amount used by the patient. Patients will be required to
bring back to the site the respective two torn parts of each packet in their respective closed 
zipper storage bags. The weighing of the 5 packets will be performed on a balance with 
sufficient precision to calculate the weight by difference of tirbanibulin administered daily with 
high accuracy. To avoid losing any study drug by leakage issues, the total weight of 5 packets 
will be measured as a whole in their respective re-sealable zipper storage bags. Additional 
details for this process are provided in the study manuals.
The dosing logs for each patient will be kept during the study. The Clinical Research Associate 
(CRA) will review treatment compliance during monitoring site visits.


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9.6
Methods for Assigning Patients to Treatment Groups
9.6.1
Patient Identification
In order to protect the patient identity and data confidentiality, each patient will be identified 
in the trial with one unique patient number. The unique patient number is a combination of 
his/her site number and a sequential number assigned by the Investigator. 
The site number will be predetermined, but the sequential number is assigned by the 
Investigator upon signing the informed consent form (ICF). At each site, the first patient is 
assigned patient number 001, and subsequent patients are assigned the next consecutive 
number.
Once assigned to a patient, the patient number will not be reused. The patient number will be 
used to identify the patient throughout the trial.
9.6.2
Randomization
This is single-arm study in which all patients are treated with tirbanibulin ointment 1%; no 
randomization is performed.
9.7
Blinding
This is an open-label study with no active or placebo comparator; no study blind will be 
applied.
9.8
Unblinding by the Investigator
Not applicable.
9.9
Pre-trial, 
Concomitant, 
and 
Post-trial 
Medications/Therapy
9.9.1
Pre-trial Medications
Patients must not have received any other IMP within 30 days or 5 half-lives of the IMP, 
whichever is longer, before the first trial drug administration. 
All medications, including over-the-counter (OTC) drugs, food supplements, herbal remedies, 
and vitamins, taken within 30 days prior to screening will be recorded at Screening. In addition, 
the use of any prohibited medications must be recorded within the timeframe described in the 
exclusion criteria to ensure proper washout is followed. Thereafter, a record of all medications 
taken during the course of the study will be made. Information regarding the total daily dose, 
route of administration, start and discontinuation dates, and indication are to be captured in the 
patient’s eCRF.
A complete study disease treatment history will be recorded in the eCRF.
Any medication taken for medical reasons (mainly diseases concomitant with studied disease) 
prior to trial entry, will be continued at the same dose and conditions during the entire 
experimental phase of the trial.


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9.9.2
Concomitant Medications
No concomitant therapy will be allowed during the entire duration of the trial, other than the 
prior allowed medication or any other required for the treatment of AEs or local tolerability. In 
such cases, the drug will need to be prescribed by the Investigator and recorded in the 
Concomitant Medication eCRF. The following items should be specified: trade name, dose and 
frequency of dosing, route, indication, date and time of first dose, and date and time of last 
dose, when applicable.
Therapies (medication and non-medication therapies) not restricted by the protocol may be 
used. The use of non-medicated therapies (eg, sunscreen and moisturizers) will also be recorded 
in the Concomitant Medication eCRF. The use of or change in the dose of any of the 
concomitant medications, either prescription or OTC, during the study will be recorded. The 
reason for use or change of dose of a concomitant therapy may need to be reported as an AE. 
Patients must be instructed to inform the Investigator of plans to take any new treatment during 
the participation in the trial, including OTC medicinal and herbal products.
9.9.3
Prohibited Concomitant Medications
The use of any non-study drug on the TF is prohibited during the study. 
The use of moisturizers and sunscreens in the TF is prohibited during the study, but can be 
applied outside of the TF, as needed. 
Patients will be reminded that AK lesions located outside the treatment field may be treated by 
physical lesion-directed treatment only (eg, cryotherapy) at the Investigator’s discretion.
All medications requiring wash-out (see Exclusion Criteria, Section 8.3) are prohibited during 
the patient’s participation in the study.
9.9.4
Post-trial Medications
Once study treatment and all visits and related study measurements are complete, patients 
should continue to take their usual medications allowed during the study and may resume other 
medications interrupted prior to study enrolment, as deemed appropriate by the Investigator. It 
is not planned to treat patients with tirbanibulin ointment 1% any further than scheduled in this 
study. No intervention or additional care is planned to follow the end of the study.
10
Trial Procedures and Assessments
10.1
General Conditions of the Trial
Informed consent will be obtained after the study has been fully explained to each patient and 
before the conduct of any screening procedures or assessments. Documentation will be required 
(documented in the patient’s medical records) to confirm that the Investigator has ensured the 
informed consent process was done correctly, and that the patient understood what to expect, 
he/she had the opportunity to ask any questions and consider other treatment options and agreed 
to participate.


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The ICF can be either in paper or electronic form. Patients will be able to download the signed 
ICF (in case of completing the electronic ICF) or will be given a hard copy (in case of 
completing the paper ICF).
Trial visits must be scheduled with respect to Baseline/Day 1. In order to adapt appointments 
to local holidays, patients´ availability or site internal organization needs, time windows are
allowed as indicated in Table 1. The CRA or CRO Medical Monitor should be contacted for 
advice in case of exceptional situations.
As applicable, laboratory tests and other assessments will be performed using supplies or 
equipment provided by the Sponsor for this trial through a specialized provider who will 
perform centralized assessment and reporting.
Optimally, the evaluations for each patient (lesion counts, review of trial drug compliance, etc.) 
should be performed by the same Investigator (or other suitably qualified and experienced 
designee) throughout the trial to avoid inter-assessor bias. 
Unless specified otherwise, the study assessments scheduled during the study visits must be 
performed before the study product administration, except on Day 5, when the study product 
application will be done by the patient at home prior to the site visit. If assessments are 
scheduled for the same nominal time, then the assessments should occur in the following order:
1. Vital signs
2. ECG
3. Blood draw for laboratory tests
Table 1 summarizes the trial procedures to be performed at each visit. Individual trial 
procedures are described in the following sections.
10.2
Patient’s General Conditions During the Trial
After the screening evaluation and while not at the research site, patients will maintain normal 
daily activities, following the instructions of the Investigator. Any event likely to interfere with 
the objectives of the trial will be communicated to the Investigator and reported without delay 
to the Sponsor.
10.3
Scheduled Activities and Trial Visits
10.3.1
Screening Period
All screening assessments will be performed after the patient provides informed consent. The 
Screening Visit (Visit 1) will occur between Day -28 and Day -1. Patient screening numbers 
will be assigned at Visit 1.
Prior to signature of the ICF, Investigators will evaluate eligibility of patients for entry in the 
trial by comparing past and current medical status, as documented in the patient’s medical 
history, to the inclusion/exclusion criteria of the trial.
Eligible patients will receive a detailed description of all activities and requirements before 
signing the ICF to ensure their understanding and compliance with sample collection and 
clinical examinations. 


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Patients who require a washout period from prohibited concomitant treatments should be seen 
and sign the ICF prior to the Screening visit, to ensure the necessary washout before. No trial 
assessments will be performed on that date and the Screening visit will be scheduled according 
to the washout length required for the specific medication stopped.
The Screening visit and assessments will be performed in accordance with schedule detailed in 
Table 1.
Demographics and Baseline Characteristics
Data on demographic (sex, age, race, ethnicity) and baseline characteristics (body weight, 
height, smoking and alcohol habits) will be collected during Screening. Height will be 
measured at Screening only.
Skin type will be recorded according to the Fitzpatrick scale (Table 2).
Table 2
Fitzpatrick Skin Type
Skin Type
Description*
I
Always burns easily, never tans (sensitive)
II
Always burns easily, tans minimally (sensitive)
III
Burns moderately, tans gradually (light brown) (normal)
IV
Burns minimally, always tans well (moderate brown) (normal)
V
Rarely burns, tans very well (dark brown) (intensive)
VI
Never burns, deeply pigmented (intensive)
*Sunburn and tanning history based on first 30 to 45 minutes of sun exposure after winter season of non-sun exposure.
Medical and Actinic Keratosis History
Medical history at Screening will include:
x Significant medical and surgical history during the last 5 years (eg, a common cold would 
not be captured unless it was ongoing at Screening)
x The initial diagnosis date of AK on the face or balding scalp and on any other part of the 
body
x Any AK treatment history of the face or balding scalp including all commercial and 
investigational products and surgical modalities dating back to the initial diagnosis
x History of and location of cancers including skin cancers, eg, BCC, SCC, melanoma
Prior Medications
All medications, including OTC drugs, food supplements, herbal remedies, and vitamins, taken 
within 30 days prior to screening will be recorded at the Screening visit (see Section 9.9.1).
Physical Examination
A complete Physical Examination includes height, weight, and an assessment of head, eyes, 
ears, nose and throat, integumentary/dermatological, gastrointestinal, cardiovascular, 
respiratory, musculoskeletal, neurological systems,
and an expanded dermatological 


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examination to cover sun-exposed areas where photo-damage is likely. Height is measured at 
Screening only. Physician examinations will be conducted in accordance with schedule 
detailed in Table 1.
Treatment Field Identification
The size of the TF must be approximately 100 cm2.
At Screening, the Investigator will select and measure the anatomical area (eg, approximately 
mid face or an area on the scalp) and will outline the TF with a marker pen over the skin. Each 
AK lesion within the TF will be also identified with a label. A photograph will be captured 
using imaging devices to be used to support the location of the same TF identified at Screening 
during the follow up study visits assessments. 
At Baseline (Day 1), the area of the TF and the number and location of lesions inside it will be 
confirmed. A baseline photograph is only required in case of any significant change from 
Screening is detected in the TF as per the investigator judgement or if the quality of the image 
captured at screening is not appropriate. If no photograph is needed at baseline, then the 
screening photograph will be considered the baseline assessment. The same field will be 
located during the study with the aid of imaging software before performing the study 
assessments. Study Manuals will be provided to describe the image procedures in detail. The 
number of AK lesions in the TF will be recorded in the eCRF and photographs will be taken 
according to the schedule in Table 1.
Pregnancy Testing
In females of childbearing potential, a highly sensitive urine pregnancy test will be performed 
at the Screening visit and according to the Schedule of Assessments (Table 1). Urine pregnancy 
test kits will be provided by the Sponsor.
Any pregnancy, whether occurring in a female patient or in the female partner of a male patient, 
for which the estimated date of conception was during the patient’s study participation must be 
reported. In addition, pregnancies in female partners of male patients for which the estimated 
date of conception was within 90 days of the last study treatment must be reported.
10.3.2
Response Assessment Period
Response Assessment Period visits and assessments will be performed in accordance with the 
schedule detailed in Table 1. See Sections 10.4 and 10.5 for details on the lesion and safety 
assessments, respectively.
The trial visit at Day 5 cannot be repeated nor skipped. The trial visits at Day 8, Day 15, Day 29,
and Day 57 may be rescheduled within the time windows allowed in this protocol, in case of:
x scheduling conflicts (weekends or holidays),
x technical problems with the equipment necessary for the visit (eg, ECG), 
x any AEs that impede conduct of the visit, 
x restrictions related to the coronavirus 2019 disease (COVID-19) pandemic.


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10.3.3
Unscheduled and Repeated Tests
Unscheduled Tests
As deemed necessary by the Investigator, additional safety test(s) can be performed at any time 
during the trial in order to follow-up the progress of any clinically relevant abnormal finding, 
investigate any potential new adverse event, etc. These additional tests outside of the initial 
schedule of the trial will be considered "unscheduled tests" and will not be associated with any 
trial visit.
Repeated Tests
Any safety test may be repeated at the Investigator’s discretion under either of the following 
situations:
x When there is any kind of problem with the first test (ie, technical problem with the ECG 
machine, blood sample hemolyzed, presence of artifacts, etc.). The Investigator should 
repeat the individual test as soon as possible.
x At the screening visit any individual test(s) may be reasonably repeated during the screening 
window to confirm the eligibility criteria (eg, laboratory sample when there is any clinically 
significant abnormality, etc.).
10.4
Lesion Assessments
To the extent possible, the Investigator who conducts the lesion count at Baseline/Day 1 and 
through the study visits according to the Schedule of Assessments (see Table 1) must be the 
same for an individual patient. All other intermediate assessment visits should be conducted 
by the same Investigator, to the extent possible.
A dermatologist (Investigator or Subinvestigator) will count all lesions in the TF for all 
subjects, according to the Schedule of Assessments (see Table 1). Details on whether the lesion 
present in the TF is new or an existing lesion at baseline will be recorded at each visit in the 
eCRF.
Lesions identified at baseline will be followed during the study using appropriate tools such as 
imaging software, where baseline lesions will be identified and new lesions appearing along 
the study recognized.
10.5
Safety and Tolerability Assessments
Safety will be assessed periodically during the study by recording AEs, including SAEs, local 
tolerability, pigmentation and scarring, and AESIs. Safety assessments also include PEs and 
vital signs measures, ECGs, clinical laboratory evaluations and pregnancy testing for WOCBP 
(see Table 1).
10.5.1
Adverse Events
10.5.1.1
Adverse Events
At each study visit, patients will be asked a general question “How have you been since the 
last visit?” before assessment of local tolerability, pigmentation, and scarring in the TF.


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Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, vital sign measurements), including those that worsen from 
baseline which are determined to be clinically significant in the medical and scientific judgment 
of the Investigator, are to be recorded as AEs or SAEs.
Local tolerability signs will be reported separately from AEs (see Section 10.5.2). The 
Investigator, or designee, may report an AE based on his or her judgement. See Section 10.5.1.2
for definitions and reporting of AESIs.
All patients who have unresolved treatment-related AEs at Day 57/Early Termination (ET) will 
return for additional follow-up every 7 to 28 days until these have resolved, have returned to 
the baseline value, or are deemed stabilized by the Investigators.
Adverse event and SAE definitions and reporting requirements are detailed in Section 10.7.
10.5.1.2
Adverse Events of Special Interest
The following have been identified as AESIs based on their relevance for the current intended 
use:
Skin Cancers
Skin cancers (including BCC, SCC, and melanoma) appearing within or outside the TF during 
the study will be reported as AESIs. Details of the skin cancer and any other associated AE 
will be recorded in the AE form in the eCRF and by using the Skin Cancer Report Form. The 
location and treatment will be recorded. In the case of an SCC arising within the TF, it will be 
recorded if an AK had been present at the same location at baseline. See Section 10.7.4 for 
reporting requirements for AESIs.
If the skin cancer meets seriousness criteria, an SAE Report Form must also be completed and 
sent along with Skin Cancer Report Form, as specified in Section 10.7.4.
10.5.2
Focused Dermatological Examination of the Treatment 
Field
The focused dermatological examination will include evaluations for local tolerability signs, 
pigmentation, and scarring in the TF.
10.5.2.1
Local Tolerability
Local tolerability assessments in the TF will be recorded per the schedule in Table 1. The 
assessment for local tolerability is to be done after the assessment for AEs. The evaluation of 
local tolerability is done by the Investigator (or an appropriate trained designee). The local 
tolerability signs to be assessed and the corresponding grading scale for each sign are provided 
in Table 3.


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Table 3
Local Tolerability Signs and Grading Scale
Local Tolerability Signs
Local Tolerability Score
Erythema
Flaking/scaling
Crusting 
Swelling
Vesiculation/pustulation
Erosion/ulceration
0=absent
1=mild (slightly, barely perceptible)
2=moderate (distinct presence)
3=severe (marked, intense)
Application site symptoms such as itching, burning, stinging, tenderness, pain etc., are not 
classified as local tolerability signs and will be reported as AEs.
All patients who have unresolved local tolerability signs in the TF at Day 57/ET will return for 
additional follow-up every 7 to 28 days until these have resolved, have returned to the baseline 
value, or are deemed stabilized by the Investigator.
Any sign of local tolerability leading to temporary or permanent discontinuation of the study 
drug application or requiring the use of concomitant medications should be reported as an AE. 
If a sign of local tolerability leads to an AE meeting the criteria of seriousness (ie, an SAE), 
the SAE form will be completed with all the available information and reported within the same 
timeframe and following the same routing as for an SAE (see Section 10.7.4).
In case of occurrence of possible contact dermatitis in the TF, an evaluation (patch test) will be 
made to confirm or rule out the diagnosis (see Appendix 2).
10.5.2.2
Pigmentation Changes and Scarring
Hypo- and hyperpigmentation and scarring in the TF will be assessed as being present or absent 
in accordance with the Schedule of Assessments (Table 1). The assessment of pigmentation 
and scarring is to be done after the assessment for AEs.
All patients who have unresolved hypo- or hyperpigmentation or scarring in the TF at 
Day 57/ET will return for additional follow-up every 7 to 28 days until these have resolved, 
have returned to the baseline value, or are deemed stabilized by the Investigator.
10.5.3
Physical Examinations and Vital Signs
Physical Examinations
A complete PE includes height, weight, and an assessment of head, eyes, ears, nose and throat, 
integumentary/dermatological, gastrointestinal, cardiovascular, respiratory, musculoskeletal, 
neurological systems, and an expanded dermatological examination to cover sun-exposed areas 
where photo-damage is likely. Height is measured at Screening only.
Vital Signs
Measurement of vital signs will include blood pressure, heart rate, respiratory rate, and body
temperature. Measurements of systolic and diastolic blood pressure will be conducted after at 
least 5 minutes resting in the supine position and preferably on the same arm. If there is any 
suspicion of unreliable measurement, blood pressure will be measured again. The value 
obtained this time will be considered as definitive and should be recorded in the eCRF. 


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Significant findings that are observed after the patient has signed the ICF and that meet the 
definition of an AE must also be recorded in the AE form in the eCRF.
10.5.4
Electrocardiograms
Electrocardiogram training, equipment, and a procedural manual will be provided to the sites 
by a central ECG vendor. Refer to the procedural manual for details.
Electrocardiograms will be performed according to the schedule in Table 1. Patients must be 
in a supine position for 5 minutes prior to ECG and ECG is to be done prior to any blood 
sampling.
Significant findings that are observed after the patient has signed the ICF and that meet the 
definition of an AE must also be recorded on the AE form in the eCRF.
10.5.5
Laboratory Testing
Routine laboratory assessments will be performed at a designated central laboratory (refer to
the laboratory manual). Tests to be performed at the central laboratory are detailed in Table 4.
Table 4
Laboratory Testing Parameters
Assessment
Specific Tests
Hematology
Red blood cells (RBC), hemoglobin, hematocrit, platelets, and white blood 
cells (WBC) with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Blood chemistry
Electrolytes: Chloride, potassium, sodium, bicarbonate (HCO3)
Liver Function Tests: alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin, 
direct bilirubin
Renal Function Tests: Blood urea/blood urea nitrogen, creatinine
Other: Total protein, albumin, calcium, cholesterol, glucose, lactate 
dehydrogenase (LDH), phosphorus, triglycerides, uric acid
Urinalysis
Hydrogen ion concentration (pH), specific gravity, protein, glucose, 
ketones, leukocyte esterase, nitrite, bilirubin, urobilinogen, blood.
Blood and urine samples for laboratory testing will be collected in appropriate sampling tubes
according to the Schedule of Assessments (Table 1). Blood samples are to be collected before 
administration of concomitant medications (if any), and after vital signs measures and ECGs
are performed. Significant findings that are observed after the patient has signed the ICF and 
that meet the definition of an AE must also be recorded on the AE form in the eCRF.
Urine pregnancy testing for WOCBP will be performed at the study site in accordance with the 
Schedule of Assessments (Table 1).


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10.6
Other
Standardized Photography
Standardized photography of each patient’s TF will be performed prior to dosing while on 
treatment (see Table 1) for illustrative purposes and to support the TF and AK lesion 
identification within the TF. Each AK lesion within the TF will be identified at the 
screening/baseline visit with a label placed over the skin, a photo will be captured as a reference 
to support AK lesion follow up during the study. Refer to the study manuals for detailed 
instructions.
Care must be taken to ensure that the same lighting, background, subject positioning relative 
to the camera, and camera settings are used for each photograph. Equipment, supplies, and 
detailed instructions for obtaining and managing the photographs will be provided to the 
clinical study site prior to the initiation of patient enrollment.
10.7
Adverse Events
The Investigator will closely monitor any AE and will adopt the necessary clinical measures to 
ensure the safety of the patient.
10.7.1
Definitions
Adverse Event
An AE is defined as any untoward medical occurrence in a clinical trial participant, regardless 
of the administration of the IMP and its causal relationship to it.
An AE can therefore be any unfavorable and unintended medical occurrence during the 
patient’s participation in the trial, including deterioration of a pre-existing medical condition, 
an abnormal value in a laboratory assessment, ECG abnormality, or an abnormal finding in the 
physical examination.
Adverse events must be temporally associated with the patient’s participation in the trial, ie,
occur after signing the ICF. At the time of the occurrence of an AE, the administration of the 
IMP does not need to have already been initiated. If initiated, it does not necessarily need to 
have a positive causal relationship to the event.
Serious Adverse Event
An SAE is an adverse event, which falls into one or more of the following categories:
x results in death
x is life-threatening (ie, an event which, in the view of the Investigator, places the patient at 
immediate risk of death from the event as it occurred.) It does not mean that the event might 
hypothetically have caused death if it was more severe or lasted longer
x requires in-patient hospitalization or prolongs existing hospitalization
x results in persistent or significant disability or incapacity
x is a congenital anomaly or birth defect


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x is any other medically important event that may jeopardize the patient or may require 
intervention to prevent one of the other above outcomes.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life-threatening or do not result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition 
above should also be considered serious. These are considered “other important medical 
events.”
Hospitalization is defined as an overnight stay at the hospital or emergency room.
Prolongation of hospitalization is defined as any extension of an in-patient hospitalization 
beyond the stay anticipated/required in relation to the original reason for the initial admission, 
as determined by the Investigator or treating physician.
10.7.2
Reporting of Adverse Events 
Adverse events either reported by the patient or observed by the Investigator must be recorded 
in the AE page of the eCRF and should be described in the following manner:
x The nature of the AE will be described in precise, standard medical terminology (ie, not 
necessarily the exact words used by the patient). If known, a specific diagnosis should be 
recorded instead of listing signs and symptoms (eg, allergic contact dermatitis)
x The duration of the AE will be described by the start date and end date
x The location for cutaneous adverse events will be described as at or just around the TF
(≤2 cm from the TF) or distant (>2 cm from the TF)
x The intensity of the AE will be described in terms of mild, moderate, or severe according to 
the Investigator’s clinical judgment, using the following definitions:
o Mild: Awareness of event, symptoms, or signs, but easily tolerated (acceptable)
o Moderate: Sufficient discomfort and interferes with usual activity (disturbing)
o Severe: Incapacitating with inability to do normal daily living activities or significantly 
affects clinical status and warrants intervention (unacceptable)
x The causal relationship of the event to use of the IMP will be described in terms of:
o Not related: Event or laboratory test abnormality, definitely not related to trial drug, as 
related to other drug, chemicals, or underlying disease
o Unlikely related: Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable; disease or other drugs, chemicals or underlying disease 
provide plausible explanations
o Possibly related: Event or laboratory test abnormality, with a reasonable time 
relationship to drug intake; could also be explained by underlying disease or other drugs 
or chemicals; information on drug withdrawal may be lacking or unclear
o Related: Event or laboratory test abnormality, with a reasonable time relationship to drug 
intake, unlikely to be attributed to underlying disease or other drugs or chemicals; 
response to withdrawal clinically reasonable (positive dechallenge)


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‘Possibly related’ and ‘related’ will be considered as ‘related’ terms for reporting purposes. 
If the events are assessed as ‘unlikely related’ or ‘not related’ to the suspect IMP, the event
does not qualify for reporting purposes. In the absence of information on causality from the 
reporting Investigator, the CRO will immediately contact the reporting Investigator to 
request a causality assessment. The case will be updated with the follow-up information and 
reported accordingly. If no causality is provided by the Investigator, the Sponsor assessment 
will be considered for submission purposes.
x The outcome of the event will be described in terms of:
o Recovered/resolved
o Recovering/resolving
o Recovered/resolved with sequelae
o Not recovered/not resolved
o Fatal
o Unknown
x The action taken on the IMP will be captured as:
o Drug withdrawn
o Dose not changed
o Not applicable
An AE will be collected only once with its maximum severity, except when the AE started 
before first IMP administration and persisted after it and worsened in severity any time after 
first IMP application. In this latter case, the AE will be collected with each respective severity. 
The AE term recorded must be exactly the same at the different time points where this AE is 
reported again in the eCRF.
10.7.3
Recording of Adverse Events
Adverse events will be collected from signature of the ICF up to Day 57/ET. Any AE reported 
by the patient up to 30 days after the last study contact (Day 57/ET) should also be captured in 
the eCRF.
Medical disorders present at the time of signing the informed consent that are part of the 
patient’s medical history will only be considered AEs if they worsen after this time.
Abnormalities detected before IMP administration in the PE, laboratory tests, ECGs, or other 
safety assessments will not be considered AEs if already known as part of the medical history 
or in relation to prior medical conditions and will be recorded in the eCRF/CRF Medical 
History/physical 
examination 
form/page. 
However,
abnormalities 
detected 
in 
screening/baseline tests, thought to be due to a trial procedure, will be considered AEs.
Abnormalities (newly occurring or worsening of previously known abnormalities) detected 
after IMP administration in physical exam, laboratory tests, ECGs, or other safety assessments, 
which are considered clinically relevant by the Investigator, or which require an intervention 
or a diagnosis test, or may result in the IMP discontinuation, should be reported as AEs.


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Reported terms should accurately characterize the adverse event. When a patient experiences
an unspecified injury, signs or symptoms, active investigation should be conducted to reach a
final diagnosis. If reached, then the disease diagnosis is the preferred reported term.
Adverse events will be elicited by asking the patients non-leading questions (eg, "How do/did 
you feel?”) and by collecting AEs spontaneously reported by the patient to the Investigator or 
a designee.
All AEs elicited by the Investigator during the defined AE collection period must be recorded 
in the eCRF. In addition, when an AE meets the criteria of seriousness (ie, an SAE), it must 
also be recorded on the SAE form and reported following the defined timelines in Section 
10.7.4.
10.7.4
Reporting of Serious Adverse Events and Adverse Events 
of Special Interest
Serious adverse events and AESIs will be collected from signature of the ICF up to Day 57/ET.
Any SAE or AESI reported by the patient up to 30 days after the last study contact (Day 57/ET)
should be collected in the eCRF.
The Investigator must report any SAE or AESI within 24 hours from the moment she/he first 
learns of it to the CRO pharmacovigilance unit on a SAE report form. This reporting will take 
place regardless of whether the Investigator considers the event to be causally related to the 
IMP(s), to any other medicinal product(s), to the clinical trial procedure or to any intervention 
undergone by the patient.
Original reports are to be kept by the Investigator in the Investigator’s File. 
Contact details and specific instructions on the flow of SAE and AESI reports will be provided 
to all sites by the CRO.
The minimum information that must be included in the initial report is:
x An event meeting the criteria of SAE or AESI.
x A qualifiable reporter, defined as an Investigator of this trial or his/her delegate.
x A qualified patient, defined as a patient who has consented to this trial.
x A suspect medicinal product.
x The Investigator’s causality assessment.
Unless the SAE or AESI has been sufficiently documented in the initial report, the Investigator 
will provide all available additional information in follow-up reports by using a new form and 
adhering to the same routing and time frames as defined for the initial report. This will be 
continued until the event has been fully documented and reported.
An event reported to the CRO pharmacovigilance unit which does not meet the SAE or AESI 
criteria shall be nullified by the Investigator by forwarding a follow up report.
Depending on the local requirements, a regulatory report of the SAE or AESI (if serious) will 
be produced by the CRO pharmacovigilance unit and submitted to relevant Competent 
Authorities and Investigators, when applicable according to local regulations.


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Serious adverse events NOT considered to require reporting to the CRO pharmacovigilance 
unit will be:
x Hospitalization for a treatment/surgical procedure which was elective or pre-planned for a 
pre-existing condition that did not worsen during the participation in the trial.
10.7.5
Follow-up of Adverse Events / Serious Adverse Events
Those AEs and SAEs, including AESIs, recorded for Screening failure patients will be 
followed-up until resolution or until otherwise agreed between the Sponsor and the 
Investigator.
All AEs and SAEs, including AESIs, that are still present after the last study visit (including 
AEs that have led to premature discontinuation), will be followed-up at least 2 weeks for AEs 
and 4 weeks for SAEs after the last trial drug administration, by means of a follow-up contact 
or visit (whichever is considered more appropriate by the Investigator). In case the AE/SAE is 
still ongoing after that time point, this will be followed-up until its resolution or until otherwise 
agreed between the Sponsor and the Investigator. The same timeframes will apply for AEs 
from screening failures which are ongoing at the time the patient is withdrawn from the trial.
Additional safety data collected at a contact/visit to follow-up the ongoing AE will not be 
included into the clinical database, if this was already locked; therefore, the clinical database 
lock will not be delayed due to this situation. Any SAE will be followed up if needed after 
clinical database lock and the information will be only stored in the safety database.
10.8
Pregnancies
There is no information about effects that tirbanibulin could have on the development of the 
fetus in humans. However, consistent with its mode of action, tirbanibulin was embryo- and 
fetotoxic in preclinical studies.
Any pregnancy, whether occurring in a female patient or in the female partner of a male patient, 
for which the estimated date of conception was during the patient’s study participation must be 
reported. In addition, pregnancies in female partners of male patients for which the estimated 
date of conception was within 90 days of the last study treatment must be reported.
In case of pregnancy during the participation in the trial, the patient will be immediately 
discontinued.
The Sponsor will be informed according to the safety reporting procedure: the Investigator 
must complete a study specific pregnancy form upon confirmation of a pregnancy and send it 
to the CRO Safety Contact within 24 hours of confirmation of the pregnancy. Pregnancy is not 
itself an AE or SAE; however, maternal/fetal complications or abnormalities will be recorded 
as AEs or SAEs, as appropriate. 
The Investigator will follow the pregnancy until completion or until pregnancy termination 
and, in the case of a live-born offspring, the follow-up period will be deemed to have ended 
when the health status of the child has been determined on its birth or after an appropriate 
period post-delivery considered necessary to monitor the development of the new-born is 
completed.


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The patient will be asked to provide information on the outcome of the pregnancy, including 
premature termination should the case arise. Spontaneous miscarriage, developmental delay, 
fetal death, SAE in a neonate, and congenital abnormalities will be reported as SAEs. The 
Investigator will inform the CRO Safety Contact of the outcome as a follow-up to the initial 
pregnancy form. All pregnancies should be reported to the sponsor and, when applicable, to 
the ethics committee.
10.9
Unblinding for Safety Reasons
Not applicable.
11
Statistics
The statistical analyses described below will be supplemented by a comprehensive Statistical 
Analysis Plan (SAP) that will be finalized before the database is locked. Any changes to the 
statistical plans will be described and justified in the final report. All statistical processing will 
be performed using the SAS® system.
11.1
Sample Size Calculation
With 100 patients and assuming an expected percentage of patients with at least one local 
tolerability sign of approximately 90%, the precision in the estimation of that percentage will 
be approximately 11%. The precision is defined as the width of the 95% confidence interval.
Furthermore, 100 patients will provide approximately 10% and 13% precision in the estimation 
of the percentage of patients with the local tolerability events of particular interest, specifically 
vesiculation/pustulation (assuming an expected percentage of 8%) and erosion/ulceration 
(assuming an expected percentage of 12%), respectively.
11.2
Structure and Methodology of the Statistical Analysis
Statistical analyses of demographic, baseline characteristics, safety, tolerability, and lesion 
count data will be performed by the CRO Biostatistics department.
The SAP will be prepared by the CRO statistician under Almirall Standard Operating 
Procedures (SOPs) prior to database lock. SAS will be the statistical software used to analyze 
the data sets. A complete set of raw data listings will be appended to the Statistical Report. All 
tables, figures, and listings will be presented in portable document format (PDF) documents 
without any manual editing, ie, they will appear unmodified as programmed by means of the 
statistical package.
Tables, figures, and listings will be compiled in the statistical report and appended to the CSR.
11.3
Analysis Populations
There will be one analysis population in this trial:
x Safety population, defined as all patients who have received at least one dose of study 
treatment.


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11.4
Descriptive Statistics
Categorical variables will be summarized with counts (n) and percentages (%). For continuous 
variables, the number of non-missing observations (n), mean, standard deviation (SD), standard 
error (SE) of the mean, 95% confidence interval (CI) of the mean, median, first (Q1) and third 
(Q3) quartiles, minimum (min) and maximum (max) will be tabulated. When applicable, these 
summaries will be provided by visit and time-point of assessment.
11.5
Demographics and Baseline Characteristics
Descriptive statistics will be used to summarize demographic and baseline characteristics.
11.6
Study and Treatment Compliance
Descriptive statistics will be used to summarize study and treatment compliance.
11.7
Prior and Concomitant Medications
The number and percentage of the patients with concomitant medications during the study will 
be summarized by anatomical therapeutic chemical class, standardized drug name.
11.8
Statistical Methods
The statistical approach for the analysis of safety and other endpoints is described below. A
more detailed description of the statistical methods to be used will be provided in the SAP.
11.8.1
Analysis of Safety Endpoints
Descriptive statistics will be provided for all safety endpoints.
Local tolerability signs composite score, and specific local tolerability scores will be analyzed 
by means of descriptive statistics and provided by visit. The maximum local tolerability score 
and maximum local tolerability composite score will be presented. The number and percentage 
of patients with hypo- or hyperpigmentation and scarring in the TF will be presented separately 
by visit as well as the number and percentage of patients with change from baseline in hypo-
or hyperpigmentation and scarring in the TF.
An AE will be considered to be a TEAE, if it was not present prior to the first dose of trial drug 
or was present prior to the first dose of trial drug but increased in severity after the date of the 
first dose of study treatment. An AE that occurs more than 57 days after the last IMP application 
will not be counted as a TEAE.
TEAEs and TESAEs recorded during the study will be presented, including the total number 
of events and the number and percentage of patients with events. Summaries of the number 
and percentage of patients with TEAEs (and number and percentage of events), study drug-
related TEAEs, TEAEs by severity, TESAEs, TESAEs with an outcome of death, and TEAEs 
leading to temporary or definite discontinuation of the study treatment will be provided. 
Specific tables describing AESIs will be also provided. The number and percentage of patients 
who experience one or more AESI will be tabulated by AESI.


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For PEs, ECGs, vital signs, and clinical laboratory parameters, the number and percentage of 
patients with normal or abnormal results will be presented at scheduled visits. Descriptive 
statistics for continuous variables will be provided at scheduled visits together with a summary 
of changes from baseline for each parameter. Shift tables will be provided when appropriate.
11.8.2
Analysis of Exploratory Endpoints
Descriptive statistics will be provided for exploratory endpoints overall and by subgroup (see 
Section 11.11). An Observed Cases approach will be used for handling missing data, as the
main analysis (see Section 11.9). Any other sensitivity analyses will be defined in the SAP.
11.9
Handling of Missing Data
No imputation will be made for missing data.
11.10
Multiplicity Strategy
Not applicable.
11.11
Subgroup Analyses
Descriptive statistics will be provided for exploratory endpoints overall and by subgroups:  age
(<65 and ≥65), gender (male/female), number of lesions at baseline (≤8 and >8), treatment 
location (face/scalp), history of skin cancer (yes/no), and Fitzpatrick skin type (I/II and 
III/IV/V/IV).
11.12
Interim Analysis
No interim analysis is planned for this trial.
12
Data Handling, Processing, and Record Keeping
The Investigator will conduct the trial in accordance with the protocol and ICH E6 GCP 
guidelines. In addition to the routine monitoring procedures, training records should be in place 
to ensure investigators and CROs understand the data processing in any of the computerized 
systems to be used to ensure the confidence in the reliability, quality, and integrity of the patient 
data.
Sponsors, CROs, data safety monitoring boards, and other authorized personnel can view the 
trial data elements in the eCRF before and after the clinical Investigator(s) has electronically 
signed the completed eCRF. Reviewing trial data dynamically will allow early detection of 
trial-related problems (eg, safety concerns, protocol deviations) and problems with conducting 
the trial (eg, missing data, data discrepancies).
According to the eCRF entry guidelines, eCRFs must be completed for each patient by 
qualified and authorized personnel. Any data entry and corrections made in the eCRF must 
have a respective audit trail where the correction is dated, the individual making the correction 
is identified, the reason for the change is stated, and the original data are not obscured. Only 
data required by the protocol for the purposes of the trial should be collected.


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A list of all authorized data originators (ie, persons, systems, devices, and instruments) should 
be developed and maintained by the CRO and made available at each clinical site.
The eCRF is an auditable electronic record of information reported to the Sponsor on each trial 
patient, according to this clinical investigation protocol. The eCRF enables clinical 
investigation data to be systematically captured, reviewed, managed, stored, analyzed, and 
reported.
12.1
Data Collection
12.1.1
Identification of the Trial Data Sources
Source data includes all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical investigation used for 
reconstructing and evaluating the investigation.
When a device or instrument is the data originator (eg, blood pressure monitoring device or 
glucometer) and data are automatically transmitted directly to the eCRF, the eCRF is the 
source.
Access to source data is critical to the review and inspections of clinical investigations. Source 
data should be attributable, legible, contemporaneous, original, and accurate (ALCOA) and 
must meet the regulatory requirements for recordkeeping.
The trial data sources are outlined below:
x Signed informed consent forms
x Patient medical history records will include trial diagnosis and inclusion/exclusion criteria 
age, sex, demographics, physical examination, medical history, vital signs, previous 
medication, original or certified copy of a laboratory reports, instrument printout, trial 
progress notes of the physician
x Laboratory test results reports (hematology, clinical chemistry, urinalysis, etc)
x Digital photographs
x ePatient diary (Study App)
x eCRF
12.1.2
Electronic Case Report Forms
To comply with the requirement to maintain accurate case histories Investigators should review 
and electronically sign the completed eCRF for each patient before the data are archived or 
submitted. Use of electronic signatures must comply with US Title 21 Code of Federal 
Regulations part 11.
For trial data elements transcribed from paper or electronic to the eCRF, the electronic or paper 
documents from which the data elements are transcribed are the source. 
These data must be maintained by the Investigators and available to the monitor or inspector if 
requested (eg, an original or certified copy of a laboratory report, instrument printout, progress 
notes of the physician, the trial patient’s hospital chart(s), nurses’ notes).


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Direct Entry of Data Into the eCRF
The direct entry of data can eliminate errors by not using a paper transcription step before entry 
in the eCRF. For the following data elements, the eCRF may be the source:
x Date of ICF signature (in the case of a paper ICF; in the case of an electronic ICF the 
eConsent will be the source)
x Inclusion and exclusion criteria confirmation (checking)
x Patient demographics and physical examination, including. age, gender, race, ethnicity 
height, weight, and Fitzpatrick skin type
x Relevant previous and concomitant therapies
x Up-to-date relevant medical history, including trial diagnosis
x TF measurements and location (face or scalp)
x Number of lesions in the TF and identification of whether each lesion is new or existed at 
baseline
x Vital signs (blood pressure, pulse, body temperature, and respiratory rate)
x Pregnancy test results
x Trial/visit dates 
x Visit assessment (checking compliance, trial diary data, drug application, blood sample 
collection, tolerability score, end of treatment)
x Drug accountability (medication given and returned and product weight before and after 
application)
x Adverse events
For the above trial data elements, the eCRF is the source. If a paper transcription step is used, 
then the paper documentation should be retained and made available for monitoring or 
inspection.
Direct data entry should meet ALCOA+ principles for data integrity in life sciences. In case 
trial data cannot be entered at the time of the patient visit, eg, laboratory tests results, then 
Investigators are requested to make their entries at the time when the report with the results is 
received.
All non-CRF entered external data (ie, images) will not be loaded into the eCRF, but it will be 
integrated in SAS datasets and reconciled frequently with the eCRF data by CRO Data 
Management.
The information directly collected in the eCRF must match the source documents. The source 
data verification will be performed by the CRO Clinical Research Associate (monitor) 
according to the requirements specified in the Monitoring Plan.
At the trial end, the CRO will generate a PDF copy of the completed CRFs which will be sent
to the Investigator(s) for all patients enrolled at his or her location.


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12.1.3
Patient Diary
During the study, patients will use a mobile application. Clinical personnel will be instructed 
on the use of the Study App in order that they further instruct the patients at the Day1/Baseline 
visit, and as many times as deemed necessary. Patients will also receive written instructions on 
the Study App use. The Study App will be installed onto the patient’s own mobile phone, and
there will also be the possibility to provide patients with a mobile phone, if necessary. The 
Study App will be installed onto the mobile phone during the baseline visit. Clinical personnel 
will check and confirm the correct installation of the Study App during the visit.
On the Study App, patients will:
x Receive notifications, communications, and reminders through the patient retention tool
x Complete the eDiary: Patients, and assisted by caregivers, as needed, will complete a diary 
to record daily the study treatment application dates and times of application. The eDiary
will be completed by the patient and will be checked by the Investigator (or designee) in 
accordance with the Schedule of Assessments (Table 1).
At the study end, the Investigator will receive a CD/DVD with the mobile application data (in 
PDF) from the patients enrolled at his/her location. The Investigator will keep this CD/DVD
with the rest of the original data for as long as required by local regulations. The mobile 
application files are relevant documentation for registration.
The mobile application data is the sole property of the Sponsor and should not be available in 
any form to third parties without the written permission of the Sponsor, except to authorized 
representatives of appropriate Competent Authorities.
12.2
Data Management and Quality Control
Data Management of the trial will be performed by the CRO Data Management department 
according to the CRO SOPs and supervised by Data Management at Almirall, according to 
Almirall SOPs.
In order to facilitate the collection of accurate and complete data, the CRO will target the risks 
associated with critical trial data and these will be documented into the Data Management Plan 
(DMP) and the Monitoring Plan.
Investigators will respond to any query generated by the Data Management group or any data 
risk indicator reported.
Main Data Management activities and procedures will be accurately described in the DMP, 
created by the CRO and approved by Almirall.
Database checks will be programmed by the CRO, based on the Data Validation Plan. The 
listings will be documented in the DMP. The checks and listings programming will be 
appropriately validated by the CRO.
Reconciliation of trial data and SAEs between Clinical and Drug Safety databases will be 
performed by the CRO on an ongoing basis and before database lock. Procedures to be followed 
will be detailed in the DMP.


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Encoding of specific data will be conducted by the CRO. For this trial, medical history, AEs, 
and concomitant medications (including rescue medications) will be coded; Medical 
Dictionary for Regulatory Activities (MedDRA) and WHO-DRUG Enhanced dictionaries will 
be used, version number of each dictionary will be documented in the DMP.
A Quality Control check to ensure the accuracy of the data will be done by the CRO, when
data are cleaned on an ongoing basis and just before the database lock. Specifications of the 
Quality Control check will be found in the DMP.
An audit trail will be maintained in order to protect the authenticity and integrity of the clinical 
data.
12.3
Investigator and Trial Master Files
The Investigator's file and Sponsor Trial Master File (TMF) will contain all trial documents 
indicated in the ICH GCP guidelines and local regulations. 
At the trial end the Investigator will receive one CD/DVD/USB key with the electronic data 
capture (EDC) data, as well as one CD/DVD with the tablet PC and electronic Patient Diary 
data from the patients enrolled at his/her location. The Investigator will keep these in the 
Investigator’s file.
The CRO will provide Almirall with an electronic TMF (eTMF). Almirall will have on-line 
access to the eTMF during the study and study documents will be reviewed, approved, and 
managed within the system. At the end of the study the eTMF and complete audit trail will be 
transferred to the TMF-dedicated Sponsor server for long-term storage. Information about 
eTMF contents, index, structure, nomenclature, metadata, and oversight metrics will be 
detailed in other documents (ie, eTMF Management Plan, CROOP, etc.).
All records must be stored in a secure facility protected from fire, flood, and unauthorized 
access where they may be readily accessed in the event of an audit or inspection.
12.4
Documents and Record Keeping
The Investigator should retain control of the records (ie, completed and signed eCRF or 
certified copy of the eCRF). The Investigator maybe requested by inspectors with access to the 
records that serve as the electronic source data. 
When data elements are transcribed from paper sources into an eCRF, the Investigator must 
also retain the paper sources, or certified copies, for later review. Other records (electronic and 
paper) required to corroborate data in the eCRF may also be requested during an inspection.
All trial data (including electronic data), all hard copies including protocol, consent forms, 
CRFs, queries and printouts, and all essential documents relating to the conduct of the clinical 
trial will be stored at the research site for a period of 25 years after completion of the trial, 
unless otherwise communicated in writing by the Sponsor.
CROs/vendors will store the databases, including audit trails and related documentation, for a 
period of 25 years after completion of the trial, unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention period 


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without the written approval of the Sponsor. No records may be transferred to another location 
or party without written notification to the Sponsor.
13
Quality Control and Quality Assurance
13.1
Training of Staff
During the set-up phase of the trial, appropriate kick-off meetings will be performed between 
Almirall and the CRO and/ or vendors (eg, eCRF, laboratories, central ECG), in order to train 
CRO staff on trial procedures.
An Investigators’ meeting will be performed, including training on GCP procedures, trial 
protocol, efficacy and safety assessments, laboratory procedures, eCRF completion, usage of 
any specific device and any other applicable process/procedure/method, as applicable.
An initiation visit will be performed at each site by the trial CRA designated by the CRO to 
assess if all the material and supplies (eg, eCRF, IMP) arrived in good conditions and to train 
the site staff for protocol compliance.
Appropriate study manuals will be provided to the research sites as written help to support all 
trainings on all trial procedures (eg, laboratory samples, eCRF). 
13.2
Monitoring
The trial will be monitored by CRO CRA/Monitors according to the details specified in the 
Monitoring Plan.
The trial CRA/Monitor will conduct monitoring visits according to a pre-agreed schedule and 
with enough frequency to perform source data verification, check the accuracy of entries in the
CRFs, the adherence to the protocol and to GCP, the progress of enrollment and to ensure that 
trial medication is being stored, dispensed, and accounted for, according to specifications and 
report any deviation as soon as possible to the Clinical Trial Manager. 
Standard monitoring reports will be produced by the trial CRA/Monitor after each visit and 
filed in the TMF. Key trial personnel must be available to assist the field CRA/Monitor during 
these visits.
The Investigator must also keep the original informed consent form signed by the patient and 
maintain source documents for each patient in the trial, case and visit notes medical records, 
all information in eCRFs must be traceable to these source documents in the patient´s file.
A close out visit to solve pending issues and to agree on the shipment of remaining trial 
materials to the Sponsor (eCRF and other data source, medication) will be performed by the 
trial CRA/Monitor once all patients have completed the trial.
13.3
Inspections and Audits
The trial site, trial processes, CRO, providers and/or trial documents may be subject to Quality 
Assurance audits by Almirall (or authorized partner companies) as well as to inspection by 
competent authorities, as applicable, during the trial or after trial completion. Audits and 
inspections may include, but are not limited to, drug supply, presence of required documents, 


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informed consent process, medical records, general protocol compliance and comparison of 
data recorded in the eCRF and queries against source documents. Investigator will ensure direct 
access to source medical records for inspection and audit purposes.
14
Ethics
This trial will be conducted in accordance with the recommendations guiding physicians in 
biomedical research involving human patients adopted by the 18th World Medical Assembly 
of Helsinki (1964), as amended in Fortaleza, Brazil (2013) (World Medical Association, 2013), 
as well as in compliance with ICH GCP guidelines, and local laws of the Countries in which 
the trial centers are located. 
14.1
Responsibilities
The Investigator is responsible for conducting the trial in accordance with the procedures 
described in this protocol. All the personnel involved in the clinical trial will be fully informed 
about the drug and the nature of the trial and will be patient to protocol procedures concerning 
their duties in the trial.
The Investigator, the CRO/vendors and the Sponsor should ensure that all work and services 
described herein, or incidental to those described herein, shall be conducted according to the 
highest standards of Good Clinical Practice (ICH GCP guidelines) and local regulations.
The Investigator, the CRO and the Sponsor will work according to the ICH guidelines, EU
Clinical Trials Directive 2001/20/EC and/or Clinical Trials Regulation No 536/2014, and Title
21 of the US Code of Federal Regulations (US Food and Drug Administration [FDA]).
The Investigator shall administer the trial medication to patients under his or her personal 
supervision or under the supervision of any co-Investigator reporting to him/her who are 
identified in the delegation of responsibilities and signatures log. The Investigator and 
designees will be responsible for the patient’s compliance throughout the trial. 
Refer to Section 9.9.4, for details on post-trial medications.
14.2
Patient Information and Informed Consent
Patients will be informed by the Investigator in detail of the characteristics of the drug to be 
administered, the nature of the clinical investigation, the risks and the discomfort that can 
reasonably be expected as a result of their participation and the uses of the data, as described 
in the Patient Information Sheet (PIS).
The patients will be informed that they are free to withdraw their consent and suspend their 
participation in the trial at any time with no penalty or loss of benefits to which the patient is 
otherwise entitled. Administration of the drug may be interrupted, and a patient withdrawn 
from the trial at the discretion of the Investigator. The Investigator should justify his decision 
in the patient's eCRF.
Any patient considered by the Investigator to be suitable for inclusion must document his or 
her willingness to participate in the trial by giving his or her informed consent in writing before 
starting any trial procedure by signing the ICF, which must be signed and dated by the patient 


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and the Investigator. Explicit consent to participate in the standardized photography procedure 
will also have to be given by patient.
At such time the patient must be given adequate time to understand the information provided 
and ask questions, if required. Any new relevant information that becomes available during the 
trial will be provided to the patient. 
The PIS and ICF will include all elements required according to the applicable legislation.
These documents or any modification will have been authorized by Almirall, S.A. and 
approved by the relevant IRB/IEC before use.
Patients will have access to the written PIS and ICF in paper or electronic format, preferably 
but not exclusively through a web system (eConsent). When using the eConsent process, the 
system will allow for on-line meetings between the patient and Investigator to facilitate 
answering patient questions and recording the responses. Patients will give their consent by 
signing electronically the ICF (eConsent). Patients will be requested to download the signed 
ICF, and/or ask the Investigator for a printed version. While they are in the study, patients will 
always have access to the PIS and ICF through eConsent. When eConsent cannot be used, the 
patient will sign a paper ICF.
14.3
Institutional Review Board/Independent Ethics Committee
This protocol, PIS and the ICF should be submitted to an IRB/IEC for review and approval. 
Notification in writing of approval must be obtained from the IRB/IEC by the Investigator 
before initiation of patient enrolment.
The Investigator must promptly report to the IRB/IEC all changes in the implementation of the 
research (protocol amendments) and will not make such changes without IRB/IEC approval 
except where necessary to eliminate apparent immediate hazards to the trial patients or 
administrative changes.
Serious adverse events reasonably related to the trial drug will be communicated by the 
Investigator/CRO to the IRB/IEC.
The Investigator is required to maintain accurate and complete records of all written 
correspondence sent to and received from the IRB/IEC and must agree to share these 
documents and any reports with the Sponsor.
14.4
Patient Data Protection
The trial patients shall be informed by the Investigator that complete confidentiality will be 
maintained concerning their identity. On eCRFs/EDC and all trial data records (eg, electronic 
patient diary) patients will be identified only by the assigned patient identification number.
A signed written ICF signifies the explicit acceptance by the individual that data from the trial 
will be available to the Investigator and his/her staff, the authorized representatives of the 
Sponsor and, if required, by the IRB/IEC and Competent Authorities. However, all data 
contained in the patient’s medical history will be considered as confidential. Almirall will treat 
data according to personal data regulations (Health Insurance Portability and Accountability 
Act [HIPAA]), and any other applicable national and international regulation.


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All clinical trial findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor.
15
Financing and Insurance
Almirall will set up a contract with the CRO with the economic aspects for trial funding. 
All patients recruited will have an insurance policy provided by Almirall to cover any possible 
risk resulting from their participation in the clinical trial.
Except in the proven case of clinical malpractice, the insurance company will indemnify 
against any claim or claims made by patients or their dependents which may result from 
administration of the IMP.
16
Publication Policy
Almirall will disclose clinical trials in a manner consistent with applicable national laws and 
rules governing personal data privacy and protection of intellectual property rights. Clinical 
trials will be registered, and results disclosed by means of recognized public databases, such 
as clinicaltrials.gov in the US and EudraCT in the European Union.
The Investigator understands and accepts that his/her name and trial center may be disclosed 
in the context of this national or international legislation.
All the information related to this clinical trial is considered strictly confidential and is the 
property of Almirall. This information will not be given to a third party without the written 
consent of Almirall.
By signing this trial protocol, the Investigator affirms to the Sponsor that he/she will maintain 
in confidence all information furnished to him/her in relation to or resulting from this trial. The 
Investigator will only divulge such information as may be necessary to the IRB/IEC, the 
members of the staff and the patients who are involved in this trial.
All relevant aspects regarding publication will be part of the contract (or similar document) 
between the Sponsor and CRO.
In all cases, the trial results shall be reported in an objective, accurate, balanced, and complete 
manner, with a discussion of the strengths and limitations of the trial. All authors will be given 
the relevant statistical tables, figures, and reports needed to support the planned publication. 
Publication and/or presentation whether complete or partial, of any part of the data or results 
of this trial will not be allowed until global publication and trial results disclosure by the 
Sponsor as per US FDA regulatory compliance obligations, and only after mutual agreement 
between the Investigator and Almirall.


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17
Other Practical Considerations
17.1
Investigator’s Brochure
The Investigator’s Brochure contains a summary of the pre-clinical and clinical data. The same 
confidentiality procedures apply for the Investigator’s Brochure as for the protocol.
The Investigator’s Brochure will be included in the Investigator file. The Investigator will sign 
a receipt form.
17.2
Final Clinical Trial Report
The CSR will be written by the CRO following the ICH guidelines requirements. It will be 
approved and signed by the Coordinating Investigator and Almirall representatives according 
to internal SOPs. 
The CSR will be audited by the CRO and/or Almirall before issuing the final version. 
The final version of the electronic CSR will be e-published (hyperlink, bookmarks, etc.) 
including all appendices according to ICH Guidelines.
The summary of the CSR will be sent to all the Investigators participating in the clinical trial.
17.3
Protocol Amendments
Modifications of the original protocol are referred to as “amendments” to the trial protocol. 
Modifications of the original protocol may only be made with Almirall approval. Two types of 
amendment maybe produced:
x Substantial Amendments (related to the safety or physical or mental integrity of the patients, 
scientific value of the trial, conduct or management of the trial or the quality or safety of 
any IMP used) must be notified to the IRB and/or Competent Authorities and approved by 
them before implementation.
x Non-substantial Amendments do not require notification but should be recorded and be 
available on request for inspection at the trial site and/or Sponsor premises as appropriate.
17.4
Protocol Deviations
Any protocol deviations during the conduct of the trial will be recorded by the CRA/Monitors
as detected or derived from data collected in the clinical database. 
Relevant deviations will be promptly reported to Almirall after detection. Major protocol 
deviations will be included in the corresponding listing of the CSR.
Additionally, protocol deviations will be reported to the IRBs/IECs and/or Competent 
Authorities according to the local regulation in each country.
18
References
Burton KA, Ashack KA, Khachemoune A. Cutaneous squamous cell carcinoma: A review of 
high-risk and metastatic disease. Am J Clin Dermatol. 2016;17(5):491-508.


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de Berker D, McGregor JM, Mohd Mustapa MF, et al. British Association of Dermatologists’ 
guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol. 2017;176(1):20-
43.
Dirschka T, Pellacani G, Micali G, et al. A proposed scoring system for assessing the severity 
of actinic keratosis on the head: actinic keratosis area and severity index. J Eur Acad Dermatol 
Venereol. 2017 Aug;31(8):1295-1302.
Dodds A, Chia A, Shumack S. Actinic keratosis: rationale and management. Dermatol Ther 
(Heidelb). 2014 Jun;4(1):11-31.
Dziunycz PJ, Schuller E, Hofbauer GFL. Prevalence of actinic keratosis in patients attending 
general practitioners in Switzerland. Dermatology. 2018;234(5-6):214-19.
Eder J, Prillinger K, Korn A, et al. Prevalence of actinic keratosis among dermatology 
outpatients in Austria. Br J Dermatol. 2014;171(6):1415-21.
Fargnoli MC, Altomare G, Benati E, et al. Prevalence and risk factors of actinic keratosis in 
patients attending Italian dermatology clinics. Eur J Dermatol. 2017 Dec 1;27(6):599-608.
Fernandez Figueras MT. From actinic keratosis to squamous cell carcinoma: pathophysiology 
revisited. J Eur Acad Dermatol Venereol. 2017;31(2):5-7.
Ferrándiz C, Plazas MJ, Sabaté M, et al. Prevalence of actinic keratosis among dermatology 
outpatients in Spain. Actas Dermosifiliogr. 2016;107(8):674-80.
Figueras Nart I, Cerio R, Dirschka T, et al. Defining the actinic keratosis field: a literature 
review and discussion. J Eur Acad Dermatol Venereol. 2018;32(4):544-63.
Flohil SC, van der Leest RJ, Dowlatshahi EA, et al. Prevalence of actinic keratosis and its risk 
factors in the general population: the Rotterdam Study. J Invest Dermatol. 2013 
Aug;133(8):1971-8.
Green AC, Olsen CM. Cutaneous squamous cell carcinoma: an epidemiological review. Br J 
Dermatol. 2017;177(2):373-81.
Goldenberg G. Treatment considerations in actinic keratosis. J Eur Acad Dermatol Venereol. 
2017 Mar;31 Suppl 2:12-16.
Hofbauer G, Anliker M, Boehncke WH, et al. Swiss clinical practice guidelines on field 
cancerization of the skin. Swiss Med Wkly. 2014;144:w14026.
Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): 
S3-Leitlinie Aktinische Keratose und Plattenepithelkarzinom der Haut, Kurzversion 1.0, 2019, 
AWMF Registernummer: 032/022OL. Available at: https://www.leitlinienprogramm-
onkologie.de/leitlinien/aktinische-keratose-und-plattenepithelkarzinom-der-haut/ 
[Accessed 
on: 02-Dec-2019].
Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell 
carcinoma. Lancet. 1988;1(8589):795-7.
Que SKT, Zwald FO, Schmults CD. Cutaneous squamous cell carcinoma: Incidence, risk 
factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78 (2):237-47.
Röwert-Huber J, Patel MJ, Forschner T, Ulrich C, Eberle J, Kerl H, et al. Actinic keratosis is 
an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol. 2007 
May;156 Suppl 3:8-12.
Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad 
Dermatol. 2000 Jan;42(1 Pt 2):4-7.


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Savary J, Tine MC, Weber AC, Dorey J. Management and clinical practice of multiple face 
and scalp actinic keratosis in France. J Mark Access Health Policy. 2019 May 14;7(1):1605787.
Tizek L, Schielein MC, Seifert F, et al. Skin diseases are more common than we think: 
screening results of an unreferred population at the Munich Oktoberfest. J Eur Acad Dermatol 
Venereol. 2019;33(7):1421-8.
Werner RN, Sammain A, Erdmann R, et al. The natural history of actinic keratosis: a systematic 
review. Br J Dermatol. 2013;169(3):502-18.
Werner RN, Stockfleth E, Connolly SM, Correia O, Erdmann R, Foley P, et al. Evidence- and 
consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League 
of Dermatological Societies in cooperation with the European Dermatology Forum - Short 
version. J Eur Acad Dermatol Venereol. 2015 Nov;29(11):2069-79.
World Medical Association. World Medical Association Declaration of Helsinki: ethical 
principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-
4.
19
Appendices
1. Highly Effective Methods of Birth Control
2. Patch test for the Assessment of Contact Dermatitis


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Appendix 1, Highly Effective Methods of Birth Control
Highly effective methods or birth control (ref. CTFG 2014 guidance document):
x
Intrauterine device, intrauterine hormone-releasing system or bilateral tubal occlusion 
or ligation (1)
x
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal or transdermal)
x
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable (1))
x
Vasectomized partner (2). Female patient must agree to implement one of the other 
highly effective methods of birth control if her lifestyle/partner changes
x
Sexual abstinence (3)
Notes
(1) Low user dependency methods from at least 3 months before trial screening
(2) Only provided that partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomized partner has received medical assessment of the surgical success.
(3) Only if defined as refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments (from Day1 to at least 30 days after the last dose of the investigations product).


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Appendix 2, Patch Test for the Assessment of Contact Dermatitis
In the event the patient experiences a skin reaction of such nature or severity that an allergic 
contact dermatitis is suspected, the patient can be treated with topical treatment with 
corticosteroids (eg, betamethasone) and oral antihistamines and should temporally discontinue 
the study medication. The event should be documented as an adverse event and the medication 
given recorded. The patient should be re-challenged using the assigned study medication (patch 
test in the back) to confirm or rule out contact dermatitis. If the diagnosis of allergic contact 
dermatitis is confirmed the patient may have an additional patch test with both the tirbanibulin-
containing ointment and the vehicle base.
The patch test will be performed at least 2 weeks after last treatment or discontinuation of the 
study medication. Patches will be applied to untreated areas on the back for 48 hours. Readings 
will be performed approximately 15 to 30 minutes and 48 hours following the removal of the 
patches. At the investigator’s discretion, a facultative additional reading might be performed at 
96 or 120 hours after removal of the patches if an equivocal reaction is observed at the previous 
reading. If allergic contact dermatitis is confirmed the patient will discontinue permanently the 
study medication, on the contrary the patient can be treated with the study medication if 
necessary.


ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
eDMS R&D Object_ID: 
$3KDVH0XOWLFHQWHU2SHQODEHO6LQJOHDUP6WXG\WR(YDOXDWH
WKH6DIHW\DQG7ROHUDELOLW\RI7LUEDQLEXOLQ2LQWPHQW$SSOLHG
WRD)LHOGRI$SSUR[LPDWHO\FPRQWKH)DFHRU%DOGLQJ6FDOS
LQ$GXOW3DWLHQWVZLWK$FWLQLF.HUDWRVLV
&OLQLFDO$SSURYDO
-DQ*07
&OLQLFDO$SSURYDO
-DQ*07
&OLQLFDO6WDWLVWLFV$SSURYDO
-DQ*07
PPD
PPD
PPD
CCI


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ALMIRALL, S.A.
Clinical Trial Protocol M-14867-32
Clinical Trial Protocol Title:
A Phase 3, Multicenter, Open-label, Single-arm
Study to Evaluate the Safety and Tolerability of 
Tirbanibulin Ointment 1% Applied to a Field of 
Approximately 100 cm2 on the Face or Balding Scalp 
in Adult Patients with Actinic Keratosis
Investigational Medicinal 
Product(s):
Tirbanibulin ointment 1% (Klisyri®)
Indication:
Actinic keratosis (AK)
Development Phase:
Phase 3
Final Protocol Version Date:
Version 2.0, 21 March 2022
Amendment(s)
Number:
1
Date:
N/A
IND Number:
122464
Sponsor:
Almirall, S.A.
Ronda General Mitre, 151
08022 Barcelona, Spain
This document is confidential. It contains proprietary information of Almirall, S.A. 
that may not be used, divulged, published, or disclosed without the prior consent of 
Almirall, S.A.


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Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date                 Description of changes
Rationale
Clinical 
Trial 
Protocol 
final
Version 
1.0
23-Jan-2022
Initial version 
Not applicable
Clinical 
Trial 
Protocol 
final
Version 
2.0
21-Mar-2022
Section 1 Protocol Synopsis 
Table 
1 
Schedule 
of 
Assessments
The footnote: j “Patients will 
complete a diary (Study 
App) to record daily dates 
and times of study treatment 
application. 
The 
diary 
(Study App) will be checked 
by 
the 
Investigator 
(or 
designee) at Visit 5.” has 
been updated to replace 
“Visit 5” by “Visit 3”.
This text has been updated to 
correct a typographical error.
Section 
8.2 
Inclusion 
Criteria Number 4 has been 
added:
“4.
Sexually 
active 
males with partners who are 
WOCBP must agree to use 
two forms of contraception, 
one of which must be barrier 
contraception, 
from 
Screening through 90 days 
after their last dose of study 
treatment. All male patients 
must agree not to donate 
sperm or attempt conception 
from Screening through 90 
days following their last 
dose of study treatment.”
This section was updated to add  
language 
regarding 
birth 
control measures for males and 
their female partners and sperm 
donation.


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Sponsor Signatures
Clinical Trial Protocol Title:
A Phase 3, Multicenter, Open-label, Single-arm 
Study to Evaluate the Safety and Tolerability of 
Tirbanibulin Ointment 1% Applied to a Field of 
Approximately 100 cm2 on the Face or Balding Scalp 
in Adult Patients with Actinic Keratosis
Trial Code:
M-14867-32
The individuals signing this clinical trial protocol declare that they have reviewed it for 
completeness, accuracy. They are responsible for the trial and agree to conduct it in adherence 
to the present document, any amendments, to International Council for Harmonisation (ICH)
Good Clinical Practices (GCP) guidelines, and to local regulatory requirements, wherever 
applicable.
Sponsor
Almirall, S.A.
Ronda General Mitre, 151
08022 Barcelona, Spain
Functional Role
Name
Signature
Date
This document was electronically signed in the eDMS R&D system.
Manifestation of the e-signatures are available at the end of this document which are the equivalent 
of handwritten signatures, in compliance with 21CFR Part 11
PPD
PPD
PPD
PPD
PPD
PPD


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Principal Investigator Signature
Clinical Trial Protocol Title:
A Phase 3, Multicenter, Open-label, Single-arm
Study to Evaluate the Safety and Tolerability of 
Tirbanibulin Ointment 1% Applied to a Field of 
Approximately 100 cm2 on the Face or Balding Scalp 
in Adult Patients with Actinic Keratosis
Trial Code:
M-14867-32
The individual signing this clinical trial protocol declares that he/she has reviewed it for 
completeness, accuracy. He/she is responsible for the trial and agrees to conduct it in adherence 
to the present document, any amendments, to International Council for Harmonisation (ICH) 
Good Clinical Practices (GCP) guidelines, and to local regulatory requirements, wherever 
applicable.
Principal Investigator
Role
Name
Signature
Date
Principal 
Investigator


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1
Protocol Synopsis
Title:
A Phase 3, Multicenter, Open-label, Single-arm Study to Evaluate the Safety and Tolerability 
of Tirbanibulin Ointment 1% Applied to a Field of Approximately 100 cm2 on the Face or 
Balding Scalp in Adult Patients with Actinic Keratosis
Investigators:
A Principal Investigator will be designated at each participating clinical trial center and a 
Coordinating Investigator will be nominated among the participating sites. The name, address, 
and affiliation of each Principal Investigator and the Coordinating Investigator will be detailed 
in the final clinical study report (CSR).
Trial Center(s):
The trial is planned to be conducted at approximately 20 centers in the United States (US).
Trial Duration:
The duration of the entire study from first patient, first visit to last patient, last visit is 
anticipated to be approximately 8 months.
Phase of Development:
This is a Phase 3 trial.
Rationale:
Tirbanibulin is an antiproliferative agent that causes cell cycle arrest and apoptosis. In two 
well-controlled Phase 3 clinical trials, tirbanibulin ointment 1% was demonstrated to be an 
effective and safe treatment for actinic keratosis (AK) of the face or balding scalp, when applied 
topically once daily for 5 consecutive days to a field of 25 cm2 containing 4 to 8 clinically 
typical, visible, and discrete AK lesions.
On the basis of the Phase 3 trial results, tirbanibulin ointment 1% was approved in the US and 
Europe for the topical treatment of AK on the face or scalp, over a field up to 25 cm2. However, 
AK often affects larger areas of ultraviolet (UV) light-damaged skin; thus, there is a need for a 
product to treat AK patients with affected fields larger than 25 cm2.
This study will assess the safety and tolerability of tirbanibulin ointment 1% administered 
under the same posology (once daily for 5 days) to a field of approximately 100 cm2 on the 
face or balding scalp containing 4 to 12 clinically typical, visible, and discrete AK lesions.
Objectives:
The primary objective is to evaluate the safety and tolerability of tirbanibulin ointment 1% 
when applied to a field of approximately 100 cm2 on the face or balding scalp.
Additionally, the treatment effect of tirbanibulin ointment 1% when applied to a field of 
approximately 100 cm2 on the face or balding scalp will be explored.


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Trial Design:
This is a Phase 3 multicenter, open-label, single-arm trial to evaluate safety and local 
tolerability of tirbanibulin ointment 1% administered topically for 5 days over a field of 
approximately 100 cm2 on the face or balding scalp in adult patients with AK.
The study consists of a 4-week (28-day) Screening Period, a 5-day Treatment Period, and a
Response Assessment Period of approximately 7 weeks (see Table 1, Schedule of 
Assessments):
x During the Treatment Period, patients will apply tirbanibulin ointment 1% once daily for 
5 days beginning on Day 1.
x All patients will be evaluated for safety, tolerability, and the presence of AK lesions in the 
treatment field (TF) until completion of the Response Assessment Period at Day 57.
Number of Patients:
Approximately 125 patients will be screened to initiate treatment in approximately 
100 patients.
Trial Population:
Male and female AK patients, aged 18 years or older, having 4 to 12 clinically typical, visible, 
and discrete AK lesions over a field of approximately 100 cm2 on the face or the balding scalp. 
A minimum of 50% of patients will be older than 65 years old and approximately two-thirds 
of the patients will be treated for AK lesions on the face and one-third on the scalp.
Test Investigational Medicinal Product, Dosage, and Mode of Administration:
Substance code/name:
Tirbanibulin
Administration route:
Topical
Strength:
1%
Dosage form:
Ointment
Tirbanibulin ointment 1% will be applied once daily for one 5-day treatment course. On Day 1, 
treatment application will occur at the investigational site in the morning under the supervision 
of clinical trial site staff. Between Days 2 and 5, the treatment will be self-administered once
daily at home.
Reference Investigational Medicinal Product, Dosage, and Mode of Administration:
Not applicable. No control arm will be included in this study.
Methodology:
Study visits and assessments will be performed in accordance with the Schedule of 
Assessments (Table 1).
Duration of Treatment:
The duration of each patient’s treatment is 5 days.


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Duration of Patients’ Participation in the Trial:
The total duration of each patient’s participation in the trial, including screening, treatment, 
and response assessment is estimated to be approximately 3 months.
Statistical Methods
Sample Size Calculation
With 100 patients and assuming an expected percentage of patients with at least one local 
tolerability sign of approximately 90%, the precision in the estimation of that percentage will 
be approximately 11%. The precision is defined as the width of the 95% confidence interval.
Furthermore, 100 patients will provide approximately 10% and 13% precision in the estimation 
of the percentage of patients with the local tolerability events of particular interest, specifically 
vesiculation/pustulation (assuming an expected percentage of 8%) and erosion/ulceration 
(assuming an expected percentage of 12%), respectively.
Endpoints
Safety Endpoints
x Local Tolerability Assessment:
o Local tolerability score by visit (0-3) for each individual sign (erythema, flaking/scaling, 
crusting, swelling, vesiculation/pustulation, and erosion/ulceration)
o Maximum local tolerability score post baseline through all the visits for each individual 
sign
o Time to maximum local tolerability score for each individual sign
o Local tolerability signs composite score (0-18) by visit, defined as the sum of the scores 
graded from 0 to 3 on all six individual tolerability sign categories
o Maximum local tolerability signs composite score post baseline through all the visits
o Time to maximum local tolerability composite score
o Pigmentation and scarring in the TF through all the visits
x Treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events 
(TESAEs), adverse events of special interest (AESIs), clinical laboratory data, and other 
safety assessments (vital signs, physical examinations [PEs], electrocardiograms [ECGs])
Exploratory Endpoints
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count from total lesions in the TF at each visit
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count, for lesions that were already present at baseline, from total lesions in the TF at each
visit
x Absolute number and percent change of new lesions from total lesions in the TF at each visit


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Statistical Analysis
All analyses will be performed on the Safety population, defined as all patients who have 
received at least one dose of study treatment.
Safety Endpoints
Descriptive statistics will be provided for all safety endpoints.
Local tolerability signs composite score, and specific local tolerability scores will be analyzed 
by means of descriptive statistics and provided by visit. The maximum local tolerability scores
and maximum local tolerability composite score will be presented. The number and percentage 
of patients with hypo- or hyperpigmentation and scarring in the TF will be presented separately 
by visit as well as the number and percentage of patients with changes from baseline in 
pigmentation and scarring in the TF.
TEAEs and TESAEs recorded during the study will be presented, including the total number 
of events and the number and percentage of patients with events. Summaries of the number 
and percentage of patients with TEAEs (and number and percentage of events), study drug-
related TEAEs, TEAEs by severity, TESAEs, TESAEs with an outcome of death, and TEAEs 
leading to temporary or definite discontinuation of the study treatment will be provided. 
Specific tables describing AESIs will be also provided. The number and percentage of patients 
who experience one or more AESI will be tabulated by AESI.
For PEs, ECGs, vital signs, and clinical laboratory parameters, the number and percentage of 
patients with normal or abnormal results will be presented at scheduled visits. Descriptive 
statistics for continuous variables will be provided at scheduled visits together with a summary 
of changes from baseline for each parameter. Shift tables will be provided when appropriate.
Exploratory Endpoints
Descriptive statistics will be provided for exploratory endpoints overall and by subgroups:  age
(<65 and ≥65), gender (male/female), number of lesions at baseline (≤8 and >8), treatment 
location (face/scalp), history of skin cancer (yes/no), and Fitzpatrick skin type (I/II and 
III/IV/V/IV).
Interim Analysis
No interim analysis is planned for this trial.






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h All patients who have unresolved local tolerability signs, hypo- or hyper-pigmentation, scarring in the TF, or treatment-related AEs at Day 57 will return for additional follow-up every 7 to 28 
days until these have resolved, have returned to the baseline value, or are deemed stabilized by the Investigators.
i Measurement of vital signs will include blood pressure, heart rate, respiratory rate, and body temperature. Measurements of systolic and diastolic blood pressure will be performed after at least 
5 minutes of rest in a supine position and preferably on the same arm.
j Patients will complete a diary (Study App) to record daily dates and times of study treatment application. The diary (Study App) will be checked by the Investigator (or designee) at Visit 3.
k TF identification (face/scalp)
l Baseline photo is only required in case of any significant change from Screening is detected in the TF as per the Investigator judgement or if the quality of the image captured at Screening is 
not appropriate. If no photo is needed at baseline, then the screening photo will be considered the baseline assessment.
m Study drug will be applied by the subject at home before study Visit 3 on Day 5, which will take place at the clinical site.


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2
Table of Contents
Protocol Amendment Summary of Changes............................................................................2
Sponsor Signatures ...................................................................................................................3
Principal Investigator Signature ..............................................................................................4
1
Protocol Synopsis.................................................................................................5
2
Table of Contents ...............................................................................................12
Table of Tables........................................................................................................................15
3
List of Abbreviations..........................................................................................16
4
Sponsor, Investigator(s) and Trial Administrative Structure...........................18
4.1
Sponsor..........................................................................................................................18
4.2
Investigator(s)...............................................................................................................18
4.3
Administrative Structure.............................................................................................18
5
Introduction........................................................................................................18
5.1
Background Information.............................................................................................18
5.1.1
Indication......................................................................................................................................18
5.1.2
Unmet Medical Need....................................................................................................................19
5.1.3
Mechanism of Action....................................................................................................................19
5.1.5
Clinical Studies.............................................................................................................................20
5.2
Summary of the Known Potential Risks and Benefits..............................................21
5.3
Scientific Rationale for the Trial ................................................................................22
6
Objectives and Endpoints...................................................................................22
6.1
Objectives......................................................................................................................22
6.2
Endpoints......................................................................................................................22
6.2.1
Safety Endpoints...........................................................................................................................22
6.2.2
Exploratory Endpoints ..................................................................................................................23
7
Trial Design and Rationale................................................................................23
7.1
Trial Design ..................................................................................................................23
7.2
Trial Rationale..............................................................................................................23
7.2.1
Rationale for Trial Design ............................................................................................................23
7.2.2
Rationale for Trial Population ......................................................................................................24
7.2.3
Rationale for Trial Dose and Regimen .........................................................................................24
7.2.4
Rationale for Trial Assessments ...................................................................................................24
8
Selection of Trial Population and Withdrawal of Patients ..............................25
8.1
Number of Patients ......................................................................................................25
8.2
Inclusion Criteria .........................................................................................................25
8.3
Exclusion Criteria ........................................................................................................25
8.4
Treatment Discontinuation Criteria...........................................................................27
8.5
Trial Withdrawal Criteria...........................................................................................28
8.6
Screening Failures........................................................................................................28
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8.7
Patient Replacement Criteria......................................................................................28
8.8
Termination of the Trial..............................................................................................29
8.8.1
End of Trial Definition .................................................................................................................29
8.8.2
Completed Patient Definition .......................................................................................................29
8.8.3
Premature Trial Termination.........................................................................................................29
9
Treatments..........................................................................................................29
9.1
Identity of Trial Investigational Medicinal Products................................................29
9.2
Packaging and Labelling .............................................................................................30
9.3
Shipment, Storage, and Accountability......................................................................30
9.4
Treatment Administration ..........................................................................................31
9.5
Treatment Compliance................................................................................................31
9.6
Methods for Assigning Patients to Treatment Groups.............................................32
9.6.1
Patient Identification.....................................................................................................................32
9.6.2
Randomization..............................................................................................................................32
9.7
Blinding.........................................................................................................................32
9.8
Unblinding by the Investigator ...................................................................................32
9.9
Pre-trial, Concomitant, and Post-trial Medications/Therapy..................................32
9.9.1
Pre-trial Medications.....................................................................................................................32
9.9.2
Concomitant Medications.............................................................................................................33
9.9.3
Prohibited Concomitant Medications............................................................................................33
9.9.4
Post-trial Medications...................................................................................................................33
10
Trial Procedures and Assessments....................................................................34
10.1
General Conditions of the Trial..................................................................................34
10.2
Patient’s General Conditions During the Trial .........................................................34
10.3
Scheduled Activities and Trial Visits..........................................................................35
10.3.1
Screening Period...........................................................................................................................35
10.3.2
Response Assessment Period........................................................................................................37
10.3.3
Unscheduled and Repeated Tests..................................................................................................37
10.4
Lesion Assessments ......................................................................................................37
10.5
Safety and Tolerability Assessments ..........................................................................38
10.5.1
Adverse Events.............................................................................................................................38
10.5.2
Focused Dermatological Examination of the Treatment Field .....................................................39
10.5.3
Physical Examinations and Vital Signs ........................................................................................40
10.5.4
Electrocardiograms.......................................................................................................................40
10.5.5
Laboratory Testing........................................................................................................................40
10.6
Other .............................................................................................................................41
10.7
Adverse Events.............................................................................................................41
10.7.1
Definitions ....................................................................................................................................41
10.7.2
Reporting of Adverse Events........................................................................................................42
10.7.3
Recording of Adverse Events .......................................................................................................43
10.7.4
Reporting of Serious Adverse Events and Adverse Events of Special Interest ............................44
10.7.5
Follow-up of Adverse Events / Serious Adverse Events ..............................................................45
10.8
Pregnancies...................................................................................................................45
10.9
Unblinding for Safety Reasons....................................................................................46
11
Statistics..............................................................................................................46


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11.1
Sample Size Calculation ..............................................................................................46
11.2
Structure and Methodology of the Statistical Analysis.............................................46
11.3
Analysis Populations....................................................................................................47
11.4
Descriptive Statistics....................................................................................................47
11.5
Demographics and Baseline Characteristics..............................................................47
11.6
Study and Treatment Compliance..............................................................................47
11.7
Prior and Concomitant Medications ..........................................................................47
11.8
Statistical Methods.......................................................................................................47
11.8.1
Analysis of Safety Endpoints........................................................................................................47
11.8.2
Analysis of Exploratory Endpoints...............................................................................................48
11.9
Handling of Missing Data............................................................................................48
11.10
Multiplicity Strategy....................................................................................................48
11.11
Subgroup Analyses.......................................................................................................48
11.12
Interim Analysis ...........................................................................................................48
12
Data Handling, Processing, and Record Keeping ............................................48
12.1
Data Collection.............................................................................................................49
12.1.1
Identification of the Trial Data Sources........................................................................................49
12.1.2
Electronic Case Report Forms ......................................................................................................49
12.1.3
Patient Diary .................................................................................................................................51
12.2
Data Management and Quality Control ....................................................................51
12.3
Investigator and Trial Master Files............................................................................52
12.4
Documents and Record Keeping.................................................................................52
13
Quality Control and Quality Assurance............................................................53
13.1
Training of Staff...........................................................................................................53
13.2
Monitoring....................................................................................................................53
13.3
Inspections and Audits.................................................................................................54
14
Ethics..................................................................................................................54
14.1
Responsibilities.............................................................................................................54
14.2
Patient Information and Informed Consent..............................................................54
14.3
Institutional Review Board/Independent Ethics Committee....................................55
14.4
Patient Data Protection................................................................................................56
15
Financing and Insurance..................................................................................56
16
Publication Policy ..............................................................................................56
17
Other Practical Considerations .........................................................................57
17.1
Investigator’s Brochure...............................................................................................57
17.2
Final Clinical Trial Report..........................................................................................57
17.3
Protocol Amendments..................................................................................................57
17.4
Protocol Deviations ......................................................................................................57
18
References ..........................................................................................................58


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19
Appendices..........................................................................................................59
Appendix 1, Highly Effective Methods of Birth Control.......................................................60
Appendix 2, Patch Test for the Assessment of Contact Dermatitis.......................................61
Table of Tables
Table 1
Schedule of Assessments......................................................................................9
Table 2
Fitzpatrick Skin Type.........................................................................................35
Table 3
Local Tolerability Signs and Grading Scale.....................................................39
Table 4
Laboratory Testing Parameters.........................................................................40


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3
List of Abbreviations
AE
Adverse event
AESI
Adverse event of special interest
AK
Actinic keratosis
ALCOA
Attributable, legible, contemporaneous, original, and accurate
BCC
Basal cell carcinoma
CDISC
Clinical Data Interchange Standards Consortium
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease 2019
CRA
Clinical Research Associate
CRO
Clinical Research Organization
CROOP
Clinical Research Organization Oversight Plan
CSR
Clinical Study Report
DMP
Data Management Plan
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EoS
End of Study
ET
Early termination
eTMF
Electronic Trial Master File
FDA
Food & Drug Administration (United States)
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MUsT
Maximum usage trial
OTC
Over-the-counter
PDF
Portable document format
PE
Physical examination
PIS
Patient Information Sheet
PK
Pharmacokinetic
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SCC
Squamous cell carcinoma


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SOP
Standard Operating Procedure
TEAE
Treatment-emergent adverse event
TESAE
Treatment-emergent serious adverse event
TF
Treatment field
TMF
Trial Master File
US
United States
UV
Ultraviolet
WOCBP
Women of child-bearing potential


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4
Sponsor, 
Investigator(s) 
and 
Trial 
Administrative 
Structure
4.1
Sponsor
Almirall, S.A. (Legal entity)
General Mitre, 151
08022 Barcelona, Spain
Almirall Research and Development Centre:
Laureà Miró, 408-410
08980 Sant Feliu de Llobregat
Barcelona, Spain
4.2
Investigator(s)
A Principal Investigator will be designated at each participating clinical trial center and a 
Coordinating Investigator will be nominated among the participating sites.  The name, address, 
and affiliation of each Principal Investigator and the Coordinating Investigator will be detailed 
in the final clinical study report (CSR).
4.3
Administrative Structure
Medical Expert appointed by the Sponsor for this trial:
, MD, PhD
Almirall Research and Development Centre
Laureà Miró, 408-410
08980 Sant Feliu de Llobregat
Barcelona, Spain
Telephone: 
Email: 
This study will be conducted by a Contract Research Organization (CRO) on behalf of the 
Sponsor; the Sponsor will maintain oversight of the CRO. Refer to the CRO Oversight Plan 
(CROOP) for details and see Section 10.7.4 for Serious Adverse Event (SAE) and Adverse 
Event of Special Interest (AESI) reporting.
5
Introduction
A summary on the indication, mechanism of action, and completed nonclinical and clinical 
studies is provided below. A detailed description of the chemistry, pharmacology, efficacy, and 
safety of tirbanibulin ointment 1% is provided in the Athenex KX2-391 (tirbanibulin) 
Investigator’s Brochure.
5.1
Background Information
5.1.1
Indication
Actinic keratosis (AK) is an ultra-violet (UV) light-induced pre-cancerous lesion of the skin 
that represents the initial clinical manifestation of intra-epidermal abnormal keratinocyte 
PPD
PPD
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proliferation (Röwert-Huber, 2007; Fernandez Figueras, 2017). Given the demonstrated 
potential for progression to invasive squamous cell carcinoma (SCC), dermatologists 
encourage and actively pursue treatment, as recommended in current national and international 
guidelines (Hofbauer, 2014; Werner, 2015; de Berker, 2017; Leitlinienprogramm Onkologie, 
2019).
Actinic keratosis presents as erythematous, scaly patches on the skin of sun-exposed areas and 
so particularly affecting the face, scalp, and extremities, either as a single lesion or multiple 
lesions and may present in as an entire field (“field cancerization”) with widespread actinic 
damage, such as in areas on the forehead or the back of the hand (Dodds, 2014; Figueras Nart, 
2018). Actinic keratosis is common in older, fair-skinned populations of European ancestry, 
and is more frequently observed in men (Flohil, 2013).
Precise estimates of AK prevalence are difficult, owing to its strong association with increased 
age. The prevalence of AK in the US has been reported to range from 11% to 26% (Salasche, 
2000). Recent studies in Europe suggest that AK prevalence there ranges from 33% to 49% for 
men and 14% to 28% for women (Eder, 2014, Tizek, 2019, Flohil, 2013, Ferrándiz, 2016,
Fargnoli, 2017, Dziunycz, 2018).
In some cases, AK represents a carcinoma in situ of the skin, and when left untreated, AK can 
progress to invasive SCC (Röwert-Huber, 2007; Werner, 2013; Fernandez Figueras, 2017).
Cutaneous SCC represents 20% to 50% of skin cancers (Que, 2018) and poses a significant 
threat due to its ability to metastasize to any organ in the body (Burton, 2016). Up to 65% of 
SCCs arise from pre-existing AK; however, the risk of progression to SCC of a single AK 
lesion per year has been reported to be very low, 0% to 0.075% in patients without a previous 
history of non-melanoma skin cancer (Marks, 1988), and up 0.53% per lesion in patients with 
a prior history of non-melanoma skin cancer (Werner, 2013; Green, 2017).
5.1.2
Unmet Medical Need
Tirbanibulin ointment 1% is approved in the US and Europe for the topical treatment of AK
on the face or scalp, over a field up to 25 cm2. However, AK often affects larger areas of UV 
light-damaged skin; thus, there is a need for a product to treat AK patients over fields larger 
than 25 cm2.
Although a limited number of AK field-directed therapies are currently available that target 
areas larger than 25 cm2, there remain unmet needs for patients with AK in terms of tolerability 
and treatment convenience/adherence. Topical therapies, such as 5-fluorouracil and 
imiquimod, frequently present safety and tolerability events during treatment that may lead to 
treatment discontinuation. While diclofenac sodium 3%, which is also used over larger fields, 
has a good safety and tolerability profile, it is administered over a longer treatment period (60 to
90 days) and drugs with shorter treatment durations are desirable, as they are associated with 
better adherence (Goldenberg, 2017). In a survey of 40 dermatologists in France, short 
treatment duration was the primary consideration in selecting a field-directed topical treatment
(Savary, 2019). Thus, there is a need in the current armamentarium for well-tolerated, short-
duration therapies targeted to areas larger than 25 cm2.
5.1.3
Mechanism of Action
Tirbanibulin has potent anti-proliferative and anti-tumor activities in vitro and in vivo by virtue 
of its ability to induce cell cycle arrest and apoptotic cell death by disrupting the cellular 


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microtubule network via direct binding to tubulins. Furthermore, it is associated with disruption 
of Src tyrosine kinase signaling.
5.1.4
Nonclinical Studies
5.1.5
Clinical Studies
The clinical development program on topical tirbanibulin includes 10 completed clinical trials 
that enrolled a total of 1338 subjects, 989 subjects who received tirbanibulin ointment 1% and 
349 subjects who received vehicle ointment. Of the 989 subjects treated with tirbanibulin 
ointment 1%, 597 were patients with AK and 392 were healthy adults.
Pharmacokinetics
Pharmacokinetic studies showed that tirbanibulin ointment 1% was minimally absorbed in 
patients with AK after topical application to 25 cm2 on the face or balding scalp once daily for 
5 consecutive days. Exposure (Cmax, AUC0-24) was higher when tirbanibulin ointment 1% was 
applied to the face versus the scalp. A proportional increase in systemic exposure (Cmax,
AUC0-24) was observed when tirbanibulin ointment 1% was applied to an area measuring 
100 cm2 on the face or balding scalp.
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Efficacy and Safety
The efficacy and safety studies included two Phase 3 double-blind, vehicle-controlled, 
randomized trials, KX01-AK-003 (N=351) and KX01-AK-004 (N=351), that were conducted 
in the US to evaluate the efficacy and safety of tirbanibulin ointment 1% compared to vehicle 
ointment in patients with AK on face or balding scalp. Tirbanibulin ointment 1% once daily 
for 5 days was effective in the treatment of AK on either the face or balding scalp, with 
statistically significantly higher rates of complete and partial clearance at Day 57 in the treated 
field as compared to control vehicle (complete clearance, 49% vs 9%, respectively). Treatment-
related adverse events (AEs) were few (16% vs 10%, respectively) and consisted of mostly 
transient mild to moderate application site pruritus and pain that required no treatment; there 
were no treatment-related SAEs. Signs assessing local tolerability were mostly mild to 
moderate erythema and flaking/scaling. Mean composite scores for local tolerability signs
peaked at Day 8 and were mostly resolved by Day 29.
The safety of treating larger AK fields (>25 cm2) was evaluated in a Phase 1, maximal usage 
trial (MUsT), in which tirbanibulin ointment 1% was applied to an area measuring 100 cm2 on
the face or balding scalp in 28 patients with AK. The most frequently reported treatment-related 
AEs were application site pruritus and application site pain. All AEs were mild or moderate in 
intensity; no severe AEs were reported. The most frequently reported local tolerability signs 
were erythema and flaking/scaling. Most local tolerability signs were mild or moderate, with 
severe erythema and flaking/scaling reported in 14.3% of patients each. Local tolerability sign 
composite scores peaked around Day 7 to 8 and were mostly resolved by Day 29.
A detailed description of the completed clinical studies is provided in the Athenex KX2-391 
Ointment 1% (tirbanibulin) Investigator’s Brochure.
5.2
Summary of the Known Potential Risks and Benefits
Actinic keratosis is a UV light–induced pre-cancerous lesion of the skin that represents the 
initial clinical manifestation of intra-epidermal abnormal keratinocyte proliferation. Given the 
demonstrated potential for progression to SCC, dermatologists generally encourage and 
actively pursue treatment, with a goal of completely eliminating AK lesions, thereby reducing 
the risk of progression to invasive SCC.
Data from the two pivotal Phase 3 studies demonstrate that treatment with tirbanibulin ointment 
1% once-daily for 5 days is effective in the treatment of AK of the face or balding scalp.
In the pivotal studies, the safety profile of tirbanibulin ointment 1% showed a low rate of 
treatment-emergent AEs and no unexpected or unanticipated safety findings. The overall 
incidence of treatment-emergent AEs (TEAEs) was similar between the tirbanibulin ointment
1% and vehicle groups, and there were no treatment-related treatment-emergent serious AEs
(TESAEs) or discontinuations due to a TEAE. There were also no long-term safety concerns 
related to tirbanibulin ointment 1% in patients followed up to 1 year after Day 57.
The most frequently reported local tolerability signs were transient, mild to moderate erythema 
and flaking/scaling. Treatment-related AEs were mostly transient, mild to moderate 
application-site pruritus or pain, and most did not require treatment.


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The safety profile of tirbanibulin ointment 1% observed in the Phase 1 maximal-use trial
M-14687-01, in which study drug was applied to 100 cm2 on the face or balding scalp, was 
consistent with that observed in the pivotal studies.
Based on the available efficacy and safety data from the completed clinical and nonclinical 
studies, the benefit-risk assessment is positive and supports the evaluation of tirbanibulin 
ointment 1% in this Phase 3 study of patients with AK of the face or scalp.
Further information regarding the nonclinical and clinical characteristics, summaries of the 
known and potential risks, as well as reasonably expected adverse reactions of the product 
under investigation, is provided in the Athenex KX2-391 (tirbanibulin) Investigator’s 
Brochure.
5.3
Scientific Rationale for the Trial
Tirbanibulin is an antiproliferative agent that causes cell cycle arrest and apoptosis. In two 
well-controlled Phase 3 clinical trials, tirbanibulin ointment 1% was demonstrated to be an 
effective and safe treatment for AK of the face or balding scalp, when applied topically once 
daily for 5 consecutive days to a field of 25 cm2 containing 4 to 8 clinically typical, visible, 
and discrete AK lesions.
On the basis of the Phase 3 trial results, tirbanibulin ointment 1% was approved in the US and 
Europe for the topical treatment of AK on the face or scalp, over a field up to 25 cm2. However, 
AK often affects larger areas of UV light-damaged skin; thus, there is a need for a product to 
treat AK patients with affected fields larger than 25 cm2.
This study will assess the safety and tolerability of tirbanibulin ointment 1% administered 
under the same posology (once daily for 5 days) to a field of approximately 100 cm2 on the 
face or balding scalp containing 4 to 12 clinically typical, visible, and discrete AK lesions.
6
Objectives and Endpoints
6.1
Objectives
The primary objective of the trial is to evaluate the safety and tolerability of tirbanibulin 
ointment 1% when applied to a field of approximately 100 cm2 on the face or balding scalp.
Additionally, the treatment effect of tirbanibulin ointment 1% when applied to a field of 
approximately 100 cm2 on the face or balding scalp will be explored.
6.2
Endpoints
6.2.1
Safety Endpoints
Safety Endpoints
x Local Tolerability Assessment:
o Local tolerability score by visit (0-3) for each individual sign (erythema, flaking/scaling, 
crusting, swelling, vesiculation/pustulation, and erosion/ulceration)
o Maximum local tolerability score post baseline through all the visits for each individual 
sign
o Time to maximum local tolerability score for each individual sign


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o Local tolerability signs composite score (0-18) by visit, defined as the sum of the scores 
graded from 0 to 3 on all six individual tolerability sign categories
o Maximum local tolerability signs composite score post baseline through all the visits
o Time to maximum local tolerability composite score
o Pigmentation and scarring in the TF through all the visits
x TEAEs, TESAEs, adverse events of special interest (AESIs), clinical laboratory data, and 
other safety assessments (vital signs, physical examinations [PEs], electrocardiograms 
[ECGs])
6.2.2
Exploratory Endpoints
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count from total lesions in the TF at each visit
x Absolute number, change from baseline, and percent change from baseline in AK lesion 
count, for lesions that were already present at baseline, from total lesions in the TF at each 
visit
x Absolute number and percent change of new lesions from total lesions in the TF at each visit
7
Trial Design and Rationale
7.1
Trial Design
This is a Phase 3 multicenter, open-label, single-arm trial to evaluate safety and local 
tolerability of tirbanibulin ointment 1% administered topically for 5 days over a field of 
approximately 100 cm2 on the face or balding scalp in adult patients with AK.
The study consists of a 4-week (28-day) Screening Period, a 5-day Treatment Period, and a
Response Assessment Period of approximately 7 weeks (see Table 1, Schedule of 
Assessments):
x During the Treatment Period, patients will apply tirbanibulin ointment 1% once daily for 
5 days beginning on Day 1.
x All patients will be evaluated for safety, tolerability, and the presence of AK lesions in the 
TF until completion of the Response Assessment Period at Day 57.
7.2
Trial Rationale
7.2.1
Rationale for Trial Design
Since tirbanibulin ointment 1% is an approved product and there is no change in the 
formulation or posology, the main objective of this study is to evaluate the safety and 
tolerability of tirbanibulin ointment 1% applied over an extended field (100 cm2) in adult 
patients with AK on the face or balding scalp.
The duration of the study considers both safety and efficacy. From a local tolerability 
perspective, most of the local signs are expected to be resolved by Day 29. However, the study 
duration is extended up to Day 57, in order to assess the treatment effect as exploratory 
endpoints.


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In addition to the overall incidence of local tolerability events, the sample size considers
detection of local tolerability signs of particular interest, specifically, vesiculation/pustulation 
and erosion/ulceration (see Section 11.1). When severe, these local tolerability signs can lead 
to permanent local events such as dyspigmentation or scarring.
7.2.2
Rationale for Trial Population
The study will be conducted in male and female AK patients, aged 18 years or older, having 
4 to 12 clinically typical, non-hypertrophic, non-hyperkeratotic, visible, and discrete AK 
lesions over a field of approximately 100 cm2 on the face or the balding scalp.
Enrollment will be controlled such that the trial population is representative of the population 
expected to use the product in terms of age and treated area. A minimum of 50% of patients 
older than 65 years old will be included and approximately two-thirds of the patients will be 
treated for AK lesions on the face and one-third on the scalp.
7.2.3
Rationale for Trial Dose and Regimen
In this study patients will be treated with tirbanibulin ointment 1% daily for 5 consecutive days 
beginning on Day 1. Treatment will be applied to a field measuring approximately 100 cm2 on
the face or balding scalp. There are no changes in treatment duration or posology. Tirbanibulin 
ointment 1% has shown effectiveness in the treatment of AK lesions and the good safety and 
tolerability profile supports the field extension to a higher area to satisfy medical needs.
In a Phase 2 trial (KX01-AK-002), efficacy and safety results of 3 and 5-day treatment 
regimens over 25 cm2 were compared. The 5-day regimen showed substantial clinical activity 
and acceptable local tolerability. The 5-day treatment regimen showed a higher proportion of
patients with 100% clearance at Day 57 compared with the 3-day regimen (43% vs 32%,
respectively), as well as a higher proportion of patients maintaining their treatment response at 
12 months (43% vs 30%, respectively). Patients in the 5-day regimen experienced slightly more 
mild/moderate erythema and flaking/scaling, but local signs were self-limited with both 
regimens and by Day 29 had essentially returned to baseline values. 
7.2.4
Rationale for Trial Assessments
In prior studies, mild to moderate erythema and flaking/scaling were the most frequently 
observed signs when assessing local tolerability. Local tolerability signs following treatment 
will be characterized and assessed throughout this study and reported separately from AEs.
Standard safety assessments will be performed throughout the study including the capture of 
AEs, SAEs, concomitant medications, laboratory testing for hematology, blood chemistry, and 
urinalysis, PEs and vital signs measures, and ECGs.
Lesion counts in the TF will be performed at Screening, Day 1/Baseline (predose), and at every 
visit from Day 5 up to Day 57 to evaluate the treatment effect of tirbanibulin ointment 1%, 
when applied to an area measuring 100 cm2 on the face or balding scalp.


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8
Selection of Trial Population and Withdrawal of Patients
8.1
Number of Patients
Approximately 125 patients will be screened to initiate treatment in approximately 
100 patients.
8.2
Inclusion Criteria
All of the following criteria must be met for inclusion of a patient in the trial:
1. Male or female and ≥18 years old at the time of consent
2. Having a TF on the face or balding scalp (excluding lips, eyelids, and inside nostrils and 
ears) that
x measures approximately 100 cm2 (eg, mid face) and
x contains 4 to 12 clinically typical, visible, and discrete AK lesions within the TF
3. If a woman of childbearing potential (WOCBP), ie, fertile, defined as a female in the life 
period from menarche and until becoming post-menopausal (no menses for 12 months 
without an alternative medical cause) or permanently sterile (with hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy at least 3 months prior to Screening), she must:
x have a negative urine pregnancy test using a highly sensitive method at screening and on 
Day 1 prior to treatment administration
x be using highly effective methods of birth control (defined in Appendix 1) for at least 
30 days or 1 menstrual cycle, whichever is longer, prior to the study treatment and must 
agree to continue use during the study period and until at least 30 days or 1 menstrual 
period, whichever is longer, after the last dose of investigational product
x agree to have pregnancy tests while in the study and at the end of the study (according to 
the Schedule of Assessments in Table 1)
4.
Sexually active males with partners who are WOCBP must agree to use two forms of 
contraception, one of which must be barrier contraception, from Screening through
90 days after their last dose of study treatment. All male patients must agree not to donate 
sperm or attempt conception from Screening through 90 days following their last dose of 
study treatment.
5. Willing to avoid excessive sunlight or UV light exposure, including the use of tanning beds, 
to the face or scalp during the study
6. Ability to understand the purpose and risks of the trial, willingness and ability to comply 
with the protocol, and provided written informed consent in accordance with institutional 
and regulatory guidelines
8.3
Exclusion Criteria
Patients will be excluded from trial enrollment if they meet any of the following criteria:
1. Presence in the TF of:
a) Clinically atypical and/or rapidly changing AK lesions in the TF


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b) Hyperkeratotic or hypertrophic lesions, recalcitrant disease (had cryosurgery on 
2 previous occasions) and/or cutaneous horn
c) Confluent AK lesions (ie, non-discrete lesions defined as per inclusion criteria)
d) History of invasive SCC, Bowen’s disease, basal cell carcinoma (BCC), or other 
malignant tumors in the TF
e) Any other dermatological disease that causes difficulty with examination
2. Location of the TF is:
x On any location other than the face or balding scalp
x Within 5 cm of an incompletely healed wound
x Within 5 cm of a suspected BCC or other neoplasia
x Periorbital, lips, or nostrils
3. Previous treatment with tirbanibulin ointment 1%.
4. Anticipated need for inpatient hospitalization or inpatient surgery from Day 1 to Day 57
5. Treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, photodynamic 
therapy, or other treatments for AK within the TF or within 2 cm of the TF, within 8 weeks 
prior to the Screening visit
6. Use of systemic retinoids (eg, isotretinoin, acitretin, bexarotene) within 6 months prior to 
the Screening visit
7. Use of the following therapies and/or medications within 4 weeks prior to the Screening 
visit:
x Cosmetic or therapeutic procedures (eg, use of liquid nitrogen, surgical excision, 
curettage, dermabrasion, medium or greater depth chemical peel, laser resurfacing) 
within the TF or within 2 cm of the selected TF
x Treatment with cytotoxic drugs (eg, cyclophosphamide, vinblastine, chlorambucil, 
methotrexate).
x Treatment with systemic medications that modulate and/or suppress the immune system 
(eg, cyclosporine, azathioprine, methotrexate, prednisone, alefacept, infliximab, 
interferons/interferon inducers).
x Therapy/treatment with UV-A or UV-B light.
8. Use of the following therapies and/or medications within 2 weeks prior to the Screening 
visit:
x Acid-containing therapeutic products (eg, salicylic acid or fruit acids, such as alpha and 
beta-hydroxyl acids and glycolic acids), topical retinoids, or light chemical peels within 
the TF or within 2 cm of the selected TF
x Topical steroids within the TF or within 2 cm of the selected TF
x Artificial tanners within the TF or within 5 cm of the selected TF
9. A history of sensitivity and/or allergy to any of the ingredients in the study medication


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10. Patients with significant abnormalities on the medical history, PE findings, vital signs, 
ECG, clinical chemistry, hematology, and urinalysis results that in the judgment of the 
Investigator may interfere with the interpretation of the results.
11. A skin disease (eg, atopic dermatitis, psoriasis, seborrheic dermatitis, eczema) or condition 
(eg, scarring, open wounds) that, in the opinion of the Investigator, might interfere with the 
study conduct or evaluations, or which exposes the patient to unacceptable risk by study 
participation
12. Significant uncontrolled or unstable medical diseases or conditions that, in the opinion of 
the Investigator, would expose the patient to unacceptable risk by study participation
13. Females who are pregnant or nursing or seeking to become pregnant
14. Participated in an investigational drug trial during which an investigational study 
medication was administered within 30 days or 5 half-lives of the investigational product, 
whichever is longer, before dosing in the current study
15. Patient who is employee or relative to employees at the research site or Almirall
8.4
Treatment Discontinuation Criteria
Any patient may discontinue from study treatment at any time during the trial at the discretion 
of the Investigator or at the request of the patient. For patients who discontinue treatment, 
efforts should be made to encourage the patient to remain in the trial and complete the trial-
related assessments. The main reason for such a premature treatment discontinuation must be 
documented in the electronic case report form (eCRF), as follows:
x Adverse event: If a patient experiences an AE, treatment discontinuation will be at the 
discretion of either the Investigator or the patient regardless of the causal relationship to the 
investigational medical product (IMP).
x Protocol deviation: Any protocol deviation detected should be corrected when possible and 
the patient should be allowed to continue. ONLY the following deviations should lead to 
treatment discontinuation: those which could affect patient's safety (eg, illness requiring 
treatment(s) which in the clinical judgement of the Investigator [or after discussion with the 
trial monitor] might invalidate the trial by interfering with the IMP) or which are due to 
patient unwillingness to comply with the trial activities or those violations of inclusion 
and/or exclusion criteria detected
x Lost to follow-up: Non-attendance. In these cases, every effort should be made by the 
Investigator to ascertain the reason and to assure patient’s attendance as soon as possible. 
Every effort (at least three documented attempts) should be made to contact the patient and 
documented in the medical records. If patient cannot be reached after that, a registered mail 
letter will be sent to the patient and documented in the medical records
x Patient's personal request: The patient is permitted to stop his/her treatment at any time 
during the trial without incurring any loss in his/her medical care. The Investigator should 
ensure that such discontinuation is not due to an AE or disease exacerbation, in which case 
the corresponding reason should be recorded
x Pregnancy


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8.5
Trial Withdrawal Criteria
Any patient may withdraw from the trial at any time during the trial at the discretion of the 
Investigator or at the request of the patient. The main reason for such a premature study 
withdrawal must be documented in the eCRF, as follows:
x Adverse event: If a patient experiences an AE, study withdrawal will be at the discretion of 
either the Investigator or the patient regardless of the causal relationship to the IMP.
x Death
x Protocol deviation: Any protocol deviation detected should be corrected when possible and 
the patient should be allowed to continue. ONLY the following deviations should lead to 
patient withdrawal: those which could affect patient's safety (eg, illness requiring 
treatment(s) which in the clinical judgement of the Investigator [or after discussion with the 
trial monitor might invalidate the trial by interfering with the IMP) or which are due to 
patient unwillingness to comply with the trial activities or those violations of inclusion 
and/or exclusion criteria detected
x Lost to follow-up: Non-attendance. In these cases, every effort should be made by the 
Investigator to ascertain the reason and to assure patient’s attendance as soon as possible. 
Every effort (at least three documented attempts) should be made to contact the patient and 
documented in the medical records. If patient cannot be reached after that, a registered mail 
letter will be sent to the patient and documented in the medical records
x Patient's personal request: The patient is permitted to stop his/her participation at any time 
during the trial without incurring any loss in his/her medical care. The Investigator should 
ensure that such withdrawal is not due to an AE or disease exacerbation, in which case the 
corresponding reason should be selected
x Trial terminated by Sponsor
8.6
Screening Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently treated in the study. A minimal set of screen failure information is required 
to be entered into the database to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from Competent Authorities. Minimal information includes 
demography, screen failure reason, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this trial (screen failures) will not 
be rescreened.
8.7
Patient Replacement Criteria 
Patients who withdraw from the trial at any time will not be replaced.


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8.8
Termination of the Trial
8.8.1
End of Trial Definition
The “end of trial” is defined as the date of the last visit of the last patient, either at Day 57 or
earlier, if the last patient discontinues prematurely. The end of trial will be communicated to
the Competent Authorities and Institutional Review Boards (IRBs) / Independent Ethics 
Committees (IECs) according to local regulations.
8.8.2
Completed Patient Definition
Patients who complete all the phases of the study, including the last visit as described in the 
Schedule of Assessments (Table 1), will be considered to be completed patients.
8.8.3
Premature Trial Termination
Almirall reserves the right to prematurely terminate (ie, suspend) the trial. 
Certain circumstances may require the premature termination of the trial including:
x The Investigator/Coordinating Investigator and the Sponsor feel that the type, number, 
and/or severity of AEs justify discontinuation of the trial.
x The Sponsor considers the applied doses of the trial drug to be no longer relevant.
x Data not known before becoming available and that raise concerns about the safety of the 
trial drug so that continuation would pose potential risks to the patient
If the trial is terminated or suspended, the Sponsor/CRO will promptly inform the Investigators. 
The IRBs/IECs should be promptly informed and provided the reason(s) for the termination or 
suspension by the Investigator, as specified by the applicable regulatory requirement(s).
The Investigator will inform the patients and will collect and keep all the data up to the date of 
discontinuation. Samples retrieved up to the date of trial termination will be analyzed as per 
protocol.
If the trial is prematurely terminated or suspended, trial results will be reported according to 
the requirements outlined in this protocol, as far as applicable.
The Clinical Data Interchange Standards Consortium (CDISC) criteria should be followed 
while recording the patient trial discontinuation reasons.
9
Treatments
9.1
Identity of Trial Investigational Medicinal Products
Investigational medicinal product manufacturing, labelling, packaging, and release will be 
done following Good Manufacturing Practice (GMP). 
Tirbanibulin is a white to off-white ointment containing tirbanibulin freebase active drug
substance. For a full product description, refer to the KX2-391 Ointment 1% (tirbanibulin) 
Investigator’s Brochure.


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Test Investigational Medicinal Product
Substance Code/Name
Tirbanibulin
Route of Administration
Topical
Dosage Form
Ointment
Strength
1%
Reference Investigational Medicinal Product
This is single arm study; no reference IMP will be used.
9.2
Packaging and Labelling
Study drug will be packed and labeled in accordance with local regulations by the Sponsor 
according to GMP conditions, including but not limited to the Sponsor contact details, protocol 
number, drug identification, storage conditions, and content of study drug. A sample label will 
be filed in the Investigator file.
On Day 1, patients will be dispensed a study kit containing 5 zipper bags each with a single-
dose packet containing 350 mg tirbanibulin ointment 1%.
Local regulatory requirements will be fulfilled for packaging and labelling (US 21 Code of 
Federal Regulations 312.6).
9.3
Shipment, Storage, and Accountability
Only participants enrolled in the trial may receive trial IMP and only authorized site staff may 
supply or administer trial IMP. All drug supplies must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the Investigator and authorized site staff.
Tirbanibulin ointment 1% must be stored at 20°C to 25°C (68°F to 77°F) with excursions 
permitted to 15°C to 30°C (59°F to 86°F). Do not refrigerate or freeze tirbanibulin ointment 
1%. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study medication received and ensure that any discrepancies 
are reported and resolved before use of the study medication. 
The Investigator, the trial staff, institution, or the head of the medical institution (where 
applicable) is responsible for clinical supplies accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). The Investigator will 
maintain accurate records of receipt of all study drugs, including dates of receipt. In addition, 
accurate records will be kept regarding when and how much study drug is dispensed and used 
by each patient in the study.
Reasons for departure from the expected dispensing regimen must also be recorded. At the 
completion of the study, to satisfy regulatory requirements regarding drug accountability, all 
study medication will be reconciled and retained or destroyed according to applicable 
regulations. Further guidance and information for the final disposition of unused 
investigational products are provided in the Study Reference or equivalent manual.


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Empty packages and unused medication will be returned to Almirall or a designated depot, 
where the remaining medication will be destroyed according to regulatory requirements.
Retention drug samples will be kept by the Sponsor or designee, during the trial and until it is 
legally required after trial completion.
The Investigator and trial staff must adhere to Good Clinical Practice (GCP) guidelines, as well 
as local or regional requirements.
9.4
Treatment Administration
Treatment will begin on Day 1, following confirmation of patient eligibility and collection of 
all pre-dose samples and assessments.
At Baseline (Day 1 pre-dose), the Investigator will confirm the TF on the face or balding scalp 
that was identified at Screening and the patients will receive instructions on how to apply the 
topical medication and how to care for the TF.
Patients will be provided with 5 single-dose packets containing tirbanibulin ointment 1%.
The first dose will be administered by the patient under the supervision of study personnel on 
Day 1 at the site. The patient will self-administer the remaining single-dose packets once daily 
at home for the next 4 consecutive days. The fifth dose should be applied by the patient at home 
before the Day 5 site visit.
Tirbanibulin ointment 1% will be applied to cover the treatment field of approximately 
100 cm2, corresponding to approximately 0.5% of the body surface area. Study medication 
should be applied each day at approximately the same time. The treatment field should not be 
wet, should be kept dry for approximately 8 hours after application, and should not be touched 
or covered with dressing. The ointment should not be applied near the eyes, mouth, or lips.
Patients will return the used medication packaging (all parts of each packet, including the torn 
opening part) and any unused study medication back to the clinical site at the next visit to check 
compliance and for drug reconciliation purposes. Further details will be given in the study 
manuals (see Section 9.5).
9.5
Treatment Compliance
Compliance with the study treatment will be assessed by site personnel on Day 5. Compliance 
will be assessed by counting the dispensed and returned used tirbanibulin ointment 1% single-
use packets. Patients will be instructed to return both the used and unused study treatment back 
to the clinical site. This information will be recorded in the eCRF.
Deviations from the prescribed dosage regimen should be also recorded in the eCRF.
Patients will record dates and times of study treatment application, including dates for study 
treatment delays in the electronic diary of the study mobile application (Study App).
The amount of study drug applied will be determined based on weight. The site will record the 
weight, as a whole, of the 5 packets each one in their respective closed zipper storage bags 
before and after dosing to quantify the amount used by the patient. Patients will be required to
bring back to the site the respective two torn parts of each packet in their respective closed 


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zipper storage bags. The weighing of the 5 packets will be performed on a balance with 
sufficient precision to calculate the weight by difference of tirbanibulin administered daily with 
high accuracy. To avoid losing any study drug by leakage issues, the total weight of 5 packets 
will be measured as a whole in their respective re-sealable zipper storage bags. Additional 
details for this process are provided in the study manuals.
The dosing logs for each patient will be kept during the study. The Clinical Research Associate 
(CRA) will review treatment compliance during monitoring site visits.
9.6
Methods for Assigning Patients to Treatment Groups
9.6.1
Patient Identification
In order to protect the patient identity and data confidentiality, each patient will be identified 
in the trial with one unique patient number. The unique patient number is a combination of 
his/her site number and a sequential number assigned by the Investigator. 
The site number will be predetermined, but the sequential number is assigned by the 
Investigator upon signing the informed consent form (ICF). At each site, the first patient is 
assigned patient number 001, and subsequent patients are assigned the next consecutive 
number.
Once assigned to a patient, the patient number will not be reused. The patient number will be 
used to identify the patient throughout the trial.
9.6.2
Randomization
This is single-arm study in which all patients are treated with tirbanibulin ointment 1%; no 
randomization is performed.
9.7
Blinding
This is an open-label study with no active or placebo comparator; no study blind will be 
applied.
9.8
Unblinding by the Investigator
Not applicable.
9.9
Pre-trial, 
Concomitant, 
and 
Post-trial 
Medications/Therapy
9.9.1
Pre-trial Medications
Patients must not have received any other IMP within 30 days or 5 half-lives of the IMP, 
whichever is longer, before the first trial drug administration. 
All medications, including over-the-counter (OTC) drugs, food supplements, herbal remedies, 
and vitamins, taken within 30 days prior to screening will be recorded at Screening. In addition, 
the use of any prohibited medications must be recorded within the timeframe described in the 
exclusion criteria to ensure proper washout is followed. Thereafter, a record of all medications 


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taken during the course of the study will be made. Information regarding the total daily dose, 
route of administration, start and discontinuation dates, and indication are to be captured in the 
patient’s eCRF.
A complete study disease treatment history will be recorded in the eCRF.
Any medication taken for medical reasons (mainly diseases concomitant with studied disease) 
prior to trial entry, will be continued at the same dose and conditions during the entire 
experimental phase of the trial.
9.9.2
Concomitant Medications
No concomitant therapy will be allowed during the entire duration of the trial, other than the 
prior allowed medication or any other required for the treatment of AEs or local tolerability. In 
such cases, the drug will need to be prescribed by the Investigator and recorded in the 
Concomitant Medication eCRF. The following items should be specified: trade name, dose and 
frequency of dosing, route, indication, date and time of first dose, and date and time of last 
dose, when applicable.
Therapies (medication and non-medication therapies) not restricted by the protocol may be 
used. The use of non-medicated therapies (eg, sunscreen and moisturizers) will also be recorded 
in the Concomitant Medication eCRF. The use of or change in the dose of any of the 
concomitant medications, either prescription or OTC, during the study will be recorded. The 
reason for use or change of dose of a concomitant therapy may need to be reported as an AE. 
Patients must be instructed to inform the Investigator of plans to take any new treatment during 
the participation in the trial, including OTC medicinal and herbal products.
9.9.3
Prohibited Concomitant Medications
The use of any non-study drug on the TF is prohibited during the study. 
The use of moisturizers and sunscreens in the TF is prohibited during the study, but can be 
applied outside of the TF, as needed. 
Patients will be reminded that AK lesions located outside the treatment field may be treated by 
physical lesion-directed treatment only (eg, cryotherapy) at the Investigator’s discretion.
All medications requiring wash-out (see Exclusion Criteria, Section 8.3) are prohibited during 
the patient’s participation in the study.
9.9.4
Post-trial Medications
Once study treatment and all visits and related study measurements are complete, patients 
should continue to take their usual medications allowed during the study and may resume other 
medications interrupted prior to study enrolment, as deemed appropriate by the Investigator. It 
is not planned to treat patients with tirbanibulin ointment 1% any further than scheduled in this 
study. No intervention or additional care is planned to follow the end of the study.


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10
Trial Procedures and Assessments
10.1
General Conditions of the Trial
Informed consent will be obtained after the study has been fully explained to each patient and 
before the conduct of any screening procedures or assessments. Documentation will be required 
(documented in the patient’s medical records) to confirm that the Investigator has ensured the 
informed consent process was done correctly, and that the patient understood what to expect, 
he/she had the opportunity to ask any questions and consider other treatment options and agreed 
to participate.
The ICF can be either in paper or electronic form. Patients will be able to download the signed 
ICF (in case of completing the electronic ICF) or will be given a hard copy (in case of 
completing the paper ICF).
Trial visits must be scheduled with respect to Baseline/Day 1. In order to adapt appointments 
to local holidays, patients´ availability or site internal organization needs, time windows are
allowed as indicated in Table 1. The CRA or CRO Medical Monitor should be contacted for 
advice in case of exceptional situations.
As applicable, laboratory tests and other assessments will be performed using supplies or 
equipment provided by the Sponsor for this trial through a specialized provider who will 
perform centralized assessment and reporting.
Optimally, the evaluations for each patient (lesion counts, review of trial drug compliance, etc.) 
should be performed by the same Investigator (or other suitably qualified and experienced 
designee) throughout the trial to avoid inter-assessor bias. 
Unless specified otherwise, the study assessments scheduled during the study visits must be 
performed before the study product administration, except on Day 5, when the study product 
application will be done by the patient at home prior to the site visit. If assessments are 
scheduled for the same nominal time, then the assessments should occur in the following order:
1. Vital signs
2. ECG
3. Blood draw for laboratory tests
Table 1 summarizes the trial procedures to be performed at each visit. Individual trial 
procedures are described in the following sections.
10.2
Patient’s General Conditions During the Trial
After the screening evaluation and while not at the research site, patients will maintain normal 
daily activities, following the instructions of the Investigator. Any event likely to interfere with 
the objectives of the trial will be communicated to the Investigator and reported without delay 
to the Sponsor.


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10.3
Scheduled Activities and Trial Visits
10.3.1
Screening Period
All screening assessments will be performed after the patient provides informed consent. The 
Screening Visit (Visit 1) will occur between Day -28 and Day -1. Patient screening numbers 
will be assigned at Visit 1.
Prior to signature of the ICF, Investigators will evaluate eligibility of patients for entry in the 
trial by comparing past and current medical status, as documented in the patient’s medical 
history, to the inclusion/exclusion criteria of the trial.
Eligible patients will receive a detailed description of all activities and requirements before 
signing the ICF to ensure their understanding and compliance with sample collection and 
clinical examinations. 
Patients who require a washout period from prohibited concomitant treatments should be seen 
and sign the ICF prior to the Screening visit, to ensure the necessary washout before. No trial 
assessments will be performed on that date and the Screening visit will be scheduled according 
to the washout length required for the specific medication stopped.
The Screening visit and assessments will be performed in accordance with schedule detailed in 
Table 1.
Demographics and Baseline Characteristics
Data on demographic (sex, age, race, ethnicity) and baseline characteristics (body weight, 
height, smoking and alcohol habits) will be collected during Screening. Height will be 
measured at Screening only.
Skin type will be recorded according to the Fitzpatrick scale (Table 2).
Table 2
Fitzpatrick Skin Type
Skin Type
Description*
I
Always burns easily, never tans (sensitive)
II
Always burns easily, tans minimally (sensitive)
III
Burns moderately, tans gradually (light brown) (normal)
IV
Burns minimally, always tans well (moderate brown) (normal)
V
Rarely burns, tans very well (dark brown) (intensive)
VI
Never burns, deeply pigmented (intensive)
*Sunburn and tanning history based on first 30 to 45 minutes of sun exposure after winter season of non-sun exposure.
Medical and Actinic Keratosis History
Medical history at Screening will include:
x Significant medical and surgical history during the last 5 years (eg, a common cold would 
not be captured unless it was ongoing at Screening)


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x The initial diagnosis date of AK on the face or balding scalp and on any other part of the 
body
x Any AK treatment history of the face or balding scalp including all commercial and 
investigational products and surgical modalities dating back to the initial diagnosis
x History of and location of cancers including skin cancers, eg, BCC, SCC, melanoma
Prior Medications
All medications, including OTC drugs, food supplements, herbal remedies, and vitamins, taken 
within 30 days prior to screening will be recorded at the Screening visit (see Section 9.9.1).
Physical Examination
A complete Physical Examination includes height, weight, and an assessment of head, eyes, 
ears, nose and throat, integumentary/dermatological, gastrointestinal, cardiovascular, 
respiratory, musculoskeletal, neurological systems,
and an expanded dermatological 
examination to cover sun-exposed areas where photo-damage is likely. Height is measured at 
Screening only. Physician examinations will be conducted in accordance with schedule 
detailed in Table 1.
Treatment Field Identification
The size of the TF must be approximately 100 cm2.
At Screening, the Investigator will select and measure the anatomical area (eg, approximately 
mid face or an area on the scalp) and will outline the TF with a marker pen over the skin. Each 
AK lesion within the TF will be also identified with a label. A photograph will be captured 
using imaging devices to be used to support the location of the same TF identified at Screening 
during the follow up study visits assessments. 
At Baseline (Day 1), the area of the TF and the number and location of lesions inside it will be 
confirmed. A baseline photograph is only required in case of any significant change from 
Screening is detected in the TF as per the investigator judgement or if the quality of the image 
captured at screening is not appropriate. If no photograph is needed at baseline, then the 
screening photograph will be considered the baseline assessment. The same field will be 
located during the study with the aid of imaging software before performing the study 
assessments. Study Manuals will be provided to describe the image procedures in detail. The 
number of AK lesions in the TF will be recorded in the eCRF and photographs will be taken 
according to the schedule in Table 1.
Pregnancy Testing
In females of childbearing potential, a highly sensitive urine pregnancy test will be performed 
at the Screening visit and according to the Schedule of Assessments (Table 1). Urine pregnancy 
test kits will be provided by the Sponsor.
Any pregnancy, whether occurring in a female patient or in the female partner of a male patient, 
for which the estimated date of conception was during the patient’s study participation must be 
reported. In addition, pregnancies in female partners of male patients for which the estimated 
date of conception was within 90 days of the last study treatment must be reported.


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10.3.2
Response Assessment Period
Response Assessment Period visits and assessments will be performed in accordance with the 
schedule detailed in Table 1. See Sections 10.4 and 10.5 for details on the lesion and safety 
assessments, respectively.
The trial visit at Day 5 cannot be repeated nor skipped. The trial visits at Day 8, Day 15, Day 29,
and Day 57 may be rescheduled within the time windows allowed in this protocol, in case of:
x scheduling conflicts (weekends or holidays),
x technical problems with the equipment necessary for the visit (eg, ECG), 
x any AEs that impede conduct of the visit, 
x restrictions related to the coronavirus 2019 disease (COVID-19) pandemic.
10.3.3
Unscheduled and Repeated Tests
Unscheduled Tests
As deemed necessary by the Investigator, additional safety test(s) can be performed at any time 
during the trial in order to follow-up the progress of any clinically relevant abnormal finding, 
investigate any potential new adverse event, etc. These additional tests outside of the initial 
schedule of the trial will be considered "unscheduled tests" and will not be associated with any 
trial visit.
Repeated Tests
Any safety test may be repeated at the Investigator’s discretion under either of the following 
situations:
x When there is any kind of problem with the first test (ie, technical problem with the ECG 
machine, blood sample hemolyzed, presence of artifacts, etc.). The Investigator should 
repeat the individual test as soon as possible.
x At the screening visit any individual test(s) may be reasonably repeated during the screening 
window to confirm the eligibility criteria (eg, laboratory sample when there is any clinically 
significant abnormality, etc.).
10.4
Lesion Assessments
To the extent possible, the Investigator who conducts the lesion count at Baseline/Day 1 and 
through the study visits according to the Schedule of Assessments (see Table 1) must be the 
same for an individual patient. All other intermediate assessment visits should be conducted 
by the same Investigator, to the extent possible.
A dermatologist (Investigator or Subinvestigator) will count all lesions in the TF for all 
subjects, according to the Schedule of Assessments (see Table 1). Details on whether the lesion 
present in the TF is new or an existing lesion at baseline will be recorded at each visit in the 
eCRF.


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Lesions identified at baseline will be followed during the study using appropriate tools such as 
imaging software, where baseline lesions will be identified and new lesions appearing along 
the study recognized.
10.5
Safety and Tolerability Assessments
Safety will be assessed periodically during the study by recording AEs, including SAEs, local 
tolerability, pigmentation and scarring, and AESIs. Safety assessments also include PEs and 
vital signs measures, ECGs, clinical laboratory evaluations and pregnancy testing for WOCBP 
(see Table 1).
10.5.1
Adverse Events
10.5.1.1
Adverse Events
At each study visit, patients will be asked a general question “How have you been since the 
last visit?” before assessment of local tolerability, pigmentation, and scarring in the TF.
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECGs, vital sign measurements), including those that worsen from 
baseline which are determined to be clinically significant in the medical and scientific judgment 
of the Investigator, are to be recorded as AEs or SAEs.
Local tolerability signs will be reported separately from AEs (see Section 10.5.2). The 
Investigator, or designee, may report an AE based on his or her judgement. See Section 10.5.1.2
for definitions and reporting of AESIs.
All patients who have unresolved treatment-related AEs at Day 57/Early Termination (ET) will 
return for additional follow-up every 7 to 28 days until these have resolved, have returned to 
the baseline value, or are deemed stabilized by the Investigators.
Adverse event and SAE definitions and reporting requirements are detailed in Section 10.7.
10.5.1.2
Adverse Events of Special Interest
The following have been identified as AESIs based on their relevance for the current intended 
use:
Skin Cancers
Skin cancers (including BCC, SCC, and melanoma) appearing within or outside the TF during 
the study will be reported as AESIs. Details of the skin cancer and any other associated AE 
will be recorded in the AE form in the eCRF and by using the Skin Cancer Report Form. The 
location and treatment will be recorded. In the case of an SCC arising within the TF, it will be 
recorded if an AK had been present at the same location at baseline. See Section 10.7.4 for 
reporting requirements for AESIs.
If the skin cancer meets seriousness criteria, an SAE Report Form must also be completed and 
sent along with Skin Cancer Report Form, as specified in Section 10.7.4.


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10.5.2
Focused Dermatological Examination of the Treatment 
Field
The focused dermatological examination will include evaluations for local tolerability signs, 
pigmentation, and scarring in the TF.
10.5.2.1
Local Tolerability
Local tolerability assessments in the TF will be recorded per the schedule in Table 1. The 
assessment for local tolerability is to be done after the assessment for AEs. The evaluation of 
local tolerability is done by the Investigator (or an appropriate trained designee). The local 
tolerability signs to be assessed and the corresponding grading scale for each sign are provided 
in Table 3.
Table 3
Local Tolerability Signs and Grading Scale
Local Tolerability Signs
Local Tolerability Score
Erythema
Flaking/scaling
Crusting 
Swelling
Vesiculation/pustulation
Erosion/ulceration
0=absent
1=mild (slightly, barely perceptible)
2=moderate (distinct presence)
3=severe (marked, intense)
Application site symptoms such as itching, burning, stinging, tenderness, pain etc., are not 
classified as local tolerability signs and will be reported as AEs.
All patients who have unresolved local tolerability signs in the TF at Day 57/ET will return for 
additional follow-up every 7 to 28 days until these have resolved, have returned to the baseline 
value, or are deemed stabilized by the Investigator.
Any sign of local tolerability leading to temporary or permanent discontinuation of the study 
drug application or requiring the use of concomitant medications should be reported as an AE. 
If a sign of local tolerability leads to an AE meeting the criteria of seriousness (ie, an SAE), 
the SAE form will be completed with all the available information and reported within the same 
timeframe and following the same routing as for an SAE (see Section 10.7.4).
In case of occurrence of possible contact dermatitis in the TF, an evaluation (patch test) will be 
made to confirm or rule out the diagnosis (see Appendix 2).
10.5.2.2
Pigmentation Changes and Scarring
Hypo- and hyperpigmentation and scarring in the TF will be assessed as being present or absent 
in accordance with the Schedule of Assessments (Table 1). The assessment of pigmentation 
and scarring is to be done after the assessment for AEs.
All patients who have unresolved hypo- or hyperpigmentation or scarring in the TF at 
Day 57/ET will return for additional follow-up every 7 to 28 days until these have resolved, 
have returned to the baseline value, or are deemed stabilized by the Investigator.


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10.5.3
Physical Examinations and Vital Signs
Physical Examinations
A complete PE includes height, weight, and an assessment of head, eyes, ears, nose and throat, 
integumentary/dermatological, gastrointestinal, cardiovascular, respiratory, musculoskeletal, 
neurological systems, and an expanded dermatological examination to cover sun-exposed areas 
where photo-damage is likely. Height is measured at Screening only.
Vital Signs
Measurement of vital signs will include blood pressure, heart rate, respiratory rate, and body
temperature. Measurements of systolic and diastolic blood pressure will be conducted after at 
least 5 minutes resting in the supine position and preferably on the same arm. If there is any 
suspicion of unreliable measurement, blood pressure will be measured again. The value 
obtained this time will be considered as definitive and should be recorded in the eCRF. 
Significant findings that are observed after the patient has signed the ICF and that meet the 
definition of an AE must also be recorded in the AE form in the eCRF.
10.5.4
Electrocardiograms
Electrocardiogram training, equipment, and a procedural manual will be provided to the sites 
by a central ECG vendor. Refer to the procedural manual for details.
Electrocardiograms will be performed according to the schedule in Table 1. Patients must be 
in a supine position for 5 minutes prior to ECG and ECG is to be done prior to any blood 
sampling.
Significant findings that are observed after the patient has signed the ICF and that meet the 
definition of an AE must also be recorded on the AE form in the eCRF.
10.5.5
Laboratory Testing
Routine laboratory assessments will be performed at a designated central laboratory (refer to
the laboratory manual). Tests to be performed at the central laboratory are detailed in Table 4.
Table 4
Laboratory Testing Parameters
Assessment
Specific Tests
Hematology
Red blood cells (RBC), hemoglobin, hematocrit, platelets, and white blood 
cells (WBC) with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Blood chemistry
Electrolytes: Chloride, potassium, sodium, bicarbonate (HCO3)
Liver Function Tests: alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin, 
direct bilirubin
Renal Function Tests: Blood urea/blood urea nitrogen, creatinine
Other: Total protein, albumin, calcium, cholesterol, glucose, lactate 
dehydrogenase (LDH), phosphorus, triglycerides, uric acid
Urinalysis
Hydrogen ion concentration (pH), specific gravity, protein, glucose, 
ketones, leukocyte esterase, nitrite, bilirubin, urobilinogen, blood.


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Blood and urine samples for laboratory testing will be collected in appropriate sampling tubes
according to the Schedule of Assessments (Table 1). Blood samples are to be collected before 
administration of concomitant medications (if any), and after vital signs measures and ECGs
are performed. Significant findings that are observed after the patient has signed the ICF and 
that meet the definition of an AE must also be recorded on the AE form in the eCRF.
Urine pregnancy testing for WOCBP will be performed at the study site in accordance with the 
Schedule of Assessments (Table 1).
10.6
Other
Standardized Photography
Standardized photography of each patient’s TF will be performed prior to dosing while on 
treatment (see Table 1) for illustrative purposes and to support the TF and AK lesion 
identification within the TF. Each AK lesion within the TF will be identified at the 
screening/baseline visit with a label placed over the skin, a photo will be captured as a reference 
to support AK lesion follow up during the study. Refer to the study manuals for detailed 
instructions.
Care must be taken to ensure that the same lighting, background, subject positioning relative 
to the camera, and camera settings are used for each photograph. Equipment, supplies, and 
detailed instructions for obtaining and managing the photographs will be provided to the 
clinical study site prior to the initiation of patient enrollment.
10.7
Adverse Events
The Investigator will closely monitor any AE and will adopt the necessary clinical measures to 
ensure the safety of the patient.
10.7.1
Definitions
Adverse Event
An AE is defined as any untoward medical occurrence in a clinical trial participant, regardless 
of the administration of the IMP and its causal relationship to it.
An AE can therefore be any unfavorable and unintended medical occurrence during the 
patient’s participation in the trial, including deterioration of a pre-existing medical condition, 
an abnormal value in a laboratory assessment, ECG abnormality, or an abnormal finding in the 
physical examination.
Adverse events must be temporally associated with the patient’s participation in the trial, ie,
occur after signing the ICF. At the time of the occurrence of an AE, the administration of the 
IMP does not need to have already been initiated. If initiated, it does not necessarily need to 
have a positive causal relationship to the event.
Serious Adverse Event
An SAE is an adverse event, which falls into one or more of the following categories:
x results in death


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x is life-threatening (ie, an event which, in the view of the Investigator, places the patient at 
immediate risk of death from the event as it occurred.) It does not mean that the event might 
hypothetically have caused death if it was more severe or lasted longer
x requires in-patient hospitalization or prolongs existing hospitalization
x results in persistent or significant disability or incapacity
x is a congenital anomaly or birth defect
x is any other medically important event that may jeopardize the patient or may require 
intervention to prevent one of the other above outcomes.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life-threatening or do not result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed in the definition 
above should also be considered serious. These are considered “other important medical 
events.”
Hospitalization is defined as an overnight stay at the hospital or emergency room.
Prolongation of hospitalization is defined as any extension of an in-patient hospitalization 
beyond the stay anticipated/required in relation to the original reason for the initial admission, 
as determined by the Investigator or treating physician.
10.7.2
Reporting of Adverse Events 
Adverse events either reported by the patient or observed by the Investigator must be recorded 
in the AE page of the eCRF and should be described in the following manner:
x The nature of the AE will be described in precise, standard medical terminology (ie, not 
necessarily the exact words used by the patient). If known, a specific diagnosis should be 
recorded instead of listing signs and symptoms (eg, allergic contact dermatitis)
x The duration of the AE will be described by the start date and end date
x The location for cutaneous adverse events will be described as at or just around the TF
(≤2 cm from the TF) or distant (>2 cm from the TF)
x The intensity of the AE will be described in terms of mild, moderate, or severe according to 
the Investigator’s clinical judgment, using the following definitions:
o Mild: Awareness of event, symptoms, or signs, but easily tolerated (acceptable)
o Moderate: Sufficient discomfort and interferes with usual activity (disturbing)
o Severe: Incapacitating with inability to do normal daily living activities or significantly 
affects clinical status and warrants intervention (unacceptable)
x The causal relationship of the event to use of the IMP will be described in terms of:
o Not related: Event or laboratory test abnormality, definitely not related to trial drug, as 
related to other drug, chemicals, or underlying disease
o Unlikely related: Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable; disease or other drugs, chemicals or underlying disease 
provide plausible explanations


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o Possibly related: Event or laboratory test abnormality, with a reasonable time 
relationship to drug intake; could also be explained by underlying disease or other drugs 
or chemicals; information on drug withdrawal may be lacking or unclear
o Related: Event or laboratory test abnormality, with a reasonable time relationship to drug 
intake, unlikely to be attributed to underlying disease or other drugs or chemicals; 
response to withdrawal clinically reasonable (positive dechallenge)
‘Possibly related’ and ‘related’ will be considered as ‘related’ terms for reporting purposes. 
If the events are assessed as ‘unlikely related’ or ‘not related’ to the suspect IMP, the event
does not qualify for reporting purposes. In the absence of information on causality from the 
reporting Investigator, the CRO will immediately contact the reporting Investigator to 
request a causality assessment. The case will be updated with the follow-up information and 
reported accordingly. If no causality is provided by the Investigator, the Sponsor assessment 
will be considered for submission purposes.
x The outcome of the event will be described in terms of:
o Recovered/resolved
o Recovering/resolving
o Recovered/resolved with sequelae
o Not recovered/not resolved
o Fatal
o Unknown
x The action taken on the IMP will be captured as:
o Drug withdrawn
o Dose not changed
o Not applicable
An AE will be collected only once with its maximum severity, except when the AE started 
before first IMP administration and persisted after it and worsened in severity any time after 
first IMP application. In this latter case, the AE will be collected with each respective severity. 
The AE term recorded must be exactly the same at the different time points where this AE is 
reported again in the eCRF.
10.7.3
Recording of Adverse Events
Adverse events will be collected from signature of the ICF up to Day 57/ET. Any AE reported 
by the patient up to 30 days after the last study contact (Day 57/ET) should also be captured in 
the eCRF.
Medical disorders present at the time of signing the informed consent that are part of the 
patient’s medical history will only be considered AEs if they worsen after this time.
Abnormalities detected before IMP administration in the PE, laboratory tests, ECGs, or other 
safety assessments will not be considered AEs if already known as part of the medical history 
or in relation to prior medical conditions and will be recorded in the eCRF/CRF Medical 
History/physical 
examination 
form/page. 
However,
abnormalities 
detected 
in 
screening/baseline tests, thought to be due to a trial procedure, will be considered AEs.


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Abnormalities (newly occurring or worsening of previously known abnormalities) detected 
after IMP administration in physical exam, laboratory tests, ECGs, or other safety assessments, 
which are considered clinically relevant by the Investigator, or which require an intervention 
or a diagnosis test, or may result in the IMP discontinuation, should be reported as AEs.
Reported terms should accurately characterize the adverse event. When a patient experiences
an unspecified injury, signs or symptoms, active investigation should be conducted to reach a
final diagnosis. If reached, then the disease diagnosis is the preferred reported term.
Adverse events will be elicited by asking the patients non-leading questions (eg, "How do/did 
you feel?”) and by collecting AEs spontaneously reported by the patient to the Investigator or 
a designee.
All AEs elicited by the Investigator during the defined AE collection period must be recorded 
in the eCRF. In addition, when an AE meets the criteria of seriousness (ie, an SAE), it must 
also be recorded on the SAE form and reported following the defined timelines in Section 
10.7.4.
10.7.4
Reporting of Serious Adverse Events and Adverse Events 
of Special Interest
Serious adverse events and AESIs will be collected from signature of the ICF up to Day 57/ET.
Any SAE or AESI reported by the patient up to 30 days after the last study contact (Day 57/ET)
should be collected in the eCRF.
The Investigator must report any SAE or AESI within 24 hours from the moment she/he first 
learns of it to the CRO pharmacovigilance unit on a SAE report form. This reporting will take 
place regardless of whether the Investigator considers the event to be causally related to the 
IMP(s), to any other medicinal product(s), to the clinical trial procedure or to any intervention 
undergone by the patient.
Original reports are to be kept by the Investigator in the Investigator’s File. 
Contact details and specific instructions on the flow of SAE and AESI reports will be provided 
to all sites by the CRO.
The minimum information that must be included in the initial report is:
x An event meeting the criteria of SAE or AESI.
x A qualifiable reporter, defined as an Investigator of this trial or his/her delegate.
x A qualified patient, defined as a patient who has consented to this trial.
x A suspect medicinal product.
x The Investigator’s causality assessment.
Unless the SAE or AESI has been sufficiently documented in the initial report, the Investigator 
will provide all available additional information in follow-up reports by using a new form and 
adhering to the same routing and time frames as defined for the initial report. This will be 
continued until the event has been fully documented and reported.


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An event reported to the CRO pharmacovigilance unit which does not meet the SAE or AESI 
criteria shall be nullified by the Investigator by forwarding a follow up report.
Depending on the local requirements, a regulatory report of the SAE or AESI (if serious) will 
be produced by the CRO pharmacovigilance unit and submitted to relevant Competent 
Authorities and Investigators, when applicable according to local regulations.
Serious adverse events NOT considered to require reporting to the CRO pharmacovigilance 
unit will be:
x Hospitalization for a treatment/surgical procedure which was elective or pre-planned for a 
pre-existing condition that did not worsen during the participation in the trial.
10.7.5
Follow-up of Adverse Events / Serious Adverse Events
Those AEs and SAEs, including AESIs, recorded for Screening failure patients will be 
followed-up until resolution or until otherwise agreed between the Sponsor and the 
Investigator.
All AEs and SAEs, including AESIs, that are still present after the last study visit (including 
AEs that have led to premature discontinuation), will be followed-up at least 2 weeks for AEs 
and 4 weeks for SAEs after the last trial drug administration, by means of a follow-up contact 
or visit (whichever is considered more appropriate by the Investigator). In case the AE/SAE is 
still ongoing after that time point, this will be followed-up until its resolution or until otherwise 
agreed between the Sponsor and the Investigator. The same timeframes will apply for AEs 
from screening failures which are ongoing at the time the patient is withdrawn from the trial.
Additional safety data collected at a contact/visit to follow-up the ongoing AE will not be 
included into the clinical database, if this was already locked; therefore, the clinical database 
lock will not be delayed due to this situation. Any SAE will be followed up if needed after 
clinical database lock and the information will be only stored in the safety database.
10.8
Pregnancies
There is no information about effects that tirbanibulin could have on the development of the 
fetus in humans. However, consistent with its mode of action, tirbanibulin was embryo- and 
fetotoxic in preclinical studies.
Any pregnancy, whether occurring in a female patient or in the female partner of a male patient, 
for which the estimated date of conception was during the patient’s study participation must be 
reported. In addition, pregnancies in female partners of male patients for which the estimated 
date of conception was within 90 days of the last study treatment must be reported.
In case of pregnancy during the participation in the trial, the patient will be immediately 
discontinued.
The Sponsor will be informed according to the safety reporting procedure: the Investigator 
must complete a study specific pregnancy form upon confirmation of a pregnancy and send it 
to the CRO Safety Contact within 24 hours of confirmation of the pregnancy. Pregnancy is not 
itself an AE or SAE; however, maternal/fetal complications or abnormalities will be recorded 
as AEs or SAEs, as appropriate. 


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The Investigator will follow the pregnancy until completion or until pregnancy termination 
and, in the case of a live-born offspring, the follow-up period will be deemed to have ended 
when the health status of the child has been determined on its birth or after an appropriate 
period post-delivery considered necessary to monitor the development of the new-born is 
completed.
The patient will be asked to provide information on the outcome of the pregnancy, including 
premature termination should the case arise. Spontaneous miscarriage, developmental delay, 
fetal death, SAE in a neonate, and congenital abnormalities will be reported as SAEs. The 
Investigator will inform the CRO Safety Contact of the outcome as a follow-up to the initial 
pregnancy form. All pregnancies should be reported to the sponsor and, when applicable, to 
the ethics committee.
10.9
Unblinding for Safety Reasons
Not applicable.
11
Statistics
The statistical analyses described below will be supplemented by a comprehensive Statistical 
Analysis Plan (SAP) that will be finalized before the database is locked. Any changes to the 
statistical plans will be described and justified in the final report. All statistical processing will 
be performed using the SAS® system.
11.1
Sample Size Calculation
With 100 patients and assuming an expected percentage of patients with at least one local 
tolerability sign of approximately 90%, the precision in the estimation of that percentage will 
be approximately 11%. The precision is defined as the width of the 95% confidence interval.
Furthermore, 100 patients will provide approximately 10% and 13% precision in the estimation 
of the percentage of patients with the local tolerability events of particular interest, specifically 
vesiculation/pustulation (assuming an expected percentage of 8%) and erosion/ulceration 
(assuming an expected percentage of 12%), respectively.
11.2
Structure and Methodology of the Statistical Analysis
Statistical analyses of demographic, baseline characteristics, safety, tolerability, and lesion 
count data will be performed by the CRO Biostatistics department.
The SAP will be prepared by the CRO statistician under Almirall Standard Operating 
Procedures (SOPs) prior to database lock. SAS will be the statistical software used to analyze 
the data sets. A complete set of raw data listings will be appended to the Statistical Report. All 
tables, figures, and listings will be presented in portable document format (PDF) documents 
without any manual editing, ie, they will appear unmodified as programmed by means of the 
statistical package.
Tables, figures, and listings will be compiled in the statistical report and appended to the CSR.


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11.3
Analysis Populations
There will be one analysis population in this trial:
x Safety population, defined as all patients who have received at least one dose of study 
treatment.
11.4
Descriptive Statistics
Categorical variables will be summarized with counts (n) and percentages (%). For continuous 
variables, the number of non-missing observations (n), mean, standard deviation (SD), standard 
error (SE) of the mean, 95% confidence interval (CI) of the mean, median, first (Q1) and third 
(Q3) quartiles, minimum (min) and maximum (max) will be tabulated. When applicable, these 
summaries will be provided by visit and time-point of assessment.
11.5
Demographics and Baseline Characteristics
Descriptive statistics will be used to summarize demographic and baseline characteristics.
11.6
Study and Treatment Compliance
Descriptive statistics will be used to summarize study and treatment compliance.
11.7
Prior and Concomitant Medications
The number and percentage of the patients with concomitant medications during the study will 
be summarized by anatomical therapeutic chemical class, standardized drug name.
11.8
Statistical Methods
The statistical approach for the analysis of safety and other endpoints is described below. A
more detailed description of the statistical methods to be used will be provided in the SAP.
11.8.1
Analysis of Safety Endpoints
Descriptive statistics will be provided for all safety endpoints.
Local tolerability signs composite score, and specific local tolerability scores will be analyzed 
by means of descriptive statistics and provided by visit. The maximum local tolerability score 
and maximum local tolerability composite score will be presented. The number and percentage 
of patients with hypo- or hyperpigmentation and scarring in the TF will be presented separately 
by visit as well as the number and percentage of patients with change from baseline in hypo-
or hyperpigmentation and scarring in the TF.
An AE will be considered to be a TEAE, if it was not present prior to the first dose of trial drug 
or was present prior to the first dose of trial drug but increased in severity after the date of the 
first dose of study treatment. An AE that occurs more than 57 days after the last IMP application 
will not be counted as a TEAE.
TEAEs and TESAEs recorded during the study will be presented, including the total number 
of events and the number and percentage of patients with events. Summaries of the number 


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and percentage of patients with TEAEs (and number and percentage of events), study drug-
related TEAEs, TEAEs by severity, TESAEs, TESAEs with an outcome of death, and TEAEs 
leading to temporary or definite discontinuation of the study treatment will be provided. 
Specific tables describing AESIs will be also provided. The number and percentage of patients 
who experience one or more AESI will be tabulated by AESI.
For PEs, ECGs, vital signs, and clinical laboratory parameters, the number and percentage of 
patients with normal or abnormal results will be presented at scheduled visits. Descriptive 
statistics for continuous variables will be provided at scheduled visits together with a summary 
of changes from baseline for each parameter. Shift tables will be provided when appropriate.
11.8.2
Analysis of Exploratory Endpoints
Descriptive statistics will be provided for exploratory endpoints overall and by subgroup (see 
Section 11.11). An Observed Cases approach will be used for handling missing data, as the
main analysis (see Section 11.9). Any other sensitivity analyses will be defined in the SAP.
11.9
Handling of Missing Data
No imputation will be made for missing data.
11.10
Multiplicity Strategy
Not applicable.
11.11
Subgroup Analyses
Descriptive statistics will be provided for exploratory endpoints overall and by subgroups:  age
(<65 and ≥65), gender (male/female), number of lesions at baseline (≤8 and >8), treatment 
location (face/scalp), history of skin cancer (yes/no), and Fitzpatrick skin type (I/II and 
III/IV/V/IV).
11.12
Interim Analysis
No interim analysis is planned for this trial.
12
Data Handling, Processing, and Record Keeping
The Investigator will conduct the trial in accordance with the protocol and ICH E6 GCP 
guidelines. In addition to the routine monitoring procedures, training records should be in place 
to ensure investigators and CROs understand the data processing in any of the computerized 
systems to be used to ensure the confidence in the reliability, quality, and integrity of the patient 
data.
Sponsors, CROs, data safety monitoring boards, and other authorized personnel can view the 
trial data elements in the eCRF before and after the clinical Investigator(s) has electronically 
signed the completed eCRF. Reviewing trial data dynamically will allow early detection of 
trial-related problems (eg, safety concerns, protocol deviations) and problems with conducting 
the trial (eg, missing data, data discrepancies).


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According to the eCRF entry guidelines, eCRFs must be completed for each patient by 
qualified and authorized personnel. Any data entry and corrections made in the eCRF must 
have a respective audit trail where the correction is dated, the individual making the correction 
is identified, the reason for the change is stated, and the original data are not obscured. Only 
data required by the protocol for the purposes of the trial should be collected.
A list of all authorized data originators (ie, persons, systems, devices, and instruments) should 
be developed and maintained by the CRO and made available at each clinical site.
The eCRF is an auditable electronic record of information reported to the Sponsor on each trial 
patient, according to this clinical investigation protocol. The eCRF enables clinical 
investigation data to be systematically captured, reviewed, managed, stored, analyzed, and 
reported.
12.1
Data Collection
12.1.1
Identification of the Trial Data Sources
Source data includes all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical investigation used for 
reconstructing and evaluating the investigation.
When a device or instrument is the data originator (eg, blood pressure monitoring device or 
glucometer) and data are automatically transmitted directly to the eCRF, the eCRF is the 
source.
Access to source data is critical to the review and inspections of clinical investigations. Source 
data should be attributable, legible, contemporaneous, original, and accurate (ALCOA) and 
must meet the regulatory requirements for recordkeeping.
The trial data sources are outlined below:
x Signed informed consent forms
x Patient medical history records will include trial diagnosis and inclusion/exclusion criteria 
age, sex, demographics, physical examination, medical history, vital signs, previous 
medication, original or certified copy of a laboratory reports, instrument printout, trial 
progress notes of the physician
x Laboratory test results reports (hematology, clinical chemistry, urinalysis, etc)
x Digital photographs
x ePatient diary (Study App)
x eCRF
12.1.2
Electronic Case Report Forms
To comply with the requirement to maintain accurate case histories Investigators should review 
and electronically sign the completed eCRF for each patient before the data are archived or 
submitted. Use of electronic signatures must comply with US Title 21 Code of Federal 
Regulations part 11.


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For trial data elements transcribed from paper or electronic to the eCRF, the electronic or paper 
documents from which the data elements are transcribed are the source. 
These data must be maintained by the Investigators and available to the monitor or inspector if 
requested (eg, an original or certified copy of a laboratory report, instrument printout, progress 
notes of the physician, the trial patient’s hospital chart(s), nurses’ notes).
Direct Entry of Data Into the eCRF
The direct entry of data can eliminate errors by not using a paper transcription step before entry 
in the eCRF. For the following data elements, the eCRF may be the source:
x Date of ICF signature (in the case of a paper ICF; in the case of an electronic ICF the 
eConsent will be the source)
x Inclusion and exclusion criteria confirmation (checking)
x Patient demographics and physical examination, including. age, gender, race, ethnicity 
height, weight, and Fitzpatrick skin type
x Relevant previous and concomitant therapies
x Up-to-date relevant medical history, including trial diagnosis
x TF measurements and location (face or scalp)
x Number of lesions in the TF and identification of whether each lesion is new or existed at 
baseline
x Vital signs (blood pressure, pulse, body temperature, and respiratory rate)
x Pregnancy test results
x Trial/visit dates 
x Visit assessment (checking compliance, trial diary data, drug application, blood sample 
collection, tolerability score, end of treatment)
x Drug accountability (medication given and returned and product weight before and after 
application)
x Adverse events
For the above trial data elements, the eCRF is the source. If a paper transcription step is used, 
then the paper documentation should be retained and made available for monitoring or 
inspection.
Direct data entry should meet ALCOA+ principles for data integrity in life sciences. In case 
trial data cannot be entered at the time of the patient visit, eg, laboratory tests results, then 
Investigators are requested to make their entries at the time when the report with the results is 
received.
All non-CRF entered external data (ie, images) will not be loaded into the eCRF, but it will be 
integrated in SAS datasets and reconciled frequently with the eCRF data by CRO Data 
Management.


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The information directly collected in the eCRF must match the source documents. The source 
data verification will be performed by the CRO Clinical Research Associate (monitor) 
according to the requirements specified in the Monitoring Plan.
At the trial end, the CRO will generate a PDF copy of the completed CRFs which will be sent
to the Investigator(s) for all patients enrolled at his or her location.
12.1.3
Patient Diary
During the study, patients will use a mobile application. Clinical personnel will be instructed 
on the use of the Study App in order that they further instruct the patients at the Day1/Baseline 
visit, and as many times as deemed necessary. Patients will also receive written instructions on 
the Study App use. The Study App will be installed onto the patient’s own mobile phone, and
there will also be the possibility to provide patients with a mobile phone, if necessary. The 
Study App will be installed onto the mobile phone during the baseline visit. Clinical personnel 
will check and confirm the correct installation of the Study App during the visit.
On the Study App, patients will:
x Receive notifications, communications, and reminders through the patient retention tool
x Complete the eDiary: Patients, and assisted by caregivers, as needed, will complete a diary 
to record daily the study treatment application dates and times of application. The eDiary
will be completed by the patient and will be checked by the Investigator (or designee) in 
accordance with the Schedule of Assessments (Table 1).
At the study end, the Investigator will receive a CD/DVD with the mobile application data (in 
PDF) from the patients enrolled at his/her location. The Investigator will keep this CD/DVD
with the rest of the original data for as long as required by local regulations. The mobile 
application files are relevant documentation for registration.
The mobile application data is the sole property of the Sponsor and should not be available in 
any form to third parties without the written permission of the Sponsor, except to authorized 
representatives of appropriate Competent Authorities.
12.2
Data Management and Quality Control
Data Management of the trial will be performed by the CRO Data Management department 
according to the CRO SOPs and supervised by Data Management at Almirall, according to 
Almirall SOPs.
In order to facilitate the collection of accurate and complete data, the CRO will target the risks 
associated with critical trial data and these will be documented into the Data Management Plan 
(DMP) and the Monitoring Plan.
Investigators will respond to any query generated by the Data Management group or any data 
risk indicator reported.
Main Data Management activities and procedures will be accurately described in the DMP, 
created by the CRO and approved by Almirall.


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Database checks will be programmed by the CRO, based on the Data Validation Plan. The
listings will be documented in the DMP. The checks and listings programming will be 
appropriately validated by the CRO.
Reconciliation of trial data and SAEs between Clinical and Drug Safety databases will be 
performed by the CRO on an ongoing basis and before database lock. Procedures to be followed 
will be detailed in the DMP.
Encoding of specific data will be conducted by the CRO. For this trial, medical history, AEs, 
and concomitant medications (including rescue medications) will be coded; Medical 
Dictionary for Regulatory Activities (MedDRA) and WHO-DRUG Enhanced dictionaries will 
be used, version number of each dictionary will be documented in the DMP.
A Quality Control check to ensure the accuracy of the data will be done by the CRO, when 
data are cleaned on an ongoing basis and just before the database lock. Specifications of the 
Quality Control check will be found in the DMP.
An audit trail will be maintained in order to protect the authenticity and integrity of the clinical 
data.
12.3
Investigator and Trial Master Files
The Investigator's file and Sponsor Trial Master File (TMF) will contain all trial documents 
indicated in the ICH GCP guidelines and local regulations. 
At the trial end the Investigator will receive one CD/DVD/USB key with the electronic data 
capture (EDC) data, as well as one CD/DVD with the tablet PC and electronic Patient Diary 
data from the patients enrolled at his/her location. The Investigator will keep these in the 
Investigator’s file.
The CRO will provide Almirall with an electronic TMF (eTMF). Almirall will have on-line 
access to the eTMF during the study and study documents will be reviewed, approved, and 
managed within the system. At the end of the study the eTMF and complete audit trail will be 
transferred to the TMF-dedicated Sponsor server for long-term storage. Information about 
eTMF contents, index, structure, nomenclature, metadata, and oversight metrics will be 
detailed in other documents (ie, eTMF Management Plan, CROOP, etc.).
All records must be stored in a secure facility protected from fire, flood, and unauthorized 
access where they may be readily accessed in the event of an audit or inspection.
12.4
Documents and Record Keeping
The Investigator should retain control of the records (ie, completed and signed eCRF or 
certified copy of the eCRF). The Investigator maybe requested by inspectors with access to the 
records that serve as the electronic source data. 
When data elements are transcribed from paper sources into an eCRF, the Investigator must 
also retain the paper sources, or certified copies, for later review. Other records (electronic and 
paper) required to corroborate data in the eCRF may also be requested during an inspection.


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All trial data (including electronic data), all hard copies including protocol, consent forms, 
CRFs, queries and printouts, and all essential documents relating to the conduct of the clinical 
trial will be stored at the research site for a period of 25 years after completion of the trial, 
unless otherwise communicated in writing by the Sponsor.
CROs/vendors will store the databases, including audit trails and related documentation, for a 
period of 25 years after completion of the trial, 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.
13
Quality Control and Quality Assurance
13.1
Training of Staff
During the set-up phase of the trial, appropriate kick-off meetings will be performed between 
Almirall and the CRO and/ or vendors (eg, eCRF, laboratories, central ECG), in order to train 
CRO staff on trial procedures.
An Investigators’ meeting will be performed, including training on GCP procedures, trial 
protocol, efficacy and safety assessments, laboratory procedures, eCRF completion, usage of 
any specific device and any other applicable process/procedure/method, as applicable.
An initiation visit will be performed at each site by the trial CRA designated by the CRO to 
assess if all the material and supplies (eg, eCRF, IMP) arrived in good conditions and to train 
the site staff for protocol compliance.
Appropriate study manuals will be provided to the research sites as written help to support all 
trainings on all trial procedures (eg, laboratory samples, eCRF). 
13.2
Monitoring
The trial will be monitored by CRO CRA/Monitors according to the details specified in the 
Monitoring Plan.
The trial CRA/Monitor will conduct monitoring visits according to a pre-agreed schedule and 
with enough frequency to perform source data verification, check the accuracy of entries in the
CRFs, the adherence to the protocol and to GCP, the progress of enrollment and to ensure that 
trial medication is being stored, dispensed, and accounted for, according to specifications and 
report any deviation as soon as possible to the Clinical Trial Manager. 
Standard monitoring reports will be produced by the trial CRA/Monitor after each visit and 
filed in the TMF. Key trial personnel must be available to assist the field CRA/Monitor during 
these visits.
The Investigator must also keep the original informed consent form signed by the patient and 
maintain source documents for each patient in the trial, case and visit notes medical records, 
all information in eCRFs must be traceable to these source documents in the patient´s file.


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A close out visit to solve pending issues and to agree on the shipment of remaining trial 
materials to the Sponsor (eCRF and other data source, medication) will be performed by the 
trial CRA/Monitor once all patients have completed the trial.
13.3
Inspections and Audits
The trial site, trial processes, CRO, providers and/or trial documents may be subject to Quality 
Assurance audits by Almirall (or authorized partner companies) as well as to inspection by 
competent authorities, as applicable, during the trial or after trial completion. Audits and 
inspections may include, but are not limited to, drug supply, presence of required documents, 
informed consent process, medical records, general protocol compliance and comparison of 
data recorded in the eCRF and queries against source documents. Investigator will ensure direct 
access to source medical records for inspection and audit purposes.
14
Ethics
This trial will be conducted in accordance with the recommendations guiding physicians in 
biomedical research involving human patients adopted by the 18th World Medical Assembly 
of Helsinki (1964), as amended in Fortaleza, Brazil (2013) (World Medical Association, 2013), 
as well as in compliance with ICH GCP guidelines, and local laws of the Countries in which 
the trial centers are located. 
14.1
Responsibilities
The Investigator is responsible for conducting the trial in accordance with the procedures 
described in this protocol. All the personnel involved in the clinical trial will be fully informed 
about the drug and the nature of the trial and will be patient to protocol procedures concerning 
their duties in the trial.
The Investigator, the CRO/vendors and the Sponsor should ensure that all work and services 
described herein, or incidental to those described herein, shall be conducted according to the 
highest standards of Good Clinical Practice (ICH GCP guidelines) and local regulations.
The Investigator, the CRO and the Sponsor will work according to the ICH guidelines, EU
Clinical Trials Directive 2001/20/EC and/or Clinical Trials Regulation No 536/2014, and Title
21 of the US Code of Federal Regulations (US Food and Drug Administration [FDA]).
The Investigator shall administer the trial medication to patients under his or her personal 
supervision or under the supervision of any co-Investigator reporting to him/her who are 
identified in the delegation of responsibilities and signatures log. The Investigator and 
designees will be responsible for the patient’s compliance throughout the trial. 
Refer to Section 9.9.4, for details on post-trial medications.
14.2
Patient Information and Informed Consent
Patients will be informed by the Investigator in detail of the characteristics of the drug to be 
administered, the nature of the clinical investigation, the risks and the discomfort that can 
reasonably be expected as a result of their participation and the uses of the data, as described 
in the Patient Information Sheet (PIS).


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The patients will be informed that they are free to withdraw their consent and suspend their 
participation in the trial at any time with no penalty or loss of benefits to which the patient is 
otherwise entitled. Administration of the drug may be interrupted, and a patient withdrawn 
from the trial at the discretion of the Investigator. The Investigator should justify his decision 
in the patient's eCRF.
Any patient considered by the Investigator to be suitable for inclusion must document his or 
her willingness to participate in the trial by giving his or her informed consent in writing before 
starting any trial procedure by signing the ICF, which must be signed and dated by the patient 
and the Investigator. Explicit consent to participate in the standardized photography procedure 
will also have to be given by patient.
At such time the patient must be given adequate time to understand the information provided 
and ask questions, if required. Any new relevant information that becomes available during the 
trial will be provided to the patient. 
The PIS and ICF will include all elements required according to the applicable legislation. 
These documents or any modification will have been authorized by Almirall, S.A. and 
approved by the relevant IRB/IEC before use.
Patients will have access to the written PIS and ICF in paper or electronic format, preferably 
but not exclusively through a web system (eConsent). When using the eConsent process, the 
system will allow for on-line meetings between the patient and Investigator to facilitate 
answering patient questions and recording the responses. Patients will give their consent by 
signing electronically the ICF (eConsent). Patients will be requested to download the signed 
ICF, and/or ask the Investigator for a printed version. While they are in the study, patients will 
always have access to the PIS and ICF through eConsent. When eConsent cannot be used, the 
patient will sign a paper ICF.
14.3
Institutional Review Board/Independent Ethics Committee
This protocol, PIS and the ICF should be submitted to an IRB/IEC for review and approval. 
Notification in writing of approval must be obtained from the IRB/IEC by the Investigator 
before initiation of patient enrolment.
The Investigator must promptly report to the IRB/IEC all changes in the implementation of the 
research (protocol amendments) and will not make such changes without IRB/IEC approval 
except where necessary to eliminate apparent immediate hazards to the trial patients or 
administrative changes.
Serious adverse events reasonably related to the trial drug will be communicated by the 
Investigator/CRO to the IRB/IEC.
The Investigator is required to maintain accurate and complete records of all written 
correspondence sent to and received from the IRB/IEC and must agree to share these 
documents and any reports with the Sponsor.


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14.4
Patient Data Protection
The trial patients shall be informed by the Investigator that complete confidentiality will be 
maintained concerning their identity. On eCRFs/EDC and all trial data records (eg, electronic 
patient diary) patients will be identified only by the assigned patient identification number.
A signed written ICF signifies the explicit acceptance by the individual that data from the trial 
will be available to the Investigator and his/her staff, the authorized representatives of the 
Sponsor and, if required, by the IRB/IEC and Competent Authorities. However, all data 
contained in the patient’s medical history will be considered as confidential. Almirall will treat 
data according to personal data regulations (Health Insurance Portability and Accountability 
Act [HIPAA]), and any other applicable national and international regulation.
All clinical trial findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor.
15
Financing and Insurance
Almirall will set up a contract with the CRO with the economic aspects for trial funding. 
All patients recruited will have an insurance policy provided by Almirall to cover any possible 
risk resulting from their participation in the clinical trial.
Except in the proven case of clinical malpractice, the insurance company will indemnify 
against any claim or claims made by patients or their dependents which may result from 
administration of the IMP.
16
Publication Policy
Almirall will disclose clinical trials in a manner consistent with applicable national laws and 
rules governing personal data privacy and protection of intellectual property rights. Clinical 
trials will be registered, and results disclosed by means of recognized public databases, such 
as clinicaltrials.gov in the US and EudraCT in the European Union.
The Investigator understands and accepts that his/her name and trial center may be disclosed 
in the context of this national or international legislation.
All the information related to this clinical trial is considered strictly confidential and is the 
property of Almirall. This information will not be given to a third party without the written 
consent of Almirall.
By signing this trial protocol, the Investigator affirms to the Sponsor that he/she will maintain 
in confidence all information furnished to him/her in relation to or resulting from this trial. The 
Investigator will only divulge such information as may be necessary to the IRB/IEC, the 
members of the staff and the patients who are involved in this trial.
All relevant aspects regarding publication will be part of the contract (or similar document) 
between the Sponsor and CRO.


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In all cases, the trial results shall be reported in an objective, accurate, balanced, and complete 
manner, with a discussion of the strengths and limitations of the trial. All authors will be given 
the relevant statistical tables, figures, and reports needed to support the planned publication. 
Publication and/or presentation whether complete or partial, of any part of the data or results 
of this trial will not be allowed until global publication and trial results disclosure by the 
Sponsor as per US FDA regulatory compliance obligations, and only after mutual agreement 
between the Investigator and Almirall.
17
Other Practical Considerations
17.1
Investigator’s Brochure
The Investigator’s Brochure contains a summary of the pre-clinical and clinical data. The same 
confidentiality procedures apply for the Investigator’s Brochure as for the protocol.
The Investigator’s Brochure will be included in the Investigator file. The Investigator will sign 
a receipt form.
17.2
Final Clinical Trial Report
The CSR will be written by the CRO following the ICH guidelines requirements. It will be 
approved and signed by the Coordinating Investigator and Almirall representatives according 
to internal SOPs. 
The CSR will be audited by the CRO and/or Almirall before issuing the final version. 
The final version of the electronic CSR will be e-published (hyperlink, bookmarks, etc.) 
including all appendices according to ICH Guidelines.
The summary of the CSR will be sent to all the Investigators participating in the clinical trial.
17.3
Protocol Amendments
Modifications of the original protocol are referred to as “amendments” to the trial protocol. 
Modifications of the original protocol may only be made with Almirall approval. Two types of 
amendment maybe produced:
x Substantial Amendments (related to the safety or physical or mental integrity of the patients, 
scientific value of the trial, conduct or management of the trial or the quality or safety of 
any IMP used) must be notified to the IRB and/or Competent Authorities and approved by 
them before implementation.
x Non-substantial Amendments do not require notification but should be recorded and be 
available on request for inspection at the trial site and/or Sponsor premises as appropriate.
17.4
Protocol Deviations
Any protocol deviations during the conduct of the trial will be recorded by the CRA/Monitors
as detected or derived from data collected in the clinical database. 


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Relevant deviations will be promptly reported to Almirall after detection. Major protocol 
deviations will be included in the corresponding listing of the CSR.
Additionally, protocol deviations will be reported to the IRBs/IECs and/or Competent 
Authorities according to the local regulation in each country.
18
References
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high-risk and metastatic disease. Am J Clin Dermatol. 2016;17(5):491-508.
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guidelines for the care of patients with actinic keratosis 2017. Br J Dermatol. 2017;176(1):20-
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Dirschka T, Pellacani G, Micali G, et al. A proposed scoring system for assessing the severity 
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Dodds A, Chia A, Shumack S. Actinic keratosis: rationale and management. Dermatol Ther 
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Figueras Nart I, Cerio R, Dirschka T, et al. Defining the actinic keratosis field: a literature 
review and discussion. J Eur Acad Dermatol Venereol. 2018;32(4):544-63.
Flohil SC, van der Leest RJ, Dowlatshahi EA, et al. Prevalence of actinic keratosis and its risk 
factors in the general population: the Rotterdam Study. J Invest Dermatol. 2013 
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Green AC, Olsen CM. Cutaneous squamous cell carcinoma: an epidemiological review. Br J 
Dermatol. 2017;177(2):373-81.
Goldenberg G. Treatment considerations in actinic keratosis. J Eur Acad Dermatol Venereol. 
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Hofbauer G, Anliker M, Boehncke WH, et al. Swiss clinical practice guidelines on field 
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S3-Leitlinie Aktinische Keratose und Plattenepithelkarzinom der Haut, Kurzversion 1.0, 2019, 
AWMF Registernummer: 032/022OL. Available at: https://www.leitlinienprogramm-
onkologie.de/leitlinien/aktinische-keratose-und-plattenepithelkarzinom-der-haut/ 
[Accessed 
on: 02-Dec-2019].


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Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell 
carcinoma. Lancet. 1988;1(8589):795-7.
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factors, diagnosis, and staging. J Am Acad Dermatol. 2018;78 (2):237-47.
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an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol. 2007 
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Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad 
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Venereol. 2019;33(7):1421-8.
Werner RN, Sammain A, Erdmann R, et al. The natural history of actinic keratosis: a systematic 
review. Br J Dermatol. 2013;169(3):502-18.
Werner RN, Stockfleth E, Connolly SM, Correia O, Erdmann R, Foley P, et al. Evidence- and 
consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League 
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4.
19
Appendices
1. Highly Effective Methods of Birth Control
2. Patch test for the Assessment of Contact Dermatitis


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Appendix 1, Highly Effective Methods of Birth Control
Highly effective methods or birth control (ref. CTFG 2014 guidance document):
x
Intrauterine device, intrauterine hormone-releasing system or bilateral tubal occlusion 
or ligation (1)
x
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal or transdermal)
x
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable (1))
x
Vasectomized partner (2). Female patient must agree to implement one of the other 
highly effective methods of birth control if her lifestyle/partner changes
x
Sexual abstinence (3)
Notes
(1) Low user dependency methods from at least 3 months before trial screening
(2) Only provided that partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomized partner has received medical assessment of the surgical success.
(3) Only if defined as refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments (from Day1 to at least 30 days after the last dose of the investigations product).


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Appendix 2, Patch Test for the Assessment of Contact Dermatitis
In the event the patient experiences a skin reaction of such nature or severity that an allergic 
contact dermatitis is suspected, the patient can be treated with topical treatment with 
corticosteroids (eg, betamethasone) and oral antihistamines and should temporally discontinue 
the study medication. The event should be documented as an adverse event and the medication 
given recorded. The patient should be re-challenged using the assigned study medication (patch 
test in the back) to confirm or rule out contact dermatitis. If the diagnosis of allergic contact 
dermatitis is confirmed the patient may have an additional patch test with both the tirbanibulin-
containing ointment and the vehicle base.
The patch test will be performed at least 2 weeks after last treatment or discontinuation of the 
study medication. Patches will be applied to untreated areas on the back for 48 hours. Readings 
will be performed approximately 15 to 30 minutes and 48 hours following the removal of the 
patches. At the investigator’s discretion, a facultative additional reading might be performed at 
96 or 120 hours after removal of the patches if an equivocal reaction is observed at the previous 
reading. If allergic contact dermatitis is confirmed the patient will discontinue permanently the 
study medication, on the contrary the patient can be treated with the study medication if 
necessary.


ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-yyyy HH:mm ‘GMT’Z)
eDMS R&D Object_ID: 
$OPLUDOO3URWRFRO0BYB0DUB)LQDO
&OLQLFDO$SSURYDO
0DU*07
&OLQLFDO$SSURYDO
0DU*07
&OLQLFDO6WDWLVWLFV$SSURYDO
0DU*07
PPD
PPD
PPD
CCI




Clinical Trial M- 14867-32
Administrative Change 1
ALMIRALL, S.A.
CONFIDENTIAL
Page 1 of 2
Almirall, S.A.
Ronda General Mitre, 151
08022 Barcelona, Spain
Letter of Protocol Clarification - Administrative Change 1
Protocol Title:
A Phase 3, Multicenter, Open-label, Single-arm Study to Evaluate the 
Safety and Tolerability of Tirbanibulin Ointment 1% Applied to a Field of
Approximately 100 cm2 on the Face or Balding Scalp in Adult Patients with 
Actinic Keratosis
Protocol Number:
M-14867-32
Date:
03-JAN-2023
Dear Investigator(s), 
After the issuance of M-14867-32 Protocol Version 2.0 dated 21 March 2022, and for the correct 
development of the trial, clarifications were determined to be needed in relation to the completion 
of patient's eDiary.
At section “12.1.3 Patient Diary”, the protocol details the usage of an electronic diary (Study App) 
to record daily the study treatment application dates and times of application for the above-
mentioned study, to be completed by subjects. However, in case of need, a paper diary was also 
developed as an alternative when needed.
This contingency plan was not included in the protocol by mistake, and therefore it is not listed in 
the section “12.1.1 Identification of the Trial Data Source” as a valid source document.
The mentioned paper diary was developed, submitted, and approved by the Ethics Committee prior 
to implementation at sites. However, since this contingency plan was not included in the Protocol,
there was the need to issue this clarification letter to specify that both the Study App and the paper 
diary, when applicable, are considered trial data sources for study treatment application dates and
times.
Since this is a minor correction, an amendment to the Protocol is not expected.
CCI



SAP_001.pdf: 
Final Report M-14867-32 
 
 
 
 
CONFIDENTIAL                                                     ALMIRALL 
 
 
 
16.1.9 Documentation of Statistical Methods 
 
M-14867-32 Statistical Analysis Plan Version 1.0, 17-JAN-2023 
 
Final Version 1.0 




 
 
 
 
 
 
 
M -1 4 8 6 7 -3 2                                   St ati sti c al A n al y si s Pl a n     St at u s:  V er si o n (1 7  J a n  2 0 2 3 )     
 
 
Gl o b al Cli ni c al  St ati sti c s  
 
 
          P a g e 2  of 3 6  
S R D -0 0 0 2 1 2 8 v 3. 0  
C O N FI D E N TI A L  
S A P R E VI SI O N S U M M A R Y  
V er si o n  
V er si o n D at e  
A ut h or  
S u m m ar y of C h a n g e s  
Fi n al v 1. 0  
1 7 -J a n -2 0 2 3  
 
I niti al v er si o n 
 
 
 
D o c u Si g n E n v el o p e I D: 3 1 8 A F 1 C 6- E 0 1 8- 4 8 C 4- 8 C 0 C- 1 A C E A 6 D 5 8 A D A
P P D


 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
Contents 
1 
Abbreviations .......................................................................................................................5 
2 
Clinical Trial Personnel ........................................................................................................7 
3 
Introduction ..........................................................................................................................8 
3.1 
Description of this Document .........................................................................................8 
3.2 
Trial Design ....................................................................................................................8 
4 
Objectives .......................................................................................................................... 13 
4.1 
Objectives .................................................................................................................... 13 
4.2 
Endpoints ..................................................................................................................... 13 
4.2.1 
Safety Endpoints ................................................................................................... 13 
4.2.2 
Exploratory Endpoints ........................................................................................... 14 
5 
Sample Size Justification ................................................................................................... 15 
6 
Structure and Methodology of Statistical Analysis ............................................................. 16 
6.1 
Descriptive Statistics .................................................................................................... 16 
6.2 
Level of Statistical Significance .................................................................................... 16 
6.3 
Baseline ....................................................................................................................... 16 
6.4 
Interim Analysis ........................................................................................................... 16 
6.5 
Reference Start Date and Analysis Day ....................................................................... 17 
6.6 
Software Version ......................................................................................................... 17 
7 
Data Handling .................................................................................................................... 18 
7.1 
Missing Data ................................................................................................................ 18 
7.2 
Computation of Derived Variables ............................................................................... 18 
7.3 
Windowing Conventions .............................................................................................. 18 
7.4 
Repeated or Unscheduled Assessments ..................................................................... 19 
8 
Analysis Populations .......................................................................................................... 20 
9 
Study Patient ..................................................................................................................... 21 
9.1 
Patient Disposition ....................................................................................................... 21 
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9.2 
Protocol Deviation ........................................................................................................ 21 
10 Demographic and Other Baseline Characteristics ............................................................. 23 
10.1 
Demographics and Baseline Characteristics ............................................................ 23 
10.2 
Medical History ......................................................................................................... 23 
11 Exposure and Compliance ................................................................................................. 24 
11.1 
Exposure to Study Medication .................................................................................. 24 
11.2 
Compliance with Study Medication ........................................................................... 24 
12 Analyses of Prior and Concomitant Medication ................................................................. 25 
13 Analyses of Exploratory Endpoints .................................................................................... 26 
13.1 
AK Lesions Count ..................................................................................................... 26 
14 Analyses of Safety and Tolerability Endpoints ................................................................... 27 
14.1 
Local Tolerability Assessment .................................................................................. 27 
14.2 
Scarring, Hypopigmentation and Hyperpigmentation ............................................... 28 
14.3 
Adverse Events ........................................................................................................ 28 
14.4 
Clinical Laboratory Parameters ................................................................................ 30 
14.5 
Vital Signs ................................................................................................................. 30 
14.6 
ECGs ........................................................................................................................ 30 
14.7 
Physical Examinations .............................................................................................. 31 
15 Additional Analyses ........................................................................................................... 32 
15.1 
Subgroup Analyses .................................................................................................. 32 
15.2 
Other Analyses ......................................................................................................... 32 
16 Changes to Analyses Specified in the Protocol ................................................................. 32 
17 References ........................................................................................................................ 34 
18 Appendices ........................................................................................................................ 35 
18.1 
Appendix 1 ................................................................................................................ 35 
18.2 
Appendix 2 ................................................................................................................ 36 
 
 
 
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1 ABBREVIATIONS 
 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AK 
Actinic keratosis 
ATC 
anatomical therapeutic chemical 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EoS 
End of Study 
EoT 
End of Treatment 
ESI 
Event of special interest 
ET 
Early termination 
ICF 
Informed Consent Form 
PE 
Physical examination 
PT 
preferred term 
Q1 
first quantile 
Q3 
third quantile 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS  
Statistical Analysis System® 
SE 
standard error 
SD 
standard deviation 
SOC 
system organ class 
TF(s) 
Treatment Field(s) 
TEAE 
Treatment-emergent adverse event 
TESAE 
treatment emergent serious adverse events 
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TLF 
tables, listings, and figures 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
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2 CLINICAL TRIAL PERSONNEL 
 
A detailed list of team members with respective role and contact information is maintained 
separately in the main study contact list. 
 
 
 
 
 
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3 INTRODUCTION 
 
3.1 Description of this Document 
 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for sponsor 
clinical protocol M-14867-32. The analyses described in the SAP are based upon the protocol 
Version 2.0 dated 21-Mar-2022. In case of discrepancies between the protocol and the SAP, 
the SAP will be used to guide the statistical analysis. 
 
This SAP has been developed prior to database lock and final analyses. All final analyses will 
be performed after the clinical trial data are entered into the database, any discrepancies in the 
data are resolved, the database is locked, and following the signature of the SAP. 
 
The signature of this SAP will act as the assignment of each patient within the populations. 
 
3.2 Trial Design 
 
This is a Phase 3, multicenter, open-label, single-arm trial to evaluate safety and local 
tolerability of tirbanibulin ointment 1% administered topically for 5 days over a field of 
approximately 100 cm2 on the face or balding scalp in adult patients with actinic keratosis (AK). 
The study consists of a 4-week (28-day) Screening Period, a 5-day Treatment Period, and a 
Response Assessment Period of approximately 7 weeks (see Table 1, Schedule of 
Assessments): 
 
• During the Treatment Period, patients will apply tirbanibulin ointment 1% once daily for 5 
days beginning on Day 1. 
• All patients will be evaluated for safety, tolerability, and the presence of AK lesions in 
the treatment field (TF) until completion of the Response Assessment Period at Day 57. 
 
Enrollment will be controlled such that the trial population is representative of the population 
expected to use the product in terms of age and treated area. A minimum of 50% of patients 
older than 65 years old will be included and approximately two-thirds of the patients will be 
treated for AK lesions on the face and one-third on the scalp.
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e On Day 5 patients are to bring all 5 study drug packets back to the site (used and unused) with their respective torn parts in the individual closed zipper storage 
bag provided in the study kit. 
f All study drug packets will be weighed together in their respective closed zipper storage bag before and after use (including the torn opening part). 
g At each study visit, patients will be asked a general question e.g. “How have you been since the last visit?” AEs will be recorded before assessments of local 
tolerability, hypo- and hyperpigmentation, and scarring in the TF. AEs will be reported separately from local tolerability signs. 
h All patients who have unresolved local tolerability signs, hypo- or hyperpigmentation, scarring in the TF, or treatment-related AEs at Day 57 will return for 
additional follow-up every 7 to 28 days until these have resolved, have returned to the baseline value, or are deemed stabilized by the Investigators. 
i Measurement of vital signs will include blood pressure, heart rate, respiratory rate, and body temperature. Measurements of systolic and diastolic blood pressure 
will be performed after at least 5 minutes of rest in a supine position and preferably on the same arm. 
j Patients will complete a diary (Study App) to record daily dates and times of study treatment application. The diary (Study App) will be checked by the Investigator 
(or designee) at Visit 3. 
k TF identification (face/scalp) 
l Baseline photo is only required in case of any significant change from Screening is detected in the TF as per the Investigator judgement or if the quality of the 
image captured at Screening is not appropriate. If no photo is needed at baseline, then the screening photo will be considered the baseline assessment. 
m Study drug will be applied by the patient at home before study Visit 3 on Day 5, which will take place at the clinical site. 
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4 OBJECTIVES 
 
4.1 Objectives 
 
The primary objective of the trial is to evaluate the safety and tolerability of tirbanibulin ointment 
1% when applied to a field of approximately 100 cm2 on the face or balding scalp. 
 
Additionally, the treatment effect of tirbanibulin ointment 1% when applied to a field of 
approximately 100 cm2 on the face or balding scalp will be explored. 
 
4.2 Endpoints 
4.2.1 Safety Endpoints 
 
Safety Endpoints 
 
• Local Tolerability Assessment: 
 
o Number and proportion of patients with each local tolerability score by visit (0-3) for 
each individual sign (erythema, flaking/scaling, crusting, swelling, 
vesiculation/pustulation, and erosion/ulceration) 
 
o Maximum local tolerability score post baseline through all the visits for each 
individual sign 
 
o Time to maximum local tolerability score for each individual sign 
 
o Local tolerability signs composite score (0-18) by visit, defined as the sum of the 
scores graded from 0 to 3 on all six individual tolerability sign categories 
 
o Maximum local tolerability signs composite score post baseline through all the visits 
 
o Time to maximum local tolerability composite score 
 
o Proportion of patients with pigmentation and scarring in the TF through all the visits 
 
• Number and proportion of patients with treatment emergent adverse events (TEAEs), 
treatment emergent serious adverse events (TESAEs), adverse events of special 
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interest (AESIs), and change from baseline in clinical laboratory data, and other safety 
assessments (vital signs, physical examinations [PEs], electrocardiograms [ECGs]) 
 
4.2.2 Exploratory Endpoints 
 
• Absolute number, change from baseline, and percent change from baseline in AK lesion 
count from total lesions in the TF at each visit 
 
• Absolute number, change from baseline, and percent change from baseline in AK lesion 
count, for lesions that were already present at baseline, from total lesions in the TF at 
each visit 
 
• Absolute number and percent change of new lesions from total lesions in the TF at each 
visit 
 
 
 
 
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5 SAMPLE SIZE JUSTIFICATION 
 
Approximately 125 patients will be screened to initiate treatment in approximately 100 patients. 
 
With 100 patients and assuming an expected percentage of patients with at least one local 
tolerability sign of approximately 90%, the precision in the estimation of that percentage will be 
approximately 11%. The precision is defined as the width of the 95% confidence interval.  
 
Furthermore, 100 patients will provide approximately 10% and 13% precision in the estimation 
of the percentage of patients with the local tolerability events of particular interest, specifically 
vesiculation/pustulation (assuming an expected percentage of 8%) and erosion/ulceration 
(assuming an expected percentage of 12%), respectively. 
 
 
 
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6 STRUCTURE AND METHODOLOGY OF STATISTICAL ANALYSIS  
6.1 Descriptive Statistics 
 
Categorical variables will be summarized with counts (n) and percentages (%). For continuous 
variables, the number of non-missing observations (n), mean, standard deviation (SD), 
standard error (SE) of the mean, 95% confidence interval (CI) of the mean, median, first (Q1) 
and third (Q3) quartiles, minimum (min) and maximum (max) will be tabulated.  
 
The 95% confidence interval for continuous data will be calculated using the normal 
approximation. If less than 30 patients with non-missing data are available (in a sub-group, if 
applicable) for a specific continuous data point, no confidence interval will be reported for this 
data point.  
 
The 95% confidence interval for proportions will be calculated using the exact Clopper-Pearson 
method.  
 
When applicable, summaries will be provided by visit of assessment. 
 
6.2 Level of Statistical Significance 
 
No statistical inferences will be performed for this study. Confidence intervals (CIs) will be two-
sided with 95% coverage. 
 
6.3 Baseline 
 
Unless otherwise specified, baseline value will be defined as the last non-missing assessment 
prior to the first study treatment dose dosing on Day 1 (including unscheduled and repeat 
assessments). If the last non-missing assessment is performed on the same date as the first 
study treatment administration and time is not available, the assessment will be considered as 
baseline, except for adverse events (AEs) not related to a pre-dose assessment and 
medications starting on the first study treatment dose administration date which will be 
considered post-baseline.  
 
6.4 Interim Analysis 
 
No interim analyses are planned. 
 
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6.5 Reference Start Date and Analysis Day 
 
Analysis day will be calculated from the first study treatment dose administration date and will 
be used to show start/end day of assessments or events.  
 
Analysis day = (Date of event – Date of first dose administration) + 1 if date of event is on or 
after the date of first dose administration of study treatment; 
 
= (Date of event – Date of first dose administration) if date of event is before the 
date of first dose administration of study treatment. 
 
In the situation where the assessment/event date is partial or missing, analysis day will be 
missing. 
 
 
6.6 Software Version 
 
All analyses will be performed using SAS® software Version 9.4 or higher. 
 
 
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7 DATA HANDLING 
 
7.1 Missing Data 
 
No imputation will be made for missing data. See Appendix 2 for handling of completely or partially 
missing dates and time for prior and concomitant medications and adverse events. 
 
7.2 Computation of Derived Variables 
 
Change from baseline will be calculated as:  
 
Assessment value at post-baseline Visit X – Baseline value. 
 
Percent change from baseline (%) will be calculated as: 
 
(Assessment value at post-baseline Visit X – Baseline value) / Baseline value * 100. 
 
Percent change from baseline will be missing in situation where baseline value equals to 0. 
 
7.3 Windowing Conventions 
 
Windowing conventions will apply to all local tolerability, hypopigmentation, hyperpigmentation 
and scarring, and AK lesions count assessments.  
 
Visits will be analyzed as scheduled. Scheduled, unscheduled, and early termination visits 
measurements will only be included if the scheduled, early termination, or unscheduled 
measurement falls within the analysis visit windows as described in Table 2. 
 
 
 
 
 
 
 
 
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Table 2  
Analysis Visit Windows  
Analysis Visit 
Target Study Day 
Local tolerability, 
Hypopigmentation, 
hyperpigmentation and Scarring, 
AK lesions count 
Baseline 
Refer to Baseline definition 
Refer to Baseline definition 
Day 5 
5 
[1 post-dose; 5] 
Day 8 
8 
[6; 11] 
Day 15 
15 
[12; 22] 
Day 29 
29 
[23; 43] 
Day 57 
57 
[44; EOS] 
 
If there is more than one assessment for a given analysis visit, the assessment closest to the 
target day will be considered. If two assessments fall at the same distance from the target day 
for a given analysis visit and one of them is a scheduled assessment, the scheduled 
assessment will be considered. If two assessments fall at the same distance from the target 
day for a given analysis visit and none of them is a scheduled assessment, the first 
assessment will be considered.  
 
 
7.4 Repeated or Unscheduled Assessments 
 
When repeated measurements are done, the repeated measurement will be considered for the 
windowing and analysis in lieu of the original measurement. 
 
For local tolerability, hypopigmentation, hyperpigmentation and scarring, and AK lesions count 
assessments, unscheduled and early termination assessments will be remapped as mentioned 
in section 7.3. All data from visits will be listed under the nominal visit, and the analysis visit will 
also be presented if it differs from the nominal visit. 
 
For other assessments, unscheduled measurements will not be summarized in by-visit 
summary tables or figures. Early Termination (ET) visit assessments will be summarized as 
part of the Day 57/ET visit. All data from unscheduled and early termination visits will be listed. 
 
 
 
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8 ANALYSIS POPULATIONS 
 
There will be one analysis population in this trial: 
 
Safety population: The safety population will include all patients who have received at least one 
dose of study treatment. 
 
 
 
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9 
STUDY PATIENT 
9.1 Patient Disposition 
 
All patients who provide informed consent will be accounted for in this study. The number of 
patients screened and number and percentage who failed screening (screen failures) will be 
presented. The reason for screen failure (count and percentage) will be presented for all 
screened patients who failed screening, if applicable. Moreover, the number of patients 
enrolled (patients will be considered as enrolled if they started Day 1) and included in the 
safety population will be presented. Study completion status and the reason for study 
discontinuation, including if related to COVID-19 or not, will also be presented both as count 
and percentages. The percentage of patients with screen failures will be calculated using the 
number of patients screened as denominator. The percentage of screen failure by reasons will 
be calculated using the number of screen failures as denominator. The percentage of patients 
with study discontinuation and reasons for discontinuation, including if related to COVID-19 or 
not, will be calculated by reasons using the number of enrolled patients who did not complete 
study as denominator. Otherwise, percentages will be calculated using the number of patients 
enrolled as denominator.  
 
Number of days in the study will be calculated as follows and summarized using descriptive 
statistics based on the safety population: 
 
Number of days in study = Date of completion/discontinuation – first study drug dose 
date +1. 
 
A listing of patients’ disposition will be provided. A listing of patients excluded from the safety 
population and associated reason, and a listing of missed visits due to the COVID-19 
pandemic will also be provided. 
 
 
9.2 Protocol Deviation 
 
All protocol deviations will be reported based on Almirall protocol deviations categories. 
Important vs. not important classification of protocol deviations will be conducted prior to the 
database lock. 
 
The number of events and the number and percentage of patients with at least one important 
protocol deviation will be summarized by deviation category and sub-category using the safety 
population. In case of a site-level protocol deviation, one protocol deviation for each patient for 
that site will be accounted for in the tables and listings. The number of events and the number 
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and percentage of patients with at least one protocol deviation related to COVID-19 will be 
summarized similarly. 
 
A listing of all protocol deviations will also be provided. 
 
 
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10 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
 
10.1 Demographics and Baseline Characteristics 
 
Descriptive statistics will be used to summarize demographic characteristics (age as collected 
at the time of Informed Consent Form, sex, Fitzpatrick skin type, race, and ethnicity) and 
baseline characteristics (height, body weight, area of face or scalp treated, number of AK 
lesions in the treatment field, presence of scarring, hypopigmentation and hyperpigmentation in 
the treatment field, and smoking and alcohol habits usage [never, current or former for 
smoking; consumption yes vs no for alcohol]), based on the safety population. Patients who 
reported more than one race will be summarized as ‘Multiple’ races in the table, and all races 
selected will be displayed in the listing.  
 
A listing of all demographics and baseline characteristics will be provided.  
 
10.2 Medical History 
 
Surgical and medical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 25.0. 
 
Non-AK surgical and medical history will be summarized by system organ class (SOC) and 
preferred term (PT) using the safety population. A patient who experienced the same non-AK 
surgical and medical history event multiple times will be counted only once for the 
corresponding PT. Similarly, if a patient experienced multiple non-AK surgical and medical 
history events within the same SOC, the patient will be counted only once for that SOC. Non-
AK surgical and medical history events will be sorted alphabetically by SOC and within each 
SOC the PT will be presented by decreasing order. 
 
A listing of all non-AK surgical and medical history events will be provided. 
 
AK disease history, including body parts and sides affected, will be summarized based on the 
safety population. The time since first AK diagnostic (in years) will be calculated as: 
 
Time since first AK diagnostic (years) = {[First study treatment dose date – first AK diagnostic 
date] + 1} / 365.25. 
 
Should any AK diagnostic date be partially or completely missing, the time since first AK 
diagnostic will be left as missing. 
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A listing of AK disease history will be provided.  
 
11 EXPOSURE AND COMPLIANCE 
 
11.1 Exposure to Study Medication 
 
Duration of exposure to study treatment, in days, will be computed as follows: 
 
[(Date of last dose of study treatment – Date of first dose of study treatment) + 1]. 
 
Descriptive statistics for the duration of exposure to study treatment will be presented based on 
the safety population. Duration of exposure will also be presented by treatment area (scalp or 
face) sub-groups. 
 
A summary of amount of product applied will be presented based on the safety population. 
Amount of product applied will be derived based on the information on the pre-dose packets 
weight and post-dose packets weight captured in the eCRF. Amount applied (in grams) will be 
computed as follows: 
 
(Sum of packets weight pre-dose on Day 1 – Sum of packets weight post-dose on Day 5). 
 
If the information on packet weight is missing for a dispensed packet (i.e., the number of 
packets returned is not equal to the number of packets dispensed), the amount applied will be 
missing. 
 
A listing of study treatment amount applied, number of packets dispensed, returned and used 
will be provided. 
 
11.2 Compliance with Study Medication 
 
 
Compliance with study treatment (%) will be calculated based on used packets as follows: 
 
Total number of used packets per the eCRF
Total duration of exposure (days) x Planned number of dose per day (i. e. , 1) x100 
 
 
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Descriptive statistics for the compliance to study treatment will be presented based on the 
safety population. Frequency distribution will also be presented for the following compliance 
categories: <80%, 80% to 120%, >120%. Compliance will also be presented by treatment area 
(scalp or face) sub-groups. 
 
If a patient did not return the full number of packets dispensed, his compliance will be left as 
missing. 
 
A listing of patient exposure, compliance and drug interruption will be provided. 
 
12 ANALYSES OF PRIOR AND CONCOMITANT MEDICATION 
 
Medications will be coded according to the World Health Organization Drug Dictionary (WHO-
DD) B3, March 2022. 
 
Prior medications are defined as any medication started and discontinued prior to the first 
study treatment dosing. Concomitant medications are defined as any medication started on the 
same day than or after the first study treatment dosing, including those who started prior to the 
first study treatment date and continued past that date. See Appendix 2 for handling of 
completely or partially missing dates and time for prior and concomitant medications.  
 
Incidence of prior and concomitant medications will be tabulated by anatomical therapeutic 
chemical (ATC) Level 3 and standardized drug name using the safety population. A patient 
with the same medication taken multiple times will be counted only once for the corresponding 
standardized drug name. Similarly, if a patient has taken more than one medication within the 
same ATC level, then the patient will be counted only once for that ATC. Prior and concomitant 
medications will be sorted alphabetically by ATC level and within each ATC level, the 
standardized drug name will be presented by decreasing order.   
 
Prior and concomitant medication information will be presented in a by-patient listing using the 
Safety population. 
 
Actinic keratosis treatment non-drug therapies and procedures during the study will be 
provided in a listing.  
 
 
 
 
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13 ANALYSES OF EXPLORATORY ENDPOINTS 
 
The analyses of exploratory endpoints will be performed on the safety population. No statistical 
inferences will be performed. 
 
13.1 AK Lesions Count 
 
At screening, the Investigator will select and measure the TF (e.g., approximately mid face or an 
area on the scalp). Each AK lesion within the TF will also been identified with a label.  A 
photograph will be captured using imaging devices to be used to support the location of the same 
TF identified at screening during the follow-up study visits assessments.  At baseline (Day 1), 
the area of the TF and location of AK lesions in the TF will be confirmed. A baseline photograph 
is only required in case of any significant change from screening is detected in the TF as per 
Investigator’s judgement or if the quality of the image captured at screening is not appropriate.  
If no photograph is needed at baseline, then the screening photograph, TF, and AK lesions count 
will be considered the baseline assessment.  At each post-baseline visit, all lesions in the TF will 
be counted and details on whether the lesion present in the TF is new or an existing lesion at 
baseline will be recorded in the eCRF. 
 
The absolute number, change from baseline, and percent change from baseline in total 
number of AK lesions in the TF (i.e., already present at baseline AND new) will be analysed 
descriptively at each visit.  
 
The absolute number, change from baseline and percent change from baseline in AK lesion 
count for lesions that were already present at baseline in the TF will be summarized at each 
post-baseline visit using descriptive statistics.  
 
The absolute number and percent change in new AK lesions since baseline in the TF will also 
be summarized at each post-baseline visit using descriptive statistics. The percent change in 
new AK lesions since baseline in the TF is defined as: 
 
Number of new AK lesions in the TF
Number of AK lesions at baseline  x 100 
 
A listing of AK lesions count will be provided. Figures of the AK lesions counts (total lesions, 
lesions that were already present at baseline, and new lesions from baseline) by visit will also 
be provided. 
 
 
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14 ANALYSES OF SAFETY AND TOLERABILITY ENDPOINTS 
 
The analyses of safety and tolerability endpoints will be performed on the safety population.  
14.1 Local Tolerability Assessment 
 
Local tolerability is assessed based on the review of the following signs in the treatment field: 
erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration 
and will be evaluated both individually and as a composite score (total of the 6 individual 
scores ranging from 0 to 18). These signs will be graded as:  0=absent, 1=mild (slightly, barely 
perceptible), 2=moderate (distinct presence), and 3=severe (marked, intense). If one or more 
individual score is missing, the composite score will be set as missing.  
 
The maximum local tolerability signs composite score across visits will be derived as the 
maximum local tolerability assessment (LTA) composite score observed post-baseline for a 
patient. The maximum local tolerability of individual signs across visits will be derived as the 
maximum LTA of an individual sign observed postbaseline for a patient. 
 
Descriptive statistics will be presented for local tolerability signs composite score by visit, and 
for maximum local tolerability signs composite score across post-baseline visits. Frequency 
and percentages by visit of patients presenting any individual and composite local tolerability 
signs and associated CI based on exact Clopper-Pearson method will be presented. The 
presence of any individual and composite local tolerability sign is defined by a score of >0. 
Frequency and percentages by visit for specific local tolerability individual signs results and 
maximum local tolerability of individual signs across post-baseline visits will also be provided. 
 
The 95% CI will be presented for the median of the maximum local tolerability composite score. 
 
Figures presenting the number of patients with each local tolerability individual sign 
(absent/mild/moderate/severe) by visit, and a figure presenting the mean local tolerability 
composite score by visit will be produced.  
 
The time to maximum LTA score for each individual sign and the time to maximum LTA 
composite score will be calculated as the time (in days) from the first dose of study treatment to 
the time of the first occurrence of the maximum LTA score observed post-baseline for each 
individual sign and composite score, respectively. That is, for each individual sign, time to 
maximum LTA, in days, will be calculated as follows: 
 
(Date of first post-baseline occurrence of maximum LTA score for an individual sign – Date of 
first dose) 
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Time to maximum composite LTA, in days, will be calculated as follows: 
 
(Date of first post-baseline occurrence of maximum composite LTA score – Date of first dose) 
 
If a patient’s maximum composite/individual sign LTA score stays at 0 throughout the study, 
the patient will be considered censored at his last LTA score observation. The time to 
maximum composite/individual sign LTA will be analyzed using Kaplan Meier estimation, 
overall and by strata as applicable. The Kaplan Meier estimates will include the 25th, 50th 
(median), and 75th percentiles along with their 95% CIs. The standard errors (SE) will be 
computed using the Greenwood’s formula. The CI for the median will be calculated as per 
Brookmeyer and Crowley and the CIs for the 25th and 75th percentiles will be calculated using 
the log-log transformation. 
 
Survival curves will also be presented and all local tolerability assessments will be listed. 
14.2 Scarring, Hypopigmentation and Hyperpigmentation 
 
The number and percentage of patients with absence or presence of scarring, 
hypopigmentation, and hyperpigmentation in the TF and associated 95% CIs will be presented 
separately at scheduled visits. 
 
Shift tables representing the change from baseline in scarring, hypopigmentation, and 
hyperpigmentation in the TF will be provided separately as well. Only patients with a baseline 
result and a result at the specified post-baseline visit for the parameter will be considered in the 
shift tables. 
 
Scarring, hypopigmentation and hyperpigmentation evaluations will be presented in a listing.  
14.3 Adverse Events 
 
AEs will be coded according to the MedDRA, Version 25.0. 
 
TEAEs will be defined as any AEs with onset date/time on or after the first study treatment 
dosing and prior to the last date of study treatment dosing + 57 days (inclusive), or as any AE 
that was present prior to the first dose of trial drug but increased in severity on or after the first 
study treatment dosing and prior to the last date of study treatment dosing + 57 days 
(inclusive). AEs starting on the first study treatment dosing date and related to a pre-dose 
study assessment will not be considered as TEAE. See Appendix 2 for handling of completely 
or partially missing dates and time for AEs. In the case where it is not possible to define an AE 
as treatment emergent or not, the AE will be classified as treatment emergent.  
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Overall summaries of AEs will be presented by number and percentages of patients with and 
number of events of AEs, TEAEs, study treatment-related TEAEs, TESAEs, TEAEs by worst 
severity, TEAEs leading to study treatment discontinuation, TEAEs leading to study 
discontinuation, application site TEAEs, AESIs, and TEAEs with an outcome of death.  
 
Frequency and percentage of patients who experience TEAE will be summarized by SOC and 
PT within SOC. Unless otherwise specified, a patient experiencing the same TEAE multiple 
times will be counted only once for the corresponding PT. Similarly, if a patient experiences 
multiple TEAEs within the same SOC, the patient will be counted only once for that SOC. 
TEAEs will be sorted alphabetically by SOC and within each SOC the PT will be presented by 
decreasing order. Treatment-emergent SAEs, TEAEs leading to study treatment 
discontinuation, TEAEs with an outcome of death and TEAEs leading to study discontinuation 
will be summarized similarly. 
 
Frequency and percentage of patients who experience TEAE will also be summarized by SOC, 
PT and worst severity (mild/moderate/severe). TEAE with an unknown severity will be 
considered as severe. If a patient experiences more than one TEAE within different severity 
categories within the same SOC/PT, the patient will be counted only once under each SOC/PT 
under the worst severity. 
 
Frequency and percentage of patients who experience study treatment-related TEAE will be 
summarized by SOC and PT. A study treatment-related TEAE is defined as any TEAE that is 
assessed by the Investigator as possibly related or related to study treatment. A not study 
treatment-related TEAE is defined as any TEAE that is assessed by the Investigator as unlikely 
or not related to study treatment. TEAE with an unknown relationship will be considered as 
treatment-related.  
 
Frequency and percentage of patients who experience application site TEAE will be 
summarized by PT. AESIs will be summarized similarly. 
 
Frequency and percentage of patients who experience TEAE in the application site pain 
preferred term will be summarized by PT and lowest level term (LLT). Unless otherwise 
specified, a patient experiencing the same TEAE multiple times will be counted only once for 
the corresponding PT/LLT. 
 
All AEs will be listed. Separate listings will also be provided for AEs leading to death, all SAEs, 
all TEAEs leading to study discontinuation, and all AESIs.  
 
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14.4 Clinical Laboratory Parameters 
 
Laboratory parameters of hematology, blood chemistry, and urinalysis will be summarized 
using descriptive statistics at baseline and at subsequent visits. Change from baseline values 
will be presented for each post-baseline assessment. Frequencies and percentages for each 
result will be provided for qualitative urinalysis data. 
 
In addition, shift tables (for hematology, blood chemistry, and quantitative urinalysis: low-
normal-high at baseline versus low-normal-high at follow-up in a 3-by-3 contingency table; for 
qualitative urinalysis: normal-abnormal at baseline versus normal-abnormal at follow-up in a 
2-by-2 contingency table) will be provided to assess changes in laboratory values from 
baseline. Only patients with a baseline result and a result at the specified post-baseline visit for 
the parameter will be considered in the shift tables. 
 
Separate listings of all data for hematology, blood chemistry, and urinalysis will be provided. In 
addition, separate listings of data for hematology, blood chemistry, and urinalysis will be 
provided for each parameter where a patient had at least one clinically significant or not 
clinically significant abnormal result. 
 
A listing will be provided for Pregnancy test results. 
14.5 Vital Signs 
 
Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, and 
body temperature) and weight will be summarized using descriptive statistics at baseline and at 
each subsequent visit. Change from baseline values will also be presented for each post-
baseline assessment.  
 
For each vital sign, shift table from baseline to each post-baseline assessments describing 
shifts to abnormality (normal-abnormal not clinically significant [NCS]-abnormal clinically 
significant [CS] at baseline versus normal-abnormal NCS-abnormal CS at post-baseline visit in 
a 3-by-3 contingency table) will be provided as well. Only patients with a baseline result and a 
result at the specified post-baseline visit for the parameter will be considered in the shift tables.  
 
A listing of all vital sign assessments, including height and weight, will be provided. In addition, 
a separate listing will be provided for each parameter where a patient had at least one clinically 
significant or not clinically significant abnormal result. 
14.6 ECGs 
 
Descriptive statistics will be presented for data related to ECGs (HR, RR, PR, QRS, QT 
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interval, QTcB interval and QTcF interval) at each scheduled visit, with change from baseline 
values presented for post-baseline assessments.  
 
Shift tables from baseline to each post-baseline assessments describing shifts to abnormality 
(normal-abnormal NCS-abnormal CS at baseline versus normal-abnormal NCS-abnormal CS 
at post-baseline visit) will be provided for overall interpretation (based on Investigator 
interpretation). Only patients with a baseline result and a result at the specified post-baseline 
visit will be considered in the shift tables. 
 
A listing of all ECG assessments will be provided. In addition, a separate listing will be provided 
for overall interpretation where a patient had at least one clinically significant or not clinically 
significant abnormal result. 
 
14.7 Physical Examinations 
 
All physical examinations will be listed. 
 
 
 
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15 ADDITIONAL ANALYSES 
15.1 Subgroup Analyses 
 
Descriptive statistics will be provided for exploratory endpoints by subgroups:  age (<65 and 
≥65), sex (male/female), number of AK lesions in the TF at baseline (≤8 and >8), treatment 
area (face/scalp), history of skin cancer (yes/no), and Fitzpatrick skin type (I/II and III/IV/V/IV). 
Figures for exploratory endpoints will only be provided for overall and by subgroup of treatment 
area (face/scalp). 
 
Additionally, exposure, compliance and local tolerability assessments will be provided by 
subgroup of treatment area (face/scalp). 
 
No other subgroup analysis is planned for this study. 
 
15.2 Other Analyses 
 
No other analyses are planned for this study. 
 
 
16 CHANGES TO ANALYSES SPECIFIED IN THE PROTOCOL 
 
The changes made to analyses specified in the protocol are presented in Table 3. 
Table 3  
 Changes to Analyses Specified in the Protocol  
Description of the Change 
Rationale 
Protocol states that Unscheduled tests will 
not be associated with any trial visit. 
However assessments performed at each 
study visit will be remapped based on 
windowing conventions specified in Section 
7.3. 
 
To minimize missing data in table reporting. 
Protocol states that the number and 
percentage of patients who experience one 
or more AESI will be tabulated by AESI. 
However the number and percentage of 
patients who experience one or more AESI 
will rather be tabulated by SOC and PT.  
The only type of AESI considered in this 
study is skin cancer.  
 
 
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Protocol states the number and percentages 
of patients with events, and number and 
percentage of events will be presented for 
TEAEs. 
Only the number and percentages of patients 
with events, and the number of events will be 
reported. Percentages of events will not be 
reported. 
Protocol states subgroup analyses for 
exploratory endpoints only. 
Exposure, compliance and local tolerability 
assessments will also be provided by 
subgroup of treatment area (face/scalp). 
 
 
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17 REFERENCES 
 
Not applicable. 
 
 
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18.2 Appendix 2 
 
Algorithm for Imputation of Start/End Date of Adverse Events and 
Prior/Concomitant Medications 
 
Event Start Date Imputation 
• Imputation of event end date should be done before imputation of event start date.  
• Completely missing: Impute to the first study treatment date. 
• Missing day and month: Impute to January 1st, unless year is the same as year of first 
study treatment dose then impute to the first study treatment date. 
• Missing day: Impute to the 1st of the month, unless month and year are the same as 
month and year of first study treatment dose then impute to the first study treatment 
date. 
• If imputed event start date is after event end date (imputed or not), set the event start 
date to the imputed event end date. 
 
Event Start Time Imputation  
• Imputation of event end time should be done before imputation of event start date.  
• If the event date (imputed or not) is not the same as the first dose date or time part of 
the first dose date is missing, impute to 00:00. 
• If the event date (imputed or not) is the same as the first dose date, impute to time part 
of first dose date. 
• If the event start date (imputed or not) is equal to event end date and imputed event 
start time is after event end time (imputed or not), set the event start time to the imputed 
event end time. 
 
Event End Date Imputation 
• Completely Missing (not flagged as "ongoing"): Impute to the last contact date. 
• Missing day and month: Impute to December 31st, unless year is the same as last 
contact date then impute to the last contact date. 
• Missing day: Impute to the last day of the month, unless year and month are the same 
as year and month of last contact date then impute to the last contact date. 
 
Event End Time Imputation  
• Impute to 23:59. 
 
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E L E C T R O NI C R E C O R D A N D SI G N A T U R E DI S C L O S U R E   
Fr o m ti me t o ti me, I n n o v a der m Researc h I nc. ( we, us or C o m pa n y) m a y be re q uire d b y la w t o 
pr o vi de t o y o u cert ai n writte n n otices or discl os ures. Descri be d bel o w are t he ter ms a n d 
c o n diti o ns f or pr o vi di n g t o y o u s uc h n otices a n d discl os ures electr o ni call y t hr o u g h t h e D oc u Si g n 
s yste m. Please rea d t h e i nf or mati o n bel o w caref ull y a n d t h or o u g hl y, a n d if y o u ca n access t his 
i nf or mati o n electr o nicall y t o y o ur satisfacti o n a n d a gree t o t his Electr o nic Rec or d a n d Si g nat ure 
Discl os ure ( E R S D), ple ase c o nfir m y o ur a gre e me nt b y selecti n g t he c hec k -b o x ne xt t o ‘I a gree t o 
use electr o ni c rec or ds a n d si g nat ur es’ bef ore clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n 
s yste m. 
 
Getti n g p a per c o pies   
At a n y ti me, y o u ma y re q uest fr o m us a pa p er c o p y of a n y rec or d pr o vi d e d or ma de a v ail a ble 
electr o nicall y t o y o u b y us. Y o u will ha ve t he a bilit y t o d o w nl oa d a n d pri nt d oc u me nts we se n d 
t o y o u t hr o u g h t he D o c u Si g n s yste m d uri n g a n d i m me diatel y after t he si g ni n g sessi o n a n d, if y o u 
elect t o create a D oc u Si g n acc o u nt, y o u ma y access t he d oc u m e nts f or a li mite d peri o d of ti me 
( us uall y 3 0 d a ys) after s u c h d oc u me nts are first se nt t o y o u. After s uc h ti me, if y o u wis h f or us t o 
se n d y o u p a per c o pies of a n y s u c h d oc u me nts fr o m o ur office t o y o u, y o u will be c har ge d a 
$ 0. 0 0  per -pa ge fee. Y o u ma y re q uest deli ver y of s uc h pa per c o pies fr o m us b y f oll o wi n g t he 
pr oce d ure descri be d bel o w.  
 
Wit h dr a wi n g y o ur c o nse nt   
If y o u deci d e t o recei ve n otices a n d discl os ures fr o m us electr o nicall y, y o u ma y at a n y ti me 
c ha n ge y o ur mi n d a n d t ell us t hat t hereafter y o u wa nt t o recei v e re q uir e d n otices a n d discl os ures 
o nl y i n pa per f or mat. H o w y o u m ust i nf or m us of y o ur decisi o n t o recei ve f ut ure n otices a n d 
discl os ure i n pa per f or mat a n d wit h dra w y o ur c o ns e nt t o recei v e n otices a n d discl os ures 
electr o nicall y is des cri be d  bel o w.  
 
C o nse q ue nces of c h a n gi n g y o ur mi n d   
If y o u ele ct t o recei ve re q uire d n otices a n d discl os ures o nl y i n p a per f or mat, it will sl o w t he 
s pee d at w hic h we ca n c o m plete certai n ste ps i n tr a nsacti o ns wit h y o u a n d deli veri n g s er vices t o 
y o u beca use we wil l nee d first t o se n d t he re q uir e d n otices or discl os ures t o y o u i n pa per f or mat, 
a n d t he n wait u ntil we recei ve bac k fr o m y o u y o ur ac k n o wle d g m e nt of y o ur recei pt of s uc h 
pa per n otices or discl os ures. F urt her, y o u will n o l o n ger be a bl e t o use t he D oc u Si g n s yste m t o 
recei v e re q uir e d n otices a n d c o nse nts electr o nicall y fr o m us or t o si g n electr o nicall y d o c u me nts 
fr o m us. 
 
All n otices a n d discl os ures will be se nt t o y o u electr o nic all y   
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e cr e at e d o n: 2 7- M a y- 2 0 2 2 | 1 2: 5 0
P arti e s a gr e e d t o: P P D


U nless y o u tell us ot her wise i n acc or da nce wit h t he pr oce d ures des cri be d h e rei n, we will pr o vi de 
electr o nicall y t o y o u t hr o u g h t he D o c u Si g n s yste m all re q uire d n otices, discl os ures, 
a ut h orizati o ns, ac k n o wle d ge m e nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u d uri n g t he c o urse of o ur relati o ns hi p  wit h y o u. T o re d u ce t he c ha n ce of y o u 
i na d verte ntl y n ot recei vi n g a n y n otice or discl os ure, we prefer t o pr o vi de all of t he re q uire d 
n otices a n d discl os ures t o y o u b y t he s a me met h o d a n d t o t he sa me a d dress t hat y o u ha v e gi ve n 
us. T h us, y o u ca n recei ve al l t he discl os ures a n d n otices electr o nicall y or i n pa per f or mat t hr o u g h 
t he pa per mail deli ver y s yste m. If y o u d o n ot a gree wit h t his pr ocess, pleas e let us k n o w as 
descri be d b el o w. Please als o see t he para gra p h i m me diatel y a b o ve t hat des cri bes t he 
c o nse q ue nces of y o ur ele cti n g n ot t o recei ve deli ver y of t he n otices a n d dis cl os ures 
electr o nicall y fr o m us.  
 
H o w t o c o nt act I n n o v a der m Res e arc h I nc.:   
Y o u ma y c o ntact us t o let us k n o w of y o ur c ha n ges as t o h o w we ma y c o nt act y o u electr o nicall y, 
t o re q uest pa per c o pies of cert ai n i nf or mati o n fr o m us, a n d t o wit h dra w y o ur pri or c o nse nt t o 
recei v e n otices a n d discl os ures electr o nicall y as f oll o ws: 
T o c o ntact us b y e mail se n d messa ges t o: 
 
 
T o a d vise I n n o v a der m Rese arc h I nc. of y o ur ne w e m ai l a d dress  
T o let us k n o w of a c h a n ge i n y o ur e mail a d dress w here we s h o ul d se n d n otices a n d discl os ures 
electr o nicall y t o y o u, y o u m ust se n d a n e mail messa ge t o us at  
 a n d i n 
t he b o d y of s uc h re q uest y o u m ust state: y o ur pre vi o us e mail a d dress, y o ur ne w e mail 
a d dress.  We d o n ot re q uire a n y ot her i nf or mati o n fr o m y o u t o c ha n ge y o ur e mail a d dress.   
If y o u create d a D oc u Si g n acc o u nt, y o u ma y u p d ate it wit h y o ur ne w e mail a d dress t hr o u g h y o ur 
acc o u nt pr efere nces.  
 
T o re q uest p a per c o pi es f r o m I n n o v a der m Res e arc h I nc.   
T o re q uest deli ver y fr o m us of pa per c o pies of t he n otices a n d discl os ures pre vi o usl y pr o vi de d 
b y us t o y o u ele ctr o nicall y, y o u m ust se n d us a n e mail t o  
 a n d i n t he 
b o d y of s u c h re q u est y o u m ust sta te y o ur e m ail a d dress, f ull na me, maili n g a d dress, a n d 
tele p h o ne n u m ber.  
 
T o wit h dr a w y o ur c o nse nt wit h I n n o v a der m Rese arc h I nc.   
T o i nf or m us t hat y o u n o l o n ger wis h t o recei ve f ut ure n otices a n d discl os ur es i n electr o nic 
f or mat y o u ma y: 
P P D
P P D
P P D


i. decli ne t o sig n a d o c u me nt fr o m wit hi n y o ur si g ni n g sessi o n, a n d o n t he s u bse q ue nt pa ge, 
select t he c h ec k-b o x i n dicati n g y o u wis h t o wit h dra w y o ur c o ns e nt, or y o u ma y;  
ii. se n d us a n e mail t o 
 a n d i n t he b o d y of s uc h re q uest y o u m ust 
state y o ur e mail, f ull na me, maili n g a d dress, a n d tele p h o ne n u m ber.  We d o n ot nee d a n y ot her 
i nf or mati o n fr o m y o u t o wit h dra w c o nse nt..  T h e c o nse q ue nces of y o ur wit h dra wi n g c o nse nt f or 
o nli ne d oc u me nts will be t hat tra nsacti o ns ma y ta ke a l o n ger ti me t o pr o cess..  
 
R e q uire d h ar d w are a n d s oft w are   
T he mi ni m u m s yste m re q uire me nts f or usi n g t he D oc u Si g n s yste m ma y c h a n ge o ver ti me. T h e 
c urre nt s yste m r e q uire me nts are f o u n d h ere: htt ps://s u p p ort. d oc usi g n.c o m/ g ui des/si g ner -g ui de -
si g ni n g-s yste m-re q uire m e nts.  
 
Ac k n o wle d gi n g y o ur access a n d c o nse nt t o recei ve a n d si g n d oc u me nts electr o nic all y   
T o c o nfir m t o us t hat y o u ca n access t his i nf or mati o n electr o nicall y, w hi c h will  be si milar t o 
ot her electr o nic n otices a n d discl os ures t hat we will pr o vi de t o y o u, pleas e c o nfir m t hat y o u ha ve 
rea d t his E R S D, a n d (i) t hat y o u are a ble t o pri nt o n pa per or electr o ni call y sa v e t his E R S D f or 
y o ur f ut ure refere n ce a n d access; or (ii) t ha t y o u are a ble t o e mail t his E R S D t o a n e mail a d dress 
w here y o u will be a ble t o pri nt o n pa per or s a ve it f or y o ur f ut ur e refere nce a n d access. F urt her, 
if y o u c o nse nt t o recei vi n g n otices a n d discl os ures e x cl usi vel y i n electr o nic f or mat as des cri be d 
herei n, t he n sel ect t he c h ec k -b o x ne xt t o ‘I a gree t o use electr o ni c rec or ds a n d si g nat ur es’ bef ore 
clic ki n g ‘ C O N TI N U E’ wit hi n t he D oc u Si g n s yst e m.  
B y sele cti n g t he c hec k -b o x ne xt t o ‘I a gree t o use electr o nic rec or ds a n d si g nat ur es’, y o u c o nfir m 
t hat: 
 
Y o u ca n access a n d rea d t his Electr o nic Rec or d a n d Si g nat ure Discl os ure; a n d  
 
Y o u ca n pri nt o n pa per t his Electr o nic Rec or d a n d Si g nat ure Discl os ure, or sa ve or se n d 
t his Electr o nic Rec or d a n d Discl os ure t o a l ocati o n w here y o u ca n pri nt it, f or f ut ure 
refere nce a n d access; a n d 
 
U ntil or u nless y o u n otif y  I n n o v a der m Res earc h I nc. as descri be d a b o v e, y o u c o nse nt t o 
recei v e e x cl usi vel y t hr o u g h el ectr o nic mea ns all n otices, discl os ures, a ut h orizati o ns, 
ac k n o wle d ge me nts, a n d ot her d oc u me nts t hat are re q uire d t o be pr o vi de d or ma de 
a vaila ble t o y o u b y I n n o v a der m Researc h I nc. d uri n g t he c ourse of y o ur relati o ns hi p wit h 
I n n o v a der m Res earc h I n c.. 
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