Open Phase IV Study to Assess the Impact of Tirbanibulin on the Wellbeing of Patients With Actinic Keratoses (TIRBASKIN)
Phase: PHASE4
Conditions: Actinic Keratosis
Sponsor: Almirall, S.A.

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ALMIRALL, S.A. 
Clinical Trial Protocol [M-14789-42]
Clinical Trial Protocol Title:
Open phase IV study to assess the impact of 
tirbanibulin on the well-being of patients with 
actinic keratoses (TIRBASKIN)
Investigational Medicinal 
Product(s):
Tirbanibulin 
Indication:
Actinic keratosis
Development Phase:
Phase 4
Final Protocol Version Date:
05-Aug-2022
Amendment(s)
Number:
None 
Date:
N/A 
EudraCT Number:
2022-001251-16
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.
Amendment 
No.
Date
Summary of Changes
Rationale
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Protocol Approvers’ Signatures
Clinical Trial Protocol Title:
Open phase IV study to assess the impact of 
tirbanibulin on the well-being of patients with 
actinic keratoses (TIRBASKIN)
Trial Code: 
M-14789-42
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 ICH GCP guidelines, and to local regulatory 
requirements, wherever applicable.
Sponsor
Almirall, S.A.
Ronda General Mitre, 151 
08022 Barcelona, Spain
Functional Role Name
Signature
 
Spain
 
 MSc
 
, PhD 
 
Spain
 
 PhD 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Functional Role Name
Signature
 
Italy
 
 MD 
 
 
 Spain
 
MD
 
Italy
, MD 
Contract Research Organization
OPIS s.r.l 
Via Giacomo Matteotti 10, 
20832 Desio MB, 
Italy
Functional Role
Name
Signature
MD MSc
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PPD
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PPD
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MSc
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Principal Investigator Signature
Clinical Trial Protocol Title:
Open phase IV study to assess the impact of 
tirbanibulin on the wellbeing of patients with 
actinic keratoses (TIRBASKIN)
Trial Code:
M-14789-42
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 ICH GCP guidelines, and to local 
regulatory requirements, wherever applicable.
Principal Investigator 
Role
Name
Signature
Date
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1
Protocol Synopsis
Title:
Open phase IV study to assess the impact of tirbanibulin on the wellbeing of patients with 
actinic keratoses (TIRBASKIN)
Short Title:
Impact of tirbanibulin on the wellbeing of patients with actinic keratoses
Coordinating Investigators:
The Coordinating Investigators for this trial will be: 
Dr. 
 
Servicio de Dermatología
Hospital Universitario Miguel Servet.
IIS Aragón
Zaragoza, Spain
Dr. 
Servicio de Dermatología 
Instituto Valenciano de Oncología
Valencia, Spain
Trial Centre(s):
The trial is planned to be conducted at 35 centres in Spain and 7 centres in Italy.
Trial Duration:
The duration of the entire trial from first patient, first visit to last patient, last visit is anticipated 
to be approximately 9 months.
Phase of Development:
This is a Phase 4 trial.
Rationale:
Tirbanibulin is a new topical treatment for actinic keratosis (AK) of the face and scalp. The 
clinical development of tirbanibulin has been carried out entirely in the US and its efficacy and 
safety have been evaluated in 2 Phase III trials. Tirbanibulin is a novel, topical first-in-class 
microtubule inhibitor with a selective anti-proliferative mechanism of action that represents a 
significant step forward in the treatment of AK due to its short treatment protocol (one 
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application daily for 5 days), proven efficacy and safety profile with very acceptable local 
tolerability. 
There is currently no clinical experience with tirbanibulin in Spain and Italy, and patient-
reported outcomes (PRO) such as wellbeing, treatment preference or satisfaction and quality 
of life (QoL) have not been assessed in patients treated with tirbanibulin. Furthermore, AK 
patients are usually elderly, and the actual meaning of wellbeing in this population may not be 
fully understood.  
Based on this lack of clinical evidence, the present study aims to identify the treatment relevant 
effects of AK in terms of wellbeing in the AK population and how tirbanibulin may address 
them. This study will focus mainly on treatment satisfaction. This study will also help to 
understand the QoL in elderly AK patients, as enrollment of an elderly population is expected.
Objectives:
Primary
The primary objective is to assess treatment satisfaction on Day 57 in patients with AK of the 
face or scalp following treatment with tirbanibulin ointment 1% administered once daily for 5 
consecutive days. 
Secondary
The secondary objective is to evaluate patient-reported outcomes, physician-reported 
outcomes, efficacy, and safety following treatment with tirbanibulin ointment 1% administered 
once daily for 5 consecutive days.  
Trial Design:
This is a multicentre single-cohort phase IV low-interventional clinical study conducted in 35 
sites in Spain and 7 sites in Italy. 
Sites will be hospitals where patients with AK are usually managed. The participating 
physicians will be dermatologists. To represent variations in current real-world patterns of care, 
where possible, sites will be selected on the basis of geographic region and institution size.
Following informed consent and verification of eligibility criteria, patients will begin treatment 
with tirbanibulin administered topically at a dose of 2.5 mg once daily for 5 consecutive days 
to a contiguous area. Tirbanibulin will be applied to evenly cover up to a 25 cm² treatment field 
on the face or scalp. Study visits will be held at screening and on Days 0 (baseline), Day 8, and 
Day 57. Only in 1 site (Hospital Clinic de Barcelona), study visits will be held at screening and 
on Day 0 (baseline), Day 8, Day 15, Day 29, and Day 57.
The total duration of the study will be approximately 9 months, including up to 6 months for 
recruitment, 1 month for screening and 2 months for treatment + follow-up. 
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Number of Patients:
Approximately 420 patients will be enrolled, a minimum of 10 patients at each site.
Trial Population: 
The study population will be made up of male and female adult patients with 4-8 non-
hyperkeratotic non-hypertrophic AK lesions of the face or scalp in a 25 cm2 area not previously 
treated in the last 6 months on the same area. In the overall population, a minimum of 30% of 
patients previously treated in other small areas (up to 25cm2) in the last >1 to <6 months to 
avoid patient recall bias from previous treatments will be enrolled.
Inclusion Criteria: 
1. Written informed consent. 
2. 0DOHVRUIHPDOHVDJHG\HDUV
3. Diagnosis of clinically typical AK in one contiguous area on the face or scalp with a 
treatment area of 25 cm2 FRQWDLQLQJ௅$.OHVLRQV
4. Patients not previously treated for AK on the current treatment area of the face or scalp 
in the last 6 months. However, previous AK treatment in other small areas (up to 25cm2) 
in the last >1 to <6 months is allowed.
5. Females must be postmenopausal (A female said to be postmenopausal should be >45 
years of age with at least 12 months of amenorrhea), surgically sterile (by hysterectomy, 
bilateral oophorectomy, or tubal ligation); or, if of child-bearing potential, must be 
using highly effective contraception for at least 30 days or 1 menstrual cycle, whichever 
is longer, prior to study treatment and must agree to continue to use highly effective 
contraception for at least 30 days following their last dose of study treatment. Highly 
effective contraception includes oral hormonal contraceptives, hormonal contraceptive 
implant, injection or patch, intrauterine device, or complete abstinence from sexual 
intercourse.
6. Sexually active males who have not had a vasectomy, and whose partner is 
reproductively capable, must agree to use barrier contraception from Screening through 
90 days after their last dose of study treatment. 
7. All subjects must agree not to donate sperm or eggs from screening through 90 days 
following their last dose of study treatment. 
8. Females of child-bearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on Day 0 prior to dose administration. 
9. Willing to avoid excessive sun or UV light exposure to the face or scalp. 
Exclusion Criteria:
1. Clinically atypical and/or rapidly changing AK lesions. 
2. Location of the treatment area is within 5 cm of an incompletely healed wound or a 
suspected basal cell carcinoma (BCC)/squamous cell carcinoma (SCC).
3. Skin disease (e.g., atopic dermatitis, psoriasis, eczema) or condition (e.g., open wounds, 
scarring) in the treatment area that might interfere with the study results or suppose an 
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unacceptable risk.
4. History of sensitivity to any of the ingredients in the tirbanibulin formulation.
5. Participated in a clinical 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.
6. Patients with a history of tirbanibulin treatment for AK lesions and patients who are 
currently on tirbanibulin treatment for AK lesions.
7. Use 
of 
immunomodulators 
(e.g., 
azathioprine), 
cytotoxic 
drugs 
(e.g., 
cyclophosphamide, vinblastine, chlorambucil, methotrexate) or interferons/ interferon 
inducers and systemic immunosuppressive agents (e.g., cyclosporine, prednisone, 
methotrexate, alefacept, infliximab) within 4 weeks prior to the Screening visit, except 
for organ transplant recipients under stable immunosuppressive therapy for 6 months.
8. Use of systemic retinoids (e.g., isotretinoin, acitretin, bexarotene) within 6 months prior 
to the Screening visit.
9. Use of the following therapies and/or medications within 2 weeks prior to the Screening 
Visit:
x
Cosmetic or therapeutic procedures (e.g., use of liquid nitrogen, surgical 
excision, curettage, dermabrasion, medium or greater depth chemical peel, laser 
resurfacing) within the treatment area or within 2 cm of the selected treatment 
area
x
Acid-containing therapeutic products (e.g., salicylic acid or fruit acids, such as 
alpha- and beta-hydroxyl acids and glycolic acids), topical retinoids, or light 
chemical peels within the treatment area or within 2 cm of the selected treatment 
area
x
Topical salves (nonmedicated/nonirritant lotion and cream are acceptable) or 
topical steroids within the treatment area or within 2 cm of the selected 
treatment area; artificial tanners within the treatment area or within 5 cm of the 
selected treatment area
10. Females who are pregnant or nursing
Test Investigational Medicinal Product, Dosage, and Mode of Administration:
Substance/name: 
Tirbanibulin 
Administration route: 
Topical application
Unit dose/strength:
2.5 mg of tirbanibulin in 250 mg ointment (1%)
Dosage form:
10 mg/g ointment (1%)
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Methodology: 
Trial visits and assessments will be performed in accordance with the Schedule of Assessments 
(Table 1).
Duration of Treatment:
Each patient is treated once daily for 5 consecutive days. 
Duration of Patients’ Participation in the Trial:
The total duration of each patient’s participation in the trial is estimated to be 3 months, 
including 1 month for screening and 2 months for treatment, and follow-up. 
Statistical Methods
Sample Size Calculation
A sample size of 420 patients allows to estimate the mean of a specific component of TSQM-
9 at Day 57 with a precision (half width) of the 95% confidence interval ranging from ±1.6 to 
±2.1 if we assume a standard deviation between 15 and 20. 
Endpoints 
Primary Endpoint 
The primary trial endpoint is Treatment Satisfaction Questionnaire for Medication Version 9 
(TSQM-9) score at Day 57.
Secondary Endpoints 
Patient-Reported Outcomes:
x
Change from baseline in Skindex-16 at Day 57. 
x
Organoleptic properties of tirbanibulin assessed on a Likert Scale at Day 8. 
x
TSQM Version 1.4 (TSQM 1.4) at Day 57. 
x
Patient treatment preference assessed through question 1 (Q1) to question 9 (Q9) of the 
Expert Panel Questionnaire (EPQ) at Day 57. 
Efficacy
x
The percentage of patients with complete (100%) clearance of all lesions within the 
application area at Day 57. 
x
The percentage of patients with partial clearance, defined as a reduction of at least 75% 
in the number of lesions within the application area at Day 57. 
x
Number of old and new AK lesions at Day 57. 
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x
Olsen characterization at baseline (Day 0; pre-dose) and Day 57.
x
Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) of 
subclinical lesions (at only one selected site: Hospital Clinic de Barcelona) at baseline 
(Day 0; pre-dose), Day 8, Day 15, Day 29, and Day 57.
Physician Reported Outcomes
x
Physician outcomes assessed through question 1 (Q1) to question 10 (Q10) of EPQ at 
Day 57.
Safety
x
Incidence and severity of adverse events.
x
Incidence and severity of local skin reactions (LSRs) (erythema, flaking or scaling, 
crusting, swelling, vesiculation or pustulation and erosions or ulcerations at the 
application-site) on a grading scale ranging from 0=absent to 3=severe. Application-
site reactions such as application-site pruritus and application-site pain (including pain, 
tenderness, stinging, and burning sensation) not classified as LSRs will be reported as 
adverse events (AE).
Adherence To the Therapy
x
Medication adherence is recorded using a self-administered Patient Diary from Day 0 
to Day 4. These questions will be related to usage pattern (dosage, frequency, and site)
of study medication application, adverse reactions, and reasons for any missed or 
delayed doses.
At baseline (Day 0, pre-dose), Day 8 and Day 57, the Investigator or a qualified staff member 
must obtain a standardized photograph of each subject’s treatment area. In the sites with 
Canfield® photography, the Investigator will utilize the Canfield® photography equipment to 
take photographs and will upload the photographs to a secure database on ongoing basis. For 
sites, without the Canfield® technology, their own cameras will be used to take photographs. 
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. These photographs will be 
attached with the eCRF.
The photographs are to document the appearance of the subjects’ treatment area and to assist
with the identification and confirmation of the location of the treatment area throughout the
study.
Statistical Analysis
All analyses will be performed by OPIS following internal standard operating procedures 
(SOPs). 
This study is low-interventional in nature and statistical analyses will be descriptive for all 
endpoints. Data from all sites will be pooled and summarized.
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Continuous data will be summarized by mean, standard deviation (SD), median, first and third 
quartiles, minimum and maximum. Categorical data will be presented by absolute and relative 
frequencies (n and %).
Bilateral 95% confidence interval (CI) will be presented as appropriate. 
Further details will be provided in the Statistical Analysis Plan (SAP).
All statistical tables, listings and analyses will be produced using SAS® release 9.3 or later 
(SAS Institute, Inc, Cary, NC, USA).  
Analysis Populations  
The Enrolled population will consist of all patients who signed the informed consent form. 
The Full analysis set (FAS) population will consist of all patients who signed the informed 
consent form and applied at least one dose of tirbanibulin.  
The Evaluable patient population will consist of FAS patients who complete the 57 days of 
observation and have the TSQM-9 assessment. 
The Safety patient population will consist of Full analysis set patients.
The primary and secondary analyses will be done on the Evaluable patient population.
Analyses of Endpoints 
Primary Endpoint
The mean or the median for Convenience, Efficacy and Total satisfaction of TSQM-9 at Day 
57 will be estimated with the corresponding 95% CI. 
Secondary Endpoints
¾ Patient-reported outcomes 
x
The mean or median change from baseline in total Skindex-16 and its components at 
Day 57 will be estimated with 95% CI.
x
The mean or median of the Likert Scale for organoleptic properties of tirbanibulin at 
Day 8 will be estimated with 95% CI.
x
The mean or median for Convenience, Efficacy, Side Effects and Total satisfaction of 
TSQM 1.4 at Day 57 will be estimated with 95% CI.
x
Treatment preference assessed through question 1 (Q1) to question 9 (Q9) of the EPQ
at Day 57 will be summarized with frequency distribution and 95% CI for proportions. 
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¾ Efficacy
x
The percentage of patients with complete (100%) clearance of all lesions within the 
application area at Day 57 will be estimated with the 95% CI for proportions. 
x
The percentage of patients with partial clearance, defined as a reduction of at least 75% 
in the number of lesions within the application area, at Day 57 will be estimated with 
the 95% CI for proportions. 
x
The mean or median number of old and new AK lesions at Day 57 will be estimated 
with corresponding 95% CI. 
x
Olsen characterization at baseline (Day 0; pre-dose) and Day 57 will be summarized 
with frequency distribution and 95% CI for proportions. 
x
RCM and OCT of subclinical lesions (at only one selected site: Hospital Clinic de 
Barcelona) at baseline (Day 0; pre-dose), Day 8, Day 15, Day 29, and Day 57 will be 
summarized.
¾ Physician Reported Outcomes 
x
Physician outcomes assessed at Day 57 through question 1 (Q1) to question 10 (Q10) 
of EPQ will be summarized with frequency distribution and 95% CI for proportions.
¾ Safety Endpoints 
All safety data collected from the study start through the last follow-up visit will be 
summarized. 
¾ Adherence To Therapy
Medication adherence will be summarized with standard summary statistics.
Interim Analysis
An intermediate descriptive analysis is planned when 50% of patients have completed the 
study. 
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Table 1 
Schedule of Assessments
Period
Screening a
Treatment
Follow-up
Visit
1 
Baseline
2 
-
-
-
-
3 
Additional
Visits *
(Applicable for one 
site: Hospital Clinic de 
Barcelona)
Final 
visit
4 
AV1
AV2
Days
-28 to -1 
0
1
2
3
4
8
15
29
57
Visit time window (days)
± 3
± 3
-
± 3
± 3
± 3
± 3
Informed consent 
X
Inclusion & exclusion criteria 
X 
Socio-demographic characteristics
X 
AK therapy history b
X 
Identification of treatment area c
X 
X d
Medical history
X
Prior and concomitant 
medications/therapies 
X 
X d
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination
X 
X 
Vital signs
X
X
X
Skindex-16
X d
X 
Organoleptic properties (Likert scale)
X
TSQM-9
X 
TSQM 1.4
X
AK lesion count
X 
X d
X 
Standardized Photography
X d
X 
X 
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Period
Screening a
Treatment
Follow-up
Visit
1 
Baseline
2 
-
-
-
-
3 
Additional
Visits *
(Applicable for one 
site: Hospital Clinic de 
Barcelona)
Final 
visit
4 
AV1
AV2
Days
-28 to -1 
0
1
2
3
4
8
15
29
57
Olsen grading
X d
X 
RCM of subclinical lesions f
X d
X 
X 
X 
X 
OCT of subclinical lesions f
X d
X 
X 
X 
X 
EPQg
X 
AEs/SAEs e
X d
X 
X 
X 
X 
X 
X 
X 
X 
LSRs
X d
X 
X 
X 
X 
X 
X 
X 
X 
Serum Pregnancy test for WOCBP
X
Urine Pregnancy test for WOCBP
X d
Tirbanibulin (Study drug) application
X 
X 
X 
X 
X 
Patient Diary
X 
X 
X 
X 
X 
Return of Study drug sachets (used and 
unused) and patient diary
X 
      Note: The duration of time window planned for this study is +/- 3 days 
Abbreviations: TSQM=Treatment Satisfaction Questionnaire for Medication; RCM=Reflectance Confocal Microscopy; OCT=Optical Coherence Tomography; EPQ=Expert Panel 
Questionnaire; AK=Actinic Keratoses; AE=Adverse Event; SAE=Serious Adverse Event; LSRs=Local Skin Reactions; WOCBP=Women of Childbearing Potential; 
* Additional visits 1 and 2 (AV1 and AV2) will be performed only in one clinical site: Hospital Clinic de Barcelona
a.
The duration for screening is 1 month. 
b.
This includes history of treatments namely topical medications freezing, laser, scraping, etc.
c.
The location and shape of the treatment area will be marked on an acetate transparency sheet for recording purposes and on the subject’s skin for identification of the
treatment area for daily self-administration of study ointment.
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d.
These are baseline procedures/assessments and will be performed before application of study medication
e.
AEs and LSRs will be reported separately. At each study visit, AEs will be recorded before assessment of LSRs in the treatment area. . From Day 0 to Day 4, AEs and 
LSRs will be recorded using patient diary. During rest of the study period, AEs and LSRs will recorded by the investigator at each visit or through telephonic follow-up 
in case of urgency.
f.
RCM and OCT assessments are applicable only for one site: Hospital Clinic de Barcelona
g.
EPQ comprises of 2 versions: patient version and clinician version. Patient version of the EPQ should be completed by the patient and clinician version by the clinicians.
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2
Table of Contents
Protocol Amendment Summary of Changes............................................................................2
Protocol Approvers’ Signatures................................................................................................3
Principal Investigator Signature ..............................................................................................6
1
Protocol Synopsis.................................................................................................7
2
Table of Contents ...............................................................................................18
3
List of Abbreviations..........................................................................................22
4
Sponsor, Investigator(s), and Trial Administrative Structure..........................25
4.1
Sponsor..........................................................................................................................25
4.2
Investigator(s)...............................................................................................................25
4.3
Administrative Structure.............................................................................................25
5
Introduction........................................................................................................26
5.1
Background Information.............................................................................................26
5.1.1
Indication......................................................................................................................................26
5.1.2
Mechanism of Action....................................................................................................................27
5.1.4
Clinical Studies.............................................................................................................................28
5.2
Summary of the Known Potential Risks and Benefits..............................................30
5.3
Scientific Rationale for the Trial ................................................................................31
6
Objectives and Endpoints...................................................................................32
7
Trial Design and Rationale................................................................................34
7.1
Trial Design ..................................................................................................................34
7.2
Trial Rationale..............................................................................................................36
7.2.1
Rationale for trial design...............................................................................................................36
7.2.2
Rationale for trial Population........................................................................................................36
7.2.3
Rationale for trial Dose and Regimen...........................................................................................36
7.2.4
Rationale for trial Assessments.....................................................................................................36
8
Selection of Trial Population and Withdrawal of Patients ..............................37
8.1
Number of Patients ......................................................................................................37
8.2
Trial Population ...........................................................................................................37
8.3
Inclusion Criteria .........................................................................................................37
8.4
Exclusion Criteria ........................................................................................................38
8.5
Treatment Discontinuation and Trial Withdrawal Criteria....................................39
8.6
Screening Failures........................................................................................................40
8.7
Termination of the Trial..............................................................................................40
8.7.1
End of Trial Definition .................................................................................................................40
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8.7.2
Completed Patient Definition .......................................................................................................40
8.7.3
Premature Trial Termination.........................................................................................................40
9
Treatments..........................................................................................................41
9.1
Identity of Trial Investigational Medicinal Product(s).............................................41
9.2
Packaging and Labelling .............................................................................................41
9.3
Shipment, Storage, and Accountability......................................................................42
9.4
Treatment Administration. .........................................................................................42
9.5
Drug Accountability and Treatment Compliance.....................................................43
9.5.1
Drug Supplies and Accountability................................................................................................43
9.5.2
Treatment Compliance..................................................................................................................43
9.6
Pre-trial, Concomitant, and Post-trial Medications/Therapy..................................44
9.6.1
Pre-trial Medications.....................................................................................................................44
9.6.2
Concomitant Medications.............................................................................................................44
9.6.3
Prohibited Medications/Therapy...................................................................................................44
9.6.4
Post-trial Medications...................................................................................................................45
10
Trial Procedures and Assessments....................................................................45
10.1
General Conditions of the Trial..................................................................................45
10.2
Patients General Conditions During the Trial ..........................................................46
10.3
Scheduled Activities and Trial Visits..........................................................................46
10.3.1
Screening Period...........................................................................................................................46
10.3.2
Treatment Period ..........................................................................................................................47
10.3.3
Follow-up Period ..........................................................................................................................47
10.4
Study Assessments........................................................................................................47
10.4.1
Patient and Physician Reported Outcome (PRO) Assessments ....................................................47
10.4.2
Efficacy Assessments ...................................................................................................................49
10.4.3
Medication Adherence Assessments.............................................................................................50
10.4.4
Standardized Photography ............................................................................................................50
10.5
Safety and Other Assessments ....................................................................................51
10.5.1
Adverse Events.............................................................................................................................51
10.5.2
Medical History, Physical Examinations, and Vital Signs............................................................51
10.5.3
Laboratory Testing........................................................................................................................53
10.5.4
LSR Assessments..........................................................................................................................53
10.6
Adverse Events.............................................................................................................54
10.6.1
Definitions ....................................................................................................................................54
10.6.2
Reporting of Adverse Events........................................................................................................54
10.6.3
Recording of Adverse Events .......................................................................................................56
10.6.4
Reporting of Serious Adverse Events...........................................................................................56
10.6.5
Follow-up of Adverse events / Serious Adverse Events...............................................................58
10.6.6
Adverse Events of Special Interest (AESI)...................................................................................58
10.6.7
Pregnancies...................................................................................................................................59
10.7
Pharmacokinetic Assessment......................................................................................60
11
Statistics..............................................................................................................61
11.1
Sample size Calculation...............................................................................................61
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11.2
Statistical Analysis .......................................................................................................61
11.2.1
General methodology....................................................................................................................61
11.2.2
Demographic and Baseline Characteristics...................................................................................62
11.3
Analysis of the Primary Endpoint ..............................................................................62
11.4
Analysis of Secondary Endpoints ...............................................................................62
11.4.1
Analysis of Safety and Tolerability Endpoints .............................................................................63
11.4.2
Analysis of Pharmacokinetic Parameters......................................................................................64
11.4.3
Pharmacokinetic/Pharmacodynamic Analysis..............................................................................64
11.5
Handling of Missing Data............................................................................................64
11.6
Multiplicity Strategy....................................................................................................64
11.7
Interim Analysis ...........................................................................................................64
12
Data Handling, Processing, and Record Keeping ............................................65
12.1
Data Collection.............................................................................................................65
12.1.1
Identification of the Trial Data Sources........................................................................................65
12.1.2
Electronic Case Report Forms ......................................................................................................66
12.1.3
Patient Diary .................................................................................................................................66
12.1.4
Patient Reported Outcome Booklets.............................................................................................66
12.1.5
Physician Reported Outcome Booklets.........................................................................................67
12.2
Data Management and Quality Control ....................................................................67
12.3
Investigator’s and Trial Master Files.........................................................................68
12.4
Documents and Record Keeping.................................................................................68
13
Quality Control and Quality Assurance............................................................69
13.1
Training of Staff...........................................................................................................69
13.2
Monitoring....................................................................................................................69
13.3
Inspections and Audits.................................................................................................70
14
Ethics..................................................................................................................70
14.1
Responsibilities.............................................................................................................70
14.2
Patient Information and Informed Consent..............................................................70
14.3
Independent Ethics Committee or Institutional Review Board Review .................71
14.4
Patient Data Protection................................................................................................72
15
Financing and Insurance..................................................................................72
16
Publication Policy ..............................................................................................72
17
Other Practical Considerations .........................................................................73
17.1
Final Clinical Trial Report..........................................................................................73
17.2
Protocol Amendments..................................................................................................73
17.3
Protocol Deviations ......................................................................................................74
18
References ..........................................................................................................75
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Table of Figures
Figure 1
Schematic Trial Design......................................................................................35
Table of Tables
Table 1
Schedule of Assessments....................................................................................15
Table 2
Laboratory Testing Parameters.........................................................................53
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3
List of Abbreviations
AE
Adverse Event
AK
Actinic Keratoses
ALCOA
Attributable, Legible, Contemporaneous, Original and Accurate
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUC0-
Area under the concentration-time cure from zero to infinity
AUC0-t
Area under the concentration-time curve from 1 to time t, where t is 
the time of the last concentration measured
BCC
Basal Cell Carcinoma
BID
Twice daily
BMI
Body Mass Index
BSA
Body Surface Area
CA
Competent Authority
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
maximum (or peak) serum concentration that a drug achieves in a 
specified compartment or test area of the body after the drug has 
been administered and before the administration of a second dose
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report
DM
Data Management
DMP
Data Management Plan
EC
European Community
EMA
European Medicines Agency
EPQ
Expert Panel Questionnaire
EQ-5D-5L
European Quality of Life survey
EU
European Union
FAS
Full Analysis Set
FDA
Food & Drug Administration (United States)
GCP
Good Clinical Practice
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GMP
Good Manufacturing Practice
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus 
HR
Heart Rate
HRQoL
Health-related Quality of Life
ICF
Informed Consent Form
ICH
International Conference on Harmonisation 
IEC
Independent Ethics Committee
IGA
Investigator’s Global Assessment 
IMP
Investigational Medicinal Product 
IND
Investigational New Drug
IRB
Institutional Review Board
IWRS/IVRS
Interactive Web/Voice Response System
LC-MS/MS
Liquid Chromatography/Tandem Mass Spectrometry 
LLOQ
Lower Limit of Quantification
LSRs 
Local Skin Reactions
MedDRA
Medical Dictionary for Regulatory Activities
nM 
Nanomolar
OCT
Optical Coherence Tomography
PGA
Physician’s Global Assessment 
PIL
Patient Information Leaflet
PRO
Patient-Reported Outcomes
QD
Once daily
RCM
Reflectance Confocal Microscopy
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCC
Squamous Cell Carcinoma 
SD
Standard Deviation
SE
Standard Error
SmPC
Summary of Product Characteristics 
SOC
System Organ Class
SoE
Schedule Of Events
SOP
Standard Operating Procedure 
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Src
non-receptor tyrosine kinase protein that in humans is encoded by 
the SRC gene
SUSAR
Suspected Unexpected Serious Adverse Reaction
TSQM
Treatment Satisfaction Questionnaire for Medication
WHO
World Health Organization
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)
The Coordinating Investigators for this trial are:
Dr. 
 
Servicio de Dermatología
Hospital Universitario Miguel Servet.
IIS Aragón
Zaragoza, Spain
Dr. 
Servicio de Dermatología 
Instituto Valenciano de Oncología
Valencia, Spain
4.3
Administrative Structure
This study will be conducted by qualified Investigators under the sponsorship of Almirall S A. 
(the Sponsor) at approximately 35 investigational sites in Spain and 7 investigational sites in 
Italy.
The name, telephone number, and email address of the Medical Monitor and other contact
personnel at the Sponsor are listed in the Investigator’s Folder provided to each site.
The clinical trial-related operations including monitoring, data management, statistical 
analyses and pharmacovigilance will be organized and performed by OPIS, a contract research 
organization (CRO).
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5
Introduction
The novel microtubule inhibitor, tirbanibulin is indicated for the field treatment of non-
hyperkeratotic, non-hypertrophic actinic keratoses (AK) of the face or scalp in adults.1
Tirbanibulin was approved by the FDA in December 2020 and the European Commission in 
July 2021. The microtubule inhibitor was developed in collaboration with Athenex and 
Almirall (Sponsor).
A summary on the indication, mechanism of action, and completed non-clinical and clinical 
studies is provided below. A detailed description of the chemistry, pharmacology, efficacy, and 
safety of tirbanibulin is provided in the Summary of Product Characteristics (SmPC).
5.1
Background Information
5.1.1
Indication
Actinic keratoses interchangeably referred to as solar keratoses are common skin lesions 
primarily caused by non-ionizing radiation, in particular ultraviolet light associated with 
chronic sun exposure. The clinical manifestations are red, irregular, scaly plaques, or papules 
on the sun exposed areas, usually found on the face, balding scalp, cleavage, ears, lips. If left 
untreated, the lesions are associated with the risk of malignant transformation in non-melanoma 
skin cancer, including squamous cell carcinoma (SCC).2 The risk of AK progression rate to 
invasive cutaneous SCC is estimated to be 0.25% to 1% each year. However, the causative 
factor of nearly 60% of SCC develops from AK.3 The presence of AK lesions in photo-exposed 
areas, such as the face and scalp, is relatively frequent among the Spanish population and 
constitutes one of the main reasons for consulting a dermatologist.2 In fact, AK prevalence is 
observed to increase with age for both sexes, reaching 60.4% of patients older than 80.2
The mainline of AK treatment modalities includes cryosurgery, skin field therapy (topical 
agents like 5-fluorouracil, imiquimod, diclofenac) and photodynamic therapy. Relatively, these 
therapies demanded a long treatment period of approximately 4-16 weeks and were associated 
with numerous local skin reactions (LSR) like irritations, pain, ulcerations, erosions, 
pigmentations and scarring of the skin. These unmet factors increased the chance of low 
treatment compliance and undermine treatment success.4,5 The novel microtubule inhibitor 
tirbanibulin, its short treatment time (5 days) and minimal adverse reactions could address the 
unmet need of patients suffering from AK lesions, thereby increasing medication adherence 
and success.6
In this study, the impact of tirbanibulin on the wellbeing of patients will be evaluated in patients 
with a diagnosis of AK of the face or scalp following treatment with tirbanibulin ointment 1% 
administered once daily for 5 consecutive days. The study will mainly focus on treatment 
satisfaction.
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5.1.2
Mechanism of Action
Tirbanibulin is a highly selective and novel synthetic microtubule inhibitor exhibiting potent 
anti-proliferative and antitumor effects both in vitro and in vivo. Tirbanibulin mediates anti-
proliferative effect by selectively inhibiting tubulin polymerization and Src signalling. 
Tirbanibulin is being developed as a topical treatment for AK and as an oral chemotherapeutic 
drug for oncology indications.7
The inhibitor promotes the disruption of microtubule network, causing arrest of cell division at 
interphase Gap 2/M and apoptosis of proliferating cells through stimulation of caspase-3 and 
PARP cleavage. In vitro, tirbanibulin has shown potential to inhibit the progression of primary 
human keratinocytes and numerous melanoma cell lines (50% growth inhibition [GI50 values] 
ӊ50 nM). This clinically validated evidence warrants that tirbanibulin has the potential to 
inhibit proliferative expansion and promote apoptosis of abnormally proliferating cells in the 
epidermal and dermal layers upon topical application. Additionally, in pathologies supported
by lymphocyte infiltration, inflammation, and/or angiogenesis, tirbanibulin has proven to 
exhibit potential benefits due to the inhibition of T cell migration and endothelial tubule 
formation in vitro.7
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5.1.4
Clinical Studies
Till date, 4 clinical studies (one phase 1, one phase 2, and 2 phase 3) have been conducted to 
evaluate the efficacy and safety of tirbanibulin ointment 1% in subjects with AK. Details of the 
4 studies are available in the Tirbanibulin ointment SmPC.
KX01-AK-01-US Study, a Phase 1, safety, tolerability, and pharmacokinetic study,
demonstrated that tirbanibulin ointment 1% had good tolerance and showed favorable clinical 
performance in 30 adults with AK manifesting on dorsal forearm when administered at 50 or 
200 mg daily over 3 or 5 consecutive days in an area of 25 or 100 cm2. Mild to moderate and 
transient LSRs were observed in the majority of the subjects. The LSRs observed in greater 
percentage were erythema and flaking/scaling that peaked around Day 5-10, before returning 
to or close to baseline. Symptoms of pruritus, stinging, and burning at the treatment area were 
generally mild and transient. There were no serious adverse events (SAEs) or deaths, and no 
subjects discontinued due to an AE. 
KX01-AK-002 Study, a Phase 2a, open-label, sequential group study, evaluated the efficacy 
and safety of tirbanibulin ointment 1% when applied daily in a treatment area of 25 cm2 for 3 
consecutive days (n=84 subjects) or 5 consecutive days (n=84 subjects) in adults with AK on 
face or scalp. 
Thirty-six of 84 subjects (43%) in the 5-day regimen and 27 of 84 subjects (32%) in the 3-day 
regimen had 100% clearance of AK lesions in the treatment area on Day 57.  
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Preliminary data showed that most of the 168 subjects treated had mild to moderate LSRs 
(primarily erythema and flaking/scaling. Eleven (6.5%) subjects had 16 treatment-emergent 
adverse events (TEAEs) considered treatment-related by the Investigator. Eight of these 
subjects had mild application-site reactions including pruritus, tenderness, or stinging. The 
remaining AEs considered by the Investigator to be treatment-related were mild headache, mild 
to moderate dizziness, mild arthralgia, or mild darkening of hair color near the treatment area. 
All treatment-related TEAEs resolved prior to or stabilized by Day 57. Four subjects reported 
5 treatment-emergent SAEs. All SAEs were considered unrelated to study drug. No subject 
discontinued treatment due to AEs. 
Plasma concentrations of tirbanibulin were measured in Study KX01-AK-002 using a validated 
liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay with a lower limit of 
quantification (LLOQ) of 0.1 ng/mL. Pharmacokinetic results showed that following 3 or 5 
consecutive days of treatment with tirbanibulin ointment 1%, low systemic exposure (< 2 
ng/mL) and limited drug accumulation were observed. 
KX01-AK-003 and KX01-AK-004 Study The efficacy and safety of tirbanibulin applied on 
the face or scalp for 5 consecutive days was studied in 2 pivotal randomised, double-blinded, 
vehicle-controlled Phase III studies (KX01-AK-003 [Trial 1] and KX01-AK-004 [Trial 2]) 
including 702 adult patients (353 patients treated with tirbanibulin and 349 patients treated with 
vehicle). Efficacy, measured as complete (primary end point: 100% clearance) and partial 
clearance rate (secondary end point 75% clearance), was assessed at day 57. 
In trial 1, complete clearance of all lesions at day 57 occurred in 44% of the patients in the 
tirbanibulin group and in 5% in the vehicle group with statistically significant results 
(P<0.001); partial clearance was achieved in 54% of the patients in the tirbanibulin group and 
in 13% in the vehicle group (P<0.001). At day 57, the mean percent reduction in the number 
of lesions was 76% in the tirbanibulin group and in 28% in the vehicle group. In trial 2, 
complete clearance of all lesions at day 57 occurred in 68% of the patients in the tirbanibulin 
group and in 16% in the vehicle group (P<0.001); partial clearance was achieved in 76% of the 
patients in the tirbanibulin group and in 20% in the vehicle group (P<0.001). The median 
percent reduction in the number of lesions, as compared with baseline, was 83% in the 
tirbanibulin group and 20% in the vehicle group in trial 1 and 100% and 25%, respectively, in 
trial 2.
After one year the pooled data indicated that the recurrence rate in patients treated with 
tirbanibulin was 73%. There was a higher recurrence rate for scalp lesions compared to facial 
lesions. Of the patients who developed recurrences, 86% had either 1 or 2 lesions. Furthermore, 
48% of patients developing recurrences reported at least 1 lesion that was not identified at the 
time of the initial treatment (i.e., newly occurring lesions counted as recurrences). By Day 57, 
there were no reported cases of SCC in both trial 1 and 2 
Across the 2 trials, the most common local reactions were erythema, flaking and scaling. The 
most common adverse reactions were application-site pruritus and application-site pain, which 
resolved without intervention. 
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5.2
Summary of the Known Potential Risks and Benefits
Known Potential Risks
The primary safety concerns associated with tirbanibulin are local skin reactions (LSRs), 
namely erythema, flaking or scaling, crusting, swelling, vesiculation or pustulation and erosion
or ulceration in the treated area that occur after topical application of tirbanibulin. LSRs are 
assessed by the Investigators using a grading scale of 0 = absent, 1 = mild (slightly, barely 
perceptible), 2 = moderate (distinct presence), and 3 = severe (marked, intense). Events of 
application-site pruritus and application-site pain (including pain, tenderness, stinging, and 
burning sensation) are also associated with tirbanibulin, which are mild to moderate in severity, 
transient in nature (mostly occurring during the first 10 days since the start of treatment).
In non-clinical fertility and early embryonic development study in rats, tirbanibulin was related 
to testicular toxicity. 
Known Potential Benefits
Topical microtubule inhibitor, tirbanibulin has been approved for treating AK of the face and 
scalp. This is due to the beneficial clinical performance demonstrated by tirbanibulin in the 4 
clinical studies (one phase 1, one phase 2, and 2 phase 3) 
Overall clinical trial results of KX01-AK-01-US and KX01-AK-002 studies validated the 
treatment protocol of tirbanibulin ointment 1% on field administration once daily for 5 
consecutive days. The study demonstrated favorable clinical performance of tirbanibulin in the 
treatment of AK lesions on both the face and scalp regions, also including dorsal forearm. Data 
from KX01-AK-002 suggest that the 5-day regimen of KX2-391 Ointment 1% has greater 
activity (43%) than the 3-day regimen (32%).
Two identical phase 3 studies showed tirbanibulin 1% ointment applied once daily for 5 days 
achieved significantly better clinical outcomes compared with vehicle in clearing AK on the 
face and scalp. With high statistical significance, results of KX01-AK-003 and KX01-AK-004 
concluded that complete (100%) clearance was achieved in 44% and 54% of patients receiving 
tirbanibulin versus with 5% and 13% of patients treated with vehicle, respectively. 
In both the studies, SDUWLDOFOHDUDQFHRIOHVLRQVwas achieved in higher frequency of 
the AK population treated with tirbanibulin versus vehicle. (68% of tirbanibulin vs 16% vehicle 
in KX01-AK-003, and 76% vs. 20% in KX01-AK-004.
Assessment of potential risks and benefits
Tirbanibulin has recently been approved for treating AK of the face and scalp. The study will 
evaluate the individual and clinical variables considered potentially determinant for the QoL
and thus the benefit/risk profile of tirbanibulin is acceptable.
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5.3
Scientific Rationale for the Trial
Most AK treatments significantly reduce AK lesions, but they cause a series of LSRs that tend 
to negatively influence QoL.8 In addition, some treatments have long treatment courses that 
can negatively influence adherence to treatment, which is associated with a bad response, and 
worse results in this disease. In consequence, both current guidelines and expert consensus 
advocate choosing the treatment schedule based not only on factors associated with AK, but 
also on the characteristics, expectations, opinions and preferences of the patients themselves.9–
11
Tirbanibulin is a novel, topical first-in-class microtubule inhibitor with a selective anti-
proliferative mechanism of action that represents a significant step forward in the treatment of 
AK due to its short treatment protocol of one application daily for 5 days, proven efficacy, and 
safety profile with very acceptable local tolerability. Tirbanibulin is a new topical treatment for 
AK of the face and scalp.6 Tirbanibulin clinical development has been performed entirely in 
the US and its efficacy and safety have been evaluated in 2 Phase III trials.12
There is no clinical experience with tirbanibulin in Spain and Italy, also PROs, such as QoL, 
well-being, treatment preference or satisfaction, have not been assessed in patients treated with 
tirbanibulin. Furthermore, AK patients are usually elderly, and the actual meaning of QoL and 
wellbeing in this population may not be fully understood. 
Based on this lack of evidence, we propose a study to find out which aspects are more relevant 
for AK patients in terms of wellbeing and QoL in this elderly population and how tirbanibulin 
may address these.
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Objectives and Endpoints
OBJECTIVES:
Primary Objective
• 
To assess treatment satisfaction on Day 57 in patients with AK of the face or scalp 
following treatment with tirbanibulin ointment 1% administered once daily for 5 
consecutive days. 
Secondary Objective
• 
To evaluate patient-reported outcomes, physician-reported outcomes, efficacy, and 
safety following treatment with tirbanibulin ointment 1% administered once daily for 5 
consecutive days.  
ENDPOINTS:
Primary Endpoint 
x
The primary trial endpoint is Treatment Satisfaction Questionnaire for Medication 
Version 9 (TSQM-9) score at Day 57.
Secondary Endpoints 
Patient-reported outcomes: 
x
Change from baseline in Skindex-16 at Day 57. 
x
Organoleptic properties of tirbanibulin assessed on a Likert Scale at Day 8. 
x
TSQM Version 1.4 (TSQM 1.4) at Day 57. 
x
Patient treatment preference assessed through question 1 (Q1) to question 9 (Q9) of the 
Expert Panel Questionnaire (EPQ) at Day 57. 
Efficacy
x
The percentage of patients with complete (100%) clearance of all lesions within the 
application area at Day 57. 
x
The percentage of patients with partial clearance, defined as a reduction of at least 75% 
in the number of lesions within the application area at Day 57. 
x
Number of old and new AK lesions at Day 57. 
x
Olsen characterization at baseline (Day 0; pre-dose) and Day 57. 
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x
Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) of 
subclinical lesions (at only one selected site: Hospital Clinic de Barcelona) at baseline 
(Day 0; pre-dose), Day 8, Day 15, Day 29, and Day 57. 
Physician reported outcomes 
x
Physician outcomes assessed through question 1 (Q1) to question 10 (Q10) of the EPQ 
at Day 57. 
Safety 
x
Incidence and severity of adverse events
x
Incidence and severity of local skin reactions (LSRs) (erythema, flaking or scaling, 
crusting, swelling, vesiculation or pustulation and erosions or ulcerations at the 
application-site) on a grading scale ranging from 0=absent to 3=severe. Application-
site reactions such as application-site pruritus and application-site pain (including pain, 
tenderness, stinging, and burning sensation) not classified as LSRs will be reported as 
adverse events (AE).
Adherence to the therapy 
x
Medication adherence is recorded using a self-administered Patient Diary from Day 0 
to Day 4. These questions will be related to usage pattern (dosage, frequency, and site) 
of study medication application, adverse reactions, and reasons for any missed or 
delayed doses. 
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7
Trial Design and Rationale
7.1
Trial Design
This is an open phase IV multicentre, single-cohort, low-interventional clinical trial, which will 
be performed at 35 clinical centres in Spain and 7 clinical centres in Italy.
Sites will be hospitals where patients with AK are usually managed. The participating 
physicians will be dermatologists. To represent variations in current real-world patterns of care, 
where possible, sites will be selected based on the geographical region and institution size.
Patients will be approached for informed consent to participate in the study. Approximately 
420 patients will be enrolled, a minimum of 10 patients at each site. The study population 
consists of adult patients with non-hyperkeratotic non-hypertrophic AK lesions of the face or 
scalp who have not been previously treated in the same area in the last 6 months. A minimum 
of 30% of patients previously treated in other small areas (up to 25cm2) in the last >1 to <6 
months to avoid patient recall bias from previous treatments will be enrolled. Tirbanibulin will 
be applied at a dose of 2.5 mg once daily for 5 consecutive days to a contiguous 25 cm² area
of the face or scalp. Study visits will be held at screening and on Days 0 (baseline), Day 8, and 
57. Only in 1 site (Hospital Clinic de Barcelona), study visits will be held at screening and on 
Day 0 (baseline), Day 8, Day 15, Day 29, and Day 57.
The total duration of the study will be approximately 9 months, including up to 6 months for 
recruitment, 1 month for screening and 2 months for treatment + follow-up.
An intermediate analysis is planned when 50% of patients have completed the study.
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The trial design is represented schematically in Figure 1. 
Figure 1 
Schematic Trial Design 
*Abbreviations: TSQM- Treatment Satisfaction Questionnaire for Medication; EPQ-Expert Panel Questionnaire; 
RCM- Reflectance Confocal Microscopy; OCT- Optical Coherence Tomography; LSR-Local Skin Reactions; AE-
Adverse Event; AV1: Additional Visit 1; AV1: Additional Visit 2; Q: Question; Note: The duration of time window 
planned for each visit is +/- 3 days. 
Patient reported outcomes:
o
Change from baseline in Skindex-
16 at Day 57.
o
TSQM-9 at Day 57
o
Organoleptic properties assessed on 
a Likert Scale at Day 8.
o
TSQM 1.4 at Day 57.
o
Patient treatment preference (Q1 to 
Q9) and physician outcome (Q1 to 
Q10) assessed through EPQ at Day 
57.
Efficacy
o
Olsen characterization at baseline 
(Day 0; pre-dose), and Day 57.
o
RCM and OCT of subclinical 
lesions (at only one selected site: 
Hospital Clinic de Barcelona) at 
baseline (Day0; pre-dose), Day 8, 
Day 15, Day 29, and Day 57.
o
Percentage of patients with 
complete (100%), partial (75%) 
clearance at Day 57.
o
Number of old and new AK lesions 
at Day 57.
Safety
o
Incidence and severity of LSRs
o
Incidence and severity of AEs
Medication adherence: 
Assessed through 
patient-kept diary 
throughout the 
treatment period
Additional Visits (AV): At only one selected 
site: Hospital Clinic de Barcelona
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7.2
Trial Rationale
7.2.1
Rationale for trial design
The limited clinical experience with tirbanibulin in Spain and Italy, and lack of data regarding 
the assessment of wellbeing and QoL in elderly patients requires the evaluation of these 
parameters in AK patients in Spain and Italy. Furthermore, AK patients are usually elderly, and 
the actual meaning of wellbeing and QoL in this population may not be fully understood. This 
study will also help to understand the well-being in elderly AK patients, as enrollment of an
elderly population is expected. 
7.2.2
Rationale for trial Population
Tirbanibulin is approved for the field treatment of non-hyperkeratotic, non-hypertrophic AK
(Olsen grade 1) of the face or scalp in adults. The trial population will consist of male and 
female adult patients with 4-8 non-hyperkeratotic non-hypertrophic AK lesions of the face or 
scalp in a 25 cm2 area who have not been previously treated in the same area in the last 6 
months. A minimum of 30% of patients previously treated in other small areas (up to 25cm2) 
in the last >1 to <6 months to avoid patient recall bias from previous treatments will be enrolled.
7.2.3
Rationale for trial Dose and Regimen
Tirbanibulin dose and regimen will be designed as per the SmPC. i.e., once daily for one 
treatment cycle of 5 consecutive days. A thin layer of ointment should be applied to cover the 
treatment field of up to 25cm2. 
7.2.4
Rationale for trial Assessments
Health-related QoL assessments: The TSQM-9, a psychometrically robust and validated 
instrument comprising 3 domains: efficacy (questions 1-3), convenience (questions 4-6), and 
global satisfaction (questions 7-9) has been chosen for evaluating the impact of tirbanibulin of 
AK patients in terms of treatment satisfaction following drug application at Day 57. 
Physician and Patient Reported Outcome assessments: Likert Scale at Day 8, Skindex-16 at
Day 0 (predose) and Day 57, Clinician and Patient versions of the EPQ at Day 57 and TSQM
1.4 at Day 57, have been chosen to understand patient treatment preference and tirbanibulin 
treatment outcomes.
Efficacy assessments: AK lesion count at Day 57, Olsen characterization at Day 0 (predose)
and Day 57, RCM, and OCT assessments of subclinical lesions at Day 8, Day 15, Day 29, and 
Day 57 have been chosen to accurately assess the clinical efficacy of tirbanibulin in AK 
patients. 
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Safety assessments: Pregnancy test for women of child-bearing potential (WOCBP), will be 
determined at screening (serum pregnancy test) and baseline (urine pregnancy test) visit to 
confirm eligibility criteria before the IMP administration. Adverse events assessment, LSR 
assessments during the treatment period will be collected through patient diary and also at each 
visit or through telephonic follow-up will be done as final safety evaluation.  
Adherence to treatment medication assessment: Medication adherence assessed using the 
patient-kept diaries during the treatment period has been chosen to monitor treatment 
compliance among the study population. 
8
Selection of Trial Population and Withdrawal of Patients
8.1
Number of Patients
The study will enroll approximately 420 patients with AK of the face and scalp. 
Approximately, 350 patients in Spain (35 sites) and 70 patients in Italy (7 sites) are expected 
to be enrolled. 
8.2
Trial Population
The study population will be made up of male and female adult patients with 4-8 non-
hyperkeratotic non-hypertrophic AK lesions of the face or scalp in a 25 cm2 area not previously 
treated in the last 6 months on the same area. A minimum of 30% of patients previously treated 
in other small areas (up to 25cm2) in the last >1 to <6 months to avoid patient recall bias from 
previous treatments will be enrolled. 
8.3
Inclusion Criteria
1. Written informed consent. 
2. 0DOHVRUIHPDOHVDJHG\HDUV
3. Diagnosis of clinically typical AK in one contiguous area on the face or scalp with a 
treatment area of 25 cm2 FRQWDLQLQJ௅$.OHVLRQV
4. Patients not previously treated for AK on the current treatment area of the face or scalp 
in the last 6 months. However, previous AK treatment in other small areas (up to 25cm2) 
in the last >1 to <6 months is allowed.
5. Females must be postmenopausal (A female said to be postmenopausal should be >45 
years of age with at least 12 months of amenorrhea), surgically sterile (by hysterectomy, 
bilateral oophorectomy, or tubal ligation); or, if of child-bearing potential, must be 
using highly effective contraception for at least 30 days or 1 menstrual cycle, whichever 
is longer, prior to study treatment and must agree to continue to use highly effective 
contraception for at least 30 days following their last dose of study treatment. Highly
effective contraception includes oral hormonal contraceptives, hormonal contraceptive 
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implant, injection or patch, intrauterine device, or complete abstinence from sexual 
intercourse.
6. Sexually active males who have not had a vasectomy, and whose partner is 
reproductively capable, must agree to use barrier contraception from Screening through 
90 days after their last dose of study treatment.
7. All subjects must agree not to donate sperm or eggs from screening through 90 days 
following their last dose of study treatment.
8. Females of child-bearing potential must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test on Day 0 prior to dose administration.
9. Willing to avoid excessive sun or UV light exposure to the face or scalp.
8.4
Exclusion Criteria
1. Clinically atypical and/or rapidly changing AK lesions.
2. Location of the treatment area is within 5 cm of an incompletely healed wound or a 
suspected basal cell carcinoma (BCC)/squamous cell carcinoma (SCC).
3. Skin disease (e.g., atopic dermatitis, psoriasis, eczema) or condition (e.g., open wounds, 
scarring) in the treatment area that might interfere with the study results or suppose an 
unacceptable risk.
4. History of sensitivity to any of the ingredients in the tirbanibulin formulation.
5. Participated in a clinical 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.
6. Patients with a history of tirbanibulin treatment for AK lesions and patients who are 
currently on tirbanibulin treatment for AK lesions.
7. Use 
of 
immunomodulators 
(e.g., 
azathioprine), 
cytotoxic 
drugs 
(e.g., 
cyclophosphamide, vinblastine, chlorambucil, methotrexate) or interferons/ interferon 
inducers and systemic immunosuppressive agents (e.g., cyclosporine, prednisone, 
methotrexate, alefacept, infliximab) within 4 weeks prior to the Screening visit, except 
for organ transplant recipients under stable immunosuppressive therapy for 6 months.
8. Use of systemic retinoids (e.g., isotretinoin, acitretin, bexarotene) within 6 months prior 
to the Screening visit.
9. Use of the following therapies and/or medications within 2 weeks prior to the Screening 
Visit:
x
Cosmetic or therapeutic procedures (e.g., use of liquid nitrogen, surgical 
excision, curettage, dermabrasion, medium or greater depth chemical peel, laser 
resurfacing) within the treatment area or within 2 cm of the selected treatment 
area
x
Acid-containing therapeutic products (e.g., salicylic acid or fruit acids, such as 
alpha- and beta-hydroxyl acids and glycolic acids), topical retinoids, or light 
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chemical peels within the treatment area or within 2 cm of the selected treatment 
area
x
Topical salves (nonmedicated/nonirritant lotion and cream are acceptable) or 
topical steroids within the treatment area or within 2 cm of the selected 
treatment area; artificial tanners within the treatment area or within 5 cm of the 
selected treatment area
10. Females who are pregnant or nursing.
8.5
Treatment
Discontinuation and 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 
discontinuation or withdrawal from the study must be documented in the eCRF.
An Investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
x Pregnancy of the female participant.
x Significant study intervention non-compliance.
x If any AE, laboratory abnormality, or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant
x Disease progression which requires discontinuation of the study intervention.
x If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation.
x Screening failure: Non-fulfilment of inclusion/exclusion criteria (only possible per 
screening period).
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 3 documented attempts) should be made to contact the patient and 
documented in the medical records. If patient cannot be reached after that, he or she will be 
considered lost to follow-up.
x Trial terminated by Sponsor
x Physician Decision
x Technical problems
The date and cause of discontinuation not only for patient’s not completing the treatment 
phase but also for screening failures will be collected in the eCRF.
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8.6
Screening Failures
Screen failures are defined as participants who consent to participate in the clinical trial but 
who do not meet the specific requirements of the trial intervention. 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.
8.7
Termination of the Trial
8.7.1
End of Trial Definition
The “end of trial” is defined as the date when all patients complete the Day 57 visit or 
prematurely discontinue from the study.
8.7.2
Completed Patient Definition
A participant is considered to have completed the study if he or she has completed all phases 
of the study including the last visit and the last scheduled procedure shown in the SoE. Only 
patients who perform the last scheduled follow-up contact will be considered trial completers. 
8.7.3
Premature Trial Termination
Almirall reserves the right to prematurely terminate (i.e., 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 Data not known before becoming available and raise concern about the safety of the trial
drug so that continuation would pose potential risks to the patient.
x The Sponsor decides to discontinue the trial due to specific other reasons.
If the trial is terminated or suspended, the Sponsor will promptly inform the Investigators and 
the Competent Authorities. The IRB/IEC should be promptly informed and provided the 
reason(s) for the termination or suspension by the Investigator/ Sponsor, 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.
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9
Treatments
9.1
Identity of Trial Investigational Medicinal Product(s)
Treatments administered will be topical tirbanibulin ointment 1%.
Investigational medicinal product (IMP) manufacturing, labelling, packaging, and release will 
be done following Good Manufacturing Practice (GMP). 
Test Investigational Medicinal Product
Substance Code/Name
Tirbanibulin 
Route of Administration
Topical (TOP)
Dosage Form
10 mg/g ointment (1%)
Unit Dose/Strength
2.5 mg of tirbanibulin in 250 mg ointment (1%)
Frequency
Once daily for 5 consecutive days
Duration
5 consecutive days
Packaging Description
Each sachet contains 2.5 mg of tirbanibulin in 250 mg 
ointment. The sachet has an inner layer of linear low-
density polyethylene
9.2
Packaging and Labelling
IMP manufacturing, labelling, packaging, and release will be conducted following GMP
(Annex 14). Tirbanibulin ointment 1% will be supplied in single use sachets, each of which 
contains 250 mg of the ointment. Each sachet is for use as a single-dose application. Complete
formulation contents for Tirbanibulin ointment 1% are provided in the SmPC.
Each eligible subject will be assigned a study kit containing 5 sachets filled with tirbanibulin 
ointment 1%. Each sachet and study kit will be labelled in accordance with national regulations. 
Detailed information regarding the study drugs, including labelling information, will be in the 
Pharmacy Manual provided to the site.
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9.3
Shipment, Storage, and Accountability
Study drug will be stored in accordance with labelled storage conditions. The product can be 
stored at 20°C-25°C. The product should not be refrigerated or frozen. Patients should not 
discard the used and unused sachets and return all these sachets to the site at Day 8.
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 labelled storage 
conditions with access limited to the Investigator and authorized site staff.
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 (i.e., receipt, reconciliation, and final disposition records), following Sponsor’s 
instructions. The Investigator and trial staff must adhere to Good Clinical Practice (GCP) 
guidelines, as well as local or regional requirements. Under no circumstances will the
Investigator allow the trial drugs to be used other than as directed by this protocol. Clinical 
supplies will be dispensed only by an appropriately qualified person and will not be dispensed 
to any individual who is not enrolled in the trial.
Empty sachets and boxes as well as unused medication will be returned to Almirall, where the 
remaining medication will be destroyed according to SOPs. Retention drug samples will be 
kept by the Sponsor during the trial and until it is legally required after trial completion.
Further guidance and information for the final disposition of unused trial interventions are 
provided in the Pharmacy Manual.
9.4
Treatment Administration.
At baseline (Day 0) prior to dosage, subjects will be administered both verbal and written 
instructions that describe the method of dosage application and treatment care through patient 
leaflet in the study kit.
Tirbanibulin will be administered topically at a dose of 2.5 mg (ointment 1%) once daily for 5 
consecutive days (Day 0 to Day 4) to a contiguous area of 25 cm2 of the face or scalp. Area of 
treatment administration will be manifested and located with indelible marker at baseline (Day 
0 pre-dose) at the investigational site. The location and shape of the treatment area will be 
marked on an acetate transparency sheet for recording purposes on the subject’s skin and 
photographed for identification of the treatment area for daily self-administration of study 
ointment. The trial participants will be given a study kit. The study kit consists of 5 single-dose 
individual sachets with an inner layer of linear low-density polyethylene. Each sachet contains 
250 mg of tirbanibulin ointment.
At the site, under the supervision of the study personnel the subjects will apply the first dose 
on Day 0. Following which, the subjects will self-administer the remaining individual sachets 
once daily at home. Preferably, the trial medication should be administered in the evening 
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(potentially before bed) and at the same time. For approximately 12 hours after the 
administration, it is imperative that the application-site remain untouched and dry. Subjects 
will be educated to wash their hands with soap and water after ointment application.
Patient leaflet can be referred for subject instructions and precautions to be followed while 
administering trial medication during the treatment period
9.5
Drug Accountability and Treatment Compliance
9.5.1
Drug Supplies and Accountability
Drug supplies must be kept in an appropriate secure area (e.g., locked cabinet) and stored 
according to the conditions specified on the drug labels.
The Investigator and study staff will be responsible for the accountability of all clinical supplies 
(e.g., shipment, dispensing, inventory, and record keeping) following the Sponsor’s 
instructions. In this matter, the Investigator and study staff must adhere to GCP guidelines, as 
well as local or regional requirements.
Under no circumstances will the Investigator allow the study drugs to be used other than as 
directed by this protocol. Clinical supplies will be dispensed only by an appropriately qualified 
person and will not be dispensed to any individual who is not enrolled in the study.
An accurate and timely record of the receipt of all clinical supplies and dispensing of study
drug to the subject must be maintained.
All forms will be provided by the Sponsor (or its designee). Any comparable forms that the 
investigational site wishes to use must be approved by the Sponsor. A copy of the drug 
accountability record must be provided to the Sponsor (or its designee).
The clinical research associate (CRA) will review drug accountability during monitoring site 
visits.
The Investigator (or site personnel) must not destroy any drug labels or any partly used or 
unused drug supply. Post-Day 57, and as appropriate during the study, the Investigator (or a 
designated pharmacist) will return all used and unused drug sachets, study kits, drug labels, 
and a copy of the completed drug disposition form.
9.5.2
Treatment Compliance
Compliance will be assessed using patient-kept diaries that record the drug accountability, 
dosage and frequency and mode of drug administration during the treatment period. The 
prescribed dosage, timing, and mode of administration of the study drugs described in this 
protocol should not be changed. Any departures from the intended regimen must be recorded 
in the eCRFs. 
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Subjects will return the used ointment sachets (or unused ointment, if not administered) back 
to the clinical site on Day 8 (Visit 3) post dose, to check compliance.
The dosing logs in the patient diary for each patient will be kept during the trial. The CRA will 
review treatment compliance during monitoring site visits. Additional visits will be done at the 
sites in case of emergency or non-compliance
9.6
Pre-trial, Concomitant, and Post-trial Medications/Therapy
Medications to be reported on the eCRF are concomitant prescription medications, over-the-
counter medications, and supplements.
9.6.1
Pre-trial Medications
Patients must not have received any IMP within the preceding 30 days from the first trial drug 
administration or any medication that could not be eliminated from the body (5 elimination 
half-lives of the IMP).
Any treatment (prescription and non-prescription including vitamins and dietary supplements) 
and procedure taken during the 28 days before Day 0 are considered as prior therapy and must 
be recorded into a specific eCRF section (previous and concomitant medication). 
A complete AK treatment history of face and scalp will be recorded on the eCRF. 
9.6.2
Concomitant Medications
Concomitant medications/therapies are any new or existing therapy received by the subject 
after signing the ICF through the final subject contact in the study. Concomitant 
medications/therapies will be recorded in the eCRF.
Sunblock usage from Day 8 onward or any topical products for treatment of LSRs in the 
treatment area allowed by the Investigator will be recorded in the concomitant medication 
eCRF up to Day 57.
During the Follow-up Period, only concomitant medications/therapies for the treatment of AEs 
in the treatment area and those that may affect the assessment of AK lesion recurrence in the 
treatment area will be entered in the eCRF.
9.6.3
Prohibited Medications/Therapy
Use of any treatment for AK lesions other than study drug on the treatment area will be
prohibited during the study. Subjects will be reminded that AK lesions located outside the 
treatment area may be treated by lesion-directed treatment only, e.g., cryotherapy or biopsy.
Prohibited medications are as follows:
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Prohibited drug products and treatments that might influence or mask the effects of treatment 
until Day 57 include: immunomodulators or immunosuppressive therapies (except for organ 
transplant 
recipients 
under 
stable 
immunosuppressive 
therapy), 
cytotoxic 
drugs, 
interferon/interferon inducers, topical or systemic steroids, 5-FU, imiquimod, diclofenac, 
topical or systemic retinoids, topical salicylic acid, bichloroacetic acid, trichloroacetic acid, 
acid-containing 
therapeutic 
products, 
benzoyl 
peroxide, 
chemo 
destruction, 
medicated/therapeutic topical salves, photodynamic therapy, psoralen plus UVA or UVB 
therapy, artificial tanner, excessive or prolonged exposure to UV light source.13
Subjects will be prohibited from applying any topical products, including but not limited to, 
lotions, creams, and ointments, moisturizers, sunscreen, artificial tanners, or make-up to the 
treatment area up until the end of Day 57 (Visit 4), except when those medications are 
prescribed by the Investigator for the management of LSRs. Subjects should avoid direct sun 
or UV exposure to the treatment area throughout the study. However, from Day 8 onward, if a 
subject is unable to avoid direct sun or UV exposure to the treatment area, the Investigator may 
allow the use of sunblock only.
During the Follow-up Period, use of treatments that may interfere with the assessment of AK 
recurrence in the treatment area will be prohibited. This includes use of AK treatment and 
medicated topical products in the treatment area and use of systemic therapies (e.g., 
immunosuppressive agents and systemic AK treatment) that may interfere with the assessment 
of AK recurrence.
Any subjects who start systemic or topical therapies for the treatment of AK will be withdrawn 
from the study.
The decision to administer a prohibited medication/treatment is made with the safety of the 
study subject as the primary consideration.
9.6.4
Post-trial Medications
Once the last IMP dose is applied and related trial measurements are completed [last visit of 
the study on Day 57 (Visit 4)], patients should continue to take their usual medications, also 
allowed during the trial, and may resume other medications interrupted prior to trial enrolment
as deemed appropriate by the Investigator. 
It is not planned to treat patients with tirbanibulin any further than scheduled in this trial. 
10
Trial Procedures and Assessments
10.1
General Conditions of the Trial
Informed consent must be obtained before performing any procedure related to the trial. This 
can be done at any time before or during the screening visit. Informed consent must be signed 
after the patient has received sufficient information about the trial and after he/she has had the 
opportunity to ask any questions and consider other treatment options. The participation in the 
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trial must be documented in the patient´s medical records and a copy of the informed consent 
will be given to the patient. The participation in the trial must be documented in the patient's 
medical records. 
Following informed consent and verification of eligibility criteria, patients will begin treatment 
with tirbanibulin administered topically at a dose of 2.5 mg once daily for 5 consecutive days 
to a contiguous area. Tirbanibulin will be applied to evenly cover up to a 25 cm² treatment field 
on the face or scalp. Except at Hospital Clinic de Barcelona, study visits will be held at 
screening and on Days 0 (baseline), 8, and 57. At only one selected site (Hospital Clinic de 
Barcelona), study visits will be held at screening and on Days 0 (baseline), 8,15, 29 and 57
Trial visits will be scheduled in the morning. At the scheduled visit (Day 0) during the 
Treatment Period, IMP dosing must occur while being witnessed by the research personnel at 
the clinic in order to ensure the proper IMP application, as well as the correct timing of 
activities to occur before and after dosing.
Also, at the scheduled visits in the follow-up period, patient reported outcome assessments, 
physician reported outcome assessments, efficacy and safety assessments will be recorded by 
the research personnel. 
An overview of the trial is provided via the schematic Trial flow chart, which summarizes the 
trial procedures to be performed at each visit. Individual trial procedures are described below.
10.2
Patients General Conditions During the Trial
There are no restrictions during the study on smoking/tobacco use, diet, alcohol/caffeine, water 
or other beverages, or physical activity.
After self-application, subjects will avoid touching or wetting the treatment area for 
approximately 12 hours. When washing the treatment area, the patient will be instructed to 
wash it gently with a mild, nonabrasive, non-medicated soap or shampoo.
The treatment area should not be occluded with bandages, and band aids. The treatment area 
should not be exposed to excessive sunlight or UV light. Refer to SmPC for all prohibited 
activity.
10.3
Scheduled Activities and Trial Visits
10.3.1
Screening Period
This period will start with the signature of the ICF and continue until Day 0 (pre-dose).
After the 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 records, to the inclusion/exclusion criteria of the trial.
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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.
The screening visit and assessments will be performed in accordance with the schedule detailed 
in Table 1. Screening (Visit 1) will occur between Day -28 and Day -1.
The eCRF must be completed to indicate whether the subject is eligible to participate in the 
study and to provide reasons for screen failure, if applicable.
10.3.2
Treatment Period
Treatment period visit (Day 0; Visit 2) 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 efficacy and 
safety assessments, respectively.
The trial visit cannot be repeated or skipped but may be postponed (if not started yet) within 
the time window of ± 3 days allowed in this protocol. 
10.3.3
Follow-up Period
Follow-up visits and assessments will be performed in accordance with the schedule detailed 
in Table 1. 
10.4
Study Assessments
The specific timing of procedures/evaluations to be done at each study visit are listed in Table 
1, SoE. 
10.4.1
Patient Reported Outcome and Physician Reported 
Outcome (PRO) Assessments
TSQM: Two versions of TSQM namely TSQM 1.4 and TSQM-9 have been used in the 
TIRBASKIN study.
x
TSQM 1.4: TSQM 1.4 is a 14-item robust instrument that psychometrically evaluates 
the treatment satisfaction of the administered medication. The instrument is designed 
with 4 scales consisting of 14 questions. These 14 questions were derived from an 
original set of 55 questions extracted from exhaustive literature review and treatment 
groups through multistep iterative process. The 4 scales focussed on efficacy (questions 
1 to 3), side effects (questions 4 to 8), convenience (questions 9 to 11) and global 
satisfaction (questions 12 to 14). The global total score ranges from 0 – 100, where 
lower scores imply less satisfaction whilst higher scores imply higher satisfaction.14
x
TSQM-9: TSQM-9 is a 9-item clinically validated psychometric instrument developed 
from the TSQM 1.4. In this self-administered questionnaire the 5 items associated with 
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side effects related to the medication were excluded. The TSQM-9 global total scores 
vary from 0 to 100 with higher score indicating higher treatment satisfaction.14
On comparing the 2 versions of TSQM, Q1 to Q3 in TSQM 1.4 is equivalent to Q1 to Q3 in 
TSQM-9, and Q9 to Q14 in TSQM 1.4 is equivalent to Q4 to Q9 in TSQM-9. To reduce 
patients’ burden in answering similar questions, only the most extensive version of TSQM i.e., 
TSQM-1.4 will be administered to the patients in PRO Booklet. 
Skindex-16: Skindex-16 may be used for patients to rate skin conditions that have occurred 
within the previous week. It is a short 16-item patient-completed assessment that are classified 
into three domains: symptoms [four items, 1-4], emotions, [seven items, 5-11] and functioning 
[five items, 12-16]. All items are scored on a seven-point numerical analogue scales (0=never 
bothered to 6=always bothered). The potential global score is the average of all 16 items 
ranging from 0 (best HRQoL) to 96 (worst HRQoL). Each item is then transformed to a linear 
scale from 0 (never bothered) to 100 (always bothered). The higher the score, the more severe 
is the impairment. 15
Likert Scale: Likert scale is an instrument used to measure the individual’s degree of 
agreement and disagreement with a variety of statements about some attitude, options, or their 
feelings. In this study, the product’s organoleptic properties are evaluated with Likert scale. 
The questionnaire is built with questions related to the product’s characteristics namely 
appearance, color, convenience, texture, smell, and the feelings experienced during drug 
application. The Likert scale offers 7 possible answers, from "totally agree" to "totally in 
disagreement."16  
EPQ: In this study, an expert panel on consensus developed a questionnaire consisting of 10 
simple items. Using a qualitative modified delphi method, the scale was developed to 
accommodate adequate validity as a real-world evidence tool to solicit patient’s treatment 
preference and physician treatment outcomes. The expert panel agreed on 10 specific items 
encompassing related to the following : 
x
Overall appearance of the skin in the treated area
x
Treatment satisfaction related to skin appearance post-treatment
x
Treatment satisfaction on ability to improve skin texture were suggested to address 
facets of cosmetic outcomes
x
Likelihood to consider treatment again, and overall satisfaction with current (topical) 
treatment were suggested to support future preference assessment 
x
Relative assessment of duration and severity of LSRs associated with topical treatments
x
Relative impact of topical treatments on patient’s QoL were suggested to assess 
perceptions of LSR 
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x
Relative ‘convenience/ease of use’ of topical treatments, considering its potential 
impact on treatment adherence.
x
IGA of severity of skin photodamage in the treated area 
These collective recommendations for the EPQ items are aligned with the consensus statement 
on core outcome set for AK.17 This question has been designed in a manner to identify both 
patient and physical treatment preference. EPQ comprises of 2 versions, namely clinician and 
patient version. Clinician version comprises 10 questions and patient version comprises 9 
questions. The questions used in both the versions are similar, but they have been reworded to 
address both clinician and patients. Clinician version of the EPQ will be administered to the 
clinician through physician reported outcome booklet. Patient version of the EPQ will be 
administered to the patients through patient reported outcome booklet. 
10.4.2
Efficacy Assessments
Actinic Keratosis Lesion Count: A dermatologist (Investigator or Sub Investigator) will 
perform a count of clinically visible AK lesions (lesion count) for all subjects at baseline (Day 
0; pre-dose). The same Investigator or Sub Investigator will conduct the lesion count at Day 
57 (Visit 4) for an individual subject. For this assessment, an AK lesion should be counted only 
if it is completely inside the treatment area.
Olsen characterization: The lesions in the identified treatment area will be classified based on 
Olsen characterization. Classification of AK lesions according to Olsen grade of baseline 
lesions are the following:18
x
Olsen Grade I: Early AK appear as single or few, differently sized (from 0.1-0.3-5.0 
cm in size, rough, blurred, less visible than palpable (palpable on the roughness of the 
surface), red, rough spots or very flat, non-edged plaques which reach into the reddish 
color and are easier to feel than to see (Olsen Grade I).
x
Olsen grade II describes advanced AK as clearly visible and palpable, flat, and 
irregularly raised, with sharp or blurred boundaries, red, rough keratinized surface. If 
the surface is more strongly keratinized, the AK can also be white, yellow, or light 
brown. After scratching effects (frequently), a black or blue-black shade may appear 
(older bleeding).
x
Olsen grade III denotes "late" AK that have existed for a longer period of time and are 
firmly anchored on the lower surface, with an irregular, humpy surface, also wart-like 
and of different colors (white, brown, black). When the horn deposits are removed, an 
erosive subsurface is formed.
RCM: RCM is a non-invasive, optical imaging technique that allows in vivo visualization of 
the epidermis until the superficial dermis at mere histologic resolution. It affords the clinicians 
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the benefit of a “virtual skin biopsy” and aids in diagnostic attributes with mitigation of skin 
biopsies. RCM in combination with dermoscopy has been widely used to delineate between 
AK and SCC. When visualized with RCM, the microscopical characteristic of AK include
hyperkeratosis, parakeratosis, architectural disarray of epidermis, atypical keratinocytes, 
mononuclear inflammatory cells infiltration, dense collagen in the dermis,distorted and dilated 
vessels. 19
OCT: OCT is a high-resolution imaging tool that provides real-time non-invasive diagnosis 
and monitoring of epidermis and superficial dermis. Comparatively, higher diagnostic accuracy 
of AK was achieved using OCT than conventional techniques. Many studies have indicated 
that OCT facilitates in vivo diagnosis of AK.20
10.4.3
Medication Adherence Assessments
Patient-kept diaries: This is a self-assessment tool that facilitates in coherently documenting 
the pattern in which the patient follows the recommended posology. Patient diaries improve 
psychological outcomes by mitigating gaps in memory and help in contextualizing the pattern 
of drug usage.21 The questions will be related to usage pattern (dosage, timing, frequency and 
site) of study medication application, possibilities of missed dose and delayed dose. The 
patients will be asked to record the AEs and LSRs experienced during the treatment period and 
other required information (e.g., symptoms and concomitant medications/therapies, etc.). 
10.4.4
Standardized Photography
The Investigator or a qualified staff member must obtain standardized photography of each 
subject’s treatment area before application of study medication. The photographs are to 
document the appearance of the subjects’ treatment area and to assist with the identification 
and confirmation of the location of the treatment area throughout the study. 
For sites with Canfield® photography, the Investigator will utilize the Canfield® photography 
equipment to take photographs and will upload the photographs to a secure database on 
ongoing basis. Further detail for trial photography will be provided in Canfield User Manual.
Research personnel will have on-line access to the photographs during the trial. 
For sites, without the Canfield® technology, their own cameras will be used to take 
photographs. For these sites, the following recommendations must be observed by the research 
personnel to ensure that the same lighting, background, subject positioning relative to the 
camera and camera settings are used for each photograph.
x
Background should be solid (blue, black, or white). 
x
Ensure that the lighting allows the lesions to be well lighted with no shadows showing.
x
Capture the full area of interest in the centre of the frame.
x
Remove all jewelry (if applicable).
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x
Use of same mobile, with same lens, settings and illumination and subject patient 
positions at each visit. (Study coordinator should use his/her own camera to collect 
photographs for study database). 
x
Camera position/distance from the lesion has to be no greater than 1.5 meters. 
x
Photos may be taken with or without flash, as needed. 
x
Preferably, the same photographer should take the pictures. 
x
Avoid taking identifiable photographs: photographs with any identifiable characteristic 
such as tattoos, scars, or piercings.
These standardized photographs will be attached with the eCRF. The photographs are 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. 
10.5
Safety and Other Assessments
10.5.1
Adverse Events
See Section 10.6 for adverse event definitions and reporting requirements 
10.5.2
Medical History, Physical Examinations, and Vital 
Signs 
Demographic characteristics
The following demographic characteristics will be obtained by the Investigator or qualified 
designee at the Screening visit and recorded in the eCRF
x
Age, Weight, Gender, Height, and Race
x
Inclusion/Exclusion Criteria
x
Fitzpatrick skin type (I, II, III, IV, V, VI)
The Fitzpatrick skin type scale classifies skin into six separate categories based on color 
and response to sunlight. Type I is the lightest in color and most sensitive to sun 
exposure; type VI is the darkest and most sun-resistant.
x
AK treatments received
x
Number of AK lesions at baseline
x
Identification of the location of treatment area (face or scalp)
At baseline (Day 0; predose), the Investigator will confirm the 25 cm2 treatment area 
affected with 4 to 8 AK lesions on the face or scalp that was identified at Screening.
The treatment area identified should contain 4-8 non-hyperkeratotic non-hypertrophic 
AK lesions of the face or scalp in a 25 cm2 area not previously treated in the last 6 
months on the same area. However, previous treatment in other areas of the body is 
allowed. Treatment area will be photographed at baseline (Day 0; predose) using 
standardized photographic conditions or Canfield® Technology for identification. Also, 
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the location and shape of the treatment area and the specific AK lesions will be recorded 
on an acetate transparency sheet gridded with 1 cm2 squares. The study personnel will
record on an acetate transparency sheet by:
1. Placing the transparency sheet over the treatment area
2. With a fine-tip indelible marker:
o
Mark at least 3 anatomical landmarks in the vicinity of the treatment area 
on the transparency sheet. Examples of landmarks could be bony 
prominences, scars, moles, seborrheic keratosis, and veins.
o
Mark the outline of the treatment area on the transparency sheet.
o
Mark the location of each of the AK lesions inside the treatment area on the 
transparency sheet.
3. On the subject’s skin, outline the treatment area with dots and dashes with the 
indelible marker. The transparency sheet will be kept at the site and will be used 
to locate the treatment area and AK lesions during the follow-up visits.
Medical History
A detailed medical history and current medical conditions including the AK clinical history 
will be obtained by the Investigator or qualified designee at the screening visit and recorded in 
the eCRF. 
Patient history should include information on clinically significant personal history including 
identification of current and past smoking history, current alcohol use, past history of 
infections, AK clinical history, history of non-melanoma skin cancer (NMSC) malignancies, 
and major cardiovascular conditions.
Physical Examinations
A complete physical examination will be performed at screening and should include, at a 
minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological 
systems. Height and weight will also be measured and recorded to allow calculation of body 
mass index (BMI). For this, patients should be in light indoor clothes without shoes. 
If it is required, symptom-directed examination may be performed at post-baseline visits, if 
clinically indicated.
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 carried out after at 
least 5 minutes resting in the supine position and always 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 informed consent form 
and that meet the definition of an AE must also be recorded in the eCRF.
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10.5.3
Laboratory Testing
Routine laboratory assessments will be performed at a local laboratory. Tests to be performed 
are detailed in Table 2.
Table 2
Laboratory Testing Parameters
Assessment
Specific Tests
Pregnancy Testing
serum pregnancy test or urine pregnancy test, as per Table 1
Blood and urine samples for laboratory testing will be collected in appropriate sampling tubes
according to the Schedule of Assessments (Table 1).
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.
10.5.4
LSR Assessments
After the assessment of AEs at the scheduled visits as mentioned in Table 1, the Investigator 
or Sub investigator will assess for LSRs in the treatment area. 
LSR signs on the treatment area at the application-site include the following: 
x
erythema/redness
x
flaking/scaling
x
crusting/scabs
x
swelling
x
vesiculation/pustulation
x
erosion/ulceration
These signs will be assessed using a 4-point grading scale; 0=absent, 1=mild (slightly, barely 
perceptible), 2=moderate (distinct presence), and 3=severe (marked, intense).
Application-site reactions such as application-site pruritus and application-site pain (including 
pain, tenderness, stinging, and burning sensation) not classified as LSRs will be reported as 
adverse events (AE). LSRs will be reported separately from AEs. The same Investigator or Sub 
investigator will conduct the LSR assessment at all visits for an individual subject.
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All application site reactions and LSRs will be followed to resolution, or if resolution is 
unlikely, to stabilization. Treatment for any LSR and other application site reactions will be 
recorded on the Concomitant Medications eCRF. Interruption/discontinuation of study 
treatment for an LSR will be recorded on the eCRF.
10.6
Adverse Events
The Investigator will closely monitor any AE and will adopt the necessary clinical measures to 
ensure the safety of the patient.
10.6.1
Definitions
Adverse Event
As defined by ICH GCP, an adverse event is as any untoward medical occurrence associated 
with the use of an intervention in humans after providing written informed consent for 
participation in the study until the end of study visit, whether considered intervention-related 
or not.
Serious Adverse Event
An AE or suspected adverse event is considered "serious" if, in the view of the Investigator, it 
results in any of the following outcomes: death, a life-threatening adverse event, in-patient
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity 
or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, 
or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.
10.6.2
Reporting of Adverse Events 
The reported or observed AEs must be recorded on 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 (i.e., not 
necessarily the exact words used by the patient). If known, a specific diagnosis should be 
recorded instead of listing signs and symptoms (e.g., 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 
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area).
x The intensity of the AE will be described in terms of mild, moderate, or severe according to 
the Investigator’s clinical judgment. And assign to 1 of the following categories:
o Mild – means awareness of symptoms or signs, but easily tolerated (acceptable).
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o Moderate – means enough discomfort to interfere with usual activity (disturbing).
o Severe – interferes significantly with ability to do work or usual activity (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)
‘Possibly related’ and ‘Related’ will be considered as ’related’ 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’s 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 reduced
o Dose increased
o Dose not changed
o Not applicable
AEs will be collected only once with its maximum severity, except when the AE started before 
first IMP administration, persisted after it and worsened in severity any time after first IMP. In 
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this latter case, the AE will be collected with each respective severity. AE term recorded must 
be exactly the same in the different time-points where AE is reported in the eCRF.
10.6.3
Recording of Adverse Events
Adverse events will be collected from signature of the informed consent up to 30 days 
following the last contact or Day 57, whichever is shorter. Any AE reported by the patient from 
the last trial contact (follow-up phone contact or visit) until Day 30 following the last contact 
or Day 57, should be collected in the eCRF.
Adverse events reported from Day 0 to Day 7 will be recorded in the patient diary. Adverse 
events from Day 8 to Day 57 informed by the patient will be recorded by the Investigator during 
the study visits or through telephonic follow-up in the AE page of 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 physical exam, pregnancy tests 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 on 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, 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 
unspecified injury, signs and symptoms, active investigation should be conducted to reach final 
diagnosis. Disease diagnosis would be the preferred reported term.
AEs will be elicited by asking the patients non-leading questions (e.g., "How do/did you feel?) 
and by collecting AEs spontaneously reported by the patient to the Investigator or a designee. 
Patients should be instructed to record AEs in the Patient Diary on a daily basis between visits. 
Any AE recorded on the Patient Diary will be transcribed in standard medical terms as AE on 
the eCRF AE page by the Investigator.
All AEs elicited by the Investigator during the defined AE collection period must be recorded 
on the eCRF. In addition, when an AE meets the criteria of seriousness (i.e., an SAE), it must 
also be recorded on the SAE form and reported following the timelines defined below.
10.6.4
Reporting of Serious Adverse Events
Serious adverse events will be collected from signature of informed consent up to 30 days 
following the last contact or Day 57, whichever is shorter. All SAEs will be reported regardless 
of causality.
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The Investigator must report any SAE within 24 hours from the moment she/he first learns of 
it to the Sponsor/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. 
Information about all SAEs will be recorded using the e-safety tool of the eCRF. The 
Investigator must complete all applicable sections, assess, and record the relationship of each 
SAE to each specific study treatment and submit the completed form within 24 hours from 
awareness. In case of technical difficulties, SAE notification can be carried out using a paper 
SAE form and by contacting OPIS, a CRO, via email at all_phv@opis.it or by fax using the 
following number: +39 0362 633622.
All SAEs will be followed until satisfactory resolution or until the site Investigator deems the 
event to be chronic. Follow-up information is submitted in the same way as the original SAE 
Report. Each reoccurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. Other supporting 
documentation of the event may be requested by the study Sponsor and should be provided as 
soon as possible. The study Sponsor will be responsible for notifying Health Authorities of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no 
case later than 7 calendar days after the Sponsor's initial receipt of the information.
Contact details and specific instructions on the flow of the SAE 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.
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 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 Sponsor/CRO pharmacovigilance unit which does not meet the SAE 
criteria shall be nullified by the Investigator by forwarding a follow-up report.
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A regulatory report of the SAE (depending on the local requirements) will be produced by the 
Sponsor/CRO pharmacovigilance unit and submitted to the Competent Authorities, IEC and/or 
Investigators, when applicable according to local regulations. 
Serious adverse events NOT considered to be reported to the Sponsor 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.
10.6.5
Follow-up of Adverse events / Serious Adverse Events
Those AEs/SAEs recorded for the screening Failure patients will be followed-up until 
resolution or until otherwise agreed between the Sponsor and the Investigator.
All AEs/SAEs that are still present after the last trial drug administration (including AEs that 
have led to premature discontinuation), will be followed-up at least 7 days for non-serious AEs 
and 30 days for SAEs, unless otherwise specified in the protocol 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 timepoint, 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 after the follow-up 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.
10.6.6
Adverse Events of Special Interest (AESI)
An AESI is one of scientific and medical interest specific to understanding of the study drug. 
An AESI may be serious or non-serious. All AESIs must be reported in an expedited manner 
similar to SAEs.
Information about all AESIs will be recorded using the e-safety tool of the eCRF and sent 
through the system within 24 hours from awareness. In case of technical difficulties, AESI 
notification can be carried out using a paper SAE form and by contacting OPIS, a CRO, via 
email to: (all_phv@opis.it) or by fax using the following number: +39 0362 633622.
Event of special interest during the Treatment and Follow-up Periods (Days 0 to 57) is as 
follows:
x
Skin cancers (including BCC, SCC, and melanoma); 
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10.6.6.1
Skin Cancer
During the Treatment and Follow-up Periods (Days 0 to 57), all skin cancers (including BCC, 
SCC, and melanoma) within the treatment area will be reported as events of special interest. 
The location and treatment will be reported. The treatment of the skin cancer will be reported. 
The Skin Cancer Report Form must be used for reporting. The skin cancer must be reported by 
electronic transmission as soon as possible but no later than 1 business day from the date the 
Investigator becomes aware of the event. The contact information for the reporting of skin 
cancers is provided in the Investigator File.
The skin cancer must be captured on the Adverse Event eCRF. Any other AEs associated with 
the skin cancer must be captured on the Skin Cancer Report Form and the Adverse Event eCRF. 
If the skin cancer is associated with an SAE, an SAE report form should be completed and sent 
along with Skin Cancer Report Form.
10.6.7
Pregnancies
Pregnant women will not be permitted to participate in this study. A negative serum and urine 
pregnancy test will be required to enter the study. The Investigator shall report all pregnancy 
exposures occurring in a female patient within 24 hours to the Sponsor using a paper pregnancy 
form and by contacting the CRO via email at all_phv@opis.it or by fax using the following 
number: +39 0362 633622. The Investigator should counsel the subject and discuss the risks 
of continuing with the pregnancy and the possible effects on the foetus potentially induced by 
participation in the study. Monitoring of the subject should continue until conclusion of the 
pregnancy. 
The pregnancy should be followed-up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
A female subject who becomes pregnant during the Treatment Period must be withdrawn from 
study treatment but may continue all study assessments and be followed for study outcome. 
Male subjects whose female partners become pregnant during the Treatment Period may 
continue with study treatment and all assessments.
A pregnant female subject should be requested to provide outcome information on any
pregnancy occurring during the Treatment Period or the Follow-up Period whether or not the 
subject elects to continue with study assessments. Male subjects whose female partners become 
pregnant within 90 days of the last study treatment should be requested to provide outcome 
information on the pregnancy.
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10.7
Pharmacokinetic Assessment
Not applicable
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11
Statistics
11.1
Sample size Calculation
A total of 420 patients will be enrolled in the trial. A sample size of 420 patients allows to 
estimate the mean of a specific component of TSQM-9 at Day 57 with a precision of the 95% 
confidence interval (CI) ranging from ±1.6 to ±2.1 and assuming a standard deviation between 
15 and 20.22 Screening failures will not be replaced. Drop-outs will not be replaced 
11.2
Statistical Analysis
Analysis Populations
The Enrolled population will consist of all patients who signed the informed consent form. 
The Full analysis set (FAS) population will consist of all patients who signed the informed 
consent form and applied at least one dose of tirbanibulin.  
The Evaluable patient population will consist of FAS patients who complete the 57 days of 
observation and have the TSQM-9 assessment.  
The Safety patient population will consist of FAS patients.  
The primary and secondary analyses will be done on the Evaluable patient population. 
All safety outcomes and other variables (i.e., concomitant medication, number of withdrawals) 
will be analyzed considering the Safety Population. 
11.2.1
General methodology
The data collected in this study will be listed and summarized as appropriate as described 
below. The data from all centres will be pooled.  
Continuous data will be summarized by mean, standard deviation (SD), median, first and third 
quartiles, minimum and maximum. Categorical data will be presented by absolute and relative 
frequencies (n and %). Bilateral 95% confidence limits will be presented as appropriate.  
All statistical tables, listings and analyses will be produced using SAS® release 9.4 or later 
(SAS Institute, Inc, Cary, NC, USA). 
Further details will be provided in the Statistical Analysis Plan (SAP).
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11.2.2
Demographic and Baseline Characteristics
Demographic and background information will be summarized using frequency distributions 
for categorical variables and descriptive statistics as mean, standard deviation, median, 
minimum, and maximum for continuous variables. 
Medical History will be coded using MedDRA and will be presented by System Organ Class
(SOC), Preferred Term (PT). 
Concomitant treatment, other than tirbanibulin, will be summarized by Anatomical Therapeutic 
Chemical (ATC) level 2 and preferred term.
11.3
Analysis of the Primary Endpoint
The mean or the median for Convenience, Efficacy and Total satisfaction of TSQM-9 at Day 
57 will be estimated with the corresponding 95% CI. 
11.4
Analysis of Secondary Endpoints
Patient-reported outcomes 
x
The mean or median change from baseline in total Skindex-16 and its components at 
Day 57 will be estimated with 95% CI.
x
The mean or median of the Likert Scale for organoleptic properties of tirbanibulin at 
Day 8 will be estimated with 95% CI.
x
The mean or median for Convenience, Efficacy, Side Effects and Total satisfaction of 
TSQM 1.4 at Day 57 will be estimated with 95% CI.
x
Treatment preference assessed through question 1 (Q1) to question 9 (Q9) of the EPQ
at Day 57 will be summarized with frequency distribution and 95% CI for proportions. 
Efficacy
x
The percentage of patients with complete (100%) clearance of all lesions within the 
application area at Day 57 will be estimated with the 95% CI for proportions. 
x
The percentage of patients with partial clearance, defined as a reduction of at least 75% 
in the number of lesions within the application area, at Day 57 will be estimated with 
the 95% CI for proportions. 
x
The mean or median number of old and new AK lesions at Day 57 will be estimated 
with corresponding 95% CI.
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x
Olsen characterization at baseline (Day 0; pre-dose) and Day 57 will be summarized 
with frequency distribution and 95% CI for proportions. 
x
RCM and OCT of subclinical lesions (at only one selected site: Hospital Clinic de 
Barcelona) at baseline (Day 0; pre-dose), Day 8, Day 15, Day 29, and Day 57 will be 
summarized.
Physician reported outcomes 
x
Physician outcomes assessed at Day 57 through question 1 (Q1) to question 10 (Q10) 
of EPQ will be summarized with frequency distribution and 95% CI for proportions. 
11.4.1
Analysis of Safety and Tolerability Endpoints
The analyses of safety and tolerability outcomes will be performed on the Safety Population. 
Safety outcomes include adverse events, blood pressure and heart rate (vital signs).
LSRs
LSRs assessment results obtained through Day 57 will be summarized by visit reporting for 
each of the six signs (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, 
and erosion/ulceration at the application-site) the number and percentage of patients 
corresponding to each of the score ranging from 0=absent to 3=severe. In addition, a composite 
score will be calculated as the sum of the scores for all six signs (range 0 to 18, with higher 
scores indicating more severe reactions) at each visit for each patient and summarized with 
standard summary statistics for continuous variables. 
Application-site reactions such as application-site pruritus or application-site pain (including 
pain, tenderness, stinging, and burning sensation) not classified as LSRs will be reported as 
adverse events (AE).. 
Adverse Events
The incidence of AEs, SAEs and AESI recorded throughout the study will be summarized by 
MedDRA SOC and PT. A summary of AEs by SOC, PT and severity will be also provided. 
All related AEs, SAEs, AEs with an outcome of death, AEs leading to treatment 
discontinuation will be summarized by MedDRA SOC and PT. Deaths will be listed together 
with all relevant information. 
The frequency of comorbidities will be analyzed descriptively.
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Vital Signs
Vital signs (blood pressure and heart rate) will be summarized at each time point and as change 
from screening value with descriptive statistics. 
Medication Adherence
Medication adherence assessed with patient-kept diary will be summarized with frequency 
distribution from Day 0 to Day 4
11.4.2
Analysis of Pharmacokinetic Parameters
Not applicable
11.4.3
Pharmacokinetic/Pharmacodynamic Analysis
Not applicable
11.5
Handling of Missing Data
In case of missing values, no imputation will be done. Further details on the handling of missing 
data will be provided in the SAP.
11.6
Multiplicity Strategy
No statistical test will be conducted, so there is no need to consider multiplicity issue.
11.7
Interim Analysis
An intermediate descriptive analysis is planned when 50% of patients have completed the 
study. Further details will be provided in the SAP.
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12
Data Handling, Processing, and Record Keeping
The Investigator will conduct the trial in accordance with the protocol and ICH E6 (R2) 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 (e.g., safety concerns, protocol deviations) and problems with 
conducting the trial (e.g., 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 on 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 (i.e., 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.
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 records will include trial diagnosis and inclusion/exclusion criteria age, 
gender, physical examination, previous medication, original or certified copy of laboratory 
reports, instrument printout, trial progress notes of the physician
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x Patient diary
x Laboratory test results reports (pregnancy)
x Images (e.g., photographs)
x Patient Reporting Outcomes Questionnaires
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 part 11 (21 CFR 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 (e.g., 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).
12.1.3
Patient Diary
The patient diary provided at baseline (Day 0) will be used to record usage pattern of the
tirbanibulin ointment applications during the Treatment Period (Day 0 to Day 4). The questions 
will be related to the posology recommendations i.e., dosage, timing, frequency, and site of
tirbanibulin ointment applications. The questions will also be related to AEs and LSRs 
experienced and any other required information (e.g., symptoms and concomitant medications, 
etc.). The diary will also aid us to document the reasons of missed dose and delayed dose. The 
information recorded by the patient will be transcribed in the corresponding eCRF page by the 
Investigator or other authorized trial personnel. The original patient diary will be kept at the 
centre. The patient diary should be returned by the patient on Day 8 (Visit 3).
The Patient Diary 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 authorize 
representatives of appropriate Competent Authorities.
12.1.4
Patient Reported Outcome Booklets
The patient reported outcome booklet is a document in paper format that consists of all 4 
questionnaires namely Skindex-16, Likert Scale, TSQM-1.4 and patient version of the EPQ.
PRO booklet will be stored at the site and will be dispensed to the patients at each visit for 
completing the respective questionnaires as per the SoE. The PROs in the booklet should be 
completed by the patients only during the designated study visits under the supervision of 
authorized trial personnel.
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12.1.5
Physician Reported Outcome Booklets
The physician reported outcome booklet is a document in paper format that consists of only 1
questionnaire, namely clinician version of the EPQ. Booklets will be stored at the site and 
should be completed by the clinicians only during the designated study visits as mentioned in 
Table 1.
12.2
Data Management and Quality Control
Data Management of the trial will be performed by the CRO Data Management department
and supervised by Data Management at Almirall, according to Almirall and CRO SOPs.
Data collection
Designated Investigator staff will enter the data required by the protocol into the eCRF using 
fully validated software that conforms to 21 CFR Part 11 requirements. Designated Investigator 
site staff will not be given access to the electronic data capture system until they are trained.
Web-based software will be used, and no installation procedure is needed. Each site will be 
authorized by the administrator to access the eCRF. Each site-qualified personnel will be 
allowed to access the eCRF by means of a ‘login mask’ requiring user ID and password and 
may read, modify, and update only the information entered at his or her site and according to 
their profile. Each page reports site code and patient code.
On-line validation programs will check for data discrepancies and generate automatic warning 
messages, allowing the Investigator to confirm or correct the data entered. The Investigator 
will certify that the data entered in the eCRF are complete and accurate.
After database lock, the Investigator will receive a CD-ROM of patient data for archiving at 
the investigational site.
Database management and quality control
The CRO working on behalf of the Sponsor will review the data entered in the eCRF by 
investigational staff for completeness and accuracy and instruct site personnel to make any 
necessary corrections or additions. The data manager will perform the cleaning session by 
reviewing the warning messages raised by on-line checks and by running post-entry checks by 
means of validation programs and data listings specific for the study. The occurrence of any 
protocol deviations will also be evaluated.
If clarifications are needed, the data manager will raise queries through the web application. 
Designated Investigator site staff will be required to respond to queries and to make the relevant 
corrections, if needed.
Data collection and query flows, as well as the on-line and off-line checks, are detailed in the 
Data Management Plan and Data Validation documents.
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Concomitant and prior medications entered in the database will be coded using the WHO Drug 
Reference List, which employs the ATC classification system. Medical history/current medical 
conditions and AEs will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA).
The database will be locked after all the aforementioned actions have been completed and the 
database has been declared complete and accurate
12.3
Investigator’s and Trial Master Files
The Investigator's file and Sponsor Trial Master File 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 with the electronic data capture 
(EDC) data, as well as one CD/DVD with the paper PRO Booklet and paper Patient Diary data 
from the patients enrolled at his/her location. The Investigator will keep these in the 
Investigator’s file.
Patient medical records, Patient Diary and PRO Booklet will be kept at the research site with 
the rest of the original data.
The Sponsor’s Trial Master File will contain at a minimum all documents indicated in the ICH 
GCP guidelines. The documents needed in the Sponsor’s file (originals and copies) generated 
or obtained by the CRO will be sent to Almirall following adequate time-points and in the 
format defined by Almirall.
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 (i.e., completed, and signed eCRF or 
certified copy of the eCRF). The Investigator may be 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 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 (e.g., CRF, IMP) arrived in good conditions and to train 
the site staff for protocol compliance.
Appropriate Trial Manuals will be provided to the research sites as written help to support all 
trainings on all trial procedures (e.g., laboratory samples, eCRF). 
13.2
Monitoring
The trial will be monitored by clinical CRO 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 on 
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 Trial Master File. Key trial personnel must be available to assist the field CRA
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 on CRFs 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/CRFs and other data source, medication) will be performed by 
the trial CRA/Monitor once all patients have completed the trial.
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13.3
Inspections and Audits
The trial site, trial processes, CRO, providers and/or trial documents may be patient to Quality 
Assurance audits by Almirall (or authorized partner companies) as well as inspection by the 
appropriate Competent Authorities 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 on 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), as well as in compliance with ICH 
GCP E6 (R2) guidelines, and local laws of the Countries in which the trial centres 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 and the Sponsor should ensure that all work and services described 
herein, or incidental to those described herein, shall be conducted in accordance with the 
highest standards of GCP and local regulations.
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. 
At the completion of treatment (or premature discontinuation) patients will be instructed to 
resume the medication they were taking before starting the clinical trial, or any other as deemed 
appropriate by the Investigator. Medical care after discharge from the trial should be provided 
by the patient's family practitioner or specialist that usually treats his/her condition
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.
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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 CRF.
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 dated by the patient and the 
Investigator. At such time the patient must be given adequate time to understand the 
information provided and ask questions. A copy of the signed ICF will be given to the patient. 
The original shall be kept on file by the Investigator and the CRO. Any new relevant 
information that becomes available during the trial will be provided to the patient. 
The Patient Information Sheet 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 IEC/IRB before use.
After the completion of the trial, lay summaries summarizing main results from the trial will 
be make available for patients.
14.3
Independent Ethics Committee or Institutional Review 
Board Review
This protocol, patient information, and the informed consent form should be submitted to an 
IRB or IEC for review and approval. Notification in writing of approval must be obtained from 
the EC by the Investigator before initiation of patient enrollment.
The Investigator/Sponsor or CRO (per regulations: i.e., Investigator in Italy and Spain or 
Sponsor in the European Union) must promptly report to the IEC/IRB all changes in research 
(protocol amendments) and will not make such changes without IEC/IRB 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 IEC/IRB.
Within 1 year after completion of the trial, the responsible person according to local 
regulations, CRO will send to the IEC/IRB and to the Competent Authority a brief summary 
explaining the results obtained in the trial.
The CRO is required to maintain accurate and complete records of all written correspondence 
sent to and received from the IEC/IRB 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 CRFs/EDC and all trial data records (e.g., electronic 
Patient Diary) patients will be identified only by the assigned patient identification number and 
year of birth.
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 IEC/IRB 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 Regulation (EU) 679/2016 of 27 April 2016, the Organic Law 
3/2018 of 5 December on the Protection of Personal Data and Guarantee of Digital Rights 
(LOPDGDD), 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, S.A. will set up a contract with the CRO with the economic aspects for trial funding. 
Almirall, S.A. has an insurance policy that complies with current Spanish (Royal Decree 
1090/2015) and Italian legislation. 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 
Spanish Clinical Trials Register (https://reec.aemps.es/) and the EU Clinical Trials Register.
e.g.www.clinicaltrials.gov and https://www.clinicaltrialsregister.eu/
The Investigator understands and accepts that his/her name and trial centre 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.
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By signing this trial protocol, the Investigator affirms to the Sponsor that he/she will maintain 
in confidence all information furnished to him/her or resulting from this trial. The Investigator
will only divulge such information as may be necessary to the IEC/IRB, 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 European Medicines Agency (EMA)/ US Food & Drug Administration (FDA)
regulatory compliance obligations, and only after mutual agreement between the Investigator 
and Almirall.
17
Other Practical Considerations
17.1
Final Clinical Trial Report
The clinical Trial Report (CSR) will be written by the CRO following the ICH guidelines 
requirements. It will be approved and signed by the Principal/Coordinating Investigators and 
Almirall representatives according to internal SOPs. 
The CSR will be audited by CRO and/or Almirall before issuing the final version. 
Final version of 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 
as well as to the IECs and/or Competent Authorities according to the local regulation.
17.2
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 IEC and/or Competent Authorities and approved by 
them before implementation.
x Non-substantial Amendments do not require approval but should be recorded and be 
available on request for inspection at the trial site and/or Sponsor premises as appropriate.
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The amendments should be notified to the IEC and/or Competent Authorities before 
implementation
17.3
Protocol Deviations
Any protocol deviations during the conduct of the trial will be recorded by 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 IECs and/or Competent Authorities
according to the local regulation in each country.
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18
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