A Randomized, Multi-Center, Double Blinded, Self-Initiated, Single Treatment Study Comparing Sitavig® (Acyclovir) 50 mg Muco-adhesive Buccal Tablet to Placebo in the Treatment of Herpes Labialis in Immunocompetent Adults
Phase: PHASE3
Conditions: Recurrent Herpes Labialis
Sponsor: Bayer

Document Type: 
Clinical Study Protocol 
 
Official Title: 
 A Randomized, Multi-Center, Double Blinded, Self-Initiated, 
Single Treatment Study Comparing Sitavig® (acyclovir) 50 mg 
Muco-adhesive Buccal Tablet to Placebo in the Treatment of 
Herpes Labialis in Immunocompetent Adults 
NCT Number: 
NCT05098938 
Document Date: 
30 Sep 2022  
 

CONFIDENTIAL 
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No. M008894 / 21755 
Version 5.0 
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Title Page 
Protocol Title: A Randomized, Multi-Center, Double Blinded, Self-Initiated, Single Treatment 
Study Comparing Sitavig® (acyclovir) 50 mg Muco-adhesive Buccal Tablet to Placebo in the 
Treatment of Herpes Labialis in Immunocompetent Adults 
Protocol Number: 21755 
Amendment Number: Amendment 4 
Compound Number: BAY M00889 
Study Phase: 3
Sponsor Name: Bayer Healthcare LLC. 
Legal Registered Address: 100 Bayer Boulevard, Whippany NJ 07981-0915, USA 
Regulatory Agency Identifier Number(s): IND 148107 
Approval Date: 30-SEP-2022 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the 
performance of the clinical investigation.  Reproduction or disclosure of this document, whether in part or 
in full, to parties not associated with the clinical investigation or its use for any other purpose without the 
prior written consent of the sponsor is not permitted.  
Throughout this document, symbols indicating proprietary names (®, TM) may not be displayed. Hence, 
the appearance of product names without these symbols does not imply that these names are not 
protected. 

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Sponsor Signatory
, BS, PharmD
, US Medical Affairs
Bayer Healthcare LLC.
Date
Medical Monitor name and contact information will be provided separately.
PPD
PPD
PPD

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Protocol Amendment Summary of Changes Table 
 
Protocol Amendment 1 (Version 2.0) 
 
The following sections were amended from Version 1.0 to Version 2.0.  Pagination was updated in 
this table to align with Amendment 2. 
 
Type of Amendment: Substantial 
 
Changes which are considered significant or substantial have been made to the following sections 
reflected below: 
 
Page 
Number 
Section 
Number 
Paragraph or bullet point/number 
17 
2.2 
Secondary objectives were to compare the efficacy of ABT 50 
mg versus placebo on the evolution of prodromal symptoms to 
aborted lesions, healing of non-primary lesions, duration of 
episode, duration of symptoms, healing of the aborted primary 
lesions and intra oral/mucosal non primary lesions, and the 
incidence of and time to recurrence during 9 months following 
treatment.  Prodromal symptoms (such as pain, tenderness, 
itching, tingling or discomfort) are early symptoms that 
herald the onset of a cold sore outbreak. 
26 
5.5 
x Withdraw of informed consent by the participant; 
x Study intervention kit not available; 
x Lack of compliance as determined by the 
Investigator/designee. 
36 
8.1.5.1 
Participants will record face images and complete 0-10 NRS HL 
symptom evaluation at 09:00, 14:00 and 19:00 that day with QoL 
OHIP scoring at the first assessment of the day.  All scoring, face 
images and QoL OHIP will be recorded in the Science 37 
Platform.  All post-dose time point assessments have an 
allowable window of ±60 minutes. 
40 
8.2.2 
Removal of a duplicate survey graphic. 
Note: Example for display only and not the licensed version.  
Specific wording for each question may slightly differ for 
participants then what is displayed in the protocol.  The OHIP-14 
is licensed by Mapi Research Trust. 
49 
10.1 
Sponsor’s medical expert for the study 
Name:  
, MD 
Title: 
, Global Medical Affairs 
Address: Bayer Healthcare 
 
100 Bayer Boulevard 
 
Whippany NJ 07981-0915 USA 
 
PPD
PPD

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Protocol Amendment 2 (Version 3.0) 
 
The following sections were amended from Version 2.0 to Version 3.0.   
 
Type of Amendment: Substantial 
 
Changes which are considered significant or substantial have been made to the following sections 
reflected below: 
 
Page 
Number(s) 
Section 
Number(s) 
Description, paragraph or bullet point/number 
12, 20 
1.1, 3.0 
Other Objectives 
x To evaluate the Global assessment at Day 14. 
x To evaluate the adhesion time of Sitavig, the incidence of 
detachment or swallowing within 6 hours of dosing, and 
the number of tablets replaced incidence of replacing the 
tablet. 
Other Endpoints 
x Time to cessation of symptoms, measured in hours from 
initial application of assigned study intervention.  
Cessation of symptoms is defined as the absence of 
sensations of pain, tenderness tingling, itching or 
discomfort  at the site of the cold sore as measured by 
NRS.  Observation period to determine healing will last 
up to 14 days (CesSymp14).   
x The change from baseline to post-dose in NRS. 
x The incidence of detachment or swallowing within 6 
hours of dosing and the number (percentage) of 
subjects with the incidence. 
x The percentage of subjects who replace the tablet 
among those with detachment or swallowing within 6 
hours of dosing. 
14 
1.2 
Modification of Study Scheme of Treatment Phase from 8-10 
days to 8-13 days.  Modification of Day 14 window from ± 1 day 
to + 2 days. 
15 
1.3 
Modification of Schedule of Activities of Treatment Phase from 
8-10 days to 8-13 days.  Modification of Day 14 window from    
± 1 day to + 2 days. 
New footnote (d): The 2-day window pertains to all Visit 3 
tasks except the NRS symptom scores, face images, QoL-
OHIP and Global assessment which should be collected at 
their respective nominal times (±60 minutes) on Day 14.   
Footnotes e, f and g were revised accordingly. 
 
 

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21 
4.1.1.3 
Additionally, participants will complete face images, symptom 
and QoL scores on Days 2 through 10 13 with a virtual visit no 
later than on Day 14 (+2 days), Visit 3 using the Science 37 
Platform. 
35 
8.1.3 
Randomized participants will start a 6-month Run-in phase 
during which they will be eligible to start study intervention.  
The start date for the Run-in phase is defined as the verified 
date of receipt of undamaged study intervention by the study 
participant. 
36 
8.1.4 
Participants who start to experience prodromal symptoms before 
the visible appearance of any signs of HL must document the 
start time of symptoms in Science 37 Platform, complete a pre-
dose (immediately before dosing) 0-10 NRS cold sore symptom 
evaluation (pain, burning sensation, itching and swelling) and a 
face image.   
37 
8.1.5.5 
Header: addition of days 11, 12 and 13. 
37, 38 
8.1.5.6 
Header: modification of Day 14 window from ± 1 day to +2 
days. 
All post-dose time point assessments have an allowable window 
of ±60 minutes.  The 2-day window pertains to all Visit 3 tasks 
except the NRS symptom scores, face images, QoL-OHIP and 
Global assessment which should be collected at their 
respective nominal times (±60 minutes) on Day 14. 
39 
8.2.1 
Assessed at Screening (pre-dose), Day 1 through the participant’s 
self-reported completion of study intervention (up to on Day 14 
post-dose ±1 day). 
41 
8.2.3 
A question Questions that rates the IMP as a cold sore treatment 
and the participant's experience at the self-reported completion 
of study intervention (14 days post-dose) using a 5-point Likert 
scale. 
New Question 
Overall, I would rate the experience (ease, comfort, 
convenience of use etc.) of the study medication as… 
x 0 = poor 
x 1 = fair  
x 2 = good  
x 3 = very good  
x 4 = excellent 
 
 

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Number(s) 
Description, paragraph or bullet point/number 
49 
10.1 
Sponsor’s medical expert for the study 
Name:  
, MD 
Title: 
, Global US Medical 
Affairs 
Address: Bayer Healthcare 
 
100 Bayer Boulevard 
 
Whippany NJ 07981-0915 USA 
51 
10.1.4 
A copy of the ICF(s) must be provided to the participant.  
Participants who are rescreened are required to sign a new ICF. 
54 
10.1.10 
Study monitors will perform ongoing source data verification to 
confirm that data entered into the eCRF and/or Science 37 
platform by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable 
regulatory requirements in accordance to the monitoring plan.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD

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Protocol Amendment 3 (Version 4.0) 
 
The following sections were amended from Version 3.0 to Version 4.0.  Pagination was updated in 
this table to align with Amendment 4. 
 
 
Type of Amendment: Substantial 
 
Changes which are considered significant or substantial have been made to the following sections 
reflected below: 
 
 
Page 
Number(s) 
Section 
Number(s) 
Description, paragraph or bullet point/number 
2 
Sponsor 
Signatory 
Sponsor’s medical expert for the study 
Name:  
 BS, PharmD 
Title: 
, US Medical Affairs 
Address: Bayer Healthcare 
 
100 Bayer Boulevard 
 
Whippany NJ 07981-0915 USA 
 
16 
1.2 
Modification of Study Scheme Screening/Randomization Phase 
Within 21 35 days of the start of the Run-in Phase 
Modification of Study Scheme Day 1 /  Day 2 – Visit 2** 
Modification of footnote ** Visit 2 may occur within 36 hours 
of Day 1 dosing time 
17 
1.3 
Schedule of Activities (SoA) 
Screening/Randomization Phase 
Within 21 35 days of Run-in start 
Treatment Phase  
Day 1 - 2 
eFace images and NRS symptom scores only required if a new 
outbreak of herpes labialis is determined suspected by the 
investigator. 
24 
4.1.1.1 
Participants will be screened for eligibility up to 21 35 days prior 
to study according to the inclusion/exclusion criteria. 
24 
4.1.1.3 
Participants will be asked to meet with the clinic via the Science 
37 Platform within 24 36 hours of the start of study intervention 
(Day 1) 
26 
5.1 
3.  Willing to avoid, during the treatment phase, the use of anti-
inflammatory (not including low-dose (81 mg) aspirin), anti-
herpetic, antibiotic and antiviral agents as well as steroids or 
other natural products that would interfere with the immune 
system response; 
PPD
PPD

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4. Female participants of childbearing potential must be using a 
medically acceptable form of birth control for at least 1 month 
prior to during screening (3 months on oral contraceptives) 
26 
5.2 
13. Known medical history of renal disease, that in the 
judgment of the investigator is severe 
28 
5.2 
21. Participants unwilling to avoid the use of any antivirals, oral 
analgesics, any lip balm or zinc oxide cream, non-steroidal anti-
inflammatory drug (including aspirin and probenecid) or topical 
pain reliever or anesthetic (e.g., benzocaine, lidocaine) as a cold 
sore treatment during the stud 
25. Use of intramuscular and intra-articular steroids is 
prohibited; oral or systemic steroids within 30 days of 
randomization 
26. Prophylactic antiviral treatment during the Follow up Phase 
up the Screening Phase, Treatment Phase and in the Follow Up 
Phase until to the first new investigator confirmed HL 
outbreak;  
29. Participants whose occupations make them unlikely to 
complete a virtual clinic visit within 24 36 hours of study 
intervention initiation; 
28 
6.1 
During screening and injury assessment, after completion of the 
pre-treatment baseline procedures/assessments participants who 
meet the entry criteria ... 
29 
6.1 
Upon successful completion of all screening assessments, 
randomization and participant’s receipt of study 
intervention, participants then enter the Run-In Phase 
32 
6.8 
For this study, any dose of study intervention greater than one 
(1) tablet being ingested will be considered an overdose.  This 
includes tablets that were accidently swallowed requiring the 
participant to apply a second (backup) buccal tablet, applying 
two tablets to the gum, or any other situation in which a 
participant ingests two tablets 
36 
8.1.1 
The Screening Phase will be up to 2135 days. 
37 
8.1.1 
Distribute urine pregnancy test kits (2)(if applicable); 
38 
8.1.4 
Prior to the start of study intervention, all female WOCBP 
participants MUST perform a urine pregnancy test, 
40 
8.1.6 
If the investigator determines suspects a HL outbreak has started, 
the participant will be instructed to record additional 0-10 NRS 
symptom scores and face images (at the discretion of the 
investigator) and document the HL outbreak in Science 37 
Platform. 
44 
8.3.1 
Vital signs will consist of 1  3 pulse and 3 blood pressure 
measurements 

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45 
8.4.5 
If a pregnancy is reported while the participant is in the 
treatment phase, the investigator will record pregnancy 
information on the appropriate form and submit it to the sponsor 
within 24 hours of learning of the female participant’s 
pregnancy. 
 
51 
10.1 
Sponsor’s medical expert for the study 
Name:  
, BS, 
PharmD 
Title: 
, US US Medical Affairs 
Address: Bayer Healthcare 
 
100 Bayer Boulevard 
 
Whippany NJ 07981-0915 USA 
 
  Phone:       
 
  E-mail:      
       
 
 
53 
10.1.4 
Additionally, the investigator or designee will personally sign 
and date the form within the Science 37 Platform. 
64 
10.4 
3.  Postmenopausal female 
x A postmenopausal state is defined as no menses for 12 24 
months without an alternative medical cause. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD

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Protocol Amendment 4 (Version 5.0) 
 
The following sections were amended from Version 4.0 to Version 5.0.  Pagination was updated in 
this table to align with Amendment 4. 
 
 
Type of Amendment: Substantial 
 
Changes which are considered significant or substantial have been made to the following sections 
reflected below: 
 
Page 
Number(s) 
Section 
Number(s) 
Description, paragraph or bullet point/number 
17 
1.1 
Synopsis  Number of Participants 
 
 
   
25 
4.1 
 
 
   
29 
5.2 
Exclusion 32.  Positive urine drug screen at Screening; except 
for participants with a prescription for a drug belonging to a 
class (such as amphetamines, benzodiazepines, tricyclic 
antidepressants, SSRIs, and barbiturates) known by 
approved labeling or a credible medical information source 
to potentially interfere with and cause a false positive UDS 
unless the medication is otherwise exclusionary (e.g., opioids).  
Participants should deny use of illicit drugs.  
 
 
 
CCI
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Table of Contents 
Title Page ................................................................................................................................... 1 
Sponsor Signatory .................................................................................................................... 2 
Protocol Amendment Summary of Changes Table ............................................................... 3 
1. 
Protocol Summary ........................................................................................................... 14 
1.1 
Synopsis ......................................................................................................................... 14 
1.2 
Scheme ........................................................................................................................... 18 
1.3 
Schedule of Activities (SoA) ......................................................................................... 19 
2. 
Introduction ..................................................................................................................... 20 
2.1 
Study Rationale .............................................................................................................. 20 
2.2 
Background .................................................................................................................... 20 
2.3 
Benefit/Risk Assessment ............................................................................................... 21 
2.3.1 
Benefit Assessment ..................................................................................................... 22 
2.3.2 
Overall Benefit: Risk Conclusion ............................................................................... 22 
3. 
Objectives and Endpoints ............................................................................................... 23 
4. 
Study Design .................................................................................................................... 25 
4.1 
Overall Design ............................................................................................................... 25 
4.1.1 
Study Design Phases ................................................................................................... 25 
4.1.1.1 
Screening/Randomization Phase ............................................................................. 25 
4.1.1.2 
Run-in Phase ............................................................................................................ 25 
4.1.1.3 
Treatment Phase ...................................................................................................... 25 
4.1.1.4 
Follow-up Phase ...................................................................................................... 26 
4.2 
Scientific Rationale for Study Design ............................................................................ 26 
4.3 
Justification for Dose ..................................................................................................... 26 
4.4 
End of Treatment Phase and End of Study Definitions ................................................. 26 
5. 
Study Population ............................................................................................................. 26 
5.1 
Inclusion Criteria ........................................................................................................... 27 
5.2 
Exclusion Criteria .......................................................................................................... 27 
5.3 
Lifestyle Considerations ................................................................................................ 30 
5.4 
Screen Failures ............................................................................................................... 30 
5.5 
Run-in Failures ............................................................................................................... 30 
5.6 
Criteria for Temporarily Delaying Study Intervention Administration ......................... 30 
6. 
Study Intervention(s) and Concomitant Therapy ........................................................ 30 
6.1 
Study Intervention Administered ................................................................................... 30 
6.2 
Identity of Study Interventions ...................................................................................... 32 
6.3 
Preparation/Handling/Storage/Accountability ............................................................... 32 
6.4 
Measures to Minimize Bias: Randomization and Blinding ........................................... 33 
6.5 
Study Intervention Compliance ..................................................................................... 34 
6.6 
Dose Modification ......................................................................................................... 34 
6.7 
Continued Access to Study Intervention after the Treatment Phase .............................. 34 
6.8 
Treatment of Overdose................................................................................................... 34 
6.9 
Concomitant Therapy ..................................................................................................... 35 
6.9.1 
Rescue Medicine ......................................................................................................... 35 
7. 
Discontinuation of Study Intervention and Participant .............................................. 36 
7.1 
Discontinuation of Study Intervention ........................................................................... 36 

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7.2 
Participant Discontinuation/Withdrawal from the Study ............................................... 36 
7.3 
Lost during the Treatment Phase ................................................................................... 36 
7.4 
Lost during the Follow-up Phase ................................................................................... 37 
8. 
Study Assessments and Procedures ............................................................................... 37 
8.1 
General Procedures ........................................................................................................ 37 
8.1.1 
Screening Phase Day 1 (Visit 1) ................................................................................. 37 
8.1.2 
Randomization ............................................................................................................ 38 
8.1.3 
Run-in Phase ............................................................................................................... 39 
8.1.4 
Treatment/Evaluation Phase (Day 1) .......................................................................... 39 
8.1.5 
Treatment/Evaluation Phase (Days 2 through 14) ...................................................... 40 
8.1.5.1 
Day 2 (Visit 2) ......................................................................................................... 40 
8.1.5.2 
Day 3 ....................................................................................................................... 40 
8.1.5.3 
Days 4, 5 and 6 ........................................................................................................ 40 
8.1.5.4 
Day 7 ....................................................................................................................... 40 
8.1.5.5 
Days 8, 9, 10, 11, 12 and 13 .................................................................................... 41 
8.1.5.6 
Day 14 +2 days (Visit 3) ......................................................................................... 41 
8.1.6 
Follow up Phase .......................................................................................................... 41 
8.2 
Efficacy Assessments ..................................................................................................... 42 
8.2.1 
Numerical Rating Scale (0-10) ................................................................................... 42 
8.2.2 
Oral Health Impact Profile (OHIP)............................................................................. 43 
8.2.3 
Global Evaluation ....................................................................................................... 44 
8.2.4 
Face Image Interpretation ........................................................................................... 44 
8.3 
Safety Assessments ........................................................................................................ 44 
8.3.1 
Vital Signs .................................................................................................................. 44 
8.3.2 
Pregnancy Testing ...................................................................................................... 45 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety Reporting .. 45 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ....................... 45 
8.4.2 
Method of Detecting AEs and SAEs .......................................................................... 45 
8.4.3 
Follow-up of AEs and SAEs....................................................................................... 46 
8.4.4 
Regulatory Reporting Requirements for SAEs........................................................... 46 
8.4.5 
Pregnancy ................................................................................................................... 46 
8.5 
Pharmacokinetics ........................................................................................................... 47 
8.6 
Genetics or Pharmacogenomics ..................................................................................... 47 
8.7 
Biomarkers ..................................................................................................................... 47 
8.8 
Immunogenicity Assessments ........................................................................................ 47 
8.9 
Health Economics .......................................................................................................... 47 
9. 
Statistical Considerations ............................................................................................... 48 
9.1 
Statistical Hypotheses .................................................................................................... 48 
9.2 
Sample Size Determination ............................................................................................ 48 
9.3 
Analysis Set ................................................................................................................... 48 
9.4 
Statistical Analyses ........................................................................................................ 49 
9.4.1 
General Considerations ............................................................................................... 49 
9.4.2 
Primary Endpoint ........................................................................................................ 49 
9.4.3 
Secondary Endpoints .................................................................................................. 49 
9.4.4 
Other Endpoints .......................................................................................................... 50 
9.4.5 
Safety Analysis ........................................................................................................... 50 
9.5 
Treatment Phase Analysis .............................................................................................. 50 
9.6 
Interim Analysis ............................................................................................................. 51 

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10. Supporting Documentation and Operational Considerations .................................... 52 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........................ 52 
10.1.1 Regulatory and Ethical Considerations ...................................................................... 53 
10.1.2 Financial Disclosure ................................................................................................... 53 
10.1.3 Funding ....................................................................................................................... 53 
10.1.4 Informed Consent Process .......................................................................................... 54 
10.1.5 Data Protection and Confidentiality ........................................................................... 55 
10.1.6 Compensation for Health Damage of Participants/Insurance ..................................... 55 
10.1.7 Committees Structure ................................................................................................. 55 
10.1.8 Dissemination of Clinical Study Data ........................................................................ 55 
10.1.9 Data Quality Assurance .............................................................................................. 56 
10.1.10 Source Documents ...................................................................................................... 56 
10.1.11 Missing Data ............................................................................................................... 57 
10.1.12 Audit and Inspection ................................................................................................... 57 
10.1.13 Archiving .................................................................................................................... 57 
10.1.14 Study and Site Start and Closure ................................................................................ 58 
10.1.15 Publication Policy ....................................................................................................... 58 
10.2 Appendix 2: Clinical Laboratory Tests .......................................................................... 59 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures ............................................. 59 
10.3.1 Definition of AE ......................................................................................................... 59 
10.3.2 Definition of SAE ....................................................................................................... 61 
10.3.3 Recording and Follow-Up of AE and/or SAE ............................................................ 62 
10.3.4 Reporting of SAEs ...................................................................................................... 64 
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ......... 64 
10.5 Appendix 5: Abbreviations ............................................................................................ 66 
11. References ........................................................................................................................ 68 
 
Table of Tables 
Table 1 – Study Interventions .................................................................................................. 32 
Table 2 – Analysis Populations ................................................................................................ 48 
 
Table of Figures 
Figure 1 – Study Scheme .......................................................................................................... 18 
 
 
 

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1. 
Protocol Summary 
1.1 
Synopsis 
 
Protocol Title: A Randomized, Multi-Center, Double Blinded, Self-Initiated, Single Treatment 
Study Comparing Sitavig® (acyclovir) 50 mg Muco-adhesive Buccal Tablet to Placebo in the 
Treatment of Herpes Labialis in Immunocompetent Adults 
 
 
 
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
x 
To compare duration of episode (DOE) of 
cold sores between Sitavig and placebo in 
participants experiencing a recurrence of 
herpes labialis (HL).   
 
x 
Duration of episode (DOE) will be measured 
in hours (using the Science 37 Platform), of a 
single treated HL lesion.  Observation period 
to determine healing will last up to 14 days 
(DurEp14).   
 
Duration of episode (DOE) is defined as the time 
from the initiation of treatment (study intervention 
initiation) to the healing of primary lesions (loss 
of crust) for participants who experience a 
vesicular lesion.  For participants whose primary 
lesions are not vesicular in nature, duration of 
episode is the time from study intervention 
initiation to the return to normal skin as 
determined by the independent blinded reader of 
the participant’s face images using a 6-point 
Likert scale or to the cessation of symptoms, 
whichever comes last. 
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Objectives 
Endpoints 
Secondary 
 
x 
To compare the incidence of aborted 
lesions between participants receiving 
Sitavig and placebo after experiencing 
prodromal symptoms of a recurrence of 
HL. 
x 
To compare the incidence of recurrence of 
primary HL lesions between participants 
receiving Sitavig and placebo during a 12-
month follow-up period. 
x 
To compare the time to recurrence of 
primary HL lesions between participants 
receiving Sitavig and placebo during a 12-
month follow-up period. 
x 
To assess safety and tolerability of the 
investigational products. 
x 
Incidence of aborted lesions, defined as 
treated HL lesions that do not progress to the 
vesicular stage.  A lesion that returns to 
normal skin without forming a vesicle or crust 
will be counted as an aborted lesion.  
Observation period to determine healing will 
last up to 14 days (Abort14).   
 
x 
Incidence of recurrence of HL lesions during 
the 12-month follow-up period (IncRec12). 
Recurrence is determined by assessment 
from the investigator and documented using 
numerical rating scale (NRS) symptom 
scores and face images using the Science 
37 Platform. 
 
x 
Time to recurrence of HL lesions, measured 
in days from resolution of the cold sore 
treated in the Treatment phase until onset of 
prodromal symptoms during the follow-up 
period (TimeRec12). 
x 
Safety and tolerability measured by the 
Incidence of Treatment-Emergent Adverse 
Events 
x 
The percentage of participants who have at 
least one recurrence during the 12-month 
follow up period will be calculated.  
 
 

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Other 
 
x 
To compare the duration of episode in 
participants who used Sitavig or placebo 
who initiated study intervention within 1 
hour of prodromal symptoms and 
participants who initiated study 
intervention after 1 hour of prodromal 
symptoms. 
x 
To compare the time to cessation of 
symptoms in patients experiencing a 
recurrence of HL in participants who used 
Sitavig and placebo. 
x 
To compare the quality of life in 
participants who used Sitavig and placebo. 
x 
To compare the 0-10 NRS HL symptoms 
by time point in participants who used 
Sitavig and placebo. 
x 
To evaluate the Global assessment at Day 
14.To evaluate the  incidence of 
detachment or swallowing within 6 hours 
of dosing, and the incidence of replacing 
the tablet. 
x 
Duration of episode (DOE) will be 
measured in hours (using the Science 37 
Platform), of a single treated HL lesion in 
participants who initiation study 
intervention within 1 hour of onset of 
prodromal symptoms and participants 
who initiated study intervention more 
than 1 hour after onset of prodromal 
symptoms. 
 
x 
Time to cessation of symptoms, 
measured in hours from initial application 
of assigned study intervention.  
Cessation of symptoms is defined as the 
absence of sensations of pain, 
tenderness tingling, itching or discomfort  
at the site of the cold sore as measured 
by NRS.  Observation period to 
determine healing will last up to 14 days 
(CesSymp14).   
 
x 
Quality of life score, as measured by the 
OHIP-14 questionnaire at 3, 7 and 14 
days post-dose. 
 
x 
Global assessment of study intervention 
at Day 14. 
 
x 
The change from baseline to post-dose 
in NRS. 
 
x 
The incidence of detachment or 
swallowing within 6 hours of dosing and 
the number (percentage) of subjects with 
the incidence. 
 
x 
The percentage of subjects who replace 
the tablet among those with detachment 
or swallowing within 6 hours of dosing. 
 
Overall Design: This is a randomized (1:1/acyclovir : placebo), self-initiated, placebo-
controlled, double-blind, multi-center parallel study. 
Brief Summary: 
This is a 14-day clinical trial (Treatment Phase) to test the hypothesis that Sitavig (acyclovir) 
buccal tablet safely and effectively reduces duration of a herpes labialis cold sore of the lip in 
immunocompetent adults.  Eligible participants who pass screening procedures will be 
randomized and moved into the Run-in Phase.  Participants will be randomly assigned one of 
two treatment groups - Sitavig (acyclovir) 50 mg buccal tablets or a placebo buccal tablet.  The 
randomization assignment is such that there is a 1 in 2 chance of receiving the placebo treatment. 
Participants will have a 6 month eligibility window in which they can self-initiate treatment 
should prodromal symptoms start.  At the start of prodromal symptoms, participants will self-

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initiate treatment and record face images as well as symptom scores over the next 14 days.   
Treatment consists of a single application (of the buccal tablet) beginning on Day 1.  Face 
images and symptom scores are captured over the 14 day Treatment Phase. 
Study Duration (Treatment Phase): 14 days 
Study Duration (Follow up Phase): 12 months 
Investigational Medicinal Product (IMP): Sitavig (acyclovir) 50 mg buccal tablet or placebo 
buccal tablet 
Treatment Duration: 1 day 
Visit Frequency: After the start of treatment, two visits within the 14 day Treatment Phase.  
Additional follow up by phone will occur at 3, 6, 9 and 12 months after treatment. 
Condition/Disease: Herpes labialis of the lips caused by herpes simplex virus type 1 (HSV-1) or 
herpes simplex virus type 2 (HSV-2). 
Study Hypothesis: Sitavig (acyclovir) buccal tablet effectively reduces the duration of a cold 
sore of the lips. 
Health Measurement/Observation: Independent blinded lesion evaluation using a 6-point 
Likert scale and 0-10 NRS symptom scores will occur pre and post treatment. 
 
 
 
 
Intervention Groups: Participants will be randomized in 1:1 fashion (active or placebo) with a 
single dose of study intervention. 
Data Monitoring/Other Committee: No 
 
 
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1.2 
Scheme 
 
Figure 1 – Study Scheme 
 
 

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1.3 
Schedule of Activities (SoA) 
a The urine pregnancy test must be performed prior to the start of study intervention and be negative (not pregnant). 
b NRS symptom scores and face images can be collected at 09:00, 14:00 and 19:00 that day.  Depending on the time study  
intervention starts, NRS symptom scores and face images may or may not be collected for Day 1. 
c Face images taken at 09:00, 14:00 and 19:00 each day. 
d The 2-day window pertains to all Visit 3 tasks except the NRS symptom scores, face images, QoL-OHIP and Global assessment 
which should be collected at their respective nominal times (±60 minutes) on Day 14. 
e Face image(s) and NRS symptom score(s) required if a new outbreak of herpes labialis is suspected by the investigator. 
f After successful completion of all screening procedures. 
g Follow up dates established using the Day 1 dosing date.
 
Screening & 
Randomization 
Phase 
Run-in 
Phase 
Treatment Phase 
Follow-Up Phaseg 
Visit Number 
1 
 
 
2 
 
3d 
 
Day or Milestone 
Within 35 days 
of Run-in start 
Six-month 
eligibility 
window 
1 1-2 3 4-6 7 8-13 
 
14 
+2d 
3 months 
(call) 
±3 days 
6 months 
(call) 
±3 days 
9 months 
(call) 
±3 days 
12 months 
(call) 
±3 days 
Virtual visit 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Participant 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medication 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
History of drug and 
alcohol use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
 
Xa 
 
 
 
 
 
 
 
 
 
 
BP and pulse 
X 
 
 
X 
 
 
 
 
X 
 
 
 
 
Platform (re)training 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
IMP dosing 
instructions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NRS symptom scores 
X 
 
Xb X 
X 
X 
X 
X 
X 
Xe 
Xe 
Xe 
Xe 
Face images 
X 
 
Xb Xc Xc Xc Xc Xc 
Xc 
Xe 
Xe 
Xe 
Xe 
Randomizationf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Virtual weekly   
check-ins 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Start of prodromal 
symptoms 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
IMP compliance 
check 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
OHIP-14 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Global assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
IMP kit return 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of Study 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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2. 
Introduction 
Herpes labialis (HL), also called cold sores of the lip, is an infection primarily caused by 
herpes simplex virus type 1 (HSV-1) and occasionally herpes simplex virus type 2 (HSV-2). 
The infection is typically spread between people by direct contact. HL is a rash of the skin 
and mucous membranes (in particular, the lips) and is characterized by erythema and blisters 
that are preceded and accompanied by tingling, itching or burning pain [1]. 
For an infection to manifest, the virus must come in contact with mucosal surfaces or abraded 
skin. The viral replication takes place at the site of primary infection (epithelial cells), either 
as an intact virion or the capsid is transported in a retrograde fashion by neurons to the dorsal 
root ganglia, where, after another round of viral replication, latency is established. After 
primary infection, the virus recedes via the sensory nerve into the respective ganglion (usually 
the trigeminal ganglion), where it lies latent throughout the individual’s lifetime. Stimuli such 
as fever, menstruation, sunlight, and upper respiratory infections can reactivate the virus, after 
which it returns to the epithelial cells via the sensory nerve [2]. 
HSV1 and HSV2 infections rest in a dormant (inactive) state until the virus is activated. 
During an active phase of infection, a visible outbreak of sores may be observed. Infrequently, 
life-threatening infection (e.g., encephalitis) may occur. The more severe the primary 
infection (as reflected by the size, number, and extent of lesions) the more likely it may be 
that recurrences may develop when triggered [3,4]. 
After a period of latency, a proper stimulus may cause reactivation. Reactivation of the virus 
becomes evident at mucocutaneous sites, appearing as skin vesicles or mucosal ulcers. The 
blisters in cold sores appear as fluid filled pockets beneath the surface of the skin around the 
mouth or on the lips. They can break open, ooze, and crust over, lasting for around 7 to 10 
days. The severity of the disease varies from person to person and the symptoms can be very 
painful. There are different products that are used to treat cold sores. There are prescription 
drugs which are very effective and there are the over the counter (OTC) products as well 
which can bring relief to the patients [3,4,5]. 
2.1 
Study Rationale 
 
 
 
 
2.2 
Background 
A randomized, double-blinded, multicentered, placebo-controlled, single-dose trial of early 
administration of Acyclovir 50-mg mucoadhesive buccal tablets was conducted to evaluate 
efficacy and safety for the treatment of herpes labialis in immunocompetent patients. This 
muco-adhesive buccal tablet is designed to allow the rapid and prolonged release of acyclovir 
in high concentrations directly into the oral cavity at the site of the infection of herpes labialis.  
The primary objective of this study was to demonstrate the efficacy of a single mucoadhesive 
acyclovir buccal tablet (ABT) compared to a single dose of a placebo. The efficacy was 
measured using the time to healing of the primary vesicular lesion (time-to-event). Secondary 
objectives were to compare the efficacy of ABT 50 mg versus placebo on the evolution of 
prodromal symptoms to aborted lesions, healing of non-primary lesions, duration of episode, 
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duration of symptoms, healing of the aborted primary lesions and intra oral/mucosal non 
primary lesions, and the incidence of and time to recurrence during 9 months following 
treatment.  Prodromal symptoms (such as pain, tenderness, itching, tingling or discomfort)  
are early symptoms that herald the onset of a cold sore outbreak. 
Local tolerability and general safety were studied. The concentration of acyclovir in the saliva 
and the adhesion time (incidence of tablets detaching and/or being swallowed within 6 hours 
after tablet placement) was evaluated as well. Two populations were analyzed in this protocol: 
the modified intent to treat (mITT) population of everyone who took at least one dose and 
whose lesion reached the vesicular stage and the intent to treat (ITT) population that took at 
least one dose of the treatment medication.  
After initiating treatment, subjects were under evaluation for up to 14 days or until the 
primary lesions healed. Subjects were told to fill out a questionnaire and visual analogue scale 
each evening to record their symptoms. Patients were to return to the clinic within 36 hours of 
application of the tablet. Evaluation took place on days 1, 3, 5, 7, and 14 (or healing 
occurred). Additionally, follow-up visits were conducted every 3 months for up to 9 months 
for recurrence. Adverse effects were to be reported.   
The demographic characteristics were similar between treatment and placebo group. All 
patients in both groups experienced at least 4 episodes of herpes labials in the last 12 months 
and more than 2/3 had at least 5 episodes per year. 
 
 
 
 
 
The results of the study showed that time to healing of primary lesion was significantly 
reduced (p=0.0150) in the ABT 50 mg group compared to the placebo group. The clinical 
reduction was 0.57 days. The secondary objectives were all improved compared to the 
placebo group. More patients had aborted lesions, and the duration of non-primary vesicular 
lesions was reduced. Data showed that ABT 50 mg reduces the occurrence of the vesicular 
lesions. The duration of the herpes episode and the duration and severity of symptoms were 
all reduced by the treatment. A notable result in this study was that there were significantly 
fewer patients in the treatment group who had recurrences of primary lesions than in the 
placebo group. The difference was even greater in patients who inserted ABT 50 mg correctly 
within 1 hour of symptoms.  
 
 
 
 
 
  
 
2.3 
Benefit/Risk Assessment 
Patients with recurrent HL will be enrolled in this study.  The study intervention will be 
used/applied in accordance with the Prescribing Information for Sitavig [6]. 
 
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During the study, patients will be closely monitored for evidence of adverse events.  
Weighing between the potential risks of antiviral medication associated with the study and 
given the ability to mitigate risks through close monitoring, this study is considered clinically 
and ethically acceptable. 
Relevant emerging safety data, e.g., serious adverse events (SAEs), suspected unexpected 
serious adverse reactions (SUSARs), and serious safety-related protocol deviations, will be 
communicated as soon as possible between the sponsor, all study sites and investigators and 
trial subjects according to the requirements of the FDA guideline on strategies to identify 
risks for clinical trials.  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of 50 mg acyclovir buccal tablets may be found in the Prescribing 
Information for Sitavig [6]. 
The potential impact of COVID-19 on study participants will be evaluated before the start of 
enrollment and monitored during the study in accordance with FDA guidance [7]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
x 
To compare duration of episode (DOE) of 
cold sores when treated with Sitavig or 
placebo in participants experiencing a 
recurrence of herpes labialis (HL).   
 
x 
Duration of episode (DOE) will be measured 
in hours (using the Science 37 Platform), of a 
single treated HL lesion.  Observation period 
to determine healing will last up to 14 days 
(DurEp14).   
 
Duration of episode (DOE) is defined as the time 
from the initiation of treatment (study 
intervention) initiation to the healing of primary 
lesions (loss of crust) for participants who 
experience a vesicular lesion.  For participants 
whose primary lesions are not vesicular in 
nature, duration of episode is the time from study 
intervention initiation to the return to normal skin 
or to the cessation of symptoms, whichever 
comes last as determined by the independent 
blinded reader of the participant’s face images 
using a 6-point Likert scale. 
Secondary 
 
x 
To compare the incidence of aborted 
lesions between participants receiving 
either Sitavig or placebo after experiencing 
prodromal symptoms of a recurrence of 
HL. 
 
x 
To compare the incidence of recurrence of 
primary HL lesions between participants 
receiving either Sitavig or placebo during a 
12-month follow-up period 
 
x 
To compare the time to recurrence of 
primary HL lesions between participants 
receiving either Sitavig or placebo during a 
12-month follow-up period. 
 
x 
To assess safety and tolerability of the 
investigational products. 
x 
Incidence of aborted lesions, defined as 
treated HL lesions that do not progress to the 
vesicular or crust stage.  A lesion that returns 
to normal skin without forming a vesicle or 
crust will be counted as an aborted lesion.  
Observation period to determine healing will 
last up to 14 days (Abort14).   
 
x 
Incidence of recurrence of HL lesions during 
the 12-month follow-up period (IncRec12). 
 
x 
Time to recurrence of HL lesions, measured 
in days from resolution of the cold sore 
treated in the Treatment phase until 
appearance of a cold sore during the follow-
up period (TimeRec12). 
x 
Safety and tolerability measured by the 
Incidence of Treatment-Emergent Adverse 
Events 
x 
The percentage of participants who have at 
least one recurrence during the 12-month 
follow up period will be calculated. The time 
to first recurrence is determined by 
assessment from the investigator and 
documented using NRS symptom scores 
and face images using the Science 37 
Platform. 
 
 
 

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Objectives 
Endpoints 
Other 
 
x 
To compare the duration of episode in 
participants who used Sitavig or placebo 
who initiated study intervention within 1 
hour of prodromal symptoms and 
participants who initiated study 
intervention after 1 hour of prodromal 
symptoms. 
 
x 
To compare the time to cessation of 
symptoms in patients experiencing a 
recurrence of HL in participants who used 
Sitavig and placebo. 
 
x 
To compare the quality of life in 
participants who used Sitavig and placebo. 
 
x 
To compare the 0-10 NRS HL symptoms 
by time point in participants who used 
Sitavig and placebo. 
 
x 
To evaluate the Global assessment at Day 
14. 
 
x 
To evaluate the incidence of detachment 
or swallowing within 6 hours of dosing, and 
the incidence of replacing the tablet. 
x 
Duration of episode (DOE) will be 
measured in hours (using the Science 37 
Platform), of a single treated HL lesion in 
participants who initiation study 
intervention within 1 hour of onset of 
prodromal symptoms and participants 
who initiated study intervention more 
than 1 hour after onset of prodromal 
symptoms. 
 
x 
Time to cessation of symptoms, 
measured in hours from initial application 
of assigned study intervention.  
Cessation of symptoms is defined as the 
absence of sensations of pain, 
tenderness tingling, itching or discomfort 
at the site of the cold sore as measured 
by NRS.  Observation period to 
determine healing will last up to 14 days 
(CesSymp14).   
 
x 
Quality of life score, as measured by the 
OHIP-14 questionnaire at 3, 7 and 14 
days post-dose. 
 
x 
Global assessment of study intervention 
at Day 14. 
 
x 
The change from baseline to post-dose 
in NRS. 
 
x 
The incidence of detachment or 
swallowing within 6 hours of dosing and 
the number (percentage) of subjects with 
the incidence. 
 
x 
The percentage of subjects who replace 
the tablet among those with detachment 
or swallowing within 6 hours of dosing. 
 
 
 
 

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4. 
Study Design 
4.1 
Overall Design 
This is a randomized, multi-center, participant-initiated, double-blinded, single treatment 
study comparing acyclovir 50 mg muco-adhesive buccal tablet (Sitavig) to matching placebo 
(i.e., study intervention) in the treatment of Herpes Labialis (HL) in immunocompetent adults. 
The study consists of a Screening Phase, Run-in Phase, Treatment Phase, Evaluation Phase 
and a Follow-Up Phase. 
 
 
A visual presentation of the overall study design is provided in . 
4.1.1 
Study Design Phases 
4.1.1.1 
Screening/Randomization Phase  
Participants will be screened for eligibility up to 35 days prior to study according to the 
inclusion/exclusion criteria.  Participants will be assigned a screening number (SNR) and 
basic health information will be collected, and the participant will be assessed by the study 
investigator/designee.  Eligible participants will be randomized into one of two study 
interventions.  Participants will enter the Run-in Phase, which starts a six-month treatment 
eligibility window. 
 
4.1.1.2 
Run-in Phase 
The Run-in Phase provides the opportunity for participants the time to spontaneously start a 
HL outbreak that would require treatment.  Participants will be in contact with Science 37 
using weekly virtual check-ins within the Science 37 Platform.  Adverse events and 
concomitant medications could be recorded.  Participants who do not develop an HL episode 
within six months will be withdrawn from the study. 
 
4.1.1.3 
Treatment Phase 
Once participants experience prodromal symptoms, they will take face images and self-
initiate treatment (study intervention) preferably within one hour and before the visible 
appearance of any signs of HL lesions according to the product instructions.  Participants will 
also be completing HL symptom scores (pain, tenderness, itching, tingling and discomfort) as 
well as Quality of Life (QoL) scoring using the Oral Health Impact Profile (OHIP) and during 
the next 10 days within the Science 37 Platform.  Participants will then be under evaluation 
for healing of the primary lesion(s) up to 14 days.  
Participants will be asked to meet with the clinic via the Science 37 Platform within 36 hours 
of the start of study intervention (Day 1) and complete face images, symptom and QoL scores 
using the Science 37 Platform.  Additionally, participants will complete face images, 
symptom and QoL scores on Days 2 through 13 with a virtual visit on Day 14 (+2 days), Visit 
3 using the Science 37 Platform. 
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4.1.1.4 
Follow-up Phase 
Participants will automatically transition to the Follow-up Phase after the completion of the 
Treatment Phase.  Participants will be in contact with the Science 37 using weekly virtual 
check-ins within the Science 37 Platform with the purpose reporting any adverse events, 
concomitant medications or new outbreaks of HL.  Potential new HL occurrences will be 
reviewed by the investigator using face images and symptom scores. 
 
The duration of each patient’s participation will be up to 20 months. For an overview on the 
trial design and trial procedures see Section 1.2. 
 
 
 
 
 
 
 
4.3 
Justification for Dose 
Participants who self-initiate study intervention are instructed to apply one (1) 50 mg buccal 
tablet from the blister package to their upper gum area consistent with the Prescribing 
Information for Sitavig [6].  The second tablet/dose in the blister is provided as a backup in 
the event the first buccal tablet cannot be applied as instructed.  See Section 6.5 related to 
applying a second buccal tablet. 
 
4.4 
End of Treatment Phase and End of Study Definitions 
The end of the Treatment Phase is study is defined as the date of the last visit in the Treatment 
Phase (Visit 3) of the last participant in the study.  The end of the study is defined as the date 
of the last follow-up visit (either by documented HL outbreak or at 12 months) of the last 
participant in the study. 
A participant is considered to have completed the study if he/she has completed all phases of 
the study up to Follow up Phase as shown in the Schedule of Activities (Section 1.3). 
 
5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions are not permitted. 
 
 
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5.1 
Inclusion Criteria 
 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Males or females, 18 years of age or older inclusive; 
Type of Participant and Disease Characteristics 
2. History of recurrent HL lesions where: 
a. Recurrence is defined as at least 4 episodes in the preceding 12 months; 
b. At least half of the episodes should be vesicular in nature; 
c. At least half of the episodes should be preceded by prodromal symptoms; 
d. Herpes labialis lesions are characterized by their localization on the cutaneous 
and/or mucosal surfaces of the lips; 
3. Willing to avoid, during the treatment phase, the use of anti-inflammatory (not 
including low-dose (81 mg) aspirin), anti-herpetic, antibiotic and antiviral agents as 
well as steroids or other natural products that would interfere with the immune 
system response; 
4. Female participants of childbearing potential must be using a medically acceptable 
form of birth control during screening [e.g., hormonal contraceptives (oral, patch, 
injectable or vaginal ring), implantable device (implantable rod or intrauterine 
device), or a double barrier], abstinence or in same sex relationship and have a 
negative pregnancy test at Screening and prior to study drug administration. Female 
participants of non-childbearing potential must be amenorrheic for at least two years 
or have undergone surgical sterilization (i.e. tubal ligation/occlusion, hysterectomy 
and/or bilateral oophorectomy); 
5. Agreement to abstain from any mechanical disruption of the prodromal area or 
lesion (i.e. scrubbing, lancing, shaving the area, rubbing with alcohol, application of 
heat emitting devices used for cold sore treatment, etc.); 
 
Informed Consent and Other 
6. Capable of giving signed informed consent as described in Section 10.1.4 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol; 
7. Ability to understand and follow study-related instructions;  
8. Be willing and able to participate in all scheduled visits, treatment plan, and trial 
procedures according to the clinical protocol. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participants who did not develop herpes prodromal symptoms within 6 months after 
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2. More than 50% of recurrences that aborted spontaneously (without intervention) in 
the past 12 months; 
3. Primary herpes lesion outside the lips (e.g., nose, chin, etc.); 
4. Abnormal peri-oral skin condition that might affect the normal course of cold sores 
(e.g., eczema, psoriasis, etc.); 
5. Oral diseases whose prodromal symptoms may mimic those of herpes labialis, 
including recurrent oral aphthous disease; 
6. Oral diseases that might interfere with the evaluation of the efficacy or safety of the 
treatments, including gingivitis, periodontitis, mucositis, oropharyngeal candidiasis, 
etc. or upon inspection of the gums and in the judgement of the investigator, are not 
suitable for study participation; 
7. Upper full or partial dentures that in the judgement of the investigator, could 
interfere with study intervention when applied to the upper gum area; 
8. History of infection known to be resistant to acyclovir family agents; 
9. Allergy to any acyclovir or its containing agents; 
10. Milk allergy or known history of hypersensitivity to one of the components of 
Sitavig; 
11. Self-reported immunocompromised condition, including self-reported Human 
Immunodeficiency Virus (HIV) positive and previous bone marrow or organ 
transplant; 
12. Self-reported galactose intolerance, lactase enzyme deficiency or glucose galactose 
malabsorption;  this does not include self-reported lactose intolerance; 
13. Known medical history of renal disease that in the judgment of the investigator is 
severe; 
14. Evidence or history of clinically significant (in the judgment of the investigator) 
hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
psychiatric, neurologic diseases, or malignancies within the last 5 years; 
15. Females who are planning to become pregnant, are pregnant or lactating; 
16. Participants with a medical disorder, condition, or history of such that could impair 
the participant’s ability to participate or complete this trial in the opinion of the 
investigator; 
 
Prior/Concomitant Therapy 
17. Previous vaccination against herpes simplex; 
18. In the opinion of the investigator, concomitant treatment likely to interfere with 
acyclovir; 
19. Use of any drugs (e.g., amikacin, cisplatin) during the study that may interact with 
acyclovir; 
20. Use of any topical cold sore treatment that is not study intervention (e.g.,  
dimethecone, menthol, camphor, benzalkonium chloride, beeswax) or cold sore 
treatment patch/bandage (e.g., Compeed®) or device during the study; 

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21. Participants unwilling to avoid the use of any antivirals, oral analgesics, any lip balm 
or zinc oxide cream, non-steroidal anti-inflammatory drug (including aspirin and 
probenecid) or topical pain reliever or anesthetic (e.g., benzocaine, lidocaine) as a 
cold sore treatment during the study; 
22. Treatment with topical steroids in the oral area within 4 weeks prior to 
Investigational Medicinal Product (IMP) administration; 
23. Patients undergoing any cancer treatment (e.g., chemotherapy); 
24. Immunomodulator medications (immuno-suppressive or immuno-stimulation) 
within 30 days of randomization; 
25. Oral or systemic steroids (intravascular, intramuscular or intra-articular, not 
including inhaled) within 30 days of randomization; 
26. Prophylactic antiviral treatment during the Screening Phase, Treatment Phase and in 
the Follow Up phase until the first new investigator confirmed HL outbreak; 
 
Other Exclusions 
27. Participants unwilling to avoid the use of cosmetics on facial area at the start of 
prodromal symptoms and throughout the Treatment Phase of the study; 
28. Facial hair that obscures complete visualization of the cold sore; 
29. Participants whose occupations make them unlikely to complete a virtual clinic visit 
within  36 hours of study intervention initiation; 
30. Participation in another therapeutic trial evaluating new drugs or which could 
interfere with the evolution of HL lesions or evaluation of the drug in the study 
within the preceding 30 days; 
31. Alcoholism or drug abuse within 2 years prior to the Screening Visit or routine 
consumption of 3 or more alcohol containing beverages per day; Alcohol containing 
beverages are defined as one beer (5%), one glass of wine (11%) and one shot (40%) 
hard liquor; 
32. Positive urine drug screen at Screening; except for participants with a prescription 
for a drug belonging to a class (such as amphetamines, benzodiazepines, tricyclic 
antidepressants, SSRIs, and barbiturates) known by approved labeling or a credible 
medical information source to potentially interfere with and cause a false positive 
UDS unless the medication is otherwise exclusionary (e.g., opioids).  Participants 
should deny use of illicit drugs.  
33. Inability to properly understand protocol requirements, to follow the study 
procedures, to fully use the Science 37 Platform or to start the self-initiation of study 
intervention; 
34. Member or first-degree relative of study staff or the Sponsor directly involved in the 
study; 
35. Unwilling or unable to comply with all requirements outlined in the protocol; 
 
Prior/Concurrent Clinical Study Experience 
36. Previous enrollment in this study. 

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5.3 
Lifestyle Considerations 
No lifestyle restrictions are required. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required 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 regulatory authorities. Minimal information includes demography, 
screen failure details, and eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) cannot 
be rescreened. 
Screen failures will be documented within the Science 37 Platform. 
5.5 
Run-in Failures 
Run-in failures are participants who successfully completed screening and randomized to a 
blinded study intervention (treatment).  Participants start a 6-month eligibility window during 
the Run-in Phase where they could potentially self-initiate treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Run-in failures and the reason for the failure will be documented in the Science 37 
Platform and stored in the clinical database. 
 
5.6 
Criteria for Temporarily Delaying Study Intervention Administration 
Not applicable 
 
6. 
Study Intervention(s) and Concomitant Therapy 
The study center/pharmacy will dispense a blinded treatment after successfully completing 
screening and baseline assessments. The blisters of investigational medicinal product (IMP) 
for each treatment will be dispensed using a computer generated randomization schedule. 
 
6.1 
Study Intervention Administered 
During screening participants who meet the entry criteria will be sequentially assigned to a 
unique number in ascending order (randomization number, RNR) according to the 
CCI

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randomization schedule prepared prior to the study.  A separate kit number (and 
corresponding kit) will be assigned by the interactive (x-voice/web) response system (IXRS) 
that correlates to the blinded study intervention assigned when the subject was randomized. 
Participants will be numbered according to the following scheme: 
14001XXXXX 
14 = country code (USA) 
001 = site number (for site 1) 
XXXXX = RNR (starting with 10001) 
Whereas the “Xs” will be replaced with a five digit sequentially assigned number as each 
subject enters the study (e.g., first subject number at Site 1 of the study will be 1400110001). 
Once a number has been assigned to a participant, it cannot be reassigned to another 
participant. 
Participants who do not meet all of the eligibility criteria will not be randomized. Upon 
successful completion of all screening assessments, randomization and participant’s receipt of 
study intervention, participants then enter the Run-In Phase in which they are eligible to start 
study intervention.  At the first sign of prodromal symptoms, participants may self-initiate 
study intervention which automatically moves them into the Treatment Phase and one of two 
blinded study interventions: 
x Sitavig® (acyclovir) 50 mg muco-adhesive buccal tablet (one tablet application on Day 1); 
x Placebo muco-adhesive buccal tablet (one tablet application on Day 1). 
Participants will apply one (1) muco-adhesive buccal tablet to the upper gum of the mouth on 
the same side of the mouth where the prodromal symptoms started.  Any dosing-related 
deviations outside of the allowable window (e.g., >1 hour after the start of prodromal 
symptoms, second tablet administered) will be documented in the Science 37 Platform (see 
Section 6.5). 
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to a study participant according to the study protocol. 

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6.2 
Identity of Study Interventions 
Table 1 – Study Interventions 
Intervention 
Test 
Reference 
UI Number 
1614773 
1614773-003 
Type  
Drug 
Placebo 
Dose Formulation 
acyclovir 
hypromellose 
milk protein concentrate  
sodium lauryl sulfate  
magnesium stearate 
microcrystalline cellulose 
povidone 
colloidal silicon dioxide 
 
hypromellose 
milk protein concentrate  
sodium lauryl sulfate  
magnesium stearate 
microcrystalline cellulose 
povidone 
colloidal silicon dioxide 
Dose Strength 
1 tablet 
1 tablet 
Dosage 
50 mg 
Not applicable 
Route of Administration 
Oral (upper gum area) 
Oral (upper gum area) 
Packaging and Labeling 
Study Intervention will be 
provided in a blister. Each 
blister will be labeled as 
required per FDA 
requirements 
Study Intervention will be 
provided in a blister. Each 
blister will be labeled as 
required per FDA 
requirements 
Batch Number 
available in the study file 
available in the study file 
Manufacturer 
Farméa 
10 rue Bouché Thomas 
ZAC d’orgemont 
49 000 Angers - France 
Farméa 
10 rue Bouché Thomas 
ZAC d’orgemont 
49 000 Angers - France 
All study drugs will be manufactured and labeled according to Good Manufacturing Practice 
(GMP) and applicable local laws. Label text will be approved according to the sponsor’s 
agreed procedures, and a copy of the labels will be made available to the study site upon 
request. 
For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients. Lists linking all numbering levels will be maintained by the sponsor’s 
clinical supplies Quality Assurance (QA) group. 
A complete record of batch numbers and expiry dates of all investigational products as well as 
the labels will be maintained in the clinical supply file. 
The source of test and reference products will be documented in the clinical supply file. 
6.3 
Preparation/Handling/Storage/Accountability 
Only participants randomized in the study may receive study intervention and only authorized 
staff may supply study intervention. All study intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to authorized staff. 
The investigator’s delegated staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in a separate document.  

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6.4 
Measures to Minimize Bias: Randomization and Blinding 
Study using Pre-
Coded 
Randomization 
provided to the 
site 
At Screening, qualified participants will be assigned a unique 
number (randomization number, [RNR]) in ascending numerical 
order.  
 
The randomization number encodes the participant’s treatment 
assignment to one of the two arms of the study, according to the 
randomization schedule generated prior to the study by the 
Statistics Department at Bayer. Each participant will be dispensed 
blinded study intervention, labeled with his/her unique 
randomization number, throughout the study. 
 
The treatment kit number will be pre-printed on the study 
intervention (treatment) kit package. 
Blind Break 
The IXRS will allow the investigator to see (unblind) the study 
intervention assignment for each participant should it be medically 
necessary (as it relates to a SAE).  Participants who are unblinded 
during the Treatment Phase of the study will not be included in the 
Treatment Phase analysis.  Participants who are unblinded during 
the Follow-up Phase will not be included in the Follow-up analysis. 
 
In case of an emergency, the investigator has the sole responsibility 
for determining if unblinding of a participant’s intervention 
assignment is warranted. Participant safety must always be the first 
consideration in making such a determination. If the investigator 
decides that unblinding is warranted, the investigator should make 
every effort to contact the sponsor prior to unblinding a 
participant’s intervention assignment unless this could delay 
emergency treatment of the participant. If a participant’s 
intervention assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. 
 
In the event of a Quality Assurance audit, the auditor(s) will be 
allowed access to unblinded study intervention records to verify 
that randomization/dispensing has been done accurately.  If 
necessary, Bayer Pharmacovigilance may unblind the intervention 
assignment for any participant with an SAE. If the SAE requires 
that an expedited regulatory report be sent to one or more 
regulatory agencies, a copy of the report, identifying the 
participant’s intervention assignment, may be sent to investigators 
in accordance with local regulations and/or sponsor policy. 
 
 
 

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6.5 
Study Intervention Compliance 
Participants will be following the dosing instructions provided for applying a single buccal 
tablet to the upper gum on the same side of the mouth as the HL symptoms.  Participants will 
record the date/time of dosing using the Science 37 Platform.  Any deviations from the dosing 
instructions (e.g., greater than 1 hour after prodromal symptoms, applying a second tablet) 
will be recorded in the electronic case report form (eCRF) and/or Science 37 Platform. 
For participants who self-administer a second tablet at the time of dosing (Day 1), the reason 
for applying a second tablet must be recorded in the eCRF and/or Science 37 Platform.  
Possible reasons are: 
x Accidentally swallowed (see Section 6.8 related to an overdose); 
x Tablet did not stick to gum when applied, not swallowed; 
x Accidentally chewed, not swallowed; 
x Lost/dropped first tablet, not used; 
x First tablet was damaged, not used; 
x Other (explanation not previously stated). 
 
6.6 
Dose Modification 
Not applicable 
 
6.7 
Continued Access to Study Intervention after the Treatment Phase 
No study intervention will be available for the Follow-up Phase.  Study participants will 
follow their own standard of care for the treatment of a new HL occurrence during the 12 
month Follow-up Phase.  Study participants cannot receive prophylactic antiviral treatment 
for HL until a new outbreak occurs.  Following a new outbreak determined by the 
investigator, participants can start prophylactic treatment for HL as advised by a healthcare 
professional. 
 
6.8 
Treatment of Overdose 
For this study, any dose of study intervention greater than one (1) tablet being ingested will 
be considered an overdose.  This includes tablets that were accidently swallowed requiring the 
participant to apply a second (backup) buccal tablet, applying two tablets to the gum, or any 
other situation in which a participant ingests two tablets. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
x Contact the Principal Investigator (or delegate) immediately; 
x Evaluate the participant to determine, in consultation with the Medical Monitor, 
whether any symptomatic or supportive care is needed; 

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x Document the quantity of the excess dose, date/time of the overdose and reason for 
using the backup tablet (see Section 6.5) in the eCRF and/or Science 37 Platform. 
6.9 
Concomitant Therapy 
Any medication (including OTC or prescription medicines, recreational drugs, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
x Reason for use; 
x Dates of administration including start and end dates; 
x Dosage information including dose and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
 
6.9.1 
Rescue Medicine 
No rescue medication will be provided for this study. 
 

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7. 
Discontinuation of Study Intervention and Participant 
7.1 
Discontinuation of Study Intervention  
Not applicable 
7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA (Section 1.3). See SoA (Section 1.3) for data to be 
collected at the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed. 
The participant will be permanently discontinued both from the study intervention and from 
the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
7.3 
Lost during the Treatment Phase 
A participant will be considered lost if he or she repeatedly fails to return/present for 
scheduled visits within the Science 37 Platform and is unable to be contacted by Science 37. 
The following actions must be taken if a participant fails to present for a required study visit: 
x Science 37 must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
x Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 2 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented within the Science 37 Platform. 
x Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
 
 

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7.4 
Lost during the Follow-up Phase 
A participant will be considered lost if he or she repeatedly fails to present for scheduled 
visits within Science 37 Platform and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to present for a required study visit: 
x The site must attempt to contact the participant to ascertain whether or not the 
participant wishes to and/or should continue in the study; 
x The site must make at least 2 attempts to contact the participant and document the 
attempted contacts in the source documentation; 
x Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
8. 
Study Assessments and Procedures 
8.1 
General Procedures 
x Study procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
x Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
x Adherence to the study design requirements, including those specified in the SoA 
Section 1.3 is essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. Science 37 Platform report will 
maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable.  
x Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA (Section 1.3) 
 
8.1.1 
Screening Phase Day 1 (Visit 1) 
Note: Visits stated in the assessment periods and their subsequent tasks/procedures will occur 
as a virtual visit including the assessment of adverse events.  This includes the shipment of 
supplies to the participant’s home required to complete the necessary testing before and after 
the start of study intervention. 
 
At the Screening visit, the Principal Investigator or appropriate designee will discuss with 
each participant the nature of the study, its requirements and its restrictions.  Written 
Informed consent will be obtained within the Science 37 Platform prior to performance of any 
protocol-specific procedures.   
 

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The Screening Phase will be up to 35 days.  The following will be determined during the 
Screening Visit: 
x Assignment of a unique SNR; 
x Signed Informed Consent Form (ICF); 
x Review inclusion and exclusion criteria; 
x Participant demographics; 
x Medical history (herpes labialis is based on the participant’s self-reported history)  
x Medication history of all prescription and over-the-counter drugs (including 
topicals, herbal products, vitamins and nutritional supplements), use of topical 
heat or cold, and other products of topical application and investigational drugs, 
taken within 30 days prior to screening; 
x History of drug and alcohol use; 
x Sitting blood pressure (BP) and pulse after sitting for at least 5 minutes; 
x Self-reported height and weight, (for a Body Mass Index [BMI] calculation); 
x Menstrual cycle information; 
x Urine pregnancy test (if applicable); 
x Urine tests for illicit drugs; 
x Distribute urine pregnancy test kits (2 if applicable); 
x Discuss the procedure to report adverse events; 
x Science 37 Platform training; 
x Baseline face image; 
x Study intervention kit with dosing instructions (randomized participants only). 
The Principal Investigator or his/her designee must review all screening results before 
proceeding to the Run-in phase of the study.  Eligible participants will receive their allotted 
study intervention kit as per randomization, pregnancy test kits and be trained on how to use 
the Science 37 Platform, study intervention and pregnancy kits prior to starting the Run-in 
phase. 
 
Participants will use their own device (e.g., smartphone) provided it is compatible with study 
requirements.   
 
8.1.2 
Randomization 
After confirmation that participants meet the inclusion and no exclusion criteria at Screening, 
qualified participants will be randomized to either Sitavig or placebo (as a blinded study 
intervention), participants will receive blinded intervention via courier service to their home 
and will be instructed to use the product upon first experience of prodromal symptoms 
according to the product directions.  Instructions on how to use Science 37 Platform will be 
provided for participants to record their face images, 0-10 NRS cold sore symptoms, QoL-
OHIP, and global evaluation as well as any adverse events. 

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8.1.3 
Run-in Phase 
Randomized participants will start a 6-month Run-in phase during which they will be eligible 
to start study intervention.  The start date for the Run-in phase is defined as the verified date 
of receipt of undamaged study intervention by the study participant.  Participants must 
develop prodromal symptoms within 6 months of the start of the Run-in phase.  Participants 
will be required to perform weekly “check-ins” within Science 37 Platform during the Run-in 
phase to verify their willingness to participate and if they have had any adverse events not 
already recorded.  Any participant experiencing prodromal symptoms can immediately start 
study intervention and proceed to the Treatment/evaluation phase.  Participants will be 
instructed to contact the Science 37 study team within 36 hours of study intervention 
initiation. 
 
Participants who do not experience any prodromal symptoms after 6 months are withdrawn 
from the study. 
 
8.1.4 
Treatment/Evaluation Phase (Day 1) 
Participants who start to experience prodromal symptoms before the visible appearance of any 
signs of HL must document the start time of symptoms in Science 37 Platform, complete a 
pre-dose (immediately before dosing) 0-10 NRS cold sore symptom evaluation (pain, burning 
sensation, itching and swelling) and a face image.  Prior to the start of study intervention, 
all WOCBP participants MUST perform a urine pregnancy test, and verify that the 
results are negative (not pregnant), and record in the Science 37 Platform.  After 
verification of a negative pregnancy test result, the participant may self-initiate study 
intervention.   
Any participant who has a positive pregnancy test or is not sure of the results must contact the 
Science 37 study team immediately.  Participants with a verified positive pregnancy test must 
not self-administer study intervention and will be withdrawn from the study. 
Participants must always record pre-dose NRS and a face image irrespective of the start 
time of prodromal symptoms in the Science 37 Platform.  After the completion of all pre-
dose procedures, participants will be instructed to self-administer one (1) tablet.  Should the 
buccal tablet adhere to the upper gum correctly, a second dose/tablet is NOT applied.  A 
second tablet in the treatment kit is provided and labeled “BACKUP”.  The backup tablet 
should only be used if an issue occurs applying the first tablet (see Section 6.5). 
 
After dosing, participants will complete the 0-10 NRS cold sore symptom evaluation, and 
face images at 09:00, 14:00 and 19:00 that day within Science 37 Platform.  Depending on 
time of day study intervention is started, some Day 1 assessments and face images may not be 
collected if the time (minus the 60 minute window) occurs before the time of dosing.  If 
dosing is started after 19:00, then post-dose NRS and face images will be collected starting 
the next day at 09:00.  All post-dose time point assessments (NRS and face images) have an 
allowable window of ±60 minutes. 
 
 
 

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8.1.5 
Treatment/Evaluation Phase (Days 1 through 14) 
 
8.1.5.1 
Day 1-2 (Visit 2) 
 
Within 36 hours after the start of study intervention, participants will present for Visit 2.  Visit 
2 can be performed on Day 1 or Day 2. The following procedures will be done for this visit: 
x Review inclusion/exclusion criteria 
x Review concomitant medications; 
x Sitting BP and pulse after at least 5 minutes in a sitting position; 
x Review Science 37 Platform data for completeness; 
x Review study intervention kit (drug accountability); 
x Review used/unused pregnancy test kits for signs of use; 
x Adverse Event assessment. 
Participants will record face images and complete 0-10 NRS HL symptom evaluation at 
09:00, 14:00 and 19:00 that day in the Science 37 Platform.  All post-dose time point 
assessments have an allowable window of ±60 minutes. 
8.1.5.2 
Day 3 
The following procedures will be done by the participant: 
x Face images at 09:00, 14:00 and 19:00 that day; 
x 0-10 NRS cold sore symptom evaluation at 09:00, 14:00 and 19:00 that day; 
x QoL-OHIP at 09:00 that day; 
All post-dose time point assessments have an allowable window of ±60 minutes. 
 
8.1.5.3 
Days 4, 5 and 6 
 
The following procedures will be done by the participant for each day: 
x Face images at 09:00, 14:00 and 19:00 each day; 
x 0-10 NRS cold sore symptom evaluation at 09:00, 14:00 and 19:00 each day. 
All post-dose time point assessments have an allowable window of ±60 minutes. 
 
8.1.5.4 
Day 7 
 
The following procedures will be done by the participant: 
x Face images at 09:00, 14:00 and 19:00 that day; 
x 0-10 NRS cold sore symptom evaluation at 09:00, 14:00 and 19:00 that day; 
x QoL-OHIP at 09:00 that day. 
All post-dose time point assessments have an allowable window of ±60 minutes. 

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8.1.5.5 
Days 8, 9, 10, 11, 12 and 13 
 
The following procedures will be done by the participant: 
x Face images at 09:00, 14:00 and 19:00 each day; 
x 0-10 NRS cold sore symptom evaluation at 09:00, 14:00 and 19:00 each day; 
All post-dose time point assessments have an allowable window of ±60 minutes. 
 
8.1.5.6 
Day 14 +2 days (Visit 3) 
 
Participants will asked to meet with the clinic via the Science 37 Platform for Visit 3.  The 
following procedures will be done for this visit: 
x Review concomitant medications; 
x Sitting BP and pulse after sitting for at least 5 minutes; 
x Face images at 09:00, 14:00 and 19:00 that day; 
x 0-10 NRS cold sore symptom evaluation at 09:00, 14:00 and 19:00 that day; 
x QoL-OHIP at 09:00 that day; 
x Global Evaluation of study intervention at 19:00 that day; 
x Initiate the return of IMP kit; 
x Review the Science 37 Platform data for completeness; 
x Adverse Event assessment. 
All post-dose time point assessments have an allowable window of ±60 minutes.  The 2-day 
window pertains to all Visit 3 tasks except the NRS symptom scores, face images, QoL-OHIP 
and Global assessment which should be collected at their respective nominal times (±60 
minutes) on Day 14. 
 
8.1.6 
Follow up Phase 
During the follow-up phase, participants will be asked to continue in the study till either a 
documented HL outbreak has occurred or for 12 months, whichever comes first.  Participants 
will be contacted by phone at 3, 6, 9 and 12 months after the start of study intervention to 
assess any concomitant medications or adverse events.  Date of the follow up visit will be 
determined from the date established on Day 1. 
Additionally, participants may at any time during the follow phase record a new 
episode/outbreak of HL.  Should a potential HL outbreak occur, the participant will contact 
Science 37 study team the study center to determine if the outbreak is related to HL.  If the 
investigator suspects a HL outbreak has started, the participant will be instructed to record 
additional 0-10 NRS symptom score(s) and face image(s) and document the HL outbreak in 
Science 37 Platform.  Participants with a documented HL outbreak are considered completed 
(see Section 4.4).  Should no HL outbreak occur, participants will complete the study at the 
end of the 12 month Follow-up Phase. 
 

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8.2 
Efficacy Assessments  
 
8.2.1 
Numerical Rating Scale (0-10) 
Assessed at Screening (pre-dose), Day 1 through the participant’s self-reported completion of 
study intervention (on Day 14).  Participants will complete a NRS 0-10 symptoms scales for 
pain, tenderness, itching, tingling and discomfort for each time point.  All post-dose time 
point assessments have an allowable window of ±60 minutes. 
My cold sore pain at this time is … 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No  
pain 
 
 
 
 
 
 
 
Worst 
possible 
pain 
The tenderness of my cold sore at this time is … 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No              
tenderness 
 
 
 
 
 
 
Worst 
possible 
tenderness 
The itching of my cold sore at this time is … 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No                
itching 
 
 
 
 
 
 
Worst 
possible 
itching 
 
The tingling of my cold sore at this time is … 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No              
tingling 
 
 
 
 
 
 
Worst 
possible 
tingling 
The discomfort of my cold sore at this time is … 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No                   
discomfort 
 
 
 
 
 
 
Worst 
possible 
discomfort 

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8.2.2 
Oral Health Impact Profile (OHIP) 
Developed from the OHIP-49 questionnaire, the OHIP-14 is a 14-part quality of life (QoL) 
questionnaire about the social impact of oral disease.  The OHIP-14 consists of a set of 
questions measuring the functional limitation, clinical pain, psychological discomfort, clinical 
disability, psychological disability, social disability and handicap of persons that could arise 
as a result of problems with the teeth or mouth.  Questions are answered using a 6-point 
Likert scale [9]. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Example for display only and not the licensed version.  Specific wording for each 
question may slightly differ for participants then what is displayed in the protocol. 
 
 

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8.2.3 
Global Evaluation 
Questions that rate the IMP as a cold sore treatment and the participant's experience at the 
self-reported completion of study intervention (14 days post-dose) using a 5-point Likert 
scale. 
 
Overall, I would rate the effectiveness of my study medication in relieving my cold sore as… 
x 0 = poor 
x 1 = fair  
x 2 = good  
x 3 = very good  
x 4 = excellent 
 
Overall, I would rate the experience (ease, comfort, convenience of use etc.) of the study 
medication as… 
x 0 = poor 
x 1 = fair  
x 2 = good  
x 3 = very good  
x 4 = excellent 
 
 
8.2.4 
Face Image Interpretation 
Participants face images pre and post-study intervention will be evaluated by an independent 
reader blinded to the study intervention administered.  Lesion interpretation will be done 
using a 6-point Likert scale. 
 
x 0 = Normal lip 
x 1 = Erythema 
x 2 = Papule 
x 3 = Vesicle 
x 4 = Ulcer 
x 5 = Crust 
 
8.3 
Safety Assessments  
All safety assessments are detailed in Sections 8.3.1 and 8.3.2.  Planned visits for all safety 
assessments are provided in the SoA (Section 1.3). 
 
8.3.1 
Vital Signs 
Blood pressure and pulse will be assessed with an automated device. 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest in a 
sitting position for the participant in a quiet setting without distractions (e.g., television, cell 
phones). 

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Vital signs will consist of 3 pulse and 3 blood pressure measurements (3 consecutive blood 
pressure readings will be recorded at intervals of at least 1 minute). The average of the 3 
blood pressure readings will be recorded [10]. 
 
8.3.2 
Pregnancy Testing 
Female participants of childbearing potential will undergo urine pregnancy testing at 
Screening and Day 1 (prior to dosing). 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other Safety 
Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.3.  The definition of unsolicited and solicited AEs can be found in Section 10.3.  
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the informed consent form (ICF)] at the time 
points specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of learning of the event, as indicated in Section 
10.3. The investigator will submit any updated SAE data to Bayer Pharmacovigilance within 
one business day of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor.  
 
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 

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8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in Section 
10.3.  
 
8.4.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements. 
For all studies except those using medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
 
8.4.5 
Pregnancy 
A subject’s participation is to be terminated immediately if a pregnancy is supposed (i.e. in 
case her pregnancy test becomes positive).  The investigator must report to the sponsor any 
pregnancy occurring in a female subject during her participation in this study.  The outcome 
of the pregnancy should be followed up carefully, and any outcome of the mother and the 
child at delivery should be reported.  
If a pregnancy is reported while participant is in the Treatment phase, the investigator will 
record pregnancy information on the appropriate form and submit it to the sponsor within 24 
hours of learning of the female participant’s pregnancy. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs, and will be reported as such. 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 8.4.4. 
While the investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
For all reports, the forms provided are to be used.  The investigator should submit them within 
the same timelines as an SAE (see Section 10.3.4).  Send the completed pregnancy forms to: 
cc-consreldept@bayer.com 
 (USA) 

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8.5 
Pharmacokinetics 
PK and pharmacodynamic parameters are not evaluated in this study. 
 
8.6 
Genetics or Pharmacogenomics 
Genetics are not evaluated in this study. 
 
8.7 
Biomarkers 
Biomarkers are not evaluated in this study. 
 
8.8 
Immunogenicity Assessments 
Not Applicable 
 
8.9 
Health Economics 
Health Economics parameters are not evaluated in this study. 
 
 
 

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9. 
Statistical Considerations  
Statistical analysis will be performed using statistical analysis software (SAS) and the version 
used will be specified in the Statistical Analysis Plan (SAP) and placed on file.  The SAP will 
contain a more comprehensive explanation than described below of the methodology used in 
the statistical analyses.  The SAP will also contain the rules and data handling conventions 
used to perform the analyses, and the procedure used for accounting for missing data. 
9.1 
Statistical Hypotheses 
The primary efficacy endpoint is the duration of episode (DOE). The treatment comparison 
between Sitavig and placebo will be made as 2-sided at the significance level of 0.05. No 
multiplicity adjustment will be made. 
9.2 
Sample Size Determination  
 
 
 
 
9.3 
Analysis Set 
For the purposes of analysis, the following analysis sets are defined: 
Table 2 – Analysis Populations 
Participant Analysis Set 
Description 
Safety 
All randomized subjects who take at least one dose of 
IMP. Safety analyses will be conducted on the safety 
population. 
Intent To Treat (ITT) 
All subjects who are randomized and provide at least one 
measure of primary efficacy parameters after the 1st dose 
of IMP. 
Per Protocol (PP) 
The Per Protocol population will include all subjects in 
ITT who complete 14-days of evaluations and do not 
have any major protocol violations. Any exclusion from 
PP Population will be determined and documented prior 
to the database lock.  
 
The primary efficacy analysis population will be PP 
population and ITT Population will be secondary. The 
same analysis on ITT Population will be repeated for the 
primary and secondary efficacy endpoints to assess the 
robustness of the results based on PP Population. 
 
 
 
CCI

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9.4 
Statistical Analyses 
 
9.4.1 
General Considerations 
The statistical analysis plan (SAP) will be developed and finalized before database lock and 
will describe the subject populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints. 
All statistical testing will be 2-sided at significance level of 0.05 and no multiplicity 
adjustment will be made. 
 
9.4.2 
Primary Endpoint 
The primary efficacy variable is:  
x Duration of episode (DOE) will be measured in hours (using the Science 37 
Platform), of a single treated HL lesion.  Observation period to determine healing 
will last up to 14 days (DurEp14).   
Duration of episode (DOE) is defined as the time from the initiation of treatment (study 
intervention) to the healing of primary lesions (loss of crust) for participants who experience 
a vesicular lesion.  For participants whose primary lesions are not vesicular in nature, 
duration of episode is the time from study intervention initiation to the return to normal skin 
as determined by the independent blinded reader of the participant’s face images using a        
6-point Likert scale or the cessation of symptoms, whichever comes last. For the subjects who 
do not demonstrate the healing of primary lesions or cessation of symptoms, the data will be 
censored at 14 days (14*24 hours) or time of loss of follow-up, whichever happens earlier. 
 
Duration of episode (DOE) will be estimated and plotted using Kaplan-Meier method and 
analyzed using log-rank test. 
 
9.4.3 
Secondary Endpoints 
x Incidence of aborted lesions, defined as treated HL lesions that do not progress to 
the vesicular or crust stage.  A lesion that returns to normal skin without forming a 
vesicle or crust will be counted as an aborted lesion.  Observation period to 
determine healing will last up to 14 days (Abort14).  The incidence of aborted 
lesions will be analyzed using Chi-square test. 
x Incidence of recurrence of HL lesions during the 12-month follow-up period 
(IncRec12) will be analyzed using Chi-square test. 
x Time to recurrence of HL lesions, measured in days from resolution of the cold 
sore treated in the Treatment phase until appearance of a cold sore during the 
follow-up period (TimeRec12). The time to recurrence is determined by 
assessment from the investigator and documented using NRS symptom scores and 
face images using the Science 37 Platform. For subjects who do not recur during 
the follow-up period, the data will be censored at the time of last follow-up. Time 
to recurrence of HL lesions will be analyzed similarly to the primary endpoint.  

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x Safety and tolerability measured by the Incidence of Treatment-Emergent Adverse 
Events 
x The percentage of participants who have at least one recurrence during the 12-
month follow up period will be analyzed using Chi-square test. 
9.4.4 
Other Endpoints 
x Duration of episode (DOE) will be measured in hours (using the Science 37 
Platform), of a single treated HL lesion in participants who initiation study 
intervention within 1 hour of onset of prodromal symptoms and participants who 
initiated study intervention more than 1 hour after onset of prodromal symptoms. 
x Time to cessation of symptoms, measured in hours from the 1st dose of assigned 
study intervention.  Cessation of symptoms is defined as the absence of sensations 
of pain, tingling, or burning at the site of the cold sore.  Observation period to 
determine healing will last up to 14 days (CesSymp14). 
x Quality of life score, as measured by the OHIP-14 questionnaire at 3, 7 and 14 
days post-dose will be analyzed using CMH method with a modified ridit score. 
x Global assessment of treatment efficacy at Day 14 using a 5-point scale (0=none, 
1=poor, 2=fair, 3=good, 4=excellent) will be analyzed using CMH method with a 
modified ridit score. 
 
9.4.5 
Safety Analysis 
Safety will be measured by adverse events (AEs) and vital signs.  Only descriptive analyses 
will be conducted on the Safety Population. No imputation will be made for missing safety data. 
Quantitative data for safety variables will be described by summary statistics for the original 
data as well as for the differences to baseline when it is appropriate. Frequency tables will be 
provided for qualitative data. No statistical test will be planned regarding the safety analyses. 
 
Only treatment-emergent AEs will be included in the summary analysis, i.e., AEs that begin or 
worsen after the first application of Investigational Medicinal Product (IMP).  The number and 
percent of subjects who experience any event and the number of events overall, by System 
Organ Class, and by Preferred Term will be displayed by treatment group. Tables will also be 
produced by severity and relationship to IMP. Seriousness, severity, relationship to IMP 
duration, and outcome will also be listed. 
 
Listings of individual data will be presented. 
 
 
9.5 
Treatment Phase Analysis 
The statistical analysis will be performed upon completion of all study participants who 
complete the Treatment Phase (up to Day 14).  The additional analysis of treatment follow-up 
will be conducted upon completion of follow-up phase (up to 12 months). The SAP will 
provide further details about those planned analyses. 
 
 

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9.6 
 Interim Analysis 
No interim analysis is planned for this study. 
 
 

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10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
Investigator(s) and other study personnel 
Sponsor’s medical expert for the study 
Name:  
 
, BS, PharmD 
Title: 
, US Medical Affairs 
Address: Bayer Healthcare 
 
100 Bayer Boulevard 
 
Whippany NJ 07981-0915 USA 
 
Phone: 
  
Email: 
  
 
Principal investigator for the study 
Name: 
Jonathan Cotliar, MD 
Title: 
Physician 
Address: Science 37 
 
 
 
Phone: 
 
Email: 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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10.1.1 
Regulatory and Ethical Considerations 
 
x This study will be conducted in accordance with the protocol and with the 
following: 
x Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
x Applicable ICH Good Clinical Practice (GCP) Guidelines 
x Applicable laws and regulations 
x The protocol, protocol amendments, ICF, Investigator Brochure and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
x Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. Any substantial 
modification of the protocol will be submitted to the competent authorities as 
substantial amendments for approval, in accordance with ICH Good Clinical 
Practice and national and international regulations. 
x Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
x The investigator will be responsible for the following: 
x Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
x Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures 
x Providing oversight of the conduct of the study at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
 
10.1.2 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
 
10.1.3 
Funding 
This study will be funded by the sponsor. 
 

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10.1.4 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the participant 
or his/her legally authorized representative and answer all questions regarding the study.  
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent within Science 37 Platform that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. Each participant will be informed about the following aspects of premature 
withdrawal: 
x Each participant has the right to withdraw from the study at any time without any 
disadvantage and without having to provide reasons for this decision. 
x The participant’s consent covers assessments as specified in the visit description 
described in Section 8.1.5.6 to be conducted after withdrawal of consent. 
x The participant’s data that have been collected until the time of withdrawal will be 
retained and statistically analyzed in accordance with the statistical analysis plan. 
x Participant-specific data on the basis of material obtained before withdrawal may 
be generated after withdrawal (e.g., image reading, analysis of biological specimen 
such as blood, urine or tissues); these data would also be retained and statistically 
analyzed in accordance with the statistical analysis plan.  The participant has the 
right to object to the generation and processing of this post-withdrawal data.  For 
this, he/she needs to sign a corresponding declaration of objection; alternatively, 
the participant’s oral objection may be documented in the participant’s source data. 
Each participant will have ample time and opportunity to ask questions. 
Only if the participant agrees to sign the informed consent form within the Science 37 
Platform and has done so, may he/she enter the study.  Additionally, the investigator, or 
designee, will personally sign and date the form within the Science 37 Platform.  The 
participant will be able to download a PDF version of the fully executed ICF from the Science 
37 Platform. 
Documentation of Informed Consent will be recorded within the Science 37 Platform which 
includes a statement that informed consent was obtained before the participant was enrolled in 
the study and the date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF. 
Participants must be consented to the most current version of the ICF(s) during their 
participation in the study.  
The informed consent form and any other written information provided to participants will be 
revised whenever important new information becomes available that may be relevant to the 
participant’s consent, or there is an amendment to the protocol that necessitates a change to 
the content of the participant information and / or the written informed consent form.  The 
investigator will inform the participant of changes in a timely manner and will ask the 
participant to confirm his/her participation in the study by signing the revised informed 
consent form within the Science 37 Platform.  Any revised written informed consent form and 
written information must receive the IRB`s approval / favorable opinion in advance of use. 
A copy of the ICF(s) must be provided to the participant. 
 

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10.1.5 
Data Protection and Confidentiality 
Participants will be assigned a unique identifier by the sponsor. Any participant records, 
datasets or biological samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
All records identifying the participant will be kept confidential and, to the extent permitted 
by the applicable laws and/or regulations, will not be made publicly available. 
Participant names will not be supplied to the sponsor.  Only the participant numbers (SNR, 
RNR and treatment kit) will be recorded on the eCRF and/or Science 37 Platform, and if the 
participant name appears on any other document (e.g., pathologist report), it must be 
obliterated before a copy of the document is supplied to the sponsor.  Study findings stored 
on a computer will be stored in accordance with local data protection laws.  As part of the 
informed consent process, the participants will be informed in writing that representatives of 
the sponsor, IRB, or regulatory authorities may inspect their medical records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. 
If the results of the study are published, the participant’s identity will remain confidential. 
The investigator will maintain a list to enable participants to be identified. 
 
10.1.6 
Compensation for Health Damage of Participants/Insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 
 
10.1.7 
Committees Structure 
Not applicable 
 
10.1.8 
Dissemination of Clinical Study Data 
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov as applicable to local regulations. 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.   

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10.1.9 
Data Quality Assurance 
Participant data necessary for analysis and reporting will be provided to the Sponsor in 
CDISC (Clinical Data Interchange Standards Consortium) standards. 
Clinical data management will be performed in accordance with applicable sponsor’s/CRO’s 
standards and data cleaning procedures.  This is applicable for data recorded on the eCRF 
and/or Science 37 platform as well as for data from other sources (e.g., laboratory).  Guidance 
on completion of eCRFs will be provided (when applicable). 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used. 
Reasons for missing data, especially inability to perform a test, must be documented. 
All participant data relating to the study will be recorded on an eCRF and/or Science 37 
platform unless transmitted to the sponsor or designee electronically (e.g., laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct by 
electronically signing the eCRF and/or Science 37 platform.  The investigator must maintain 
accurate documentation (source data) within the Science 37 Platform that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan or applicable monitoring SOP. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  The sponsor assumes accountability for actions delegated to 
other individuals (e.g., Contract Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF and/or Science 37 platform by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for  20 years  after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
 
10.1.10 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed within the Science 37 Platform.   
Data reported on the eCRF and/or Science 37 platform that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records (if applicable). 

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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF and/or Science 37 platform. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF and/or Science 37 platform by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory 
requirements in accordance to the monitoring plan. 
 
10.1.11 
Missing Data 
Reasons for missing data, especially inability to perform a test, must be documented. 
 
10.1.12 
Audit and Inspection 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or a 
designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study site and of the study documents originating there.  The 
investigator/institution will be informed of the audit outcome. 
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection. 
The investigator/institution agrees to allow the auditor or inspector direct access to all relevant 
documents and allocate his/her time and the time of his/her staff to the auditor/inspector to 
discuss findings and any issues.  Audits and inspections may occur at any time during or after 
completion of the study. 
 
10.1.13 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Participant files will be archived according to local regulations and in accordance with the 
maximum period of time permitted by the hospital, institution or private practice.  Where the 
archiving procedures do not meet the minimum timelines required by the sponsor, alternative 
arrangements must be made to ensure the availability of the source documents for the required 
period. 
The investigator / institution notifies the sponsor if the archival arrangements change (e.g., 
relocation or transfer of ownership). The investigator site file is not to be destroyed without 
the sponsor’s approval. The contract with the investigator/institution will contain all 
regulations relevant for the study center. 
 
 
 

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10.1.14 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first subject screened and is considered the first act of 
recruitment and will be the study start date. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
x Discontinuation of further study intervention development 
For site termination: 
x Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
x Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
x Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
 
10.1.15 
Publication Policy 
x The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
x The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
x Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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10.2 
Appendix 2: Clinical Laboratory Tests 
Not applicable 
 
10.3 
Appendix 3: AEs and SAEs: Definitions and Procedures 
10.3.1 
Definition of AE 
 
AE Definition 
x An AE is any untoward medical occurrence in a clinical study participant, 
associated with the use of study intervention, whether or not considered related to 
the study intervention. 
x NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention. 
 
Definition of Unsolicited and Solicited AE 
x An unsolicited adverse event is an adverse event that was not solicited using a 
Participant Diary and that is communicated by a participant who has signed the 
informed consent. Unsolicited AEs include serious and non-serious AEs. 
x Potential unsolicited AEs may be medically attended (i.e., symptoms or illnesses 
requiring a hospitalisation, or emergency room visit, or visit to/by a health care 
provider). The participants will be instructed to contact the site as soon as possible 
to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant concern. Detailed information about reported 
unsolicited AEs will be collected by qualified site personnel and documented in the 
participant’s records. 
x Unsolicited AEs that are not medically attended nor perceived as a concern by 
participant will be collected during interview with the participants and by review of 
available medical records at the next visit. 
x Solicited AEs are predefined local at the application site and systemic events for 
which the participant is specifically questioned, and which are noted by the 
participant in their diary.  
 
Events Meeting the AE Definition  
x Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital 
signs measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator 
(i.e., not related to progression of underlying disease). 

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x Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected intervention-
intervention interaction. 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study intervention or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
x The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
 
Events NOT Meeting the AE Definition  
x Any clinically significant abnormal laboratory findings or other abnormal 
safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s 
condition. 
x The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
x Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
x Situations in which an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital). 
x Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
 
 

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10.3.2 
Definition of SAE 
 
An SAE is defined as any AE that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
x The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant was at risk of death at the time of the event. It does not 
refer to an event, which hypothetically might have caused death, if it were more 
severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
x In general, hospitalization signifies that the participant has been admitted 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
x Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
x Invasive treatment during any hospitalization may fulfill the criterion of 
‘medically important’ and as such may be reportable as an SAE dependent on 
clinical judgment.   
d. 
Results in persistent or significant disability/incapacity 
x The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
x This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
x Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious. 

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x Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
 
10.3.3 
Recording and Follow-Up of AE and/or SAE 
 
AE and SAE Recording 
x When an AE/SAE occurs, it is the responsibility of the investigator to review 
all documentation (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
x The investigator will then record all relevant AE/SAE information. 
x It is not acceptable for the investigator to send photocopies of the participant’s 
medical records in lieu of completion of the required form. 
x There may be instances when copies of medical records for certain cases are 
requested. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission. 
x The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
x Action taken with study treatment (i.e. investigational product withdrawn, 
interrupted, changed, unknown), any remedial drugs therapy and the outcome 
of the AE is recorded.  Outcomes may be: 
o Recovered/resolved 
o Recovering/resolving 
o Recovered/resolved with sequelae 
o Not recovered/not resolved 
o Fatal 
o Unknown 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories:  
x Mild: An event that is easily tolerated by the participant, causing 
minimal discomfort and not interfering with everyday activities. 
x Moderate: An event that causes sufficient discomfort to interfere with 
normal everyday activities. 
x Severe: An event that prevents normal everyday activities. An AE that 
is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and 
SAEs can be assessed as severe. 

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An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as 
severe. 
 
 
Assessment of Causality 
x The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. 
x A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out. 
x The investigator will use clinical judgment to determine the relationship. 
x Alternative causes, such as underlying disease(s), concomitant therapy, and 
other risk factors, as well as the temporal relationship and de-challenge/re-
challenge (if applicable) of the event to study intervention administration will 
be considered and investigated. 
x The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment. 
x For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
x There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data. 
x The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
x The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
Follow-up of AEs and SAEs 
x The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals. 
x New or updated information will be recorded in the originally submitted 
documents. 
x The investigator will submit any updated SAE data within 24 hours of receipt 
of the information. 
 

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10.3.4 
Reporting of SAEs 
 
SAE Reporting to Bayer Pharmacovigilance via Paper Data Collection Tool 
x Email transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to Bayer Pharmacovigilance.   
x In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
x Initial notification via telephone does not replace the need for the investigator 
to complete and sign the SAE data collection tool within the designated 
reporting time frames. 
x Contacts for SAE reporting: cc-consreldept@bayer.com (USA) 
 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
x Documented hysterectomy 
x Documented bilateral salpingectomy 
x Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records or medical history interview. 
 

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3. Postmenopausal female 
x A postmenopausal state is defined as no menses for 24 months without an 
alternative medical cause. 
x Females on hormone replacement therapy (HRT) and whose menopausal status is 
in doubt will be required to use one of the non-estrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 
 
Contraception Guidance: 
 
Female participants who become pregnant  
x The investigator will collect pregnancy information on any female participant who 
becomes pregnant during the Treatment phase. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
x The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
x A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
x Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in Section 
8.4.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous 
reporting.  
x Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
 
 
 

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10.5 
Appendix 5: Abbreviations 
ABT 
acyclovir buccal tablet 
AE 
adverse event 
BAY no. 
BAY number is the main identifier for compounds within the Bayer HealthCare 
Organization 
BMI 
body mass index: weight [kg] / (height [m])² 
BP 
blood pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
consolidated standards of reporting trials 
CRO 
contract research organization 
DOE 
duration of episode 
eCRF 
electronic case report form 
e.g. 
exempli gratia (for example) 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GMP 
good manufacturing practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HL 
herpes labialis 
HRT 
hormonal replacement therapy 
HSV-1 
herpes simplex virus type 1 
HSV-2 
herpes simplex virus type 2 
i.e. 
id est (that is) 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
ITT 
intent to treat 
IXRS 
interactive (x-voice/web) response system 
kg 
kilogram 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent to treat 
NRS 
numerical rating scale 
OHIP 
oral health impact profile 
OTC 
over-the-counter 
PP 
per protocol 
QA 
quality assurance 

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QoL 
quality of life 
RNR 
randomization number 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
SNR 
screening number 
SoA 
Schedule of Activities 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
UI 
unique identifier (drug formula) 
USA 
United States of America 
WOCBP 
woman of childbearing potential 
 
 
 
 
 
 

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11. 
References 
1. Opstelten et al., Treatment and Prevention of Herpes Labialis. Canadian Family 
Physician. Dec 2008; 54: 1683-7. 
 
2. Wheeler CE Jr. The herpes simplex problem. J Am Acad Dermatol 1988;18(1 Pt 
2):163-8. 
 
3. Whitley R, Kimberlin DW, Prober CG. Pathogenesis and disease. In: Arvin A, 
Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, 
Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. 
Chapter 32. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47449. 
 
4. Fatahzadeh M, Schwartz RA. Human herpes simplex virus infections: epidemiology, 
pathogenesis, symptomatology, diagnosis, and management. J Am Acad Dermatol. 
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5. Rosen T. Recurrent Herpes Labialis in Adults: New Tricks for an Old Dog. J Drugs 
Dermatol. 2017;16(3):s49-s53. 
 
6. Prescribing Information: Sitavig® (acyclovir) buccal tablets, Revised December 2019. 
 
7. Food Drug Administration Center for Drugs Evaluation Research (January 2021), 
Guidance for Industry: Conduct of Clinical Trials of Medical Products During the 
COVID-19 Public Health Emergency Guidance for Industry, Investigators, and 
Institutional Review Boards (FDA Maryland). 
 
8. Food Drug Administration Center for Drugs Evaluation Research (November 2017), 
Guidance for Industry: Recurrent Herpes Labialis: Developing Drugs for Treatment 
and Prevention (FDA Maryland). 
 
9. Slade GD. Derivation and validation of a short-form oral health impact profile. 
Community Dent Oral Epidemiol. 1997;25(4):284-290. 
 
10. Food Drug Administration Center for Drugs Evaluation Research (May 2018), Draft 
Guidance on Assessment of Pressor Effect of Drugs (FDA Maryland).