Conditions: Recurrent Herpes Labialis
Keywords: Herpes Labialis Cold Sore
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 451
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if Merlin, a mixture of ethanol and glycolic acid, is safe and effective in the treatment of cold sores.

Subjects who meet the requirements to participate in the study will be put randomly, and equally, into one of two groups: 1) a group receiving Merlin to treat their cold sore; or 2)a group receiving a placebo of just ethanol to treat their cold sore. Neither the subject nor the site will know which treatment they will be getting. Once the subject has been assigned to a treatment group, they will be given a kit containing a bottle of the treatment and special swabs to apply the liquid. The subject will be told to take the kit home and wait until they think they are starting to get a cold sore.

Once a subject begins to see something that they think is the start of a cold sore, they are to immediately call the clinic. Once the clinic confirms that the subject is in fact starting to get a cold sore, the subject will be told to open the kit and begin treatment. From the start of treatment, there will be twelve (12) treatments, with either Merlin or placebo, applied six (6) hours apart, up to 3 per day, over the next 96 hours (4 days). Each treatment of Merlin or placebo is made up of three (3) applications given twenty (20) minutes apart, for a total of thirty-six (36) applications. For each application, the subject will use the special swab to put the Merlin or placebo solution on their cold sore.

Subjects will need to report daily to the clinic for a minimum of 3 consecutive days, until either the cold sore is completely healed or 14 days from the start of treatment, whichever comes first. At each clinic visit the cold sore will be observed to determine at what stage it is at or if it has healed. The subject will also be asked how they are feeling.

Subjects will also be told to record in a diary the time of each application of Merlin or placebo. They will also be asked to record the stage of their lesion and how much pain, if any, related to the cold sore, that they are feeling.

Detailed description:

Arms:
arm 1: glycolic acid and ethanol mixture arm 2: None

Interventions: intervention 1: Merlin intervention 2: Ethanol
Intervention descriptions: intervention 1: glycolic acid/ethanol solution intervention 2: Ethanol solution

Protocol document:
Prot_000.pdf: 
Protocol:  TR-H-212 
 
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CONFIDENTIAL 
Date: 18 April 2017 
Topical Remedy, LLC 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Protocol TR-H-212 
 
A Multicenter, Placebo-Controlled, Randomized, Double-Blind Study of 
the Safety and Efficacy of Merlin (ethanol and glycolic acid mixture) for 
the Episodic Treatment of Recurrent Herpes Labialis  
 
Version 1 
 
 
Protocol History: 
Original 
18 April 2017 
 
 
 
 
 
Topical Remedy, LLC. 
c/o Benu BioPharma, Inc. 
5 Commonwealth Rd., Suite 2A 
Natick, MA USA  01760 
Telephone: (508) 651-3700 
 
 
 
 
 
 
Disclosure Statement 
The confidential information in the following document is provided for your review as an 
investigator, potential investigator, or consultant. Do not disclose the information contained in 
this document to others without the written permission of Topical Remedy, LLC, except as 
required for review by your staff or Institutional Review Board or in obtaining informed consent 
from study subjects. 


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PROTOCOL FOR TOPICAL REMEDY, LLC 
 
CLINICAL STUDY 
 
TITLE: A Multicenter, Placebo-Controlled, Randomized, Double-Blind Study of the 
Safety and Efficacy of Merlin (ethanol and glycolic acid mixture) for the 
Episodic Treatment of Recurrent Herpes Labialis 
 
Topical Remedy, LLC 
IND Number:  116,789 
Sponsor’s Representative: Eric Morrel, PhD 
VP, Clinical Research 
Phone: (508) 651-3714 
Fax: 
(508) 651-3703 
Mobile: (508) 208-5634 
 
 
 
 
 
 
 
 
 
Signature 
 
Date 
 
 
Medical Monitor: 
 
Nadia Tullio, MD 
Assistant Director Medical Affairs, Accelovance Inc. 
Phone: (240) 238-4961  
e-mail:  atullio@accelovance.com 
 
Sponsor: 
Topical Remedy, LLC  
 
c/o Benu BioPharma, Inc. 
 
 
 
5 Commonwealth Rd. 
Phone: (508) 651-3700  
Suite 2A 
Fax: 
(508) 651-3703  
Natick, MA  01760 
 
 
 
 
 
 
 
 
 
The above signed confirms herewith to have read and understood this study protocol, furthermore, to 
accomplish this study according to the protocol and the Good Clinical Practice guidelines, as well as local 
regulations, and to accept respective revisions conducted by authorized personnel of Topical Remedy, LLC 
and by competent authorities. 


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TABLE OF CONTENTS 
1. 
STUDY SYNOPSIS ............................................................................................................ 5 
2. 
INTRODUCTION .............................................................................................................. 9 
3. 
STUDY OBJECTIVES .................................................................................................... 11 
4. 
SUMMARY OF STUDY DESIGN ................................................................................. 12 
5. 
SUBJECT SELECTION .................................................................................................. 14 
5.1 
SOURCE OF SUBJECTS .....................................................................................................................14 
5.2 
STUDY ENROLLMENT ELIGIBILITY CRITERIA .................................................................................14 
5.3 
STUDY TREATMENT PHASE ELIGIBILITY CRITERIA ........................................................................17 
5.4 
RESTRICTIONS DURING THE TREATMENT PHASE ............................................................................20 
6 
MATERIALS .................................................................................................................... 20 
6.1 
DRUG SUPPLY ................................................................................................................................20 
6.2 
DRUG IDENTIFICATION ...................................................................................................................21 
6.3 
DRUG STORAGE..............................................................................................................................21 
6.4 
RANDOMIZATION ...........................................................................................................................21 
6.5 
DRUG ACCOUNTABILITY/RETENTION .............................................................................................22 
7 
STUDY CONDUCT ......................................................................................................... 23 
7.1 
SCREENING AND ENROLLMENT VISIT .............................................................................................25 
7.2 
STUDY TREATMENT PHASE (TREATMENT DAY) .............................................................................26 
7.3 
FOLLOW-UP VISITS (VISIT DAYS 1-14) ..........................................................................................31 
8 
ADVERSE EVENTS ........................................................................................................ 34 
9 
REMOVAL OF SUBJECTS FROM STUDY ................................................................ 37 
10 
STATISTICAL METHODS ............................................................................................ 37 
10.1 
INTRODUCTION ...............................................................................................................................37 
10.3 
STUDY POPULATIONS .....................................................................................................................38 
10.4 
GENERAL METHODOLOGY .............................................................................................................39 
10.5 
BASELINE DEMOGRAPHICS .............................................................................................................39 
10.6 
SAFETY AND TOLERABILITY ANALYSIS ..........................................................................................39 
10.7 
EFFICACY ANALYSIS ......................................................................................................................40 
11 
ADMINISTRATIVE REQUIREMENTS ...................................................................... 43 
11.1 
GOOD CLINICAL PRACTICE ............................................................................................................43 
11.2 
ETHICAL CONSIDERATIONS ............................................................................................................43 
11.3 
SUBJECT INFORMATION AND INFORMED CONSENT .........................................................................43 
11.4 
SUBJECT CONFIDENTIALITY ...........................................................................................................44 
11.5 
PROTOCOL COMPLIANCE ................................................................................................................44 
11.6 
STUDY MONITORING ......................................................................................................................44 
11.7 
ON-SITE AUDITS .............................................................................................................................45 
11.8 
CASE REPORT FORM COMPLETION AND DATA MANAGEMENT.......................................................45 
11.9 
CLINICAL TRIAL MATERIAL ACCOUNTABILITY ..............................................................................46 
11.10 PREMATURE CLOSURE OF THE STUDY ............................................................................................46 
11.11 RECORD RETENTION ......................................................................................................................46 
11.12 LIABILITY AND INSURANCE ............................................................................................................47 


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12 
USE OF INFORMATION ............................................................................................... 47 
13 
REFERENCES ................................................................................................................. 47 
14. 
INVESTIGATOR AGREEMENT .................................................................................. 49 
 
 


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1. STUDY SYNOPSIS 
 
Name of 
Sponsor/Company:   
Topical Remedy, LLC 
Individual Study Table 
Referring to Part of the 
Dossier 
 
Volume: 
 
Page: 
(For National Authority 
Use only) 
Name of Finished Product:  
Merlin 
Name of Active Ingredient:  
Ethanol and Glycolic Acid 
Title of Study:  A Multicenter, Placebo-Controlled, Randomized, Double-Blind Study of 
the Safety and Efficacy of Merlin (ethanol and glycolic acid mixture) for the Episodic 
Treatment of Recurrent Herpes Labialis 
Study Centers:  There will be approximately 5 - 10 study centers.  
Publication (reference):  Not applicable 
Study Duration: Approximately 9 months 
Objectives:   The primary efficacy endpoint of this study is the clinician assessed 
duration of the classical lesion. 
Methodology:  This is a multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the safety and efficacy of Merlin (10 % ethanol and 0.6% glycolic acid) for 
the treatment of herpes labialis lesions.  Subjects who meet the eligibility requirements at 
the screening/randomization visit will be randomized in a 1:1 ratio to one of two 
treatment groups: 1) twelve  (12) treatments with Merlin solution, administered 6  hours 
apart (up to 3 per day) over the ensuing 96 hours (4 days) from the time of the first 
treatment; or 2) twelve (12) treatments with  10% ethanol, as a placebo, administered 6  
hours apart (up to 3 per day) over the ensuing 96 hours (4 days) from the time of the first 
treatment. Each treatment of Merlin or placebo consists of applying the solution three (3) 
times, within a time period of 40 minutes or less, while allowing time for the solution to 
dry on the lesion between applications; this will result in a total of thirty six (36) 
applications over 96 hours (4 days). The first treatment will be administered on 
Treatment Day (Day 0), and then repeated at 6 and 12 hours after the first treatment, time 
permitting. 


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Name of 
Sponsor/Company:   
Topical Remedy, LLC 
Individual Study Table 
Referring to Part of the 
Dossier 
 
Volume: 
 
Page: 
(For National Authority 
Use only) 
Name of Finished Product:  
Merlin 
Name of Active Ingredient:  
Ethanol and Glycolic Acid 
Methodology (cont.):   
 
After being enrolled and randomized into the study, subjects will be sent home with a kit 
containing a bottle filled with either Merlin (active) or the 10% ethanol placebo solution 
and a packet of foam-tipped applicators sufficient to apply three (3) study treatments 
(nine (9) applications). The subject will be instructed to contact the clinic by telephone at 
the first signs and/or symptoms of a recurrent herpetic episode (Stage 0, prodrome, Stage 
1, erythema, or Stage 2, papule/edema).  The lesion and lesion stage then will be 
confirmed by telephone interview with the subject. Subjects reporting either a Stage 1 or 
Stage 2 lesion will be instructed to begin treatment immediately, thereby initiating the 
Treatment Phase of the study.  Subjects reporting only Stage 0 symptoms, i.e. no visible 
signs of a cold sore lesion, will be instructed to monitor their lesion and to call the clinic 
immediately upon observing any early visible signs of a cold sore, i.e. redness or 
swelling, representing a Stage 1 or Stage 2 lesion.  Once the subject calls in and confirms 
by telephone interview that their lesion has reached Stage 1 or 2, they will be instructed 
to begin treatment immediately. The subject will be told to continue treatment for the 
remainder of the day with the treatment schedule outlined above, and to continue to treat 
with a set of three (3) applications, three (3) times each day, for a total of twelve (12) 
treatments resulting in thirty-six (36) applications in total. The subject also will be 
instructed to return to the clinic within 24 hours of the initial treatment for evaluation of 
the stage of the herpetic lesion. 
 
Subjects will report daily for a minimum of 3 consecutive days, with the last clinic visit 
at the time of complete healing (Stage 7 - normal skin) or at 14 days, whichever is earlier.  
Subjects will be contacted by phone, for a safety assessment, 2 weeks after they complete 
the Treatment Phase of the study. 
Number of Subjects: Approximately four hundred and fifty (450) subjects will be 
enrolled into the study, 225 into the active treatment group and 225 into the placebo 
treatment group. At least 75 subjects in the active treatment group, and 75 subjects in the 
placebo treatment group, will enter the Treatment Phase of the study and administer 
treatments. 
Diagnosis and Main Criteria for Inclusion: All enrolled subjects must be 18 to 75 
years of age. To be enrolled, he or she must also have a history of recurrent herpes 
labialis and report at least 3 recurrences during the preceding 12 months. To enter the 
Treatment Phase of the study, the subject must have a herpes labialis lesion assessed by 
the subject and confirmed by telephone contact to be at either Stage 1 (erythema) or 
Stage 2 (papule/edema), and the subject must be able to report to the clinic for an initial 
lesion assessment within 24 hour of detection of first signs and/or symptoms of a herpetic 
episode. The subject must also be able to report to the clinic for up to 14 days. 


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Name of 
Sponsor/Company:   
Topical Remedy, LLC 
Individual Study Table 
Referring to Part of the 
Dossier 
 
Volume: 
 
Page: 
(For National Authority 
Use only) 
Name of Finished Product:  
Merlin 
Name of Active Ingredient:  
Ethanol and Glycolic Acid 
Test Product and Mode of Administration:  Merlin is the name given to a novel 
formulation intended for the treatment of topical viral infections. The formulation 
consists of 10% ethanol and 0.6% glycolic acid, with a pH of 2.5. A single-use, foam-
tipped applicator will be used for application to the skin. 
Duration of Treatment:  Each subject, for each set of treatments, will administer three 
(3) applications of Merlin or placebo, depending upon how a subject has been 
randomized, within a time period of 40 minutes or less, while allowing time for the 
solution to dry on the lesion between applications.  A total of twelve (12) Merlin 
treatments, i.e. thirty-six (36) applications, will be administered over the ensuing 96 
hours (four (4) days), following the time of the first treatment.  On each day, treatments 
will be administered six (6) hours apart, with a maximum of three (3) treatments each 
day. The first treatment will be administered on Treatment Day (Day 0), and then 
repeated at 6 and 12 hours after the first treatment, time permitting. 
 
Reference Therapy, Dose and Mode of Administration:  The reference therapy will be 
a set of three (3) applications of 10% ethanol, applied twenty (20) minutes apart with the 
same dosing schedule as outlined above in “Duration of Treatment.” 
Criteria for Evaluation:  The primary efficacy endpoint is the clinician assessed 
duration of the classical herpetic lesion.  
 
Secondary efficacy endpoints are as follows: 
 
• Clinician assessed duration of the herpetic episode 
• Clinician assessed duration of complete healing of the herpetic episode 
• Clinician assessed prevention of progression to a classical lesion 
• Clinician assessed lesion size (maximum lesion area; cumulative lesion area) 
• Clinician assessed duration of the herpetic lesion hard scab 
 
Based on patient diary entries, other efficacy endpoints will be: 
• Subject assessed duration and severity of lesion pain 
• Subject assessed duration of the classical herpetic lesion 
• Subject assessed duration of the herpetic episode 
• Subject assessed duration of complete healing of the herpetic episode 
• Subject assessed prevention of progression to a classical lesion 
• Subject assessed duration of the herpetic lesion hard scab 
 
 
The only safety endpoint is adverse events. 
 


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Date: 18 April 2017 
Name of 
Sponsor/Company:   
Topical Remedy, LLC 
Individual Study Table 
Referring to Part of the 
Dossier 
 
Volume: 
 
Page: 
(For National Authority 
Use only) 
Name of Finished Product:  
Merlin 
Name of Active Ingredient:  
Ethanol and Glycolic Acid 
Statistical Methods:   Generally, statistical hypothesis tests will be two-tailed, and 
statistical significance will be declared when the p-value is less than 0.05. Continuous 
variables will be summarized using descriptive statistics, specifically the mean, median, 
standard deviation, minimum and maximum. Categorical variables will be summarized 
by frequencies and percentages.  
 
All subjects who received (at least some) treatment, whether they were formally entered 
into the Treatment Phase of the study or applied the test material without formal 
authorization, will be included in the Safety Population. The safety analysis will be 
performed on the Safety Population.   
 
All subjects who have been entered into the Treatment Phase of the study will be 
included in the Modified Intent to Treat (MITT) population. The MITT population will 
be used as the primary analysis population. All subjects who have been entered into the 
Treatment Phase of the study and have been followed successfully until their lesion 
healed, or until 14 days, whichever is earlier, will be included in the Efficacy Evaluable 
population. The efficacy analysis will be performed on both the MITT and the Efficacy 
Evaluable populations. 
 
No imputation of missing data will be performed for the efficacy analyses for the 
Efficacy Evaluable population. 
 
The duration of the classical herpetic lesion (both clinician and patient assessed) will be 
analyzed using the Hodges-Lehmann method as the primary efficacy analysis method for 
estimating the median difference between the two arms. Duration of the herpetic episode 
(both clinician and patient assessed), duration of complete healing of the herpetic episode 
(both clinician and patient assessed), duration of the herpetic lesion (both clinician and 
patient assessed), duration of the herpetic lesion hard scab (both clinician and patient 
assessed), and duration of pain will be analyzed in the same manner as the duration of the 
classical lesion.  
 
The proportions of subjects in each treatment group who do not display classical lesions 
(prevention of progression to classical lesions) will be compared using Fisher’s Exact 
Test.  
 
For pain, the maximum severity will be analyzed using the Cochran-Mantel-Haenszel 
Test to test for differences between treatment groups. 
 
 


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2. INTRODUCTION 
 
Topical Remedy, LLC. is developing Merlin, a novel topical formulation that can be used 
to treat viral infections of the skin.  It is composed of two commonly used compounds, 
glycolic acid (0.6%) and ethanol (10%), each with known safety and side effect profiles.  
This product, intended for over-the-counter distribution, will consist of single treatment 
foam applicators pre-filled with the Merlin solution. 
 
Approximately 20 to 40% of the adult population experience recurrent outbreaks of 
herpes labialis, or cold sores.1  In almost all cases, the disease is due to reactivation of 
chronic, latent herpes simplex virus type 1 infection from the ganglion of the trigeminal 
nerve.  When the latent infection is activated by any one of a variety of triggers, virions 
descend through the sensory nerve axons and reinfect the peripheral epithelium.  The new 
herpes labialis lesion matures within 8 hours after onset2, leaving very little time for 
successful chemotherapeutic intervention.  
 
The current standard of care for recurrent herpes labialis involves an oral or topical 
antiviral given episodically at the onset of each recurrence. A variety of topical over-the-
counter preparations are available, but in most cases the mechanism of action is 
ambiguous and very few clinical trials have been performed to define their efficacy. 
Studies of acyclovir ointment have provided little evidence of efficacy for herpes labialis 
in immunocompetent subjects.3,4 Acyclovir and penciclovir cream-based formulation are 
both approved for treatment of herpes labialis, but while both do penetrate the skin more 
effectively than the acyclovir ointment, both exhibit relatively limited efficacy with 
regard to shortening the duration of a herpetic episode.5,6 Docosanol 10% cream (Abreva; 
GlaxoSmithKline) is the most well-studied over-the-counter product, with 2 randomized 
trials suggesting some efficacy of treatment.  However, because an unrelated placebo was 
used in these studies, the true level of efficacy cannot be objectively determined.7  All 
these approved topical treatments, as well as Valtrex and Famvir, the approved oral 
treatments, provide, at best, approximately a one day shortening of the duration of a 
herpetic episode, and none of them results in a reduction in the percent of the worst 
outbreaks, the so-called classical lesions.  Even the most recently approved new 
treatment, Xerese, a combination of acyclovir and hydrocortisone, provides less than one 
day shortening of the herpetic episode, and an only slightly better, 1.5 day, decrease in 
the time until complete healing of the outbreak.  Xerese does claim to significantly 
reduce the percent of classical lesion outbreaks, but the increase in the percent of so-
called “aborted lesions” with Xerese is only modestly better than the essentially 
ineffective acyclovir cream (42% for Xerese versus 35% for acyclovir cream).7  
 
A pilot clinical study (Protocol TR-H-111) was performed by the sponsor to investigate 
the potential skin irritancy of Merlin. The study involved the application in 40 subjects, 
of a total of thirty-six (36) treatments over four (4) days.  More specifically, each subject 
administered three (3) applications of Merlin or placebo, depending on how a subject was 
randomized, twenty (20) minutes apart, for each set of treatments.  These sets of 
treatments were repeated two (2) more times at six (6) and twelve (12) hour after the start 
of the initial treatments, for a total of nine (9) treatments of active or placebo on Day 1.  
The sets of treatments were then re-applied three (3) times each day for three (3) 


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additional days, resulting in the above noted total of four (4) days of treatment with 
thirty-six (36) applications of active or placebo.  
 
On Day 1, scoring of the skin reaction was performed at the treatment site within 5 min 
prior to each initial application in a set of 3 applications, and within 5 minutes after the 
third application in the set of 3 applications.   On Days 2 through 4, scoring of the 
treatment site was performed only for the first set of applications, when the subject was in 
the clinic for the first set of test article applications.  Similarly to the timing for the 
evaluations on Day 1, scoring of the skin reaction in the treatment site was performed 
within 5 min prior to the initial application in the first set of 3 applications, and within 5 
minutes after the third application in the first set of 3 applications.   Skin reaction scoring 
on Day 5 was performed at 24 hours (± 1 hour) from the time of the first treatment on 
Day 4. Any skin reactions noted on Day 5 were to be followed either with daily clinic 
visits or telephone contacts, as deemed appropriate, until the event was resolved. 
 
The results of the skin irritation portion of the study revealed that all treatments were 
very well tolerated by all subjects, with no significant skin irritation and only a few, mild 
adverse events.  Minimal erythema was the most notable reaction observed immediately 
after treatment in three subjects, and this resolved in all subjects within 1 hour. The only 
other reported adverse drug related adverse event was mild burning on treatment 
application in one subject; this also resolved rapidly.  
 
Merlin, therefore, appears to be safe as the only reported adverse events were very mild 
skin irritation in three subjects and mild burning on application in one subject. 
 
This was followed by Phase 2 study (TR-H-211) the primary objective of which was to 
assess the efficacy of Merlin as compared to a placebo treatment, on the clinician 
assessed duration to complete healing of the herpetic episode. Other endpoints included 
the clinician assessed:  1) prevention of progression to a classical lesion associated with 
herpes labialis; 2) duration of classical herpetic lesions; and 3) duration of the herpetic 
episode.  The safety of Merlin was also evaluated. 
 
A total of 469 subjects were enrolled in the study with 172 subjects actually treated.  
After being enrolled and randomized into the study, subjects were sent home with a kit 
containing a bottle filled with either Merlin (active) or the 10% ethanol placebo solution 
and a packet of foam-tipped applicators sufficient to apply three study treatments (nine 
(9) applications). The subject was instructed to contact the clinic by telephone at the first 
signs and/or symptoms of a recurrent herpetic episode (Stage 0 or 1, prodromal or 
erythema).  The lesion then was confirmed by telephone interview with the subject, and 
upon confirmation of the lesion, the subject was instructed to begin treatment 
immediately, thereby initiating the Treatment Phase of the study.  The subject was told to 
continue treatment for the remainder of the day with the treatment schedule as described 
above for the Phase 1 study, and to continue to treat with a set of three (3) treatments, 
three times each day, for a total of twelve (12) sets of treatments resulting in thirty-six 
(36) applications in total. The subject also was instructed to return to the clinic within 24 
hours of the initial treatment for evaluation of the stage of the herpetic lesion. 
 


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Subjects reported daily for a minimum of 3 consecutive days, with the last clinic visit at 
the time of complete healing (Stage 7 - normal skin) or at 14 days, whichever is earlier.  
Subjects will be contacted by phone, for a safety assessment, 2 weeks after they complete 
the Treatment Phase of the study. 
 
The results of this study found that twelve (12) treatments with Merlin solution, 
administered 6 hours apart (up to 3 per day) over 96 hours, was generally safe and 
tolerable in the treatment of subjects with lesions associated with herpes simplex labialis. 
The majority of treatment-related AEs were classified as mild in intensity.  No treatment 
related AEs in any cohort were classified as severe. 
 
An a priori analysis found that those subjects, who treated with Merlin at first visible 
signs of a herpetic lesion, erythema, rather than immediately at first symptoms of a 
herpetic lesion, the prodromal stage, exhibited statistically significant efficacy as 
compared to placebo for the duration of the classical lesion.  The same a priori analysis 
found trends towards significance for the endpoints of complete healing, duration of the 
herpetic episode, cumulative lesion size, duration of the hard scab, and the subject 
assessed severity of lesion pain. 
 
This current clinical study is a follow-up Phase 2 trial using the same Merlin formulation 
as was used in the studies described above. This trial, as the previous Phase 2 study, will 
have two treatment arms comparing the safety and efficacy of Merlin solution to that of a 
placebo (10% ethanol) with treatment at first visible signs of a herpetic episode.  
 
 
3. STUDY OBJECTIVES 
 
The primary objective of this study is to assess the efficacy of Merlin solution on the 
clinician assessed duration of the classical herpetic lesion as compared to placebo 
treatment. The duration of a classical lesion is defined as the time, in hours, from the 
beginning of treatment to the onset of Stage 6, or, if Stage 6 is never observed, Stage 7. A 
classical lesion is defined as one that progresses through any of the vesicle/pustule, ulcer, 
or crust stages (stages 3, 4 or 5). 
 
The secondary objectives of this study are to compare the active and placebo treatment 
arms with regard to: 
 
 
1. The clinician assessed duration of the herpetic episode.  For a classical lesion, 
the duration of the herpetic episode is defined as the time, in hours, from the 
beginning of treatment until the loss of hard crust (stage 6; residual erythema 
can be present after loss of hard crust). For non-classical (aborted) lesions, 
duration is defined as the time, in hours, from the beginning of treatment until 
complete resolution of all local signs and symptoms (stage 7).  
 
2. The clinician assessed duration until complete healing of the herpetic episode 
(classical and non-classical lesions) as compared to placebo treatment.  For 


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both classical and non-classical lesions, the duration until complete healing of 
the herpetic episode is defined as the time, in hours, from the time of 
treatment until complete resolution of all local signs and symptoms (Stage 7).   
 
 
3. The clinician assessed prevention of progression to a classical lesion 
associated with herpes labialis. 
 
4. The clinician assessed lesion size (maximum lesion area; cumulative lesion 
area). 
 
5. The clinician assessed duration of the herpetic lesion hard scab (end of stage 
5/beginning of stage 6). 
 
6. The safety of Merlin 
 
Based on patient diary entries, other objectives of this study are to compare the active and 
placebo treatment arms with regard to: 
 
7. Subject assessed duration and severity of lesion pain 
 
8. Subject assessed duration of the classical herpetic lesion 
 
9. Subject assessed duration of the herpetic episode 
 
10. Subject assessed duration of complete healing of the herpetic episode 
 
11. Subject assessed prevention of progression to a classical lesion 
 
12. Subject assessed duration of the herpetic lesion hard scab 
 
13. Subject assessed duration and severity of lesion pain. 
 
More detailed explanations of these endpoints are provided in Section 10.7. 
 
 
4. SUMMARY OF STUDY DESIGN 
 
This current clinical study is a Phase 2 trial using the same Merlin formulation as was 
used in the Phase 1 TR-H-111 and Phase 2 TR-H-211 trials.  The TR-H-111 study 
showed that Merlin appears to be safe to use even with repeated dosing over several days 
in healthy normal subjects. The Phase 2 TR-H-211 trial similarly demonstrated that 
Merlin was generally safe and tolerable in the treatment of subjects with lesions 
associated with herpes simplex labialis.  TR-H-211 also revealed, in an a priori analysis, 
that those subjects who treated with Merlin at the first visible signs of a herpetic lesion, 
erythema, rather than immediately at first symptoms of a herpetic lesion, the prodromal 
stage, exhibited statistically significant efficacy as compared to placebo for the duration 


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of the classical lesion. The same a priori analysis found trends towards significance for 
the endpoints of complete healing, duration of the herpetic episode, cumulative lesion 
size, duration of the hard scab, and the subject assessed severity of lesion pain. 
  
The present trial is designed to examine the efficacy and safety of treatment with Merlin 
as compared to treatment with placebo (10% ethanol) in subjects treating at first visible 
signs of a herpes labialis lesion (i.e. erythema [Stage 1] or papule/edema [Stage 2]).   
 
Approximately four hundred and fifty (450) subjects, 18 to 75 years of age, who meet the 
eligibility criteria, including a history of at least 3 recurrences of herpes labialis in the 
preceding 12 months, will be enrolled into the study. Eligible subjects will be randomized 
in a 1:1 ratio to one of two treatment groups: 1) a treatment of three (3) applications of 
Merlin solution, performed within a time period of 40 minutes or less, while allowing 
time for the solution to dry on the lesion between applications; or 2) a treatment of three 
(3) applications of 10% ethanol, as a placebo, performed within a time period of 40 
minutes or less, while allowing time for the solution to dry on the lesion between 
applications.  A total of twelve (12) Merlin or placebo treatments, i.e. thirty-six (36) 
applications, will be administered over the ensuing ninety-six (96)  hours (four (4) days) 
after the first treatment.  On each day, treatments will be administered six (6) hours apart, 
with a maximum of three treatments each day. The first treatment will be administered on 
Treatment Day (Day 0), and then repeated at 6 and 12 hours after the first treatment, time 
permitting. 
 
After being enrolled and randomized into the study, subjects will be sent home with a 
sealed kit containing a bottle filled with either Merlin (active) or 10% ethanol (placebo) 
and a packet of foam-tipped applicators sufficient to apply three study treatments (nine 
(9) applications). At first signs and/or symptoms of a recurrent herpetic episode (Stage 0, 
prodrome Stage 1, erythema, or Stage 2, papule/edema), subjects will call the clinic to 
confirm by telephone interview, the presence of a lesion and the lesion stage.  Subjects 
reporting either a Stage 1 or Stage 2 lesion will be interviewed to review the eligibility 
criteria.  If they meet all the eligibility criteria they will then be instructed to begin 
treatment immediately, thereby initiating the Treatment Phase of the study.  Though 
subjects reporting a Stage 2, papule/edema, lesion will be allowed to treat, subjects 
should be strongly encouraged to call at the first visible signs of a herpetic lesion.  A 
subject observing a lesion at Stage 1, erythema, therefore, should call in immediately 
rather than assume they may wait until their lesion reaches Stage 2, papule/edema, to call 
in.  Subjects reporting only Stage 0 symptoms, i.e. no visible signs of a cold sore lesion, 
will be instructed to monitor their lesion and to call the clinic immediately upon 
observing any early visible sign of a cold sore, i.e. a Stage 1 or Stage 2 lesion.  Once the 
subject calls in and confirms by telephone interview that their lesion has reached Stage 1 
or 2, and that they still meet all eligibility criteria, they will be instructed to begin 
treatment immediately. Subjects will then be instructed to return to the clinic as soon as 
possible within 24 hours of starting treatment. 
 
Subjects will report daily for a minimum of 3 consecutive days, with the last clinic visit 
at the time of complete healing (Stage 7 - normal skin) or at 14 days, whichever is earlier.  
Subjects will be contacted by phone, for a safety assessment, 2 weeks after they complete 


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the Treatment Phase of the study. Subjects will also be provided a diary that he or she 
will be instructed to fill out daily from the first day of treatment until the lesion is healed. 
 
Both treatment groups will continue to accept subjects into the Treatment Phase of the 
study until there are at least seventy five (75) subjects in each group. Once the enrollment 
objectives for the Treatment Phase of the study have been met, the study will be closed to 
any further enrollment. 
 
 
Table 4-1: 
Treatment Groups and Sample Sizes 
 
Group 
Treatment 
 
Approximate 
Number of 
Randomized 
Subjects 
Minimum Number 
of Subjects 
Entering 
Treatment Phase 
A 
Merlin (10% ethanol; 0.6% 
glycolic acid) 
225 
75 
B 
Placebo (10% ethanol) 
225 
75 
 
Aside from any placebo effect, there should be no efficacy with the 10% ethanol solution.  
 
 
 
5. SUBJECT SELECTION 
 
5.1 
Source of Subjects 
 
Non-institutionalized subjects consisting of members of the community at large will be 
used in this study.  
 
Approximately four hundred and fifty (450) subjects with a history of recurrent herpes 
labialis, who meet the eligibility requirements, will be randomly assigned to one of two 
treatment groups and provided with study materials. Upon noticing visible signs of a 
herpes labialis lesion which meet the study criteria, the subject will call their clinical 
study site at which time he or she will be required to answer specific questions to confirm 
if he or she meets the eligibility requirements. If the subject is eligible for entry into the 
Treatment Phase of the study, the subject will be instructed to begin treatment 
immediately. The study will continue until at least 75 subjects have entered the Treatment 
Phase in each group (Table 4-1), at which time the study will be closed to any further 
enrollment. 
 
5.2 
Study Enrollment Eligibility Criteria 
 
The following criteria will be used for the initial Screening-Randomization visit.  The 
Vice President of Clinical Research at Topical Remedy, their designee, or the Medical 
Monitor, should be consulted to confirm the eligibility of a subject if there is any question 
as to whether they meet all of the Inclusion or Exclusion criteria. 
 


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5.2.1 Inclusion Criteria 
 
1. Male or female subject 18-75 years of age 
 
2. Female subjects must be using a medically acceptable form of birth control during 
the study.  Acceptable birth control measures include, but are not limited to: 
abstinence, oral contraceptive pills or patch, injectable contraception, barrier 
contraceptives (condom, diaphragm with spermicide), IUD, vaginal contraceptive 
ring, surgical (hysterectomy, tubal ligation), vasectomized partner, and natural 
post-menopausal inability to conceive.  Menopause is defined for this protocol as 
starting one year after the time of the last menstrual period. 
 
3. Subject must have a history of recurrent herpes labialis and report at least 3 
separate recurrences (i.e. multiple herpetic lesions in one outbreak count as only 
one episode) during the preceding 12 months. 
 
4. Subject must have a history of experiencing prodromal symptoms of cold sores 
(e.g. itching, tingling, or burning) during at least half of their previous cold sore 
episodes. 
 
5. Subject must have a history of at least half of their cold sore episodes producing 
classical lesions (i.e., episodes that progressed through macule, papule, vesicle, 
crust, and healed). 
 
6. Subject must provide voluntary written informed consent to participate in this 
study. 
 
 
 


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5.2.2 Exclusion Criteria 
 
1. Subjects with evidence of active malignancy or immunodeficiency disease within 
the last 30 days.  Subjects who have completed therapy and are considered 
unlikely to relapse or who have had surgery and do not have any evidence of 
disease, are eligible for the study. 
 
2. Subject requires chronic use of immunomodifying drugs (e.g. systemic steroids) 
or topical steroids on or near the face; use of inhaled steroids does not exclude a 
subject from the study.  If a subject is unlikely to get through the Treatment Phase 
of the protocol without requiring the use of an immunomodifying drug for a 
chronic condition the subject should be excluded. 
 
3. Subject requires chronic use of anti-viral medication. 
 
4. In females of childbearing potential, a positive urine pregnancy test at time of 
screening. 
 
5. Nursing mothers. 
 
6. Subject is considered unreliable or unable to understand or follow the protocol 
directions or is unable to comprehend or satisfactorily assess a herpetic lesion as 
determined by Investigator or designee at screening.  
 
7. Subject has abnormal skin conditions (e.g. acne, eczema, rosacea, psoriasis, 
albinism, or chronic vesiculobullous disorders) that occur in the area ordinarily 
affected by cold sores or has significant facial hair in the area of the cold sore that 
might affect the normal course of the cold sore or might impair accurate 
evaluation of the cold sore lesion. 
 
8. Subject has had a vaccine for herpes simplex virus type 1 (typically oral herpes) 
or 2 (typically genital herpes). 
 
9. Subject is currently enrolled in another clinical trial involving the use of a drug 
and/or a device. 
 
10. Subject has previously participated in the current study (TR-H-212). 
 
11. Subject requires chronic use of analgesics or non-steroidal anti-inflammatory 
agents (NSAIDs) except for low doses of aspirin (≤ 325 mg/day) used for 
cardiovascular purposes.  If a subject is unlikely to get through the Treatment 
Phase of the protocol without requiring the use of analgesia for a chronic 
condition, e.g. back pain, recurrent daily headaches, the subject should be 
excluded. 
 
12. Subject has a recent history of renal dysfunction or serious hepatic disease. 
 


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Renal dysfunction encompasses both acute and chronic renal failure, the former 
resulting from the sudden loss of the ability of the kidneys to excrete wastes, 
concentrate urine, and conserve electrolytes and the latter the gradual and 
progressive loss of these capabilities. 
 
Examples of serious hepatic disease would include alcoholic liver disease, chronic 
hepatitis, autoimmune hepatitis and a variety of inherited diseases. The underlying 
cause of a documented recent mild increase in liver enzymes should be considered 
when deciding whether or not to exclude such a subject. 
 
13. Subject has a history of alcoholism or drug abuse within the preceding 12 months. 
A subject with a history of a pathological pattern of alcohol use that causes a 
serious impairment of social or occupational functioning should be excluded.  
Such subjects may exhibit symptoms of tolerance and withdrawal along with 
other behavioral symptoms. 
 
14. Subject shares a household with another subject already enrolled in the study (TR-
H-212).  If the other household member has already completed the study, then the 
currently enrolling subject is not excluded. 
 
15. Subject is institutionalized.  
 
16. Any history which, in the Investigator’s judgment, makes the subject ineligible or 
places the subject at undue risk. 
 
 
5.3 
Study Treatment Phase Eligibility Criteria 
 
The following criteria will be used to enter subjects into the study Treatment Phase when 
a subject previously enrolled into the study calls to report first visible signs of a herpes 
simplex labialis lesion. Subjects who call in to report experiencing prodromal symptoms 
(e.g. tingling, itching) are not to be screened for eligibility until they report observing 
visible signs of a cold sore lesion.  The Vice President of Clinical Research at Topical 
Remedy, their designee, or the Medical Monitor, should be consulted to confirm the 
eligibility of a subject if there is any question as to whether they meet all of the Inclusion 
or Exclusion criteria. 
 
 
5.3.1 Inclusion Criteria  
 
1. Subject has a visible herpes simplex labialis lesion, in an area around the mouth, 
assessed by the subject, and confirmed by telephone contact, to be at the erythema 
stage (Stage 1) or Papule/Edema stage (Stage 2) as defined below: 
 
Stage 1: 
Erythema stage is defined as any redness with no skin swelling or 
other signs of advanced stages. 
 


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Stage 2: 
Papule/Edema stage is defined as any skin swelling or solid raised 
area above the normal surface without evidence of more advanced 
stages such as fluid filled blisters. 
 
2. Female subjects must be using a medically acceptable form of birth control during 
the study.  Acceptable birth control measures include but are not limited to: 
abstinence, oral contraceptive pills or patch, injectable contraception, barrier 
contraceptives (condom, diaphragm with spermicide), IUD, vaginal contraceptive 
ring, surgical (hysterectomy, tubal ligation), vasectomized partner, and natural 
post-menopausal inability to conceive.  Menopause is defined for this protocol as 
starting one year after the time of the last menstrual period.  
 
3. Subject has immediate access to the kit containing the clinical trial material. (The 
subject will demonstrate access to the clinical trial material kit by reading the 
Randomization Number printed on the label on the kit.) 
 
4. Subject is able to appear for a clinic visit within 24 hours from the time of 
enrollment into the Treatment Phase of the study (from the time the subject called 
to establish entry into the Treatment Phase of the study) and is able to return to 
the clinic for the full 14 day duration of the study if necessary. 
 
5.3.2 Exclusion Criteria  
 
1. Subjects with any evidence of active malignancy or immunodeficiency disease 
within the last 30 days.  Subjects who have completed therapy and are considered 
unlikely to relapse or who have had surgery and do not have any evidence of 
disease, are eligible for the study. 
 
2. Subject using topical steroids on or near the face or immunomodifying drugs, e.g. 
systemic (oral, intravenous) steroids within the last 30 days; use of inhaled 
steroids does not exclude a subject from the study. 
 
3. Subject using an NSAID, except for low doses of aspirin (≤ 325 mg/day) used for 
cardiovascular purposes, or any other analgesic, within 12 hours of calling clinic 
to report visible signs of a herpetic lesion. 
 
4. Subject has used an investigational drug and/or device within the last 30 days. 
 
5. Subjects who have used any anti-viral drug, or any other systemic or topical 
medications, including home remedies, intended to treat cold sores (e.g. lysine, 
topical tea tree oil, topical honey) within the last 30 days. 
 
6. Subject has had a vaccine for herpes simplex virus type 1 (typically oral herpes) 
or 2 (typically genital herpes). 
 
7. Subject is more than 75 years of age. 
 


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8. Subject is pregnant, as checked by subject questioning prior to dosing. 
 
9. Subject has abnormal skin conditions (e.g. acne, eczema, psoriasis, albinism, or 
chronic vesiculobullous disorders) that occur in the area of the cold sore lesion, or 
has significant facial hair in the area of the cold sore, that might affect the normal 
course of the cold sore or might impair accurate evaluation of the cold sore lesion. 
 
10. Subject is currently enrolled in another clinical trial involving a drug and/or 
device. 
 
11. Subject requires chronic use of analgesics or NSAIDs, except for low doses of 
aspirin (≤ 325 mg/day) used for cardiovascular purposes. If a subject is unlikely to 
get through the treatment phase of the protocol without requiring the use of 
analgesia for a chronic condition, e.g. back pain, recurrent daily headaches, the 
subject should be excluded. 
 
12. Subject has a recent history of renal dysfunction or serious hepatic disease. 
 
Renal dysfunction encompasses both acute and chronic renal failure, the former 
resulting from the sudden loss of the ability of the kidneys to excrete wastes, 
concentrate urine, and conserve electrolytes and the latter resulting from the 
gradual and progressive loss of these capabilities. 
 
Examples of serious hepatic disease would include alcoholic liver disease, chronic 
hepatitis, autoimmune hepatitis and a variety of inherited diseases. The underlying 
cause of a documented recent mild increase in liver enzymes should be considered 
when deciding whether or not to exclude such a subject. 
 
13. Subject has a history of alcoholism or drug abuse within the preceding 12 months. 
A subject with a history of a pathological pattern of alcohol use that causes a 
serious impairment of social or occupational functioning should be excluded.  
Such subjects may exhibit symptoms of tolerance and withdrawal along with 
other behavioral symptoms. 
 
14. Subject is institutionalized. 
 
15. Any history which, in the Investigator’s judgment, makes the subject ineligible or 
places the subject at undue risk. 
 
16. Subject is unwilling to comply with the restrictions outlined in Section 5.4 below. 
 
 


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5.4 
Restrictions During the Treatment Phase 
 
5.4.1 The subject is not to use any oral or topical prescription or over-the-counter 
medications to treat the current herpes labialis lesion, or apply any cosmetics, lip 
balms, ointments, moisturizers or home remedies to the affected area. 
 
5.4.2 The subject is not to use any pain medication or non-steroidal anti-inflammatory 
agent (NSAID), except low doses of aspirin (≤ 325 mg/day) used for 
cardiovascular purposes, during the Treatment Phase of the study. 
 
5.4.3 The subject is not to mechanically disrupt the lesion (i.e. scrubbing, lancing, 
shaving the area, rubbing with alcohol, etc.). 
 
5.4.4 Merlin contains an alpha hydroxyl acid that may increase the skin’s sensitivity to 
the sun and particularly the possibility of sunburn.  Subjects should therefore limit 
sun exposure while using Merlin, and for one week afterwards. 
 
A subject who does not meet one or more of the Inclusion Criteria or certain Exclusion 
Criteria may still be eligible for continuing in the study.  Those subjects would be 
instructed that they cannot be entered into the Treatment Phase of the study at that time, 
but must wait until their next outbreak at which time they can call in again to see if they 
qualify to begin the study treatment.  See Section 7.2.3 for further details. 
 
 
 MATERIALS 
 
6.1 
Drug Supply 
 
All study materials will be supplied by Topical Remedy, LLC and dispensed by the clinic 
pharmacy at the study site.  
 
Test treatment: 
 
Merlin (10% Ethanol and 0.6% glycolic acid, pH 2.5) 
 
Placebo treatment: 
 
10% Ethanol 
 
Merlin, or the placebo, will be supplied in 4.0 mL HDPE bottles along with single-use 
foam swabs for application to the skin.  The clinic pharmacy will be supplied 
preassembled Treatment kits, consisting of sealed, hinge top containers, each containing 
one bottle of Merlin or placebo solution, the bottle blinded with a label noting only the 
study number, along with one (1) pouch containing nine (9) single-use foam swabs, 
sufficient for three (3) treatments (9 applications).   Based upon how a subject is 
randomized, Merlin or placebo group, an appropriate Treatment kit will be assigned to 
that subject.  
 


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For Visit Days 1, 2, and 3 study materials, the pharmacy will be supplied in bulk with 
pouches, each containing nine (9) foam swabs, one for each application over the next 24 
hours. The study site will provide a new pouch of foam swabs to the subject each study 
day after the evaluation of the treatment site. 
 
6.2 
Drug Identification 
 
Bottles (4.0 mL HDPE), containing either Merlin or placebo, will be supplied. For 
blinding purposes, the lot number label on the bottle will be over-labeled by the Sponsor 
with a label noting only the Study Number along with other required regulatory 
information. That bottle will be placed in the Treatment kit along with a supply of foam 
swabs. The pouch of foam swabs will be labeled with the Study Number, a listing of the 
contents, and the Sponsor address.  The Treatment kit will have a double tear-off label. 
The label adhering to the container will: 1) list the Study Number; 2) have a pre-printed 
Randomization Number; 3)  have a space for filling in the Subject Number associated 
with that Randomization Number; and 4) contain other required regulatory information 
and the Sponsor address.  The tear-off portion of the label will: 1) list the Study Number; 
2) have a pre-printed Randomization Number; 3) have a space for filling in the Subject 
Number associated with that Randomization Number; and 4) have a pre-printed lot 
number which will be used for unblinding if necessary.  
 
Randomization to a treatment group will be accomplished through a pre-determined 
sequence at each site. When a subject is randomized, the site will assign the next 
available randomization number which corresponds to an identical Randomization 
Number on the label on the Treatment kit. Once assigned, the pharmacist, or designee, 
will complete the double, tear-off label on the container by filling in the appropriate 
Subject Number.  The tear-off portion of the label will then be removed and placed into 
the pharmacy study record. 
 
 
As noted in Section 6.1, the site will also be supplied, in bulk, with pouches, each 
containing nine (9) swabs.  The study site will provide a new pouch of foam swabs to the 
subject on Visit Days 1, 2, 3, 4 (if needed on Days 4 and 5), after the evaluation of the 
treatment site. As with the pouch in the Treatment kit, these pouches will be labeled with 
the Study Number and Sponsor address.   
 
6.3 
Drug Storage 
 
All clinical trial materials should be stored at the clinical site at controlled room 
temperature in a limited access area.  
 
6.4 
Randomization 
 
Approximately four hundred and fifty (450) subjects will be randomized into one of two 
treatment groups in a 1:1 ratio and will be assigned a sealed kit consisting of enough 
single use swabs for three (3) treatments (9 applications) and either: 1) Merlin (10% 


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ethanol and 0.6% glycolic acid, pH 2.5); or 2) placebo (10% ethanol). The randomization 
code will be generated by Topical Remedy, LLC, or its designee. 
 
A total of at least one hundred and fifty (150) of these subjects, with at least seventy-five 
(75) subjects in each group, will be instructed to administer drug upon a qualifying lesion 
outbreak. 
 
 
6.4.1 Blinding Procedure and Code Breaks 
 
The study will be double-blinded for all treatment arms.  Only in the case of an 
emergency, when knowledge of the study drug is essential for the clinical management or 
welfare of the subject, may the Investigator request that a subject’s study treatment 
assignment be unblinded.  Wherever possible the Investigator (or designee) must contact 
the Medical Monitor prior to breaking the blind.  Should it be determined that the blind 
needs to be broken, the Medical Monitor will contact the Vice President of Research and 
Development at Topical Remedy who will be able to perform any required unblinding. 
The Investigator must document the reason for breaking the code. The randomization 
code will be broken in order to perform the statistical analysis only after all the data of 
the study have been cleaned and audited and the database locked. 
 
6.5 
Drug Accountability/Retention 
 
Clinical Trial Material Accountability Logs must be kept current and should contain the 
following information: 
• Identification of the subject to whom a kit was dispensed including 
randomization numbers and initials 
• The date a kit was dispensed to a subject 
• The date a kit was sent back to Topical Remedy. 
• The date and quantity of any disposed kits, and the initials of the person who 
disposed of the kits. 
 
The method of destruction of any used kits will be documented in a material of 
destruction form that will be maintained in the Regulatory Binder and with the Clinical 
Trial Materials Accountability Log. 
 
The inventory will be maintained in a limited access area and must be available for 
inspection by the study monitor.  A clinical trial material inventory and storage facility 
inspection will be conducted at appropriate time intervals throughout the clinical 
investigation, depending on enrollment and the length of the study. Clinical trial material 
inventory must be current and reflect all used and unused materials.   Any discrepancy 
and/or deficiency must be accounted for by the Principal Investigator or designee.  
 
Clinical trial materials, including unused kits, must be returned at the end of the study to 
Topical Remedy, LLC.  Any missing supplies will be indicated on the Clinical Trial 
Materials Accountability Log; the original Clinical Trial Materials Accountability Log 
will be retained in the Trial Master File and a copy retained in the Investigator’s 


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Regulatory Binder. Any used kits returned with the HDPE bottles of test material must 
be destroyed at the site and not returned to Topical Remedy. 
 
 STUDY CONDUCT 
 
This section describes the study procedures to be followed. These procedures are 
summarized in Table 7.1 on the next page.


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Table 7-1: 
 Summary of Events 
 
 
EVENT 
Screening 1 
(Day 0) 
Treatment 
Day7 
Visit 
Day 
1 
Visit 
Day 
2 
Visit 
Day 
38 
Visit 
Day 
4 
Visit 
Day 
5 
Visit 
Day 
6 
Visit 
Day 
7 
Visit 
Day 
8 
Visit 
Day 
9 
Visit 
Day 
10 
Visit 
Day 
11 
Visit 
Day 
12 
Visit 
Day 
13 
Visit 
Day 
14 
 
F/U11 
Clinic visit2 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
eligibility criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Phase 
eligibility criteria 
 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history; 
Physical Exam and 
Vitals 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
(see footnote 6) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
X4 
X4 
X4 
X4 
(X)4 
(X)4 
(X)4 
 
 
 
 
 
 
 
 
 
Subject Diary2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diary Review2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinician lesion 
assessment2 
 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events2,10 
 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con meds2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
1 To be conducted prior to dosing. At this time, subject is instructed on how to apply Merlin and given study materials to take home. If the subject comes into the clinic for screening with an already 
existing lesion that meets the study criteria, then the subject could begin treatment immediately. In that instance the Screening and Treatment Day would coincide with the Visit Day 1 clinic visit. 
2 All subjects will be followed daily until Stage 7, reporting daily for a minimum of 3 consecutive days, with the last clinic visit at the time of complete healing or at 14 days, whichever is earlier.  
3  Treatment Phase eligibility criteria are checked via telephone prior to dosing. 
4 To be performed by subject. Merlin administrations will begin on Treatment Day. Most typically, it is expected that subjects will treat outside of the clinic on Treatment Day, and come in within 24 
hours, (on Visit Day 1), for their first lesion evaluation.  If, however, a subject can come in to the clinic for a lesion evaluation the same day as their treatment starts, then Treatment Day and Visit Day 
1 will coincide.  Treatments will continue through at least Visit Days 1, 2, and 3. If Treatment Day and Visit Day 1 are separate days, then treatment on Visit Day 4 will be administered only if the 
subject was unable to complete all three (3) sets of treatments on Treatment Day.  If Treatment Day and Visit Day 1 coincide, then treatment on Visit Day 5 will be administered only if the subject was 
unable to complete all three (3) sets of treatments on Treatment Day (Visit Day 1). In either instance a total of twelve (12) treatments (36 applications) over 96 hours from the time of the first treatment 
is the maximum duration of treatments. 
5  The first lesion scores, up until first visible signs of a herpetic lesion, are determined by the subject prior to the first treatment.  All other lesion scores are determined in the clinic by the Investigator or 
the Investigator’s trained designee. 
6 For women with child-bearing potential. On Treatment Day “Pregnancy Status” will be determined by asking the subject if she is pregnant or if she has changed her contraceptive practice such that 
there might be a significantly increased likelihood that she could have become pregnant. 
7 Treatment Day is the first day a subject reports visible signs of a herpetic lesion, as confirmed by telephone, and is instructed to begin treatment. If the subject can visit the clinic that same day, 
Treatment Day will coincide with Visit Day 1. 
8 Minimum duration of study for all subjects, i.e., three (3) consecutive days of clinic visits for lesion, adverse event and concomitant medication assessment.  
9 Treatment Day Adverse Events will be reported to clinic at the first clinic visit on Visit Day 1.  
10  Subjects who discontinue prior to Visit Day 3 but have administered any treatment should be followed for safety until at least Visit Day 3. 
11 The follow-up (F/U) study visit for safety is to be conducted by telephone 2 weeks, or up to 3 weeks, if there are scheduling issues, after the subject completes the Treatment Phase of the study


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7.1 
Screening and Enrollment Visit 
 
7.1.1 Screening 
 
The following items must be assessed and collected by the Investigator or his/her 
designee prior to enrolling the subject into the study. 
 
1. Informed Consent. All prospective subjects will have the study explained by a 
member of the research team. The nature of the Merlin solution to be 
evaluated will be explained together with potential hazards involving allergies 
and possible adverse reactions to the test material.  
 
Prior to enrollment into the study, acknowledgment of the receipt of this 
information and the subject’s freely-tendered offer to participate will be 
obtained in writing from each subject in the study using an IRB-approved 
informed consent form. The subject will be given a copy of the signed 
informed consent form. 
 
 
2. Enrollment Eligibility Criteria. The subject’s potential eligibility to participate 
in the study will be evaluated using the inclusion and exclusion criteria listed 
in Section 5.2. 
 
3. Medical History. A thorough medical history will be obtained including 
significant medical conditions over the previous 10 years and a subject’s 
history of herpes labialis including the number of separate outbreaks per year 
(i.e. multiple lesions during one outbreak are counted as only a single 
outbreak). 
 
4. Physical Exam and Vital Signs.  A baseline physical examination and vital 
signs collection should be performed with all subjects following collection of 
the Medical History. 
 
5. Pregnancy Test. 
All female subjects of child-bearing potential will be given 
a urine pregnancy test. 
 
6. Concomitant Medications. A determination will be made of the medications 
currently being taken by the subject.  Concomitant medications will be 
collected for the 30 days prior to enrollment into the study, the 30 days prior 
to enrollment into the Treatment Phase of the study, and throughout the 
Treatment Phase of the study.   For any exclusionary medications that have 
been discontinued prior to entry into the Treatment Phase, stop dates for those 
medications must be obtained prior to allowing the subject into the Treatment 
Phase with particular attention as to whether the medications were 
discontinued within the appropriate timeframe.   
 


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7.1.2 Enrollment into Study 
 
The subject’s potential eligibility to participate in the study will be evaluated using the 
inclusion and exclusion criteria listed in Section 5.2. If the subject meets all of the 
inclusion and none of the exclusion criteria in Section 5.2, the subject will be enrolled 
into the study and assigned the next available Randomization Number at the study site.  
The assigned Randomization Number corresponds to an identical Randomization 
Number on the label on the Treatment kit, as described in Section 6.1, which is to be 
allocated to the enrolled subject.  The label on the Treatment kit will include a duplicate 
tear-off label that will also have a space for entry of the Subject Number, the preprinted 
Randomization Number, and the preprinted Lot Number. This tear-off label will be 
separated from the Treatment kit prior to dispensing to the subject, and that label will be 
placed into the pharmacy study record. The label in the pharmacy study record will 
provide confirmation of the Randomization Number on the Treatment kit the subject was 
assigned along with the lot number representing which group, active or placebo, into 
which the subject was randomized.  Neither the pharmacy, nor anyone else at the study 
site, will be aware of which lot number represents the active and which represents the 
placebo treatment. 
 
At the time of enrollment, the subject will be trained in application of the clinical trial 
material for later at-home application.  Subjects will also be provided a diary in which 
he/she will record the lesion stage, the patient assessed severity and duration of pain of 
the herpes lesion, and assessment of attributes as listed in Section 3. Subjects will be 
instructed to call in to the clinic as soon as possible in order that they may begin 
treatment no more than 1 hour after detecting first signs and/or symptoms of an incipient 
herpes labialis lesion. The subject will be given training to enable them to assess the stage 
of their lesion when he or she subsequently calls in to the clinical site to report a lesion 
and for completion of the diary. 
 
 
7.2 
Study Treatment Phase (Treatment Day) 
 
7.2.1 Subject Eligibility Determination 
 
Immediately upon noticing first signs and/or symptoms of a herpes labialis lesion, the 
subject is to call in to the study clinic.  Subjects will then be questioned to determine if 
they in fact are experience a herpetic outbreak and, if so, the stage of the lesion.   
 
Subjects reporting a lesion at the erythema stage (Stage 1) or the papule/edema stage 
(Stage 2) will then be asked to answer specific questions to confirm whether they meet 
the inclusion/exclusion criteria described in Section 5.3 so that they may enter the 
Treatment Phase.  Note that while subjects will be allowed to begin treatment at the 
papule/edema stage (Stage 2), subjects should be strongly encouraged to call in to begin 
treatment at the erythema stage (Stage 1), if at all possible. The clinic will also inquire 
about any concomitant medications taken in the last 30 days including a review of any 
changes in concomitant medications as reported by the subject at the time of enrollment 
into the study.  All exclusionary concomitant medications must have a stop date noted. 


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Subjects calling in to report a herpetic lesion at the prodrome stage (Stage 0) should be 
instructed to begin frequently monitoring their lesion so as to be able to call the study 
clinic again at the first visible signs of the lesion, erythema or papule/edema.  As 
mentioned above, while subjects will be allowed to treat at the papule/edema stage, they 
should be strongly encouraged to call in when their lesion reaches the erythema stage, if 
at all possible. Once subjects call in to report a visible lesion, the subjects will then be 
screened to confirm whether they meet the inclusion/exclusion criteria described in 
Section 5.3 so that they may begin the Treatment Phase.  The clinic also will inquire, as 
described above, about any concomitant medications.  All exclusionary concomitant 
medications must have a stop date noted. 
 
If a subject who has first called in to report a lesion at the prodrome stage has not called 
back to report visible signs of the lesion, the clinic should try to contact the subject by 
telephone 6 -18 hours after the time of the initial phone contact. (Subjects should be 
contacted later the same day of their initial phone call, if possible.) If, when contacted, 
the subject reports visible signs of a herpetic lesion (Stage 1 or 2, but not a later stage), 
they should be screened, as described above, for entry into the Treatment Phase of the 
protocol.  Otherwise, if the subject is still reporting prodromal symptoms, they should be 
reminded to continue to monitor their lesion for any visible signs of the lesion or until 
their lesion resolves without any visible signs of a cold sore.  Should, after the first clinic 
call, the subject still not call in to report visible signs of a lesion or resolution of the 
episode, the clinic should continue to contact the subject by telephone every 6 -18 hours 
until the subject reports visible signs of a lesion or until the subject reports that the lesion 
has resolved without exhibiting any visible signs of a cold sore. If a subject does not 
report visible signs of a herpetic lesion within 96 hours of initially calling to report 
prodromal symptoms, the site may discontinue contacting the subject; the subject, 
however, should be instructed to contact the clinic if their lesion progresses to a visible 
stage or if they experience a new herpetic outbreak.  If the subject’s lesion progresses 
beyond stage 2 prior to, or when calling to enter the treatment phase of the study, the 
subject should be instructed that they no longer will be able to treat the current outbreak, 
but may try again, at their next lesion outbreak, to enter the treatment phase of the study. 
 
7.2.2 Lesion Assessment 
 
Subjects will have been trained at screening to recognize whether they are at the 
prodromal stage (Stage 0), the erythema stage (Stage 1), the papule/edema stage (Stage 2) 
or a more advanced herpetic stage, with particular attention to distinguishing between 
Stage 2 and any later stages.  Only subjects with a lesion in Stage 1 or Stage 2, the early 
visible signs of a herpetic outbreak, will be entered into the Treatment Phase of the study 
and therefore allowed to treat themselves.  Subjects reporting a more advanced herpetic 
lesion, beyond Stage 2, will be instructed that they are still in the study but must wait 
until their next lesion outbreak before again calling in to attempt to enter the Treatment 
Phase of the study.  Subjects reporting a lesion in the prodromal stage, Stage 0, will be 
instructed to monitor their lesion for first visible signs of a cold sore, and followed as 
described above.  If a subject has two or more distinct lesions, the subject will treat the 
first lesion that appeared as long as it has not progressed beyond Stage 2.  If any lesions 


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have progressed beyond Stage 2, as noted above, the subject will be instructed to wait 
until their next outbreak before calling to enter the Treatment Phase of the study.  
 
 
7.2.3 Entry into Study Treatment Phase 
 
If a subject has met all the inclusion and exclusion criteria described in Section 5.3, and 
has a herpes labialis lesion in Stage 1 or Stage 2, the subject will then be allowed into the 
Treatment Phase of the study and instructed to open the Treatment kit containing the 
study material and begin treatment. The subject will be asked to schedule their Visit Day 
1 clinic visit for later that day, if possible; otherwise the visit must be scheduled as early 
as possible the following day anytime within 24 hours of the time at which a subject calls 
and is allowed to enter the Treatment Phase of the study. 
 
A subject who does not meet one or more of the Inclusion Criteria (Section 5.3.1), or 
certain Exclusion Criteria (specifically Treatment Phase Exclusion Criteria #1 - #5; 
Section 5.3.2) may still be eligible for continuing in the study.  Those subjects will be 
instructed that they cannot be entered into the Treatment Phase of the study at that time, 
but must wait until their next outbreak at which time they can call in again to see if they 
qualify to begin the study treatment.  The list of those criteria where subjects who do not 
meet those criteria can still participate in the study, but must defer their entrance into the 
Treatment Phase until their next cold sore recurrence, is provided below: 
 
• The subject reports a lesion stage later than Stage 2 (Treatment Phase Inclusion 
Criterion #1). 
 
• A female subject is not using a medically acceptable form of birth control 
(Treatment Phase Inclusion Criterion #2).  In this instance, the subject will be 
instructed to return to the clinic for another pregnancy test.  Once that test is 
shown to be negative, the subject will be told to resume proper contraception and 
can then call in again at the next lesion outbreak. 
 
• The subject does not have immediate access to the clinical trial material kit 
(Treatment Phase Inclusion Criterion #3).   In this case they will be asked to call 
again when he or she has the kit at hand. At the time of their second phone call 
they also will be asked again about the stage of their lesion to be certain that the 
lesion has not progressed beyond Stage 2. 
 
• The subject cannot appear for a clinic visit within 24 hours from the time of 
enrollment into the Treatment Phase of the study (the time of the subject’s call to 
establish entry into the Treatment Phase of the study), or is unable to return to the 
clinic daily for the full 14 day duration of the study if necessary (Treatment Phase 
Inclusion Criterion #4). 
 
• The subject has any evidence of active malignancy or immunodeficiency disease 
within the last 30 days (Treatment Phase Exclusion Criterion #1). As also noted in 


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Exclusion Criterion #1, subjects who have completed therapy and are considered 
unlikely to relapse or who have had surgery and do not have any evidence of 
disease, are eligible for the study and therefore could begin the study treatment 
provided they meet all other inclusion and exclusion criteria. 
 
• A subject has used topical steroids on or near the face or systemic (oral, 
intravenous) steroids within the last 30 days (Treatment Phase Exclusion Criterion 
#2). As also noted in Exclusion Criterion #2, use of inhaled steroids does not 
exclude a subject from the study; such subjects, providing they meet all other 
criteria, can be entered into the Treatment Phase of the protocol. 
 
• A subject has used an NSAID within the last 12 hours of calling the clinic to 
report the lesion (Treatment Phase Exclusion Criterion #3). 
 
• A subject has used an investigational drug and/or device within the last 30 days 
(Treatment Phase Exclusion Criterion #4). 
 
• A subject has used any anti-viral drug, or any other medication, including home 
remedies, intended to treat cold sores (e.g. lysine, tea tree oil, honey) within the 
last 30 days, or used any topical medication to treat the current active herpes 
simplex labialis lesion (Treatment Phase Exclusion Criterion #5).  
 
Except for those Treatment Phase Exclusion Criteria noted above, specifically #1 - #5, a 
subject meeting any of the other exclusion criteria will no longer be able to participate in 
the study and he or she will be asked to report to the clinic in order to return their sealed 
kit. 
 
7.2.4 Drug Administration 
 
Each subject, upon entering the Treatment Phase of the study, will be instructed to treat 
their lesion immediately using the solution and single-use applicators in the Treatment 
kit. The subjects, according to the randomization scheme, will begin self-administration 
of the applications of either Merlin or placebo solution. Treatment Day is the first day of 
treatment for all subjects.  
 
At the time of the subject’s call to enter the Treatment Phase of the study, the clinic 
should review the method and schedule of treatment applications with the subject.   
 
For the first and all subsequent treatments, each subject will administer three (3) 
applications of Merlin or placebo, depending upon how a subject has been randomized, 
performed within a time period of 40 minutes or less, while allowing time for the solution 
to dry on the lesion between applications.  A total of twelve (12) Merlin or placebo 
treatments, i.e. thirty-six (36) applications, will be administered over the ensuing 96 
hours (4 days) from the time of the first treatment.  On each day, treatments will be 
administered six (6) hours apart (± 1 hour), with a maximum of three treatments each 
day. The first treatment will be administered on Treatment Day (Day 0), and then 
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Subjects who, upon self-examination outside of the clinic, or upon evaluation in the 
clinic, are found to have herpetic lesions that have reached the ulcer/soft crust stage 
(Stage 4) should be instructed to discontinue all remaining treatments. If the observation 
of the lesion reaching Stage 4 is made by the subject outside of the clinic, the subject 
should call into the clinic as soon as possible after making this observation to confirm the 
accuracy of their assessment and to report the event. 
 
Subjects who are unable to begin treatment for any reason, aside from those listed in 
Section 7.2.3, are to be discontinued from the study; those subjects are to return to the 
clinic to turn in their clinical trial materials and are not to be followed for safety or 
efficacy.  Subjects, though, who are able to complete any part their treatment, even only a 
single application of the solution to the face, are to continue to participate in the study as 
planned, including appearing for all safety and lesion assessment clinic visits.  
 
7.2.5 Subject Diaries 
 
Each subject will be instructed to record into their diaries the date and time of their first 
treatment, the stage of their lesion, and his or her assessments of pain as described in this 
section.  The recording of the assessments of lesion stage and pain level are to be done 
three times per day, just prior to initiation of each treatment (i.e. just prior to the first 
application in a set of three (3) applications). After the course of treatment is completed, 
assessment of lesion stage and pain level will continue 3 times daily with approximately 
6 hours in between each assessment until the lesion is healed. The subject will also be 
instructed to bring the diary to each office visit so that the Investigator or trained 
designee can review it.  
 
 
7.2.5.1 Pain Assessment 
 
At the time of the subject’s call to enter the Treatment Phase of the study, the clinic will 
ask the subject to provide the time of the onset of any pain caused by the herpes lesion to 
be treated along with the severity of any lesion pain. 
 
The severity of lesion pain will be based on the following rating scale: 
 
1 = None 
No pain 
 
2 = Mild 
Pain is present in such a way that the subject is only vaguely 
aware of it and it does not interfere with daily activities 
 
3 = Moderate 
The subject is aware of pain at all times, but it does not 
interfere with daily activities 
 
4 = Severe 
Level of discomfort of pain is such that it interferes with daily 
activities. 
 


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As noted in Section 7.2.5, the subject will also record in the diary, just prior to each 
treatment, the severity of any lesion pain.  After the course of treatment is completed, 
assessment of pain level will continue 3 times daily with approximately 6 hours in 
between each assessment until the lesion is healed.  
 
 
 
7.3 
Follow-up Visits (Visit Days 1-14) 
 
Each subject entered into the Treatment Phase of the study is to come in for an office 
visit every day, (preferably about the same time of day each day, if possible), following 
treatment until the clinician or trained designee determines that the treated lesion has 
reached Stage 7, up until at least Visit Day 3 and at most until Visit Day 14. As subjects 
might call any time of the week, and the Treatment Phase of the study could last as many 
as 14 days, clinics must be staffed with personnel, trained in lesion assessment, 7 days a 
week. Every effort should be made to get the subject to come to all their study visits. If a 
subject misses a visit, the study clinic visits still end for them on Visit Day 3 if their 
lesion has reached Stage 7 by then, or on the day their lesion reaches Stage 7, or Visit 
Day 14, whichever comes first.  
 
7.3.1 Clinical Lesion Assessment 
 
When possible, clinical lesion assessment of a subject should be performed by the same 
evaluator on each day. If the same lesion evaluator cannot perform all the lesion 
assessments for a given subject, the person taking over the lesion assessment of that 
subject should observe the lesion with the previous assessor to ensure they are in 
agreement with the stage. (The name(s) of any clinical staff member(s) involved in the 
evaluation of a given subject’s lesion stage for that day should be noted in the subject’s 
source documents.)  The Investigator, or trained designee, acting as the lesion evaluator, 
will mark, on the first clinic visit, the location of the treated lesion on a facial diagram 
included in the subject’s source records and will score the lesion on each subject at each 
visit. A trained designee should be a member of the clinical personnel who is a 
dermatologist/ physician or someone with a clinical background with the ability to 
evaluate the stages of a herpetic lesion.  
   
The herpes lesion treated by the subject will be considered part of the primary recurrence 
for evaluation.  Any other herpes lesions that appear within 10 mm of that first lesion, on 
the same calendar day, will also be considered part of the primary lesion complex.  All 
other lesions located at least 10 mm from the first lesion, or occurring within 10 mm of 
the first lesion on any other day after the day of the first lesion outbreak, will be defined 
as secondary lesions.  Only lesions within the primary lesion complex will be scored for 
lesion staging for efficacy analysis.  Secondary lesions will not be scored for lesion 
staging.  If the Investigator determines that secondary lesions are typical for a given 
subject, then the observation of such secondary lesions in that subject need not be 
captured in the CRF.  If, however, the Investigator concludes that secondary lesions are 
not usual for a given subject, then the observance of a secondary lesion in that subject 
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The lesion scores are defined as follows: 
 
0. Prodrome 
1. Erythema 
2. Papula/edema 
 
3. Vesicle/pustule 
 
4. Ulcer/soft crust 
5. Hard crust 
6. Residual swelling/dry flaking 
7. Normal skin 
 
Classical lesions are those lesions that pass through Stages 3, 4 or 5 at any lesion 
assessment.  Non-classical (aborted) lesions are lesions that never pass through Stages 3, 
4, or 5 prior to healing at Stage 7.   
 
A herpetic lesion typically progresses to higher level stages and therefore would not be 
expected to proceed from a higher number stage to a lower number stage.  The exception 
to this would be the case where a subject has a Stage 5, hard crust, lesion in which the 
scab is inadvertently knocked off, e.g. while washing.  In that instance, the lesion would 
“go backwards” from a Stage 5 lesion to a Stage 4. This expected progression of the 
herpetic lesion should be kept in mind as a guideline in the evaluation of the lesion stage.  
Any time, therefore, a lesion is observed to “go backwards,” a note should be made in the 
CRF as to why, if the reason can be determined, the lesion reversed its progression. 
 
The study clinic visits end for a subject when (1) the treated lesion is no longer present 
(Lesion Stage 7 for both classical and non-classical lesions) and there have been clinic 
assessments every day up until at least Visit Day 3, or (2) at Visit Day 14, whichever 
occurs earlier.  
 
7.3.2   Diary Review 
 
At each clinic visit, the investigator, or trained designee, will assess the subject’s cold 
sore lesion before reviewing entries in the diary.  In reviewing the diary, the investigator, 
or trained designee, will review the subject assessments for consistency and 
completeness.  Should any apparent errors or incomplete entries be found in the diary, the 
subject will be informed of these issues, and instructed as to how to properly complete 
the diary in the future; no retroactive changes, though, are to be made in the diary.  Any 
blanks that should have been completed prior to the clinic visit should be marked by the 
diary reviewer, so as to prevent later completion, and initialed and dated by the reviewer. 
 
 
 


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7.3.3 Lesion Size Assessment 
 
At each clinic visit, the Investigator, or trained designee, will use a disposable ruler, 
supplied by the sponsor, to measure the lesion size.  Two measurements will be taken: 1) 
the length of the longest dimension of the lesion; 2) the maximum length of the lesion 
dimension perpendicular to the axis of the first measurement taken. 
 
7.3.4 Pain Assessment 
 
At each clinic visit, the Investigator, or trained designee, will review the subject entries in 
the diary. In reviewing the diary, the Investigator, or trained designee, will inspect the 
subject entries for timing of dosing and pain assessments with regard to consistency and 
completeness. Should any apparent errors or incomplete entries be found in the diary, the 
subject will be informed of these issues, and instructed as to how to properly complete 
the diary in the future; no retroactive changes, though, are to be made in the diary.  Any 
blanks that should have been completed prior to the clinic visit should be marked by the 
diary reviewer, so as to prevent later completion, and initialed and dated by the reviewer. 
 
7.3.5 Safety Assessments 
 
The subjects will be questioned concerning their well-being at the time of each clinic 
visit. Questions will be posed in a non-specific manner so as not to bias the response. The 
subjects will also be instructed to inform the study physician and/or nurses of any adverse 
events that may occur at any time during the study.  On Visit Day 1 the subject should be 
asked about any adverse events occurring since treatment on Treatment Day, so as to 
capture any adverse events that took place since their treatment.  Subjects who 
discontinue prior to Visit Day 3 but have administered any treatment must be followed 
for safety, by telephone or clinic visits, as deemed appropriate by the Investigator, until at 
least Visit Day 3. 
 
7.3.5.1 Pregnancies 
 
Any subject who becomes pregnant during the course of treatment will be instructed to 
immediately stop all treatments and will be discontinued from the study.  Also, any 
subject who becomes pregnant in the two week period following their completion of the 
treatment phase of the study, or their discontinuation from the study (for reasons other 
than pregnancy), will be instructed to contact the clinic to report the pregnancy.  All 
treated study subjects who report a pregnancy during the course of the trial will be 
followed during the course of their pregnancy by the study doctor to determine the 
outcome of the pregnancy. 
 
7.3.6 Concomitant Medications 
 
The identity of all concomitant medications taken 30 days prior to enrollment into the 
study, 30 days prior to enrollment into the Treatment Phase of the study, and during the 
Treatment Phase of the study, as well as their total daily dose, duration of use, and 


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indication for use, will be reported on the case report form (CRF).  Any possible 
exclusionary medication must have a stop date prior to eligibility for treatment. 
 
7.3.7 Subject Return of Unused Test Material to the Clinic 
 
All subjects will be instructed to return their Treatment kit, with any unused test 
materials, to the clinical site on whichever is the first clinic visit following completion of 
all their treatments. The subjects should have disposed of the used swabs at home. 
 
At the conclusion of the study, those subjects who have been enrolled, but never entered 
the Treatment Phase of the study, will be contacted and asked to return their unused 
Treatment kit. Should a subject not return their clinical trial material when requested, at 
least one additional phone call should be made, and, if necessary, a certified letter should 
be sent to request return of those materials. If these efforts are unsuccessful the subject’s 
clinical trial materials will be considered missing. The return of both used study solution 
bottles and unused clinical trial materials is important with regard to drug accountability. 
 
Study subjects who have entered the Treatment Phase of the study and administered their 
lesion treatment, will be offered compensation for bringing in their used clinical study 
solution bottle after completion of all their study treatments. This incentive is important 
as the immediate return of the materials to the clinic will minimize loss or misuse.  Those 
subjects who forget to bring in their used clinical materials immediately after completion 
of all their study treatments will be offered a lower compensation to return the materials 
at a later date.  Those subjects who were enrolled into the trial but did not enter the study 
Treatment Phase will be offered compensation for the return of all unused clinical trial 
materials at the termination of the study.  
 
7.4 
Follow-Up Telephone Assessment 
 
Two weeks, or up to 3 weeks, if there are scheduling issues, after the subject has 
completed the Treatment Phase of the study (complete healing of the herpetic episode or 
Visit Day 14, whichever is earlier) the clinic will contact the subject by phone for a final 
safety evaluation.  Any new adverse events that have occurred since the subject’s last 
clinic visit should be collected at this time. 
 
 
 ADVERSE EVENTS 
 
All adverse events occurring during the Treatment Phase of this clinical trial will be 
recorded on the case report form provided. Adverse events occurring before the onset of 
treatment will be classified as non-treatment emergent adverse events and will not be 
captured on the CRF. Adverse events occurring after the application of study treatment 
will be assigned as treatment emergent adverse events and will be recorded on the CRF. 
The Investigator will review each event and assess its relationship to the treatment (not 
related, unlikely, possible, probable and highly probable). The following definitions will 
be used for rating relationship to treatment:  
 


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• Not related – The event is clearly related to other factors such as the subject’s clinical 
state, therapeutic interventions, or concomitant medications administered to the 
subject. 
• Unlikely – The event was most likely produced by other factors such as the subject’s 
clinical state, therapeutic interventions, or concomitant medications administered to 
the subject; and does not follow a known response pattern to the investigational 
product. 
• Possible – The event follows a reasonable temporal sequence from the time of 
investigational product administration; and/or follows a known response pattern to 
the study treatment; but could have been produced by other factors such as the 
subject’s clinical state, therapeutic interventions, or concomitant medications 
administered to the subject. 
• Probable – The event follows a reasonable temporal sequence from the time of 
investigational product administration; and follows a known response pattern to the 
investigational product; and cannot be reasonably explained by other factors such as 
the subject’s clinical state, therapeutic interventions, or concomitant medications 
administered to the subject. 
• Highly Probable – The event follows a reasonable temporal sequence from the time 
of investigational product administration; and follows a known response pattern to 
the investigational product; and cannot be reasonably explained by other factors such 
as the subject’s clinical state, therapeutic interventions, or concomitant medications 
administered to the subject; and either occurs immediately following investigational 
product administration, or improves on stopping the investigational product, or 
reappears on repeat exposure, or there is a positive reaction at the application site. 
 
Each adverse event reported will be graded on a 3-point severity scale (mild, moderate, or 
severe) and the date and time of onset, time relationship to treatment, duration, and 
outcome of each event will be noted on the case report form. 
 
The following definitions for rating severity will be used: 
 
• Mild – easily tolerated, causing minimal discomfort and not interfering with normal 
everyday activities. 
• Moderate – sufficiently discomforting to interfere with normal everyday activities. 
• Severe – incapacitating and/or prevents normal everyday activities. 
 
If any of the above adverse events are serious, as defined by the FDA Code of Federal 
Regulations (CFR), Title 21, special procedures will be followed. All serious adverse 
events will be reported within 24 hours by fax or e-mail to the Drug Safety Group at 
(866) 857-8839, whether or not the serious events are deemed treatment-related. The 


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Drug Safety Group will notify Topical Remedy’s Vice President of Clinical Research of 
the serious adverse event.  All serious event reporting will adhere to 21 CFR 312.32 for 
IND drugs. The central IRB and other study sites will be notified by Topical Remedy, 
LLC of the Alert Reports per FDA regulations.  Sites using their own institutional IRB 
will be instructed by Topical Remedy, LLC to notify their institutional IRB of the Alert 
Report. 
 
The following is the definition for serious adverse events per FDA regulations: 
 
A Serious Adverse Event is any adverse drug experience occurring at any dose that 
results in any of the following outcomes:  death, a life-threatening adverse drug 
experience, in-patient hospitalization or prolongation of hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect. Important medical 
events that may or may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate 
medical judgment, they may jeopardize the subject or subject may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 
If a serious adverse event occurs to a subject on this study, the Investigator will complete 
the SAE form provided and fax it, along with the front cover sheet provided, to the Drug 
Safety Group at (866) 857-8839.  The Medical Monitor will be responsible for ensuring 
completeness of the SAE form and for reviewing the SAE versus source documentation 
and the CRF.   
 
Once the SAE form is complete, the Medical Monitor will forward it, by email, to the 
Vice President of Clinical Research at Topical Remedy (email: emorrel@benubio.com; 
fax: 508-651-3703) for review.  The Vice President of Clinical Research will send any 
comments to Drug Safety.  Drug Safety will track the SAE information and forward a 
desk copy of the complete SAE report to Topical Remedy, LLC.  
  
Adverse events, whether serious or non-serious, will be followed to resolution or until the 
condition stabilizes, is otherwise explained, or the subject is lost to follow-up, up to a 
maximum of 30 days following the subject’s last clinic visit. Adverse events, whether 
serious or non-serious, will be captured up to 2 weeks following the last clinic visit, and 
followed up to a maximum of 30 days following the subject’s last clinic visit. Where 
appropriate, medical tests and examinations will be performed to document resolution of 
event(s). Outcome may be classified as resolved, improved, unchanged, worse, fatal, or 
unknown (lost to follow-up). Following the resolution of any study associated adverse 
events or after the completion of the Treatment Phase of the study, there will be no 
further adverse event reports for that subject. 
 
While pregnancy itself is not considered to be an AE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or 
SAE (as appropriate).  A spontaneous abortion is always considered to be a SAE. 
 
 


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 REMOVAL OF SUBJECTS FROM STUDY 
 
Subjects will be advised that they are free to withdraw from the study at any time without 
consequence. The Investigator may remove a subject if he/she feels this action is in the 
best interest of the subject. When a subject withdraws from the study after treatment, all 
of the necessary safety and tolerability assessments should be obtained if possible. 
Subjects experiencing adverse events should be followed until the event has resolved or 
until the condition stabilizes, is otherwise explained, or the subject is lost to follow-up, up 
to a maximum of 30 days following the subject’s last study visit. Appropriate supportive 
and/or definitive therapy will be administered as required. As with other subjects in this 
study, compensation will be offered for return of a used or unused study kit. 
 
Subjects withdrawn from this study cannot re-enter or be used as replacements for other 
subjects in this study. 
 
 
 STATISTICAL METHODS 
 
10.1 
Introduction 
 
This trial will be conducted to test the superiority of the Merlin solution to placebo 
solution in the treatment of recurrent herpes labialis at first visible signs and/or symptoms 
of a herpetic lesion.  The primary efficacy endpoint for the study will be the clinician 
assessed duration of the classical herpetic lesion. The duration of a classical lesion is 
defined as the time, in hours, from the beginning of treatment to the onset of Stage 6, or, 
if Stage 6 is never observed, Stage 7. A classical lesion is defined as one that progresses 
through any of the vesicle/pustule, ulcer, or crust stages (stages 3, 4 or 5). Duration of the 
classical herpetic lesion will be analyzed using the Hodges-Lehmann method as the 
primary efficacy analysis method for estimating the median difference between the two 
arms. Duration of the herpetic episode, duration of complete healing of the herpetic 
episode, duration of the herpetic lesion, duration of the herpetic lesion hard scab, and 
duration of pain will be analyzed in the same manner as the duration of the classical 
lesion.  
 
 
10.2 
Study Endpoints 
 
10.2.1 Efficacy Endpoints 
 
Primary: 
• Clinician assessed duration of the classical herpetic lesions 
 
Secondary: 
 
• Clinician assessed duration until of the herpetic episode 
• Clinician assessed duration of until complete healing of the herpetic episode  
• Clinician assessed prevention of progression to a classical lesion 


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• Maximum clinician assessed lesion size 
• Clinician assessed duration of the herpetic lesion hard scab 
• Clinician assessed duration and severity of lesion associated pain 
 
 
 
Other Endpoints: 
 
• Subject assessed duration and severity of lesion pain 
• Subject assessed duration of the classical herpetic lesion 
• Subject assessed duration of the herpetic episode 
• Subject assessed duration of complete healing of the herpetic episode 
• Subject assessed prevention of progression to a classical lesion 
• Subject assessed duration of the herpetic lesion hard scab 
 
 
10.2.2 Safety Endpoints 
 
• Adverse events (AEs) 
 
10.3 
Study Populations 
 
10.3.1 Safety Population 
 
All subjects who have been entered into the Treatment Phase of the study and self-
administered any treatment will be included in the safety population. A subject will be 
included in a treatment group for analysis based upon the treatment actually 
administered, rather than the group to which he or she has been assigned. For example, a 
subject who is randomized to receive placebo treatments but inadvertently receives active 
treatment will be included in the group receiving active treatment.  
 
Should a subject gain access to their clinical trial materials and treat themselves without 
having called in to the clinic and been given permission to open their Treatment kit, that 
subject will also be included in the safety population if follow-up safety data are 
available. 
 
10.3.2 Efficacy:  Modified Intent-to-Treat (MITT) Population 
 
All subjects who have been entered into the Treatment Phase of the study will be 
included in the MITT population. It is considered a “modified” intent to treat population 
in that it does not include all randomized subjects but includes only those randomized 
subjects who access their treatment, i.e., are told to open their kit. The MITT population 
will be used as the primary analysis population. A subject will be included in a treatment 
group for analysis based upon the treatment to which he or she has been assigned.  


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10.3.3 Efficacy Evaluable (EE) Population 
 
All subjects who have been entered into the Treatment Phase of the study were reported 
to have successfully completed treatment, and have been followed successfully until their 
lesion heals, or until 14 days, whichever is earlier, will be included in the efficacy 
evaluable population. Prior to breaking the study blind, study data will be reviewed to 
determine which subjects need to be excluded from the efficacy evaluable population. A 
subject will be included in a treatment group for analysis based upon the treatment 
actually administered, rather than the group to which he or she has been assigned.  For 
example, a subject who is randomized to receive a placebo treatment but inadvertently 
receives an active treatment will be included in the group receiving an active treatment, 
and vice versa. Only actual observations will be included in the analyses; no imputation 
for missing data will be performed.  
 
10.4 
General Methodology 
 
All statistical tests will be done using two-sided tests and a Type I error rate of 0.05.  
 
Data listings will be based on all subjects in the safety population.  
 
Continuous variables will be summarized using descriptive statistics, specifically the 
mean, median, standard deviation, minimum and maximum values. Categorical variables 
will be summarized by frequencies and percentages.  
 
The primary analyses will compare the active treatment arm to the placebo control arm. 
Aside from any placebo effect, there should be no efficacy associated with the placebo 
solution.  As a secondary analysis, all statistical comparisons will be performed with the 
treated subjects stratified based on whether they treated at erythema (Stage 1) or 
papule/edema (Stage 2). 
 
10.5 
Baseline Demographics 
 
Baseline demographic information will be summarized for the safety population. For 
continuous variables, summary statistics (mean, median, standard deviation, minimum, 
and maximum) will be provided. For categorical variables, the frequency and percent in 
each category will be presented.  
 
10.6 
Safety and Tolerability Analysis 
 
The safety analysis will be performed on the safety population. Assessment of safety and 
tolerability will be based on adverse events. Each AE will be graded with respect to its 
relationship to treatment using five categories:  not related, unlikely, possible, probable, 
and highly probable. Each AE will also be graded on a three-point severity scale:  mild, 
moderate, and severe. Adverse events will be coded by body system and preferred term 
using the MedDRA (Medical Dictionary for Regulatory Activities) dictionary.  
 


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The number and percentage of subjects experiencing adverse events will be tabulated for 
each treatment group by body system and preferred term. The number and percentage of 
subjects experiencing AEs will also be tabulated by relationship to drug treatment and by 
severity. If an AE is reported more than once for a subject, only the most related event 
will be counted in the analysis by relationship to drug treatment. For the analysis by 
severity, if an AE is reported more than once for a subject, only the most severe event 
will be counted in the analysis.  
 
10.7 
Efficacy Analysis 
 
The efficacy analysis will be performed on both the MITT and the efficacy evaluable 
populations.  For all duration endpoints the following matrix will be used for analyses: 
 
Population Analysis 
Description 
Methods 
MITT 
Main 
Analysis 
Impute duration for subjects 
who drop out prior to healing 
with a duration of 336 hours (14 
days x 24 hours). 
Hodges-Lehmann 
estimation methods; 
Wilcoxon rank sum test to 
compare arms 
 
Sensitivity 
Analysis 
Subjects who drop out prior to 
healing will be considered 
censored. 
Kaplan-Meier estimation 
methods; Log-rank test to 
compare arms 
EE 
Main 
Analysis 
No imputation required since 
these are complete cases. 
Hodges-Lehmann 
estimation methods; 
Wilcoxon rank sum test to 
compare arms 
For all endpoints on the occurrence of prevention of progression, counts and percentages 
will be summarized, and chi-square tests, or Fisher’s exact test will be used to compare 
arms, as appropriate.  Fisher’s exact tests will be used if any of the expected cell counts 
in the RxC crosstabulations are less than 5. 
 
For size endpoints, means, medians, standard deviations and ranges will be summarized. 
T-tests will be used to compare arms if the sizes are approximately normally distributed, 
or Wilcoxon rank sum tests will be used if the sizes are markedly non-normally 
distributed. 
 
For the severity endpoints, counts and percentages will be summarized, and Cochran- 
Mantel-Haenszel tests will be used to compare the arms. 
 
In order to assess whether there are differences among centers in treatment effects, a Cox 
proportional hazards model analysis of the duration of herpetic episode will also be 
performed for the primary duration endpoint and for both the MITT and EE populations.  
The model will include terms for treatment, center, and treatment by center interaction. A 
test will be performed to test for the significance of the interaction. This test will be 
conducted at the 0.10 level of significance. If the interaction is found to be significant, 
estimates of treatment effect will be provided by center, as well as overall. 
 


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10.7.1 Duration of Classical Lesions (clinician and patient assessed) 
 
A classical herpetic lesion is defined as one that passes through any of Stages 3, 4 or 5 
(vesicle/pustule, ulcer/soft crust, or hard crust). Therefore, all aborted lesions will be 
excluded from this analysis. The duration of a classical lesion is defined as the time, in 
hours, from the beginning of treatment to the onset of Stage 6, or, if Stage 6 is never 
observed, Stage 7.  
 
  
 
10.7.2 Duration of Herpetic Episode (clinician and patient assessed) 
 
Duration of herpetic episode is measured by assessment of treated lesion stage daily up 
until Stage 6 for classical lesions or Stage 7 for non-classical lesions for a maximum of 
14 days, with a minimum of 3 consecutive days of assessment. For a classical lesion, the 
duration of the herpetic episode is defined as the time, in hours, from the beginning of 
treatment until the loss of hard crust (Stage 6, residual erythema can be present after loss 
of hard crust). A classical lesion is defined as one that progresses through any of the 
vesicle/pustule, ulcer/soft crust, or hard crust stages (stages 3, 4 or 5). For non-classical 
lesions, duration of herpetic episode is defined as the time from the beginning of 
treatment until complete resolution of all local signs and symptoms (Stage 7).  
 
  
 
10.7.3 Duration until Complete Healing of the Herpetic Episode (clinician and 
patient assessed) 
 
Duration until complete healing of the herpetic episode is defined as the time, in hours, 
from the beginning of treatment to the onset of Stage 7, for both classical and non-
classical lesions.  All subjects will visit the clinic daily, for a minimum of 3 days and a 
maximum of 14 days, until the lesion reaches Stage 7 with no signs or symptoms of a 
herpetic lesion.  
 
 
 
10.7.4 Prevention of Progression to Classical Lesions (clinician and patient 
assessed) 
 
A classical herpetic lesion is defined as one that passes through any of Stages 3, 4 or 5 
(vesicle/pustule, ulcer/soft crust, or hard crust). Prevention of progression to classical 
lesions will be analyzed by comparing the proportions of subjects in each treatment group 
who do not display classical lesions. (These are considered aborted lesions.)   
 
10.7.5 Clinician Assessed Lesion Size 
 
For each subject, the subject’s maximum lesion area (length x width) for ulcerative 
lesions during the vesicular, ulcerative, and hard crust stages will be determined.  In 


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addition,  the cumulative lesion area, for which ulcerative lesion areas, day by day, will 
be added. Last, the cumulative lesion area “all lesions” will be determined; for this 
parameter, all patients will be included (i.e. both ulcerative and non-ulcerative 
recurrences).  
 
10.7.6 Duration of the Herpetic Lesion Hard Scab (clinician and patient assessed) 
 
Duration of the hard scab will be defined as the assessed duration of the hard crust, stage 
5, for all subjects experiencing known classical lesions.  This duration will represent the 
onset of stage 5 until the time of classical lesion healing at stage 6 or 7, whichever occurs 
earlier.  Only known classical lesions will be included in this analysis.  For lesions that 
bypass stage 5, duration of hard scab phase will be calculated as time between the two 
adjacent assessments either side of stage 5. 
 
10.7.7 Duration of Pain (subject assessed) 
 
Duration of pain will be evaluated based on the subject’s diary, where the subject will 
record, just prior to each treatment and three times daily once treatment is complete, the 
level of pain caused by the defined lesion. The rating scale for pain assessment has four 
levels:  none (1), mild (2), moderate (3), and severe (4). For each subject, duration of pain 
will be measured in hours from the time of the first occurrence of a pain level of mild, 
moderate, or severe until a consistent score of a pain level of none has been achieved 
over at least 2 consecutive pain assessments, or until the lesion is completely healed, 
whichever occurs first .  
 
Subjects who do not reach the no-pain level within 14 days will be considered censored 
immediately following their last pain assessment. Subjects who never reach a pain level 
of mild, moderate, or severe will be assigned a duration of pain value of 0 hours. 
 
10.7.8 Severity of Lesion Pain  
 
The maximum severity (over time) of lesion pain will be summarized. 
 
10.7.9  Sample Size Determination 
 
The sample size for this study was based upon the results of the previous Phase 2 study, 
TR-H-211. In that study, Merlin demonstrated a statistically significant (p=0.0276) effect 
on the duration of classical lesion endpoint for subjects beginning treatment at Stage 1 
(erythema) with only 32 subjects treated with Merlin and 22 placebo subjects. Clinical 
investigations with Famvir and other independent studies, that initiate treatment within 
hours of the onset of prodromal symptoms (Stage 0) have demonstrated that 1/3 of all 
subjects enrolled in herpes labialis studies will have spontaneously aborted lesion. Any 
calculation of clinical trial size, therefore, must consider that factor.  When, however, 
treatment is initiated at the erythema stage (Stage 1), as in the Merlin Phase 2a (TR-H-
211) study, the incidence of spontaneously aborted lesions declines to 25%. As a result, a 
larger percentage of subjects will demonstrate classical lesions in Merlin studies than was 
seen in the Famvir, or similar previous studies. This was factored in when performing 


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power calculations for this Phase 2b clinical study. Those calculations determined that 
144 subjects would provide a 95% likelihood of statistical significance for the herpetic 
episode endpoint. Merlin decreased the duration of herpetic episode in subjects that 
began treatment at stage 1 by 41 hours, with a p-value of 0.055 in the Phase 2a study. The 
herpetic episode endpoint includes the subjects with aborted lesions. 
 
As a result, a 150 subject clinical trial will have approximately 60 subjects progress to 
classical lesions in each treatment arm and we can be highly confident of having the 
power to demonstrate a highly significant difference for the duration of classical lesion 
endpoint, as shown in the Phase 2a results. In addition, a 150 subject clinical trial should 
have greater  than 95% likelihood of demonstrating a statistically significant Merlin 
effect on herpetic episode as a secondary endpoint. 
  
 
 
 ADMINISTRATIVE REQUIREMENTS 
 
11.1 
Good Clinical Practice 
 
The study will be conducted in accordance with the International Conference on 
Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master Files should be 
established at the beginning of the study, maintained for the duration of the trial and 
retained according to the appropriate regulations. 
 
 
11.2 
Ethical Considerations 
 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) will review all appropriate study documentation in order to safeguard 
the rights, safety and well-being of the subjects. The study will only be conducted when 
IRB/IEC approval has been obtained. The protocol, Investigator Brochure, informed 
consent, recruitment advertisements (if applicable), written information given to the 
subjects, safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the Investigator. 
 
11.3 
Subject Information and Informed Consent 
 
After the study has been fully explained, written informed consent will be obtained from 
either the subject or his/her guardian or legal representative prior to study participation. 
The method of obtaining and documenting the informed consent and the contents of the 
consent will comply with GCPs and all applicable regulatory requirement(s). 
 


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11.4 
Subject Confidentiality 
 
In order to maintain subject privacy, all CRFs, study clinical trial material accountability 
records, study reports and communications will identify the subject only by initials and 
the assigned study-specific Randomization Number. The Investigator will grant 
monitor(s) and auditor(s) from Topical Remedy, LLC, or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data 
gathered on the CRFs and to audit the data collection process. The Sponsor, or designee 
of the Sponsor, also may observe the study in progress. The subject’s confidentiality, per 
HIPAA regulations, will be maintained except as required by the applicable laws and 
regulations. 
 
11.5 
Protocol Compliance 
 
The Investigator will conduct the trial in compliance with the protocol provided by 
Topical Remedy, LLC, and given approval/favorable opinion by the IRB/IEC and the 
appropriate regulatory authority(ies). Modifications to the protocol should not be made 
without written agreement of both the Investigator and Topical Remedy, LLC. Changes 
to the protocol will require written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory authority(ies) 
permit, expedited review and approval/favorable opinion for minor change(s) in ongoing 
trials that have the approval/favorable opinion of the IRB/IEC. Topical Remedy, LLC 
will submit all protocol modifications to the regulatory authority(ies) in accordance with 
the governing regulations. 
 
When immediate deviation from the protocol is required to eliminate an immediate 
hazard(s) to subjects, the Investigator will contact Topical Remedy, LLC, if 
circumstances permit, to discuss the planned course of action. Any departures from the 
protocol must be approved by Topical Remedy, LLC and fully documented in the CRF 
and source documentation. 
 
11.6 
Study Monitoring 
 
Monitoring and auditing procedures developed by Topical Remedy, LLC, or its designee, 
will be followed, in order to comply with GCP guidelines. On-site checking of the CRFs 
for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed. 
 
The study will be monitored by Topical Remedy, LLC, or its designee. Monitoring will 
be done by personal visits from a representative of the sponsor (site monitor) who will 
review the CRFs and source documents. The site monitor will verify that the 
investigation is conducted according to protocol design and regulatory requirements and 
will document their findings in frequent communications (email, letter, telephone, and 
fax). 
 


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All unused study materials that have not already been returned during the course of the 
clinical study, as per instructions from Topical Remedy, LLC, are to be returned to 
Topical Remedy, LLC, or their designee, after the clinical phase of the trial has been 
completed. 
 
11.7 
On-site Audits 
 
Regulatory authorities, the IEC/IRB, and/or Topical Remedy, LLC.’s Vice President of  
Clinical Research, or designee may request access to all source documents, CRFs, and 
other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the Investigator, who must provide support for these 
activities. 
 
11.8 
Case Report Form Completion and Data Management 
 
Topical Remedy, LLC, or its designee, will provide the study sites with a CRF for each 
subject. A subject screening log will be used to document any reason for screen failure.  
For each subject who has given informed consent, meets the study enrollment eligibility 
criteria, and is randomized into the trial, a CRF will be completed.  The Principal 
Investigator will certify that the subjects were seen and evaluated by qualified site staff 
and that he/she has delegated responsibilities for subject evaluation as identified in the 
Study Site Roles and Responsibilities Log maintained in the study master file.   
As appropriate, all source documents or CRF pages should be filled out during (or 
immediately after) a subject assessment.  The text should be written with a black or blue 
ballpoint pen and must be legible. If a source document or CRF entry needs correction, 
the error should be crossed out with a single line (not obliterated or covered with 
correction fluid) and the correct information should be written next to the original entry. 
The change must be initialed and dated by the Investigator or designee. 
The study monitor at the study site will review source documents, CRFs and any queries 
will be highlighted to the Investigator or designee enabling the errors to be addressed 
prior to collection of the CRF pages.  Errors detected by subsequent in-house CRF review 
may necessitate clarification or correction. 
 
Documentation of all data management activities should allow step-by-step retrospective 
assessment of data quality and study performance.  This includes maintenance of 
documentation to support any changes or corrections applied to the CRFs. 
 
Data collected on the CRFs will be entered into Topical Remedy, LLC designee’s 
database by a dual entry system.  The database will be checked for internal consistency, 
and the critical data will be compared with the original CRFs. 
 
Queries arising during data processing/consistency checking will either be provided to 
the site for clarification and approval by the Investigator, or handled by the designee’s 
Data Managers. 


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11.9 
Clinical Trial Material Accountability 
 
Accountability for the clinical trial materials at the trial site is the responsibility of the 
Investigator. The Investigator will ensure that the clinical trial materials are used only in 
accordance with this protocol. Where allowed, the Investigator may choose to assign 
some of the clinical trial material accountability responsibilities to a pharmacist or other 
appropriate individual. Clinical trial material accountability records indicating the clinical 
trial material delivery date to the site, inventory at the site, use by each subject, return of 
used or unused clinical trial material by the subject to the site, and return to Topical 
Remedy, LLC (or disposal of the drug, if approved by Topical Remedy, LLC) will be 
maintained by the clinical site. These records will adequately document that the subjects 
were provided the clinical trial materials as specified in the protocol and should reconcile 
all study clinical trial materials received from Topical Remedy, LLC. Accountability 
records will include dates, quantities, and Randomization Numbers. The sponsor or its 
designee will review clinical trial material accountability at the site on an ongoing basis 
during monitoring visits.  Accountability records must be current and up to date. 
 
All unused and used study clinical trial materials will be retained at the site until they are 
inventoried by the monitor. All unused study drug will be returned to Topical Remedy, 
LLC, or if authorized, disposed of at the study site and documented.  
 
11.10 Premature Closure of the Study 
 
This study may be prematurely terminated, if in the opinion of the FDA or Topical 
Remedy, LLC, there is sufficient reasonable cause. Written notification documenting the 
reason for study termination will be provided to the Investigator by Topical Remedy, 
LLC.  
 
Circumstances that may warrant termination include, but are not limited to: 
 
• Determination of unexpected, significant, or unacceptable risk to subjects 
• Failure to enter subjects at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of Merlin 
 
Should the study be closed prematurely, all study materials (completed, partially 
completed, and blank CRFs, study clinical trial materials, etc.) must be returned to 
Topical Remedy, LLC. 
 
11.11 Record Retention 
 
The Investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least two years after the last 
marketing application approval or two years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 


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requirement(s). The Sponsor will notify the Investigator when these time periods have 
elapsed. If the Investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility. 
Topical Remedy, LLC must be notified in writing if a custodial change occurs. 
 
11.12 Liability and Insurance 
 
Topical Remedy, LLC has subscribed to an insurance policy covering, in its terms and 
provisions, its legal liability for injuries caused to participating persons and arising out of 
this research performed strictly in accordance with the scientific protocol as well as with 
applicable law and professional standards. 
 
 
 USE OF INFORMATION 
 
All information regarding the Merlin solution supplied by Topical Remedy, LLC to the 
Investigator is privileged and confidential information. The Investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent 
from Topical Remedy, LLC. Any manuscript, abstract, or other publication or 
presentation of results or information arising in connection with the study must be 
prepared in conjunction with Topical Remedy, LLC.  It is understood that there is an 
obligation to provide Topical Remedy, LLC with complete data obtained during the 
study. The information obtained from the clinical trial will be used towards the 
development of the Merlin solution and may be disclosed to regulatory authority(ies), 
other Investigators, corporate partners, or consultants as required. 
 REFERENCES 
 
1. Spruance SL, Kriesel JD. Treatment of herpes simplex labialis. Herpes 2002; 
9:64-69. 
 
2. Spruance SL, Wenerstrom G. Pathogenesis of herpes simplex labialis. IV. 
Maturation of lesions within 8 hours after onset and implications for antiviral 
treatment. Oral Surg Oral Med Oral Path 1984; 58:667-71. 
 
3. Spruance SL, Crumpacker CS, Schnipper LE, et al. Early, patient initiated 
treatment of herpes labialis with topical 10% acyclovir. Antimicrob Agents 
Chemother. 1984;25:553–555. 
 
4. Raborn GW and Grace M. Recurrent Herpes Labialis: Selected Therapeutic 
Options. J Can Dent Assoc. 2003;5569(8): 498-503. 
 
5. Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T. Acyclovir 
cream for treatment of herpes simplex labialis: results of two randomized, double-
blind, vehicle-controlled, multicenter clinical trials. Antimicrob Agents 
Chemother. 2002;46:2238–2243. 
 


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6. Raborn GW, Martel AY, Lassonde M, Lewis MA, Boon R, Spruance SL. 
Effective treatment of herpes simplex labialis with penciclovir cream: combined 
results of two trials. J Am Dent Assoc. 2002;133:303–309. 
 
7. Sailer CA, Spruance SL, and Hull CM. Acyclovir and hydrocortisone cream for 
the early treatment of recurrent cold sores. Virus Adaption and Treatment 2001; 
3:1-6. 
 
 
 
 


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14. 
INVESTIGATOR AGREEMENT 
 
I have read Protocol TR-H-212: A Multicenter, Placebo Controlled, Randomized, Double 
Blind Study of the Safety and Efficacy of Merlin (ethanol and glycolic acid mixture) for 
the Episodic Treatment of Recurrent Herpes Labialis 
 
 
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for 
Good Clinical Practice and applicable regulatory requirements and to inform all who 
assist me in the conduct of this study of their responsibilities and obligations. 
 
 
Principal Investigator printed name 
 
 
 
Principal Investigator signature 
Date 
 
 
Investigational site or name of institution and location (printed) 
 

SAP_001.pdf: 
Topical Remedy, LLC 
Protocol:  TR-H-212 
  
Statistical Analysis Plan   
Page 1 of 21 
 
 
 
 
 
 
 
 
 
Topical Remedy, LLC 
PROTOCOL TR-H-212 
 
 
 
A Multicenter, Placebo-Controlled, Randomized, Double-Blind Study of the 
Safety and Efficacy of Merlin (ethanol and glycolic acid mixture) for the 
Episodic Treatment of Recurrent Herpes Labialis 
 
 
STATISTICAL ANALYSIS PLAN 
Version 1.0 
August 23, 2017 
 
 
 
CONFIDENTIAL 


 
Topical Remedy, LLC 
Protocol: TR-H-212 
  
Statistical Analysis Plan   
 
 
 
 
 
 
 
SIGNATURE PAGE 
 
Prepared by: 
£ 
 
- 
8/23/17 
 
 
 
Michelle Secic, MS 
Secic Statistical Consulting, Jnc. 
Date 
 
 
Approved by: 
 
 
 
Anthony West 
Accelovance, lnc. 
Date 
 
 
 
Eric Morre! / 
Topical Remed ·, LLC 
I 
' 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 21 
 
 
 
 
 
 
 


Topical Remedy, LLC 
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Statistical Analysis Plan   
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Version 
Date 
Description/Changes 
1.0 
Aug 23, 2017 
Initial Draft 


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Statistical Analysis Plan   
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AE 
adverse event 
EE 
efficacy evaluable 
MedDRA 
MITT 
Medical Dictionary for Regulatory Activities 
modified intent-to-treat 
NASID 
non-steroidal anti-inflammatory drug 
PT 
SOC 
TEAE 
preferred term 
system organ class 
treatment emergent adverse event 


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Section 
TABLE OF CONTENTS 
 
Page 
1 
Introduction 
7 
2 
Trial Design 
7 
2.1 
Study Objectives 
7 
2.2 
Study Design 
8 
3 
Sample Size 
9 
4 
Inclusion/Exclusion Criteria 
9 
4.1 
Inclusion Criteria 
9 
4.2 
Exclusion Criteria 
10 
4.3 
Restrictions During the Treatment Phase 
11 
5 
Summary of Events 
12 
6 
Study Endpoints 
13 
6.1 
Efficacy Endpoints 
13 
6.1.1 
Primary Efficacy Endpoint 
13 
6.1.2 
Secondary Efficacy Endpoints 
13 
6.1.3 
Other Efficacy Endpoints 
13 
6.1.4 
Efficacy Endpoint Definitions 
13 
6.2 
Safety Endpoints 
15 
7 
Data Analysis and Statistical Considerations 
15 
7.1 
Analysis Populations 
15 
7.1.1 
Safety Population 
15 
7.1.2 
Modified Intent-to-Treat (MITT) Population 
15 
7.1.3 
Efficacy Evaluable (EE) Population 
15 
7.2 
General Analysis 
16 
7.3 
Disposition 
16 
7.4 
Demographics 
16 
7.5 
Medical History 
16 
7.6 
Prior and Concomitant Medication 
16 
7.7 
Physical Examinations 
16 
7.8 
Vital Signs 
16 
7.9 
Pregnancy 
17 
7.10 
Compliance 
17 
7.11 
Diaries 
17 
7.12 
Safety Data 
17 
7.13 
Efficacy Analyses 
17 
7.13.1 
Duration 
18 
7.13.2 
Prevention of Progression 
18 
7.13.3 
Area 
18 
7.13.4 
Pain Severity 
18 
7.13.5 
Analysis Matrix 
19 
7.13.6 
Pooling of Centers 
19 
8 
Handling of Missing Data 
19 


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9 
Changes from the Protocol 
20 
10 
Tables 
21 


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1 
Introduction 
Topical Remedy, LLC is developing Merlin, a novel topical formulation that can be used to 
treat viral infections of the skin.  It is composed of two commonly used compounds, glycolic 
acid (0.6%) and ethanol (10%), each with known safety and side effect profiles.  This product, 
intended for over-the-counter distribution, will consist of single treatment foam applicators 
pre-filled with the Merlin solution. 
 
2 
Trial Design 
2.1 
Study Objectives 
The primary objective of this study is to assess the efficacy of Merlin solution on the clinician 
assessed duration of the classical herpetic lesion as compared to placebo treatment. Duration is 
based on staging of the lesion. Staging is graded as follows: 0=prodromal, 1=erythema, 
2=papula/edema, 3=vesicle/pustule, 4=ulcer/soft crust, 5=hard crust, 6=residual swelling/dry 
flaking, 7=normal skin. The duration of a classical lesion is defined as the time, in hours, from 
the beginning of treatment to the onset of Stage 6, or, if Stage 6 is never observed, Stage 7. A 
classical lesion is defined as one that progresses through any of stages 3, 4 or 5. 
 
The secondary objectives of this study are to compare the active and placebo treatment groups 
with regard to: 
• clinician assessed 
• duration of the herpetic episode (classical and non-classical) 
• duration until complete healing of the herpetic episode (classical and non-classical) 
• prevention of progression to a classical lesion 
• maximum lesion area of the classical lesions 
• cumulative lesion area of the classical lesions 
• cumulative lesion area of all lesions 
• duration of classical herpetic lesion hard scab 
• safety 
 
Based on patient diary entries, other objectives of this study are to compare the active and 
placebo treatment groups with regard to: 
• subject assessed: 
• duration of the classical herpetic lesion 
• duration of the herpetic episode (classical and non-classical) 
• duration of complete healing of the herpetic episode (classical and non-classical) 
• prevention of progression to a classical lesion 
• duration of classical herpetic lesion hard scab 
• severity of lesion pain 
• duration of lesion pain 


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2.2 
Study Design 
This current clinical study is a Phase 2 trial using the same Merlin formulation as was used in 
the Phase 1 TR-H-111 and Phase 2 TR-H-211 trials.  This trial will have two treatment groups 
comparing the safety and efficacy of Merlin solution to that of a placebo (10% ethanol) with 
treatment at first visible signs of a herpetic episode. 
 
The present trial is designed to examine the efficacy and safety of treatment with Merlin as 
compared to treatment with placebo (10% ethanol) in subjects treating at first visible  signs of 
a herpes labialis lesion (i.e. erythema [Stage 1] or papule/edema [Stage 2]). 
 
Approximately four hundred and fifty (450) subjects will be enrolled into the study, with a 
goal of approximately one hundred and fifty (150) of these subjects who will actually enter the 
Treatment Phase of the study. Eligible subjects will be randomized  in a 1:1 ratio to one of 
two treatment groups: 
1) treatment of three (3) applications of Merlin solution or 
2) treatment of three (3) applications of 10% ethanol, as a placebo, 
performed within a time period of 40  minutes or less, while allowing time for the solution to 
dry on the lesion between  applications. 
 
A total of twelve (12) Merlin or placebo treatments, i.e. thirty-six (36) applications, will be 
administered over the ensuing ninety-six (96) hours (four (4) days) after the first treatment.  On 
each day, treatments will be administered six (6) hours apart, with a maximum of three 
treatments each day. The first treatment will be administered on Treatment Day (Day 0), and 
then repeated at 6 and 12 hours after the first treatment, time permitting. 
 
After being enrolled and randomized into the study, subjects will be sent home with a sealed 
kit for either Merlin (active) or 10% ethanol (placebo). At first signs and/or symptoms of a 
recurrent herpetic episode (Stage 0, prodrome Stage 1, erythema, or Stage 2, papule/edema), 
subjects will call the clinic to confirm by telephone interview, the presence of a lesion and the 
lesion stage. Subjects reporting either a Stage 1 or Stage 2 lesion will be interviewed to review 
the eligibility criteria. If they meet all the eligibility criteria they will then be instructed to 
begin treatment immediately, thereby initiating the Treatment Phase of the study.  Subjects will 
then be instructed to return to the clinic as soon as possible within 24 hours of starting 
treatment. Subjects reporting only Stage 0 symptoms, i.e. no visible signs of a cold sore lesion, 
will be instructed to monitor their lesion and to call the clinic immediately upon observing any 
early visible sign of a cold sore, i.e. a Stage 1 or Stage 2 lesion. 
 
Subjects will report daily for a minimum of 3 consecutive days, with the last clinic visit at the 
time of complete healing (Stage 7 - normal skin) or at 14 days, whichever is earlier. Subjects 
will be contacted by phone, for a safety assessment, 2 weeks after they complete the Treatment 
Phase of the study. Subjects will also be provided a diary that he or she will be instructed to fill 
out daily from the first day of treatment until their final clinic visit. 


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Both treatment groups will continue to accept subjects into the Treatment Phase of the study 
until there are at least seventy five (75) subjects in each group. 
 
3 
Sample Size 
The sample size for this study was based upon the results of the previous Phase 2 study, TR-H- 
211. In that study, Merlin demonstrated a statistically significant (p=0.0276) effect on the 
duration of classical lesion endpoint for subjects beginning treatment at Stage 1 (erythema) 
with only 32 subjects treated with Merlin and 22 placebo subjects. Clinical investigations with 
Famvir and other independent studies, that initiate treatment within hours of the onset of 
prodromal symptoms (Stage 0) have demonstrated that 1/3 of all subjects enrolled in herpes 
labialis studies will have spontaneously aborted lesion. Any calculation of clinical trial size, 
therefore, must consider that factor. When, however, treatment is initiated at the erythema 
stage (Stage 1), as in the Merlin Phase 2a (TR-H-211) study, the incidence of spontaneously 
aborted lesions declines to 25%. As a result, a larger percentage of subjects will demonstrate 
classical lesions in Merlin studies than was seen in the Famvir, or similar previous studies. 
This was factored in when performing power calculations for this Phase 2b clinical study. 
Those calculations determined that 144 subjects would provide a 95% likelihood of statistical 
significance for the herpetic episode endpoint. Merlin decreased the duration of herpetic 
episode in subjects that began treatment at stage 1 by 41 hours, with a p-value of 0.055 in the 
Phase 2a study. The herpetic episode endpoint includes the subjects with aborted lesions. 
 
As a result, a 150 subject clinical trial will have approximately 60 subjects progress to classical 
lesions in each treatment group and we can be very confident of having the power to 
demonstrate a highly significant difference for the duration of classical lesion endpoint, as 
shown in the Phase 2a results. In addition, a 150 subject clinical trial should have greater than 
95% likelihood of demonstrating a statistically significant Merlin effect on herpetic episode as 
a secondary endpoint. 
 
4 
Inclusion/Exclusion Criteria 
4.1 
Inclusion Criteria 
1. Subject has a visible herpes simplex labialis lesion, in an area around the mouth, 
assessed by the subject, and confirmed by telephone contact, to be at the erythema 
stage (Stage 1) or Papule/Edema stage (Stage 2) as defined below: 
Stage 1: 
Erythema stage is defined as any redness with no skin swelling or 
other signs of advanced stages. 
Stage 2: 
Papule/Edema stage is defined as any skin swelling or solid raised 
area above the normal surface without evidence of more advanced 
stages such as fluid filled blisters. 
2. Female subjects must be using a medically acceptable form of birth control during 
the study.  Acceptable birth control measures include but are not limited to: 
abstinence, oral contraceptive pills or patch, injectable contraception, barrier 
contraceptives (condom, diaphragm with spermicide), intrauterine device, vaginal 


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contraceptive  ring, surgical (hysterectomy, tubal ligation), vasectomized partner, and 
natural  post-menopausal inability to conceive.  Menopause is defined for this 
protocol as  starting one year after the time of the last menstrual period. 
3. Subject has immediate access to the kit containing the clinical trial material. (The 
subject will demonstrate access to the clinical trial material kit by reading the 
Randomization Number printed on the label on the kit.) 
4. Subject is able to appear for a clinic visit within 24 hours from the time of 
enrollment into the Treatment Phase of the study (from the time the subject called  to 
establish entry into the Treatment Phase of the study) and is able to return to  the 
clinic for the full 14 day duration of the study if necessary. 
4.2 
Exclusion Criteria 
1. Subjects with any evidence of active malignancy or immunodeficiency disease 
within the last 30 days.  Subjects who have completed therapy and are considered 
unlikely to relapse or who have had surgery and do not have any evidence of 
disease, are eligible for the study. 
2. Subject using topical steroids on or near the face or immunomodifying drugs, e.g. 
systemic (oral, intravenous) steroids within the last 30 days; use of inhaled  steroids 
does not exclude a subject from the study. 
3. Subject using a nonsteroidal anti-inflammatory drug (NSAID), except for low doses 
of aspirin (≤ 325 mg/day) used for cardiovascular purposes, or any other analgesic, 
within 12 hours of calling clinic  to report visible signs of a herpetic lesion. 
4. Subject has used an investigational drug and/or device within the last 30 days. 
5. Subjects who have used any anti-viral drug, or any other systemic or topical 
medications, including home remedies, intended to treat cold sores (e.g. lysine, 
topical tea tree oil, topical honey) within the last 30 days. 
6. Subject has had a vaccine for herpes simplex virus type 1 (typically oral herpes)  or 
2 (typically genital herpes). 
7. Subject is more than 75 years of age. 
8. Subject is pregnant, as checked by subject questioning prior to dosing. 
9. Subject has abnormal skin conditions (e.g. acne, eczema, psoriasis, albinism, or 
chronic vesiculobullous disorders) that occur in the area of the cold sore lesion, or 
has significant facial hair in the area of the cold sore, that might affect the normal 
course of the cold sore or might impair accurate evaluation of the cold sore lesion. 
10. Subject is currently enrolled in another clinical trial involving a drug and/or 
device. 
11. Subject requires chronic use of analgesics or NSAIDs, except for low doses of  
aspirin (≤ 325 mg/day) used for cardiovascular purposes. If a subject is unlikely to 
get through the treatment phase of the protocol without requiring the use of  analgesia 
for a chronic condition, e.g. back pain, recurrent daily headaches, the  subject should 
be excluded. 
12. Subject has a recent history of renal dysfunction or serious hepatic disease. 
Renal dysfunction encompasses both acute and chronic renal failure, the former 
resulting from the sudden loss of the ability of the kidneys to excrete wastes, 


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concentrate urine, and conserve electrolytes and the latter resulting from the  gradual 
and progressive loss of these capabilities. 
Examples of serious hepatic disease would include alcoholic liver disease, chronic 
hepatitis, autoimmune hepatitis and a variety of inherited diseases. The underlying 
cause of a documented recent mild increase in liver enzymes should be considered 
when deciding whether or not to exclude such a subject. 
13. Subject has a history of alcoholism or drug abuse within the preceding 12 months. A 
subject with a history of a pathological pattern of alcohol use that causes a  serious 
impairment of social or occupational functioning should be excluded. Such subjects 
may exhibit symptoms of tolerance and withdrawal along with  other behavioral 
symptoms. 
14. Subject is institutionalized. 
15. Any history which, in the Investigator’s judgment, makes the subject ineligible or 
places the subject at undue risk. 
16. Subject is unwilling to comply with the restrictions outlined in Section 5.4 below. 
4.3 
Restrictions During the Treatment Phase 
1. The subject is not to use any oral or topical prescription or over-the-counter 
medications to treat the current herpes labialis lesion, or apply any cosmetics, lip 
balms, ointments, moisturizers or home remedies to the affected area. 
2. The subject is not to use any pain medication or NSAID agent, except low doses 
of aspirin (≤ 325 mg/day) used for cardiovascular purposes, during the 
Treatment Phase of the study. 
3. The subject is not to mechanically disrupt the lesion (i.e. scrubbing, lancing, 
shaving the area, rubbing with alcohol, etc.). 
4. Merlin contains an alpha hydroxyl acid that may increase the skin’s sensitivity to 
the sun and particularly the possibility of sunburn.  Subjects should therefore 
limit  sun exposure while using Merlin, and for one week afterwards. 
 
A subject who does not meet one or more of the Inclusion Criteria or certain Exclusion Criteria 
may still be eligible for continuing in the study. Those subjects would be instructed that they 
cannot be entered into the Treatment Phase of the study at that time, but must wait until their 
next outbreak at which time they can call in again to see if they qualify to begin the study 
treatment. 


 
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5 
Summary of Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6 
Study Endpoints 
6.1 
Efficacy Endpoints 
 
6.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the clinician assessed duration of the classical herpetic 
lesions. 
 
6.1.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints include: 
• clinician assessed 
• duration of the herpetic episode (classical and non-classical) 
• duration until complete healing of the herpetic episode (classical and non-classical) 
• prevention of progression to a classical lesion 
• maximum lesion area of the classical lesions 
• cumulative lesion area of the classical lesions 
• cumulative lesion area of all lesions 
• duration of classical herpetic lesion hard scab 
 
6.1.3 Other Efficacy Endpoints 
Based on patient diary entries, the other efficacy endpoints include: 
• subject assessed: 
• duration of the classical herpetic lesion 
• duration of the herpetic episode (classical and non-classical) 
• duration of complete healing of the herpetic episode (classical and non-classical) 
• prevention of progression to a classical lesion 
• duration of classical herpetic lesion hard scab 
• severity of lesion pain 
• duration of lesion pain 
 
6.1.4 Efficacy Endpoint Definitions 
Definitions of the efficacy endpoints are detailed below. 
 
Duration of the classical herpetic lesion:  Duration is based on staging of the lesion.  
Staging is graded as follows: 0=prodromal, 1=erythema, 2=papula/edema, 3=vesicle/pustule, 
4=ulcer/soft crust, 5=hard crust, 6=residual swelling/dry flaking, 7=normal skin. The 
duration of a classical lesion is defined as the time, in hours, from the beginning of treatment 
to the onset of Stage 6, or, if Stage 6 is never observed, Stage 7. A classical lesion is defined 
as one that progresses through any of stages 3, 4 or 5. 
 
Duration of the herpetic episode (classical and non-classical): For a classical lesion, the 
duration of the herpetic episode is defined as the time, in hours, from the beginning of 
treatment until the loss of hard crust (stage 6; residual erythema can be present after loss of 


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hard crust). For non-classical (aborted) lesions, duration is defined as the time, in hours, from 
the beginning of treatment until complete resolution of all local signs and symptoms (stage 
7). 
 
Duration until complete healing of the herpetic episode (classical and non-classical): 
Duration until complete healing of the herpetic episode is defined as the time, in hours, from 
the beginning of treatment to the onset of Stage 7, for both classical and non- classical lesions. 
All subjects will visit the clinic daily, for a minimum of 3 days and a maximum of 14 days, 
until the lesion reaches Stage 7 with no signs or symptoms of a herpetic lesion. 
 
Prevention of progression to a classical lesion:  Prevention of progression to classical lesions 
will be defined as yes for subjects who experience a classical herpetic lesion (i.e., one that 
passes through any of Stages 3, 4 or 5 (vesicle/pustule, ulcer/soft crust, or hard crust)) and as 
no for subjects with only aborted, non-classical lesions. 
 
Maximum lesion area of the classical lesions:  Maximum lesion area of the classical lesions 
is defined as the maximum lesion area (length x width) for classical lesions during the 
vesicular, ulcerative, and hard crust stages. 
 
Cumulative lesion area of the classical lesions: Cumulative lesion area of the classical 
lesions is defined as the cumulative lesion area, for which classical lesion areas, day by day, 
will be added. 
 
Cumulative lesion area of all lesions:  Cumulative lesion area of all lesions is defined as the 
cumulative lesion area of both classical and non- classical recurrences. 
 
Duration of classical herpetic lesion hard scab:  Duration of classical herpetic lesion hard 
scab will be defined as the assessed duration of the hard crust, stage 5, for the classical lesions. 
This duration will represent the onset of stage 5 until the time of classical lesion healing at 
stage 6 or 7, whichever occurs earlier.  For lesions that bypass stage 5, duration of hard scab 
phase will be calculated as time between the two adjacent assessments either side of stage 5. 
 
Severity of lesion pain:  Pain will be evaluated based on the subject’s diary, where the subject 
will record, just prior to each treatment and three times daily once treatment is complete, the 
level of pain caused by the defined lesion. The rating scale for pain assessment has four levels 
for severity: none (1), mild (2), moderate (3), and severe (4). 
 
Duration of lesion pain:  Duration of pain will be measured in hours from the time of the 
first occurrence of a pain level of mild, moderate, or severe until a consistent score of a pain 
level of none has been achieved over at least 2 consecutive pain assessments, or until the 
lesion is completely healed, whichever occurs first. Subjects who do not reach the no-pain 
level within 14 days will be considered censored immediately following their last pain 
assessment. Subjects who never reach a pain level of mild, moderate, or severe will be 
assigned a duration of pain value of 0 hours. 


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6.2 
Safety Endpoints 
Adverse events (AEs) are the only safety endpoints captured in this study. 
 
7 
Data Analysis and Statistical Considerations 
Statistical summary tables and subject data listings will be prepared using SAS Version 9 or 
higher (SAS Institute, Cary, North Carolina, USA). 
7.1 
Analysis Populations 
 
7.1.1 Safety Population 
All subjects who have been entered into the Treatment Phase of the study and self- 
administered any treatment will be included in the Safety Population. A subject will be 
included in a treatment group for analysis based upon the treatment actually administered, 
rather than the group to which he or she has been assigned. For example, a subject who is 
randomized to receive placebo treatments but inadvertently receives active treatment will be 
included in the group receiving active treatment. 
 
Should a subject gain access to their clinical trial materials and treat themselves without having 
called in to the clinic and been given permission to open their Treatment kit, that subject will 
also be included in the Safety Population if follow-up safety data are available. 
 
The Safety Population will be used for all subject listings and for summary tables of the safety 
endpoints.  No formal statistical analyses are planned for the safety endpoints. 
 
7.1.2 Modified Intent-to-Treat (MITT) Population 
All subjects who have been entered into the Treatment Phase of the study will be included in 
the modified intent-to-treat (MITT) Population. It is considered a “modified” intent to treat 
population in that it does not include all randomized subjects but includes only those 
randomized subjects who access their treatment, i.e., are told to open their kit. A subject will 
be included in a treatment group for analysis based upon the treatment to which he or she has 
been assigned; imputation on the primary endpoint only is planned for the MITT Population – 
see section 7.13. The MITT Population will be used as the primary analysis population and for 
all efficacy analyses. 
 
7.1.3 Efficacy Evaluable (EE) Population 
All subjects who have been entered into the Treatment Phase of the study were reported to 
have successfully completed treatment, and have been followed successfully until their lesion 
heals, or until 14 days, whichever is earlier, will be included in the efficacy evaluable  (EE) 
Population. Prior to breaking the study blind, study data will be reviewed to determine which 
subjects need to be excluded from the EE Population. A subject will be included in a treatment 
group for analysis based upon the treatment actually administered, rather than the group to 
which he or she has been assigned.  For example, a subject who is randomized to receive a 
placebo treatment but inadvertently receives an active treatment will be included in the group 


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receiving an active treatment, and vice versa. Only actual observations will be included in the 
analyses; no imputation for missing data will be performed. The EE Population will be used 
for all efficacy analyses. 
7.2 
General Analysis 
All statistical tests will be done using two-sided tests and a Type I error rate of 0.05. 
Data listings will be based on all subjects in the Safety Population. 
Continuous variables will be summarized using descriptive statistics, specifically the mean, 
median, standard deviation, minimum and maximum values. Categorical variables will be 
summarized by frequencies and percentages. 
 
The primary analyses will compare the active treatment group to the placebo control group. 
Aside from any placebo effect, there should be no efficacy associated with the placebo 
solution.  In addition to the overall analyses, all statistical comparisons will be performed with 
the subjects stratified based on whether they were treated at erythema (Stage 1) or 
papule/edema (Stage 2).  Inference testing will be completed on efficacy data to compare the 
groups.  Safety data will be summarized with descriptive statistics, but no inference testing will 
be completed to compare the groups statistically. 
7.3 
Disposition 
The number and percentage of subjects completing the study and terminating early, with the 
reason for termination, will be summarized for each treatment and overall for the Safety 
Population. The number of subjects screened, randomized and in each study population will be 
summarized for each treatment and overall for the Safety Population. 
7.4 
Demographics 
Demographics and baseline characteristics will be summarized with descriptive statistics by 
treatment and overall for all three analysis populations.  For continuous variables, summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be provided. For 
categorical variables, the frequency and percent in each category will be presented. 
7.5 
Medical History 
Medical history will be summarized by treatment and overall for all three analysis populations. 
7.6 
Prior and Concomitant Medication 
A listing of concomitant medications will be provided for the Safety Population. 
7.7 
Physical Examinations 
A listing of physical examination findings will be provided for the Safety Population. 
7.8 
Vital Signs 
A listing of vital signs will be provided for the Safety Population. 


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7.9 
Pregnancy 
A listing of vital signs will be provided for the Safety Population. 
7.10 Compliance 
Estimating compliance with diary data is subjective and often unreliable.  Attempts will be 
made to estimate compliance and calculate confidence intervals.  It will be more informative, 
however, to use individual data rather than summary data.  Subject listings with combined 
data, therefore, will be provided, including: when the clinical lesion assessment reached stage 
4, expected number of treatments, actual number of treatments, and time between treatments 
from the diaries. 
7.11 Diaries 
Diary data will be summarized by treatment group and visit for the Safety Population.  Severity 
(1=none, 2=mild, 3=moderate, 4=severe) and stage (0=prodromal, 1=erythema, 
2=papula/edema, 3=vesicle/pustule, 4=ulcer/soft crust, 5=hard crust, 6=residual swelling/dry 
flaking, 7=normal skin) will be summarized with counts and percentages. 
7.12 Safety Data 
The Safety Population will be used for all summaries of safety data. The safety analysis will be 
performed on the Safety Population. Assessment of safety and tolerability will be based on 
AEs. Each AE will be graded with respect to its relationship to treatment using five categories: 
not related, unlikely, possible, probable, and highly probable. Each AE will also be graded on a 
three-point severity scale: mild, moderate, and severe. AEs will be coded by body system and 
preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). 
 
The number and percentage of subjects experiencing treatment emergent adverse events 
(TEAE) will be tabulated for each treatment group by system organ class (SOC) and preferred 
term (PT). TEAEs are those occurring on or after first dose of study product. A subject having 
the same TEAE more than once over the course of the study will be counted only once in the 
incidence calculation for that TEAE.  Similarly, if a subject had more than one TEAE in a 
SOC, the subject will be counted only once in the total number of subjects with TEAEs for that 
SOC. The number and percentage of subjects experiencing TEAEs will also be tabulated for 
those related to treatment (i.e., including possible, probable and highly probable), those that are 
severe, and those that are serious. If a TEAE is reported more than once for a subject, only the 
most related event will be counted in the summary for related TEAEs. For the summary of 
severe TEAEs, if a TEAE is reported more than once for a subject, only the most severe event 
will be counted in the summary. For the summary of serious TEAEs, if a TEAE is reported 
more than once for a subject, only the most serious event  will be counted in the summary. 
7.13 Efficacy Analyses 
The efficacy analysis will be performed on both the MITT and the EE Populations; and 
stratified based on whether they were treated at erythema (Stage 1) or  papule/edema (Stage 
2).  Groups will be compared at each visit for which the endpoint of interest is captured. 


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7.13.1 Duration 
Imputation will only be used for analyses of duration endpoints and only in the MITT 
Population.  Duration for subjects who drop out prior to healing will be imputed with a 
duration of 336 hours (14 days x 24 hours) for the main analyses of duration endpoints in the 
MITT Population.  Hodges-Lehmann technique will be used for estimation and Wilcoxon rank 
sum tests will be used to compare the groups on duration endpoints in the MITT Population. 
In addition, subjects who drop out prior to healing will be considered censored in a sensitivity 
analysis of duration endpoints in the MITT Population and Kaplan-Meier estimation methods 
will be used with log-rank tests for comparison of the groups. 
 
For analysis of duration in the EE Population, no imputation is required since these are 
complete cases. Hodges-Lehmann technique will be used for estimation and Wilcoxon rank 
sum tests will be used to compare the groups on duration endpoints in the EE Population. 
 
7.13.2 Prevention of Progression 
For all endpoints on the occurrence of prevention of progression, counts and percentages 
will be summarized, and chi-square tests, or Fisher’s exact test will be used to compare 
groups, as appropriate.  Fisher’s exact tests will be used if any of the expected cell counts 
in the RxC crosstabulations are less than 5. 
 
7.13.3 Area 
For area endpoints, means, medians, standard deviations and ranges will be summarized. 
T-tests will be used to compare groups if the sizes are approximately normally distributed, 
or Wilcoxon rank sum tests will be used if the sizes are markedly non-normally distributed. 
 
7.13.4 Pain Severity 
For pain severity, counts and percentages will be summarized for all levels of severity, 
and Cochran-Mantel-Haenszel tests will be used to compare the groups. 


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7.13.5 Analysis Matrix 
For all efficacy endpoints the following matrix will be used for analyses: 
 
Endpoint 
Popu- 
lation 
Analysis 
Description 
Methods 
Duration 
MITT 
Main 
Analysis 
Impute duration for subjects 
who drop out prior to healing 
with a duration of 336 hours (14 
days x 24 hours). 
Hodges-Lehmann estimation 
methods; Wilcoxon rank sum 
test to compare groups 
Sensitivity 
Analysis 
Subjects who drop out prior to 
healing will be considered 
censored. 
Kaplan-Meier estimation 
methods; Log-rank test to 
compare groups 
EE 
Main 
Analysis 
No imputation required 
since these are complete 
cases. 
Hodges-Lehmann 
estimation methods; 
Wilcoxon rank sum test to 
compare groups 
Prevention of 
Progression 
MITT/ 
EE 
Main 
Analysis 
No imputation 
chi-square or Fisher’s exact 
test to compare groups 
Area 
MITT/ 
EE 
Main 
Analysis 
No imputation 
t-test or Wilcoxon rank sum 
test to compare groups 
Pain Severity 
MITT/ 
EE 
Main 
Analysis 
No imputation 
Cochran-Mantel-Haenszel 
test to compare groups 
*All analyses in this matrix will be completed for all subjects in the specified Analysis Population, then the 
analyses will be stratified for subjects treated at Stage 1 and those treated at Stage 2. 
 
7.13.6 Pooling of Centers 
This is a multi-center study planned at multiple investigational sites. As all sites will be 
functioning under the same protocol, it is assumed that no substantial differences between sites 
will be evidenced in the data and the data from all centers will be pooled together for analyses. 
However, formal statistical assessment of these assumptions will be explored.  In order to 
assess pooling of data from multiple centers or whether there are differences among centers in 
treatment effects, a Cox proportional hazards model analysis of the duration of herpetic 
episode will also be performed for the primary duration endpoint and for both the MITT and 
EE Populations. The model will include terms for treatment, center, and treatment by center 
interaction. A test will be performed to test for the significance of the interaction. This test will 
be conducted at the 0.10 level of significance. If the interaction is found to be significant, 
estimates of treatment effect will be provided by center, as well as overall. 
 
8 Handling of Missing Data 
All missing data will be queried. Missing efficacy data on duration endpoints for subjects in 
the MITT Population which are not retrievable through queries will be handled using 
imputation of 336 days. Other missing data, including missing safety data, will not be imputed. 


Topical Remedy, LLC 
Protocol:  TR-H-212 
  
Statistical Analysis Plan   
Page 20 of 21 
 
 
 
 
 
9 Changes from the Protocol 
No changes in the analyses described in the original protocol or subsequent amendments are 
planned. If changes are made prior to unblinding, this document may be amended and such 
changes will be described. Changes made after unblinding will be noted in the clinical study 
report. 


Topical Remedy, LLC 
Protocol:  TR-H-212 
  
Statistical Analysis Plan   
Page 21 of 21 
 
 
 
 
10 Tables 
 
Disposition 
Demographics – Safety 
Demographics – MITT 
Demographics – EE 
Medical History – Safety 
Medical History – MITT 
Medical History – EE 
Efficacy – Duration Endpoints – MITT 
Efficacy – Duration Endpoints – EE 
Efficacy – Prevention of Progression – MITT 
Efficacy – Prevention of Progression – EE 
Efficacy – Area Endpoints – MITT 
Efficacy – Area Endpoints – EE 
Efficacy – Pain Severity – MITT 
Efficacy – Pain Severity – EE 
Summary of Subjects with TEAEs – Safety 
Occurrence of TEAEs by SOC and PT – Safety 
Occurrence of TEAEs Related to Treatment by SOC and PT – Safety 
Occurrence of Severe TEAEs by SOC and PT – Safety 
Occurrence of Serious TEAEs by SOC and PT – Safety