LIP: Phase 3 Clinical Study for the Treatment of Cold Sore

• Sponsor: Onxeo (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00769314
• Collaborator: (none)
• Enrollment: 1,727
• Locations: 53
• Arms: 2
• Duration (Months): 27
• Patients Per Site: 32.6
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

To demonstrate the efficacy of a single dose of acyclovir Lauriad® 50mg muco-adhesive buccal tablet versus a single dose of matching placebo on the primary vesicular lesion of cold sore.

Condition or Disease	Intervention/Treatment	Phase
Herpes Labialis	Drug: Acyclovir Lauriad; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1727 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomised, Double-Blind, Single Dose, One-Day Early Administration, Multicentre Study Comparing the Efficacy and Safety of Acyclovir Lauriad® 50 mg Muco-adhesive Buccal Tablet to Matching Placebo, in the Treatment of Herpes Labialis in Immunocompetent Patients.
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Acyclovir Lauriad 50mg	Drug: Acyclovir Lauriad; 50 mg muco-adhesive buccal tablets, single application on the gum
Placebo Comparator: 2	Drug: Placebo; 50 mg muco-adhesive buccal tablets, single application on the gum

Outcome Measures

Primary Outcome Measures

1. Time to Healing (TTH) of Vesicular Primary Lesion [Assessed from time of treatment initiation through Day 14]

   Healing was defined as the loss of crust (erythema may be present) as assessed by the investigator. TTH was the time from treatment initiation to healing as defined above and was assessed from the time of treatment initiation through Day 14. The primary vesicular lesion was the first developed lesion located on the lip and was not to have extended more than 1 cm outside the lip.

Secondary Outcome Measures

1. Abortion of Primary Lesions [Assessed from the time of treatment initiation through Day 14]

   Aborted lesions were defined as herpetic lesions preceded by prodromal symptoms that did not progress beyond the papule stage.

2. TTH of Non-primary Lesions (Aborted Lesions Excluded) [Assessed from the time of treatment initiation through Day 14]

   TTH of non-primary lesions was defined as the time from treatment initiation to healing of all non-primary vesicular lesions. Non-primary lesions were those that developed in addition to and/or in 1 or more days after the primary vesicular lesion and that were located at least 1 cm from the primary lesion. Aborted lesions were not included in this parameter. TTH was to be assessed by the investigator.

3. Duration of Episode (DOE) [Assessed from initiation of treatment to Day 14]

   For patients who experienced a vesicular lesion, DOE was defined as the time from treatment initiation to healing of primary and secondary vesicular lesions (loss of crust). For subjects whose primary and secondary lesions were not vesicular in nature, DOE was defied as the time from treatment initiation to return to normal skin or to cessation of symptoms, whichever came last.

4. Time to Cessation of Symptoms [Assessed from time of treatment initiation through Day 14]

   Time to cessation of symptoms was defined as the time from treatment initiation to cessation of all symptoms: pain, burning, itching, tingling, tenderness and discomfort. It was to be assessed by the investigator.

5. TTH of Aborted Primary Lesions [Assessed from time of treatment initiation through Day 14]

   TTH of aborted primary lesions was defined as the time from treatment initiation to healing of the primary lesion (erythema or papule) or cessation of symptoms, whichever came last. It was to be assessed by the investigator.

6. Time to Recurrence of Non-aborted Lesions During 9-month Follow-up [From time of initial healing through the 9-month follow-up]

   Time to recurrence was the time from the healing of all lesions of the initial episode to the occurrence of new lesions.

7. Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up [From time of initial healing through the 9-month follow-up]

   Recurrence was the occurrence of new lesions and was evaluated in a subgroup of patients who agreed to record recurrences during the 9-month follow-up period.

8. Symptom Intensity (Visual Analogue Scale [VAS]) [Assessed on Days 1, 3, 5, 7 and 14 (or within 24 hours of healing)]

   Patients were asked to place a tick mark on a 10 centimeter VAS indicating their symptom intensity. Scale ratings ranged from a minimum of 0 (none at all) to a maximum of 10 (worst possible). The location of the tick mark from "0" was measured in millimeters (0 - 100) and recorded.

9. Patient Satisfaction With Treatment [Assessed on Day 14 (or within 24 hours of healing)]

   At the end of study (Day 14 [or within 24 hours of healing]), patients were asked whether they were satisfied with treatment (yes/no).

10. Patient Assessment of Efficacy of the Treatment [Assessed on Day 14 (or within 24 hours of healing)]

    At the end of study (Day 14 [ or within 24 hours of healing]), patients were asked to rate efficacy of treatment using a 4-point scale (inactive, mildly active, moderately active, or very active).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• History of recurrent herpes labialis lesions where:

• At least 50% of previous episodes produced classical lesions to the vesicular stage (i.e. episodes that progressed through macula, papule, vesicle, crust and healed);

• Prodromal symptoms (itching, tingling, pain etc.) should precede herpes labialis lesions in at least 50% of the previous herpes episodes

• Good general health (ECOG < 2), immunocompetent

• Signed and dated written informed consent

• Women of childbearing potential must have effective contraception method

Exclusion Criteria:

• More than 50% of recurrences that aborted spontaneously in the past 12 months

• Primary herpes lesion outside the lips (e.g. nose, chin, etc.)

• Abnormal peri-oral skin condition that might affect the normal course of cold sores (e.g. eczema, psoriasis…)

• Oral diseases whose prodromal symptoms may mimick those of herpes labialis, including recurrent oral aphthous disease

• Oral diseases that might interfere with the evaluation of the efficacy or safety of the treatments, including gingivitis, parondotis, mucositis, oropharyngeal candidiasis…

• History of infection known to be resistant to acyclovir family agents

• Previous vaccination against herpes

• Concomitant treatment likely to interfere with acyclovir

• Allergy to any acyclovir containing agents

• Immunocompromised condition, including HIV+

• Unability to properly understand protocol requirements, to follow the study procedures, to complete the patient diary or to start the self-initiation of the treatment

• Upper full or partial dentures with acrylic border in the canine fossa

• Milk allergy or known history of hypersensitivity to one of the components of the products

• Rare hereditary problems of galactose intolerance.

• Lactase enzyme deficiency or glucose galactose malabsorption

• Clinically significant abnormal level of serum creatinine

• Patients whose occupations make them unlikely to return to the clinic within 24h of treatment initiation

• Pregnancy or breast-feeding

• Investigational drug or immunomodulator treatment in the 30 days prior randomisation

• Prior enrollment in this study

• Participation in another therapeutic trial evaluating new drugs or which could interfere with the evolution of herpes labialis or the evaluation of the drug in the study within preceding 30 day.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Radiant Research, Inc.,	Scottsdale	Arizona	United States	85251
2	Radiant Research, Inc.,	Tucson	Arizona	United States	85710
3	Dermatology Private Practice	San Fransisco	California	United States	94114
4	Front Range Clinical Research	Wheat Ridge	Colorado	United States	80033
5	St. Luke's Family Health,	Meridian	Idaho	United States	83642
6	Clinvest, a Division of Banyan Group, Inc.,	Springfield	Missouri	United States	65807
7	Rochester Clinical Research, Inc.,	Rochester	New York	United States	14609
8	Stony Brook University Medical Center	Stony Brook	New York	United States	11794-8091
9	Center for Clinical Studies	Houston	Texas	United States	77030
10	Center for Clinical Studies, Ltd., LLP.	Houston	Texas	United States	77058
11	Taylor Square Private Clinic	Sydney		Australia	Darlinghurst, NSW 2010
12	Central Brunswick Medical Centre	Sydney		Australia	QLD 4006
13	General Teaching Hospital, Dep. Of Dermatology	Opava		Czech Republic	128 08 Praha 2
14	U zastavky 16	Opava		Czech Republic	747 00
15	Central military hospital Dept. of Dermatology	Praha		Czech Republic	169 02 Praha 6
16	University Hospital Bulovka 3rd Clinic of Inf. Diseases	Praha		Czech Republic	180 81 Praha 8
17	University Hospital Bulovka Dept. of Dermatology	Praha		Czech Republic	180 81 Praha 8
18	Hôpital St Jacques Service de Dermatologie	Besancon		France	25030 BESANCON CEDEX
19	Private Practice	Martigues		France	13500
20	Hopital Fournier, Service de dermatologie	Nancy		France	54000
21	Private Practice	Nice		France	06000
22	Hôpital L'Archet 2, Service de Dermatologie	Nice		France	06202 NICE Cedex
23	Private Practice	Paris		France	75005
24	Hôpital Tenon, Dermatology department	Paris		France	75020
25	Hôpital Saint Louis Paris, Service de Dermatologie 1	Paris		France	75475 PARIS Cedex 10
26	Service de Stomatologie et chirurgie Maxilo-Faciale.Hôpital de la pitié Salpétrière	Paris		France	75651 Paris Cedex 13
27	Hôpital Nord, Service de dermatologie	St. Etienne		France	42065 St ETIENNE Cedex 2
28	Hôpital TROUSSEAU	Tours		France	37044 TOURS Cedex
29	Praxis Dres. Dörzapf und Partner	Augsburg		Germany	86153
30	Charité Universitätsmedizin Berlin Klinik für Dermatologie, Venerologie und Allergologie	Berlin		Germany	10117
31	Praxis	Berlin		Germany	10789
32	Polikum Friedenau	Berlin		Germany	12157
33	Gemeinschaftspraxis	Berlin		Germany	12353
34	Laserclinic Drs. Steinert	Biberach		Germany	88400
35	Klinik und Poliklinik für Dermatologie des Universitätsklinikums Bonn	Bonn		Germany	53105
36	Praxis	Frankfurt		Germany	60326
37	Raiffeisenstr. 15b	Oberkirch		Germany	77704
38	Ludwig-Erhard-Platz 9-11	Rodgau-Dudenhofen		Germany
39	Katedra i Klinika Dermatologii Collegium Medicum	Bydgoszcz		Poland	85-096
40	Centrum Medyczne Diabet	Chrzanów		Poland	32-500
41	Naukowo-Badawczy i Naukowo-Dydaktyczny Ośrodek Dermatologii Estetycznej, Dermatochirurgii i Fotodermatologii	Gdynia		Poland	81-366
42	Niepubliczny Zaklad Opieki Zdrowotnej GCP Dobra Praktyka Lekarska	Grudziądz		Poland	86-300
43	NZOZ Atopia, Al. J.	Kraków		Poland	31-159
44	Niepubliczny Zakład Opieki Zdrowotnej Specjalistyczna Przychodnia Lekarska Medikard	Płock		Poland	09-402
45	Niepubliczny Zakład Opieki Zdrowotnej "Nasz Lekarz" Praktyka Grupowa Lekarzy Rodzinnych z Przychodnią Specjalistyczną	Toruń		Poland	87-100
46	Gabinet Internistyczny	Warszawa		Poland	03-003
47	NZOZ Praktyka Lekarska Iga Gilas - Mirkiewicz	Wrocław		Poland	50-354
48	Specjalistyczne Gabinety Lekarskie Dermed	Łódź		Poland	90-265
49	Cossington House Surgery	Canterbury		United Kingdom	CT1 3HX
50	School of Dentistry, Cardiff University	Cardiff		United Kingdom	CF14 4XN
51	Sidley Surgery	East Sussex		United Kingdom	TN39 5HE
52	Sea Road Surgery	East Sussex		United Kingdom	TN40 1JJ
53	Saltash Health Centre	Saltash		United Kingdom	PL12 6DL

Sponsors and Collaborators

• Onxeo

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Onxeo
• ClinicalTrials.gov Identifier: NCT00769314
• Other Study ID Numbers: BA2005/21/02
• First Posted: Oct 9, 2008
• Last Update Posted: Dec 21, 2012
• Last Verified: Nov 1, 2012

• Additional relevant MeSH terms: Herpes Labialis; Acyclovir

Study Results

Participant Flow

Recruitment Details	Patients were screened beginning March 2007 and the last patient was treated in October 2008. The study was conducted at 47 sites in Australia, the Czech Republic, France, Germany, Poland, the United Kingdom and the United States.
Pre-assignment Detail	Per protocol, a total of 1950 patients were to be randomized. Following randomization, patients were not to start treatment until a new labial herpes episode occurred. Thus, of those randomized, only 780 patients were planned to be treated (390 patients per treatment group) and 1170 patients were to be randomized, but not treated.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Period Title: Overall Study
STARTED	378	397
COMPLETED	361	384
NOT COMPLETED	17	13

Baseline Characteristics

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group	Total
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet/Intent-to-Treat population	muco-adhesive buccal tablet with placebo/Intent-to-Treat population	Total of all reporting groups
Overall Participants	376	395	771
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40 (12.97)	41.9 (13.33)	41.0 (13.18)
Sex: Female, Male (Count of Participants)
Female	258 68.6%	271 68.6%	529 68.6%
Male	118 31.4%	124 31.4%	242 31.4%
Region of Enrollment (participants) [Number]
United States	71 18.9%	72 18.2%	143 18.5%
France	41 10.9%	49 12.4%	90 11.7%
Czech Republic	47 12.5%	50 12.7%	97 12.6%
Poland	74 19.7%	70 17.7%	144 18.7%
Australia	53 14.1%	68 17.2%	121 15.7%
Germany	79 21%	77 19.5%	156 20.2%
United Kingdom	11 2.9%	9 2.3%	20 2.6%

Outcome Measures

1. Secondary Outcome

Title	Abortion of Primary Lesions
Description	Aborted lesions were defined as herpetic lesions preceded by prodromal symptoms that did not progress beyond the papule stage.
Time Frame	Assessed from the time of treatment initiation through Day 14

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the Intent-to-Treat (ITT) population, which consisted of all randomized patients who received at least one dose of study medication and who had complete information recorded for the application time.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	376	395
Aborted Lesions = Yes	130 34.6%	109 27.6%
Aborted Lesions = No	242 64.4%	279 70.6%
Aborted Lesions = Missing	4 1.1%	7 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0419
	Comments	p-value < 0.05 considered significant
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.0685
	Confidence Interval	(2-Sided) 95%; 0.0025 to 0.1339
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference was the proportion of patients with aborted lesions in the acyclovir Lauriad group minus the proportion of patients with aborted lesions in the placebo group.

2. Secondary Outcome

Title	TTH of Non-primary Lesions (Aborted Lesions Excluded)
Description	TTH of non-primary lesions was defined as the time from treatment initiation to healing of all non-primary vesicular lesions. Non-primary lesions were those that developed in addition to and/or in 1 or more days after the primary vesicular lesion and that were located at least 1 cm from the primary lesion. Aborted lesions were not included in this parameter. TTH was to be assessed by the investigator.
Time Frame	Assessed from the time of treatment initiation through Day 14

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using a subgroup of patients in the ITT population with non-primary lesions.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	39	62
Median (95% Confidence Interval) [Days]	7.00	9.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0683
	Comments	p-value < 0.05 considered significant
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Duration of Episode (DOE)
Description	For patients who experienced a vesicular lesion, DOE was defined as the time from treatment initiation to healing of primary and secondary vesicular lesions (loss of crust). For subjects whose primary and secondary lesions were not vesicular in nature, DOE was defied as the time from treatment initiation to return to normal skin or to cessation of symptoms, whichever came last.
Time Frame	Assessed from initiation of treatment to Day 14

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the ITT population.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	373	395
Median (95% Confidence Interval) [Days]	5.57	6.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0033
	Comments	p-value < 0.05 considered significant
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Time to Cessation of Symptoms
Description	Time to cessation of symptoms was defined as the time from treatment initiation to cessation of all symptoms: pain, burning, itching, tingling, tenderness and discomfort. It was to be assessed by the investigator.
Time Frame	Assessed from time of treatment initiation through Day 14

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the ITT population.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	373	393
Median (95% Confidence Interval) [Days]	3.57	4.16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0098
	Comments	p-value < 0.05 considered significant
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	TTH of Aborted Primary Lesions
Description	TTH of aborted primary lesions was defined as the time from treatment initiation to healing of the primary lesion (erythema or papule) or cessation of symptoms, whichever came last. It was to be assessed by the investigator.
Time Frame	Assessed from time of treatment initiation through Day 14

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the subgroup of patients within the ITT population with aborted lesions.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	108	85
Median (95% Confidence Interval) [Days]	2.57	2.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8005
	Comments	p-value < 0.05 considered significant
	Method	Log Rank
	Comments

6. Primary Outcome

Title	Time to Healing (TTH) of Vesicular Primary Lesion
Description	Healing was defined as the loss of crust (erythema may be present) as assessed by the investigator. TTH was the time from treatment initiation to healing as defined above and was assessed from the time of treatment initiation through Day 14. The primary vesicular lesion was the first developed lesion located on the lip and was not to have extended more than 1 cm outside the lip.
Time Frame	Assessed from time of treatment initiation through Day 14

Outcome Measure Data

Analysis Population Description

The modified Intent-to-Treat (mITT) population was the population used for analysis of this endpoint. The mITT population included all randomized patients who received at least one dose of study medication and who reached the vesicular stage (ie, episodes that progressed through macula, papule, vesicle, crust and healing).

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	242	279
Median (95% Confidence Interval) [Days]	7.00 (0.18)	7.32 (0.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p-value < 0.05 considered significant
	Method	Log Rank
	Comments

7. Secondary Outcome

Title	Time to Recurrence of Non-aborted Lesions During 9-month Follow-up
Description	Time to recurrence was the time from the healing of all lesions of the initial episode to the occurrence of new lesions.
Time Frame	From time of initial healing through the 9-month follow-up

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the follow-up population, a subgroup of the ITT population who continued to the 9 month follow-up and had at least 1 diary assessment during that period. The follow-up population was defined as patients whose lesions were healed at the end of Day 14 and had no recurrence within 15 days of healing of all lesions.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	232	246
Median (95% Confidence Interval) [Days]	205.0 (19.4)	165.0 (9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0412
	Comments	p-value < 0.05 considered significant
	Method	Log Rank
	Comments

8. Secondary Outcome

Title	Patient Incidence of Recurrence of Non-aborted Lesions During 9-month Follow-up
Description	Recurrence was the occurrence of new lesions and was evaluated in a subgroup of patients who agreed to record recurrences during the 9-month follow-up period.
Time Frame	From time of initial healing through the 9-month follow-up

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the follow-up population, a subgroup of the ITT population who continued to the 9 month follow-up and had at least 1 diary assessment during that period. The follow-up population was defined as patients whose lesions were healed at the end of Day 14 and had no recurrence within 15 days of healing of all lesions.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	267	270
Recurrence during 9-month follow-up = yes	149 39.6%	181 45.8%
Recurrence during 9-month follow-up = no	83 22.1%	65 16.5%
Recurrence during 9-month follow-up = missing	35 9.3%	24 6.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0271
	Comments	p-value < 0.05 considered significant
	Method	Chi-squared
	Comments

9. Secondary Outcome

Title	Symptom Intensity (Visual Analogue Scale [VAS])
Description	Patients were asked to place a tick mark on a 10 centimeter VAS indicating their symptom intensity. Scale ratings ranged from a minimum of 0 (none at all) to a maximum of 10 (worst possible). The location of the tick mark from "0" was measured in millimeters (0 - 100) and recorded.
Time Frame	Assessed on Days 1, 3, 5, 7 and 14 (or within 24 hours of healing)

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the safety population, which consisted of all randomized patients who took at least 1 dose of study medication.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	378	397
Day 1	30.5 (22.37)	31.1 (22.07)
Day 3	21.2 (22.88)	22.9 (22.60)
Day 5	12.7 (17.60)	17.3 (20.70)
Day 7	8.2 (13.63)	10.7 (18.48)
Day 14 (or within 24 hours of healing)	1.0 (5.14)	0.9 (3.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments	Analysis conducted between treatment groups at Day 1 timepoint.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5695
	Comments	p-value < 0.05 considered significant
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments	Analysis conducted between treatment groups at Day 3 timepoint
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1824
	Comments	p-value < 0.05 considered significant
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments	Analysis conducted between treatment groups at the Day 5 timepoint
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0078
	Comments	p-value < 0.05 considered significant
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments	Analysis conducted between treatment groups at the Day 7 timepoint
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3303
	Comments	p-value < 0.05 considered significant
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments	Analysis conducted between treatment groups at the Day 14 timepoint
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6045
	Comments	p-value < 0.05 considered significant
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Patient Satisfaction With Treatment
Description	At the end of study (Day 14 [or within 24 hours of healing]), patients were asked whether they were satisfied with treatment (yes/no).
Time Frame	Assessed on Day 14 (or within 24 hours of healing)

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the ITT population.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	376	395
Satisfied with treatment = yes	297 79%	275 69.6%
Satisfied with treatment = no	66 17.6%	105 26.6%
Missing	13 3.5%	15 3.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acyclovir Lauriad Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments	p-value < 0.05 considered significant
	Method	Chi-squared
	Comments

11. Secondary Outcome

Title	Patient Assessment of Efficacy of the Treatment
Description	At the end of study (Day 14 [ or within 24 hours of healing]), patients were asked to rate efficacy of treatment using a 4-point scale (inactive, mildly active, moderately active, or very active).
Time Frame	Assessed on Day 14 (or within 24 hours of healing)

Outcome Measure Data

Analysis Population Description

This endpoint was analyzed using the ITT population.

Arm/Group Title	Acyclovir Lauriad Group	Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet	muco-adhesive buccal tablet with placebo
Measure Participants	376	395
Inactive	50 13.3%	79 20%
Midly active	49 13%	44 11.1%
Moderately active	100 26.6%	104 26.3%
Very active	154 41%	146 37%
Missing	23 6.1%	22 5.6%

Adverse Events

Time Frame	Adverse events were recorded during the 14 day treatment period.
Adverse Event Reporting Description	The safety population included all randomized patients who took at least 1 dose of study drug, including 378 patients in the acyclovir Lauriad group and 397 patients in the placebo group.
Arm/Group Title	Acyclovir Lauriad Group		Placebo Group
Arm/Group Description	Acyclovir Lauriad 50mg muco-adhesive tablet		muco-adhesive buccal tablet with placebo
All Cause Mortality
	Acyclovir Lauriad Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Acyclovir Lauriad Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/378 (0%)		1/397 (0.3%)
Immune system disorders
Allergic reaction	0/378 (0%)	0	1/397 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Acyclovir Lauriad Group		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/378 (5.3%)		22/397 (5.5%)
Gastrointestinal disorders
nausea	1/378 (0.3%)	1	6/397 (1.5%)	6
General disorders
Application Site Pain	4/378 (1.1%)	4	4/397 (1%)	4
Infections and infestations
Nasopharyngitis	4/378 (1.1%)	4	3/397 (0.8%)	3
Nervous system disorders
headache	12/378 (3.2%)	12	12/397 (3%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.