RANDOMIZED CLINICAL STUDY COMPARING COMPEED® COLD SORE PATCH TO ACYCLOVIR CREAM 5% IN THE TREATMENT OF HERPES SIMPLEX LABIALIS

By:

Tonny Karlsmark, MD, MDSc1; J. John Goodman, MD2; Yorik Drouault, MD3; Laura Lufrano, RPh4; Gordon W. Pledger, PhD5; and the Cold Sore Study Group1Bispebjerg Hospital, Copenhagen, Denmark; 2Hill Top Research, West Palm Beach, Florida; 3Dermexpert, Paris, France; 4Johnson & Johnson, Skillman, New Jersey; 5Johnson & Johnson consultant statistician, Hamilton, Texas

For presentation at:14th Meeting of the International Herpes Management Forum

October 10-11, 2007

ABSTRACTBackground: Hydrocolloid technology has been proven

effective in treating dermal wounds. A previous study showed that a newly developed thin hydrocolloid patch (Compeed® Cold Sore Patch [CSP]) provided multiple wound healing benefits across all stages of a herpes simplex labialis (HSL) outbreak.

Methods: An assessment of CSP efficacy and safety was conducted in an international, multi-center, assessor-blinded study that enrolled 728 subjects with a history of recurrent HSL. Of these, 351 experienced a HSL outbreak and were randomized to use CSP (n = 179) or acyclovir cream 5% (Zovirax®, n = 172) at the onset of symptoms until the lesion healed, for a maximum of 10 days. The primary end point was the subject’s global assessment of therapy (SGAT) (0 - 10 scale, 10 = excellent response). Multiple secondary end points included clinician-assessed healing time and subject assessment of lesion protection, noticeability and social embarrassment.

Results: CSP and acyclovir were highly effective (mean SGAT = 7.89 and 8.00, respectively), with no significant difference observed (P=0.65). The difference in median healing times between products was not significant (7.57 days with CSP vs 7.03 days with acyclovir, P=0.37). Both treatments were well tolerated. CSP-treated subjects reported a high level of protection, less noticeable lesions and greater relief of social embarrassment.

Conclusions: This study confirms the efficacy and safety of CSP in treating HSL lesions as a wound. CSP using hydrocolloid technology provides an alternative to topical antivirals in managing HSL lesions, while affording additional benefits of wound protection, discretion and relief of social embarrassment.

INTRODUCTION• Herpes simplex labialis (HSL) is characterized by

recurrent cold sores resulting primarily from herpes simplex virus type 1 infection of the lips and perioral skin. HSL is prevalent, occurring in approximately 15%-40% of adults worldwide1-4

• Topical antiviral therapies, such as acyclovir or penciclovir, are the current standard of care for subjects with HSL.5,6 Overall benefits of these therapies are limited by several factors, including:

− need for frequent application

− lack of protection of the lesion

− aesthetic factors relating to the visibility/appearance of the scab during the healing process

• Many of the limitations of standard topical therapy may be addressed by a hydrocolloid adhesive patch, which provides continuous wound protection while maintaining a moist healing environment7-10

• Compeed® Cold Sore Patch (CSP) is a semi-occlusive, transparent, hydrocolloid bandage used for the treatment of cold sores. In a noncomparative study conducted in Denmark in 2004, CSP was effective in providing discrete wound-healing benefits to subjects with HSL lesions11

• No study to date has evaluated the efficacy and safety of a hydrocolloid patch, such as CSP, in comparison with standard antiviral topical therapy in the treatment of HSL lesions.

OBJECTIVETo evaluate and compare the efficacy and safety of CSP and

acyclovir cream 5% in the treatment of HSL.

Study Design

• Randomized, assessor-blinded, parallel-group study conducted at 6 international clinical sites

• Subjects aged 18 years or older with recurrent HSL of the lips who had received prior treatment with acyclovir or other cold sore therapies were eligible for enrollment

• Therapy initiated within 1 hour of onset of the first sign or symptom of cold sore outbreak

• Subjects instructed to apply acyclovir cream 5% five times daily or to wear CSP continuously until lesions were completely healed, for a maximum of 10 days

• Clinical assessments made within 24 and 48 hours after initiating treatment and every other day thereafter, until day 10 or until completion/discontinuation if before day 10.

Study Assessments

• Clinical assessments (including lesion size and stage and other assessments) were performed at each clinic visit. Global assessment of therapy (0-10 scale, 10 = excellent response) was recorded by the clinician at the end of therapy visit

• Subject assessments were recorded in diary entries and the Treatment Use Questionnaire and included:

− subject’s global assessment of therapy (SGAT) at end of therapy (0-10 scale, 10 = excellent response)

− individual signs and symptoms (0-10 scale, 10 = most severe)

− lesion protection/hygiene, lesion noticeability, and relief of social embarrassment

• Subjects and clinicians reported adverse events (AEs) for the duration of the study. Treatment-emergent AEs were defined as those started on or after study therapy initiation.

Outcome Measures

• Primary efficacy variable was subject’s global assessment of therapy (0-10 scale, 0 = no response and 10 = excellent response)

• Key secondary efficacy variable was the clinician-assessed time to complete healing.

Statistical Analyses

• Sample size of 300 subjects (150 per treatment group) was estimated to achieve a statistical power of 0.8 to detect a 0.5-point mean difference between treatment groups in the SGAT

• Efficacy and safety analyses were based on the intent-to-treat (ITT) population, defined as all randomized subjects who initiated study treatment

• Data were compared between the 2 treatment groups using analysis of variance (ANOVA) for quantitative variables and Chi-square tests for categorical variables

• Primary and key secondary efficacy end point were analyzed stepwise as follows:

- If P<.05 in favor of CSP, or equivalently, if the 95% confidence interval (CI) for the difference between treatment groups lies entirely above 0, then CSP is considered superior

- If P>.05, a noninferiority (NI) test was performed. The NI margin used was 0.25, half of the estimated minimal clinically significant effect size

• Other secondary endpoints were analyzed without adjustment for multiple comparisons. Thus, P-values reported for these endpoints are considered nominal; interpretations are not based on a strict P<0.05 criterion but on consistency of trends and patterns in the results.

METHODS

RESULTS

Subject Disposition (Figure 1)

Baseline Demographics of ITT Population

• Mean age was 42.7 ± 13.7 years

• 82% were female

• 92% were Caucasian.

Efficacy Analyses

• SGAT ratings were highly favorable and similar in both treatment groups (Figure 2)

- mean ratings of 7.89 and 8.00 on 0-10 scale in the CSP and acyclovir groups, respectively, with about half of each group having ratings of 9 or 10 and 80% of each group having ratings of at least 7

- no statistically significant difference in SGAT between CSP and acyclovir at the end of therapy (P=0.65)

- blinded clinician global assessment at the end of therapy likewise indicated no statistically significant difference between treatment groups (P=0.99). Of note, the mean global ratings were identical (7.85) in both treatment groups

• Clinician-assessed time to complete healing (Figure 3) was similar for the two groups as reflected visually by the Kaplan-Meier curves

- median healing time, estimated via Kaplan-Meier analysis, was 7.57 days in the CSP group and 7.03 days in the acyclovir group; P=0.37

- 11% difference in healing time in favor of acyclovir (hazard ratio = 1.110) was not considered clinically significant

- among subjects whose lesions healed and who therefore had a lesion of known duration, mean healing times were comparable between the CSP and acyclovir groups (6.70 and 6.49 days, respectively; P=0.43)

• Results of subject-assessed mean peak severity and mean duration for individual signs and symptoms are shown in Table 1

• CSP-treated subjects reported a high level of protection/hygiene with mean ratings of approximately 7 on the 0-10 scale (Table 2). In contrast, mean ratings were in the 4-5 range in the acyclovir group

• CSP-treated subjects believed that the study treatment made their cold sore less noticeable and helped to hide sores and blemishes while they were healing (mean rating of 3.25 on 1-4 scale) (Table 3)

• A majority of CSP-treated subjects (75%) felt that the study treatment helped relieve the social embarrassment and anxiety of having a cold sore (Table 4)

CSPn = 366

TreatmentInitiatedn = 179

Did Not ExperienceCold Sore Outbreak

n = 187

Completedn = 172

Withdrawnn = 7

Subject Choice(withdrew consent) 1Lost to Follow-up 0Adverse Event 3Other 3

Acyclovir Cream 5%n = 362

RandomizedN = 728

TreatmentInitiatedn = 172

Did Not ExperienceCold Sore Outbreak

n = 190

Completedn = 167

Withdrawnn = 5

Subject Choice(withdrew consent) 0Lost to Follow-up 0Adverse Event 1Other 4

60

50

40

30

20

10

0

3 3 3 30 0

7 610 10 11

22

2928

10

26 2630

55

2 1

57

CSP (N = 173)Mean Rating: 7.89

Numberof

Subjects

Acyclovir Cream 5% (N = 169)Mean Rating: 8.00

Di�erence in Mean Rating (CSP - Acyclovir) = -0.11 (-0.58, 0.36)

Between-Treatment ANOVA P Value = 0.65

Rating Scale*: 0 1 2 3 4 5 6 7 8 9 10

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Proportionnot

Healed

0 2 4 6 8 10 12 14

Day

CSP

Acyclovir Cream 5%

CONCLUSIONS• CSP was comparable with acyclovir cream 5% for the

treatment of lesions associated with HSL, and both treatments were well tolerated by subjects in the study

• This study established that a hydrocolloid patch, such as CSP, may provide a safe and effective alternative to topical antivirals in treating HSL lesions as a wound, while affording additional benefits of wound protection, discretion, and relief of social embarrassment.

REFERENCES1. Embil JA, Stephens RG, Manuel FR. Can Med Assoc J. 1975;113:627-630.

2. Löwhagen GB, Bonde E, Eriksson B, Nordin P, Tunbäck P, Krantz I. Scand J Infect Dis. 2002;34:664-667.

3. Malvy D, Ezzedine K, Lançon F, et al. J Eur Acad Dermatol Venerol. In press.

4. Young TB, Rimm EB, D’Alessio DJ. Am J Epidemiol. 1988;127:612-625.

5. Arduino PG, Porter SR. Oral Dis. 2006;12:254-270.

6. Evans TG, Bernstein DI, Raborn GW, Harmenberg J, Kowalski J, Spruance SL. Antimicrob Agents Chemother. 2002;46:1870-1874.

7. Fletcher J. Nurs Times. 2003;99:57.

8. Falanga V. Arch Dermatol. 1988;124:872-877.

9. Field CK and Kerstein MD. Am J Surg. 1994;167(1A):2S-6S.

10. Haimowitz JE and Margolis DJ. Moist wound healing. In: Krasner D, Kane D, eds. Chronic Wound Care. 2nd ed. Wayne, PA: Health Management Publications, Inc.; 1997:49-56.

11. Karlsmark T. Presented at the Annual Meeting of the Congress of the European Academy of Dermatology and Venerology; October 4-8, 2006; Rhodes, Greece.

Table 1. Mean peak severity and mean duration for subject-assessed signs and symptoms (ITT population)

Mean peak severity* Mean duration (days)‡

Sign/symptomCSP(N=179)

AcyclovirCream 5%(N=172)

CSP(N=179)

AcyclovirCream 5%(N=172)

(n) (n)

Pain 3.28 3.13 3.55 (116) 3.41 (113)

Discomfort 4.03 3.85 3.90 (131) 3.64 (128)

Itching 3.26 2.90 2.99 (115) 3.61 0(93)

Burning 3.11 2.94 2.92 (107) 2.46 (100)

Tingling 3.42 2.95 2.55 (121) 2.45 (111)

Swelling 4.09 3.80 3.39 (131) 3.00 (134)

Soreness/ tenderness 4.16 3.92 3.95 (127) 3.81 (132)

Blisters 4.07 3.47† 3.57 (127) 2.96 (119)

Scab or crust 3.34† 4.10 3.86 0(83) 4.06 0(92)*Rating scale: 0=none, 10=most severe. †P<0.05. ‡Mean duration data based on subjects (n) who reported the symptom. P values not reported for mean duration due to variation in n values.

Table 4. Subject-assessed relief of social anxiety and embarrassment

Rating* CSP (N=173)†Acyclovir Cream 5% (N=169)

No. % No. %

Agree strongly 60 35 44 26

Agree slightly 69 40 47 28

Disagree slightly 26 15 39 23

Disagree strongly 18 10 39 23*Subjects were asked to rate their response to the following statement: “The study medication helped to relieve the social anxiety and embarrassment of having a cold sore.” †P=0.0002.

Figure 3. Time to complete healing, rated by the clinician (ITT population).

Figure 1. Subject disposition.

Figure 2. Frequency of ratings in the subject’s global assessment of therapy (SGAT) in the ITT population.

*Rating scale: 0-10; 0 = no response, 10 = excellent response.

Figure 4. Subject treated with CSP until time to complete healing.

• Figure 4 shows 6 progressive photographs of a subject treated with CSP until time to complete healing.

Adverse Events

• Both treatments were well tolerated and no serious AEs were identified

• 18 (10.1%) CSP-treated subjects and 15 (8.7%) acyclovir-treated subjects reported AEs

• 4 AEs deemed very likely to be related to study treatment were reported in the CSP group (mild bleeding of lip, erythema and/or irritation) and 2 in the acyclovir group (mild bleeding of lip, erythema/irritation).

Table 2. Subject-assessed lesion protection/hygiene (ITT population)*

Time point CSP (N=179)Acyclovir Cream 5% (N=172)

Mean (n) Mean (n)6-12 hours 7.15† (172) 4.13 (171)Day 1 7.03† (172) 4.15 (171)Day 2 7.07† (172) 4.27 (170)Day 3 6.84† (168) 4.37 (165)Day 4 7.00† (151) 4.78 (139)Day 5 6.97† (140) 4.49 (128)Day 6 6.95† (113) 4.69 (105)Day 7 7.26† 0(98) 4.64 0(85)Day 8 7.55† 0(69) 5.17 0(58)Day 9 7.10 0(51) 5.88 0(43)

Day 10/end of therapy 7.94 0(32) 6.13 0(24)

*Rating scale: 0=no protection, 10=most protection. †P<0.05.

Table 3. Subject-assessed noticeability of lesion (ITT population)

CSP (N=179)Acyclovir Cream 5% (N=172)

Noticeability of cold sore* 3.25† 2.47*Subjects were asked to rate their response to the following statement on a 4-point scale: “The study medication made my cold sore less noticeable and helped to hide the sores and blemishes while they were healing.” †P<0.05 Rating scale: 1 = strongly disagree, 4 = strongly agree.