randomized clinical study comparing compeed® cold sore patch

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 Group
Bispebjerg Hospital, Copenhagen, Denmark; 2Hill Top Research, West Palm Beach, Florida; 3Dermexpert, Paris, France; 4Johnson & Johnson, Skillman, New Jersey; 5Johnson & Johnson consultant statistician, Hamilton, Texas
1
For presentation at:
14th Meeting of the International Herpes Management Forum
October 10-11, 2007
INTRODUCTION
ABSTRACT
Background: 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, assessorblinded 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.
•
•
METHODS
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
Study Design
Outcome Measures
•
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
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 clinicianassessed time to complete healing.
•
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.
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 intentto-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:
Study Assessments
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.
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)
OBJECTIVE
•
•
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.
− lesion protection/hygiene, lesion noticeability,
and relief of social embarrassment
To evaluate and compare the efficacy and safety of CSP and
acyclovir cream 5% in the treatment of HSL.
-
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.
RESULTS
Subject Disposition (Figure 1)
•
Figure 1. Subject disposition.
Randomized
N = 728
-
CSP
n = 366
Treatment
Initiated
n = 179
Completed
n = 172
Acyclovir Cream 5%
n = 362
Did Not Experience
Cold Sore Outbreak
n = 187
Withdrawn
n=7
Treatment
Initiated
n = 172
Completed
n = 167
Subject Choice
(withdrew consent)
Lost to Follow-up
Adverse Event
Other
Clinician-assessed time to complete healing (Figure 3)
was similar for the two groups as reflected visually by
the Kaplan-Meier curves
Did Not Experience
Cold Sore Outbreak
n = 190
-
Withdrawn
n=5
Subject Choice
(withdrew consent)
Lost to Follow-up
Adverse Event
Other
1
0
3
3
-
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)
Figure 3. Time to complete healing, rated by the clinician
(ITT population).
0
0
1
4
1
CSP
Acyclovir Cream 5%
0.9
Baseline Demographics of ITT Population
0.8
•
Mean age was 42.7 ± 13.7 years
0.7
•
82% were female
•
92% were Caucasian.
-
-
0.1
0
0
2
4
6
8
10
12
0(32)
6.13
(n)
(171)
(171)
(170)
(165)
(139)
(128)
(105)
0(85)
0(58)
0(43)
0(24)
57
55
50
40
30
29 28
26 26
22
20
10 11
10 10
2
0 0
CSP (N = 173)
Mean Rating: 7.89
1
Difference in Mean Rating (CSP - Acyclovir) = -0.11 (-0.58, 0.36)
•
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).
CONCLUSIONS
Sign/symptom
CSP
(N=179)
Acyclovir
Cream 5%
(N=172)
Noticeability of cold sore* 3.25†
Acyclovir Cream 5%
(N=172)
•
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.
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.
*
Mean duration (days)‡
CSP
(N=179)
Acyclovir
Cream 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)
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)
1.
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.
CSP (N=173)
Acyclovir Cream 5%
(N=169)
3.
Malvy D, Ezzedine K, Lançon F, et al. J Eur Acad Dermatol Venerol. In press.
No.
%
No.
%
4.
Young TB, Rimm EB, D’Alessio DJ. Am J Epidemiol. 1988;127:612-625.
Table 4. Subject-assessed relief of social anxiety and
embarrassment
Rating
*
REFERENCES
†
Soreness/
tenderness
4.16
3.92
3.95
(127)
3.81
(132)
Blisters
4.07
3.47†
3.57
(127)
2.96
(119)
Agree strongly
60
35
44
26
5.
Arduino PG, Porter SR. Oral Dis. 2006;12:254-270.
Scab or crust
3.34†
4.10
3.86
0(83)
4.06
0(92)
Agree slightly
69
40
47
28
6.
Disagree slightly
26
15
39
23
Evans TG, Bernstein DI, Raborn GW, Harmenberg J, Kowalski J, Spruance SL.
Antimicrob Agents Chemother. 2002;46:1870-1874.
Disagree strongly
18
10
39
23
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.
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.
Acyclovir Cream 5% (N = 169)
Mean Rating: 8.00
14
Results of subject-assessed mean peak severity and
mean duration for individual signs and symptoms are
shown in Table 1
Mean peak severity*
*
3 3 3
Adverse Events
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)
CSP (N=179)
Table 1. Mean peak severity and mean duration for subjectassessed signs and symptoms (ITT population)
60
• Figure 4 shows 6 progressive photographs of a subject
treated with CSP until time to complete healing.
Table 3. Subject-assessed noticeability of lesion (ITT population)
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
0
7.94
(n)
(172)
(172)
(172)
(168)
(151)
(140)
(113)
0(98)
0(69)
0(51)
Day
•
3
Mean
4.13
4.15
4.27
4.37
4.78
4.49
4.69
4.64
5.17
5.88
•
no statistically significant difference in SGAT
between CSP and acyclovir at the end of therapy
(P=0.65)
7 6
6-12 hours
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Mean
7.15†
7.03†
7.07†
6.84†
7.00†
6.97†
6.95†
7.26†
7.55†
7.10
Rating scale: 0=no protection, 10=most protection.
P<0.05.
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
10
CSP (N=179)
†
0.2
Number
30
of
Subjects
Time point
Acyclovir Cream 5%
(N=172)
*
0.3
Figure 2. Frequency of ratings in the subject’s global assessment of
therapy (SGAT) in the ITT population.
Figure 4. Subject treated with CSP until time to complete healing.
Table 2. Subject-assessed lesion protection/hygiene
(ITT population)*
0.4
SGAT ratings were highly favorable and similar in both
treatment groups (Figure 2)
-
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
Day 10/end of
therapy
Proportion 0.6
not
Healed
0.5
Efficacy Analyses
•
•
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.
*
Between-Treatment ANOVA P Value = 0.65
Rating Scale*:
0
1
2
3
4
5
*Rating scale: 0-10; 0 = no response, 10 = excellent response.
6
7
8
9
10