Klearsen Corporation has received
hundreds of testimonials describing the benefits of using
DermaSeptic
for the treatment of various skin care infections - including
Cold Sores, Fever Blisters, Warts, Genital Warts and Genital
Herpes. Although testimonials are a good indication
of the effectiveness of the product, they only provide anecdotal
evidence of the products value. To provide a true test,
a double blind, placebo controlled cross-over study by a
reputable, disinterested third party medical organization
must be performed.
In the Fall of 2003, Klearsen
began such a study - performed and overseen by the University
of Colorado Health Sciences Center, Denver,
Colorado. The
purpose of this study is to test the efficacy of DermaSeptic
against Cold Sores. The protocol for this clinical
study was to recruit subjects who have a history of numerous
Cold Sore outbreaks a year. Each of these subjects
are being tracked through two outbreaks. The
subjects were given either a live DermaSeptic device
or a placebo DermaSeptic (disabled) device. Each
subject received instruction on the use of the
product. Neither
the subject nor the administering health care staff knew
which device the subject received.
Randomized,
Placebo-controlled,
Cross-over Study of the
Safety and Efficacy of a
Silver Iontophoretic Device to Treat
Recurrent
Herpes Labialis
Breeana K. Saffell and Steve Frank
June 24, 2005
| Abstract:
Herpes labialis is generally treated with oral cream, or ointment anti-viral
therapies. The treatment tested in this clinical trial is a silver
iontophoretic device that injects antiviral silver ions below the surface
of the skin at the site of an HSV lesion. In this study, 12 subjects with
a history of herpes labialis used both a test and a placebo device in two
separate episodes in order to treat HSV lesions. The results of the study
revealed a significant reduction in the time until the cessation of pain and
a notable reduction in the time until healed in the test device episodes in
comparison to the placebo device episodes. The time until crusting was
found to vary significantly among subjects and episodes, which produced a
slightly greater reduction in the placebo device episodes or little
difference at all. The results of this preliminary study bring awareness
to the potential of the device and to the improvements to be made in future
research.
Background:
Perioral herpes simplex virus (HSV) infection is a chronic malady that
affects more than 40 million people in the USA (12). This infection
typically causes painful and very visible sores near the border of the
lips and/or around the nose. Perioral HSV can be induced by fever, strong
sunlight, and local trauma, and is said to occur more commonly at times of
increased stress (8, 9). Perioral HSV has been treated with topical
applications of anti-viral therapy such as acyclovir, pencyclovir,
valacyclovir, docosanol, and undecylenic acid. The resulting reduction
of lesion duration is generally one-half day. Similar minimal reduction
in duration and pain is achieved with the use of oral anti-herpes drug
therapies (10,11). The following study examines the safety and efficacy
of an iontophoretic device (ID) (Klearsen DermaSeptic) that injects
antiviral silver ions below the surface of the skin at the presumed site
of the HSV replication. More than 10,000 ID's have been used without any
serious adverse events being reported (2).
Methods:
Subjects were recruited from COMIRB-approved advertisements and all study
visits were conducted at the Clinical Trials Center of the University of
Colorado Health Sciences Center under the direction of the investigator.
Subjects were required to have a history of perioral HSV occurring 4 or
more time per year and to be 18 years of age or older. Subjects were
disqualified if they used any other therapy in the 7 days prior to and
during an outbreak. Upon enrollment, subjects were randomly given one
of two devices to begin using at the first onset of an outbreak. They
were then given the other device to use for their second outbreak. The
two devices used were the ID and a placebo device that applied the current
in the reversed direction, using an inactive placebo gel. Subjects were
instructed to begin using the assigned device when they initially identified
either the onset of the prodrome, a local erythema, or a tender papule
(but before a vesicle forms), that they believe is due to perioral HSV.
Subjects were told to apply the device every 3 hours for 5 minutes while
awake through Day 4 and 3 times daily with no less than 4-hour intervals
up to and including Day 10, or until healing takes place, whichever comes
first. The Participant Use Log allowed the subjects to record pre-
application pain on a scale of 1-5 (1=no pain, 5=very painful), lesion
appearance (A-G), the number of device applications, and any discomforts
noted. Lesion appearance was ranked by letters A-G, which each described
the stage of the lesion (Table 1) (5). |
| Letter | Stage | Definition |
| A | Prodrome | A warning sign that often
indicates
the beginning of a cold sore. |
| B | Erythema | Redness of the skin where
the cold sore
is beginning or has been. |
| C | Papule | A small circumscribed
elevated are of the
skin. |
| D | Vesicle | A small circumscribed
elevation area of
the skin that contains fluid. |
| E | Ulcer | A local defect or excavation
of the surface
of the skin. |
| F | Crust | A scab |
| G | Healed | Return to normal skin
with the cessation
of signs or symptoms, including loss of crust if a vesicle
formed; residual erythema (redness) may be present. |
| Table 1: |
Lesion stage definitions that were listed on the
Participant Use Log and used to assess the state of the lesion by
the clinician, the review board, and the subject. |
| The subject was required to report to the clinic daily for the first five
days and then on the tenth day or at the point that healing occurred. The
visits consisted of the clinician taking a photograph of the lesion and
filling out a Visit Log/Progress Note. The clinician recorded their
assessment of the lesion (A-G), the participant's usage of the device,
the presence of any brown discoloration, the condition of the tip of the
device, and the functionality of the device on the tester (5).
Data Analysis:
The review board examined and analyzed every photograph taken at the subject
visits and made treatment-blinded assessments of the stages of the lesions
in order to compare an additional perspective to the clinician and subject
assessments. The data collected from the Visit Logs and the Subject Logs
was compiled and placed onto three different timelines. Each of these three
timelines was applied to the clinician, the subject, and the review board's
assessments of the time until crusting and the time until healing. In
addition, the three timelines were applied to the subject assessments of
the time until the cessation of pain. The first timeline was based on the
first visit being 0 days, assuming the visit to be in the morning, unless
otherwise specified. The second timeline was based on the predicted
initiation of symptoms based upon the stage of the lesion at the first
visit. It was assumed that the prodrome and erythema stages were beginning
symptoms (0 days), that the papule stage was 0.5 days into the outbreak,
that the vesicle stage was 1 day into the outbreak, and that the ulcer
stage was 2 days into the outbreak. The third timeline was based on the
time that treatment began. This was assumed to be at the first visit,
unless otherwise specified, or if the subject showed brown discoloration
during the first visit. Discoloration present at the first visit could
only indicate previous usage of the test device, so it is possible that
the placebo device had been used previous to the first visit, but it was
not visible. Therefore, it is possible that the timeline based on the
beginning of treatment could have been greater for the placebo device
episodes. A paired t-Test was run on the data in order to find statistical
significance (5).
Results:
Data from 12 subjects (22 episodes) was compiled and analyzed. Data
analysis revealed average values for three parameters including the
time until cessation of pain, the time until crusting, and the time
until healed. Each of these parameters was viewed based on three timelines
and were assessed by the clinician, the review board, and the subject.
In all three of the timelines for the parameter of the time until cessation
of pain, the test device showed a significant reduction (p less than 0.05)
in comparison to the placebo device (Table 2). A reduction in the test
group was also demonstrated in the parameter of the amount of time until
healed based on all three assessments and all three timelines (Table 3).
The parameter of the time until crusting showed no reduction in the test
device in comparison to the placebo device (Table 4).
The adverse events reported in this study were not serious. One adverse
event was brown discoloration that occurred on the site of application
while using the test device, which was an adverse event that was known
previous to the study. The subjects were informed prior to the study
that there may be some brown discoloration due to usage of the device.
The discoloration led to the drop-out of only one subject. In addition,
subjects with significant crusting reported the tip of the device sticking
to the scab and occasionally removing it, which occurred in both the test
and the placebo devices. Additional adverse events that were reported for
both the test and placebo devices were tolerable tingling and burning, and
additional pain from touching the device to the sensitive sore. |
Time Until Cessation of Pain
| | Timeline 1: visit 1(days) |
Timeline 2: initial symptoms (days) |
Timeline 3: beginning of treatment (days) |
| Test | Placebo | Test | Placebo |
Test | Placebo |
| SubjectAssessment | 2.7 | 4.4 | 3.3 |
5.4 | 2.7 | 4.5 |
| Table 2: | Average number of days until
cessation of pain elapsed on
three different timelines based on assessments made by the subject.
Results show a significant reduction (p less than 0.05) in time in the
test device in comparison to the placebo device. |
Time Until Healing
| | Timeline 1: visit 1(days) |
Timeline 2: initial symptoms (days) |
Timeline 3: beginning of treatment (days) |
| Test | Placebo | Test | Placebo | Test |
Placebo |
| Clinician Assessment | 5.4 | 7 | 6 | 7.9 |
5.3 | 7.1 |
| Review Board Assessment | 5.9 | 7 | 6.5 |
7.9 | 5.8 | 7.1 |
| Subject Assessment | 6.1 | 6.5 | 6.7 |
7.4 | 6.1 | 6.6 |
| Table 3: | Average number of days until healing
elapsed on three different
timelines based on assessments made by the clinician, the review board,
and the subject. Results show reduction in time in the test device in
comparison to the placebo device. |
Time Until Crusting
| | Timeline 1: visit 1(days) |
Timeline 2: initial symptoms (days) |
Timeline 3: beginning of treatment (days) |
| Test | Placebo | Test | Placebo | Test |
Placebo |
| Clinician Assessment | 3 | 1.7 | 3.7 | 2.7 |
2.9 | 1.8 |
| Review Board Assessment | 1.8 | 1.5 | 2.4 |
2.4 | 1.7 | 1.5 |
| Subject Assessment | 2.7 | 2.2 | 3.4 |
3.1 | 2.7 | 2.3 |
| Table 4: | Average number of days until crusting
elapsed on three different
timelines based on assessments made by the clinician, the review board,
and the subject. Results show no reduction in time in the test device
in comparison to the placebo device. |
| Discussion
Overall, the results of the present study show safety and some parameters
showed efficacy. Due to the small number of subjects completed in the
study, it is difficult to show statistical significance of the measured
parameters. However, statistical significance seen in the reduced time
until the cessation of pain and the reduction in the time until healed
that were seen in the test device in comparison to the placebo device,
demonstrate the potential benefits of the treatment.
The results show statistically significant reduction using the test device
in the time until cessation of pain based on all three timelines
(1.7, 2.1, 1.8 days respectively; p less than 0.05). The amount of time
until the cessation of pain in the test group is comparable to other
clinically studied treatments such as acyclovir and valacyclovir, which
range from 1.1 days to 3.1 days (3, 4, 6, 8).
The results of the time until healed parameter show a reduction in time
when using the test device that is significant considering the low number
of subjects and the amount of reduction seen in the other clinically studied
treatments. The average times until healed based on the clinician, review
board and subject assessments for the three timelines were 5.8, 6.4, 5.7
days respectively. In other clinical studies, anti-herpes therapies such
as acyclovir with hydrocortisone cream and famcyclovir have shown time
until healed to be an average of 8.6 days (1,7), which is significantly
greater than the duration seen in this study. In addition, the amount of
reduction seen in the test device in comparison to the placebo device for
all three timelines was 1.6, 1.9, and 1.8 days respectively, based on the
clinician's assessment, was 1.1, 1.4, and 1.3 days respectively, based on
the review board's assessment (Table 5). These are much greater reductions
than are seen in other treatments such as acyclovir with hydrocortisone
cream that average a reduction of 0.5 to 1 day (1,7). The reductions and
overall durations of this parameter show potential of the ID for efficacy
in reducing the healing time of a lesion. |
Reduction in Time Until Healed in the Test Device
| | Timeline 1: visit 1(days) |
Timeline 2: initial symptoms (days) |
Timeline 3: beginning of treatment (days) |
| Clinician Assessment | 1.6 | 1.9 | 1.8 |
| Review Board Assessment | 1.1 | 1.4 | 1.3 |
| Subject Assessment | 0.4 | 1.0 | 0.5 |
| Table 5: | Reduction in time until
healing in the
test device episodes in comparison to the placebo device episodes
for all three timelines and based on the assessments of the
clinician, the review board, and the subject. |
| The results showed little difference between the time until
crusting and showed that the placebo group was less than the test
group. However, this parameter showed the greatest amount of variation
within and between subjects. Therefore, it is not surprising that the
results showed more efficacy in the placebo and little variation overall.
This study has led to a better understanding of the usage of the device.
The cases in which the subject demonstrated good compliance of usage, the
difference between the test and placebo devices was greater. An example
of good versus poor compliance in this study is the comparison of the
results from two subjects. The more compliant subject used the test
device approximately 4 times daily for the first 3 days and the less
compliant subject used the test device 3 times daily for the first 3
days. The more compliant subject had much more brown discoloration and
had a greater difference between the test and placebo device episodes
based upon all three assessments in all three timelines for the parameters
of the time until healed and until the cessation of pain (Table 6).
In addition, the actual amount of time until healing is less in the test
episode for the more compliant subject for the average of the assessments
in all three timelines (6, 6.5, and 7.5 days respectively for the more
compliant versus 8, 8.5, and 8 days respectively for the less compliant
subject). The same trend is seen in the time until the cessation of pain
for all three timelines (2, 2.5, and 1.5 days respectively for the more
compliant versus 4, 4.5, and 4 days respectively for the less compliant
subject). The placebo device episodes were approximately the same for
both of the subjects. |
Differences between Test and Placebo Devices Due to Compliance
| | Timeline 1: visit 1(days) |
Timeline 2: initial symptoms (days) |
Timeline 3: beginning of treatment (days) |
| Healed:More Compliant | 1.5 | 2.0 | 2.0 |
| Healed:Less Compliant | 0.0 | 0.5 | 0.0 |
| Cessation of Pain:More Compliant | 2.0 | 2.5 | 2.5 |
| Cessation of Pain:Less Compliant | 1.0 | 1.5 | 1.0 |
| Table 6: | Differences in number of days until
healed and the cessation of
pain between the test and placebo devices for a more and a less compliant
subject. The more compliant subject demonstrates a greater difference,
with the test device episodes being the lesser numbers. |
| Good compliance depends upon the initiation of treatment, the frequency
of applications, and the quality of applications. It is very important
for the initiation of the treatment to occur as soon as possible at the
onset of symptoms, and definitely before the progression to the vesicle
stage, which was the stage at which treatment was begun in four of the test
device episodes. This is important because the viral activity primarily
occurs during the early stages of the lesion formation, which is generally
the first two days, making it the critical time for anti-viral treatment.
Unfortunately, many of the subjects in this study were unable to initiate
treatment in this window of time.
The frequency of applications is also a very important aspect of good
compliance. The subjects were instructed to use the device every 3 hours
per day for the first 5 days of treatment and then 3 times daily for the
remaining 5 days of the study. As demonstrated in the previously mentioned
example cases, subjects who applied the device more in the first 3 days,
showed more efficacy in the test device episodes. It is theoretically
ideal to be applying repeated anti-viral treatment during the first 12
hours of the outbreak. The other important aspect of good compliance is
the quality of each application. The silver from the test device leaves
a brownish discoloration at the site of application, which can demonstrate
the quality and frequency of patient applications. Some of the lesions
seen in this study may have required multiple applications due to the large
areas, which was not anticipated or accounted for in the original protocol.
It is interesting to note that the results that have been received from
customer feedback of the test device show much greater reductions than
the present study. It is believed that the reason for this is that the
customers have more experience using the device and have learned how to
more effectively use it at the first signs of tingling, therefore getting
better results (2). In future trials to test this device, the amount of
training given to the subjects for usage of the device will be much more
thorough than in the present study. Additionally, they will be instructed
to treat the entire lesion area equally in order to account for lesions
larger than the tip of the device.
Due to the low number of subjects in the present study, it is difficult to
make any strong statistical claims about the efficacy of the device.
However, the reductions seen in this preliminary study certainly begin
to illustrate the potential of the device, and strongly suggest further
research. |
References
|
1) Evans, T. G., Bernstein, D. I., Raborn, G. W., Harmenberg, J., Kowalski,
J., Spruance, S. L. 2002. Double-blind, randomized, placebo-controlled
study of topical 5% Acyclovir-1% Hydrocortisone cream (ME-609) for
treatment of UV radiation-induced Herpes Labialis. Antimicrobial Agents
and Chemotherapy 46(6):1870-1874.
2) Frank, S.R. 1998. Klearsen Corporation Data.
3) Jensen, L. A., Hoehns, J. D., Squires, C. L. 2004. Oral antivirals
for the acute treatment of recurrent herpes labialis. The Annals of
Pharmacotherapy 38: 705-709.
4) Madigosky, W. S., Meadows, S. 2004. Does acyclovir help herpes
simplex virus cold sores if treatment is delayed? The Journal of Family
Practice 53(11): 923-924.
5) Saffell, B.K. 2005. Review board procedures, protocols and raw data.
Klearsen Corporation.
6) Spruance, S. L., Jones, T. M., Blatter, M. M., Vargas-Cortes, M.,
Barber, J., Hill, J., Goldstein, D., Schultz, M. 2003. High-dose,
short-duration, early valcyclovir therapy for episodic treatment of
cold sores: Results of two randomized, placebo-controlled, multicenter
studies. Antimicrobial Agents and Chemotherapy 47(3): 1072-1080.
7) Spruance, S. L., McKeough, M. B. 2000. Combination treatment with
Famciclovir and a topical corticosteroid gel versus Famciclovir alone for
experimental ultraviolet radiation-induced Herpes Simplex Labialis: A pilot
study. J. Infectious Diseases 181:1906-10.
8) Spruance, S. L., Nett, R., Marbury, T., Wolff, R., Johnson, J.,
Spaulding, T. 2002. Acyclovir cream for treatment of herpes simplex
labialis: Results of two randomized, double-blind, vehicle-controlled,
multicenter clinical trials. Antimicrobial Agents and Chemotherapy
46(7): 2238-2243.
9) Spruance, S.L., Rea, T.L., Thoming, C., et al. 1997. Penciclovir cream
for the treatment of herpes simplex labialis. A randomized, multicenter,
double-blind, placebo-controlled trial. JAMA 277" 1374-1379.
10) Spruance, S.L., Stewart, J.C.B., Freeman, D.J., et al. 1990. Treatment
of recurrent herpes simplex labialis with oral acyclovir. J Infect Dis 161:
185-190.
11) Valacyclovir (Valtrex) for herpes labialis. Med Lett Drugs Ther, 2002;
44: 95-96.
12) Yeung-yee KA, Brentjens MH, Lee PC, Tyring SK. 2002. Herpes simplex
viruses 1 and 2. Dermatol Clin. 20:249-266. |
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