Trial Information

Randomized Double Blind Study Comparing Liquid Nitrogen Cryotherapy With Nd:YAG in the Treatment of Verruca Vulgaris

Outcome measures: The primary outcome will be complete resolution of the lesion defined as:
clinical absence of verruca vulgaris with redevelopment of skin lines on the dorsal surface
and dermatoglyphics (ridges of the skin) on the inner surface of the palms and feet, as
determined by a blinded clinician investigator blinded to the treatment will evaluate each
lesion and determine whether the lesion. A secondary outcome will include: time to complete
resolution of the lesion.

2. Objectives and Specific Aims 1.1. Primary objective: To evaluate the efficacy of the
Cutera CoolGlide 1064nm Nd:YAG laser in the treatment of verruca vulgaris of the hands and
feet versus conventional therapy with liquid nitrogen cryotherapy.

2. Research Design and Methods This a single site double blind (faculty observer and
patient blinded; operator/clinician non-blinded), randomized controlled clinical trial to
evaluate the efficacy of the Nd:YAG laser (Cutera) in the treatment of verruca vulgaris of
the hands and feet versus conventional therapy with liquid nitrogen in 52 patients.

2.2 Study Procedures Informed consent A signed informed consent form will be obtained from
each patient prior to entering the study

Physical examination A brief physical examination of the skin including the affected area
will be performed. Photographs will be taken of affected areas, prior to and after each
treatment from baseline through the fifth treatment follow-up. The investigator will
document the number, size and location of each lesion.

Laboratory tests No laboratory testing will be performed for this research project.

Procedure Visit

Initial Visit (DAY 1):

Prior to the clinic visit and treatment:

1. The patient will be screened for inclusion by a study team member using a screening
questionnaire (Appendix A).

2. A sub-investigator will review the screening criteria to validate that the patient
meets eligibility criteria.

3. Written informed consent will be obtained from the patient before participation in the
study (Appendix B).

Treatment 1:

1. The qualifying eligible patient who has consented to participate in the study will be
assigned to receive either Nd:YAG laser treatment or liquid nitrogen therapy using a
previously established block randomization schema prepared by the research
statistician.

2. All lesions will be evaluated and pared with a #15 surgical blade if thickness, a
callous, crust or debris is noted, or if hyperkeratosis or other skin thickening is
evident which would impede evaluation of the wart.

3. The attending faculty physician will confirm the diagnosis with use a dermatoscope and
will be blinded to the treatment assignment.

4. Photos will be taken of the lesions, after paring with a #15 blade to remove any crust
or thickened skin above the wart, prior to treatment, and after treatment. A
consistent photography procedure (Appendix C) will be used. Each wart will be
numbered; size and location will be documented on the Dermatology Study Wart Assessment
and Treatment Records (Appendix D). Photographs will be taken before and after
treatment.

5. All lesions will be anesthetized with topical lidocaine (LMX 4%) applied under
occlusion for 15minutes prior to treatment.

6. All patients will be prepared for treatment in the same manner. They will wear the
protective goggles used in laser treatment and will use head phones to muffle the sound
of treatment. Both treatment modalities will be turned on prior to the treatment so
sounds may not be predictive of the treatment.

8. The patients that have been randomly selected to receive Nd:YAG laser treatment will be
fully treated with the following parameters for the laser. If the warts are greater than
3mm the following settings will be used: 20 millisecond pulse width, fluence 180 J/cm2, spot
size 5 mm. If warts are 3mm or less in diameter, the laser settings will be: 180 J/cm2, spot
size 3mm, pulse width 15 milliseconds. No laser gel will be used during treatment. After
each laser pulse, the treated area can be briefly cooled with the tip of the laser. If more
than one pulse is needed to cover the entire area of the wart, 10% overlap will be used and
area outside of the wart border will not be treated.

9. The patients that have been randomly selected to receive liquid nitrogen treatment will
receive liquid nitrogen spray gun for 5-7 seconds creating and maintaining a 1-2 mm freeze
halo around lesion for the duration of the application. Use nozzle extender for warts less
than 3 mm.

10. Patients will be instructed to avoid treating the warts at home, but they may use
vaseline, aquaphor, or plain petrolatum and a band aid as needed for comfort until the next
visit .

11. Patients will schedule a return visit in two weeks for assessment of the effects of
treatment.

12. Patient treatments will be documented on the appropriate Dermatology Study Wart
Treatment Record (Appendix D). Revision of the Dermatology Study Wart Treatment Record is
attached with the Request for Revision.

12.1 Document the patient's medications on the Master Medication Record 12.2 Document the
patient's warts on the Master Record of Warts

1. Treatments #2, 3, 4, 5 (DAY 14, 28, 42, 56; +/- 7 days) Patient will return at 2week
intervals for evaluation and documentation of lesions.

2. An objective faculty observer blinded to treatment, will evaluate wart persistence or
clearance at treatments #2, 3, 4, and 5, after the lesion is pared. Faculty will
document findings on the Wart Study Attending Faculty Observer Assessment Tool Appendix
E).

3. Photos will be taken after paring lesions with a #15 blade; number, size, and location
of lesions will be documented, as well as occurrence of any new warts.

1. If the patient has no clinical lesions present as determined by a blinded faculty
clinician, the patient will move on to follow up phase, see below.

2. If there is still clinical evidence of persisting lesions the patient will be
retreated with the same randomized modality as in treatment #1.

3. If new warts are identified, the investigators will document the number, size, and
location of the warts, and photograph the new warts before and after treatment.

4. Treatment of new warts will be with the same randomized treatment modality to
avoid patient un-blinding.

4. All lesions will be anesthetized with topical lidocaine (LMX 4%) applied under
occlusion for 15 minutes prior to treatment.

5. All patients will be prepared for treatment in the same manner. They will wear the
protective goggles used in laser treatment and will use head phones to muffle the sound
of treatment. Both treatment modalities will be turned on prior to the treatment so
sounds may not be predictive of the treatment.

6. Proceed with treatment of warts in the same manner as randomization. Complete steps 9-
11 as listed under the initial treatment.

Follow-Up Phase: Clinical Clearance Once a lesion is clinically clear, the patient will
move on to the follow up phase. No lesion will be treated more than 5 times. Patients who
do not clear after the evaluation of the 5th treatment will be considered treatment failure
and will be removed from the study. Patients who fail study treatment will be offered
continuing treatment outside of the study through Dermatology Clinic. The patient will be
responsible for standard charges for any additional treatment through Dermatology Clinic.

Patients who clear will return to the clinic for evaluation at 1 and 2 months after clinical
clearance to determine continued clearance or recurrence. Recurrence will be defined as a
new clinical evident lesion that appear in the same location(s) as the previously treated
wart(s) up to 2 months post treatment.

1 and 2 Month Follow Up

1. Clinician will perform an examination of the treated areas as in previous visits.

2. Photos will be taken.

3. Size and location of new lesions, if any, will be documented.

4. Recurrence of previously treated lesions will be documented.

4 Month Follow-up

At 4 months following the clearance date, a structured telephone interview will investigate
the status of the lesion(s). If the patient is unsure of the status of clearance, the
patient will be asked to return for evaluation by the sub-investigator. If the wart recurs
or persists, the patient will be offered additional treatment using other options and will
be billed for any post-study treatment.

3. Data management and statistical analysis Data Collection and management Data will be
collected on paper Case Report forms by the resident physician treating the subject. See
data collection tools (Appendix D) and rules in the Procedure Book. Double data entry will
be provided by data entry staff into two separate excel spread sheets. Data comparison will
be completed by the research statistician. Any discrepancies will be reviewed by the study
team. Issues in need of adjudication will be decided by the PI.

Sample size determination: Sample size was calculated based on a formula for effective
sample size in a randomized clustered design with binary outcomes. On average, patients
will present with approximately three lesions (usually between 1 and 5) requiring treatment.
An estimate of a 50% cure rate, using cryotherapy for plantar warts, was drawn from a
Cochrane review published in 2006 [10, 11]. We will consider a clinically significant
improvement, if at least 80% of the warts treated by Nd:Yag laser are completely resolved at
the 6 month visit. We will assume a moderate intra-cluster correlation coefficient of 0.3.
Given the cluster design, enrolling 52 patients with, on average, 3 warts each, randomized
to one of two treatments, will be needed to provide 84% power to show a statistically
significant difference in cure rate. Significance will be set at p<0.05.

Data Management and Analysis All analyses will be done using SAS® 9.2. Demographic and
clinical variables will be summarized using means, medians and percentages, as appropriate.
To determine whether the primary outcome, complete resolution of each lesion at 2 and 4
months follow-up, is different between treatment groups, we will use a generalized linear
mixed model with a binomial distribution, and with initial lesion size and duration, as
covariates in the model. The correlation of outcomes within patient will be modeled using a
random effect. The secondary outcome, time to complete resolution will be analyzed using a
using a multilevel survival model with patient as a random effect and initial lesion size
and duration as covariates in the model. To see whether the results are sensitive to missing
data, both models will be analyzed with and without the self-reported 4-month outcomes.