A Multicenter, Prospective, Randomized, Comparison IDE Study Between the Pulse Biosciences CellFX System and Cryosurgery for the Treatment of Cutaneous Non-Genital Common Warts
Phase: NA
Conditions: Warts, Warts Hand, Verruca
Sponsor: Pulse Biosciences, Inc.

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Clinical Investigational Plan 
 
 
Study Title: A Multicenter, Prospective, Randomized, Comparison IDE Study between the 
Pulse Biosciences CellFX® System and Cryosurgery for the Treatment of Cutaneous    
Non-Genital Common Warts 
 
 
 
Short Title: CellFX Comparison to Cryosurgery in Cutaneous Non-Genital Common Warts 
 
 Protocol No: NP-WC-015 
Version 5.0 
16-APR-2021 
 
 
IDE Number: G200348 
NCT:04738734 
 
 
Study Sponsor: 
 
Pulse Biosciences, Inc. 
3957 Point Eden Way 
Hayward, CA 94545 
 
 
 
 
 
This document is a confidential communication of Pulse Biosciences, Inc.  The recipient agrees that no unpublished information 
contained herein will be published or disclosed without prior written approval of Pulse Biosciences, Inc. except that this document 
may be disclosed to appropriate institutional review boards, ethics committees or duly authorized representatives of the U.S. Food 
and Drug Administration or other responsible regulatory authorities under the condition that confidentiality is maintained. 
 

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PROPRIETARY AND CONFIDENTIAL 
TABLE OF CONTENTS 
 
STUDY CONTACTS .............................................................................................................................. 5 
1.0 INTRODUCTION AND BACKGROUND ......................................................................................... 6 
1.1 Common Warts of Hand and Fingers ............................................................................................ 6 
1.2 Current Care .................................................................................................................................. 6 
1.3 Non-Surgical Approach ................................................................................................................. 6 
1.4 Surgical Approach ......................................................................................................................... 7 
1.5 Alternative Approach .................................................................................................................... 7 
1.6 Study Rationale ............................................................................................................................. 9 
2.0 STUDY DEVICE DESCRIPTION .................................................................................................. 10 
2.1 Pulse Bioscience CellFX® System .................................................................................................10 
2.2 Proposed Indication for Use .......................................................................................................12 
2.3 Cryosurgical System ....................................................................................................................12 
3.0 PROTOCOL ................................................................................................................................... 12 
3.1 Study Objectives .........................................................................................................................12 
3.2 Study Design................................................................................................................................12 
3.3 Randomization ............................................................................................................................13 
3.4 CellFX Procedure .........................................................................................................................13 
3.5 Standard Cryosurgical Procedure ...............................................................................................14 
3.6 Site Selection ...............................................................................................................................14 
3.7 Number of Subjects ....................................................................................................................14 
3.8 Clinical Study Duration ................................................................................................................14 
4.0 STUDY PROCEDURES ................................................................................................................ 14 
4.1 Screening .....................................................................................................................................14 
4.2 Subject Selection .........................................................................................................................15 
4.2.1 Inclusion Criteria ..................................................................................................................15 
4.2.2 Exclusion Criteria .................................................................................................................15 
4.3 Process for Obtaining Informed Consent ....................................................................................16 
4.3.1 Process for Obtaining Informed Consent ............................................................................16 
4.3.2 Addition of New Information ..............................................................................................16 
4.4 Schedule of Events and Evaluations ...........................................................................................17 
4.5 Screening / Enrollment Procedures ............................................................................................18 
4.6. 7-Day Follow-up Visit .................................................................................................................18 
4.7  30-Day Follow-up Visit (CellFX/Cryosurgical Treatment #2, if required) ...................................19 
4.8  60-Day Follow-up Visit (CellFX/Cryosurgical Treatment #3, if required) ...................................19 
4.9  90-Day Follow-up Visit ...............................................................................................................20 
4.10  120-Day Follow-up Visit ...........................................................................................................20 
4.11  150-Day Follow-up Visit ...........................................................................................................21 
4.12 Subject Withdrawal ...................................................................................................................21 
5.0 BENEFITS AND RISKS................................................................................................................. 21 
5.1 Benefits .......................................................................................................................................21 
5.2 Risks ............................................................................................................................................21 
5.3 Mitigation of Risks.......................................................................................................................21 
6.0 STATISTICAL CONSIDERATIONS .............................................................................................. 22 
6.1 Co-primary Endpoints .................................................................................................................22 
6.1.1 Co-primary Safety Endpoints ...............................................................................................22 
6.1.2 Primary Effectiveness Endpoint ...........................................................................................23 

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6.1.3  Justification of Non-Inferiority Design and Margin ............................................................23 
6.1.4  Type I Error Control and Study Success ..............................................................................24 
6.2 Secondary Endpoints ..................................................................................................................24 
6.3 Sample Size Determination .........................................................................................................26 
6.5 Sub-Group Analyses ....................................................................................................................27 
6.6 Missing Data ................................................................................................................................27 
7.0 EXPLORATORY ENDPOINTS ..................................................................................................... 28 
7.1 Exploratory Efficacy Endpoint .....................................................................................................28 
7.1.1 Subject-level clearance of all warts at 30 days post last treatment ....................................28 
7.2 Exploratory Safety Endpoints ......................................................................................................28 
7.2.1 Subject-level wound healing adverse events at 30 days post last treatment .....................28 
7.2.2 Subject-level skin change adverse events at 90 days post last treatment ..........................28 
8.0 CLINICAL PHOTOGRAPHY ......................................................................................................... 28 
9.0 INDEPENDENT PANEL REVIEW ................................................................................................. 28 
10.0  ADVERSE EVENTS .....................................................................................................................29 
10.1 Adverse Event Definitions .........................................................................................................29 
10.1.1 Adverse Event (AE): (ISO 14155:2011 3.2) ........................................................................29 
10.1.2 Adverse Device Effect (ADE): (ISO 14155:2011 3.1) ..........................................................30 
10.1.3 Serious Adverse Event (SAE) (ISO 14155:2011 3.37) .........................................................30 
10.1.4 Serious Adverse Device Effect (SADE): (ISO 14155:2011 3.36) .........................................30 
10.1.5 Unanticipated Adverse Device Effect (UADE): (21CFR812.3) ............................................30 
10.2 Device Deficiencies (ISO 14155:2011 3.15) ..............................................................................30 
10.2.1 Definitions .........................................................................................................................30 
10.3 Safety Reporting Requirements ................................................................................................31 
10.3.1 Blinded Live Assessment of Adverse Events ......................................................................31 
10.3.2 Safety Monitor ...................................................................................................................31 
10.3.3 Investigator Responsibilities ..............................................................................................31 
11.0  STUDY MANAGEMENT (SPONSOR RESPONSIBILITIES) ..................................................... 32 
11.1 Sponsor Ethical and Regulatory Considerations .......................................................................32 
11.2 Selection of Clinical Sites ..........................................................................................................32 
11.3 Site Training ..............................................................................................................................33 
11.4  Investigator Training ................................................................................................................33 
11.5 Monitoring of Study Sites .........................................................................................................33 
11.5.1 Monitoring Methods .........................................................................................................33 
11.5.2 Periodic Monitoring Visits (Onsite and Remote) ...............................................................33 
11.5.3 Site Close-out Visit .............................................................................................................34 
11.6 Protocol Deviations ...................................................................................................................34 
11.7 Study Completion......................................................................................................................34 
11.8 Audits / Inspections ..................................................................................................................35 
11.9 Publication Policies ...................................................................................................................35 
11.10 Data Management ..................................................................................................................35 
11.11 Case Report Forms /Transmission of Data .............................................................................35 
11.12 Data Retention ........................................................................................................................35 
12.0  INVESTIGATOR RESPONSIBILITIES ....................................................................................... 36 
12.1 IRB Approval and Informed Consent ........................................................................................36 
12.2 Data Collection and Reporting ..................................................................................................36 
12.3 Source Documents / Records Retention ...................................................................................37 
12.4 Device Accountability................................................................................................................37 
13.0   REFERENCES .......................................................................................................................... 38 

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14.0 APPENDICES ............................................................................................................................. 39 
14.1 Appendix A: Patient Informed Consent ....................................................................................39 
14.2 Appendix B: Case Report Forms ................................................................................................39 
APPENDIX A: Patient Informed Consent will be provided as a separate attachment ......................40 
APPENDIX B: Case Report Forms will be provided as a separate attachment..................................41 

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STUDY CONTACTS 
 
Name, Address and Contact 
Study Sponsor 
Pulse Biosciences, Inc. 
3957 Point Eden Way 
Hayward, CA 94545 
  
Official Sponsor Correspondent 
William A. Knape   
VP, Clinical, Regulatory, and Quality Affairs 
Pulse Biosciences, Inc. 
3957 Point Eden Way 
Hayward, CA 94545 
Phone: 919.757.2033  
bknape@pulsebiosciences.com 
Central Institutional Review Board 
Advarra Institutional Review Board 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 USA 
Phone: 410.884.2900 
Clinical Photography 
 
Canfield Scientific, Inc. 
4 Wood Hollow Road 
Parsippany, NJ 07054 
 
 
 

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1.0 INTRODUCTION AND BACKGROUND 
1.1  Common Warts of Hand and Fingers 
Non-genital warts (verruca vulgaris) are an extremely common, benign, and usually a self-limited skin 
disease. Infection of epidermal cells with the human papillomavirus (HPV) results in cell proliferation 
and a thickened, round, raised papule on the skin ranging in size from a pinhead to 10 mm. The 
appearance of warts is determined by the type of virus and the location of the infection. There are 
several reasons why some individuals are affected by warts, and other remain trouble free.  These 
include: the type and strength of the viral strain, the health of the exposed person, and the strength 
of an individual’s immune response.  Any area of skin can be infected, but the most common sites 
are the hands and feet. Common warts are most often seen on the hands and present as skin-colored 
papules with a rough 'verrucous' surface.  
 
1.2 Current Care 
Current treatments for common warts involve destruction of the infected cells either chemically or 
physically and treatment depends on the size, location, number, type, age of the patient, risk of 
scarring and patients’ commitment to the therapy.  The clinical management of these warts is 
challenging, and no current treatment is singularly effective, especially against warts that are 
recalcitrant. These include non-surgical, pharmacologic, and surgical treatment modalities: topical 
peeling methods like salicylic acid; immune modulators using contact immunotherapies; intralesional 
candida antigen or bleomycin; cryotherapy; duct tape occlusion; photodynamic treatment; pulsed 
dye laser; and general surgical procedures. 
 
1.3 Non-Surgical Approach  
Chemical Destruction:  
Salicylic Acid 
The use of salicylic acid is one of the two most commonly used treatments for warts. Dermatologists 
prescribe chemical destruction treatments where patients apply an over-the-counter preparation, 
usually less than 17% salicylic acid or prescription salicylic acid containing up to 70% salicylic acid at 
home every day.  Treatment response rates of 40-84% with an average of 61% have been reported 
as an effective therapy for non-genital cutaneous warts.1  Minor skin irritation was reported 
occasionally in some of the other trials, but generally there were no major harmful effects of topical 
salicylic acid.2  A systematic review of local treatments of cutaneous warts by Mitsuishi et al., found 
evidence that topical treatments with salicylic acid have a therapeutic effect, with a cure rate of 75 
percent compared with 34-48 percent in placebo controls.1,3 Other agents used for chemical 
destruction are monochloracetic acid, dichloracetic acid, trichloroacetic acid, silver nitrate, glycolic 
acid and 80% phenol in solution.  Complications associated with using chemicals include pain, 
hyperpigmentation, hypopigmentation, burning sensation and erythema.4    
 
Cantharidin 
Cantharidin is used as an agent in the clinic by "painting" the wart causing oxidative stress by 
inhibiting phosphatases 1 and 2A that damages both DNA single- and double-strand breaks and 
triggers p53 dependent apoptosis.4   Cantharidin causes a blister to form under the wart. In a week 
or so, the patient returns to the office and the dermatologist clips away the dead wart. 
 
 

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Immune Modulators 
This treatment uses the patient’s own immune system to fight the warts. Forms of immune 
modulators include imiquimod, intralesional immune modulators using Candida antigen or anti-
cancer such as Bleomycin; contact immunotherapy, cimetidine, zinc, and retinoids. Because wart 
proliferation is controlled by the immune system, various methods have been used to stimulate the 
immunologic response to HPV. This treatment is used when the warts remain despite using other 
treatments and the ability to treat many lesions simultaneously. One type of immunotherapy 
involves applying a chemical diphenylcyclopropenone (DPCP). Among these are topically applied 
inorganic molecules capable of eliciting contact hypersensitivity, such as imiquimod and intralesional 
interferons5 to the warts. A mild allergic reaction occurs around the treated warts which stimulates 
the body’s innate response to fight the virus. 
 
Physical Destruction 
Liquid Nitrogen Cryotherapy 
For common warts in adults and older children, cryotherapy is a standard treatment and can be done 
in the physician’s office.  Cryotherapy involves freezing a wart using a very cold substance (usually 
liquid nitrogen). The liquid nitrogen application usually takes less than a minute and most warts 
require 1 to 4 treatments, with 1 to 3 weeks between each treatment. Pain from cryotherapy can 
last up to 3 days. Healing is generally quick (7 to 14 days) with little or no scarring.6  It can cause dark 
spots in people who have dark skin. With cryotherapy, it is common for repeat treatments. 
 
Laser 
Laser treatment is an option, mainly for warts that have not responded to other therapies. Before 
laser treatment, the dermatologist may numb the wart with an anesthetic injection.  
 
1.4 Surgical Approach 
Electrosurgery and Curettage 
Electrosurgery (burning) is an available treatment for common warts, filiform warts, and foot warts. 
Curettage involves scraping off (curetting) the wart with a sharp knife or small, spoon-shaped tool. 
These two procedures often are used together. The dermatologist may remove the wart by scraping 
it off before or after electrosurgery. 
 
Excision 
The wart may be cut off or surgically excised in combination to using other applications previously 
mentioned.  
 
1.5 Alternative Approach  
CellFX® System 
 
The CellFX System is intended to clear the skin of benign, undesired skin lesions as an alternative to 
surgery and other more destructive methods for removing non-neoplastic benign lesions. The CellFX 
System utilizes non-thermal, localized delivery of a timed series of low energy, nanosecond electrical 
pulses that can trigger regulated cell death.  The non-thermal effect on tissue takes place in a very 
shallow depth of skin directly below the sterile treatment tip. Histology of skin treated with CellFX 
has demonstrated selective non-thermal effects on cellular structures, including melanocytes, 
epidermal cells, and sebaceous glands, with no apparent damage to the adjacent acellular dermis.   

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The device delivers less energy to tissue, but none of these emit thermal energy unlike laser, electro-
surgery, or electro-cautery equipment. 
 
PRIOR CLINICAL STUDIES SUMMARY 
Twelve (12) clinical studies have been or are currently being conducted using IRB approved non-
significant risk protocols and consent with the Nano-Pulse Stimulation (NPS) device. A combined total 
of approximately 3,125 NPS application cycles have been delivered to over 680 adult subjects. 
Anatomic locations where NPS has been used include the face, abdomen, truncal, back, arms, legs, 
hands, and feet. Discomfort in all protocols was managed with localized injected buffered Lidocaine 
with or without epinephrine. Side effects consisted of relatively minor reactions consistent with 
routine wound healing. No device or procedure complications and no serious related adverse events 
were reported. Only minor expected adverse skin effects have been reported and they were resolved 
within days of the procedure. 
 
Previous Wart Studies Using CellFX System 
Nineteen (19) adult subjects were enrolled with the requirement of having a minimum of 2 and up 
to 5 non-genital, off-face cutaneous warts with one of the warts designated as a sham control. 
Subjects received an initial NPS treatment and returned for follow-up evaluations at 7-, 30- and 60 
days post-last treatment.  Each wart was evaluated for size reduction at 30-days for eligibility for 
retreatment and at 60-days post-last NPS session using a 5-point size scale. At the end of the study, 
all subjects were asked about their satisfaction with each treated lesion clearance based on a 5-point 
scale from 1 equaling highly dissatisfied and 5 being satisfied.7 
 
Six (6) of the nineteen subjects were male (32%) and 13 were female (68%). Subjects ranged in age 
from 23 to 71, with an average age of 47. Fitzpatrick skin types were distributed across Type I (5%), 
Type II (58%), and Type III (37%). Fifty-two percent (52%) of warts were recalcitrant with 69% 
common warts located on the hands, fingers, and shoulders and the remaining 31% plantar warts. A 
total of 58 warts were enrolled in the study, 40 treated and 18 controls including one subject having 
all warts treated without a  sham control. Two subjects withdrew early from the study giving a total 
per protocol population cohort of 37 treated and 16 control warts for evaluating wart reduction and 
clearance rates at 60-days post-treatment. Fifty-one percent (51%) of treated warts (19/37) received 
two treatments and 65% (n=20 common and 4 plantar) showed greater than 50% reduction in size 
with 51% (n=19) rated completely clear at 60-days post-treatment. Three (3) out of 16 sham control 
warts (18.8%) showed 100% reduction in size, suggesting a possible immune response involved with 
use of NPS. There were no observations of hypopigmentation and only 3 cases of hyperpigmentation 
at 60 days. No serious adverse events were reported, however in a few cases local bruising or 
formation of blood blisters post-treatment were noted that resolved by Day 7 or Day 30. Based on 
these initial results of achieving a high rate of wart size reduction, inclusive of recalcitrant warts, and 
with a single NPS session, a pivotal clinical study was initiated to further evaluate energy parameter 
settings of NPS technology for optimal clinical outcome.7 
 
The IRB-approved NSR Protocol# NP-WP-010 pivotal study was designed as a prospective, non-
randomized, multicenter study to evaluate the safety and efficacy of the CellFX System with 
expanding the number of clinical sites to 5 and using larger tip sizes as well as increasing the number 
of retreatments for investigators to clear cutaneous non-genital warts. Similar to the feasibility study 
each subject had to have a minimum of 2 warts with one wart serving as the subject’s internal 
control. Additionally, at the 30-day, 60-day and 90-day visits the Investigator had the option to 
retreat any previously treated wart and were followed for 30 and 60-days post last CellFX treatment 
(NCT04554394). 

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A total of 62 subjects and 267 study warts (195 treated and 62 sham controls) with an average of 4.1 
warts per subject were enrolled and evaluated at 60-days post last treatment. Forty-two subjects 
were female (68%) and 20 were male (32%) with an average age of 47.3. Fitzpatrick skin types were 
distributed across Type I (5%), Type II (44%), Type III (32%) and Type IV (19%). More than 70% of all 
treated warts were located on the hands, knee, ankle, arm, leg, neck, and torso while the remaining 
30% were plantar warts. Pre-treatment with intralesional injection of sodium bicarbonate buffered 
1-2% lidocaine with 1:100,000 epinephrine was used to control pain (mean, 1.0ml). Subjects reported 
a median 4.0 at the time of treatment based on a 11-point visual pain scale, with 47.8% reporting a 
score of 0 or 1.   
 
Overall efficacy at 60-days post-last treatment showing greater than 90% reduction in size was 
observed in 77.4% of common (72/93) and 43.8% of plantar warts (14/32). Single treatment efficacy 
at 60-days post-last treatment showed 81% (51/63) in patients with common warts and 31.6% (6/19) 
with plantar warts. Subject satisfaction at the end of study was reported in 73.7% (98/133) of 
subjects being satisfied with final results. As previously described in the wart feasibility study, there 
were 11 sham control warts (17.7%) showing 100% reduction in size. A total of 31 cases of transient 
hyperpigmentation (22.8%); 61% mild, 35% moderate, 3% mod/severe and 8 observations of 
hypopigmentation (5.9%) were observed at 60-days post-last treatment. No serious adverse events 
were reported however, 9 treatment-related adverse events (6 mild and 3 moderate severity) of 
transient pain, numbness, or infection were reported. These AEs occurred on the hands (n=5) or 
plantar area (n=4) and all were resolved with no associated sequela.8 
 
This new wart comparison study under Protocol NP-WC-015 will evaluate safety and efficacy using 
the CellFX System with pre-defined treatment energy profiles for all primary and secondary 
treatments based on the tip size.  The comparator group will be treated with cryosurgery with liquid 
nitrogen for the treatment of warts. 
 
1.6   Study Rationale  
The rationale for this IDE study is to compare the safety and effectiveness of the CellFX System to 
the comparator group, Cutaneous Cryosurgery performed with direct application with liquid nitrogen 
for the treatment of cutaneous, non-genital common warts in healthy adult subjects. 
 
 

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2.0  STUDY DEVICE DESCRIPTION 
The study device being evaluated is the Pulse Bioscience CellFX® System. 
 
2.1 Pulse Bioscience CellFX® System  
The CellFX System consists of an electrical pulse console (similar to devices used to electro-coagulate 
tissue) combined with a handpiece which is held by the clinician during application of pulses to the 
skin surface. The handpiece is coupled to a sterile, single patient-use treatment tip.  
Once the electrical pulse console is turned on and a predetermined treatment energy setting is 
selected, a sequence of pre-programmed electrical pulses is administered to an area of skin directly 
beneath the treatment tip.  A common commercially available sterile contact gel may be applied to 
the skin or treatment tip surface to ensure good electrical contact to the tissue. The three system 
components are as follows, shown in Figures 1-3.  
1. CellFX Console including a built-in touch screen for setting selection. 
2. CellFX Handpiece (re-usable) 
3. Sterile Single Patient-Use CellFX Tip (multiple different tip sizes available) 
 
Figure 1: CellFX Console 
 
Touchscreen Display
Accessories Drawer
Standby Indicator
Handpiece Connector
Locking Casters

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Figure 2: CellFX Handpiece 
 
 
 
 
 
Figure 3: CellFX Treatment Tips 
 
 
 
 
 
 
 
 
LED Indicator
Side Button –
Treatment Level 
Selectio
n
10 Ft. Cable
Tip Receptacle
Hook – For Hanging Handpiece
Finger Switch – Cycle Start
Console Connector

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2.2 Proposed Indication for Use 
The Pulse Biosciences’ CellFX System is investigational in the U.S. and the system is indicated for 
dermatologic procedures requiring ablation and resurfacing of the skin including the treatment of 
common warts. 
 
2.3 Cryosurgical System 
The comparator device that will be used in this study is the standard of care procedure using  liquid 
nitrogen to treat warts. The liquid nitrogen procedure uses a single freeze thaw cycle, with warts 
placed in contact with a metal probe (spray tip) held at liquid nitrogen temperature until a 2 to 3 mm 
halo is visible around each wart.   All physicians are required to use the same Cryosurgical System. 
 
3.0 PROTOCOL 
3.1 Study Objectives 
The primary objective of this study is to compare the safety and effectiveness of the CellFX System 
to Cryosurgery for the clearance of cutaneous non-genital common warts on all areas of the body, 
excluding the scalp, nose, within the orbital region of the face, plantar or periungual area in healthy 
adult subjects.  
The following objectives are to evaluate the overall response to CellFX and Cryosurgery: 
• 
Wart response after treatment vs. the pre-treated appearance of the same lesion 
• 
Wart response at various points in time over several weeks following the initial treatments 
vs. the same pre-treated wart 
• 
Overall wart clearance (generally accepted as complete clearance of warts from the 
treated area) 
• 
Comparisons of reduction from baseline in wart size of treated warts 
• 
Document the condition of skin in the treatment areas over the course of various time 
periods post-initial CellFX and Cryosurgery, and  
• 
Document all safety related issues that may be considered as adverse side effects or 
serious adverse events 
 
3.2 Study Design  
This study is designed as a prospective, multicenter, single-blinded, randomized comparison IDE 
study between CellFX System and Cryosurgery. The Principal Investigator will select a sub- 
investigator to be the blinded investigator to classify the healing characteristics and wart clearance 
and/or reduction assessment of each subject’s selected warts at baseline,  post treatment and at 7-
days, 30-days, 60-days, and 90-days following the last CellFX treatment or Cryosurgical procedure.  
This sub investigator will be blinded to the treatment assignment. The subject may not be blinded 
to the treatment assignment. The Principal Investigator can choose to be the blinded investigator 
and select a sub investigator to be the treating investigator. 
 
Eligible subjects with a minimum of 2 and up to 8 warts meeting the inclusion and exclusion criteria 
will be enrolled. If the subject has more than 8 warts, the subject is excluded from the study. Warts 
may be present anywhere on the face except the scalp, nose and within the orbital region of the 
face. Plantar warts are also excluded.  Subjects will be randomized to receive either a CellFX 
treatment or Cryosurgery. Selected warts for each treatment modality must be clearly separated in 
distance from each other so that wart treatment and side effects can be assessed by the blinded site 
investigator. 
 

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All eligible warts will receive at least one CellFX or Cryosurgical treatment. Each subject will be 
evaluated by the blinded site investigator at 7-days, 30-days, 60-days, and 90-days post-initial CellFX 
and Cryosurgical treatments. At the 30-day or 60-day follow-up visit, if any wart is classified as “not 
resolved” ,  the wart must receive an additional treatment. In case of a second or third retreatment, 
the subject will be evaluated by the blinded site investigator at 30-days, 60-days, and 90-days post-
retreatment. Photography of the warts will be captured along with the blinded site investigator 
assessments at all visits.  
 
Numbness (diminished/altered sensation) Assessment: The treating investigator will conduct a 
“light touch” exam to all treated areas at baseline, 7 days and 30 days post initial treatment and  30 
days post retreatment(s).  Light touch is tested with a cotton wisp, feather, and/or even light finger 
touch. The subject will be asked how one area feels compared to another. 
 
Note 1:  
Eligible warts that should be treated and do not receive a retreatment will be considered a protocol 
deviation. The reason(s) for not receiving an additional treatment will be collected on the electronic 
case report form (eCRF). These subjects will remain in the study and will be included in the ITT 
population. 
 
Additionally, subjects can only receive two additional treatments or up to a maximum of three CellFX 
or Cryosurgical procedures. 
 
Non-Treated Wart Criteria: Data will be collected on ineligible or non-treated warts for all enrolled 
subjects. Non-treated warts are defined as flat, periungual, subungual, mosaic, plantar, filiform 
and/or common warts that are excluded due to anatomic location. Photography of the non-treated 
warts will be captured at baseline and the last study visit.  
 
3.3 Randomization 
All enrolled subjects will be randomized according to the total number of warts and will  receive 
either CellFX or Cryosurgery. Randomization will be implemented through the Electronic Data 
Capture (EDC) system and will be stratified by the total number of eligible warts (2-4 warts or 5-8 
warts).  The randomization assignment will include the type of treatment and all randomized subjects 
will be included in the intent-to-treat (ITT) analysis. 
 
3.4  CellFX Procedure 
The intended CellFX treatment device is described as the CellFX® System using the skin contacting 
component referred to as the “tip” ranging in sizes from 1.5 mm x 1.5 mm to 10.0 mm x 10.0 mm in 
length and width and may range from 1.0 to 3.0 mm in depth depending on the wart location and 
size. Each tip will be used with pre-determined energy settings displayed on the CellFX Console and 
are provided in Table 1.  These energy settings do not exceed the maximum safe ranges of settings 
previously tested in clinical studies. A local anesthetic will be used to manage potential treatment 
discomfort during the CellFX treatment. All subjects will be monitored for muscle “twitching” during 
each CellFX treatment and the subjects will be asked whether they felt any muscle “twitch” during 
the treatment. 
 
 
                                                                 
 

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Table 1: Energy Settings per Tip Size 
Tip 
Size 
(L x W, mm) 
Treatment Level 
mJ/mm3 
1.5 x 1.5 
575 
2.5 x 2.5 
345 
5.0 x 5.0 
155 
7.5 x 7.5 
85 
10.0 x 10.0 
85 
 
                            
3.5  Standard Cryosurgical Procedure 
Cryosurgery will be standardized across all investigational sites. Investigators will perform the 
Cryosurgical procedure using the Brymill Cry-Ac B700 Liquid Nitrogen Sprayer. Laser or curettage 
post Cryosurgery will be prohibited.  Pulse Biosciences will provide a training video on how to 
perform the Cryosurgical procedure for training non-blinded treating investigators. 
 
3.6 Site Selection 
The study will be conducted at up to 10 clinical research sites. The sites will be selected based on the 
appropriate patient population, board certified dermatologist, and sufficient resources to support 
this IDE study. 
 
3.7 Number of Subjects 
Up to 150 subjects at up to 10 sites will be enrolled.  
 
3.8 Clinical Study Duration 
It is anticipated that the enrollment of subjects in this study will take approximately 3-4 months in 
duration. All subjects who only receive one treatment will return for follow-up visits at 7-days, 30 
days, 60-days, and 90-days or up to a total of 5 study visits. For subjects who receive additional CellFX 
or Cryosurgery retreatments, at the 30-day or 60-day follow up visit, will return for additional follow-
up for 90-days post last treatment or up to a total of 6 or 7 study visits. The total study duration will 
be approximately 9 months. 
 
4.0 STUDY PROCEDURES 
4.1 Screening 
Recruitment will be conducted via direct communication by the investigator and/or his/her 
designated staff, advertisement and/or office ads. The Informed Consent discussion and signature 
process will be conducted by the investigator and/or designated staff. No study-specific assessments 
will be performed prior to obtaining consent. 
 
A Screen Failure will be defined as a subject who did not meet one or more of the following criteria: 
• 
Did not meet all of the inclusion and/or exclusion criteria 

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• 
Did not sign informed consent 
• 
Did not receive a randomization assignment 
• 
Did not undergo the randomized treatment procedure (e.g. CellFX or Cryosurgery)  
 
A screen failure will not be assigned a subject ID and information on this subject will not be entered 
in the electronic database. Information will be transcribed on the enrollment/screen failure log. 
 
4.2 Subject Selection 
4.2.1 Inclusion Criteria 
Candidates for this study must meet ALL the following criteria: 
1. Subject is at least 18 and no older than 80 years of age. 
2. Subject has a Fitzpatrick Skin Type I, II, III or IV. 
3. Subject gives voluntary, written informed consent to participate in this clinical investigation 
and from whom consent has been obtained. 
4. Subject must comply with study procedures including all follow-up visits. 
5. Subject is willing to have warts treated in a single treatment session and understands that 
their warts may undergo multiple treatment sessions at subsequent visits. 
6. Subject must have a minimum of 2 warts and up to 8 warts to be treated. 
7. Subject with a clinical diagnosis of common warts located on hands and fingers or other 
body areas that are not located on the scalp, nose, within the orbital region of the face, 
plantar, genital or periungual area.  
8. For study purposes, the warts must be no greater than 3 mm in height and must not exceed 
10 mm x 10 mm at their largest dimension. 
9. Each wart must appear alone and discrete and not appear in clusters. 
10. Each wart must have been present for at least 4 weeks.  
11. Subject consents to have photographs taken of the warts. 
12. Subject agrees to refrain from taking an antihistamine including those used for gastric 
symptoms(e.g.,Loratadine, Desloratadine, Cetirizine, Fexofenadine, Levocetirizine,           
Azelastine, Ranitidine, Cimetidine, Famotidine, and Nizatidine) up to 48 hours before 
enrollment and each scheduled follow-up visit, to facilitate an adequate wash-out period. 
13. Subject agrees to refrain from using all other wart removal products or treatments (e.g. 
topical medication including over-the-counter medications) during the study period. 
 
4.2.2 Exclusion Criteria 
Candidates will be excluded from the study if ANY of the following apply: 
1. Subject with more than 8 visible warts in total anywhere on the body. 
2. Presence of genital or anal warts will exclude subject participation in study, including 
treatment of warts on other areas.  
3. Periungual, subungual, mosaic, plantar, or filiform warts will not be treated in the study. 
However, presence of these wart types in addition to warts that meet inclusion criteria 
will not exclude a participant from the study. 
4. Subject has an implantable electronic medical device.(i.e., pacemaker, implantable 
cardioverter defibrillator) 
5. Subject has an active infection or history of infection in designated test area within 90 
days prior to first treatment. 
6. Subject is prone to Koebnerization or has any of the following conditions (e.g., psoriasis, 
vitiligo, lichen planus, or an autoimmune disorder of the skin) 
7. Subject is not willing or able to sign the Informed Consent. 

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8. Subject is known to be immune compromised. 
9. Subject has allergies to Lidocaine or Lidocaine-like products. 
10. Subject is a member of a vulnerable population including pregnant women and individuals 
employed by the Sponsor, clinic site, or entity associated with the conduct of the study. 
11. Have any condition or situation which, in the Investigator’s opinion, puts the subject at 
significant risk, could confound the study results, or may interfere significantly with the 
subject’s participation in the study.  
12. Use of any other investigational drug, therapy, or device within the past 30 days of 
enrollment or concurrent participation in another research study. 
13. Subject was previously treated with CellFX for warts. 
 
 
4.3 Process for Obtaining Informed Consent 
Prior to undergoing any study-specific tests or procedures, the subject must sign and date the 
site’s current and approved Institutional Review Board (IRB) informed consent form in order to be 
eligible for study participation. The informed consent must contain all elements required by 21 
CFR Part 50 and ISO 14155:2011/AC:2011 and comply with the ethical principles of the Declaration 
of Helsinki. 
 
4.3.1 Process for Obtaining Informed Consent 
The patients will be informed by the Investigator or Investigator’s designee that they are free to 
refuse participation in this research study. If they elect to participate, it will be made clear that 
they may withdraw from the study at any time without prejudicing further care. 
 
The Investigator or the Investigator’s designee will inform patients that their medical records will 
be subject to review by the sponsor or appropriate regulatory bodies. This information will be 
used during the analysis of the results of the clinical study, but the patients’ identities will be 
treated as confidential. Patients will be assigned a unique study subject code that will not reveal 
the patients’ identity, and this code will be used on all data and data collection forms during the 
study period. The Investigator will explain the conditions of the study, giving the patient 
sufficient time to ask questions and to consider whether to participate. Eligible patients who 
agree to participate will be asked to sign and date an IRB-approved informed consent. If the 
patient agrees, an IRB-approved consent form will be provided to the patient for signature and 
date. One copy shall be returned to the Investigator and filed in the patient’s case history; the 
other copy is for the patient to keep. 
 
4.3.2 Addition of New Information 
Pulse Biosciences, Inc. will revise the written informed consent form whenever new information 
becomes available that may be relevant to the subject’s confirmed participation in the study. 
The revised information will be sent to the Investigator for approval by the IRB. After approval 
of the IRB, a copy of this information must be provided to the participating subjects, and the 
informed consent process as described above needs to the repeated. Please follow the central 
IRB guidelines on the process of re-consenting subjects. 
 
 
 
 

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4.4 Schedule of Events and Evaluations 
Schedule of events and evaluations required for this study are provided in Table 2. 
 
                                                                                                  Table 2: Schedule of Events 
 
Study Activity/ 
Procedure 
Visit 1 
Enrollment 
1st TX 
Visit 2 
7-days 
Post-  
1st TX 
Visit 3 
30-days 
Post- 
1st TX 
Visit 4 
60-days 
Post-    
1st TX 
Visit 5 
90-days 
Post- 
1st TX 
Visit 6 
120-days 
Post- 
1st TX 
Visit 7 
150-days 
Post- 
1st TX 
Visit Range 
±3 days 
±10 days 
±10 days 
±10 days 
±10 days 
±10 days 
Consent / 
Wart Eval / 
Tx 1  
Wart 
Eval 
Wart Eval   / 
Tx 2 
 
Wart Eval / 
Tx 3 
 
Wart Eval /  
Final Visit 
Subject 
Satisfaction 
Wart Eval 
Final Visit 
Subject 
Satisfaction 
Wart Eval 
Final Visit 
Subject 
Satisfaction 
Informed Consent 
✔ 
 
 
 
 
 
 
Demographics, Medical HX, 
Fitzpatrick Skin Type, 
Baseline Wart Size 
✔ 
 
 
 
 
 
 
Photographs of Non-treated 
Warts  
✔ 
 
 
 
 
✔ 
 
✔ 
 
✔ 
Subject Randomization 
✔ 
 
 
 
 
 
 
1st TX (CellFX or Cryosurgery) 
✔ 
 
 
 
 
 
 
2nd TX (CellFX or Cryosurgery) 
 
 
✔ 
If required 
 
 
 
 
3rd TX (CellFX or Cryosurgery) 
 
 
 
✔ 
If required 
 
 
 
Photographs of Pre and Post 
Treated Warts  
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
Wart Healing Characteristics  
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
Assessment of Numbness in 
the Treated Area 
✔ 
✔ 
✔ 
✔* 
✔* 
 
 
 Wart Clearance/Resolution 
 
 
 
 
✔ 
✔ 
✔ 
✔ 
✔ 
Wart Reduction Assessment 
 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
Pain Score/ Assessment for 
muscle twitching: Treated 
Warts  
✔ 
 
✔ 
✔ 
 
 
 
6 Point Subject Satisfaction 
Scale (SSS) 
 
 
 
 
✔ 
✔ 
✔ 
Adverse Event Assessment 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
✔ 
Study Exit 
 
 
 
 
✔ 
✔ 
✔ 
*Numbness assessment will be performed at Visit 4 for those subjects who are retreated at the 30 day follow up visit. 
*Numbness assessment will be performed at Visit 5 for those subjects who are retreated at the 60 day follow up visit. 
 
 
 

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4.5 Screening / Enrollment Procedures 
The following evaluations are required at the time of the subject screening/baseline visit.  
4.5.1  Activities prior to or on same day as study enrollment 
• 
Evaluation for Inclusion/Exclusion criteria. 
• 
Collect Demographic information and medical history including but not limited to age,    
                gender, race, ethnicity, dermatologic conditions, and Fitzpatrick skin type.                      
• 
Sign the consent form prior to any study activities.  
• 
Receive a copy of the signed consent form. 
 
4.5.2  Definition of Enrollment 
Once the subject has been consented, randomized, and has received a CellFX or Cryosurgery 
procedure, the subject will be considered enrolled and each enrolled subject will be assigned a 
unique Study Identification Number. 
4.5.3 CellFX / Cryosurgical Procedures 
• 
Up to 8 clinically diagnosed warts that meet study criteria will be selected by the treating 
investigator prior to assigning warts or taking baseline enrollment photos 
• 
The treating investigator will conduct a numbness assessment on the selected warts that 
will be treated  
• 
Photographic images will be collected on all non-treated warts  
• 
The site will log onto the Captivate EDC system. The randomization will include the type of 
treatment (CellFX or Cryosurgery) that the subject will be assigned 
• 
A template may be used to determine which CellFX treatment tip size will be used for each 
wart – sizes range between 1.5 mm x 1.5 mm and 10.0 mm x 10.0 mm. Each wart  will be 
numerically labeled using the Canfield two dot system 
• 
The blinded site investigator will perform the baseline/enrollment wart(s) assessment 
(wart healing characteristics)  
• 
Photographic images of each wart will be taken prior to using local anesthesia/numbing 
• 
Local anesthesia/numbing will only be applied to warts treated with CellFX 
• 
Each subject randomized to CellFX will be treated with pre-determined energy settings; 
each subject randomized to Cryosurgery will be treated as defined in Section 3.5  
• 
The subject will be asked to rate his/her pain immediately after each wart treated with the 
CellFX and Cryosurgical procedure by using a numerical rating score 
• 
The subjects will be asked whether they felt muscle twitching immediately after each 
lesion treated with CellFX 
• 
Immediately post-procedure,  a wart healing characteristics assessment will be performed 
by the blinded site investigator 
• 
Photographic images of all treated warts will be taken post-treatment 
• 
A light bandage and/or any physician recommended dressing may be applied before the 
subject leaves the clinic 
• 
Any adverse events will be identified and documented with a live assessment by the 
blinded site Investigator 
 
4.6. 7-Day Follow-up Visit  
• 
Photographic images of  treated warts will be taken with pre- and post- wart markings  
• 
The blinded site investigator will  perform wart(s) assessments (wart healing 
characteristics and wart reduction)  

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• 
Assessment of numbness in the treated area will be performed by the treating 
investigator 
• 
Any adverse events will be identified and documented with a live assessment by the 
blinded site investigator 
 
4.7  30-Day Follow-up Visit (CellFX/Cryosurgical Treatment #2, if required)  
• 
Photographic images of  all treated warts will be taken with pre- and post- wart markings 
• 
All warts will be clinically assessed by the blinded site investigator (wart healing 
characteristics, wart clearance  and wart reduction assessments) 
• 
Assessment of numbness in the treated area will be performed by the treating 
investigator 
____________________________________________________________________________ 
• 
If any wart is classified as “not resolved”, a second treatment with CellFX or Cryosurgery will 
be performed to the previously treated wart(s) 
 
 In case of a second CellFX or Cryosurgical treatment is required: 
▪ Local anesthesia/numbing will be applied to each wart designated for a CellFX 
retreatment  
▪ Each wart designated for a CellFX retreatment will be treated using pre-
determined energy settings 
▪ Each wart designated for Cryosurgical retreatment will be performed as outlined in 
protocol Section 3.5  
▪ The subject will be asked to rate his/her pain immediately after each wart 
treated with CellFX and/or Cryosurgery by using a numerical rating score 
▪ The subjects will be asked whether they felt muscle twitching immediately after 
each lesion treated with CellFX 
▪ Immediately post-procedure, a wart healing characteristics assessment will be 
performed by the blinded site investigator 
▪ Photographic images of all retreated warts will be taken post-treatment 
▪ A light bandage and/or any physician recommended dressing may be applied before 
the subject leaves the clinic 
▪ Any adverse events will be identified and documented with a live assessment by the 
blinded site investigator 
 
4.8  60-Day Follow-up Visit (CellFX/Cryosurgical Treatment #3, if required) 
•   Photographic images all treated warts will be taken with pre- and post-wart markings 
• 
All warts will be clinically assessed by the blinded site investigator (wart healing 
characteristics, wart clearances and wart reduction assessments) 
• 
Assessment of numbness in the treated area will be performed by the treating 
investigator (only for those subjects who received a retreatment at the 30-day follow-up 
visit) 
__________________________________________________________________________ 
• 
If any wart is classified as “not resolved”, a third treatment with CellFX or Cryosurgery will 
be performed to the previously treated wart(s) 

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In case of a third CellFX or Cryosurgical treatment is required: 
▪ Local anesthesia/numbing will be applied to each wart designated for a CellFX 
retreatment  
▪ Each wart designated for a CellFX retreatment will be treated using pre-determined 
energy settings 
▪ Each wart designated for Cryosurgical retreatment will be performed as outlined in 
protocol Section 3.5  
▪ The subject will be asked to rate his/her pain immediately after each wart treated 
with CellFX and/or Cryosurgery by using a numerical rating score 
▪ The subjects will be asked whether they felt muscle twitching immediately after 
each lesion treated with CellFX 
▪ Immediately post-procedure, a wart healing characteristics assessment will be 
performed by the blinded site investigator 
▪ Photographic images of all retreated warts will be taken post-treatment 
▪ A light bandage and/or any physician recommended dressing may be applied before 
the subject leaves the clinic 
▪ Any adverse events will be identified and documented with a live assessment by the 
blinded site investigator 
 
4.9  90-Day Follow-up Visit  
•  This is the Final Study visit for any subject for whom  all wart(s) were only treated one time 
•  Photographic images of all treated warts will be taken with pre and post wart markings 
•  All treated warts will be classified as “resolved” or “not resolved” by the blinded site  
      investigator  
• Wart healing characteristics and wart reduction assessment will be performed by the blinded  
      site investigator 
• 
Assessment of numbness in the treated area will be performed by the treating 
investigator (only for those subjects who received a retreatment at the 60-day follow-up 
visit) 
•  6-point subject satisfaction scale (for those subjects exiting the study) 
•  Photographic images will be collected on all non-treated warts (for those subjects exiting the 
study) 
• Any adverse events will be identified and documented with a live assessment by the blinded   
     site investigator 
 
4.10  120-Day Follow-up Visit 
•  This is Final Study visit for any subject who have undergone only 2 treatments and/or the last  
       treatment performed at the 30-day follow-up  
•  Photographic images of all treated warts will be taken with pre and post wart markings 
•  All treated warts will be classified as “resolved” or “not resolved” by the blinded site  
      investigator  
• Wart healing characteristics and wart reduction assessment will be performed by the blinded  
      site investigator 
 

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•  6-point subject satisfaction scale (for those subjects exiting the study) 
•  Photographic images will be collected on all non-treated warts (for those subjects exiting the 
study) 
• Any adverse events will be identified and documented with a live assessment by the blinded    
     site investigator 
   
4.11  150-Day Follow-up Visit 
• This is Final Study visit for any subject for whom wart(s) were retreated at the 60-day  
       follow-up  
•  Photographic images of all treated warts will be taken with pre and post wart markings 
• 
All treated warts will be classified as “resolved” or “not resolved” by the blinded site investigator 
•  Wart healing characteristics and wart reduction assessment will be performed by the  
       blinded site investigator 
• 6-point subject satisfaction scale  
•  Photographic images  will be collected on all non-treated warts  
• Any adverse events will be identified and documented with a live assessment by the blinded site 
investigator 
 
4.12 Subject Withdrawal 
A study subject has the right to discontinue participation at any time without penalty or loss of 
benefits to which the subject is otherwise entitles. A withdrawn subject will be treated according to 
standard of medical care and will not be replaced. 
 
5.0 BENEFITS AND RISKS 
5.1 Benefits 
There are no guaranteed benefits from participation in this study. Participation in the study offers 
another dermatological approach to accomplish the same clinical effect as the typical treatment 
devices currently used to treat patients with warts. The information learned from this study may 
contribute to the ultimate use of a safer and more effective device and the availability of the device 
to treat benign lesions as an alternative for use in future patients.  
 
5.2 Risks 
For detailed information on the risks of the devices used in the study procedure, including a 
complete list of warnings, precautions, and potential adverse events, please refer to the 
Instructions for Use (IFU) for the Pulse Bioscience CellFX® System. 
5.3 Mitigation of Risks 
As with any dermatological procedure, appropriate safety precautions will be followed. Risks 
observed or theoretical adverse events have been mitigated through the Instructions for Use, 
physician training, and patient selection in the study protocol. 
All efforts will be made to minimize these risks by: 
• 
Site Selection 
• 
Patient Population that represents the demographics of the U.S. with a uniform 

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distribution of Fitzpatrick Skin Types I, II, III and IV 
• 
Ensuring compliance to the protocol and IFU 
• 
Study monitoring 
• 
Safety processes-protocol adverse events reporting requirements  
 
6.0 STATISTICAL CONSIDERATIONS 
Further details of planned analyses can be found in the statistical analysis plan (SAP). 
 
6.1 Co-primary Endpoints 
Clinical acceptance of treatment with the CellFX System for common warts requires non-inferior 
clearance response (effectiveness), non-inferior healing processes and non-inferior rates of adverse 
skin changes (safety) versus cryosurgery. Because these features are critically important for 
treatment acceptability, this study is designed with 3 co-primary endpoints. The endpoints must 
demonstrate non-inferiority for the study to be considered successful. 11 
 
All 3 co-primary endpoints are assessed with wart as the unit of analysis, but the analyses will be 
adjusted for within-subject correlation. The co-primary safety endpoints are the proportion of warts 
with adverse events related to wound healing (scabbing, swelling, crusting, blister, scar or ulcer) at 
30 days after the last treatment and adverse skin changes (the presence of hyperpigmentation, 
hypopigmentation or scarring) at 90 days post last treatment. The co-primary effectiveness endpoint 
is the proportion of warts classified as “resolved” at 30 days post last treatment. 
 
6.1.1 Co-primary Safety Endpoints 
The wound healing safety endpoint is the presence or absence of a wound healing safety event 
at 30 days from the last CellFX or Cryosurgical treatment as assessed by the blinded site 
investigator. The wound healing safety event is defined as the presence of scabbing, swelling, 
crusting, blister, scar or ulcer. The timing of the evaluation of this endpoint is wart specific as 
some warts may not require multiple treatments with CellFX or Cryosurgery. Warts will be 
categorized as having a primary safety event if any component (scabbing, swelling, crusting, 
blister, scar or ulcer) is present at the follow-up visit 30 days after the last treatment.  
 
The statistical hypotheses to be evaluated for the wound healing primary safety endpoint are: 
H0: pCellFX - pCryo ≥ 15% at 30 days post last treatment, versus 
HA: pCellFX - pCryo < 15% at 30 days post last treatment  
 
Where pCellFX and pCryo are the proportion of warts with a composite wound healing safety event 
(scabbing, swelling, crusting, blister, scar or ulcer) in each treatment group. The null hypothesis 
will be rejected if the upper bound of the 2-sided 95% confidence interval for the difference in 
proportions (pCellFX - pCryo) is less than 15%. This approach is equivalent to a 1-sided test with a 
2.5% type I error rate. 
 
The skin change safety endpoint is the presence or absence of a skin change safety event at 90 
days from the last CellFX or Cryosurgical treatment as assessed by the blinded site investigator. 
The skin change safety event is defined as the presence of hyperpigmentation, 
hypopigmentation, or scarring. The timing of the evaluation of this endpoint is wart specific as 
some warts may not require multiple treatments with CellFX or Cryosurgery. Warts will be 

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Page 23 of 41 
 
categorized as having a skin change safety event if any component (hyperpigmentation, 
hypopigmentation, or scarring) is present at the follow-up visit 90 days after the last treatment.  
 
The statistical hypotheses to be evaluated for the skin change primary safety endpoint are: 
H0: pCellFX - pCryo ≥ 15% at 90 days post last treatment, versus 
HA: pCellFX - pCryo < 15% at 90 days post last treatment  
Where pCellFX and pCryo are the proportion of warts with a composite skin change safety event 
(hyperpigmentation, hypopigmentation, or scarring) in each treatment group. The null 
hypothesis will be rejected if the upper bound of the 2-sided 95% confidence interval for the 
difference in proportions (pCellFX - pCryo) is less than 15%. This approach is equivalent to a 1-sided 
test with a 2.5% type I error rate. 
 
6.1.2 Primary Effectiveness Endpoint 
The primary effectiveness endpoint is wart clearance, defined as “resolved” versus “not 
resolved” at 30 days following the last CellFX or Cryosurgical treatment (30 days post-last 
treatment) based on the classification of the blinded site investigator. The timing of the 
evaluation of this endpoint is wart specific as some warts may not require more than 1 
treatment with the CellFX System or Cryosurgery. The investigator, blinded to treatment 
assignment, will classify each wart as “resolved” or “not resolved”.  
 
The primary effectiveness analysis will be a comparison between CellFX and Cryosurgical 
treatment groups based on 30-day post treatment clearance rate, defined as the proportion of 
warts classified as “resolved”. This binary outcome classifies warts as completely clear versus 
not completely clear. The 30-day time-point was selected to reduce the impact of spontaneous 
wart resolution unrelated to treatment. 
 
The statistical hypotheses to be evaluated for the primary efficacy endpoint are: 
 
H0: pCellFX - pCryo ≤ -15% at 30 days post last treatment, versus 
HA: pCellFX - pCryo > -15% at 30 days post last treatment 
 
Where pCellFX and pCryo are the proportion of warts classified as “resolved” in each treatment 
group. The null hypothesis will be rejected if the lower bound of the 2-sided 95% confidence 
interval for the difference in proportions (pCellFX - pCryo) is greater than -15%, which is equivalent 
to a 1-sided test with a 2.5% type I error rate. 
 
6.1.3  Justification of Non-Inferiority Design and Margin 
The selection of a non-inferiority design for this study is based on the choice of an active 
comparator (cryosurgery), the acceptability of the design to subjects seeking treatment for 
common warts, and feasibility considerations11. Although cryosurgical treatment for warts was 
found to have numerically higher efficacy compared to placebo15, the many variations in timing, 
frequency and delivery of cryosurgery preclude a meta-analysis-based margin derivation for the 
technique selected for this study. Safety outcomes are inconsistently reported in publications, 
and no estimates of the composite endpoint of skin changes proposed for this study was 
available. Thus, non-inferiority margins of 15% were selected based on clinical judgement for the 
primary safety and effectiveness endpoints. Clinical justifications for this non-inferiority margin 

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for safety include existing CellFX safety data that demonstrate no serious adverse events, and a 
comparable safety profile compared to the predicate devices for this indication with the 
suggestion of faster healing. Clinical justifications for a 15% non-inferiority margin for 
effectiveness include consistency of treatment and ease of use with the CellFX system. 
 
6.1.4  Type I Error Control and Study Success 
Study success requires the demonstration of non-inferiority for the primary safety and efficacy 
endpoints.11  Thus, no type I error adjustment for multiple testing is required. No formal 
hypotheses will be tested for secondary endpoints. 
 
6.2 Secondary Endpoints 
Details of the planned analyses for secondary endpoints can be found in the statistical analysis plan. 
No formal hypotheses will be tested for secondary endpoints. The ITT population will be used for all 
analyses of secondary endpoints. 
1. Wart Resolution Determined by Photographic Review 
Wart resolution will be assessed by three independent observers, blinded to treatment 
assignment, who will classify the response for each wart based on photographs taken at 30 days 
post last treatment. The 3 observers will classify each wart as “resolved” or “not resolved” 
described in Section 6.1.2. The wart will be classified as “resolved” if 2/3 blinded observers 
classify the wart as “resolved”, and as “not resolved” if 2/3 blinded observers classified the wart 
as “not resolved”. The difference in proportion of warts classified as “resolved” will be assessed 
using the GEE model  as described in the statistical analysis plan with the photo review endpoint 
replacing the endpoint derived from the blinded site investigator classification.  
2.   Wart Resolution after Single Treatment 
The proportion in each treatment group and the difference in proportion classified as 
“resolved” between CellFX and Cryosurgery assigned by the blinded site investigators at 30-
days post initial treatment (as opposed to the efficacy endpoint, which is 30 days post last 
treatment) will be assessed using the GEE model described in the statistical analysis plan with 
the 30 day endpoint classified by the blinded site investigator. 
3.   Wart Resolution at 60 Days Post Last Treatment 
The proportion in each treatment group and the difference in proportion classified as 
“resolved”  between CellFX and Cryosurgery assigned by the blinded site investigators from 
baseline to 60-days post last treatment will be assessed using the GEE model described in the 
statistical analysis plan with the 60 day post last treatment endpoint based on the blinded 
investigator classification as “resolved” or “not resolved”. 
4.   Within Subject Effectiveness 
The ratio of cleared warts (classified as “resolved”) to all treated warts will be calculated at 30 
days post last treatment. The proportion of subjects with complete clearance of all warts (ratio 
1) will be calculated for each treatment group, as well as the proportions with > 50% and > 75% 
of treated warts cleared. 
5.   Change in Wart Size 
The mean difference in reduction from baseline in wart size of treated warts at 30 days post last 
treatment will be calculated using a mixed model for repeated measures, with treatment, 
number of warts stratification and baseline size included as fixed effects. An exchangeable 
correlation matrix will be used to adjust for within-subject correlation. Least-square mean 
change, difference, and 95% confidence intervals will be calculated from this model. 

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6.   Wart Resolution Over Time 
The rate of wart resolution of the treated warts over time and up to 90 days post last treatment 
will be calculated.  
 
7.   Lesion Observations 
Lesion observations at 7-days, 30-days, 60-days, and 90-days post last treatment between 
CellFX and Cryosurgery.  Lesion evaluation includes the following: 
• 
Blister Formation 
• 
Bruising 
• 
Crusting 
• 
Erythema 
• 
Hyperpigmentation 
• 
Hypopigmentation 
• 
Scabbing 
• 
Scarring 
• 
Swelling or Edema 
• 
Ulceration 
 
The rate of each event individually and a composite of any of these events will be calculated for 
each treatment using the GEE model described in the statistical analysis plan, along with the 
95% confidence interval as described for the primary safety endpoint. 
 
8. Satisfaction with Treatment 
A 6-point Treatment Satisfaction Scale will be used to measure subject’s satisfaction with the 
treatment of each wart. 
 
                                        Table 3: Treatment Satisfaction Scale 
 
 
 
 
 
 
 
 
 
The proportion with each response will be summarized. An analysis will be performed using the 
binary endpoints of satisfied (“Very Satisfied” or “Satisfied”) versus not satisfied  (“Somewhat 
Satisfied”, “Somewhat Dissatisfied”, “Dissatisfied”, “Very Dissatisfied”) to compare satisfaction 
across treatment groups. As with treatment-level clearance, the counts and proportions of 
warts categorized as satisfied will be reported. A GEE model to estimate the treatment 
difference in the proportion of warts with satisfactory treatment will be performed using the 
methods described in the statistical analysis plan.  
 
9. Acute Pain Assessment 
Face Pain Scale with an assigned numerical rating between 0 (smiling) and 10 (crying) will be 
used to assess pain immediately after the CellFX and Cryosurgical treatments at Day 0, and Days 
30, or 60, if applicable. The face pain scale will be assessed immediately after each wart 
treatment. Please see pain scale chart on the next page. 
 
Rating 
Description 
6 
Very Satisfied 
5 
Satisfied 
4 
Somewhat Satisfied 
3 
Somewhat Dissatisfied 
2 
Dissatisfied 
1 
Very Dissatisfied 

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11. 
The number and percent will be tabulated for each level of pain for first, second, or third 
treatments separately. A histogram of scores will be produced. If the scores are not markedly 
skewed, mixed models using score as a continuous dependent variable and treatment as a fixed 
covariate (adjusted for within-subject correlation) will be used to compare the least-square 
mean difference in pain scores across treatment groups. A model including all treatments and 
adjusted for treatment number (initial, first retreatment, second retreatment) may be 
performed for comparison, convergence permitting. 
 
6.3 Sample Size Determination 
Power for the primary endpoints was assessed and calculated using the formula for standard non-
inferiority designs12 and then inflating the total number of warts required to account for correlation 
within subjects. 13 Several assumptions were estimated using a previous study of warts. 8 An average 
of 3 eligible warts per subject was assumed, based on the median number of observed common 
warts.  
 
The efficacy response rate (classified as “resolved” versus “not resolved”) was approximated using 
the complete clearance rate for common warts, yielding an estimated CellFX clearance rate at 30 
days post last treatment of 75.5%. The within-subject correlation for this endpoint was estimated 
to be 0.3. The composite wound healing safety event at 30 days post last treatment was estimated 
to be 37.6%, and the within-subject correlation was estimated to be 0.55. The composite skin 
change safety event rate at 90 days post last treatment was estimated to be 32.5%, and the within-
subject correlation for this endpoint was estimated to be 0.55. For cryosurgery, the 30 day post last 
treatment clearance rate was estimated to be 70%14,10 and the 90 day post last treatment safety 
event rate was estimated to be 40% (based on 29% hypopigmentation reported and 11% 
hyperpigmentation assumed). 15 The wound healing safety event rate for cryotherapy was assumed 
to be 43%. The within-subject correlation for warts was assumed to be identical for CellFX and 
cryosurgery. No type-1 error adjustment is needed to account for multiple endpoints as the 
effectiveness response rate and safety event rate are co-primary. In order to maintain at least 88% 
power to test the primary hypotheses using 15% non-inferiority margins, approximately 97 warts 
(33 subjects) would be required in each arm. After accounting for within-subject correlation, at 
least 63 subjects (189 warts) are needed in each arm. To account for approximately 15% loss to 
follow-up, a total of 150 subjects will be enrolled. 
 
6.4 Populations for Analyses 
The primary analysis dataset for study outcomes will be the intent-to-treat (ITT) population wherein 
data from all randomized warts will be analyzed based on the intended randomization assignment. 
The intent of this protocol is to apply up to 3 sessions of each treatment, but no warts will be 

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excluded from the ITT population based on the number of treatments actually received. The primary 
efficacy analysis will be performed using the ITT population. A modified intent-to-treat population 
will include all warts that received at least one treatment, and the primary efficacy analysis will also 
be calculated for this population for comparison. The modified ITT population will be the analysis 
population for the primary safety endpoint. 
 
Study outcomes will also be analyzed using a per-protocol (PP) population. The PP population 
includes all subjects who had no pre-specified inclusion and exclusion violations, received either 
CellFX or Cryosurgery, and repeated the treatments per protocol for any warts classified as “not 
resolved” at the 30-day and/or 60-day visit. 
 
6.5 Sub-Group Analyses 
Primary and secondary endpoints will be evaluated for the ITT and PP populations, as well as 
analyzed in strata based on the following sub-groups: 
 
• 
Number of treated warts (2 to 4 or 5-8) 
• 
Age 
• 
Prior treatment for treated warts 
• 
Gender 
• 
Clinical Site 
• 
Treatment Energy Level 
• 
Size of CellFX Treatment Tip 
• 
Total Energy Density 
• 
Number of Treatments 
 
These analyses are meant to assess consistency of treatment effects only, and this study is not 
powered for inference within subgroups. 
 
6.6 Missing Data 
All possible efforts will be made to minimize missing data in this study. Based on previous studies, 
any missing data that does occur is likely due to missed follow-up visits, so all study warts for subjects 
with a missed visit will have missing endpoints. The timing of the co-primary effectiveness and wound 
healing events at 30 days should minimize missed visits related to study fatigue. The generalized 
estimating equation model can yield valid results when data are missing completely at random, and 
the sensitivity analysis using a mixed model can yield valid results when data are missing at random. 
Additionally, the sensitivity of the final results to missing data for the skin change safety outcome 
will be examined by comparing the primary outcomes to the results using a longitudinal model with 
both the 30-day, 60-day and 90-day post treatment results, and a tipping-point analysis will be 
performed for the endpoints at 90 days to determine whether the missing data could change the 
inference compared to the primary models. 
 
 
 
 
 
 
 
 

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7.0 EXPLORATORY ENDPOINTS 
The primary outcomes are wart-level endpoints that account for within-subject correlation. The 
exploratory endpoints are patient-level calculations of these endpoints, which lack sufficient statistical 
power for formal hypothesis tests. 
 
7.1 Exploratory Efficacy Endpoint 
7.1.1 Subject-level clearance of all warts at 30 days post last treatment 
The number and percent of subjects with all warts “resolved” at 30 days post last treatment 
and the number of subjects with at least 1 wart “not resolved” at 30 days post last treatment 
will be calculated. 
 
7.2 Exploratory Safety Endpoints 
7.2.1 Subject-level wound healing adverse events at 30 days post last treatment 
The number and percent of subjects with any wound healing event in any wart (composite of 
scabbing, swelling, crusting, blister, scar or ulcer) and no wound healing events in any wart at 
30 days post last treatment will be calculated. 
 
7.2.2 Subject-level skin change adverse events at 90 days post last treatment 
The number and percent of subjects with any skin change event in any wart (scar, 
hypopigmentation or hyperpigmentation) and no skin change events in any wart at 90 days 
post last treatment will be calculated. 
 
8.0 CLINICAL PHOTOGRAPHY    
The Canfield Handheld 2D Imaging System and the Canon SL2 camera with ranging lights and MM Scale 
will be provided by the photography vendor, Canfield Scientific, Inc. (Parsippany, NJ) to document 
Investigator selected warts at enrollment,  post treatment and at 7-days, 30-days, 60-days, and 90- days 
following the last CellFX treatment or Cryosurgical procedure.  All consenting subjects’ study 
photographs will be captured using the equipment, supplies, and guidelines provided by Canfield to have 
consistent visual representation of the AD appearance during the study treatment.  Images will be 
captured, viewed, and uploaded using Canfield Capture software which automatically checksums, 
encrypts, packages, and transfers the data to a secure, validated, and compliant web server hosted by 
Canfield.   Detailed instructions for all aspects of the photography procedures will be supplied separately 
in the investigator user manual to be provided by Canfield. 
 
9.0 INDEPENDENT PANEL REVIEW  
To meet the  requirements of the secondary endpoint, an Independent Panel  will evaluate the treatment 
response from each study device. In order to enhance objectivity and reduce potential for bias, the Panel 
shall be independent of the Sponsor as well as the study sites/investigators.  
 
The Panel is made up of three  clinicians with pertinent expertise in dermatology who are not participants 
in the study and who do not have any other real or potential conflicts of interest. The Panel will be 
provided photographs of all treated warts at baseline and 30 days post last treatment and will be trained 
on specific criteria used to classify the response to treatment as noted in study Section 6.1.2. 
 

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An Independent Panel review will be conducted by Canfield Scientific based on prior standard 
methodology.  
 
 
10.0  ADVERSE EVENTS 
Pulse Biosciences will classify each reported Adverse Event according to ISO 14155:2011. All protocol 
specific AEs, whether device-related or not, will be recorded on the AE case report form and reported. 
Data to be collected will include the description of the AE, onset, and resolution dates (or whether the 
AE is ongoing), severity, management/treatment, outcome, and determination of the relationship to 
the device and/or procedure. All AEs related to a treated wart  should be reported and classified by the 
blinded site Investigator and to be followed by the treating Investigator to determine the relationship 
of the AE to the device or the study procedure.   
All AE information will be collected at each study visit from enrollment through 90 days following the last 
CellFX and Cryosurgical procedures. All AEs will be followed until the event has resolved (in the case of 
permanent impairment, the event will be followed until it stabilizes, and the overall clinical outcome has 
been ascertained).  
 
When reporting AEs/SAEs, the Investigator should include the following information: 
• 
Description of event  
• 
Onset of event 
• 
Duration of event  
• 
Severity 
• 
Relationship to device or procedure 
• 
Action taken 
• 
Subject outcome 
 
Severity describes the intensity of an event and will be assessed as: 
• 
Mild: The AE does not interfere in a significant manner with the subject’s normal functioning 
level.  
• 
Moderate: The AE produces some impairment of function but not hazardous to health. 
• 
Severe: The AE produces significant impairment of function or incapacities and/or it is a hazard 
to the subject. 
 
Relationship to device or procedure will be assessed as: 
• 
Unlikely: There is no indication that the AE was caused by the investigational or standard of 
care device.  
• 
Possibly: It cannot be excluded that the AE was caused by the investigational or standard of 
care device. 
• 
Likely: A causal relationship between the investigational or standard of care device and the 
AE is at least a reasonable possibility; i.e. there is evidence or argument suggesting a causal 
relationship.  
 
10.1 Adverse Event Definitions  
10.1.1 Adverse Event (AE): (ISO 14155:2011 3.2)  
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users, or other persons, whether or not 
related to the investigational medical device.  

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NOTE 1: This definition includes events related to the investigational medical device or the    
comparator.  
NOTE 2: This definition includes events related to the procedures involved. 
*For the purposes of this protocol, only dermatologic AEs will be reported to the Sponsor. 
 
10.1.2 Adverse Device Effect (ADE): (ISO 14155:2011 3.1)  
Adverse event related to the use of an investigational medical device  
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device.  
NOTE 2: This definition includes any event resulting from use error or from intentional misuse 
of the investigational medical device  
 
10.1.3 Serious Adverse Event (SAE) (ISO 14155:2011 3.37)  
 Adverse event that  
a) led to death,  
b) led to serious deterioration in the health of the subject, that either resulted in  
1) a life-threatening illness or injury, or  
2) a permanent impairment of a body structure or a body function, or  
3) in-patient or prolonged hospitalization, or  
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function,  
 c) led to fetal distress, fetal death or a congenital abnormality or birth defect.  
NOTE 1: Planned hospitalization for a pre-existing condition, or a procedure required by the 
CIP, without serious deterioration in health, is not considered a serious adverse event. 
 
10.1.4 Serious Adverse Device Effect (SADE): (ISO 14155:2011 3.36)  
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event  
 
10.1.5 Unanticipated Adverse Device Effect (UADE): (21CFR812.3)  
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the investigational plan or application, or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, 
or welfare of subjects.  
 
10.2 Device Deficiencies (ISO 14155:2011 3.15)  
10.2.1 Definitions 
Device Deficiency is an Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance.  
 
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labelling. 
 
Device Malfunction is a failure of the study device to perform in accordance with its   intended 
purpose when used in accordance with the instructions for use or study protocol. 
 
 

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10.3 Safety Reporting Requirements 
The following sections will summarize the safety reporting requirements for the Sponsor and site 
Investigators. The NP-WC-015 IDE study will also include an early safety assessment on the first 20 
subjects treated with CellFX. 
 
10.3.1 Blinded Live Assessment of Adverse Events 
The Blinded Investigator from each of the clinical research sites will conduct a live safety 
assessment on all enrolled subjects at each study visit. The blinded investigator will ensure that 
all adverse events that are related to the stopping rules in Section 10.3.2.1 are reported to the 
Sponsor within three calendar days. 
 
10.3.2 Safety Monitor 
The Sponsor will select an independent Safety Monitor to oversee dermatological adverse 
events. The First 20 subjects who are treated with CellFX will have their data analyzed when 
they complete the 30 day follow up visit or 30 days post initial treatment. A table describing 
the 30 days status of the subjects will be prepared. Adverse events will be presented as the 
percentage of subjects who experience an event, the number of events and the event rate per 
30 days. The photographic images of the dermatological adverse events will also be presented 
to the Safety Monitor. 
 
10.3.2.1 Stopping Rules 
a) Full dermal thickness ulcer in any subject, of any duration; 
b) Any depth ulcer or erosion lasting ≥30 days, in more than 2 of the first 20 subjects treated 
with CellFX or more than 10% of subjects treated after the first 20 subjects; and 
c) Scab or crust that is so severe at the 30 day visit that it would preclude additional 
treatment that day, in more than 2 of the first 20 subjects treated with CellFX or more 
than 10% of subjects treated after the first 20 subjects. 
 
 
10.3.3 Investigator Responsibilities 
The Investigator is responsible for reporting adverse events, including device malfunctions and 
device deficiencies as defined in the protocol. Table 4 summarizes the time sensitive 
requirements for reporting adverse events and device deficiencies.  The Sponsor is the contact 
person for these reporting requirements.  
 
                             Table 4: Investigator Responsibilities for Submitting Adverse Events to the Sponsor 
Type of Adverse Event 
Reporting Timeframe 
*Serious Adverse Device Effects 
(SADE), including Unanticipated 
Serious Adverse Device Effect (USADE) 
and dermatological events as 
described in section 9.3.2.1 
As soon as possible, but in no case later than 3 calendar days after the clinical 
site first learns of the event or of new information in relation with an already 
reported event  
**Serious Adverse Events (SAE)  
 
As soon as possible, but in no case later than 3 calendar days after the clinical 
site first learns of the event or of new information in relation with an already 
reported event  
Adverse Device Effects (ADE)  
 
As soon as possible, but in no case later than 3 calendar days after the clinical 
site study team first learns of the event or of new information in relation with 
an already reported event 
All other AEs  
 
Submit in a timely manner after the clinical site first learns of the event  

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Type of Adverse Event 
Reporting Timeframe 
**Device Deficiency with SADE 
potential  
 
As soon as possible, but in no case later than 3 calendar days after the clinical 
site study team first learns of the deficiency or of new information in relation 
with an already reported deficiency  
All other Device Deficiencies  
 
Submit in a timely manner after the clinical site first learns of the deficiency  
 
*The Sponsor will report the results of an evaluation of an unanticipated serious or serious adverse 
device effect to the FDA and all reviewing IRBs and investigators within 10 working days after the 
Sponsor first received notice of the adverse effect per 21 CFR 812.150.  
 
**It is the responsibility of the investigator to inform their IRB of serious adverse events and device 
deficiencies as required by their IRB guidelines. 
 
 
11.0  STUDY MANAGEMENT (SPONSOR RESPONSIBILITIES) 
11.1 
Sponsor Ethical and Regulatory Considerations 
As the Sponsor of this clinical study, Pulse Biosciences has the overall responsibility for the conduct 
of the study, including assurance that the study meets US federal and local regulatory requirements 
appropriate to the conduct of the study and is conducted according to the Declaration of Helsinki, 
Protection of Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). The study sponsor will adhere to sponsor general 
duties as described in ISO 14155:2011, Clinical investigation of medical devices for human subjects – 
Good clinical practice, and CFR Part 812, 50, 56, 54 and the World Medical Association Declaration 
of Helsinki. 
 
To maintain confidentiality, all evaluation forms, reports, and other records will be identified by a 
unique subject identification code (ID number). All study records will be kept in a locked file cabinet 
and clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA. The Investigator must also comply with all applicable privacy 
regulations (e.g., Health Insurance Portability and Accountability Act of 1996). 
 
General Duties 
Pulse Biosciences will ensure that the application is submitted to the appropriate regulatory 
authorities, obtaining copies of IRB approvals and ensuring documentation of IRB approvals prior to 
the shipping of devices, ensuring proper clinical site monitoring, ensuring patient informed consent 
is obtained, providing quality data that satisfies regulations and informing the Investigators and IRBs 
of unanticipated adverse device effects, events, and deviations from the protocol as appropriate. 
 
11.2 Selection of Clinical Sites 
The primary requirements of site and Investigator selection and continued participation in the Trial 
include adequate experience, commitment to safety, consistency in adherence to the protocol, and 
patient volume. The clinical site must have facilities that are capable of processing patients in the 
manner prescribed by the protocol. 
 
The study sponsor, Pulse Biosciences, and its designees will select qualified Investigators, ship, or 
deliver devices only to participating Investigators, obtain signed study agreements, and provide 
Investigators with the information necessary to conduct the study. 

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11.3 Site Training 
The training of appropriate clinical site personnel will be the responsibility of the Sponsor designee. 
The Investigator is responsible for ensuring that his/her staff conduct the study according to the 
protocol. To ensure proper device usage, uniform data collection, and protocol compliance, the 
Sponsor or designee will present a formal training session to study site personnel which will review 
the Instructions for Use of the device, the Investigational Plan, instructions on data collection, 
schedules for follow-up with the study site coordinators, and regulatory requirements. Detailed 
feedback regarding completion of forms will be provided by the Sponsor or designee through the 
regular site monitoring. 
 
11.4  Investigator Training 
The Sponsor will provide appropriate Investigator training on the use of the CellFX System, 
Handpiece, and Treatment Tips. Training will take place prior to the initiation of the clinical 
investigation. Training will address topics including indications for use of the device, management of 
complications, and instructions to subjects. Training will be documented for each physician on a 
training log, signed by both the physician and training representative.  
All treating investigators will be required to watch a training video on how to perform the 
Cryosurgical procedure for this study. 
Canfield Scientific, Inc. will provide training to the sites on the photography equipment and services 
as described in Section 8.0. 
 
11.5 Monitoring of Study Sites 
11.5.1 Monitoring Methods 
Monitoring functions for this study will be conducted by  Pulse Biosciences. The study will be 
monitored to ensure that the protocol, applicable regulations, and Good Clinical Practice 
Guidelines are followed. The study monitor will ensure that the rights and well-being of subjects 
are protected, and the clinical trial data are accurate, complete, and verifiable. Specific 
monitoring requirements are detailed in the study specific Monitoring Plan. 
 
Prior to subject enrollment, the Sponsor will obtain the essential regulatory documents 
required to initiate the study. The Sponsor will be responsible for the review and approval of 
the following essential documents: 
 
• 
Current Protocol Revision 
• 
Investigator Agreement 
• 
IRB approval letter for the protocol and consent form 
• 
IRB approved consent form 
• 
IRB membership roster or assurance number 
         
Copies of file documents will be maintained by the Sponsor. 
 
11.5.2 Periodic Monitoring Visits (Onsite and Remote) 
Periodic monitoring visits will be made at the investigational site throughout enrollment of the 
clinical study to assure that the Investigator obligations are fulfilled, and all applicable regulations 
and guidelines are being followed. These visits will assure that the facilities are still acceptable; 
the protocol and investigational plan are being followed, the IRB/HREC has been notified of 
approved protocol changes as required, complete records are being maintained, appropriate and 

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timely reports have been made to the Sponsor and the IRB, device and device inventory are 
controlled and the Investigator is carrying out all agreed activities. The monitor will verify 
accuracy of CRF or EDC completion against source documents maintained at the site. 
During monitoring visits, the Monitor will perform a review of study eligibility, 
Inclusion/Exclusion criteria, informed consent, all reports of device malfunction, all events 
meeting criteria for serious adverse event reporting as well as safety and efficacy endpoints. 
Additional review will be performed on a site-by-site basis, as warranted by the findings of 
previous monitoring visits. 
 
The monitor will ensure that Investigators are aware of the regulatory requirement to maintain 
information in the study subject’s medical records which corroborate data collected on the CRF 
or EDC system.  To comply with these regulatory requirements, the following information will be 
maintained and made available as required by the sponsor and/or regulatory inspectors: 
 
The monitor will compare key variables (demographics, inclusion/exclusion criteria, and safety) 
on the CRFs or EDC database with each subject’s source documents. Any discrepancies will be 
noted and resolved.  
 
11.5.3 Site Close-out Visit 
Upon completion of the clinical study (when all subjects enrolled have completed the follow-up 
visits and the CRFs or EDC and queries have been completed), the Sponsor will notify the site of 
closeout and a study closeout visit will be performed. All CRFs, unused study devices, and any 
unused study materials will be collected and returned to the Sponsor. The Monitor will ensure 
that the Investigator’s regulatory files are up to date and complete and that any outstanding 
issues from previous visits have been resolved. Other issues which will be reviewed at this visit 
include discussing retention of study files, possibility of site audits, publication policy, and 
notifying the IRB of study closure.  
 
11.6 Protocol Deviations 
A protocol deviation is defined as an event where the clinical Investigator or site personnel did not 
conduct the study according to the Investigational Plan or the Investigator Agreement. 
 
Deviations shall be reported to the Sponsor regardless of whether medically justifiable, pre- 
approved, or taken to protect the subject in an emergency. Subject specific deviations will be 
reported on the provided protocol deviation form. Non-subject specific deviations will be reported 
to the sponsor in writing. Investigators will also adhere to procedures for reporting study deviations 
to their IRB in accordance with their specific IRB reporting policies and procedures. 
Good Clinical Practice (GCP) regulations require that Investigators maintain accurate, complete, and 
current records, including documents showing the dates and reasons for each deviation from the 
protocol. 
 
 
11.7 Study Completion 
The study is considered completed after all subjects have undergone all of their protocol required 
follow-up visits, all eCRFs have been submitted, all queries have been resolved, and all action items 
have been closed. All unused study materials and study devices will be collected and returned to 
Pulse Biosciences or appropriately discarded as per instruction. After study closure, a final report will 
be completed. 

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11.8 Audits / Inspections 
Pulse Biosciences,  national/international regulatory authorities and IRBs may conduct initiated 
audits or inspections at the study sites during the course of, or after completion of the study. The 
Investigator shall allow access to the original medical records and provide all requested information. 
 
11.9 Publication Policies 
Publications based on the results of the study will follow the process outlined in the Investigator 
Agreement.  The study will be registered on www.clinicaltrials.gov. 
 
11.10 Data Management 
Pulse Biosciences will be responsible for database creation and validation. Prior to finalizing and 
locking the database, all decisions concerning the inclusion or exclusion of data from the analysis for 
each subject will be determined by appropriate clinical and statistical personnel. All exclusions 
related to either safety or efficacy will be documented in subject listings.  
 
11.11 Case Report Forms /Transmission of Data 
All required data for this study will be collected via web-based electronic data capture (EDC) system 
and entered in electronic Case Report Forms (eCRFs).  A unique study identifier will be assigned to 
each study subject. The database will contain only the study identifier to identify the subject.  
Required data will be recorded on the appropriate electronic Case Report Forms at the time of or as 
soon as possible after the subject visit. This will enable timely monitoring visits. 
Any data discrepancies identified during data review or a monitoring visit will be queried by Pulse 
Biosciences and must be resolved by the site staff and Investigator in a timely manner. 
 
11.12 Data Retention 
Pulse Biosciences will maintain copies of correspondence, data, shipment of devices, adverse device 
effects, Investigator agreements and other records related to the clinical study. All study records and 
reports will remain on file at the sites for a minimum of 2 years after completion of the Study and 
will further be retained in accordance with local guidelines as identified in the clinical study 
agreement. Study records are to be discarded only upon notification by the study Sponsor. The 
Investigator must contact the study Sponsor before the destruction of any records and reports 
pertaining to the study to ensure they no longer need to be retained. In addition, the Sponsor should 
be contacted if the Investigator plans to leave the investigational site. All required data for this study 
will be collected on standardized CRFs or an electronic data capture system. All information and data 
sent to the Sponsor concerning subjects or their participation in this study will be considered 
confidential. All data used in the analysis and reporting of this evaluation will be used in a manner 
without identifiable reference to the subject. The Principal Investigator consents to visits by the staff 
of the Sponsor and its authorized representatives and the U.S. Food and Drug Administration or any 
other local governmental body to review the study subjects’ medical records including any test or 
laboratory data that might have been recorded on diagnostic tests media (e.g., photographs, etc.). 
 
 
 

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12.0  INVESTIGATOR RESPONSIBILITIES 
The role of the Principal Investigator is to implement and manage the conduct of the clinical study at 
their site, as well as ensure data integrity and the rights, safety, and well-being of the participating 
subjects. 
The Investigator shall ensure that all work and services described herein, or incidental to those 
described herein, shall be conducted in accordance with the highest standards of medical and clinical 
research practice. The Investigator will provide current copies of the study protocol to all Sub-
Investigators or other site personnel responsible for study conduct. 
Upon completion or termination of the study, the Investigator will submit a final written summary to 
the IRB. The summary should be submitted to the Sponsor within three (3) months of study completion 
or termination. The Investigator will provide the Sponsor with copies of all IRB/HREC actions regarding 
the study. 
 
12.1 IRB Approval and Informed Consent 
The clinical study must be reviewed and approved by the IRB before subject enrollment may begin. 
All proposed changes to the investigational plan must be reviewed and approved by Pulse 
Biosciences. Prior to shipment of study devices, a signed copy of the IRB Committee approval letter 
identifying the clinical study must be submitted to Pulse Biosciences, signifying study approval. 
Investigators are responsible for obtaining and maintaining approval of the study by the IRB. 
 
Written informed consent is mandatory and must be obtained from all subjects prior to performing 
any study procedures in this clinical study. Pulse Biosciences will provide the site with a Sponsor 
approved consent template. Each site is expected to modify the template, if necessary, to meet their 
facilities requirements. Modified ICF templates must be reviewed by the Sponsor prior to submission 
to their IRB. 
 
Informed consent must be obtained and shall inform the subject as to the objective and procedures 
of the study and possible risks involved. The subjects must be informed about their right to withdraw 
from the study at any time and for any reason without sanction, penalty, or loss of benefits to which 
the subject is otherwise entitled and that withdrawal from the study will not jeopardize their future 
medical care. The clinical study informed consent must be used in addition to any institutional 
standard consent form for participation in clinical research. The institutional standard subject 
consent form does not replace the study consent form. 
 
It is the responsibility of the investigator to obtain both an authorization for patient health 
information and study consent. 
 
The IRB approved Informed Consent Forms must be retained at the site along with the other 
investigational case report forms or source documents. A signed copy of the consent form must be 
given to each subject enrolled in the study. 
 
12.2 Data Collection and Reporting 
Case report forms or source documents will be used to record demographic, procedural, and follow-
up data, as well as any adverse events which may occur during the study period. The AEs and 
incidence of morbidity and mortality will be reviewed with Investigators to assess the safety of the 
device and the procedure. 
The Investigator must comply with the safety reporting requirements specified in (Section 9.3) 

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Qualified study staff at each clinical site will perform primary data collection drawn from source- 
document (hospital or clinic chart) reviews. The Monitor will perform clinical monitoring, including 
review of CRFs, source documents and/or Electronic Data Capture (EDC) system with verification of 
study eligibility, informed consent process, scheduled follow-up visits and AEs to the source 
documentation. 
 
12.3 Source Documents / Records Retention 
The investigator shall maintain accurate, complete, and current records relating to the investigator's 
participation in an investigation including records of each subject's case history and exposure to the 
device. Case histories include the case report forms and supporting data including, for example, 
signed and dated consent forms and medical records including, progress notes of the physician, the 
individual's hospital or clinic chart(s), and the nurses' notes. Such records shall include: 
 
1. 
Documents evidencing informed consent and, for any use of a device by the investigator without 
informed consent, any written concurrence of a licensed physician and a brief description of the 
circumstances justifying the failure to obtain informed consent. The case history for each subject 
shall document that informed consent was obtained prior to participation in the study. 
 
2. 
All relevant observations, including records concerning adverse device effects (whether 
anticipated or unanticipated), information and data on the condition of each subject upon 
entering, and during the investigation, including information about relevant previous medical 
history and the results of all diagnostic tests. 
 
Investigator files containing all records and reports of the investigation should be retained for a 
minimum of 5 years after the completion or termination of the investigational study or until two 
years after they are no longer needed to support product approval. They may be discarded upon 
notification by Pulse Biosciences. To avoid any error, the Investigator should contact Pulse 
Biosciences before destroying any records and reports pertaining to the study to ensure they no 
longer need to be retained. 
 
12.4 Device Accountability 
The Investigator shall maintain adequate records of the receipt and disposition of all study devices. 
When the enrollment is complete, the Investigator shall return any unused devices to the Sponsor. 
At the completion of the study, all devices shall be returned to the Sponsor. The Investigator’s copy 
of the Device Accountability Log must document devices that have been returned to the sponsor. 
 
The device accountability log will include records of receipt, use or disposition of a device that relate 
to: 
 
1. 
The type and quantity of the device, the dates of its receipt, and the lot number. 
2. 
The names of all persons who received, used, or disposed of each device. 
3. 
Why and how many device(s) were returned to the Sponsor, or otherwise disposed of. 
 
 

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13.0   REFERENCES 
1. Bacelieri R, Marchese Johnson S. Cutaneous Warts: An Evidence-Based Approach to Therapy. Am 
Fam Physician 2005; 72:648-652. 
2. Gibbs S, Harvey I, Sterling J, Stark R. Local treatments for cutaneous warts: systematic review. 
BMJ 2002; 325:461. 
3. Mitsuishi T, Iida K, Kawana S. Cimetidine treatment for viral warts enhances IL-2 and IFN-y 
expression but no IL-18 expression in lesional skin. European J Dermatol 2003; 13(5):445-448.  
4. Banihashemi M, Pezeshkpoor F, Yazdanpanah M J, Family S. Efficacy of 80% phenol solution in 
comparison with cryotherapy in the treatment of common warts on hands. Singapore Med J 
2008; 49(12):1035. 
5. Horn T, Johnson S, Helm R, Roberson P. Intralesional Immunotherapy of Warts with Mumps, 
Candida and Trichophyton Skin Test Allergens. Arch Dermatol 2005; 141:589-594. 
6. Habif TP, et al. (2011). Viral infections. In Skin Disease: Diagnosis and Treatment, 3rd ed., pp. 210-
245. Edinburgh: Saunders. 
7. Ross EV, Munavalli GS, Jauregui L, Knape WA. Non-Thermal Nano-Pulse Stimulation (NPS) 
Technology for Treating Cutaneous, Non-Genital Warts: A Feasibility Study. Abstract Accepted for 
Podium Presentation, ASLMS Annual Conference on Energy-Based Medicine & Science, April 29-
May 3, 2020. 
8. Lain E, LaTowsky B, Loss L, Munavalli GS, Ross EV, Johnston L, Knape WA. A Prospective, Non-
Randomized, Multicenter Pivotal Study of Nano-Pulse Stimulation (NPS) for Treatment of 
Cutaneous Non-Genital Warts. Abstract Accepted for Podium Presentation, American Society for 
Dermatologic Surgery (ASDS), ASDS Annual Conference, Oct. 8-11, 2020. 
9. Liang K-YaZ, S. L. Longitudinal Data Analysis Using Generalized Linear Models. Biometrika.     
1986;73:13-22. 
10. Adalatkhah H, Khalilollahi H, Amini N, Sadeghi-Bazargani H. Compared therapeutic efficacy 
between intralesional bleomycin and cryotherapy for common warts: a randomized clinical trial. 
Dermatol Online J. 2007;13(3):4. 
11. Food and Drug Administration. Multiple Endpoints in Clinical Trials Guidance for Industry (Draft 
Guidance). January 2017. 
12. Blackwelder, WC. Proving the Null Hypothesis in Clinical Trials. Control. Clin. Trials 1982; 3:345-
353. 
13. Liu, Guanghan, and Liang, Kung-Yee. Sample Size Calculations for Studies with Correlated 
Observations. Biometrics 53.3 (1997): 937-47. Web. 
14. Muhaidat, JM, Al-qarqaz, FA, Alshiyab, DM, Alkofahi, HS, Khader, Y, and Ababneh, 
MY._Comparison of the Efficacy and Safety of Two Cryotherapy Protocols in the Treatment of 
Common Warts: A Prospective Observational Study. Dermatology and Research Practice. Vol 
2020; Article ID 2309309, 1-5. 
15. Kwok, CS, Holland, R, and Gibbs, S. Efficacy of Topical Treatments for Cutaneous Warts: A Meta-
Analysis and Pooled Analysis of Randomized Controlled Trials. British Journal of Dermatology 
2011; 165:233-246. 
 
 

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14.0 APPENDICES 
 
14.1 Appendix A: Patient Informed Consent 
14.2 Appendix B: Case Report Forms  
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: Patient Informed Consent will be provided as a separate 
attachment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX B: Case Report Forms will be provided as a separate attachment