CLINICAL EVALUATION TO ASSESS THE THERMAL  EFFECTS OF A NOVEL PLASMA GENERATING DEVICE ON HEALTHY HUMAN TISSUE  

Protocol Identifying Number: NEO19-NV-01 

Version Number: v. 1.0  

05 November 2019 

 

1. ABBREVIATIONS

 

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2. STATEMENT OF COMPLIANCE

The trial will be conducted in accordance with International Conference on  Harmonization Good Clinical Practice (ICH GCP) and applicable United States (US) Code  of Federal Regulations (CFR). The Principal Investigator will assure that no deviation  from, or changes to the protocol will take place without documented approval from the  Institutional Review Board (IRB), except where necessary to eliminate an immediate  hazard(s) to the trial participants. All personnel involved in the conduct of this study  have completed Human Subjects Protection and ICH GCP Training. 

The protocol, informed consent form(s), recruitment materials, and all participant  materials will be submitted to the IRB for review and approval. Approval of both the  protocol and the consent form must be obtained before any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the  changes are implemented to the study. All changes to the consent form will be IRB  approved; a determination will be made regarding  

_________________________________________ 

Principle Investigator Print name 

__________________________________________ 

Principle Investigator Signature  

______________________ 

Date 

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1 PROTOCOL SUMMARY 

1.1 SYNOPSIS  

Title: Clinical Evaluation to Assess the Thermal Effects of a Novel Plasma  Generating Device on Healthy Human Tissue 

Study Description: Open label, prospective study conducted at a single study center  examining the histological effects of a novel battery-operated plasma  

generating device on healthy human tissue. The study will enroll up to 5  

subjects to receive a single study treatment to the back or shoulder. Up to  

4 biopsy samples will be obtained: control area (adjacent), immediately  

post-treatment, 24 hours post-treatment, 7 days post-treatment and 14  

days post-treatment. Samples will undergo hematoxylin-eosin (HE) 

staining by a qualified pathologist. Histological results at the  

predetermined time points will be compared to the control sample to  

evaluate the thermal effects and injury profile. Adverse events (AE) will be  

monitored throughout the study duration to evaluate safety.  

Objectives: Primary Objective 

• The objective of this clinical study is to characterize and monitor  

the thermal effects of the investigational hand held plasma  

generating device on healthy human tissue. 

Safety Objective 

• To assess the safety and tolerability of a single treatment with the  

investigational study device.  

Endpoints: Primary Endpoints 

• To characterize and monitor the thermal effects of the  

investigational device on healthy human tissue through  

histological analysis of serial tissue sampling at determined time  

points. 

Safety Endpoints 

• To determine the proportion of subjects experiencing a  

treatment-related AE and frequency, duration and severity of  

treatment-related AEs 

Study Population: The study will enroll up to 5 healthy male or female subjects, 18-60 years  of age, who are willing to undergo hand held plasma generating treatment  

and biopsy.

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Phase: Pre-market Number of Study Sites: One study site 

Description of Study  Device: 

The investigational device (Nu-VissaTM) is a DC powered wireless hand held  plasma generating pen that produces a high-voltage, low amperage, low  power (2 Watts) sinusoidal signal. The handpiece comprises an electric  generator which generates an electric signal that is applied to an electrode  shaped as a needle located at the end of the handpiece. The needle can  transfer concentrated energy resulting in superficial fulguration. The  electrical signal and sinusoidal signal have a maximum power value of 2  Watts. The signal has an operating voltage of 110 Volts and a frequency of  50-60Hz. 

Study Duration: 3 months 

Participant Duration: 1 month 

1.2 SCHEMATIC OF STUDY DESIGN  

Execution of the treatment is as follows. 

1. a) Energy level for all treatments from the NeuVissa device is standard at 2 Watts. b) The size of the punch biopsy for all patients will be 3mm. Up to 4 biopsy samples  will be obtained: control area (adjacent), immediately post-treatment, 24 hours  post-treatment, 7 days post-treatment and 14 days post-treatment. c) For ease of biopsy location each patient will receive (4) 0.5 circles placed on the  back or shoulder each circle will be separated by 1cm and treatment with the  NeuVissa device will occur within the full circle. 

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Visit 1 

Day 0  

Visit 2 

Day 1  

Visit 3 

1 Week  

Visit 4 

2 Weeks  

Visit 5/ 

Follow up  

Phone call 

7-10 days post visit 4 

Urine pregnancy test, concomitant medications. Administer study treatment. 

Punch biopsy of control area (adjacent to treatment area) Punch biopsy of treatment area  

Record AEs 

Punch biopsy of treatment area 

Record AEs 

Punch biopsy of treatment area 

Record AEs 

Remove sutures (if applicable) 

Punch biopsy of treatment area 

Record AEs 

Remove sutures (if applicable) 

Record AEs 

Remove sutures (if applicable) 

Final Assessments 

H&E staining  

Pathologist review

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1.3 SCHEDULE OF ACTIVITIES (SOA) 

 

*Screening and biopsy visit 1 to occur on same day  

a.Urine pregnancy test for women of child-bearing potential 

2 INTRODUCTION 

2.1 STUDY RATIONALE  

The use of electrocautery technology is safe and effective for the treatment of various  dermatologic conditions including acne scars, actinic keratoses, superficial skin lesions, small  angiomas and molluscum.1,2 Additionally, it is safe and effective method for hemostasis in  cutaneous surgeries.1,2 Its application is well established in the current literature and is a  commonly used technique in various minor surgical procedures in dermatology, ophthalmology,  otolaryngology, plastic surgery and urology.3 The objective of this clinical study is to evaluate the  safety and histological effects of the Nu-Vissa, a handheld battery-operated plasma generating device, on healthy human tissue.  

The use of the Nu-VissaTM has been determined to present a non-significant risk in accordance  with 21 CFR 812.3 for the intended use in this study, because the device is not: • Intended as an implant. 

• purported or represented to be for use in supporting or sustaining human life; • for use of substantial importance in diagnosing, curing, mitigating, or treating disease, or

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otherwise preventing impairment of human health; or 

• Otherwise presenting a potential for serious risk to the health, safety, or welfare of a subject. 

Furthermore, use of electrocautery has been reported without significant complications or  incident in various clinical studies.1,2, 

2.2 BACKGROUND  

Electrocautery refers to a process in which heat is generated by way of an alternating or direct  electrical current that is passed through a resistant metal wire electrode. The heated electrode  is then applied to the skin to achieve desirable amounts of tissue destruction.4 Unlike  electrosurgery, the electrical current does not pass through the patient. This is particularly  important in patients who are not ideal candidates for electrosurgery due to the presence of  implanted devices and the risk for external electromagnetic interference.5,6 Although stark  differences are evident between electrocautery and electrosurgery, the two share several  common indications for use including, small angiomas, seborrheic keratoses, molloscum, wart  removal, skin tags and chronic epistaxis.1,2 Electrocautery is also commonly used in minor  surgical procedures in which hemostasis is required and has been beneficial in procedures such  as functional occlusion related to dry eye syndrome.1,7,8,9  

Several studies have been done that examine the safety, tolerability and efficacy of  electrocautery for various conditions and is well supported in the current literature.10.11 The  current study aims to evaluate the histological effects of a single plasma generated treatment to  human tissue. A more in depth understanding of the wound healing and injury process taking  place on a cellular level after treatment will assist in broadening the safety profile of the device  and provide possible evidence for its use in other indications in future studies.  

2.3 RISK/BENEFIT ASSESSMENT  

2.3.1 KNOWN POTENTIAL RISKS  

Electrofulguration Risks 

Anticipated adverse events associated with hand held plasma generating devices include mild  and transient discomfort, skin irritation, localized edema and minimal bleeding. In addition,  other complications include injury to surrounding structures, blood vessels or nerves, scarring,  thermal injury, infection and interference with pacemakers or implantable cardioversion  defibrillators. 

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Punch Biopsy Risks  

Possible risks associated with biopsies include pain, edema, erythema, bleeding, scarring,  ecchymosis and infection.  

Surgical Marker Risks  

A surgical marker may be used to outline the treatment area. There are minimal risks associated  with the use of a surgical marker, but it may produce erythema or contact dermatitis. It is  possible that markings may remain visible on the skin for 1-3 days, but alcohol may be used to  remove markings.  

Anesthetic Risks (Lidocaine with or without 1% epinephrine) 

Potential risks associated with lidocaine include mild bruising, rash, erythema, pruritus, edema,  nerve damage and/or temporary loss of sensation or muscle function at the injection site.  Though rare, a serious complication to lidocaine is allergic-type reactions which include  anaphylaxis.  

Potential risks will be mitigated by conducting this protocol with an investigator who will be  trained by the sponsor on the use of the device. Subjects will undergo thorough screening to  ensure the study criteria is met prior to enrollment. The study site staff will confirm subjects  continue to meet the enrollment criteria throughout the duration of the study.  

1. 2.3.2 KNOWN POTENTIAL BENEFITS  

If the subject agrees to participate in this study, he/she will be contributing to the  understanding of the 

thermal effects and safety of this investigational device on healthy human tissue. As the study is  evaluating the effects of the device on healthy human tissue, participants may not experience  any direct benefits from treatment. However, a better understanding of the safety and effects of  the device on healthy human tissue may lead to optimization of treatments for future  procedures. 

3 OBJECTIVES AND ENDPOINTS 

3.1 OBJECTIVES  

Primary Objective  

To characterize and monitor the thermal effects of a single hand held plasma treatment on  healthy human tissue. 

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Safety Objective  

To evaluate the safety and tolerability of the investigational hand held plasma device after a single  treatment. 

3.2 END POINTS  

Primary Endpoint 

• To characterize and monitor the thermal effects of the device on healthy human tissue  through histological analysis of tissue samples obtained immediately post-treatment, 24  hours post-treatment, 7 days post-treatment and 14 days post-treatment. Safety Endpoint
• Determine the proportion of subjects experiencing a treatment-related adverse event. ● Determine the frequency, duration and severity of adverse events associated with  treatment.  

4 STUDY DESIGN 

This is an open label, single site, prospective study. 

4.1 STUDY SUMMARY  

Up to five (5) subjects with healthy tissue on their back or shoulder(s) and who meet the  inclusion criteria will be enrolled at a single study site. Each subject will receive a single hand held plasma treatment with the Nu-VissaTM device. Each treatment will consist of marking the  treatment area in India ink prior to doing the treatment. The treatment will consist of delivering  15 individual shots using the Neuvissa device. The NeuVissa device will deliver a maximum of 2  watts of energy with each shot. The treatment area will be confined to a 3” x 3” area of the  shoulder or back. One punch biopsy will be obtained on the day of treatment, immediately post treatment adjacent to the treatment area, which will be used as a control for comparative  analysis. Subjects will attend 3 more visits at which time an additional biopsy within the  treatment area will be obtained; one biopsy at 1-day post-treatment, 7 days and 14 days post treatment. Suture removal will occur approximately 7-10 days post biopsy visits, if applicable.  Adverse events will be monitored at each visit. 

An additional follow up visit or follow-up phone call will take place 7 days after the final biopsy  visit to assess for adverse events.  

Tissue samples will be sent to a board-certified pathologist for analysis. Routine hematoxylin eosin (HE) methods will be used to generate a histology report to evaluate the thermal effects of  the Nu-VissaTM device on healthy human tissue.  

4.2 STUDY COMPLETION  

A participant is considered to have completed the study if he or she has completed all phases of  the study including the last visit or the last scheduled procedure shown in the Schedule of  Activities (SOA), Section 1.3.

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5 SUBJECT SELECTION 

5.1 INCLUSION CRITERIA 

1. Healthy male or female between 18-60 years of age.  
2. Willingness to receive a single treatment with the Nu-VissaTM device and agrees to  undergo up to 4 biopsies. 
3. Agrees to comply with all study procedures and is available to attend all scheduled visits  for the duration of the study period.  
4. Women of child-bearing age are required to use a reliable method of birth control for at  least 3 months prior to study enrollment and for the duration of the study; a negative  Urine Pregnancy test at baseline is required. 

5.2 EXCLUSION CRITERIA 

1. Is a female and pregnant, has been pregnant in the past 3 months, is currently  breastfeeding or is planning to become pregnant during the study period. 2. Open wounds, lesions, sores or active infection in the treatment area.  3. Have a pacemaker, implantable loop recorder or other electrical implanted devices.  4. A history of epilepsy disorder.  
2. Any disease associated with immune system impairment, including auto-immune  diseases, HIV and transplantation patients or use of immunosuppressive or  immunomodulatory medications 6 months prior to and during the course of the study. 
3. History of hyperlipidemia, diabetes mellitus, hepatitis, blood coagulopathy or excessive  bleeding. 
4. Current smoker and/or regular user of other nicotine-containing products (e.g.,  patches). 
5. Average consumption of more than 14 units of alcohol per week. 
6. Use of antiplatelet medications (81 mg acetylsalicylic acid daily permitted),  anticoagulants, thrombolytics or anti-inflammatory medications within 2 weeks of  treatment. 
7. Having a history of skin cancer or any other cancer in the areas to be treated, including  the presence of malignant or premalignant pigmented lesions. 
8. Having a permanent implant in the treatment area such as metal plates or an injected  chemical substance such as silicone or parenteral gold therapy (gold sodium  thiomalate). 
9. Tattoos in the treatment area. 
10. Participation in another clinical study involving the same anatomical area(s) within the  last 6 months. 

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14. History of keloid or hypertrophic scar formation or poor wound healing in the treatment  area. 
15. Sensitivity or allergic reaction to lidocaine or its derivatives.  

5.3 STRATEGIES FOR RECRUITMENT AND RETENTION 

Up to 5 subjects will be enrolled at a single study site. It is anticipated that this study will take 1  month to complete. Subjects will be enrolled primarily through the investigator’s clinic. Any  advertising campaigns and materials will be reviewed and approved by an institutional review  board (IRB) before implementation. Subjects will receive compensation of $100.00 USD per  biopsy obtained; up to $400.00 USD. The amount due will be paid in full at the end of  participation in the study. Amount due will be paid regardless of completion or withdrawal from  study for the number of biopsies obtained from the participant.  

6 STUDY INTERVENTION 

6.1 DEVICE DESCRIPTION AND SPECIFICATIONS 

The Nu-VissaTM electrocautery device used in this study is considered investigational because  the handpiece has not yet been cleared for use by the U.S. Food and Drug Administration (FDA). 

The investigational device (Nu-VissaTM) is a high voltage, low amperage, hand-held plasma  generating pen. The portable device uses direct current (DC) to generate a sinusoidal signal that  is applied to an electrode shaped as a needle located at the end of the handpiece. Concentrated  energy is transferred by way of high voltage, low amperage electrons that create a spark  (ionization) when approximately 1mm from the tissue resulting in superficial fulguration. After  treatment the tissue cools down by evaporation of lesional fluids without the overheating of  surrounding tissues. The electrical signal and sinusoidal signal have a maximum power value of 2  Watts. The signal has an operating voltage of 750VAC and a frequency of 50-60Hz. 

The Nu-VissaTM needle is designed for one time use only and should be disposed of after each  treatment.  

Device Specifications 

Device Name: Nu-Vissa 

Manufacturer: Neoteric Medical 

Power supply: 100 to 240 VAC / 50 – 60 Hz 

IEC protection class: II 

Type of device: With an applied part of the BF type 

Type of power supply source: DA12-050EU-M  

Input of power supply: 100-240 VAC / 50 – 60 Hz 

Output of power supply: 5VDC, max. 2.0 A 

Consumption of power supply: max. 12 VA 

Weight: approx. 350 grams 

Range of relative air humidity: 30% – 75% 

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Range of environment temperature: +10°to +40°C 

Working environment: the device should not be used close to flammable anesthetic compounds  with air or flammable anesthetics mixed with oxygen or nitrous oxide 

6.2 DEVICE STORAGE, MAINTENANCE AND SAFETY 

Storage 

• Storage temperature: 5 – 40 °C 
• Store indoors in well-aired places and protect from direct sunlight and humidity. ● Store unplugged from charging station. 

Regular maintenance, cleaning a periodical safety technical check 

• Maintenance – No regular maintenance is required. 
• Cleaning – The body of the device can be disinfected by moist cloth only. ● Battery – Contains one Lithium Battery. The battery on full charge should last 90  minutes. If the battery fails to last 90 minutes, contact the company for replacement. ● Disinfection – No disinfection needed. The needles are considered disposable and are  intended for one-time use. 

Safety technical checks 

Technical safety checks should be performed at least once a month. 

Labeling 

Labeling and directions for use can be found in the Operator’s Manual for the device.  

Disposal of the product 

The waste consisting of electrical or electronic devices may contain substance that may be  harmful for the environment or health. The device should be considered as electric waste and  after the end of its lifespan, it must not be disposed of in communal waste. 

7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT  DISCONTINUATION/WITHDRAWAL 

7.1 PREMATURE TERMINATION OR SUSPENSION OF STUDY 

The sponsor may suspend or prematurely terminate the entire study for significant and  documented reasons. 

A principal investigator (PI), IRB, or regulatory authority may suspend or prematurely terminate participation in the study at the investigation site for which they are responsible. 

If suspicion of an unacceptable risk to subjects arises during the study, or when so instructed by  the IRB

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or regulatory authorities, the sponsor shall suspend the clinical investigation while the risk is  assessed. The sponsor shall terminate the study if an unacceptable risk is confirmed.  

The sponsor shall consider terminating or suspending the participation of the investigation site  or investigator in the study if monitoring or auditing identifies serious or repeated deviations on  the part of an investigator. 

If suspension or premature termination occurs, the terminating party shall justify its decision in  writing 

and promptly inform the other parties with whom they are in direct communication. The  principal investigator and sponsor shall keep each other informed of any communication  received from either the 

IRB or the regulatory authority. 

If, for any reason, the sponsor suspends or prematurely terminates the study at the  investigation site, the sponsor shall inform the responsible regulatory authority as appropriate  and ensure that the IRB is 

notified, either by the principal investigator or by the sponsor. If the suspension or premature  termination was in the interest of safety, the sponsor shall inform all other principal  investigators. 

If suspension or premature termination occurs: 

1. a) the sponsor shall remain responsible for providing resources to fulfill the obligations  from the protocol and existing agreements for following up the subjects enrolled in the  study. 
2. b) the principal investigator or authorized designee shall promptly inform the enrolled  subjects at the investigation site, if appropriate. 

In case of early termination, final study activities according to the protocol, including the follow up visits and procedures to assess the safety and efficacy of the device will be conducted,  regardless of the sponsor’s interest in the study. Follow-up activities will be conducted so that  device deficiencies can be identified, and appropriate safety measures can be implemented. At  the completion or termination of the study, the Investigator will return all remaining clinical  supplies to Sponsor along with a copy of the device supply and inventory records. 

Circumstances that may warrant termination or suspension include, but are not limited to: ● Determination of unexpected, significant, or unacceptable risk to participants  (examples of findings that might trigger a safety review are the number of SAEs overall,  the number of occurrences of a particular type of SAE, severe AEs/reactions, or  increased frequency of events). 

• Demonstration of performance that would warrant stopping 
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination of futility

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Study may resume once concerns about safety, protocol compliance, data quality and the like,  as the case may be, are addressed and satisfy the sponsor, IRB and/or regulatory authorities. 

7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY Subjects are free to withdraw from participation in the study without prejudice at any time upon request. In the event that a subject drops out of the study or is withdrawn from the study, the  End of Study/Early Discontinuation CRF form should be completed. On the withdrawal page, the  Investigator should record the date of the withdrawal and the reason for withdrawal. 

Reasonable effort should be made to contact any subject lost to follow up during the course of  the study in order to complete assessments and retrieve any outstanding data. The records of  subjects who terminate prior to completing the study will be retained and the reason for  termination will be documented. 

An investigator may terminate participation in the study if: 

• Any clinical adverse event (AE), laboratory abnormality, or other medical condition or  situation occurs such that continued participation in the study would not be in the best  interest of the subject. 
• The subject meets an exclusion criterion (either newly developed or not previously  recognized) that precludes further study participation. 

7.3 LOST TO FOLLOW-UP 

A participant will be considered lost to follow-up if he or she fails to return for 2 of the  scheduled site visits and is unable to be contacted by the study site staff.  

The following actions must be taken if a participant fails to return to the clinic for a required  study visit: 

• The site will attempt to contact the participant and reschedule the missed visit and  counsel the participant on the importance of maintaining the assigned visit schedule  and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make  every effort to regain contact with the participant. These contact attempts should be  documented in the participant’s medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have  withdrawn from the study with a primary reason of lost to follow-up. 

8 STUDY ASSESSMENTS AND PROCEDURES 

8.1 STUDY SPECIFIC PROCEDURES  

The following procedures will be done as part of this study: 

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1. Demographics (Visit 1) 
2. Medical/surgical history  
3. Concomitant medications 
4. Assessment of eligibility (inclusion/exclusion criteria) 
5. Urine pregnancy test for women of child-bearing potential (Visit 1 only) 6. Adverse event reporting  
6. Treatment area marking (Visit 1) 

8.2 LABORATORY EVALUATION  

Women of child-bearing potential will be asked to provide a urine sample for a urine  pregnancy test to be performed according to local site standards. Urine pregnancy  required within 24 hours of study intervention. A negative result must be available prior  to administration of the treatment. 

A staff member will explain how the pregnancy test will be performed at the screening  visit depending on which type of pregnancy test is available at the study center.  Instructions will include: 

• Hold the pregnancy test stick directly under your urine for 5-10 seconds until. ● Alternatively, you may be asked to urinate into a specimen cup and dip the  pregnancy test stick into the urine for 5-10 seconds.  
• Results are typically available within 2-5 minutes but some tests take as long as  10 minutes. 
• A positive results indicating pregnancy will usually be a colored line or plus  symbol in the result window. A negative result indicating no pregnancy will  usually be absence of a colored line or a negative symbol.  

8.3 SCHEDULE  

8.3.1 SCREENING (VISIT 1) 

The Principal Investigator or his/her designee will assess the subject eligibility for participation in  the clinical study using the inclusion/exclusion criteria (Sections 5.1; 5.2). Subjects meeting the  study criteria for enrollment will be asked to sign an informed consent document. The Principal  Investigator or his/her designee will obtain informed consent from the subject. All subjects must  clearly indicate his/her understanding of the requirements and possible risks involved with study  participation. Once subjects sign the informed consent document, they will be assigned a unique  identifying number that will be composed of a two-digit site number and a three-digit subject  number in sequence. This unique identifier will be used throughout the entire study and will be  entered in the subject’s case report form (CRF) and for each biopsy visit.

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During the screening visit, the Principal Investigator or his/her designee will review the subjects  medical/surgical history, demographic information, concomitant medication and examine the  treatment area.  

Women of child-bearing potential will be asked the date of their last menstrual cycle and  required to provide a urine sample for a urine pregnancy test. A negative result is required  within 24 hours of treatment for participation in study. The investigator will inquire about  contraceptive use to confirm they meet the inclusion criteria. 

Treatment and screening may take place on the same day if negative pregnancy test is  confirmed and the subject meets all criteria for enrollment.  

8.3.2 PRETREATMENT (VISIT 1) 

Pre-treatment 

The practitioner will identify an area of approximately 3 inches x 3 inches of healthy tissue on  your shoulder or back that will be treated with the Nu-Vissa device. The area will be cleansed  and a local anesthetic, such as lidocaine, may be injected or applied topically to the treatment  area prior to biopsy.  

A surgical marker may be used to outline the treatment area.  

The following pre-treatment instructions will be reviewed:  

• Shave any dense hair in the treatment area prior to procedure  
• Avoid any constrictive clothing on the day of treatment  
• Ensure treatment area is free of any open wounds or active infection  

Standard pre-treatment instructions will be reviewed, and the subject will be instructed to  adhere to the following: 

• Do not receive other treatments within the study area for the duration of the study. ● Do not apply any products, including lotion and sunblock, to the general area for at least  12 hours prior to each study visit. 
• The treatment area must remain free of any open lesions or active infections. ● General recommendations such as proper hydration and avoidance of alcohol several  days prior to treatment and biopsies is encouraged. 

8.3.3 TREATMENT (VISIT 1) 

The investigator will confirm that the subject continues to meet the inclusion criteria and none  of the exclusion criteria if treatment is scheduled on a different date than screening visit. 

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The treatment area will be cleansed with a non-alcohol-based cleanser, such as chlorhexidine. 

Lidocaine 1% either with or without epinephrine (at investigator discretion) will be injected into  the treatment area per clinic protocol.  

A needle will be secured into the receptacle of the NuVissa device and tightened. The device will  be turned on and put into the “continuous mode” setting. The device will be held approximately  1mm away from skin during treatment. The treatment will last approximately 1 minute. The  investigator will monitor for adverse events throughout procedure. Once the treatment is  complete, device will be turned off and needle will be disposed of in an appropriate sharp’s container.  

Biopsy will take place within 5 minutes post treatment. 

A 2-3mm punch biopsy will be obtained adjacent to the treatment area as the control specimen.  Additional lidocaine may be injected into this area if needed. Ensure area is properly  anesthetized and patient reports numbness for procedure. 

Punch biopsy procedure: 

1. This is a sterile procedure. Follow clinic protocol and ensure sterile field and sterile  gloves are worn. 
2. Using a sterile 3mm skin punch, the investigator will apply pressure and twist in a  “drilling” motion until the blade of the skin punch has pierced the epidermis of the skin.  The blade should be about ½ exposed. It is normal for the patient to experience a  pressure and twisting sensation, but they should not experience pain.  
3. As the punch enters the subcutaneous fat, resistance will lessen. At this point, the punch  should be removed.  
4. Great care should be taken not to damage the epidermis by crushing it with forceps or  by cutting it with a scalpel unnecessarily. Forceps can be used to grab the dermis of the  cored skin, pulling up the core to reveal excess dermis and subdermal fat, and with a  scalpel in one or two cutting motions the core skin can be cut free. Alternatively, curved  iris scissors may be used without using forceps. 
5. If the tissue core does not pop up, it may be elevated by use of a hypodermic needle or  fine-tooth forceps. A portion of the subcutaneous fat should be included in the  specimen. 
6. The specimen should be placed in the specimen container. Ensure proper labeling.  Once labeled, specimen will be sent to the dermatopathology lab for analysis.  7. Hemostasis can be achieved by applying pressure with a 2×2 gauze pad. 

If sutures are required, investigator will suture incision per clinic protocol.  

Any adverse events will be recorded in subject’s CRF. 

8.3.4 POST-TREATMENT INSTRUCTIONS

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Standard post-treatment instructions will be reviewed, and the subject will be instructed to  adhere to the following: 

1. The local anesthetic used for the biopsy will usually last for 1 to 2 hours after the  procedure. After it wears off, you may have some mild, localized tenderness and slight  redness at the biopsy site over the next day or two. Acetaminophen (Tylenol) or  Ibuprofen can be used for discomfort.  
2. If you experience symptoms of infection including fever, increased pain or redness,  swelling, pus or excessive drainage contact the study site immediately.  
3. There should be no excessive bleeding after the procedure. If the incision site does  bleed, apply firm pressure for 10-20 minutes. If the site continues to bleed despite  pressure call the study site immediately.  
4. Keep the wound dry. Avoid hot tubs, swimming or any other activity where the incision  may be soaked. Avoid soaking the incision site for at least 14 days.  
5. When showering takes special care not to rub or pick at the incision. Trauma to the area  increases the risk for scarring.  
6. After showering, gently pat the area dry. Petroleum jelly may be applied to the incision  area twice daily to prevent formation of a hard scab or crusting. This will also minimize  scarring.  
7. The dry dressing can be removed 24 hours after the procedure. You may wish to apply  an adhesive bandage over the wound to prevent irritation or rubbing of the treatment  area. 
8. The biopsy site may appear slightly darker than the rest of your skin. You can expect this  discoloration to gradually fade over the next few months to a year.  
9. You may take a shower 1 day after the procedure. Take care to not scrub the treated  and lightly pat dry. 
10. Do not over bend or stretch the incision site.  
11. If suture removal is required, you will be asked to return to the study site 7-10 days after  the biopsy for removal per the study protocol. If the provider used steri-strips, they will  fall off on their own but the incision must be kept dry for 7-10 days, as they separate  easily when wet. 
12. Once the sutures are removed, continue to put petroleum jelly on the incision area to  keep the wound from crusting.  

8.3.5 BIOPSY (VISITS 2, 3, 4) 

Subjects will return for subsequent biopsies at 24 hours post-treatment, 7 days post-treatment  and 14 days post-treatment. 

Adverse events and concomitant medications will be recorded at the start of each visit. If a side  effect or adverse event is tracked, the site will continue to call the subject until the event  resolves. If deemed necessary by the investigator, the subject may attend an unscheduled visit  for side effect assessment.

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If suture removal is required, it will be done 7 days (+/- 3 days) post each biopsy. This timeline  coincides with the additional biopsy visits.  

Lidocaine 1% without epinephrine will be injected per clinical protocol to the defined treatment  area. 

One (1) 2-3mm punch biopsy specimen will be obtained inside the defined treatment area at  visits 2, 3 and 4.  

8.3.6 FOLLOW-UP VISIT OR PHONE CALL  

At 7 days post-biopsy visit 4 the subject may be asked to return to the clinic for evaluation of the  biopsy site and for suture removal (if applicable).  

Alternatively, a follow-up phone call can be done in place of the follow up visit if sutures were  not required. Principal investigator or his/her designee will contact subject to inquire about  adverse events. Adverse events will be recorded in subject’s CRF. If a side effect is tracked, the  site will continue to call the subject until the event resolves. If deemed necessary by the  investigator, the subject may attend an unscheduled visit for side effect assessment. 

8.3.7 HISTOLOGY 

Specimen procurement kits will be provided by sponsor and shipped to study site prior to study  initiation.  

All tissue samples obtained will be labeled with the subjects’ unique identifier, date and time of  harvest. 

Sample should be placed in appropriate test tube in procurement kit and preserved in 10%  formalin. Place specimen in supplied mailer and send to the specified laboratory for analysis.  Investigator is to ensure that all required information is completed on specimen label and  request form.  

Collected biopsy samples will be mailed to specified laboratory for tissue processing, embedding  (paraffin blocks) microtomy, slide preparation. Hematoxylin-eosin stain slides will be prepared  from each paraffin block per the laboratory’s protocol. Using routine light microscopy, the slides  were histologically evaluated. 

Pathologist(s) will be blinded to applied treatment characteristics until the completion of the  study. 

Tissue response may be assessed using the common histological characteristics of wound  healing (amount of granulation tissue, inflammatory infiltrate, collagen fiber orientation, pattern 

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of collagen, amount of early collagen, migration of keratinocytes, bridging of cells,  keratinization).  

8.4 UNSCHEDULED VISITS  

 An unscheduled visit may be performed at any time during the study at the subject’s request or  as deemed necessary by the site Investigator. The date and reason for the unscheduled visit will  be recorded in the source documentation. If the unscheduled visit is the result of an adverse  event, the event will be recorded on the adverse event CRF. 

8.5 DATA REPORTING, COLLECTION AND MONITORING 

The investigational device will be sent to the investigator by sponsor. The study site will require  protocol and device training, which will be done by the Sponsor. The sponsor will monitor the  site periodically during the duration of the study. Case Report Forms (CRFs) will be reviewed as  will regulatory binders. The sponsor will collect all data at the completion of the study. The  sponsor will list the study on clinicaltrials.gov as required by FDA regulations. 

8.6 CONCOMITANT MEDICATIONS  

All concomitant prescription medications taken during study participation will be recorded on  the case 

report forms (CRFs). For this protocol, a prescription medication is defined as a medication that  can be 

prescribed only by a properly authorized/licensed clinician. Other medications to be reported in  the CRF 

are concomitant over-the-counter medications and non-prescription medications, including  vitamins and herbal supplements.  

8.7 PROHIBITED MEDICATIONS, TREATMENTS OF PROCEDURES The use of immunosuppressive medications, antiplatelet medications, thrombolytics, anti inflammatory and anticoagulant medications are to be avoided (see section 5.2). The  exception to this is acetaminophen (up to 3000 mg/daily) for local pain.  

8.8 PROPHYLACTIC MEDICATIONS, TREATMENTS OR PROCEDURES  None. 

8.9 RESCUE MEDICATION, TREATMENTS OF PROCEDURES  

In the event that the subject experiences pain, the principal investigator may recommend any analgesic deemed appropriate to the level of pain. Acetaminophen (up to 3000 mg  daily) may be recommended for the pain associated with this treatment.

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9 SAFETY REPORTING 

9.1 DEFINITION OF ADVERSE EVENTS  

Adverse event means any untoward medical occurrence associated with the use of an  intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 

9.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 

NOTE: The term serious is not synonymous with severity, which may be used to describe the  intensity of 

an event experienced by the subject). An AE that does not meet any of the below criteria will be  classified as non-serious. 

A serious AE is any event that: 

• Results in, or contributes to a death; 
• Is immediately life threatening (injury or illness); 
• Results in hospitalization, or prolongs an existing hospitalization; 
• Results in permanent impairment of body structure or function, or in persistent or  significant disability/incapacity; 
• Results in an injury that requires medical intervention to prevent permanent  impairment of body structure or function; 
• Is a device malfunction or deterioration in the characteristics and/or performance of the  device that results in death or serious deterioration in health; 
• Is a device malfunction or deterioration in the characteristics and/or performance of the  device that, if it were to occur again, could result in death or serious deterioration in  health; 
• Results in a congenital anomaly or birth defect. 
• Is any medically significant injury, event or experience that requires medical/surgical intervention to prevent one of the outcomes listed above; 
• Results in end organ toxicity, including hematological, renal, cardiovascular, hepatic, gastrointestinal, and central nervous system events 

9.3 DEFINITION OF UNANTICIPATED PROBLEMS 

This definition includes an unanticipated adverse device effect, 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 (including a supplementary plan or  application), or any other unanticipated serious problem associated with a device that relates to  the rights, safety, or welfare of subjects (21 CFR 812.3(s)).

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9.4 CLASSIFICATION OF AN ADVERSE EVENT 

9.4.1 SEVERITY OF EVENT 

For adverse events (AEs) not included in the protocol defined grading system, the following  guidelines will be used to describe severity.  

• Mild – Events require minimal or no treatment and do not interfere with the  participant’s daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the  therapeutic measures. Moderate events may cause some interference with functioning. • Severe – Events interrupt a participant’s usual daily activity and may require systemic  drug therapy or other treatment. Severe events are usually potentially life-threatening  or incapacitating. Of note, the term “severe” does not necessarily equate to “serious”.] 

9.4.2 RELATIONSHIP TO STUDY INTERVENTION 

All adverse events (AEs) must have their relationship to study intervention assessed by the  clinician who examines and evaluates the participant based on temporal relationship and  his/her clinical judgment. The degree of certainty about causality will be graded using the  categories below. In a clinical trial, the study product must always be suspect.  

• Related – The AE is known to occur with the study intervention, there is a reasonable  possibility that the study intervention caused the AE, or there is a temporal relationship  between the study intervention and event. Reasonable possibility means that there is  evidence to suggest a causal relationship between the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study  intervention caused the event, there is no temporal relationship between the study  intervention and event onset, or an alternate etiology has been established. 

9.4.3 EXPECTEDNESS  

Expected adverse reactions are AEs that are common and known to occur for the study agent  being studied.  

Adverse Events Associated with Electrocautery Treatment 

Anticipated adverse events associated with electrocautery include mild and transient skin  tenderness, minimal bleeding, erythema and edema lasting 1-3 days after treatment.  Adverse Events Associated with Punch Biopsy 

Anticipated adverse events associated with punch biopsy include tenderness, discomfort,  edema, erythema, minimal bleeding, scarring and ecchymosis lasting 1-2 weeks after the  procedure. 

Adverse Events Associated with Surgical Marker  

There are minimal risks associated with the use of a surgical marker but it may produce  temporary erythema or contact dermatitis.

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Adverse Events Associated with Lidocaine  

Anticipated adverse events associated mild and transient ecchymosis, erythema and edema.  Resolution typically occurs soon after injection.  

The site investigator or his/her designee will be responsible for determining whether an adverse  event (AE) is expected or unexpected. An AE will be considered unexpected if the nature,  severity, or frequency of the event is not consistent with the risk information previously  described for the study intervention. 

9.4.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the  attention of study personnel during study visits and interviews of a study participant presenting  for medical care, or upon review by a study monitor. 

All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured  on the appropriate case report form (CRF). Information to be collected includes event  description, time of onset, clinician’s assessment of severity, relationship to study product  (assessed only by those with the training and authority to make a diagnosis), and time of  resolution/stabilization of the event. All AEs occurring while on study must be documented  appropriately regardless of relationship. All AEs will be followed to adequate resolution. 

Any medical condition that is present at the time that the participant is screened will be  considered as baseline and not reported as an AE. However, if the study participant’s condition  deteriorates at any time during the study, it will be recorded as an AE.  

Changes in the severity of an AE will be documented to allow an assessment of the duration of  the event at each level of severity to be performed. AEs characterized as intermittent require  documentation of onset and duration of each episode. 

The site investigator or his/her designee will record all reportable events with start dates  occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days  (for SAEs) after the last day of study participation. At each study visit, the investigator will  inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome  information until resolution or stabilization. 

9.5 ADVERSE EVENT REPORTING 

All AEs will be recorded on the appropriate CRF and will include information about the start and  stop dates, severity and relatedness. There should be an attempt to report a “diagnosis” rather  than the individual signs, symptoms and abnormal laboratory values associated with the  diagnosis. However, a diagnosis should be reported only if, in the Investigator’s judgment, it is  relatively certain (i.e. definite or possible). Otherwise individual signs, symptoms and abnormal  laboratory values should be reported as distinct adverse events.

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9.5.1 SERIOUS ADVERSE EVENT REPORTING  

All serious AE, whether deemed expected or device related, must be reported to the sponsor  immediately or within 24 hours by telephone (see contact details below). 

Name: Jeff Allen 

Phone: 1.954.629.9326 

Email: Jeff@mintmedicalaesthetics.com 

Address: 7460 NW 127th Terrace Parkland, FL 33076 

A written report prepared by the Principal Investigator must follow within seven working days to  the clinical monitor and should include a full description of the event and sequence. The study investigator shall complete a Serious Adverse Event / Serious Adverse Device Effect  Form and submit to the study sponsor and to the reviewing IRB as soon as possible, but in no  event later than 10 working days after the investigator first learns of the effect. The study  sponsor is responsible for conducting an evaluation of an unanticipated adverse device effect  and shall report the results of such evaluation to the FDA or local regulatory agency and to all  reviewing IRBs and participating investigators within 10 working days after the sponsor first  receives notice of the effect. Thereafter the sponsor shall submit such additional reports  concerning the effect as the FDA or local regulatory agency requests. 

9.5.2 UNANTICIPATED PROBLEM REPORTING  

Incidents or events that meet the criteria for UPs require the creation and completion of an UP  report form. It is the site investigator’s responsibility to report UPs to their IRB and to the study  sponsor.  

The UP report should include the following information: 

• Protocol identifying information: protocol title and number, PI’s name, and the IRB  project number; 
• A detailed description of the event, incident, experience, or outcome; ● An explanation of the basis for determining that the event, incident, experience, or  outcome represents an UP; 
• A description of any changes to the protocol or other corrective actions that have been  taken or are proposed in response to the UP. 

Site investigator shall submit to the sponsor and to the reviewing IRB a report of any  unanticipated adverse device effect occurring during an investigation as soon as possible, but in  no event later than 10 working days after the investigator first learns of the effect (21 CFR  812.150(a)(1)), A sponsor who conducts an evaluation of an unanticipated adverse device effect  under 812.46(b) shall report the results of such evaluation to Health Canada, the FDA or local  regulatory agency and to all reviewing IRB’s and participating investigators within 10 working  days after the sponsor first receives notice of the effect. Thereafter the sponsor shall submit  such additional reports concerning the effect as FDA (21 CFR 812.150(b)(1)) or local regulatory  agency requests.

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9.5.3 REPORTING OF PREGNANCY  

If a subject becomes pregnant during the study, the subject will be terminated from the study as  they no longer meet the eligibility criteria to participate in the study. The pregnancy will be  immediately reported to the sponsor and to the IRB using the same reporting timelines as a SAE.  The investigator will follow the pregnancy until completion and will report the outcome of the  pregnancy to the sponsor on the Notification of Subject or Partner Pregnancy Outcome form  and the IRB within 10 business days. 

10 CLINICAL MONITORING 

Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects  are protected, that the reported trial data are accurate, complete, and verifiable, and that the  conduct of the trial is in compliance with the currently approved protocol/amendment(s), with  GCP, and with applicable regulatory requirement(s). 

• Monitoring for this study will be performed by the sponsor or designate. • On-site monitoring will occur within 10 weeks of first enrolled subject and will occur at  a frequency described in the Monitoring Plan. 
• Variables to be monitored will be described in the Monitoring Plan. 
• The Study Director or designate will be provided copies of monitoring reports within 15  business days of visit. 

11 STATISTICAL ANALYSIS 

11.1 SAMPLE SIZE DETERMINATION 

A total sample size of 5 healthy volunteers will be investigated. This number of subjects is  justified as the primary objective is to profile the wound healing and tissue injury profile. No  formal power calculation was performed given the exploratory character of the study. 

11.2 DESCRIPTION OF STATISTICAL METHODS 

Endpoints will be summarized using descriptive statistics including mean score, standard  deviation, standard error and range. Frequency and percentage of subjects within each category  will be presented for categorical data. If applicable, Wilcox t-test may be used to determine if  two sets of data are significantly different from one another. If p-value is below the level of  statistical significance for effectiveness analyses (α = 0.05) for all tests of differences, then the  null hypothesis is rejected in favor of the alternative hypothesis. Rejection of null hypotheses  will establish that: 

• The two-sided 95% confidence interval for the difference between the means excludes  zero. 
• The two means are statistically significantly different at the 5% level (P < 0.05) two sided.

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Upon rejection of null hypotheses, further statistical test tools such as, Confidence Interval,  and/or One- way ANOVA and/or descriptive statistical tools may be used to determine the  performance of the treatment. 

11.2.1 SAFETY ANALYSES 

The safety analysis will be done by analyzing spontaneous reports of adverse events (AE),as well  as analysis of immediate response reports by the principal investigator from his/her  observation/examination of the treated area. Appropriate Medical Dictionary for Regulatory  Activities (MedDRA) code will be used to describe all spontaneously reported events or other  study related adverse events. 

Summaries of spontaneously reported or other study related adverse events will be presented  as: 

• Number (%) of subjects with any AE 
• Number (%) of subjects with any serious adverse events (SAE) 
• Number (%) of subjects permanently withdrawn from treatment due to AE Summaries of analysis of immediate response reports by the principal investigator examination  will be displayed on a bar or pie chart and/or a table as; 
• the overall frequency of subjects with each event (pain during treatment,  hemorrhage, burn, erythema, edema, purpura, etc.) 
• Frequency of subjects with specific severity/intensity for each event using a 5- point scale: 1=none; 2=trace; 3=moderate; 4=marked; 5=severe 
• The overall proportion of subjects observed with marked or severe intensity of  any event will be calculated and compared to those with none, trace or  

moderate severity/intensity 

11.2.2 BASELINE DESCRIPTIVE STATISTICS 

Subjects baseline demographics will be compared using descriptive statistics such as mean  score, standard deviation, standard error and range. Data will be displayed in tables or graphical  presentation. 

12 MEASURES TO MINIMIZE BIAS  

12.1 ENROLLMENT/RANDOMIZATION/MASKING PROCEDURES  

At screening, once a subject has signed the informed consent, and inclusion/exclusion criteria  has been met, a unique subject number will be assigned. The identifying number will be  composed of a two-digit site number and a three-digit subject number in sequence. This unique  identifier will be used throughout the entire study and will be entered in the subject’s case  report form (CRF) and for each treatment.  

In this clinical study trial subjects will not be randomized; this is an open-label, baseline controlled, evaluator-blinded study; Only the independent reviewers/pathologists will be  blinded. 

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13 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS Each participating site will maintain appropriate medical and research records for this trial, in compliance with ICH E6, ISO 14155:2011, HIPAA and regulatory and institutional requirements  for the protection of confidentiality of participants. Each site will permit authorized  representatives of the study sponsor and regulatory agencies to examine (and when permitted  by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits,  and evaluation of the study safety, progress, and data validity. 

Source data are all information, original records of clinical findings, observations, or other  activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples  of these original documents and data records include, but are not limited to, hospital records,  clinical and office charts, laboratory notes, memoranda, participants’ memory aids or evaluation  checklists, pharmacy dispensing records, recorded audio tapes of counseling sessions, recorded  data from automated instruments, copies or transcriptions certified after verification as being  accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x rays, and participant files and records kept at the pharmacy, at the laboratories, and medico technical departments involved in the clinical trial. 

It is acceptable to use CRFs as source documents. Demographic data, medical/surgical history,  adverse event reporting and procedural notes will be collected on the CRFs with the remainder  collected from other sources. It is not acceptable for the CRF to be the only record of a subject’s  participation in the study. This is to ensure that anyone who would access the patient medical  record has adequate knowledge that the patient is participating in a clinical trial. 

14 QUALITY ASSURANCE AND QUALITY CONTROL 

Prior to any independent use of the Nu-VissaTM investigational device, study personnel will  receive proper training from the sponsor. Site personnel will be trained on the use of the device  prior to study initiation at the site. Additional training requirements will be discussed during  study initiation and will include site responsibilities, study reporting and study documentation.  In addition, the sponsor will provide protocol specific training for site personnel. The site will  document which individual has been assigned to a specific task and will ensure that appropriate  training has occurred for that task. 

Regular monitoring and an independent audit, if conducted, may be performed according to  ICH-GCP and ISO 14155:2011. 

Quality control (QC) procedures will be implemented beginning with the data entry monitoring  and data quality control checks. Any missing data or data anomalies will be communicated to  the site(s) for clarification and resolution. Monitors will verify that the clinical trial is conducted  and data are generated, documented (recorded), and reported in compliance with the protocol,  GCP, and the applicable regulatory requirements.

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The investigational site will provide direct access to all trial related materials, source  data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and  inspection by local and 

regulatory authorities. 

15 ETHICAL CONSIDERATIONS AND PROTECTION OF HUMAN SUBJECTS 

15.1 ETHICAL STANDARD  

The investigator will ensure that this study is conducted in full conformity with Regulations for  the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR  Part 56, and/or the ICH E6, the Declaration of Helsinki, Council for International Organizations of  Medical Science (CIOMS) and ISO 14155:2011. 

15.2 INSTITUTIONAL REVIEW BOARD 

The protocol, informed consent form(s), recruitment materials and all participant materials  must be submitted to the IRB for review and approval. Approval of both the protocol and the  consent form must be obtained before any participant is enrolled and study is initiated. Any  amendment to the protocol requires review and approval by the IRB before the changes are  implemented to the study. All changes to the consent form must be IRB approved; a  determination will be made regarding whether previously consented participants need to be re consented at that time. 

15.2.1 PROTOCOL DEVIATION  

A protocol deviation is any noncompliance with the clinical trial protocol, International  Conference on Harmonization Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP)  requirements. The noncompliance may be either on the part of the participant, the investigator,  or the study site staff. As a result of deviations, corrective actions are to be developed by the  site and implemented promptly.  

These practices are consistent with ICH GCP:  

• 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 5.1 Quality Assurance and Quality Control, section 5.1.1  
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  

It is the responsibility of the site investigator to use continuous vigilance to identify and report  deviations within 10 working days of identification of the protocol deviation, or within 10  working days of the scheduled protocol-required activity. All deviations must be addressed in  study source documents. Protocol deviations must be sent to the reviewing Institutional Review  Board (IRB) per their policies. The site investigator is responsible for knowing and adhering to  the reviewing IRB requirements. Further details about the handling of protocol deviations will be  included in the MOP.

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15.3 INFORMED CONSENT PROCESS  

Informed consent is a process that is initiated prior to the individual’s agreeing to participate in  the study and continues throughout the individual’s study participation. Consent forms will be  Institutional Review Board (IRB)-approved and the participant will be asked to read and review  

the document. The investigator will explain the research study to the participant and answer  any questions that may arise. A verbal explanation will be provided in terms suited to the  participant’s comprehension of the purposes, procedures, and potential risks of the study and of  their rights as research participants. Participants will have the opportunity to carefully review  the written consent form and ask questions prior to signing. The participants should have the  opportunity to discuss the study with their family or surrogates or think about it prior to  agreeing to participate. The participant will sign the informed consent document prior to any  procedures being done specifically for the study. Participants must be informed that  participation is voluntary and that they may withdraw from the study at any time, without  prejudice. A copy of the informed consent document will be given to the participants for their  records. The informed consent process will be conducted and documented in the source  document (including the date), and the form signed, before the participant undergoes any  study-specific procedures. The rights and welfare of the participants will be protected by  emphasizing to them that the quality of their medical care will not be adversely affected if they  decline to participate in this study. 

15.4 CONFIDENTIALITY AND PRIVACY 

Participant confidentiality and privacy is strictly held in trust by the participating investigators,  their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover  testing of biological samples and genetic tests in addition to the clinical information relating to  participants. Therefore, the study protocol, documentation, data, and all other information  

generated will be held in strict confidence. No information concerning the study or the data will  be released to any unauthorized third party without prior written approval of the sponsor.  

All research activities will be conducted in as private a setting as possible. 

The study monitor, other authorized representatives of the sponsor, representatives of the  Institutional Review Board (IRB), regulatory agencies may inspect all documents and records  required to be maintained by the investigator, including but not limited to, medical records  (office, clinic, or hospital) and laboratory records for the participants in this study. The clinical  study site will permit access to such records. 

The study participant’s contact information will be securely stored at each clinical site for  internal use during the study. At the end of the study, all records will continue to be kept in a  secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or  sponsor requirements. 

Study participant research data, which is for purposes of statistical analysis and scientific  reporting, will be transmitted to and stored at the Sponsor location. This will not include the 

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participant’s contact or identifying information. Rather, a unique study identification number  will identify individual participants and their research data. The study data entry and study  management systems used by clinical sites and by NuVissa research staff will be secured and  password protected. At the end of the study, all study databases will be de-identified and  archived at the Sponsor’s location. 

15.5 FUTURE USE OF STORED SPECIMENS AND DATA 

Data collected for this study will be analyzed and stored at the Sponsor’s location 

Research participants may request withdrawal/destruction of their tissue samples up until the  time that samples are used for histology analysis by asking a study investigator. Should any  research participants withdraw from study participation, they will be specifically asked if their  collected samples may be studied per protocol. During the duration of the study, an individual  participant can choose to withdraw consent to have biological specimens stored for future  research. However, withdrawal of consent with regard to bio sample storage may not be  possible after the study is completed. 

15.6 DATA COLLECTION AND RECORD KEEPING  

15.6.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  

Data collection is the responsibility of the clinical trial staff at the site under the supervision of  the site investigator. The investigator is responsible for ensuring the accuracy, completeness,  legibility, and timeliness of the data reported. 

All source documents should be completed in a neat, legible manner to ensure accurate  interpretation of data.  

Hardcopies of the study visit worksheets will be provided for use as source document  worksheets for recording data for each participant enrolled in the study. Data recorded in the  electronic case report form (eCRF) derived from source documents should be consistent with  the data recorded on the source documents.  

Clinical data (including adverse events (AEs), concomitant medications, and expected adverse  reactions data) and clinical laboratory data will be entered into excel spreadsheets a 21 CFR Part  11-compliant data capture system provided by the Sponsor. The data system includes password  protection and internal quality checks, such as automatic range checks, to identify data that  appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the  source documents. 

15.6.2 STUDY RECORDS RETENTION  

Study documents should be retained for a minimum of 2 years after the last approval of a  marketing application in an International Conference on Harmonization (ICH) region and until 

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there are no pending or contemplated marketing applications in an ICH region or until at least 2  years have elapsed since the formal discontinuation of clinical development of the study  

intervention. These documents should be retained for a longer period, however, if required by  local regulations. No records will be destroyed without the written consent of the sponsor, if  applicable. It is the responsibility of the sponsor to inform the investigator when these  

documents no longer need to be retained. 

15.7 CONFLICT OF INTEREST POLICY  

The independence of this study from any actual or perceived influence is critical. Therefore, any  actual conflict of interest of persons who have a role in the design, conduct, analysis,  

publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who  have a perceived conflict of interest will be required to have such conflicts managed in a way  that is appropriate to their participation in the design and conduct of this trial. The study  

leadership has established policies and procedures for all study group members to disclose all  conflicts of interest and will establish a mechanism for the management of all reported dualities  of interest. 

15.8 RESULTS OF THE STUDY

 

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Effects of Hand Held Plasma Device on Healthy Tissue Version 1.0 Protocol # NEO19-NV-01 05 November 2019 

3. 16 REFERENCES
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