dermaPACE System

DEN160037 · Sanuwave, Inc. · PZL · Dec 28, 2017 · General, Plastic Surgery

Device Facts

• Record ID: DEN160037
• Device Name: dermaPACE System
• Applicant: Sanuwave, Inc.
• Product Code: PZL · General, Plastic Surgery
• Decision Date: Dec 28, 2017
• Decision: DENG
• Submission Type: Direct
• Regulation: 21 CFR 878.4685
• Device Class: Class 2
• Attributes: Therapeutic

Intended Use

The SANUWAVE dermaPACE System is indicated to provide acoustic pressure shockwaves in the treatment of chronic, full-thickness diabetic foot ulcers with wound areas measuring no larger than 16 cm², which extend through the epidermis, dermis, tendon, or capsule, but without bone exposure. The dermaPACE System is indicated for adult (22 years and older), diabetic patients presenting with diabetic foot ulcers greater than 30 days in duration and is indicated for use in conjunction with standard diabetic ulcer care.

Device Story

The dermaPACE System is an extracorporeal shock wave device used in clinical settings to treat chronic diabetic foot ulcers. The device generates acoustic pressure shockwaves internally, which are then focused and transferred to the patient's dermal tissue via an acoustic interface. The system is operated by healthcare professionals as an adjunct to standard diabetic ulcer care. By delivering these shockwaves to the wound site, the device aims to promote healing in chronic, full-thickness ulcers. The system requires specific safety measures, including the use of hearing protection for both the operator and the patient to prevent potential hearing loss. Clinical benefit is derived from the application of acoustic energy to the wound environment.

Clinical Evidence

Two prospective, randomized, double-blind, sham-controlled, multi-center studies (N=336 total) evaluated safety and effectiveness over 24 weeks. Primary endpoint: complete wound closure at 12 weeks. Pooled data showed dermaPACE superior to sham at 24 weeks (37.79% vs 26.22%, p=0.023). 12-week closure rates were comparable (22.67% vs 18.29%, p=0.320). Safety analysis indicated an association between osteomyelitis and >7 treatments; device-related adverse events included pain and hematoma. Bench testing confirmed acoustic pressure field characterization per IEC 61846 and IEC 60601-2-36.

Technological Characteristics

Extracorporeal shock wave device; generates acoustic pressure shockwaves; utilizes an acoustic interface for tissue delivery. Requires biocompatibility evaluation of patient-contacting components, electrical safety and electromagnetic compatibility (EMC) testing, and reprocessing validation for reusable components. Includes software for system control.

Indications for Use

Indicated for adult (≥22 years) diabetic patients with chronic, full-thickness diabetic foot ulcers (1-16 cm²) extending through epidermis, dermis, tendon, or capsule, without bone exposure, present for >30 days. Used with standard diabetic ulcer care. Contraindicated for pediatric use, osteomyelitis, active cellulitis, purulent/malodorous exudates, active Charcot foot, recent biomechanical surgery, lymphedema, or recent chemotherapy.

Regulatory Classification

Identification

An extracorporeal shock wave device for treatment of chronic wounds is a prescription device that focuses acoustic shock waves onto the dermal tissue. The shock waves are generated inside the device and transferred to the body using an acoustic interface.

Special Controls

*Classification.* Class II (special controls). The special controls for this device are:(1) Non-clinical performance testing must be conducted to demonstrate that the system produces anticipated and reproducible acoustic pressure shock waves. (2) The patient-contacting components of the device must be demonstrated to be biocompatible. (3) Performance data must demonstrate that the reusable components of the device can be reprocessed for subsequent use. (4) Performance data must be provided to demonstrate the electromagnetic compatibility and electrical safety of the device. (5) Software verification, validation, and hazard analysis must be performed. (6) Performance data must support the use life of the system by demonstrating continued system functionality over the labeled use life. (7) Physician labeling must include: (i) Information on how the device operates and the typical course of treatment; (ii) A detailed summary of the device's technical parameters; (iii) Validated methods and instructions for reprocessing of any reusable components; and (iv) Instructions for preventing hearing loss by use of hearing protection. (8) Patient labeling must include: (i) Relevant contraindications, warnings, precautions, adverse effects, and complications; (ii) Information on how the device operates and the typical course of treatment; (iii) The probable risks and benefits associated with the use of the device; (iv) Post-procedure care instructions; and (v) Alternative treatments.

Submission Summary (Full Text)

{0}------------------------------------------------

#### DE NOVO CLASSIFICATION REQUEST FOR DERMAPACE SYSTEM

#### REGULATORY INFORMATION

FDA identifies this generic type of device as:

Extracorporeal shock wave device for treatment of chronic wounds. An extracorporeal shock wave device for treatment of chronic wounds is a prescription device that focuses acoustic shock waves onto the dermal tissue. The shock waves are generated inside the device and transferred to the body using an acoustic interface.

NEW REGULATION NUMBER: 21 CFR 878.4685

CLASSIFICATION: II

PRODUCT CODE: PZL

#### BACKGROUND

DEVICE NAME: dermaPACE System

SUBMISSION NUMBER: DEN160037

DATE OF DE NOVO: July 25, 2016

SANUWAVE Health. Inc. CONTACT: 11475 Great Oaks Way #150 Alpharetta, GA 30022

#### INDICATIONS FOR USE

The SANUWAVE dermaPACE System is indicated to provide acoustic pressure shockwaves in the treatment of chronic. full-thickness diabetic foot ulcers with wound areas measuring no larger than 16 cm', which extend through the epidermis, dermis, tendon, or capsule, but without bone exposure. The dermaPACE System is indicated for adult (22 years and older), diabetic patients presenting with diabetic foot ulcers greater than 30 days in duration and is indicated for use in conjunction with standard diabetic ulcer care.

#### LIMITATIONS

Prescription use only: Federal (USA) law restricts this device to sale by or on the order of a physician.

Limitations on device use are also achieved through the following statements included in the instructions for use:

{1}------------------------------------------------

#### Warnings:

The dermaPACE System is not indicated for pediatric use.

The noise emitted during a dermaPACE procedure may lead to a risk of hearing impairment. All persons in the treatment area should wear hearing protection in the form of foam ear plugs or ear muffs specified by the manufacturer with a noise reduction rating of at least 20dB.

Do not use the dermaPACE in oxygen enriched environments, near flammable anesthetic gas mixtures or other potentially explosive/flammable environments.

Ensure that cleaning agents and disinfectants have evaporated completely before turning the dermaPACE Console into the ON position. Some cleaning agents and disinfectants can produce explosive gases.

When the dermaPACE device is considered for use in treatment of unresponsive wounds the patient and practitioner should carefully monitor for osteomyelitis There may be an increased risk of developing osteomyelitis when more than 7 treatments are given.

Due to the treatment with the dermaPACE, patients can experience discomfort, but the discomfort normally y resolves without intervention directly after the treatment or in the following days.

Reddening of the skin and petechiae in the treatment area has been observed in individual cases and usually resolves without intervention shortly after treatment.

Hematomas have been reported in rare cases.

It may be possible that migraine, nausea, and syncope can be induced in rare cases.

Effects on subsequent graft success are unknown and have not been evaluated.

Employing more than 4 treatments may increase risks of developing Treatment Emergent Serious Adverse Events in patients.

#### PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

The dermaPACE System has not been evaluated in:

- a foot ulcer which involves osteomyelitis diagnosed prior to initial treatment -
- active cellulitis either at the site of, or in the surrounding area of, the target ulcer; -
- patients who had a target ulcer that has visually purulent exudates or that has malodorous exudates on examination:
- active Charcot foot;

{2}------------------------------------------------

- patients who had a surgical procedure to correct biomechanical abnormities (e.g .. 318 lengthening of the Achilles tendon, correction of hammer toe, correction of Charcot foot) within eight weeks of initiation of treatment;
- patients with clinical evidence of lymphedema; =
- patients who had chemotherapy within 60 days prior to initiation of treatment. -

## DEVICE DESCRIPTION

The dermaPACE System consists of a bench-top Control Console and the PACE Applicator (Figure 1). The PACE Applicator is connected to the Control Console via a six-feet-long cable. The Control Console and PACE Applicator are intended to be reusable. Single use, disposable, sterile sleeves are used to cover the applicator during use. Sterile ultrasound coupling gel ensures proper transfer of the acoustical waves to the treatment area. Both the sterile sleeves and the coupling gel are provided with the device.

Image /page/2/Picture/5 description: The image shows two medical devices. The device on the left has a white and silver body with a screen that displays information. A white handle is attached to the top of the device with a cord. The device on the right is a white handle with a cord attached to a white probe.

Figure 1: dermaPACE Control Console (left) and PACE Applicator (right).

The PACE Applicator generates shock waves by the electrohydraulic method. A high voltage current (18,000-23,000 Volts) (b) (4)

the applicator

at its tip which contacts the patient (Figure 2a and b).

Image /page/2/Picture/10 description: The image shows a white and black SANUWAVE device. The device has a white handle with the word "SANUWAVE" printed on it. The head of the device is black and has red dashed lines emanating from it. There are also white arrows pointing away from the center of the device's head.

Figure 2a: Applicator

{3}------------------------------------------------

Image /page/3/Picture/0 description: The image shows a gray rectangle with the text "(b) (4)" at the top. Below the rectangle, the text "Figure 2b: Schematic representation of the focusing of shockwaves F1 and F2 (focus point of the shockwaves) (b) (4)" is visible. The image appears to be a figure from a scientific paper or report.

The acoustic pressure shock waves generated by the device consist of a dominant compressive pressure pulse, low negative pressures, and the tensile wave (Figure 3).

Image /page/3/Figure/2 description: This image is a graph showing pressure over time. The graph shows a sharp increase in pressure, followed by a gradual decrease. The graph also shows the pulse width and the positive and negative pressure values. The x-axis is labeled "time" and the y-axis is labeled "p".

Figure 3: Pressure changes in the tissue during each pulse delivered by the device.

The device has multiple output settings, but the software will default to a standard setting of 500 pulses and a frequency of 4 pulses per second.

## SUMMARY OF NONCLINICAL/BENCH STUDIES

rise time

## BIOCOMPATIBILITY/MATERIALS

The dermaPACE Control Console, PACE Applicator housing, and cable are not patient contacting. No biocompatibility testing was conducted on these components of the device system.

The PACE Applicator coupling membrane was evaluated per the FDA guidance, "Use of

F1

{4}------------------------------------------------

International Standard ISO 10993-1, 'Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" (June 16, 2016). The PACE Applicator is covered with a sterile sleeve during treatment application. The PACE Applicator coupling membrane, while not patient contacting, may come into contact with the patient if there is an unintended breach in the sterile sleeve during treatment application. The coupling membrane has undergone a biocompatibility assessment, including intracutaneous toxicity, muscle implantation, systemic toxicity, and sensitization testing. Table 1 below summarizes the biocompatibility testing that was conducted on the coupling membrane.

| Biocompatibility Test | Acceptance Criteria | Results |
|-------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------|
| Cytotoxicity (Neutral<br>Red Uptake Test) | Test system suitability conditions must be met;<br>viability % level is (b)(4)% or greater | Pass |
| Cytotoxicity (MTT Test) | Test system suitability conditions must be met;<br>viability % level is (b)(4)% or greater | Pass |
| USP Intracutaneous | The cumulative average erythema and edema<br>score for each test extract and corresponding<br>control is calculated. For each extract, a<br>difference in average scores (test minus control)<br>of (b)(4) or less is considered acceptable. | Acceptable |
| Sensitization (Kligman<br>Maximization) | Use of Magnusson and Kligman Scale and USP<br>Sensitization Classification | The material is<br>classified as a<br>non-sensitizer |
| USP Muscle Implant | The requirements were met if the difference<br>between test and control score averages was not<br>greater than (b)(4) | Pass |
| USP Systemic Toxicity | The test mice must not show a significantly<br>greater reaction than the control mice | Pass |

| Table 1: Biocompatibility testing conducted on PACE Applicator membrane | | | |
|-------------------------------------------------------------------------|--|--|--|
|-------------------------------------------------------------------------|--|--|--|

The biocompatibility of single-use. sterile probe sleeves was demonstrated in K980210 and for the transmission gel in K802146.

#### USE LIFE/STERILITY

The dermaPACE system is provided non-sterile. To prevent cross-contamination to both user and patients, a sterile sleeve is placed over the PACE Applicator and cable prior to treatment. Upon completion of treatment, the sleeve is removed and discarded.

Both the Control Console and PACE applicator are reusable. The use life of the Control Console is indefinite with proper maintenance and repair. The PACE applicator was shown to deliver (b) (4) repeatable shock wave pulses with bench testing. The PACE applicator is software deactivated and needs to be replaced after delivering (6)(4) pulses.

{5}------------------------------------------------

#### CLEANING/REPROCESSING

The dermaPACE configuration consists of the Control Console and the PACE Applicator. The PACE Applicator is connected to the Control Console via a six-feet-long cable. The PACE Applicator is covered by a single-use sterile sleeve and does not make contact with the patient. The sterile sleeve provided to the user is 120 cm long and covers the entire applicator head and most of the attached cable. No uncovered part of the device should contact the patient during normal use.

Both cleaning and low level disinfection validations of the PACE applicator were conducted in accordance with the guidance "Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling Guidance for Industry and Food and Drug Administration Staff'. A cleaning validation was conducted following artificial soiling with clinically relevant test soil. Two clinically relevant soil markers (protein and hemoglobin) were quantified to show removal of residual soil following cleaning using the worst case cleaning instructions provided to the end user. Following this, a disinfection validation was conducted following the worst case disinfections provided to the end user. Based on the risk of the device and its potential patient contact, it was determined low level disinfection is adequate. A low level disinfection validation was conducted showing a minimum 3 log reduction of clinically relevant bacteria. Also, a reusability study confirmed that the PACE applicator can deliver its pre-programmed (b) (4) shock waves following multiple rounds of reprocessing. In this study, The PACE applicator was used to deliver shock wave pulses at a continuous rate to simulate use and the pulses were monitored to ensure regularity. Applicators were made to deliver pulses until a missed discharge or misfire was recorded at which point the total number of pulses was recorded. This test was repeated on (6) (4) applicators, and an average value for maximum number of pulses that can successfully be delivered was found. To incorporate a safety factor, the maximum number of allowed pulses was set as 19 % of total number of successful pulses, resulting in a final use life expectancy of (6) (4) pulses for the applicator.

#### ELECTROMAGNETIC COMPATIBILITY AND ELECTRICAL SAFETY

The dermaPACE system was tested in accordance with the following consensus standards and passed the following electromagnetic compatibility (EMC), electrical, mechanical, and thermal safety tests:

| Standard | Test/Function | Results |
|---------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| ANSI/AAMI ES60601-<br>1:2005/(R2012) +<br>A1:2012 | Medical electrical equipment - Part 1: General<br>requirements for basic safety and essential performance<br>(IEC 60601-1:2005, MOD) | Complies |
| IEC 60601-1-2: 2007 | Medical electrical equipment - Part 1-2: General<br>requirements for basic safety and essential performance<br>- Collateral standard: Electromagnetic compatibility -<br>Requirements and tests | Complies |

Table 2: EMC and electrical, mechanical and thermal safety testing

#### SOFTWARE

{6}------------------------------------------------

Software documentation was provided based on the software documentation requirement at a MAJOR software level of concern per FDA guidance: "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices", as follows:

- Software Requirements Specification .
- . Software and architecture design specification
- . Requirements to validation traceability analysis
- Software Configuration Description ●
- Fault insertion and white box verification testing .
- . Software validation testing
- . Revision Level History
- . Unresolved Anomalies report
- Usability validation per IEC 60601-1-6 .

Adequate documentation describing the software development program as required per the guidance document was provided and deemed adequate. Verification and Validation (V&V) testing was conducted to address the potential hazards with satisfactory results. The software development procedures provide the foundation that the software will operate in a manner as described in the specifications.

The software documentation is in sufficient detail to provide reasonable assurance that the software performs as intended and all software-related risks have been adequately mitigated.

## PERFORMANCE TESTING - BENCH

Additional bench testing was performed to characterize the acoustic shock waves delivered by the dermaPACE system and to ensure that the shock waves were consistent and repeatable. Technical parameters of the device that may affect the treatment were measured. These parameters included but were not limited to: volume of the pressure field, focal volume, peak compression and rarefaction acoustic pressures, energy flux density, energy per pulse, acoustic energy (audible noise). The performance testing represented normal clinical use conditions. As the dermaPACE device included a flexible membrane applicator that can be pressed against the patient's skin, the characterization of the pressure shockwaves was repeated for no compression, typical compression during normal use, and at maximum compression of the membrane. The following FDA recognized consensus standards were used:

| Specification or<br>Applied Standard | Test/Function | Results |
|--------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| IEC 61846 : 1998 | Pressure field characterization testing | Complies |
| IEC 60601-2-36: 2014 | Focal volume, peak compression and rarefaction<br>acoustic pressures, energy flux density, and<br>energy per pulse, and acoustic energy<br>measurements | Complies |

{7}------------------------------------------------

#### SUMMARY OF CLINICAL INFORMATION

The dermaPACE system was evaluated using two studies. The studies were designed as prospective, randomized, double-blind, parallel-group, sham-controlled, multi-center 24-week studies at 39 centers. There were 206 subjects enrolled in Study 1 and 130 subjects in Study 2 for a total of 336 subjects enrolled and treated with dermaPACE plus standard of care or standard of care alone. Standard of care included, but was not limited to, debridement, saline-moistened gauze, and pressure reducing footwear. The objective of the studies was to compare the safety and effectiveness of the dermaPACE device to sham-control application, when administered with standard of care.

Study subjects were enrolled using pre-determined inclusion criteria to obtain a homogenous study population with chronic diabetes who had a diabetic foot ulcer that persisted for a minimum of 30 days with an area between 1cm and 16cm , inclusive. Subjects were enrolled at Visit 1 and followed for a run-in period of two weeks. At two weeks (Visit 2 – Day 0), the first treatment was applied (either dermaPACE or sham control application) if subjects met inclusion/exclusion criteria. Applications with either dermaPACE or sham control were then made at Day 3 (Visit 3), Day 6 (Visit 4), and Day 9 (Visit 5) with the potential for 4 additional treatments in Study 2 which were administered every other week (patients with unhealed wounds were eligible for additional treatments). Subject progress including wound size was observed on a bi-weekly basis for up to 24 weeks, at a total of 12 visits (Weeks 2-24; Visits 6-17).

#### Study Protocols Description

The dermaPACE Diabetic Foot Ulcer study has been conducted under two separate studies using two near-identical protocols.

The first subject for Study 1 was randomized and treated in October 2007. A total of 206 subjects were enrolled in the first dermaPACE Study at 22 centers in US, 1 in England, and 1 in Germany. The last subject completed the study in September 2010.

The first subject for Study 2 was randomized and treated in June 2013. A total of 130 subjects were enrolled in the second dermaPACE Study at 18 participating centers in the United States and 1 site in Canada. The last subject completed Study 2 in May 2015.

#### Study Procedures

Each subject assigned to active application in Study 1 and 2 was to undergo a dermaPACE application with a total of 500 pulses (shock waves), with a pulse frequency of 4.0Hz (i.e., 4 pulses per second, 240 pulses per minute), and delivered at a power setting of E2. The minimum active application time was 2 minutes. For subjects randomized to sham application, a dummy treatment head (non-energized treatment applicator that was not connected to the generator) was applied to the subject's wound area. All subjects, in both the treatment and control groups, were positioned such that the application was not visible. While the non-energized applicator was passed across the wound area in a simulated application, 500 pulses were discharged on a second, separate applicator that was connected to the generator. The energized applicator did not contact the subject and was used only to provide the sound-effect of dermaPACE delivery.

{8}------------------------------------------------

For subjects with 2 qualifying ulcers, the oldest, largest volume or deepest ulcer was chosen (in that order). For subjects with 3 or more qualifying ulcers, the ulcer that was the median (in age, volume and depth) was chosen.

The difference between the two study designs was the number of treatment applications of the dermaPACE device. Study 1 (DERM01; n=206) prescribed four (4) device applications/treatments over a two-week period (non-responders did not receive more than 4 treatments), whereas, Study 2 (DERM02; n=130) prescribed up to eight (8) device applications (4 within the first two weeks of randomization, and 1 treatment every two weeks thereafter up to a total of 8 treatments over a 10-week period). Therefore, the length of follow-up between the last treatment and the 12 week analyses was shorter for subjects who received more than 4 treatments in Study 2. Furthermore, subjects who had non-responsive wounds by treatment 4 received as many as 8 treatments in Study 2. If the wound was determined closed by the primary investigator (PI) during the treatment regimen, additional planned applications were not performed.

## Subject Selection

In both studies, subjects were required to meet all inclusion criteria and none of the exclusion. criteria to be considered eligible for study participation. Prior to being randomized, all subjects' wounds were traced (Study 1) or imaged (Study 2) and were assessed for response to standard of care during the 2-week run-in period. Any subject with > 50% reduction in wound volume were removed from the study.

Overall, the inclusion and exclusion criteria were similar across both studies. The minimum age was 18 years for Study 1 and 22 years for Study 2. This did not have an impact on the overall mean age as a similar mean age was seen in both studies. Similar target ulcer criteria (i.e., wound size, duration, and penetration) and severity of diabetes were utilized in the two studies. The inclusion and exclusion criteria across studies are shown below in Tables 4 and 5.

| Inclusion Criteria | |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Study 1 | Study 2 |
| Is male or female ≥ 18 years of age; | Is male or female ≥ 22 years of age at Visit 1; |
| If female of child-bearing potential, the subject must: | If female of child-bearing potential, both of the following must be met at Visit 1: |
| • Practice one of the following methods of<br>contraception (administered for at least one<br>month prior to the start of initial application and<br>maintained per prescribed schedule) and<br>continues through the duration of the study:<br>hormonal contraceptives, intrauterine device<br>(IUD), spermicide and barrier or implantable<br>device, and | • Practices one of the following methods of<br>contraception (administered for at least one<br>month prior to the start of initial application and<br>maintained per prescribed schedule) and<br>continues through the duration of the study:<br>hormonal contraceptives, intrauterine device<br>(IUD), spermicide and barrier or implantable<br>device, and |
| • Have a negative urine qualitative β-HCG<br>pregnancy test within two weeks of Visit 2; | • Has a negative urine qualitative β-HCG<br>pregnancy test; |
| If female and post-menopausal, the subject must:<br>Have had a complete hysterectomy, bilateral | If female and post-menopausal one of the<br>following must be met at Visit 1: |

| Table 4: Inclusion Criteria for Study 1 and Study 2 | | | | | | | |
|-----------------------------------------------------|--|--|--|--|--|--|--|
|-----------------------------------------------------|--|--|--|--|--|--|--|

{9}------------------------------------------------

| Inclusion Criteria | |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Study 1 | Study 2 |
| salpingo-oophorectomy or tubal ligation or<br>otherwise be incapable of pregnancy, or<br>Be postmenopausal for at least one year (absence<br>of menses for 12 consecutive months, including<br>spotting); | Has had a complete hysterectomy, bilateral<br>salpingo-oophorectomy or tubal ligation or<br>otherwise be incapable of pregnancy, or<br>is postmenopausal for at least one year (absence of<br>menses for 12 consecutive months, including<br>spotting): |
| Has at least one diabetic foot ulcer that is located<br>in the ankle area or below that has persisted a<br>minimum of 30 days prior to the study Screening<br>visit. Subjects may have more than one diabetic<br>foot ulcer, but only one will be treated in this<br>study. The target ulcer will be determined via<br>utilization of a flow chart in Section 4.1 of the<br>study protocol. | Has at least one diabetic foot ulcer that is located<br>in the ankle area or below that has persisted a<br>minimum of 30 days prior to Visit 1. Subjects may<br>have more than one diabetic foot ulcer, but only<br>one, the target ulcer, will be treated in this study.<br>The target ulcer will be determined via utilization<br>of a flow chart in Section 3 of the study protocol. |
| Note: Target Ulcer on Toe(s)<br>For a target ulcer located on the toe(s), the tip of<br>the dermaPACE applicator must be able to be held<br>perpendicular to the target ulcer and must be able<br>to be applied to the entire surface of the target<br>ulcer including the area 1 cm beyond the surface<br>of the ulcer in each direction at Visit 2.<br>Is diabetic (Diabetes Mellitus) with a HbA1c ≤ 12%; | NOTE: Target Ulcer on Toe(s)<br>For a target ulcer located on the toe(s), the tip of<br>the PACE Applicator must be able to be held<br>perpendicular to the target ulcer and must be able<br>to be applied to the entire surface of the target<br>ulcer including the area 1 cm beyond the surface<br>of the ulcer in each direction at Visit 2.<br>Has Type I or Type II Diabetes Mellitus with a<br>HbA1c ≤ 12% at Visit 1; |
| Is capable of wound care at home; | Is capable of wound care at home; |
| Has a target ulcer ≥ 1.0 cm² and ≤ 16 cm²; | Has a target ulcer ≥ 1.0 cm² and ≤ 16 cm² at Visits<br>1 and 2 |
| Has a target ulcer which has an Ulcer Grade 1 or 2,<br>Stage A according to the University of Texas<br>Diabetic Wound Classification system:<br>Grade 1: Superficial wounds through the epidermis<br>or epidermis and dermis that have not penetrated to<br>tendon, capsule or bone<br>Grade 2: Wounds that penetrate to tendon or<br>capsule (but not to bone or into the joint)<br>Stage A: Clean wounds (non-infected, non-<br>ischemic); | Has a target ulcer that is Grade 1 or 2, Stage A<br>according to the University of Texas Diabetic<br>Wound Classification system, at Visits 1 and 2):<br>Grade 1: Superficial wounds through the epidermis<br>or epidermis and dermis that have not penetrated to<br>tendon, capsule or bone<br>Grade 2: Wounds that penetrate to tendon or<br>capsule (but not to bone or into the joint)<br>Stage A: Clean wounds (non-infected, non-<br>ischemic): |
| Has an Ankle Brachial Index (ABI) ≥ 0.7 and ≤<br>1.2, OR toe pressure > 50 mmHg, OR tcPO₂ > 40<br>mmHg; | In the leg with the target ulcer has an ABI ≥ 0.7<br>and ≤ 1.2 OR if the ABI is >1.20 has a toe pressure<br>> 50 mmHg OR tcpO₂> 40 mmHg at Visit 1; |
| Subject agrees, or if applicable the subject's legal<br>representative agrees for the subject, to participate<br>in the study, including all study related procedures<br>and evaluations and documents this agreement by<br>signing the IRB/EC-approved informed consent<br>form. | Subject agrees, or if applicable, the subject's legal<br>representative agrees that the subject can<br>participate in the study, including all study related<br>procedures and evaluation and documents this<br>agreement by signing the IRB/EC-approved<br>informed consent form at Visit 1 and prior to any<br>study specific procedures. |
| Table 5: Exclusion Criteria for Study 1 and Study 2<br>Exclusion Criteria | |
| Study 1 | Study 2 |
| Female subjects who are currently pregnant or<br>plans to become pregnant during the study;<br>Female subjects who are nursing or actively<br>lactating; | Is female and is currently pregnant or plans to<br>become pregnant during the study; Is nursing or<br>actively lactating; |
| Is morbidly obese (Body Mass Index ≥ 40); | Is morbidly obese (Body Mass Index ≥ 40) at<br>Visit 1; |
| Is on dialysis; | Has clinically significant renal disease and/or<br>impaired renal function defined as having an<br>estimated creatinine clearance of $<$ 40mL/min at<br>Visit 1; |
| Has either a foot ulcer which involves<br>osteomyelitis or has osteomyelitis (Note: In order<br>to rule out osteomyelitis on the foot, an x-ray of<br>the foot in 3 views should be performed); | Has osteomyelitis in the foot or ankle on which<br>the target ulcer is located at Visit 1 or 2<br>*Note: For a prior episode of osteomyelitis in the<br>foot or ankle on which the target ulcer is located,<br>the subject must have completed systemic<br>antimicrobial therapy 60 or more days prior to the<br>screening visit to be eligible for this study. If any<br>portion of the systemic antimicrobial regimen for<br>osteomyelitis is given within 60 days prior to the<br>screening visit, the subject is excluded from this<br>study. |
| Has evidence of prior ulcer in the same area as<br>the target ulcer; | Has evidence of a prior ulcer in the same<br>anatomic location as the target ulcer, and it has<br>healed and re-opened within the previous 60 days; |
| Has a target ulcer that has decreased in volume<br>by 50% or more (based on Canfield's web-based<br>system) at the end of the two-week Run-in period<br>(wound tracing at the time of randomization) as<br>compared to the Screening visit; | Has a target ulcer that has decreased in volume by<br>50% or more at Visit 2 as compared to the volume<br>at Visit 1*<br>*Note: If volume of target ulcer is zero or not<br>measurable at Visit 1 or Visit 2, then a decrease in<br>area by 50% or more at Visit 2, as compared to<br>the area at Visit 1, will exclude the subject from<br>the study. |
| Has multiple foot ulcers that are connected by<br>fistulas or has an ulcer(s) that are within 5 cm of<br>the target ulcer; | Has multiple foot ulcers that are connected by<br>fistulas or has an ulcer(s) that are within 5 cm of<br>the target ulcer at Visit 1 or 2; |
| Has a target ulcer that tunnels into wound tracks<br>which cannot be fully visualized from the wound<br>surface; | Has a target ulcer that tunnels into wound tracks<br>which cannot be fully visualized from the wound<br>surface at Visit 1 or 2; |
| Has active cellulitis either at the site of, or in the<br>surrounding area of, the target ulcer; | Has active cellulitis either at the site of, or in the<br>surrounding area of, the target ulcer at Visit 1 or<br>2; |
| Has a target ulcer that has visually purulent<br>exudates or that has malodorous exudates on<br>examination; | Has a target ulcer that has visually purulent<br>exudates or that has malodorous exudates on<br>examination at Visit 1 or 2; |
| Exclusion Criteria | |
| Study 1 | Study 2 |
| Has peripheral vascular disease, per Doppler<br>Ultrasound, requiring vascular surgery<br>intervention; | Has peripheral vascular disease (PVD), per<br>Doppler Ultrasound, requiring vascular surgery<br>intervention at Visit 1 or 2; |
| Requires off-loading for the foot intended for<br>study application for a reason other than for a<br>target ulcer on the plantar surface of the foot; | Requires use of off-loading Diabetic Walker<br>device for the foot intended for study application<br>for a reason other than for a target ulcer on the<br>plantar surface of the foot at Visit 1 or 2; |
| Has had a lower extremity revascularization<br>procedure (e.g., percutaneous transthoracic<br>angioplasty, vein graft bypass, etc.) within eight<br>weeks of the study Screening visit (Visit 1); | Has had a lower extremity revascularization<br>procedure (e.g., percutaneous transluminal<br>angioplasty, vein graft bypass, etc.) of the index<br>lower extremity within eight weeks prior to Visit<br>1; |
| Has active Charcot foot; | Has active Charcot foot of the index foot at Visit<br>1 or 2; |
| Has had a surgical procedure to correct<br>biomechanical abnormities (e.g., lengthening of<br>the Achilles tendon, correction of hammer toe,<br>correction of Charcot foot) within eight weeks of<br>the study Screening visit (Visit 1); | Has had a surgical procedure to correct<br>biomechanical abnormities of the index foot (e.g.,<br>lengthening of the Achilles tendon, correction of<br>hammer toe, correction of Charcot foot) within<br>eight weeks prior to Visit 1; |
| Has had a deep vein thrombosis within six<br>months of study Screening visit (Visit 1); | Has had a deep vein thrombosis (DVT) of the<br>index lower extremity within six months prior to<br>Visit 1; |
| Has clinical evidence of lymphedema; | Has clinical evidence of lymphedema of the index<br>lower extremity at Visit 1; |
| Has had chemotherapy within 60 days prior to<br>the study screening visit; | Has had chemotherapy within 60 days prior to<br>Visit 1; |
| Has a life expectancy ≤ 2 years; | Has a life expectancy ≤ 2 years; |
| | Has previously participated in a dermaPACE<br>diabetic foot ulcer study; |
| Has had treatment of the target ulcer with growth<br>factors, prostaglandin therapy, negative pressure<br>or vasodilator therapy within two weeks of the<br>study Screening visit (Visit 1); | Has had treatment of the target ulcer with growth<br>factors, prostaglandin therapy, negative pressure<br>or vasodilator therapy within two weeks of Visit<br>1; |
| Is receiving ≥ 10 mg of steroid therapy per day<br>(includes topicals, inhalers, etc.); | Is receiving ≥10 mg/day of steroid therapy; |
| Has sickle cell anemia; | Has sickle cell anemia; |
| Has a known immunodeficiency disorder to<br>include, but not be limited to, Acquired<br>Immunodeficiency Syndrome (AIDS), Human<br>Immunodeficiency Virus (HIV), etc.; | Has a known immunodeficiency disorder to<br>include, but not be limited to: Acquired<br>Immunodeficiency Syndrome (AIDS), Human<br>Immunodeficiency Virus (HIV), etc. at Visit 1 or<br>2; |
| Has received radiation treatment within 120 days<br>of the study Screening visit (Visit 1); | Has received radiation treatment within 120 days<br>prior to Visit 1; |
| Has received treatment with immunosuppressants,<br>or biologically active cellular products, e.g. | Has received treatment with immunosuppressants<br>within sixty days prior to Visit 1; |
| Exclusion Criteria | |
| Study 1 | Study 2 |
| Apligraf, Dermagraft, etc. within sixty (60) days<br>of the study Screening visit (Visit 1); | Has received treatment with biologically active<br>cellular products on the target ulcer, e.g. Apligraf,<br>Dermagraft, etc. within sixty days prior to Visit 1; |
| Has received treatment with acellular (collagen-<br>based) products, e.g. Alloderm, Integra, etc.<br>within 30 days of the study Screening visit (Visit<br>1); | Has received treatment with acellular (collagen-<br>based) products on the target ulcer, e.g. Alloderm,<br>Integra, etc. within 30 days prior to Visit 1; |
| Has a current history of substance abuse (current<br>is defined as within 120 days of the study<br>Screening visit (Visit 1); | Has a current history of substance abuse (current<br>is defined as within 120 days prior to Visit 1); |
| Has a history of major systemic infections<br>requiring hospitalization within three months of<br>the study Screening visit (Visit 1); | Has a history of major systemic infections<br>requiring hospitalization within three months<br>prior to Visit 1; |
| Has a current malignancy or a history of<br>malignancy within the past five years, except for<br>basal cell carcinoma that has been treated with<br>local excision and is no longer present; | Has a current malignancy or a history of<br>malignancy within five years, of Visit 1 except for<br>basal cell carcinoma that has been treated with<br>local excision and is no longer present; |
| Has a physical or mental disability or<br>geographical concerns (e.g., residence not within<br>reasonable travel distance) that would inhibit<br>compliance with required study visits; | Has a physical or mental disability or<br>geographical concerns (e.g., residence not within<br>reasonable travel distance) that would inhibit<br>compliance with required study visits; |
| Is planning to undergo an exclusionary treatment<br>or procedure during the study; | Is planning to undergo an exclusionary treatment<br>or procedure during the study; |
| Is an employee of the Investigator or study site<br>with direct involvement in the proposed study or<br>other studies under the direction of that<br>Investigator or study site; | Is an employee of the Investigator or study site<br>with direct involvement in the proposed study or<br>other studies under the direction of that<br>Investigator or study site; |
| Has participated in another clinical investigation<br>within 30 days prior to study Screening visit<br>(Visit 1); or | Has participated in another clinical investigation<br>within 30 days of Visit 1; or |
| Is believed by the Investigator to be unwilling or<br>unable to comply with study protocol<br>requirements, including the application of<br>dermaPACE or sham procedure, standard-of-care<br>requirements, and all study-related follow up visit<br>requirements.…