Predicate Devices

Not Found

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The document describes a device that generates acoustic pressure shockwaves using an electrohydraulic method. There is no mention of AI, ML, image processing, or any data analysis or learning capabilities within the device description or performance studies. The software mentioned only defaults to a standard setting.

Therapeutic

Yes
The device is indicated for the treatment of chronic, full-thickness diabetic foot ulcers, which is a therapeutic purpose.

Diagnostic

No

The device is indicated to provide acoustic pressure shockwaves for the treatment of chronic diabetic foot ulcers, which is a therapeutic function, not a diagnostic one.

SaMD (Software as a Medical Device)

No

The device description clearly outlines physical hardware components including a Control Console and a PACE Applicator that generates shock waves. This is not a software-only device.

IVD (In Vitro Diagnostic)

Based on the provided text, the SANUWAVE dermaPACE System is not an In Vitro Diagnostic (IVD) device.

Here's why:

Intended Use: The intended use clearly states that the device is used to treat chronic, full-thickness diabetic foot ulcers by providing acoustic pressure shockwaves. This is a therapeutic application, not a diagnostic one.
Device Description: The description details a system that generates and applies physical energy (shockwaves) to the patient's body. This is consistent with a therapeutic device.
Lack of Diagnostic Elements: There is no mention of the device analyzing biological samples (blood, tissue, etc.) or providing information about a patient's health status based on such analysis. IVDs are designed to perform tests on samples taken from the body.
Performance Studies: The performance studies evaluate the device's effectiveness in achieving wound closure, which is a measure of therapeutic outcome, not diagnostic accuracy.

In summary, the dermaPACE System is a therapeutic device used for the treatment of diabetic foot ulcers, not a device used for in vitro diagnostic testing.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / 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.

Product codes

PZL

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.

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).

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).

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.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

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Anatomical Site

ankle area or below

Indicated Patient Age Range

Adult (22 years and older)

Intended User / Care Setting

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

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

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Summary of Performance Studies

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 1:

Study type: Prospective, randomized, double-blind, parallel-group, sham-controlled, multi-center, 24-week study.
Sample size: 206 subjects (107 dermaPACE, 99 sham-control).
Key results:
- Primary Endpoint (Complete Wound Closure): At 12 weeks, 20.6% dermaPACE subjects had complete wound closure vs. 15.2% sham (p = 0.363). At 24 weeks, 39.3% dermaPACE vs. 26.3% sham (p = 0.054).
- Mean Wound Area Reduction: At 24 weeks, mean wound reduction for dermaPACE subjects was 1.92 cm² compared to 0.16 cm² in the control group (p=0.047).
- Safety Endpoints: Overall adverse event rates were comparable (80.4% dermaPACE vs. 78.8% sham, p=0.725). Device-related TEAEs were 6.5% for dermaPACE vs. 2.0% for sham (p=0.117).
- Wound Pain: No significant change in target ulcer pain from baseline, and no significant difference between groups.

Study 2:

Study type: Prospective, randomized, double-blind, parallel-group, sham-controlled, multi-center, 24-week study.
Sample size: 130 subjects (65 dermaPACE, 65 sham-control).
Key results:
- Primary Endpoint (Complete Wound Closure): At 12 weeks, 26.2% dermaPACE subjects had complete wound closure vs. 23.1% sham (p = 0.684). At 24 weeks, 35.4% dermaPACE vs. 26.2% sham (p = 0.254).
- Mean Wound Area Reduction: At 24 weeks, mean wound reduction for dermaPACE subjects was 2.43 cm² compared to 1.73 cm² in the control group.
- Safety Endpoints: Overall adverse event rates: 61.5% dermaPACE vs. 52.3% sham. Increased rate of SAE and TESAE in the dermaPACE cohort; osteomyelitis emerged in the dermaPACE cohort (13.8% dermaPACE vs. 7.7% sham).

Pooled Effectiveness Outcomes:

dermaPACE demonstrated comparable wound closure at 12 weeks compared to the control (22.67% vs. 18.29%; p=0.320, respectively).
dermaPACE trend towards clinically and statistically better wound closure at 24 weeks compared to the control (37.79% vs. 26.22%; p=0.023, respectively).

Key Metrics

Study 1 Effectiveness

Complete Wound Closure (12 Weeks): dermaPACE: 20.6%, Sham Control: 15.2% (p=0.363)
Complete Wound Closure (24 Weeks): dermaPACE: 39.3%, Sham Control: 26.3% (p=0.054)
Mean Wound Area Reduction (12 Weeks): dermaPACE: 1.90 cm², Sham Control: 0.16 cm² (p=0.0046)
Mean Wound Area Reduction (24 Weeks): dermaPACE: 1.92 cm², Sham Control: 0.16 cm² (p=0.0471)

Study 1 Safety

All Adverse Events (24-Weeks): dermaPACE: 80.4%, Sham Control: 78.8% (p=0.725)
Treatment-Emergent AEs: dermaPACE: 54.2%, Sham Control: 50.5% (p=0.545)
Serious AEs: dermaPACE: 31.8%, Sham Control: 37.4% (p=0.384)
Treatment-Emergent Serious AEs: dermaPACE: 11.2%, Sham Control: 20.2% (p=0.069)
Device-Related Treatment-Emergent AEs: dermaPACE: 6.5%, Sham Control: 2.0% (p=0.117)
Recurrence Rate: dermaPACE: 7.1%, Sham Control: 15.4%
Partial Amputation Rate: dermaPACE: 1.9%, Sham Control: 5.1%
Target Foot Amputation Rate: dermaPACE: 3.7%, Sham Control: 11.1%

Study 2 Effectiveness

Complete Wound Closure (12 Weeks): dermaPACE: 26.2%, Sham Control: 23.1% (p=0.684)
Complete Wound Closure (24 Weeks): dermaPACE: 35.4%, Sham Control: 26.2% (p=0.254)
Mean Wound Area Reduction (12 Weeks): dermaPACE: 2.07 cm², Sham Control: 1.43 cm² (p=0.2440)
Mean Wound Area Reduction (24 Weeks): dermaPACE: 2.43 cm², Sham Control: 1.73 cm² (p=0.4474)

Study 2 Safety

All Adverse Events (24 Weeks): dermaPACE: 61.5%, Control: 52.3%
Treatment-Emergent AEs: dermaPACE: 58.5%, Control: 52.3%
Serious AEs: dermaPACE: 32.3%, Control: 21.5%
Treatment-Emergent Serious AEs: dermaPACE: 32.3%, Control: 21.5%
Device-Related Treatment-Emergent AEs: dermaPACE: 3.1%, Control: 3.1%
Recurrence Rate: dermaPACE: 8.7%, Control: 5.9%
Partial Amputation Rate: dermaPACE: 3.1%, Control: 0%
Target Foot Amputation Rate: dermaPACE: 0%, Control: 0%

Osteomyelitis Occurrence by Study and Number of Treatments

Study 1 (1-4 treatments): dermaPACE: 0%, Sham: 3%
Study 2 (1-7 treatments): dermaPACE: 3%, Sham: 3.3%
8 treatments (pooled data): dermaPACE: 13.2%, Sham: 9%

Predicate Device(s)

Not Found

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

Regulation Number and Section

§ 878.4685 Extracorporeal shock wave device for treatment of chronic wounds.

(a)
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.(b)
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.

Summary

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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:

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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;

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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

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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

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

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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-
1:2005/(R2012) +
A1:2012	Medical electrical equipment - Part 1: General
requirements for basic safety and essential performance
(IEC 60601-1:2005, MOD)	Complies
IEC 60601-1-2: 2007	Medical electrical equipment - Part 1-2: General
requirements for basic safety and essential performance

Collateral standard: Electromagnetic compatibility -
Requirements and tests | Complies |

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

SOFTWARE

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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

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

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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.

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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
contraception (administered for at least one
month prior to the start of initial application and
maintained per prescribed schedule) and
continues through the duration of the study:
hormonal contraceptives, intrauterine device
(IUD), spermicide and barrier or implantable
device, and	• Practices one of the following methods of
contraception (administered for at least one
month prior to the start of initial application and
maintained per prescribed schedule) and
continues through the duration of the study:
hormonal contraceptives, intrauterine device
(IUD), spermicide and barrier or implantable
device, and
• Have a negative urine qualitative β-HCG
pregnancy test within two weeks of Visit 2;	• Has a negative urine qualitative β-HCG
pregnancy test;
If female and post-menopausal, the subject must:
Have had a complete hysterectomy, bilateral	If female and post-menopausal one of the
following must be met at Visit 1:

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

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Inclusion Criteria
Study 1	Study 2
salpingo-oophorectomy or tubal ligation or
otherwise be incapable of pregnancy, or
Be postmenopausal for at least one year (absence
of menses for 12 consecutive months, including
spotting);	Has had a complete hysterectomy, bilateral
salpingo-oophorectomy or tubal ligation or
otherwise be incapable of pregnancy, or
is postmenopausal for at least one year (absence of
menses for 12 consecutive months, including
spotting):
Has at least one diabetic foot ulcer that is located
in the ankle area or below that has persisted a
minimum of 30 days prior to the study Screening
visit. Subjects may have more than one diabetic
foot ulcer, but only one will be treated in this
study. The target ulcer will be determined via
utilization of a flow chart in Section 4.1 of the
study protocol.	Has at least one diabetic foot ulcer that is located
in the ankle area or below that has persisted a
minimum of 30 days prior to Visit 1. Subjects may
have more than one diabetic foot ulcer, but only
one, the target ulcer, will be treated in this study.
The target ulcer will be determined via utilization
of a flow chart in Section 3 of the study protocol.
Note: Target Ulcer on Toe(s)
For a target ulcer located on the toe(s), the tip of
the dermaPACE applicator must be able to be held
perpendicular to the target ulcer and must be able
to be applied to the entire surface of the target
ulcer including the area 1 cm beyond the surface
of the ulcer in each direction at Visit 2.
Is diabetic (Diabetes Mellitus) with a HbA1c ≤ 12%;	NOTE: Target Ulcer on Toe(s)
For a target ulcer located on the toe(s), the tip of
the PACE Applicator must be able to be held
perpendicular to the target ulcer and must be able
to be applied to the entire surface of the target
ulcer including the area 1 cm beyond the surface
of the ulcer in each direction at Visit 2.
Has Type I or Type II Diabetes Mellitus with a
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
1 and 2
Has a target ulcer which has an Ulcer Grade 1 or 2,
Stage A according to the University of Texas
Diabetic Wound Classification system:
Grade 1: Superficial wounds through the epidermis
or epidermis and dermis that have not penetrated to
tendon, capsule or bone
Grade 2: Wounds that penetrate to tendon or
capsule (but not to bone or into the joint)
Stage A: Clean wounds (non-infected, non-
ischemic);	Has a target ulcer that is Grade 1 or 2, Stage A
according to the University of Texas Diabetic
Wound Classification system, at Visits 1 and 2):
Grade 1: Superficial wounds through the epidermis
or epidermis and dermis that have not penetrated to
tendon, capsule or bone
Grade 2: Wounds that penetrate to tendon or
capsule (but not to bone or into the joint)
Stage A: Clean wounds (non-infected, non-
ischemic):
Has an Ankle Brachial Index (ABI) ≥ 0.7 and ≤
1.2, OR toe pressure > 50 mmHg, OR tcPO₂ > 40
mmHg;	In the leg with the target ulcer has an ABI ≥ 0.7
and ≤ 1.2 OR if the ABI is >1.20 has a toe pressure

50 mmHg OR tcpO₂> 40 mmHg at Visit 1; |
| Subject agrees, or if applicable the subject's legal
representative agrees for the subject, to participate
in the study, including all study related procedures
and evaluations and documents this agreement by
signing the IRB/EC-approved informed consent
form. | Subject agrees, or if applicable, the subject's legal
representative agrees that the subject can
participate in the study, including all study related
procedures and evaluation and documents this
agreement by signing the IRB/EC-approved
informed consent form at Visit 1 and prior to any
study specific procedures. |
| Table 5: Exclusion Criteria for Study 1 and Study 2
Exclusion Criteria | |
| Study 1 | Study 2 |
| Female subjects who are currently pregnant or
plans to become pregnant during the study;
Female subjects who are nursing or actively
lactating; | Is female and is currently pregnant or plans to
become pregnant during the study; Is nursing or
actively lactating; |
| Is morbidly obese (Body Mass Index ≥ 40); | Is morbidly obese (Body Mass Index ≥ 40) at
Visit 1; |
| Is on dialysis; | Has clinically significant renal disease and/or
impaired renal function defined as having an
estimated creatinine clearance of $7 | 74 | 14 | 18.9% | 66 | 10 | 15.1% |

Table 11a: Study 1 Results Stratified by Demographic Characteristics at 12 Weeks (% Wound Closure by 12 weeks)

The total number of subjects in each demographic cohort

2The number of subjects with wound closure in each cohort

Table 11b: Study Results Stratified by Demographic Characteristics at 24 Weeks
(% Wound Closure by 24 weeks)

Demographic		dermaPACE			Sham Control
		N1	n2	%	N1	n2	%
Age	70	63	29	46.0%	57	12	21.1%
Ulcer Age
(months)	7	74	28	37.8%	66	19	28.8%

1 The total number of subjects in each demographic cohort

2The number of subjects with wound closure in each cohort

Mean Wound Area Reduction

The mean wound area reduction for both cohorts in Study 1 is presented below in Table 12. As the table demonstrates, the mean wound reduction for dermaPACE subjects at 24 weeks was 1.92cm2 compared to 0.16 cm- in the control group (p=0.047). Because means can be influenced by outliers in the data, the median wound reduction was also reported and favored dermaPACE.

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| Study Visit | Wound Area Reduction from Baseline
dermaPACE | | | Sham Control | | T-test
p-value | |
|-------------|-------------------------------------------------|------------|------------|--------------|------------|-------------------|--------|
| | N | Mean (cm²) | Med. (cm²) | N | Mean (cm²) | Med. (cm²) | |
| Week 12 | 86 | 1.90 | 1.36 | 73 | 0.16 | 1.14 | 0.0046 |
| Week 24 | 72 | 1.92 | 1.47 | 67 | 0.16 | 1.28 | 0.0471 |

Table 12: Mean Wound Area Reduction

Additional descriptive analyses related to wound closure rate association with these variables will be discussed in the Post HOC analyses section to follow.

Safety Results Study 1

Adverse event rates between the dermaPACE and control subjects were reported through 24 weeks follow-up. The primary safety endpoint was all adverse events. A total of 80.4% (86 out of 107) of dermaPACE and 78.8% (78 out of 99) of control subjects experienced an adverse event (p = 0.725). Secondary safety endpoints included treatment emergent adverse events (TEAE), serious adverse events, and device-related adverse events. The dermaPACE device demonstrated comparable AE rates overall with lower rates of SAE and treatment emergent SAE (TESAE). Also, the device group appeared to have lower rates of recurrence, partial amputation rates and target foot amputation rates (see Table 13).

Table 13: Safety Endpoints of Study 1 (All subjects received 1-4 treatments)

| Safety Endpoints | dermaPACE
(n=107) | Sham-
Control
(n=99) | p-value |
|---------------------------------------|----------------------|----------------------------|---------|
| Primary Endpoint | n (%) | n (%) | |
| All Adverse Events (24-Weeks) | 86 (80.4%) | 78 (78.8%) | 0.725 |
| Secondary Endpoints | | | |
| Treatment-Emergent AEs | 58 (54.2%) | 50 (50.5%) | 0.545 |
| Serious AEs | 34 (31.8%) | 37 (37.4%) | 0.384 |
| Treatment-Emergent Serious AEs | 12 (11.2%) | 20 (20.2%) | 0.069 |
| Device-Related Treatment-Emergent AEs | 7 (6.5%) | 2 (2.0%) | 0.117 |
| Additional Safety Analyses | | | |
| Recurrence Rate2 | 3 (7.1%) | 4 (15.4%) | 0.415 |
| Partial Amputation Rate | 2 (1.9%) | 5 (5.1%) | 0.265 |
| Target Foot Amputation Rate | 4 (3.7%) | 11 (11.1%) | 0.059 |

Note:

1 Fisher's Exact test (2-sided)

2 Recurrence rates determined as 3/42 (7.1%) and 4/26 (15.4%), respectively.

Serious AEs were defined as AEs which required medical intervention and were disruptive to the daily activities of the subject.

Device related Treatment-Emergent AEs were defined as AEs which were determined by the Investigators to be possibly or probably related to the treatment.

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Changes in Baseline Values in Wound Pain Assessed by Visual Analog Scale (VAS)

The Visual Analog Scale (VAS) was used to assess target ulcer pain at each visit throughout the trial. The VAS was used to assess target ulcer pain only, not related to neuropathic pain. The VAS scale was a 10-cm line with no pain beginning at 0-cm to worst pain at 10-cm. The final results showed there was no significant change in target ulcer pain from baseline and there was no significant difference in target ulcer pain between the dermaPACE and Sham-control groups throughout the application, treatment and follow-up periods of the study.

There was no significant difference in pain between the dermaPACE and Sham-control groups, at 12 weeks. 53.1% of dermaPACE subjects experienced a 30 % decrease in pain vs. 54.1% in the Sham-Control. By 24 weeks, 76.2% of the dermaPACE subjects showed a 30% decrease in pain compared to 54.3% of control.

DermaPACE Device Malfunctions

There were twelve instances where replacement of the initial console was required. Reasons for the twelve replacements included Console to Applicator contact errors, high voltage system time-outs, and hard shut-down anomalies. The clinical sites that had control consoles due for routine electrical safety checks or experienced a console related error message that required attention by SANUWAVE were sent another console immediately. The sites were instructed to discontinue using the console until they received a replacement console. None of the device malfunctions resulted in any safety related issues with the study subjects.

Treatment-Emergent Adverse Events (TEAEs)

A treatment-emergent adverse event (TEAE) was defined as an event that started or worsened in severity during or after the initial application with the study device through 30 days after the last device application. Subjects who reported more than one event for a System Organ Class or Preferred Term were only counted once for each category.

The overall rate of treatment-emergent adverse events did not differ significantly between the two treatment groups. There were 58 out of 107 (54.2%, 95% C1: [44.3, 63.9]) dermaPACE subjects that experienced at least one TEAE. Likewise, there were 50 out of 99 (50.5%, 95% CI: [40.3.60.7]) sham-control subjects that experienced at least one TEAE. The rate of treatmentemergent adverse events between dermaPACE and sham-control was not statistically different at the 0.05 level (p=0.5452).

Treatment Emergent Serious Adverse Events (TESAE) and TEAE). Study 1
	Safety Endpoints	dermaPACE	Control
Identified
Safety Risk	Related Adverse Event	(N=107)
n (%)	(N=99)
n (%)
Adverse Tissue
Reaction	Wound Complication	0 (0.0%)	1 (1.0%)
	Wound Drainage Procedure	0 (0.0%)	0 (0.0%)
	Excoriation	2 (1.9%)	1 (1.0%)
	Post Procedural Hematoma	1 (0.9%)	0 (0.0%)

Table 14: Treatment Emergent AEs
(Treatment Emergent Serious Adverse Events (TESAE) and TEAF): Study

21

Safety Endpoints			Study 1
		dermaPACE	Control
	Application Site Complication*	3 (2.8%)	2 (2.0%)
	Inflammation	0 (0.0%)	0 (0.0%)
	Bacterial Infection***	1 (0.9%)	0 (0.0%)
	Infected Skin Ulcer**	0 (0.0%)	0 (0.0%)
	Localized Infection	0 (0.0%)	0 (0.0%)
	Osteomyelitis	0 (0.0%)	2 (2.0%)
	Paronychia	0 (0.0%)	0 (0.0%)
	Any Abscess Bacterial	0 (0.0%)	2 (2.0%)
	Cellulitis	10 (9.4%)	7 (7.0%)
Infection	Application Site Infection/Cellulitis	14 (13.1%)	15 (15.1%)
	Any Wound Infection	3 (2.8%)	2 (2.0%)
	Sepsis	0 (0.0%)	0 (0.0%)
	Septic Shock	0 (0.0%)	0 (0.0%)
	Tinea Pedis	0 (0.0%)	1 (1.0%)
	Gangrene	0 (0.0%)	0 (0.0%)
	Other	16 (15%)	4 (4.0%)
	Percentage of subjects with at least 1 Infection	30 (28%)	25 (25.3%)
Application Site
Pain	Procedural Pain at application site	2 (1.1%)	0 (0%)
	Application Site Pain	5 (4.7%)	12 (12.1%)
	Extremity Pain	3 (2.8%)	0 (0.0%)

*Necrosis, Erythema, Irritation

**Includes Diabetic Foot Infection

** Includes AE classified as Infection other than ulcer infection, cellulitis or osteomyelitis

		Table 15: Investigator Assessed Device Related Treatment Emergent Adverse Events Study 1

| Study
No. | Subject
Number | Treatment
Assignment | Event Verbatim Term | Study Device
Causality |
|--------------|-------------------|-------------------------|---------------------------------------------------------------------------------------------------|---------------------------|
| 1 | 16015 | dermaPACE | Burning Sensation Left Foot Secondary to
dermaPACE Treatment | Probable |
| 1 | 16015 | dermaPACE | Enlargement Left Target Ulcer | Possible |
| 1 | 16015 | dermaPACE | Left Foot Bacterial Infection – Target Ulcer | Possible |
| 1 | 23007 | dermaPACE | Burning of the Right Foot at the Target Ulcer
After the First Application | Possible |
| 1 | 26001 | dermaPACE | Headache | Probable |
| 1 | 26001 | dermaPACE | Headache | Probable |
| 1 | 28004 | dermaPACE | Target Wound with Light Staphylococcus,
Klebsiella/ Enterobacter-Like Diptheroids
Infection | Possible |
| 1 | 06009 | Sham-control | Increased Sensation More Feeling Not Pain
Target Ulcer Left Foot | Possible |
| 1 | 23005 | Sham-control | Burning in Left Foot After Application of the
Foot in General | Possible |

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Serious Adverse Events (SAEs)

The overall rate of serious adverse events after randomization was slightly higher in the shamcontrol group but did not differ in a clinically significant manner between the two treatment groups. There were 34 out of 107 (31.8%, 95% CI: [23.1, 41.5]) dermaPACE subjects that experienced at least one SAE. Likewise, there were 37 out of 99 (37.4%, 95% CI: [27.9, 47.7]) sham-control subjects that experienced at least one SAE. The rate of serious adverse events between dermaPACE and sham-control was not statistically different at the 0.05 level (p=0.3835).

Treatment-Emergent Serious Adverse Events (TESAEs)

The overall rate of treatment-emergent serious adverse events (TESAEs) was lower in the dermaPACE group. There were 12 out of 107 (11.2%, 95% CI: [5.9, 18.8]) dermaPACE subjects that experienced at least one TESAE. Likewise, there were 20 out of 99 (20.2%, 95% CI: [12.8. 29.5]) sham-control subjects that experienced at least one TESAE. The rate of TESAEs between dermaPACE and sham control was not statistically significant at the 0.05 level (p=0.0688).

	Trial 1
Adverse Event	dermaPACE
N=107	Sham-Control
N=99
Infections and infestations	7 (6.5%)	15 (15.2%)
Abscess	0 (0.0%)	2 (2%)
Abscess limb	0 (0.0%)	1 (1%)
Cellulitis	1 (0.9%)	1 (1%)
Gangrene	0 (0.0%)	0 (0.0%)
Application Site Infection	4 (3.7%)	7 (7.1%)
Infected skin ulcer	0 (0.0%)	0 (0.0%)
Localized infection	0 (0.0%)	0 (0.0%)
Pneumonia	1 (0.9%)	0 (0.0%)
Osteomyelitis	0 (0.0%)	3 (3%)
Scrotal abscess	0 (0.0%)	0 (0.0%)
Sepsis	0 (0.0%)	0 (0.0%)
Septic shock	0 (0.0%)	0 (0.0%)
Urinary Tract Infection	0 (0.0%)	1 (1%)
Wound infection	1 (0.9%)	0 (0.0%)

Table 16: Infections and Infestations Study 1 referenced in Table 14 TESAE

As seen in Table 16, the largest contributor to the overall TESAE adverse event rate was the system organ class of Infections and Infestations. Within this system organ class, specific to subjects with TESAEs, 7 of the 107 (6.5%) dermaPACE subjects had a TESAE in the System Organ Class of Infections and Infestations. However, 15 of the 99 (15.2%) sham-control subjects

23

had a TESAE in this System Organ Class with 7 of the 15 subjects having an application siterelated TESAE.

Related to investigator assessed AE which were related to the device, there were 7 out of 107 (6.5%) dermaPACE subjects that experienced at least one related TEAE. and 2 out of 99 (2.0%) sham-control subjects that experienced at least one related TEAE (p=0.117) see table 15.

STUDY 2

Demographics

The total number of subjects screened in the dermaPACE trial at the 18 clinical sites was 261with 87 screen failures resulting in a total randomized population of 130 subjects; 65 randomized to dermaPACE and 65 randomized to sham-controls.

A comparison across these cohorts was completed for each demographic (Table 17). The average age for all subjects treated with dermaPACE was higher than subjects treated with shamcontrol, 59.1±9.4 years versus 56.8±10.7 years (p=0.195) with a median age of 59 and 57, respectively. Target ulcers treated with dermaPACE were not as old as than those in shamcontrol subjects, there were more smokers in the dermaPACE treatment group compared to sham, and the sham treatment group had about 15% more subjects with poor glycemic control.

Demographic	Study 2
	dermaPACE	Sham Control
Age (years)	$59.1\pm9.4$	$56.8\pm10.7$
Gender (% Male)	83.1%	75.4%
Height (inches)	$69.6\pm3.9$	$70.7\pm4.8$
Weight (pounds)	$217.2\pm45.0$	$225.5\pm49.0$
BMI (kg/m²)	$31.4\pm5.6$	$31.6\pm5.5$
Smokers	18.5%	13.9%
Target Ulcer Size (cm²)	$3.71\pm2.83$	$3.73\pm2.82$
Target Ulcer Age (weeks)	$44.6\pm53.4$	$49.7\pm59.2$
HbA1c 12	32	6

Table 21: Results Stratified by Demographic Characteristics at 12 Weeks (% Wound Closure)

NThe total number of subjects in each demographic cohort

"The number of subjects with wound closure in each cohort

Demographic		dermaPACE			Sham Control			p-value
		N	n	%	N	n	%
Age
(years)	70	37	16	43.24	35	6	17.14	0.0163

Table 22: Results Stratified by Demographic Characteristics at 24 Weeks (% Wound Closure)

27

Demographic	dermaPACE			Sham Control
	N	n	%	N	n	%
Ulcer Age
(months)	32 seemed to have lower rates of wound closure when thev received more than 4 treatments compared to subjects with BMI