Negative Pressure Wound Therapy as a Drug Delivery System
Phase: NA
Conditions: Diabetic Foot Ulcers
Sponsor: University of Texas Southwestern Medical Center

Negative Pressure Wound Therapy as a Drug
Delivery System
NCT02463487
01.25.2018

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The University of Texas Southwestern Medical Center at Dallas
Institutional Review Board
Title: Negative Pressure Wound Therapy as a Drug Delivery System
Principal Investigator: Lawrence A. Lavery, DPM, MPH
Sponsor: American Diabetes Association
1. Introduction and Purpose:
The aim of this study is to improve wound healing in high risk diabetic patients that require
surgical debridement or open amputation for an infected foot wound. The most common
reason for hospitalization and amputation amongst people with diabetes is an infected foot
wound. Negative Pressure Wound Therapy (NPWT) [1, 2] has dramatically changed the
outcomes of complex wounds, especially in the diabetic foot. Compared to standard
wound care, diabetic patients treated with NPWT are 1.4 times more likely to heal and 2.5
times less likely to require amputation [2-4]. Our preliminary work suggests that using
irrigation with NPWT provides an additional dramatic improvement in healing compared to
“traditional NPWT”. NPWT with irrigation is analogous to the benefit of drug-eluting stents
compared to bare metal stents for cardiovascular disease [5, 6]. Irrigation increases the
effectiveness of NPWT by reducing bacterial load, accelerating wound healing, and
decreasing the cost of wound treatment [7-11]. Thus, the combination of
NPWT
and
irrigation solution could significantly improve clinical outcomes and reduce the economic
burden in this seriously ill population.
Traditional Negative Pressure Wound Therapy delivers subatmospheric pressure to a
wound using a foam dressing that is sealed with an occlusive dressing. The addition of
irrigation with antiseptic solution is delivered to the sealed wound using additional tubing from
an IV bag attached to the NPWT device. Our preliminary data suggest that when traditional
NPWT is combined with antiseptic irrigation, there is a higher rate of wound closure, fewer
surgeries, and shorter length of hospitalizations for complex infected diabetic foot wounds
(Preliminary Study 2).
We propose a randomized clinical study of 151 patients with infected, diabetic foot wounds
that require hospitalization. Hospital patients with surgical diabetic foot wounds will be
randomized to receive NPWT with polyhexanide irrigation or “conventional” NPWT with no
irrigation.
Aim 1: Compare clinical outcomes with Negative Pressure Wound Therapy with
irrigation and Negative Pressure Wound Therapy without irrigation. We expect that
patients treated with NPWT with irrigation will a have higher proportions of wounds that heal,
fewer surgeries, and faster wound healing trajectories when compared to patients treated
with traditional NPWT without irrigation.
Aim 2: Compare quantitative cultures and clinical infections in patients treated with
NPWT with irrigation compared to conventional NPWT. We hypothesize that patients

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treated with NPWT and irrigation will have a significantly lower bacterial load, and fewer and
less severe clinical infections.
Aim 3: Compare health function and well-being of patients treated with NPWT with
irrigation compared to conventional NPWT. We hypothesize that patients treated with
NPWT and continuous irrigation will have significantly higher indicators of functional health
and well-being as compared with standard NPWT.
2. Background:
There is a worldwide epidemic of diabetes. According to data from the World Health
Organization, the world prevalence of diabetes among adults was 6.4% in 2010, affecting 285
million people worldwide. The prevalence of diabetes is expected increase to 7.7% by 2030
(439 million adults).[12] The U.S. Centers for Disease Control and Prevention estimate that
26 million people in the US have diabetes.[13] Over the past five years in the United States,
the prevalence of diabetes has increased 26% and the cost has increased 41% to $245
billion a year [14, 15].
Diabetic Foot Wounds and Amputations: Diabetic foot wounds are common, complex and
costly.[16-18] One of the most frequent causes of hospitalization among persons with
diabetes is an infected foot wound.[13] In the United States in 2007, approximately one-
quarter of the total cost of diabetes treatment was spent on lower extremity complications
($43.5 billion). [19-21] The incidence of diabetic foot ulcers in Medicare enrollees is about 7%
[22, 23], and approximately 61% of foot wounds become infected. Twenty-percent of patients
with infected foot wounds end up with amputation of the foot or leg.[16] The incidence of
lower extremity amputation is 0.5-1.0% (90,000 per year). The annual mortality rate for
diabetics with foot ulcers is about 11%, and after a lower extremity amputation, mortality is
nearly 22%.[14, 24-32] [17, 33-39]
Negative Pressure Wound Therapy (NPWT) has dramatically changed the care of complex
diabetic foot wounds. Compared to standard wound care, patients treated with NPWT are 1.4
times more likely to heal and 2.5 times less likely to require amputation.[40] [2-4]
NPWT
is
used
extensively
to
treat
infected
wounds.
Experimental
studies
in
pigs
demonstrated a reduction in quantitative cultures from 108 to 106 colony forming units with
NPWT [41, 42] However in clinical trials “traditional NPWT” has not been shown to reduce the
risk of infection. For instance, Armstrong and Lavery reported that 16.9% of NPWT patients
were treated for infection compared to 9.4% of patients that received “standard of care” in a
randomized clinical trial (RCT) of diabetic foot wounds. The addition of antiseptic irrigation
provides
a
significant
reduction
in
bacterial
load
compared
to
“traditional
NPWT”
(Preliminary Work: Study 2). We expect it will translate into fewer clinical infections [11],
fewer surgeries and faster wound healing.
SIGNIFICANCE OF NEW INTERVENTION We will use NPWT with irrigation as a drug
delivery system. This application is analogous to the benefit of drug-eluting stents compared
to bare metal stents for cardiovascular disease [5, 6]. We believe delivering topical
medications to the wound bed will dramatically improve wound healing, reduce infections and
reduce amputations. Our preliminary work has shown that irrigation reduces bacterial load
significantly more than NPWT alone (Preliminary Work: Study 3) [11]. In addition a higher

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proportion of patients treated with NPWT and irrigation had their wounds surgically closed,
required fewer surgeries, and shorter hospitalizations (Preliminary Work: Study 2).
Irrigation Solution Selection: There are many potential irrigation products to decrease
bacteria in wounds. Povidone iodine, Dakin’s solution, silver nitrate, and polyhexanide are
effective to eliminate bacteria. However, some of these have been shown to damage
fibroblasts and are thought to impede healing. Irrigation with Polyhexanide solution (PHMB)
seems to be the best choice to treat infected diabetic foot wounds because it is a very
effective antiseptic, and it promotes wound healing. Polyhexanide, marketed under
the
names Prontosan and Lavasept, is polyhexamethylene biguanide (PHMB). It is a strong base
and interacts with acidic phospholipids in the cell membrane, leading to increased
permeability and cell death.[43] PHMB has a broad antimicrobial spectrum, including Gram-
positive and Gram-negative bacteria, and biofilm-forming organisms.[44] A >5 log 10
reduction after 5 minutes of application is achieved with 0.02% polyhexanide against S.
aureus, E. coli, E. faecium, P. aeruginosa and C.albicans.[45]
Polyhexanide Improves Wound Healing: Several studies indicate that PHMB solution and
gel improve
wound healing. Kramer [47] compared
PHMB and octenidine and Ringer’s
lactate solution in superficial 20 mm diameter wounds in pigs (n=108 wounds). There were no
differences in histology or tissue compatibility in the treatment groups. There was faster
wound healing in PHMB animals compared to the other treatments (PMHB 22.9 vs. Ringers
24.1 and octemidine 28.3 days, p<0.05). Schmit-Neuerburg conducted a double-blinded RCT
in contaminated wounds and compared 0.2% PHMB (n=45) and Ringers lactate solution
(n=35). The PHMB group had better wound healing and faster reduction of Gram positive
infections.[46] Valenzuela [48] evaluated PHMB in a RCT in chronic wounds (n=142). They
compared “standard of care” to 0.1% PHMB gel. Patients in the PHMB groups demonstrated
reversal of positive cultures (p=0.004), decreased surface area (p=0.013), and increased
granulated tissue (p=0.001) compared to standard of care treatments.
Polyhexanide Irrigation with NPWT: Several retrospective studies have used Polyhexanide
irrigation with NPWT compared to patients treated standard wound care.[7-10] Timmers
reported the results of a retrospective study of 30 patients with osteomyelitis of the pelvis or
lower extremity that received NPWT with PHMB irrigation compared to 90 patients that
received standard of care. The PHMB irrigation subjects had fewer recurrent infection (10%
vs. 59%, p<0.001), Hospital stay 36 (15-75) vs. 73 days (6-149) p<0.001), and fewer surgical
procedures 2 (range: 1-4) vs. 5 (range: 2-42) p<0.001.
INNOVATIONS:
1. NPWT as a drug delivery system. NPWT has dramatically changed wound care in the
last 10 years. Our initial focus is to deliver antiseptic solution to the wound bed to reduce the
bacterial load and accelerate wound healing. In the future, we plan to use the same approach
to deliver growth factors and anti-inflammatory medications to wounds. Our preliminary data
suggests that when “traditional” NPWT is combined with irrigation, there is a synergistic
effect. A higher proportion of wounds are closed with fewer surgeries in the operating room
and shorter hospital stays. This is the first Clinical Effectiveness Research study that
compares clinical and economic outcomes with NPWT and NPWT with irrigation. This is the
first NPWT RCT in infected diabetic wounds. Figure 2, above shows simultaneous irrigation
with NPWT. Irrigation solution is directed to the wound through IV tubing. It flows across the

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wound bed and then is collected through a separate suction system that also maintains
constant pressure of 125 mm Hg on the wound bed.
2. Determine the effect of NPWT and NPWT with continuous irrigation on serial
quantitative bacterial cultures and clinical infections: This is the first study to evaluate
serial tissue cultures in infected diabetic foot wounds to evaluate (1) the effect of NPWT on
bacterial load and (2) the role of bacterial load on wound healing. Our results may help
redefine “infection” as it pertains to wound healing in persons with diabetes and as a pivotal
factor in wound failure.
3. Selection Bias: Industry sponsored research routinely excludes high-risk patients with
significant PAD, poor glucose control and co-morbidities, even though the excluded
population is often the population that needs advanced wound therapies the most. The
industry sponsored RCTs previously referenced systematically excluded high-risk patients
with moderate peripheral artery disease (PAD) (ABI <0.70), glycated hemoglobin >10%,
active infection, and end stage renal disease requiring dialysis [49].
4. Dropouts: Dropouts are common in wound studies (20-35%) and are categorized as
failures in intent-to-treat studies. With their consent, we will continue to follow patients that
elect to drop out or whose physicians believe it is in their best interest to stop participation.
We will continue to see them and evaluate their wound and document any adverse events.
To our knowledge, no studies in the wound healing literature have been designed to follow
subjects that elect to drop out. We will document their treatments, but no protocol-specific
treatments will be provided once they withdraw from the active treatment phase. This will
allow us to estimate adherence effectiveness, as well as intent-to-treat.
C. PRELIMINARY DATA
Preliminary Studies: Drs. Lavery’s team has completed several NPWT studies [3, 26, 34,
40, 50-54] to support this research. They have used investigator initiated, industry funding
from KCI, ITI, Convatec, Smith Nephew and Thermotek to execute preliminary animal and
human studies to gather preliminary NPWT data.
Our Preliminary Work with NPWT indicates:
1. NPWT patients have a higher proportion of wounds that heal compared to “standard
wound care” [1, 4, 53]. (Preliminary Work: Study 1)
2. NPWT is less expensive than “standard wound care” in diabetic foot wounds [54].
3. NPWT with irrigation provides a higher proportion of wound closure, fewer surgeries
and shorter length of hospitalization in diabetic foot wounds. (Preliminary Work:
Study 2)
4. NPWT with irrigation with polyhexanide biguanide (PHMB) significantly reduces
Pseudomonas
aeruginosa
compared to “traditional
NPWT” in a swine model.
(Preliminary Work: Study 3)
5. There is no difference in wound healing in diabetic foot wounds treated with high (125
mm Hg) and low (75mm Hg) continuous pressure. (Preliminary Work: Study 4)

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0/26/2015
Multicentre, Randomised Controlled Trial. The Lancet, 2005[40]
Study 1: Negative Pressure Wound Therapy After Partial Diabetic Foot Amputation: a
Kaplan-Meier Estimates For Duration on Randomized Treatment (Days)
Protocol VAC2001-07
Diabetic Foot Wound Study
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
10
20
30
40
50
60
70
80
90
100
110
Time on Treatment (Days)
This study demonstrated that NPWT is superior to “standard wound care” to heal complex
diabetic foot wounds. We enrolled 162 patients into a 16-week, randomized clinical trial.
Inclusion criteria consisted of diabetic patients with partial foot amputation wounds. Patients
were randomly assigned to NPWT (n=77) or standard moist wound care (n=85). The treating
physician had discretion regarding the level (80-200 mm Hg) and mode of pressure
(continuous or intermittent). More patients healed in the NPWT group than in the control
group
56% vs. 39%, p=0.04). Recurrent infection was higher in the NPWT group (NPWT 16.9%
9.4%), but the difference was not statistically significant.
Kaplan Meier Analysis: The survival analysis shows a significant difference in the time to
healing. The median time to wound closure was 59 days for patients in the NPWT group and
106 days for controls.
Study 2: The Impact of Negative Pressure Wound Therapy with Instillation Compared
to Negative Pressure Wound Therapy. Plast Reconstr Surg 2013 This study shows that
NPWT with two different doses of Prontosan irrigation solution decreases the number of
surgeries, length of hospitalization, and increases the proportion of wounds that are closed
compared to “traditional NPWT”. We conducted a retrospective study of hospitalized patients
with infected lower extremity wounds that received NPWT without irrigation (n=74), NPWT
with irrigation with polyhexanide biguanide (PHMB) for 6 minutes every hour (n=34), and
NPWT with irrigation with polyhexanide biguanide (PHMB) for 20 minutes every hour (n=34).
The proportion of wounds that were surgically closed was significantly higher, and
the
number of surgeries was significantly less in patients that received NPWT with 6 minutes of
irrigation compared to standard NPWT without irrigation. Similar trends were
seen
with
NPWT with 20 minutes of irrigation.
Control
VAC
Survival Distribution Function Estimate

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Pseudomonas
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Study 3: Simultaneous irrigation and negative pressure wound therapy enhances
wound healing and reduces wound bioburden in a porcine model. Wound Repair
Regen 2013. The objective of the study was to compare wound healing and reduction in
pseudomonas on acute wound using a swine model. We evaluated six wound treatments (1.)
control wound (2.) NPWT 125 mm Hg continuous pressure with foam interface (3.) NPWT
with low volume irrigation (15 cc/hr) with Saline (4.) NPWT with low volume irrigation (15
cc/hr) with 1% polyhexanide biguanide (PHMB) (5) NPWT with high volume irrigation (40
cc/hr) with Saline (6) NPWT with high volume irrigation (40 cc/hr) with 1% PHMB. Each
wound was inoculated with ~500 CFU
of Pseudomonas aeruginosa, packed
with
saline-moistened
gauze
and
covered with Tegaderm. After 3 days
post
inoculation,
dressings
were
removed; wounds were treated for 21
days with dressing changes twice a
week.
With
Control
treatment,
Pseudomonas aeruginosa bioburden
increased
~5x107 over
the
21-day
time course.
This proliferation was
substantially
reduced
with
the
application of NPWT or NPWT with
irrigation, except for low flow rate
treatment with saline (p=0.068). There was a significant and sustained reduction in wound
area reduction in NPWT wounds compared to control wounds over the duration of the study
(p<0.05). There was no difference in wound area reduction among the NPWT and NPWT
with irrigation groups in healthy young pigs.
Study 4: Randomized Clinical Trial to Compare Negative Pressure Wound Therapy
Approaches with Low and High Pressure, Silicone-Coated Dressing and Polyurethane
Foam Dressings. Plast Reconstr Surg 2013 This RCT demonstrates that wound volume
reduction is the same in patients treated with high (125 mm hg) and low (75 mm Hg) NPWT.
We evaluated 40 patients in a 4-week RCT. This study compared a low pressure NPWT
device using 75 mm Hg continuous pressure with a silicone coated gauze interface
(Convatec, NJ) and the “standard of care approach” using 125 mm Hg continuous pressure
with a sponge interface (KCI San Antonio, TX). There was no difference in the percent wound
volume reduction at 4 weeks (87% vs. 92%), or the proportion of wounds with complete
closure (50% for 75 mm Hg vs. 60% for 125 mm Hg). Wound closure was achieved with split
thickness skin grafts, rotational flaps or delayed primary closure. No wounds healed by
secondary intention during the 4 week evaluation period. NPWT using 125 mm Hg pressure
with a foam interface and 75 mm Hg pressure with silicone coated gauze interface had
almost identical wound healing outcomes.
% of Day 0

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3. Concise Summary of Project:
Study Design: We plan a randomized clinical trial of 151 patients with infected diabetes-
related lower extremity wounds to compare the clinical and economic effectiveness of
negative pressure wound therapy with continuous irrigation and negative pressure wound
therapy without irrigation.
Rationale for Treatment Groups
(1.) Treatment Group 1 Standard NPWT: We chose 125 mm Hg constant pressure with
polyurethane foam because this is one of the most common setting used in clinical practice
and reported in clinical studies with diabetic foot wounds (Preliminary Work: Studies 1-4).
(2.) Treatment Group 2 (NPWT with continuous irrigation): Constant pressure therapy
from 125 mm Hg will be used. However, we will program the NPWT device to provide
continuous irrigation at a rate of 40 cc/hour. This rate is based on findings from our
preliminary work (Preliminary Work: Study 3).
Table 2 NPWT Operating Characteristics of Comparative Devices
Pressure
125
mm
Hg
continuous
pressure
125 mm Hg continuous pressure
Irrigation
None
1% Polyhexanide irrigation 40 cc/hour
Interface
Polyurethane Foam
Polyurethane Foam
Population and Recruitment: We will enroll 151 patients from two centers: The University of
Texas Southwestern University Hospital and Parkland Hospital over the period of three
years.. We will screen and enroll patients with wounds in the inpatient setting. Patients will be
randomized to receive traditional NPWT or NPWT with continuous irrigation while they are
hospitalized. The average hospitalization for patients that receive NPWT is 13.3 days.
Patients that do not have their wound surgically closed during hospitalization will be
discharged with negative pressure wound therapy without irrigation. After discharge from the
hospital, subjects will be seen twice weekly by home health, and we will evaluate subjects in

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clinic during routine post-operative visits up to a total of 16-week period or until 30 days after
the wound heals. A study flow chart is provided below.
NOTE: Subjects who continue on NPWT after hospital discharge will receive NPWT without
irrigation for home use
4. Study Procedures:
Screening Procedures
·
Review and sign the Informed Consent and HIPAA Authorization
·
The study doctor will review the inclusion and exclusion criteria
·
Demographics (such as age, gender, race or ethnicity)
·
Collection of Sitting blood pressure and pulse at admission
·
Collection of Height and weight at admission
·
Collection of the medical and surgical history
·
Collection of the history of the wound
·
Wound assessment(s) – wound etiology, wound history, location of study wound and
infection assessment
·
Hyperspectral imaging within 30 days of screening
·
Vascular/Neurological evaluation - we will do various tests and measurements to
assess the sensation (feeling) and circulation (blood flow) in the subject’s feet and

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lower legs. To assess the sensation, we will do a monofilament sensory test and a
vibration threshold perception test on the study foot. We will calculate the
neuropathy disability score of both feet. To assess circulation, we will record Skin
Perfusion Pressures in the study foot using a Sensilase System (Väsamed, Eden
Prairie, MN) within 30 days of screening. We will calculate the ankle brachial index
(ABI) at screening and collect available arterial doppler data from the medical
record within 6 months of screening. None of these tests are invasive (using
needles), uncomfortable or have risks greater than standard care.
·
Results of standard-of-care laboratory tests including a white blood cell count, blood
chemistry (tests to see how well organs, such as the liver and kidneys are working),
glycated hemoglobin, albumin, prealbumin, erythrocyte sedimentation rate, C-reactive
protein and blood glucose. Results of a serum pregnancy test (standard care for
women of child-bearing potential as part of pre-op labs) will also be collected.
Collection of a list of the subject’s current antibiotics
·
We will provide the SF-36 Questionnaire and other patient-reported outcomes
questionnaires and collect them while subjects are inpatient.
This visit will last about 2 hours.
If the subject qualifies for the study, they will participate in the following procedures:
Group Assignment
If the researchers believe the subject can take part in this study, s/he will be assigned
randomly (like a flip of a coin) to receive one of the following therapies:
·
Negative Pressure Wound Therapy with Irrigation
·
Negative Pressure Wound Therapy without Irrigation
The group is assigned randomly (like flipping a coin). The sponsor or researchers do not
know in advance what group assignment each subject will receive. Neither the subject
nor the researchers will be allowed to choose which group s/he is assigned to.
Study Intervention
The subject will receive either:
·
Quantum™+Simultaneous Irrigation (NPWTi) – Negative Pressure Wound
Therapy with Prontosan®, or
·
Quantum™(NPWT) –Negative Pressure Wound Therapy (without
Prontosan®)
Assigned therapy will continue in the hospital until the physician determines that the
wound is ready for closure. If the subject’s wound is healing, study therapy will be
discontinued and standard dressings will be applied. If surgical closure is needed, the
subject will return to the Operating Room for a procedure to close the wound.
If the wound is not ready for closure during the hospital stay, subjects will continue NPWT
at home. NPWT at home will be without irrigation.

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Procedures and Evaluations during the Research
The study therapy will only be given while the subject is in the hospital. If the subject’s wound
is not ready for closure during the hospital stay, the subject will continue NPWT at home.
NPWT at home will be without irrigation.. Once the therapy is stopped s/he will continue to
be followed by the study doctor. After the subject is released from the hospital s/he will need
to see the study doctor during regular post-operative visits. The study doctor will continue to
check the wound. If the wound closes, s/he will see the study doctor 30 days later to have
the closed wound checked.

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Day of First Surgery:
·
3D images after the surgery with eKare Insight device
·
Tissue and bone samples – the doctor will take 2 small samples of tissue from the
subject’s wound before debridement (removal of dead or unhealthy tissue), and after
debridement (clean margins) and 1 sample of bone before debridement in case of
bone infection, and these tissue samples will be kept and tested for the amount and
type of bacteria that are present (qPCR analysis/laboratory analysis).
·
Wound measurements after the surgery
·
The study doctor will decide if the subject still qualifies to be in the study
·
Randomization (like flipping a coin) to either Quantum™NPWT with Irrigation or
Quantum™NPWT without Irrigation
·
Placement of therapy on the wound
·
Collection of current antibiotics
·
Collection of adverse event information (any changes in health)
Daily Treatments (while in the hospital):
·
Collection of current antibiotics
·
Collection of adverse event information
This will take about 15 minutes.
Additional Surgery (if needed to remove dead tissue/bone or to close the wound):
·
Tissue sample – the doctor will take 2 small samples of tissue from the subject’s
wound after debridement (clean margin), and these tissue samples will be kept and
tested for the amount and type of bacteria that are present (qPCR analysis/laboratory
analysis)
·
3D images of the wound after the surgery/debridement at bedside with eKare Insight
device if the wound is still open.
·
Wound measurements after the surgery/debridement at bedside
·
Wound closure or placement of therapy on the wound
·
Collect current antibiotics
·
Collect adverse event information
If the subject’s wound is not closed upon hospital discharge, NPWT will continue at home
without irrigation.
Home Health Visits
If the subject continues to receive NPWT after hospital discharge, the subject will be seen
twice weekly by a home health nurse for dressing changes. The home health nurse will
collect sitting blood pressure and pulse rate. Amount, type and character of wound drainage
will be documented, as well as any adverse events and changes to concomitant medications.
Offloading will be reapplied after dressing changes.
Follow-Up Visits per standard of care (after therapy has stopped):
·
Dressing change / removal/ Offloading
·
Wound measurements and infection assessment

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·
Results of standard-of-care laboratory tests including a white blood cell count, blood
chemistry (tests to see how well organs, such as the liver and kidneys are working),
glycated hemoglobin, albumin, prealbumin, erythrocyte sedimentation rate, C-reactive
protein and blood glucose.
·
3D image of the wound with eKare device (if indicated, if the wound is still open)
·
Collection of current antibiotics
·
Collection of adverse event information
These visits will take about 30 minutes.
End of Study - Wound Closure Follow-up Visit (after the wound closes, if it closes
within 16 weeks from Day of First Surgery) or Week 16:
·
Closed wound assessment
·
For subjects whose wound has not closed:
o
3D images of the wound with eKare device
o
Return to standard care
·
Collection of current antibiotics
·
Collection of adverse event information
·
SF-36 Questionnaire and other patient-reported outcomes questionnaires
This visit will take about 30 minutes.
5. Sub-Study Procedures:
N/A
6. Criteria for Inclusion of Subjects:
Diagnosis of diabetes mellitus
Men/women ≥21 years old
Post-operative
foot
or
ankle
wounds
sized > 5 cm
ABI≥0.5 or toe pressures >30 mmHg
7. Criteria for Exclusion of Subjects:
Active Charcot arthropathy
Unable to use NPWT at home
Untreated bone or soft tissue infection
Unable to keep research appointments
Active alcohol (> 14 drinks per week over the
last 3 months) or substance abuse (current
use of cocaine, heroine or
methamphetamine or if drug or alcohol use
will interfere with follow up visits in foot clinic
in the opinion of the investigator)

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8. Sources of Research Material:
The Researchers will collect demographics (age, gender, ethnic origin), medical history;
medications; results of laboratory testing including pregnancy testing, operative reports,
results of study tests and procedures, vital signs, height and weight, examinations and
images of the wound, off-loading, results of analysis of tissue samples, adverse events and
treatment and information about the costs of the subject’s healthcare.
9. Recruitment Methods and Consenting Process:
Subjects will be identified by the PI or Sub-I's from the investigators' patients scheduled for
surgery.
The PI, Sub-I, or study coordinator will carefully review this research study with the subject
and any family members or caregivers. Any questions will be answered, and it will be
emphasized that participation in the research is voluntary. When all questions are answered,
and the subject has agreed to participation in the research, the subject will sign the Consent
and HIPAA Authorization. The subject will receive copies of the signed documents.
Since this is a study that is initiated during an inpatient stay, the research study procedures
and activities will be reviewed with the patient and any friend or family member who may also
participate in the consent interview. Adequate time will be provided to read the consent, and
any questions will be answered. It will be emphasized that participation in the study is
voluntary, and that a decision not to participate will not affect the care that the subject will
receive.
10. Potential Risks:
Quantum™NPWT and Quantum™NPWTTherapy with Irrigation:
·
Skin and tissue reaction or allergic reaction
·
Mild pain or discomfort
·
Bleeding
·
Slowing of the heart beat (vagal response, bradycardia)
·
Lung compromise
·
Study solution accidentally entering a body cavity
·
Infection at the wound
·
Autonomic dysreflexia (in patients with spinal cord injuries)
·
Foam left in the wound
·
Difficulty moving around because of the weight and attachment to the therapy unit
·
Possible entanglement or tripping on tubing or electrical cords attached to the
therapy unit
·
Incorrect programming of therapy unit
·
Creating tunnels in the wound bed
·
Delayed healing of the wound
·
Worsening of the condition of the wound
·
Severe allergic reaction
·
Burn from therapy unit or electrical cord malfunction

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The FDA has issued a warning about bleeding and infection. In the past two years, FDA
received six death and 77 injury reports associated with NPWT devices. Most deaths
occurred at home or in a long-term care facility. Bleeding was the most serious complication,
with reports of bleeding associated with six deaths and 17 injuries. Patients with bleeding
required emergency room visits and/or hospitalization and were treated with surgery and
blood transfusions.
Of the 83 reports to FDA, 27 reports indicated worsening infection from original open infected
wounds or from pieces of dressing that remained in the wound, and 32 reports noted injury
from foam dressing pieces and foam sticking to tissues or clinging to the wound. Most of
these patients required surgery, additional hospitalization, and antibiotics.
These rare, but serious complications of NPWT will be monitored for while subjects are in
the hospital and at study visits to the clinic.
Prontosan® Wound Irrigation Solution:
·
Skin sensitivity or allergic reaction
·
Severe allergic reaction
Prontosan® is a wound cleansing solution. Polyhexamethylene biguanide (PHMB), a product
contained in Prontosan® is suspected to cause cancer in laboratory or animal studies, but
there is no definite data connection with humans. These findings are linked to the use of
PHMB in a higher concentration than the amount contained in Prontosan.
Additional potential risks include Loss of Confidentiality; Risks to Embryo, Fetus or Breast-fed
Infant and Other Risks which may be unknown at this time.
11. Subject Safety and Data Monitoring:
The principal investigator will monitor the experience of the subjects at least monthly and the
conduct of the protocol, including:
·
Study accrual rate
·
Experience of study participants
·
Study attrition including participant withdrawals/dropouts
·
Patterns of AEs and/or unanticipated events
·
Patterns of protocol deviations and/or violations
·
Changes in risk/benefit
We will also employ a study monitoring committee which will include Drs. La Fontaine and
Lavery, as well as our team statistician and study coordinator. We plan to meet once a month
to discuss the progress of the study. We will also install a data safety monitoring
board to review the data of the study on an annual basis. We will also use this
forum to discuss specific issues and decisions that may arise during the implementation of
the study.
12. . Procedures to Maintain Confidentiality:
All study visits and procedures will be conducted in the patient's room at Parkland Hospital or
in the private treatment rooms at the Parkland Foot Wound Clinic.

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Subjects will be assigned a unique Subject Number upon consent. All study documents and
specimens will contain this number and no unique identifying information. The subject
number will be used on all data and samples that leave campus. No personal identifying
information will be included.
Hard copy data (source files) will be kept separately in the locked coordinator's office. The
link between the subject's name and the subject number will be kept in a password-protected
computer file with access limited to members of the research team.
Electronic data will be password protected with access limited to members of the research
team in the departmental 'R' drive.
No identified data will leave the campus.
13. Potential Benefits:
There may or may not be direct benefits to the subject from participation in this research.
Quantum™NPWT or Quantum™NPWT with Irrigation may help to heal the wound, but this
cannot be guaranteed.
However, results of this research may contribute new information that will help and benefit
other people who have surgically debrided wounds in the future. Information gained from this
research could lead to better treatment.
14. Biostatistics:
Sample Size: In a preliminary study, the proportion of subjects with closed wound was 62%
using traditional NPWT and 94% using NPWT with irrigation (Preliminary Work: Study 3).
For the sample size, we used a more conservative estimate of wound closure and estimated
80% wound closure with NPWT with irrigation. Using a two-sided Chi-square with alpha of
1.5
and 80% power and a 20% drop out rate, a sample size of 70 subjects per group (total
of 151) is required with 62% healing in NPWT group and 80% in the NPWT with irrigation
treatment group.
Analysis Plan: We will examine the descriptive statistics, frequency distribution and graphic
plots of each variable to detect the data errors, outlying values, number and pattern of
missing data and normality of distributions. The natural log transformation will be applied to
variables which are highly skewed. Baseline characteristics of study population will be
presented as means (standard deviation) for continuous variables with normal distribution,
median (inter-quartile ranges) for continuous variables with high skewed distribution or
proportion for categorical variables according to the treatment groups. The difference in
means between treatment groups will be compared using the two-sample t-test. The
difference in distribution will be compared using Wilcoxon rank-sum test. The difference in
percentage treatment groups will be compared using the Chi-square test.
Study Population:
·
Intention-to-Treat (ITT) Population: The ITT population will include all randomized
subjects who at least received one treatment and had at least one post-baseline
efficacy assessment. The ITT population will be used for the primary efficacy
analysis.

Version 7.0 1.25.18
Page 16 of 20
·
Per Protocol Population (PP): The PP population will consist of subjects in the ITT
population who did not have major protocol violations. The review of protocol
violations will be performed and signed off prior to study database lock and
unblinding. The primary efficacy analysis and secondary analyses will be conducted
on the PP population as part of a sensitivity analysis.
·
Safety Population: The Safety population will include all subjects who received
treatment. The safety population will be used for the safety analysis.
Missing Data Imputation: For the primary outcomes with ITT analysis, we will use multiple
imputation procedure to impute the missing data. The sensitivity analysis will be performed to
evaluate the effect of assumption of imputation. For the secondary outcomes and safety
analysis, missing data will not be imputed.
Multiplicity: Stepwise Holm’s test will be used to adjust for the multiple comparisons.
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85.
Lavery, L.A., et al., Risk Factors for Foot Infections in Persons with Diabetes Mellitus.
Diabetes Care, 2006. 29: p. 1288-1293.
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Protocol Activity
Screening
Baseline
Day 0 –
Day of
Surgery
Week
1 Inpatient
(may
continue
into Week
2)**
Home
Health
Visits
Weeks 2-4
Week
s
2-15
ASC
End of
Study-
after
wound
closure or
Week 16
Informed Consent
X
Demographics and
Medical/Surgical History
X
Collected Sitting blood
pressure & pulse rate
X
X
Inclusion/Exclusion
Criteria
X
History of the wound
X
Collected Weight/Height
X
Blood testing -
Standard of care
X
X
Vascular/Neurological
Evaluation
X
Wound imaging (eKare
device) if the wound is
X
X
X
X
Hyperspectral imaging
(within 30 days of
screening)
X
Wound Assessment
X
X
X
X
X
X
Tissue and bone samples
for qPCR cultures &
bioburden analysis –
obtained during surgery
or routine debridement
X
X (in case of
additional
surgery)
NPWT/NWPT (i)
randomization and
therapy
placement/dressing
application/changes
X (initial
application
post-op per
Investigator/
WOCN)*
X
X
X
SF-36 Questionnaire &
other patient-reported
outcomesquestionnaires
X***
X
Offloading
X
X
X
X
Adverse Events
X
X
X
X
X
Current antibiotics
X
X
X
X
X
*
At bedside, NPWT or NPWT(i) for ≤4 weeks
** Week 1 inpatient includes procedures done at bedside and/or if the patient returns to the OR for additional surgery and
discharge from the hospital.
*** Obtained while subject is in patient