Clinical trial NCT03615807
Conditions: Diabetic Foot
Keywords: diabetic foot infections antibiotic reduction osteomyelitis soft tissue infections
Sponsor: University Hospital, Geneva
Start date: 2017-02-16; Completion date: 2020-03-31
Enrollment: 182 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, unblinded, single-centre study. After eventual surgical debridement (not amputation), patients will be randomized to receive 1 of 2 targeted antibiotic regimens, in the ratio 1:1.

For diabetic toe osteomyelitis, the patients will be randomized between a 3 and a 6 week's arm, for soft tissue infections between 10 and 20 days. The final assessments used in the primary efficacy analysis will be obtained at the test-of-cure (TOC) visit approximately 60 days after treatment is stopped.

Detailed description:
Diabetic foot infections (DFI) are frequent and are associated with a high burden of morbidity, costs, recurrence risk or new episodes of infections. About two-third of recurrent DFI may reveal other microorganisms than in the previous period, suggesting new episodes of infection due to the underlying problem, and/or selection by prior antimicrobial therapy. Osteomyelitis in the diabetic toe is almost always established by contiguous spread of infection from a chronic ulcer. It occurs in up to 15% of patients with a diabetic foot ulcer and about 20% of all DFI (and over half of severe infections) involve bone at presentation. The severity of a diabetic foot infection is based on the local and systemic signs and symptoms of infection and has been categorically defined in the Infectious Disease Society of America guidelines for the "Diagnosis and Treatment of Diabetic Foot Infections" (IDSA guidelines).

Knowing the potential for poor outcomes, many clinicians have tended to treat DFIs with a long duration of antibiotic therapy, with many side effects, development and spreading of antibiotic resistance, and associated costs. Data from recent comparative trials has shown that 1-2 weeks is sufficient for most soft tissue infections, and 4 to 6 weeks appears adequate in those with (unresected) infected bone. Retrospective reviews over the past two decades have demonstrated that about two-thirds of selected patients with diabetic foot osteomyelitis can achieve remission with antibiotic therapy alone (i.e., without bone resection). One recent randomized trial found that treatment with only antibiotic therapy (given for 90 days) gave similar clinical outcomes to treatment with conservative surgery (removal only of the infected bone) along with just a short course of antibiotic therapy. Another randomized trial compared a 6-week against 12-week course of antibiotic therapy, without concomitant surgery, for diabetic foot osteomyelitis and also found similar outcomes.

Likewise, the optimal antibiotic duration for any skin and soft tissue infection is unknown. According to some databases of University of Geneva Hospitals, among 378 skin and soft tissue infections in 346, overall cure was achieved in 330 episodes (87%) after a median antibiotic administration of 15 days. In multivariate Cox regression analysis, duration of antibiotic therapy (HR 1.0, 95%CI 0.96-1.02) did not influence treatment failure among patients with positive MRSA carriage.

Our study intends to optimize the duration of antibiotic therapy in DFI; for skin and soft tissue infections as well as for diabetic toe osteomyelitis that is not amputated.

Arms: arm 1: 10 days for soft tissue infections 3 weeks for osteomyelitis arm 2: 20 days for soft tissue infections 6 weeks for osteomyelitis
Interventions: intervention 1: Surgical debridement (if needed) intervention 2: Microbiological sampling intervention 3: Revascularisation (if needed). intervention 4: Off-loading intervention 5: Patient's education and instructions intervention 6: Wound debridement intervention 7: Antibiotic duration
Intervention descriptions: intervention 1: Surgical debridement intervention 2: Microbiological sampling intervention 3: Revascularisation (if needed). intervention 4: Off-loading by Special shoes intervention 5: Patient's education and instructions by specialized nurses intervention 6: Regular wound debridement by specialized nurses intervention 7: Systemic antibiotic duration according to the study arms

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
Randomized study comparing different durations of antibiotic 
treatment for diabetic foot infections 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol: 2 July 2016 
Classification of Study: Class A 
 
Investigateur principal (PI)   
 
 
 
PD Dr. med. Ilker Uçkay 
 
Geneva, 2 July 2016                                                                
 


 
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1. 
PROTOCOL SYNOPSIS 
OBJECTIVES 
Primary Objective 
• To determine the non-inferiority of 3 weeks of antibiotic treatment compared to 6 
weeks for diabetic foot toe osteomyelitis, and 10 days compared to 20 days for 
non-bacteraemic diabetic foot soft tissue infections (including erysipelas). 
DESIGN 
This is a randomized, unblinded, single-centre study. After eventual surgical 
debridement (not amputation), patients will be randomized to receive 1 of 2 targeted 
antibiotic regimens, in the ratio 1:1.  
For diabetic toe osteomyelitis, the patients will be randomized between a 3 and a 6 
week’s arm, for soft tissue infections between 10 and 20 days. The final assessments 
used in the primary efficacy analysis will be obtained at the test-of-cure (TOC) visit 
approximately 60 days after treatment is stopped.  
NUMBER 
PATIENTS 
Approximately 120 subjects will be enrolled (60 for osteomyelitis and 60 for soft 
tissue infections). 
STUDY SITE 
University of Geneva Hospitals. Others centers might participate. 
PATIENT 
POPULATION 
Inclusion criteria 
1. Is aged ≥ 18 
2. Has diabetes mellitus, according to the American Diabetes Association (ADA) 
criteria. 
3. Has at least one visible inflammation with the following clinical manifestations 
of a moderate or severe infection based on the Infectious Disease Society of 
America (IDSA) guidelines for the “Diagnosis and Treatment of Diabetic Foot 
Infections”. 
Local Infection is defined as having ≥ 2 manifestations of inflammation (local 
welling or induration, erythema, local tenderness or pain, local warmth, 
purulent discharge (thick, opaque to white or sanguineous secretion). 
Moderate infection is defined as: local infection (as described above) with 
erythema > 2cm, or involving structures deeper than skin and subcutaneous 
tissues and no systemic signs.  
4. Has received appropriate surgical intervention to remove all necrotic tissue or 
tenotomy. 
5. Osteomyelitis limited to bone contact, inflammation and cortical lesions in X-
ray.  
 
Exclusion criteria 
6. Has a diabetic foot infection with implanted device. 
7. Has received > 96 hours of potentially effective systemic antibiotic therapy and 
the wounds are clinically improving. If a patient is not improving or deep-tissue 
culture results indicate that the infecting pathogen is not susceptible to that 
antibiotic, the patient may be enrolled at any time. 
8. Patient wants or accepts proposed amputation of infection and/or ischemia. 


 
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9. Destructive osteomyelitis with fractures, sequestra, shattering upon bone contact, 
and radiological vanishing of bone beyond the cortical level. 
10. Concomitant infections requiring more than 14 days of other antibiotic therapy. 
TREATMENT 
GROUPS 
For diabetic toe osteomyelitis 
Treatment A: 3 weeks of targeted antibiotic therapy 
Treatment B: 6 weeks of targeted antibiotic therapy 
For diabetic foot soft tissue infection 
Treatment A: 10 days of antibiotic therapy 
Treatment B: 20 days of antibiotic therapy 
TEST ARTICLE 
No placebo. All antibiotic prescription will be according to international guidelines 
(IDSA guidelines) and recommendations and are freely available on the Swiss market. 
STUDY CONDUCT 
At enrollment (Day 1), the investigator will prescribe empiric antibiotic treatment 
based on instructions provided in the protocol and determine the most appropriate 
route of administration (oral or IV) according to the patient’s condition. Patients will 
be randomized to 1of the 2 study treatments in the ratio 1:1 with stratification between 
patient populations with osteomyelitis and soft tissue infections. 
Treatment Period and Visits 
Patients will be treated for approximately 10 to 42 days. If a patient achieves clinical 
cure (defined by Tx Visit 4), the investigator will stop study treatment at that visit. 
The treatment period includes the following study visits: 
Tx visit 1 – Enrollment (Day 1) 
Tx visit 2 – Day 8 (+/- 4 days) 
Tx visit 3 – Day 20 (+/- 4 days) 
Tx visit 4 – Day 40 (+/- 4 days) (only if still receiving study treatment after Tx visit 3) 
Follow-Up Visit 
Approximately 60 days after the EOT visit, patients will attend the primary Test-of-
Cure (TOC) visit.  
STUDY DURATION Patients’ participation in the study will include the treatment period of up to 28 days 
and the follow-up period of up to approximately 60 days after treatment has stopped. 
EFFICACY 
VARIABLES 
Efficacy Variables 
Primary 
• The primary efficacy variable is the percent of patients with a clinical outcome of 
“clinical cure” at the TOC visit 
• Adverse events of antibiotic therapy 


 
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1.       INTRODUCTION 
1.1 
Background and Rationale 
Diabetic foot infections (DFI) are frequent and are associated with a high burden of 
morbidity, costs, recurrence risk or new episodes of infections. About two-third of 
recurrent DFI may reveal other microorganisms than in the previous period, suggesting 
new episodes of infection due to the underlying problem, and/or selection by prior 
antimicrobial therapy. Osteomyelitis in the diabetic toe is almost always established by 
contiguous spread of infection from a chronic ulcer. It occurs in up to 15% of patients 
with a diabetic foot ulcer1 and about 20% of all DFI (and over half of severe infections) 
involve bone at presentation.2 The severity of a diabetic foot infection is based on the 
local and systemic signs and symptoms of infection and has been categorically defined in 
the Infectious Disease Society of America guidelines for the “Diagnosis and Treatment of 
Diabetic Foot Infections” (IDSA guidelines).3  
Knowing the potential for poor outcomes, many clinicians have tended to treat DFIs with 
a long duration of antibiotic therapy, with many side effects, development and spreading 
of antibiotic resistance, and associated costs.4,5 Data from recent comparative trials has 
shown that 1-2 weeks is sufficient for most soft tissue infections, and 4 to 6 weeks 
appears adequate in those with (unresected) infected bone.6 Retrospective reviews over 
the past two decades have demonstrated that about two-thirds of selected patients with 
diabetic foot osteomyelitis can achieve remission with antibiotic therapy alone (i.e., 
without bone resection). One recent randomized trial found that treatment with only 
antibiotic therapy (given for 90 days) gave similar clinical outcomes to treatment with 
conservative surgery (removal only of the infected bone) along with just a short course of 
antibiotic therapy.7 Another randomized trial compared a 6-week against 12-week course 
of antibiotic therapy, without concomitant surgery, for diabetic foot osteomyelitis8 and 
also found similar outcomes. 
Likewise, the optimal antibiotic duration for any skin and soft tissue infection is 
unknown. According to some databases of University of Geneva Hospitals, among 378 
skin and soft tissue infections in 346, overall cure was achieved in 330 episodes (87%) 
after a median antibiotic administration of 15 days. In multivariate Cox regression 
analysis, duration of antibiotic therapy (HR 1.0, 95%CI 0.96-1.02) did not influence 
treatment failure among patients with positive MRSA carriage.9 
Our study intends to optimize the duration of antibiotic therapy in DFI; for skin and soft 
tissue infections as well as for diabetic toe osteomyelitis that is not amputated. 
 
1.2    Summary of Potential Risks and Benefits 
A potential risk of participation in this study is experiencing a recurrence or a new 
episode of diabetic foot infection. 
The potential benefit of participation in this study is receiving effective short-term 
antibiotic therapy to promote or accelerate clinical cure of the infections, with less side 
effects. 


 
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2. 
ETHICS 
This study will be conducted in compliance with the Declaration of Helsinki and its 
amendments, the International Conference on Harmonisation (ICH) principles of Good 
Clinical Practice, and other Swiss regulations, as appropriate. It is the responsibility of 
the Investigator and collaborators to ensure that written informed consent is obtained 
from the patient before any activity or procedure is undertaken that is not part of routine 
care. 
3. 
OBJECTIVES 
To determine the efficacy of 3 weeks of targeted antibiotic therapy compared to 6 weeks 
for non amputated diabetic toe osteomyelitis; and 10 days compared to 20 days for 
diabetic foot soft tissue infections. 
4. 
STUDY DESIGN 
This is a randomized, unblinded, single-centre study conducted in 2 sustrata of patients 
with diabetic foot infections: Toe osteomyelitis and skin and soft tissue infections. 
Patients will be randomized to receive 1 of 2 systemic antibiotic durations; 3 versus 6 
weeks for osteomyelitis, and 10 versus 20 days for skin and soft tissue infections. Patients 
will be treated for approximately 10 to 242 days and, if treated as outpatients, will return 
to the clinic for safety and efficacy assessments. The final assessments used in the 
primary efficacy analysis will be obtained at the test-of-cure (TOC) visit approximately 
60 days after treatment is stopped.  
5. 
PATIENT POPULATION 
5.1 
Selection of Study Population 
120 subjects will be enrolled; 60 for osteomyelitis and 60 for soft tissue infections. 
5.1.1   Study Criteria 
 
Inclusion criteria 
• Is aged ≥ 18 years. 
• Has diabetes mellitus, according to the American Diabetes Association 
(ADA) criteria. 
• Has at least one visible inflammation with the following clinical 
manifestations of a moderate or severe infection based on the Infectious 
Disease Society of America (IDSA) guidelines for the “Diagnosis and 
Treatment of Diabetic Foot Infections”. 
• Local Infection is defined as having ≥ 2 manifestations of inflammation 
(local welling or induration, erythema, local tenderness or pain, local 
warmth, purulent discharge (thick, opaque to white or sanguineous 
secretion). 


 
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• Moderate infection is defined as: local infection (as described above) with 
erythema > 2cm, or involving structures deeper than skin and subcutaneous 
tissues and no systemic signs.  
• Has received appropriate surgical intervention to remove all necrotic tissue 
or tenotomy. 
• Osteomyelitis limited to bone contact, inflammation and cortical lesions in 
X-ray.  
 
Exclusion criteria 
• Has a diabetic foot infection with implanted device. 
• Has received > 96 hours of potentially effective systemic antibiotic therapy 
and the wounds are clinically improving. If a patient is not improving or 
deep-tissue culture results indicate that the infecting pathogen is not 
susceptible to that antibiotic, the patient may be enrolled at any time. 
• Patient wants or accepts proposed amputation of infection and/or ischemia. 
• Destructive osteomyelitis with fractures, sequestra, shattering upon bone 
contact, and radiological vanishing of bone beyond the cortical level. 
• Concomitant clinical infections requiring more than 14 days of (other) 
antibiotic therapy. 
5.1.2 
Removal of Patients from Therapy  
All patients are free to withdraw from participation in this study at any time, for any 
reason, and without prejudice. A patient who withdraws consent by refusing to continue 
with study procedures/observations will be terminated from the study. The reason for 
withdrawal of consent should be clearly documented wherever possible. 
The investigator should make every effort to address non-compliance issues and ensure 
that relevant study data are obtained from patients whenever possible.  
To enable collection of follow-up data, the investigator may stop study treatment at any 
time without withdrawing the patient from the study (e.g. the patient experiences 
intolerable or unacceptable AEs possibly related to study treatment and where such 
treatment cannot be modified within the confines of the protocol). 
On rare occasions, the investigator may terminate a patient from the study to protect the 
patient’s best interest. If a patient is withdrawn before completing the study, the reason 
for withdrawal will be entered in the case report form (CRF). Whenever possible and 
reasonable, the evaluations that are required at the next scheduled visit will be performed 
at early termination.  
6. 
TREATMENTS 
Antibiotic treatment starts after surgical debridement (if not amputated). For 
osteomyelitis cases, bone biopsy will be performed first. Re-vascularisation, off-loading, 
and local care are permitted and encouraged throughout the study and the follow-up 


 
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period. The antibiotic choice will be according to IDSA guidelines3 and the clinical 
pathway for diabetic foot infections of University of Geneva Hospitals; with agents freely 
available on the Swiss market and in our hospital. There is no protocol for the switch 
from intravenous to oral therapy, which is at the discretion of the treating physician. 
Equally, the choice of the molecule, among those recommended, is not standardized in 
the study protocol. 
6.1.1 Standard Diabetic Ulcer Care 
Standard diabetic ulcer care for all patients will include wound debridement (during 
hospitalization or at clinic visits and only if clinically indicated ), daily care with dressing 
changes to all ulcers (target and non-target), pressure off loading and diabetes control. 
6.2 
Prior and Concomitant Therapy 
Potentially effective successful antibiotic therapy beyond 48 hours prior to screening is 
not permitted. A 72 hour window is permitted, if the evolution is not successful. There is 
no time window if the patient requires a new antibiotic agent based on microbiological 
results, independently of the duration of prior antibiotic therapy with the ineffective 
antimicrobial agent. 
7. 
STUDY PROCEDURES 
7.1 
Treatment Period 
Patients will be treated for approximately 10-42 days. If a patient achieves clinical cure 
(defined in Section 7.1.2) by Treatment (Tx) visit 3 or 4, the investigator will stop study 
treatment at that visit. The treatment period includes the following study visits: 
Tx visit 1 – Enrollment (Day 1) 
Tx visit 2 – Day 8 (+/- 4 days) 
Tx visit 3 – Day 14 (+/- 4 days) 
Tx visit 4 – Day 40 (+/- 4 days) (only if still receiving study treatment after Tx visit 3) 
The End-of-treatment (EOT) visit is defined as the patient’s last visit (Tx visit 2, 3, 4, or 
Early-termination visit) at which study treatment is stopped for any reason.  
7.1.1 Treatment Visit 1 (Enrollment [Day 1]) 
Screening procedures will be performed at Tx visit 1. Patients will sign an Informed 
Consent Form (ICF) before any study-related procedures are performed. Patients will be 
assessed by an investigator and the diagnosis of infected foot ulcer will be confirmed in 
accordance with the appropriate inclusion criteria. 
Screening Procedures: 
1. Obtain written informed consent. 
2. Assign a screening number. 
3. Record medical history and demographics. 


 
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4. Measure and record height and weight. 
5. Perform physical examination [simple review of systems, weight, and vital signs 
{sitting systolic and diastolic blood pressure (BP), heart rate, respiratory rate and 
body temperature}]. 
6. Perform appropriate wound debridement (as clinically indicated) including 
appropriate bone biopsy (in patients with osteomyelitis; with the foot surgeon.)  
7. Obtain suitable tissue specimens for bacterial cultures (aerobic and anaerobic) from 
the base of the target infection using biopsy or tissue curettage. Wound aspiration 
may be used if deemed appropriate. Swabs are not suitable for diagnostic culture. 
8. Determine the total DFI wound score and its sub-totals (Appendix V, Section 10.2).  
9. Review inclusion/exclusion criteria. 
 
Study procedures can commence if the patient meets all study entry requirements 
(except those related to clinical laboratory testing which are normally reviewed at 
Treatment Visit 2). 
 
Study Procedures 
1. Collect samples of for routine clinical laboratory tests (hematology, serum chemistry 
and Hemoglobin A1c). 
2. Record the anatomical location of the target infection and determine infection 
severity (moderate or severe). 
3. Perform standard X-ray and clinical and angiologic assessment of the vascular status. 
4. Determine the most appropriate route of administration (oral or IV) and empoirical 
choice of the agent according to the severity of the infection and according to IDSA 
guidelines, local clinical, pathway recommendations, and the patient’s co-morbidities 
and (pseudo)allergies. 
5. Randomize the patient via an electronic database or sealed envelops. 
6. If the patient has any ulcer on the bottom of the foot, fit a removable cast walker 
(RCW) or similar device to provide off-loading. 
7. Remind patient that he or she should continue to receive diabetic clinical management 
according to the local clinical pathway and IDSA guidelines. 
7.1.2 Treatment Visit 2 
Outpatients will return to the clinic (assessments can be performed in the hospital for 
inpatients), where the following assessments will be performed: 
1. Record any concomitant medications as well as any additional interventions required 
(except wound or bone debridement performed as part of standard care). 


 
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2. Review clinical lab results from previous visit. If any results fall outside of the 
permitted inclusion criteria, the patient should be early terminated from the study and 
excluded from the mITT population. 
3. Adaptation of (empirical) antibiotic therapy, if not done before. 
4. Perform physical examination [simple review of systems, weight and vital signs 
(sitting BP, heart rate, respiratory rate and body temperature)].  
5. Assess adverse events of long-term antibiotic therapy. 
6. Administer appropriate ulcer debridement and cleansing. 
7. Only if clinically indicated (e.g. worsening infection), obtain tissue specimens for 
bacterial cultures (aerobic and anaerobic) from the base of the target infection using 
biopsy or curettage. Wound aspiration may be used if deemed appropriate. Swabs are 
not suitable for diagnostic culture. 
8. Assess the clinical status of the target infection and complete the DFI wound score. 
With reference to the general wound parameter components of the DFI wound score 
recorded at baseline and any additional signs and symptoms of infection, determine 
clinical outcome according to the following definitions: 
Clinical Cure: Resolution of all clinical signs and symptoms of infection. 
Clinical Improvement: Improvement of at least 1 AND no worsening of any 
clinical signs and symptoms of infection. 
No Improvement: No improvement and no worsening of any clinical signs and 
symptoms of infection. 
Worsening: Worsening of 1 or more clinical signs and symptoms of infection. 
9. Collect blood samples for routine clinical laboratory tests (hematology and serum 
chemistry). 
10. If the patient has any ulcer on the bottom of the foot, fit a RCW or similar device to 
provide off-loading. 
11. For inpatients, ensure that test article and sufficient ulcer care supplies are available 
in the hospital. Prescribe systemic antibiotic as appropriate. If an inpatient is 
discharged before the next scheduled visit, dispense appropriate test article and 
sufficient ulcer care supplies to last until the next scheduled visit. Prescribe systemic 
antibiotic(s) to last the remaining duration of the expected treatment period 
7.1.3 Treatment Visits 3 and End of Treatment 
Outpatients will return to the clinic (assessments can be performed in the hospital for 
inpatients), where the following assessments will be performed: 
1. Record any concomitant medications as well as any additional interventions (except 
wound or bone debridement performed as part of standard care). 
2. Review clinical lab results from previous visit. 


 
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3. Perform physical examination [simple review of systems, weight and vital signs 
(sitting BP, heart rate, respiratory rate and body temperature)]. 
4. Assess adverse events of long-term antibiotic therapy. 
5. Administer appropriate ulcer debridement and cleansing. 
6. Only if clinically indicated (eg, worsening infection), obtain tissue specimens for 
bacterial cultures (aerobic and anaerobic) from the base of the target ulcer using 
biopsy or curettage. Wound aspiration may be used if deemed appropriate. Swabs are 
not suitable for diagnostic culture. 
7. Assess the clinical status of the target infection and complete the DFI wound score. 
With reference to the general wound parameter components of the DFI wound score 
recorded at baseline and any additional signs and symptoms of infection, determine 
clinical outcome according to the following definitions: 
Clinical Cure: Resolution of all clinical signs and symptoms of infection. 
Clinical Improvement: Improvement of at least 1 AND no worsening of any 
clinical signs and symptoms of infection. 
No Improvement: No improvement and no worsening of any clinical signs and 
symptoms of infection. 
Worsening: Worsening of 1 or more clinical signs and symptoms of infection. 
8. 
Determine whether treatment will be stopped, continued or changed. If new culture 
results are available assess whether additional/alternative antibiotic coverage is 
needed according to the antibiotic decision tree. If treatment will not be continued, 
this is the EOT visit and appropriate assessments should be performed (ie, tissue 
samples as instructed per Tx visit 5), otherwise proceed as follows: 
9. Collect blood samples for routine clinical laboratory tests (hematology and serum 
chemistry).  
10. If the patient has any ulcer on the bottom of the foot, fit a RCW or similar device to 
provide off-loading. 
11. For inpatients, ensure that test article and sufficient ulcer care supplies are available 
in the hospital. Prescribe systemic antibiotic as appropriate. If an inpatient is 
discharged before the next scheduled visit, dispense appropriate test article and 
sufficient ulcer care supplies to last until the next scheduled visit. Prescribe systemic 
antibiotic(s) to last the remaining duration of the expected treatment period 
7.1.4 Test-of-Cure (TOC) Visit 
Every effort will be made to ensure that final efficacy assessments (ie, primary outcome 
data) are available for all subjects. Outpatients should return to the clinic (assessments 
can be performed in the hospital for inpatients), where the following assessments will be 
performed: 
1. Record any concomitant medications as well as any additional interventions required 
(except wound or bone debridement performed as part of standard care). 


 
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2. Review clinical lab results from the EOT visit. 
3. Record a digital photographic image of the target ulcer with a ruler in the field of 
view. 
4. Perform an X-ray control. 
5. Administer appropriate ulcer debridement (as clinically indicated) including 
appropriate bone debridement (in patients with osteomyelitis) and cleansing. 
6. Obtain tissue specimens (if suitable culture material is available) for bacterial cultures 
(aerobic and anaerobic) from the base of the target ulcer using biopsy or curettage. 
Wound aspiration may be used if deemed appropriate. Swabs are not suitable for 
diagnostic culture. 
7. Assess the clinical status of the target ulcer and complete the DFI wound score. With 
reference to the general wound parameter components of the DFI wound score 
recorded at baseline and any additional signs and symptoms of infection, determine 
clinical outcome according to the following definitions: 
Clinical Cure: Resolution of all clinical signs and symptoms of infection. 
Clinical Improvement: Improvement of at least 1 AND no worsening of any 
clinical signs and symptoms of infection. 
No Improvement: No improvement and no worsening of any clinical signs and 
symptoms of infection. 
Worsening: Worsening of 1 or more clinical signs and symptoms of infection. 
8. Determine and record the DFI wound score for any non-target ulcers (as assigned at 
baseline). 
7.1.5 Early Termination 
Patients who withdraw consent or who, in the opinion of the investigator, are no longer 
able or eligible to participate in the study (including patients who require antibiotic 
therapy beyond Tx visit 5) will be early terminated. Where possible, such patients will 
complete an Early-termination visit to undergo all assessments applicable to the 
corresponding (or next) scheduled study visit. 
7.2 
Assessments 
7.2.1 Clinical Assessments of Infection 
Patients will be assessed for clinical outcome by the investigator at each treatment visit 
(interim assessments) and at the TOC visit (final/primary assessment). The Investigator 
will assess clinical outcome by comparing the clinical condition of the target ulcer to that 
at baseline according to the following criteria:  
Clinical Outcome Definitions  
• Clinical Cure: Resolution of all clinical signs and symptoms of infection. 


 
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• Clinical Improvement: Improvement of at least 1 AND no worsening of any clinical 
signs and symptoms of infection. 
• No Improvement: No improvement and no worsening of any clinical signs and 
symptoms of infection. 
• Worsening: Worsening of 1 or more clinical signs and symptoms of infection. 
Every effort will be made to ensure that final efficacy assessments are available for all 
subjects in the mITT population. 
7.2.2 Microbiological Assessments 
Aerobic and anaerobic cultures of ulcers will be performed by a local lab at baseline, the 
EOT visit (and/or at early termination), and at the TOC visit. Cultures may also be 
obtained at other Tx visits if clinically indicated (e.g. worsening of infection). Suitable 
culture material must be obtained using biopsy or curettage at the base of the target ulcer, 
or by needle aspiration. Swab cultures of ulcer surfaces are not permitted. If suitable 
culture material is not available due to healing of the ulcer, this will be documented by 
the investigator. 
From the baseline culture results, the investigator will determine the baseline pathogen(s) 
(defined as any microorganism presumed responsible for, or contributing to, the 
infection) for each patient’s target infection. 
The eradication/persistence of each baseline pathogen will be determined on the basis of 
culture results reported by the local laboratory. If a patient’s culture result is missing for 
the EOT visit or the TOC visit, the baseline pathogen will be presumed eradicated if a) 
ulcer closure is achieved, b) as a result of ulcer healing there is a lack of suitable tissue 
sample/culturable material (as documented by the investigator), or c) the culture result is 
otherwise missing and pathogen eradication was achieved in the last available culture 
result. In all other circumstances, baseline pathogen persistence (ie, not eradication) will 
be presumed. 
According to the documented or presumed eradication of a patient’s baseline pathogen(s), 
the following definitions apply: 
• A patient with “baseline pathogen eradication” is defined as a patient with 
eradication of all baseline pathogens.  
• A patient with “baseline pathogen improvement” is defined as a patient with 
eradication of at least 1 but not all baseline pathogens. 
• A patient with “baseline pathogen response” is defined as a patient with “baseline 
pathogen eradication” or “baseline pathogen improvement”. 
According to the patient’s baseline pathogen eradication/response at the TOC visit and 
taking account of the patient’s final clinical outcome at the TOC visit, the patient’s 
microbiological outcome will be assigned according to the following definitions [Note: If 
there is no culture result at the TOC visit, no microbiological outcome will be assigned 
unless a) ulcer closure is achieved, or b) as a result of ulcer healing there is a lack of 


 
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suitable tissue sample/culturable material (as documented by the investigator), in which 
case a microbiological outcome of “microbiological success” will be presumed]:  
7.2.3 Wound Assessments 
At each study visit, the target infection will be assessed for ulcer closure and DFI wound 
score (total, general wound parameters sub-total, and wound measurement parameters 
sub-total). The DFI wound score is included as Appendix. 
7.2.3.1 Physical Examination 
A physical examination [simple review of systems, weight and vital signs (sitting systolic 
and diastolic BP, heart rate, respiratory rate and body temperature)] will be performed at 
all treatment visits.  
7.2.3.2 Vital Signs 
Vital signs, including sitting BP, pulse, respiratory rate and body temperature will be 
measured after the patient has been in a sitting position for 5 minutes. Vital signs will be 
measured at every visit during the treatment period and at the TOC visit. 
7.2.3.3 Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at every visit during the 
treatment period and at the TOC visit. 
Hematology (complete blood count [CBC]): 
Serum Chemistry: 
Hemoglobin 
White blood cell (WBC) count 
WBC differential with Neutrophils 
Creatinine 
Glucose 
C-reactive protein 
 
7.3 
Sample Size Determination 
It is difficult to predict failure rates. Assuming a failure rate of 35% in the 6 weeks’ arm 
and a non-inferiority margin of 10%, we estimate the necessity to enroll 120 patients (60 
for osteomyelitis and 60 for soft tissue infections). 
7.4 
Statistical Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided and a 
difference resulting in a P value of less than or equal to 0.05 will be considered 
statistically significant. 
7.4.1 Analysis Populations 
The intent-to-treat (ITT) population will consist of all randomized patients. Patients will 
be analyzed according to treatment group assignment regardless of whether the patient 
receives any study treatment or the wrong treatment. Patient disposition and baseline 
characteristics will be based on the ITT population. 
The per-protocol (PP) population will consist of all randomized patients who complete 


 
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the study (or who are otherwise defined as a treatment failure) and who have not deviated 
significantly from the protocol. All efficacy analyses will be repeated using the PP 
population. Any analysis involving microbiological assessments will exclude patients 
without an assigned baseline pathogen. 
7.4.2 Disposition 
The numbers of patients randomized and completing the study will be tabulated overall 
and by treatment group. For any patient that is early terminated, the reason(s) for early 
termination will be tabulated overall and by treatment group. The number of patients and 
percentages in each analysis population will be reported. 
7.4.3 Patient Characteristics 
Demographic and baseline characteristics such as age, gender, height, weight, BMI, 
baseline DFI wound score and severity (according to IDSA guidelines) for the target 
infection, diagnosis of osteomyelitis, and any other relevant baseline information (e.g. 
initial administration route of systemic antibiotic, anatomical location of target infection, 
number of infected ulcers at baseline, initial size and number of test articles assigned) 
will be summarized with appropriate descriptive statistics (sample size, missing, mean, 
standard deviation [SD], median and minimum and maximum for continuous variables; 
number and percentage for categorical variables) by treatment group and overall.  
7.4.4 Efficacy 
All efficacy analyses will be performed using the mITT population and repeated with the 
PP population. No imputations for missing data will be performed for any primary or 
secondary efficacy analysis (except for the following rules governing any microbiological 
presumptions). 
If a patient is early terminated before the TOC visit or if study treatment is otherwise 
stopped, no baseline pathogen eradication result will be presumed for the TOC visit. If 
there is no culture result at the TOC visit, no microbiological outcome will be assigned 
unless a) ulcer closure is achieved, or b) as a result of ulcer healing there is a lack of 
suitable tissue sample/culturable material (as documented by the investigator), in which 
case a microbiological outcome of “microbiological success” will be presumed. 
For the exploratory analyses of DFI wound score and its sub-totals, the last-observation-
carried-forward (LOCF) approach will be used to impute any missing data.  
7.4.4.1 Efficacy Definitions 
For the purpose of the efficacy variables, the following definitions apply: 
• “Clinical response” is defined as a clinical outcome of “clinical cure” or clinical 
improvement”. 
• “Treatment failure” is defined as either (i) a final/primary clinical outcome of “no 
improvement” or “worsening” at the TOC visit, or (ii) antibiotic therapy is 
prescribed beyond Tx visit 5. 
• Adverse events of antibiotic therapy. 


 
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7.4.4.2 Variables 
The primary efficacy variable is the percent of patients with a clinical outcome of 
“clinical cure” at the TOC visit. 
The exploratory efficacy variables are as follows: 
• Change in DFI wound score (total, general wound parameters sub-total, and 
wound measurement parameters sub-total) from baseline for the target infection at 
each study visit. 
7.4.4.3 Exploratory Analyses 
The change in DFI wound score (total, general wound parameters sub-total, and wound 
measurement parameters sub-total) will be summarized descriptively and compared 
across treatment groups at each study visit (including the EOT visit) using pairwise 
comparisons. 
Sub-group analyses of the percent of patients with a clinical outcome of “clinical cure” at 
the TOC visit according to baseline infection severity (moderate or severe) and according 
to route of administration of initial antibiotic therapy prescribed on Tx visit 1 (oral or IV) 
will be performed. Eradication of baseline pathogens by bacterial species will be 
performed. 
Other sub-group and exploratory analyses (as needed) may be performed using 
appropriate statistical methodology. 
7.4.5 Interim Analysis 
 
An interim analysis is planned after 6 months or the inclusion of the first 40 patients. 
8. 
QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include review of protocol procedures 
with the investigator and associated personnel prior to the study. 
8.1 
Source Documents  
All information recorded in the CRF will be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not 
limited to, hospital records, clinic and office charts, laboratory notes, and recorded data 
from automated instruments, memoranda, and pharmacy dispensing records. In some 
cases, the source documents may be electronic. 
8.2 
Database Lock 
The database will be locked in order to protect write access after the following 
preconditions are fulfilled: 
• All data are entered in the database 
• Decisions have been made and agreed to as to the identities of all protocol violators 


 
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9. 
BUDGET, STUDY NURSE AND TIMELINE 
   
  This study needs an experienced study nurse at 10% during 2 years.  
    
  
  Scheduled financial expenditures (in Swiss francs) are listed below.  
  Additional financing sources might be sought. 
 
Total 
1st year 
2nd year 
a. Technical support 
0 
0 
0 
b. Various (and reserve) 
1’000 
500 
500 
c. Consumable material  
500 
250 
250 
d. Ethical Comittee approval 
1’000 
1’000 
0 
e. Voyages 
0 
0 
0 
f. Salary at 10% (study nurse) 
21’627 
10’813 
10’813 
g. Social charges (for Geneva) 
5’070 
2’535 
2’535 
TOTAL Swiss francs 
29’196 
15’098 
14’098 
  
10. 
STUDY TERMINATION 
The end of this study is defined as the date of the last follow-up visit of the last patient.  
The study may be terminated prematurely for any reason and at any time in accordance 
with the requirements of the local Ethics Committee. 
10. 
FINAL CLINICAL STUDY REPORT 
The final clinical study report will be written within 1 year of completion of the clinical 
part of the study. This report will include a summary of the study results based on a 
statistical evaluation and clinical assessment. The results will be published and may be 
preliminarily used for various scientific congresses by any of the co-investigators. 


 
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12.      REFERENCES 
 
1. Ramsey SD, Newton K, Blough D, et al. Incidence, outcomes, and cost of foot ulcers in patients 
with diabetes. Diabetes Care 1999; 22:382-387. 
2. Uçkay I, Gariani K, Pataky Z, Lipsky BA. Diabetic foot infections: state-of-the-art. Diabetes Obes 
Metab 2014; 16:305-316. 
3. Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America (IDSA) 
clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis 
2012; 54:132-173. 
4. Schindler M, Bernard L, Belaieff W, et al. Epidemiology of adverse events and Clostridium 
difficile-associated diarrhea during long-term antibiotic therapy for osteoarticular infections. J Infect 
2013; 67:433-438. 
5. Agostinho A, Renzi G, Haustein T, et al. Epidemiology and acquisition of extended-spectrum beta-
lactamase-producing Enterobacteriaceae in a septic orthopedic ward. SpringerPlus 2013; 2:91. 
6. Uçkay I, Aragón-Sánchez J, Lew D, Lipsky BA. Diabetic foot infections: what have we learned in the 
last 30 years? Int J Infect Dis 2015; 40:81-91. 
7. Lázaro-Martínez JL, Aragón-Sánchez J, García-Morales E. Antibiotics versus conservative surgery for 
treating diabetic foot osteomyelitis: A randomized comparative trial. Diabetes Care 2014; 37:789-795. 
8. Tone A, Nguyen S, Devemy F, et al. Six-week versus twelve-week antibiotic therapy for nonsurgically 
treated diabetic foot osteomyelitis: a multicenter open-label controlled randomized study. Diabetes Care 
2015; 38:302-307. 
9. Reber A, Moldovan A, Dunkel N, et al. Should the methicillin-resistant Staphylococcus aureus carriage 
status be used as a guide to treatment for skin and soft tissue infections? J Infect 2012; 64:513-519. 


 
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APPENDICES  
 
 
Allowed Antibiotic Doses  
  
 
Antibiotic 
Allowed Dosing Regimens 
Allowed Total Daily Dose Range 
Levofloxacin PO 
750 mg q.24h or 500 mg q.12h 
750 to 1000 mg 
Levofloxacin IV 
750 mg q.24h or 500 mg q.12h 
750 to 1000 mg 
Amoxicillin/clavulanate PO 
500/125 mg q.12h. or q.8h 
1000/250 mg to 1500/375 mg  
Amoxicillin/clavulanate IV 
1000/200 mg q.12h or q.8h 
2000/400 mg to 3000/600 mg 
 
 
 
Clindamycin PO 
300 mg or 450 mg q.6h  
 1200 mg to 1800 mg 
Linezolid PO 
600 mg q.12h 
1200 mg 
Linezolid IV 
600 mg q.12h 
1200 mg 
Metronidazole PO 
400 mg or 500 mg q.8h or 500 
mg q.6h 
1200 mg to 2000 mg 
Metronidazole IV 
500 mg q.8h or q.6h 
1500 mg to 2000 mg 
Aztreonam IV 
1 g or 2 g q.12h or q.8h 
2 g to 6 g 
Piperacillin/tazobactam IV 
3000/375 mg q.6h or 4000/500 
mg q.8h 
12000/1500 mg (12 g/1.5 g)  
 


 
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10.1 
APPENDIX III Standard of Care 
Ulcer Standard of Care 
The following outlines the Ulcer Standard of Care, which will be standardized at all sites 
and for all treatment groups: 
1. Sharp surgical debridement 
Debridement will be defined as sharp surgical debridement, which includes removal 
of all necrotic tissue, chronic granulation tissue, bone sinus tracts, undermined 
borders and callus to produce a viable ulcer bed. Debridement should be carried out 
until healthy bleeding tissue is reached.  
If osteomyelitis has been diagnosed, surgical intervention to remove all necrotic and 
infected bone is required. 
All ulcers will be prepared in the following standard method:  
• All necrotic tissue should be excised until a brisk capillary bleeding from all ulcer 
surfaces is attained. 
• All culture specimens will be taken from deep tissue excised after the superficial 
tissue has been excised. The initial debridement will be performed prior to the test 
article application. The test article will not be applied to the ulcer bed until 
complete hemostasis has been attained. Further debridement will be performed as 
required throughout the treatment period, as determined by the investigator or 
designee. 
• Debridement may be performed by either the investigator or designee but should 
be performed by the same individual throughout the duration of the clinical study, 
whenever possible. If the individual who routinely performs the debridement is 
unavailable for any reason at any time during the study, the name of the 
replacement will be noted in the investigator files. 
2. Maintenance of a clean, moist ulcer environment: 
The ulcer and periulcer area will be cleansed to minimize bioburden and maceration. Two 
dressings will be applied to the target ulcer: a primary, nonadherent dressing and a 
secondary dressing.  
• Cleansing: The investigator or designee will irrigate the ulcer with sterile normal 
saline solution delivered from a 10-mL syringe attached to a 20-gauge flexible 
angiocatheter. Sterile gauze will be used to pat the ulcer dry. 
• Primary Dressing: The primary dressing will consist of the test article covered 
with a nonadherent, moisture permeable dressing. 
• Secondary Dressing: The secondary dressing will be a saline-moistened gauze. 
The saline-moistened gauze will cover the nonadherent dressing and the 
remaining area of the ulcer. 


 
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• Roll gauze will be wrapped circumferentially to keep the dressings in place. An 
adhesive covering of nonirritating tape will secure the dressings. 
• The dressing will be changed daily. Patients will be provided with the 
nonadherent dressings, commercially prepared moist saline dressings, roll gauze 
and nonirritating tape and will be instructed to change the dressing on the days 
they do not make study visits. If a primary or secondary dressing change occurs at 
the study site outside a protocol visit, this will be documented as an unplanned 
visit. 
3. Pressure relief 
If the ulcer is on the bottom of the foot, the patient will be fitted with an off-loading 
device or removable cast walker (RCW). Off-loading is defined as avoidance of all 
mechanical stress on the injured extremity and is essential for healing. Avoidance of 
weight bearing is essential. Trauma causes most plantar ulcers and ongoing trauma 
prevents healing. Because off-loading (not bearing ANY weight) is so critical to the 
healing process, patients will be instructed to wear the RCW at all times except when 
bathing and to use an RCW at all times when walking or standing is required. Strategies 
for off-loading will be standardized for all patients as follows: 
All patients with an ulcer on the bottom of the foot will be fitted with an RCW or other 
off-loading device during the Baseline/Randomization Visit, according to the following 
procedure:  
• The size of the walker will be determined based on the patient’s correct shoe size. 
• The appropriate size of the insole will be inserted into the RCW. 
• Once the target ulcer has been debrided, assessed, cleansed, dressed and secured, 
the RCW will be applied according to the manufacturer’s instructions for use. 
• The investigator or designee will ensure that the patient and family members are 
able to unfasten, remove and reapply the RCW properly according to the 
manufacturer’s instructions for use. 
 
Patients will be instructed to wear the RCW at all times except when bathing. When 
bathing, the patient will be instructed to wear a slipper with a plastic bag worn over the 
slipper and tied at the ankle or higher. 


 
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10.2 
APPENDIX Diabetic Foot Infection Wound Score 
 
 
General Wound Parameters 
0 
1 
2 
3 
Purulent Drainage 
Absent 
 
 
Present 
Non-purulent Drainage 
Absent 
Mild 
Moderate 
Severe 
Erythema 
Absent 
Mild 
Moderate 
Severe 
Induration 
Absent 
Mild 
Moderate 
Severe 
Tenderness (sign) 
Absent 
Mild 
Moderate 
Severe 
Pain (symptom) 
Absent 
Mild 
Moderate 
Severe 
Local Warmth Increase 
Absent 
Mild 
Moderate 
Severe 
General Wound Parameters Subtotal 
 
Wound Measurements 
Size (cm2) 
<1 
1-2 
>2-5 
>5-10 
>10-30 
> 30 
 
0 
1 
3 
6 
8 
10 
Depth (mm) 
<5 
5-9 
10-20 
>20 
 
0 
3 
7 
10 
Undermining (mm) 
<2 
2-5 
>5 
 
3 
5 
8 
General Wound Measurements Subtotal 
 
TOTAL WOUND SCORE (General Parameters Subtotal 
+ Wound Measurements Subtotal 
 
 
Purulent drainage: 
A viscous, yellowish-white or green fluid formed in infected 
tissue. 
Graded: 
Absent or Present 
 
Non-purulent drainage: 
A serous, sanguinous, or sero-sanguinous collection of 
fluid in the tissue surrounding the wound.  
Graded: 
Absent: 
No drainage 
Mild: 
Scant drainage noticed on dressing (≤0.5 cm diameter) but 
not requiring the additional use of dressings 
Moderate: 
Greater than scant but less than copious drainage noticed on 
the dressing (>0.5 to ≤2 cm diameter); possibly requiring 
additional dressings 
Severe: 
Copious drainage on dressing (>2 cm diameter) requiring 
additional dressing changes 
 


 
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Erythema: 
Congestion or exudative redness surrounding the wound caused by 
engorgement of the capillaries in the lower layers of the skin.  
Graded: 
 
Absent: 
Absent 
Mild: 
Pink, barely perceptible 
Moderate: 
Pale red, defined edges 
Severe/Extreme: Red to dark red 
 
Induration: Inflammatory hardening or thickening of tissues; may be referred to as 
limb brawny edema.  
Graded: 
 
Absent: 
Absent 
Mild: 
Localized at the site of infection 
Moderate: 
Appears in a limited area at the site of the infection 
Severe: 
Involvement extending from the site of infection and 
involving a significant portion of the affected lower 
extremity or the entire lower extremity. 
 
Tenderness (sign):  
Palpation at the site of infection elicits reports of tenderness by 
the patient as measured by a 0 to 10 scale, with 0 being no report 
of tenderness upon palpation and 10 being worst or significant 
tenderness on palpation.  
Graded: 
 
Absent: 
No tenderness on palpation 
Mild: 
Tenderness upon palpation reported as  5/10 
Moderate: 
Tenderness upon palpation reported as 6 to 8/10 
Severe: 
Tenderness upon palpation reported as 9 to 10/10 
 
Pain:  
Subjective and voluntary reporting of discomfort or the perception of pain that 
is experienced by the patient at the site of infection as measured by a 0 to 10 
scale, with 0 being no pain and 10 being the worst pain.  
Graded: 


 
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Absent: 
No complaints of pain 
Mild: 
Patient complains of pain  5/10 
Moderate: 
Patient complains of pain as 6 to 8/10 
Severe: 
Patient complains of pain as 9 to 10/10 
 
Local Warmth:  Increase relative to the uninfected contralateral foot.  
Graded: 
 
Absent 
 
Mild 
 
Moderate 
 
Severe 
 
Wound Measurements: 
 
Size (cm2):  
The ulcer contour traced with a fine-tipped pen on a sterile clear plastic 
film applied over the ulcer. For the purpose of the DFI Wound Score, the 
dimensions are measured and the total wound surface area estimated. 
 
Graded: <1 
1 to 2 
>2 to 5 
>5 to 10 
>10 to 30 
>30 cm2 
 
Depth (mm): Measure the wound at its deepest part at a 90 angle to the skin. Use a 
sterile swab as an aid. 
 
Graded: 
<5 
5 to 9 10 to 20 
> 20 mm 
 
Undermining (mm):  Measure the deepest part of any tunneling or shearing. Use a 
sterile swab as an aid. 
 
Graded: 
<2 
2 to 5 > 5 mm