Clinical trial NCT02673229
Conditions: Burn, Partial Thickness
Keywords: Santyl Burn Partial Thickness Burn Second Degree Burn Minor Burn Bacitracin Scar Appearance
Sponsor: University of Kansas Medical Center
Start date: 2013-09-30; Completion date: 2020-03-30
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
By doing this study, researchers hope to learn if applying Santyl to the burn during the healing process affects the appearance of the resulting scar.

Detailed description:
Subjects who have minor, second degree burns may be enrolled in this study. Subjects will receive either Santyl ointment or bacitracin ointment to apply to the burn until it heals. Bandages will be used to keep the burn covered while it heals. Second degree burns generally leave a scar. Once the burn heals, lotion and an appropriate bandage will be used to try to minimize the appearance of a scar.

The study hypothesis is that burns treated with Santyl will have a better scar appearance than burns treated with bacitracin.

Subjects enrolled in this study will make once a week visits to the University of Kansas Medical Center outpatient burn clinic until the burn heals. The burn will be assessed for healing at these visits. Once healed, visits to the clinic will be at 60 \& 180 days, up to 6 months. At these visits, the appearance of the scar will be evaluated.

This study was originally funded by Smith and Nephew, but Smith and Nephew is no longer providing support for the study.

Arms: arm 1: Applied topically (2 mm thickness once daily) arm 2: Applied topically (2 mm thickness) once daily
Interventions: intervention 1: Collagenase Santyl intervention 2: Bacitracin
Intervention descriptions: intervention 1: A sterile, enzymatic debriding agent which contains 250 collagenase units per gram of white petrolatum, United States Pharmacopeia (USP). intervention 2: One gram is equal to 500 bacitracin units; one unit of bacitracin is equivalent to 0.026 milligrams.

Protocol documents:
Prot_SAP_000.pdf: 
 
Page 1 of 31 
 
Comparison of Collagenase Santyl® Ointment with Antibiotic Ointment in the Outpatient Care of 
Minor Partial Thickness Burns  
Principle Investigator: Dhaval Bhavsar, MD 
Version 4: 7MAR2018 
NCT02673229 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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1.0 Synopsis 
 
 
 
 
 
 
 
 
 
Test Article(s) / Products: 
1) Collagenase Santyl Ointment 
2) Bacitracin Ointment  
Study Dosage / Usage: 
1) Daily application to the burn, approximately 2 mm thick 
2) Daily application to the burn, approximately 2 mm thick 
Active Ingredients: 
1) Collagenase enzymes derived from Clostridium 
histolyticum 
2) Bacitracin antimicrobial peptides 
Route of Administration: 
Topical 
 
 
 
 
 
 
 
 
Objective(s): 
The primary objectives are to compare the proportion of 
subjects healed at 3 weeks after initiation of Collagenase 
Santyl ointment to Bacitracin ointment, in addition to time to 
healing, and incidence of burn wound infection between 
treatment groups.   The secondary endpoint is to compare 
Collagenage Santyl ointment with Bacitracin ointment based 
on the scar assessment scores at 90 days after the initiation of 
treatment. and at 180 days after the initiation of treatment. 
Exploratory endpoints are number of burn wounds open 
compared to number of burn wounds closed and cutometer 
values at each scar assessment visit. 
Study Population: 
Children and adults 2 – 75 years of age, presenting with a 
minor burn defined as a partial thickness burn involving 
< 10% of the total body surface area (TBSA) that does not 
require hospitalization or a skin graft. 
 
 
 
 
 
 
 
 
Structure: 
X Parallel Group 
Duration of Treatment: 
1- 6 weeks 
 
 
 
Duration of Assessment: 
26 weeks 
 
 
Crossover 
N/A 
 
 
 
 
 
 
 
 
Other 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Blinding: 
X None 
 
 
 
Observer-Blind 
 
 
 
Subject-Blind 
 
 
 
Double-Blind 
 
 
 
 
 
 
 
 
 
Randomization: 
X Yes 
Group Assignment Ratio: 1:1 
 
 
No 
 
 
 
 
 
 
 
 
 
Concurrent  
 
No Treatment 
 
Control: 
X Standard Care 
bacitracin ointment 
 
 
Placebo 
N/A 
 
 
Active 
 N/A 
 
 
Other 
 N/A 
 
 
 
 
 
 
 
 
Estimated Total Sample Size: 
A total of 80 subjects will be enrolled with an expectation to 
complete 80 subjects at 90 days after the initiation of treatment. 
Statistical Rationale Provided: 
X 
Yes 
Refer to Section 11 for Sample Size 
Justification. 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
Variable(s): 
PRIMARY: 
Proportion healed at 21 days after initiation of treatment, 
time to healing, and incidence of burn wound infection,).  
 
 
 
 
SECONDARY: 
 Scar appearance (Vancouver Scar Scale) at 90 days and 180 
days after initiation of treatment 
 
 
 
 
EXPLORATORY: 
Burn wound status (open or closed),  
 
 
 
 
SAFETY: 
Local reactions, adverse events 
 
 
 
 
PK: 
N/A 
 
 
Refer to Section 7 for Statistical Design. 
 
 
 
 
 
 


 
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1.1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADR 
Adverse Drug Reaction(s) 
AE 
Adverse Event(s) 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST/SGOT 
Aspartate Transaminase 
CIB 
Clinical Investigator’s Brochure 
cm2 
Centimeters squared or square centimeters (area) 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
g 
Microgram 
m2 
Meters squared or square meters (area) 
N 
Sample Size 
N/A 
Not Applicable 
NDA 
New Drug Application 
QD 
Once Daily 
SAE 
Serious Adverse Event(s) 
SAS 
Statistical Analysis Software, SAS® Institute, Cary, NC 
TBSA 
Total Body Surface Area 
TM 
Trademark 
UPT 
Urine Pregnancy Test 


 
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2. INTRODUCTION 
2.1 
BACKGROUND  
Burns are injuries caused by heat, electricity, chemicals, radiation, or light (1). In the US about 450,000 
people per year receive medical burn care through hospital emergency departments, hospital outpatient 
clinics, free-standing urgent care centers and private physician offices (2). Most burns only affect the 
epidermal and dermal tissues, but more severe burns can also involve muscle, bone, tendons and blood 
vessels. Burns are generally classified in terms of depth and severity. First degree burns are superficial, 
involve the epidermis only, and will heal spontaneously within a week or less. Second degree (partial 
thickness) burns extend into the dermis, are characterized by blisters, and may take up to several weeks 
to heal. Second degree burns can also become infected, and result in scarring and/or contractures which 
may require excision and skin grafting. Burns that extend through the entire dermal layer are classified 
as third degree burns. These burns require excision and in addition to scarring and contractures, may 
result in amputations. 
The American Burn association has further classified burns as minor, moderate, or major depending on 
several factors including total body surface area (TBSA) burned, involvement of specific anatomical 
zones, the age of the person, and associated injuries (3). Briefly, moderate and major burns generally 
require hospitalization, while minor burns do not. A minor burn is one that is partial thickness involving 
< 15% TBSA for persons 10 to 50 years of age, or is a partial thickness burn involving < 10% TBSA for 
individuals younger than 10 or older than 50 years of age. 
Collagenase Santyl® Ointment was approved by the FDA in 1965 and is currently distributed by  Smith 
and Nephew as an enzymatic debriding agent indicated for use on chronic dermal ulcers and severely 
burned tissue (4,5). Santyl is a sterile and anhydrous product formulated in a white petrolatum base. The 
product contains a mixture of enzymes, most prominently collagenases that effectively attack human 
fibrillar collagen both from the end and the middle of the triple-helix molecule. 
Collagenase enzymes are uniquely able to cleave intact collagen, thereby freeing devitalized tissue on 
the wound surface from its granulation base. Although collagenase is understood to act by cleaving 
native collagen, it has been observed that Santyl does not impede wound healing or otherwise damage 
healthy granulation tissue. The explanation for this is unknown. Candidate hypotheses include actions 
by tissue inhibitors occurring only in healthy granulation tissue, or a strictly kinetic mismatch between 
rates of tissue collagen production and rates of proteolysis by topical collagenases. 


 
Page 6 of 31 
 
In addition to its safety and effectiveness in debriding the wound surface, Santyl has been reported to 
promote wound healing. The mechanism by which this might occur is likely to be complex, with various 
lines of evidence suggesting that additional mechanisms are at work beyond debridement. Observations 
of improved healing in patients treated with Santyl correlated with improved healing in animal burn 
models according to work by Zimmerman in the 1970s (6). By contrast, pancreatic enzyme preparations 
(Tripure Novo, Pancrazym-N) and another bacterial enzyme preparation (Fibrolan, Pfizer, Inc.) showed 
debridement without healing. Later studies comparing Santyl to Silvadene® Ointment in burn victims 
suggested both a faster rate of healing with the collagenase preparation (7,8) and a decrease in the 
incidence of hypertrophic scarring (9). 
In the early 1990’s, Saarialho-Kere and colleagues recognized that basal keratinocytes at the edge of a 
cutaneous wound express matrix metalloproteinase-1 (MMP-1), also known as interstitial collagenase 
(10). Their findings were confirmed by others (11), and more recently it has been found that non-healing 
wounds are marked by a lack of MMP-1 expression by leading edge keratinocytes (12). As reported by 
Riley (13), keratinocytes plated on biosynthesized matrices showed a 2-fold increase in proliferation and 
post-injury migration in the presence of clostridial collagenase. When this collagenase was added to the 
growth media, there was an additional doubling of growth and migration, yielding approximately 5-fold 
enhancement of keratinocyte proliferation and migration overall. In the same report, Riley noted that a  
double-blind study of full-thickness wounds on the backs of Yucatan micro pigs showed that purified 
clostridial collagenase improved wound healing by all parameters measured, including granulation tissue 
formation, inflammation, re-epithelialization, and time to wound closure. Thus clostridial collagenase 
has been found to affect the interaction between keratinocytes and matrix both in vitro and in vivo. 
Another intriguing potential mechanism in vivo may be the attraction of M2-type macrophages by 
collagen type-1 fragments (14). 
The use of Collagenase Santyl Ointment for treatment of burn injuries was well described in 1972 by 
Zimmerman, who noted that good results were obtained in terms of both healing and reduced scarring 
(6). More than 30 years later, the observation of decreased incidence of hypertrophic scars following use 
of Collagenase Santyl Ointment on burn wounds has again been published (9). Santyl has been used in 
combination with antibiotics for burn wounds with good results (7), and animal studies indicate that it 
may be used safely without antibiotics in experimental wounds contaminated with E. coli (15). Given 
the continuing, if not growing desirability of a pharmacologic agent which reduces scar formation or 


 
Page 7 of 31 
 
improves the appearance of scars (16), this clinical study has been designed to prospectively evaluate 
potential benefits of Santyl in partial thickness burn wounds compared to antibiotic only treatment. 
A summary of known and potential risks and benefits to humans of the test articles can be found in the 
Package Inserts for Collagenase Santyl Ointment and bacitracin ointment. 
2.2 
RATIONALE  
Outpatient management of partial thickness burns normally involves the application of an ointment, 
which may contain an antibiotic. Concerns about the promotion of antibiotic resistant staphylococci, 
combined with known risks of allergic hypersensitivity reactions to certain topical antibiotics, support 
the exploration of alternative treatments. Bacitracin ointment has been compared against white 
petrolatum in the management of post-procedural wounds among 922 patients with 1249 wounds (17). 
No significant difference was observed in infection rates (2% in the petrolatum group vs. 0.9% in the 
bacitracin group) or healing rates. No patients in the white petrolatum group developed allergic contact 
dermatitis compared with 4 patients (0.9%) in the bacitracin group. In a separate study of 142 patients, 
147 Mohs micrographic surgery wounds on the ear were postoperatively treated with either gentamicin 
ointment or petrolatum. No significant differences were seen between treatments in the incidence of 
suppurative chondritis infections (4.76% in the gentamicin group; 6.67% in the petrolatum group), 
whereas there was a higher incidence of inflammatory chondritis in the gentamicin group (11.90% vs. 
3.33% for petrolatum) (18). In the 1990s, the North American Contact Dermatitis Group (NACDG) 
listed bacitracin among the top 10 allergens, based on skin testing. Approximately 9% of bacitracin tests 
were positive.  
. Bacitracin ointment is selected for this study because it is a standard treatment used by the 
Investigators, and is widely used in burn care. A significant cost difference exists between bacitracin and 
other ointments, such as Collagenase Santyl.  The therapeutic intent for this study is to see if there is a 
cost reduction  benefit as well as reduction in healing time for two standard of care treatment options for 
partial thickness burn wounds.  
This trial does not include a rigorous evaluation of local infection, as quantitative bacteriology from 
biopsied tissue would be required, nor does it include a rigorous evaluation of hypersensitivity reactions, 
as de-challenge / re-challenge or measurement of specific humoral and cellular immune responses would 
be required. Instead, the appearance of the wound bed and periwound tissue will be evaluated, with 


 
Page 8 of 31 
 
particular attention to the description of any rashes. Clinically diagnosed infections may be treated, but 
use of topical treatment will require that the subject exit the trial. 
3. OBJECTIVE 
The primary objectives are to compare Collagenase Santyl ointment with Bacitracin ointment in the 
proportion healed at 3 weeks after initiation of treatment, time to healing (in weeks), and incidence of 
burn wound infection.  The secondary endpoint is scar assessment scores at 90 and 180 days after the 
initiation of treatment. 
Exploratory endpoints are number of burn wounds open compared to number of burn wounds closed and 
cutometer values at each scar assessment visit. 
4. TEST ARTICLES 
4.1 
IDENTIFICATION 
Test Articles:  
1) Collagenase Santyl Ointment 
A sterile, enzymatic debriding agent which contains 250 collagenase units per 
gram of white petrolatum, USP. 
 
2) Bacitracin Zinc Ointment 
One gram is equal to 500 bacitracin units; one unit of bacitracin is equivalent 
to 0.026 milligrams. 
4.2 
USAGE 
Santyl and bacitracin will be applied daily to the thickness of a nickel (2 mm) on the burn until the 
wound heals, with a maximum application period of six weeks.  
5. SUBJECTS 
5.1 
SUBJECT POPULATION 
Up to 80 study subjects, aged 2 – 75 years who meet all study inclusion and exclusion criteria, will be 
enrolled. 
5.2 
INCLUSION CRITERIA 
Subjects will be considered qualified for enrollment if they meet the following criteria: 


 
Page 9 of 31 
 
1. Provide written informed consent, which will consist of reading, signing, and dating 
the informed consent document after the Investigator, sub-Investigator or other 
designated study staff member has explained the study procedures, risks, and contact 
information. For subjects not able to provide informed consent (e.g., minors), a parent 
or legally authorized representative must provide consent. Assent must be provided as 
required by the IRB.  
2. Age 2 – 75 yrs, either sex, any race. 
3. Have one or more acute burns which: 
• 
are thermal, chemical or electrical in etiology 
• 
in aggregate cover <10% TBSA 
• 
are each  72 hrs old 
• 
are each no more than deep partial thickness (2nd degree) 
• 
are not visibly infected 
4. Able to take in oral fluids. 
5. Able to comply with the requirement for daily dressing changes, or have a caretaker 
who is able to comply. 
6. Willing to make all required study visits. 
5.3 
EXCLUSION CRITERIA 
Any one (1) of the following criteria will disqualify a potential Subject from participation in the study: 
1. Contraindications or hypersensitivity to the use of the test article or their components 
(e.g., known hypersensitivity to bacitracin). 
2. Embedded foreign bodies in the burn wound which cannot be immediately removed. 
3. The burned tissue includes or is within 1 cm of the eye or genitalia. 
4. Severe perioral burns. 
5. Airway involvement or aspiration of hot liquids. 


 
Page 10 of 31 
 
6. Suspicion of physical abuse. 
7. Burn wound requires a skin graft. 
8. Outpatient management of the burn wound is not appropriate.  
9. Participation in another investigational clinical study within thirty (30) days of the 
Screening Visit. 
10. The Investigator may declare any subject ineligible for a valid medical reason. 
. Current or recent (< 6 months) history of severe, unstable, or uncontrolled 
neurological, cardiovascular, gastrointestinal, hematological, hepatic, and/or renal 
disease or evidence of other diseases based upon a review of medical history that, in 
the opinion of the Investigator, would preclude safe subject participation in the study. 
11. Test articles are cost-prohibitive for subjects 
6. STUDY DESIGN 
6.1 
STUDY DESIGN 
This is an active comparator, parallel group study in which subjects with burns meeting the study criteria 
will be randomly assigned to outpatient treatment with Santyl or bacitracin in a 1:1 ratio. Subjects who 
appear eligible will be presented with the study, and consent / assent will be obtained prior to any study 
procedures being conducted. The safety variables include adverse events and, specifically, burn wound 
infection or allergic contact dermatitis during treatment. Efficacy variables include time to complete 
healing and scar appearance. Both the Investigators and the subjects will contribute to these evaluations. 
Enrolled, randomized subjects will be prescribed with test article (Santyl or bacitracin) and burn wound 
dressing supplies sufficient to last until burn wound has healed. Scar assessments will occur at 3 months 
and 6 months post burn healing.  
Recruitment bias will exist, as any subject with a known contact dermatitis to bacitracin will be 
excluded. This will artificially reduce the number of allergic contact rashes in the bacitracin group, but 
the effect on the primary endpoint is unlikely to be significant. Study Procedure 
For a summary of the required procedures by visit, refer to Table 12: Study Plan. 


 
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6.2 
VISITS AND EXAMINATIONS 
6.2.1 Visit 1 – Presentation for Evaluation and Treatment 
1. Explain the purpose and nature of the study, and have the subject or the subject’s legally 
authorized representative read, sign, and date the IRB-approved informed consent 
document. In addition, the informed consent document must be signed and dated by the 
individual who consents the subject. Provide a photocopy of the signed informed consent 
document to the subject or subject representative, and place the original signed document 
in the subject’s medical record. If the subject is unable to read or sign the informed 
consent, unable to comprehend the information provided in the consent process, or is 
younger than the legal age of consent, the parents, legal guardian, decision making proxy 
or next of kin must provide written consent, and the subject must provide assent as 
required by the IRB. 
2. Determine the etiology, extent (TBSA), age (date of burn and number of hours since 
burn), burn depth, burn wound perfusion measurement with laser Doppler, and location 
of the burn. Use the provided figure for estimation of TBSA (Appendix 13). 
If there are multiple burn wounds on a subject, the TBSA for all burn wounds combined 
must be <10%. Each burn wound must meet study criteria, only the data from the largest 
burn wound (“target wound”) will be recorded in the case report forms and utilized for 
data analysis. If two or more burn wounds are within 1 cm of each other, the burn 
wounds can be evaluated as if they were a single burn wound. 
3. Photograph the burn per standard of care.  
4.  Determine the Fitzpatrick skin type (refer to Section 13). 
5. Obtain demographic information and medical history, including information on all 
concomitant medications. 
6. Perform any required procedures for standard burn care (e.g., debridement, pain relief, 
tetanus vaccination).  


 
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7. Obtain baseline measures of the burn wound bed, including the area (in cm2) of the target 
wound. These measures include exudate type and amount, odor, presence of eschar, 
presence of epithelial islands, epithelialization of the burn, peri-burn skin characteristics, 
pain, itching, and state of the burn wound (must be “open”). Refer to Section 13 for 
details. 
8. If the subject meets all of the inclusion criteria, the subject should be randomized. 
If the subject does not meet all of the inclusion, the subject will be considered a screen 
failure. 
9. Ensure that the subject has enough test article and dressings to last the subject for 
10 days. Dispensed supplies may include  sterile tongue depressors (for test article 
application), Xeroform gauze, gauze, paper tape (as needed), and compression 
bandage/garment. 
10. A staff member should apply the test article and the dressings to the burn wound while 
demonstrating to the subject (or caregiver) the proper application of ointment and 
dressing(s). 
Instruct the subject (or caregiver) that: 
a. Only the ointment and dressings prescribed should be applied to the burn wound 
during the study. 
b. Application of the study ointment and changing the dressings must occur each 
day. 
c. Test articles are not to be used on any other person or to treat any other wound. 
11. Instruct subject (or caregiver) to refrain from using excluded medications, to treat as 
instructed, and to return to the outpatient burn center for Visit 2 in 7 (± 2) days. Make 
any necessary arrangements for that visit. Remind subject (or caregiver) to bring all 
study supplies with them to Visit 2. 


 
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6.2.2 Visits 2 to 6 [weekly (±2 days) visits after 1st visit] 
1. Query subject (or caregiver) regarding any changes in general health and the use of 
concomitant medications. 
2. If any adverse events are observed or reported, they must be recorded as instructed in 
Section 9, Adverse Events. 
3. Assess the burn wound. The assessments include exudate type and amount, odor, presence 
of eschar, presence of epithelial islands, peri-burn skin characteristics & rash, pain, and 
itching (refer to Section 13). 
If it is decided that topical antibiotics will be initiated to treat a burn wound infection, the 
subject must be discontinued from the study. The use of systemic antibiotics does not 
require subject discontinuation. 
4. Evaluate re-epithelialization of the burn wound. Complete the visit based on the status of 
the burn wound as outlined below. 
If the burn wound is not completely re-epithelialized (“open”), complete the following 
steps: 
1. A staff member should apply the test article and the dressings to the burn wound 
while demonstrating to the subject (or caregiver) the proper application of 
ointment and dressing(s).  
Instruct the subject (or caregiver) that: 
a. Only the ointment and dressings prescribed should be applied to the burn 
wound during the study. 
b. Application of the study ointment and changing the dressings must occur each 
day. 
c. Test articles are not to be used on any other person or to treat any other burn 
wound.  
2. Instruct subject (or caregiver) to refrain from using excluded medications, to treat 
the burn wound as instructed, and to return to the office for the next sequential 
visit. 


 
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If the burn wound is completely re-epithelialized (“closed”), complete the following 
steps:  
1. Photograph the burn wound per standard of care. 
2. Only moisturizer (Aveeno with Oatmeal) and compression dressing may be used 
on the scar until the next scheduled study visit. Moisturizer should be used two 
times per day and as needed. Compression should be used at all times 
(approximately 23 hours per day).  
3. Instruct the subject (or caregiver) to continue avoiding any prohibited concomitant 
medications and to return for the next evaluation at day 90 (±2 weeks). Any 
scheduled study visits between the current visit and first scar assessment visit not 
be completed. 
4. Instruct subject to return to clinic for follow up scar assessment visits 7-8. 
 
 
 
6.2.3 Scar Assessment visits  7 to 8 [ 90 (± 2 weeks), and 180 (±2 weeks),  Days After Visit 1]  
1. Query subject (or caregiver) regarding any changes in general health and the use of 
concomitant medications. 
2. If any adverse events are observed or reported, they must be recorded as instructed in 
Section 9, Adverse Events. 
3. Per SOC photograph the scar at all visits or at any other visit if the subject is 
discontinuing. 
4. Provide subject (or caregiver) with the Subject Scar Assessment Scale and ask them to 
complete an assessment without input from study personnel beyond simple instructions 
and explanations of terms (refer to Section 13). 
5.  Ask the subject to rate the pain and itch of the scar (refer to Section 13). 
6. The Investigator or sub-investigator completes the Vancouver Scar Scale (refer to Section 
13). 
  


 
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7. Once wound healing is confirmed, the subject (or caregiver) will  use compression and 
moisturizer daily 4 weeks post wound healing. Moisturizer should be used two times per 
day and as needed. Compression should be at all times (approximately 23 hours per day). 
 The subject (or caregiver) will use compression and moisturizer for 6 months after wound 
healing is confirmed only if instructed by the investigator. 
8. At all visits, remind the subject (or caregiver) to avoid any prohibited concomitant 
medications and to return for the next evaluation per the protocol visit schedule. 
6.2.4 Unscheduled Visits 
Unscheduled exams may be conducted at the discretion of the Investigator with all obtained information 
recorded in the source documents and on the Unscheduled/Interim Visit pages within the CRF. 
6.2.5 Concomitant Medications 
A concomitant medication is any drug or substance administered from Day 1 of the study through the 
last study visit. Any product applied topically to the burn wound (except as specified by the protocol) 
and/or any product intended or claiming to alter the formation or appearance of a scar (e.g., silicone, 
steroids, Vitamin E, etc) may not be used during the study. The use of concomitant medication must be 
recorded on the subject's CRF. Adverse events related to administration of these medications must be 
documented on the appropriate CRF. 
6.2.6 Concomitant Therapy 
A concomitant therapy is any therapy administered from Day 1 of the study through the last study visit. 
Any therapy intended or claiming to alter the formation or appearance of a scar (e.g., use of lasers, 
cryotherapy, radiation, surgical intervention, etc) may not be used during the study. 
The use of concomitant therapies must be recorded on the subject's CRF. Adverse events related to 
administration of these therapies must be documented on the appropriate CRF. 


 
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6.3 
DISCONTINUED SUBJECTS 
6.3.1 Definition and Procedures 
Discontinued subjects are those who voluntarily discontinue participation, who are withdrawn for safety 
reasons, or who have missed 2 or more consecutive study visits or 3 or more consecutive test article 
doses so as to be ineligible for continued study participation. Subjects who discontinue the study prior to 
completing all of the regularly scheduled visits should complete the visit procedures for the visit at 
which the subject is being discontinued. If appropriate, the Investigator should also advise the subject of 
subsequent therapy and/or procedures necessary for their medical condition. 
6.3.2  Delinquent Subjects 
In the case of subjects who persistently fail to return for scheduled visits, three attempts must be made to 
contact the subject (or caregiver) for the purpose of scheduling an Exit Visit. The third attempt should be 
via registered mail, return receipt requested. If a subject is unable to return to clinic for the 90 or 180 day 
assessments the Subject Scar Assessment may be collected over the phone. 
6.4 
SUBJECT PREGNANCY 
Women of child-bearing potential are not excluded from the study, nor is birth control required. Both 
Santyl and bacitracin are FDA approved products and will be used per their respective package inserts; 
neither product has any pregnancy precautions. If a woman becomes pregnant during the study, she is 
not automatically discontinued from study participation. She and the investigator will determine if the 
potential benefits outweigh the potential risks of continued study participation.  
6.5 
STUDY METHODS AND MEASUREMENTS 
Redcap will be used for data collection. The data to be collected, and the methods of collection, are 
described below. The exact variables to be measured are detailed in the Appendix section.  
6.5.1 Burn Wound Bed Appearance and Rash Evaluation  
At each weekly visit, the Investigator will note the appearance of the burn wound bed and surrounding 
tissue. The variables are exudate, odor, presence of eschar, presence of epithelial islands, and peri-burn 
skin characteristics. If a rash is observed, the rash will be evaluated separately. 


 
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6.5.2 Pain and Itching 
Pain and itching will each be measured on a scale of 0-10. The subject will be asked to rate pain and 
itching as a whole number. The anchor points for pain are 0=no pain and 10=worst pain imaginable. The 
anchor points for itch are 0= no itch and 10= worst itch imaginable. 
NOTE: Data from the pain and itch scales will be recorded in the case report forms for subjects who are 
age 12 and older.  
6.5.3 Burn Wound Closure 
At each weekly visit, the Investigator will assess epithelialization (as a percentage of the burn wound). 
When the burn wound is fully re-epithelialized (i.e., 100%), without drainage and without need of a 
dressing, the burn wound will be considered “closed”. 
6.5.4 Laser Doppler 
A commercially available instrument (PeriScan, Perimed AB) will be used to measure the perfusion of 
the burn wound. The data will be obtained per the manufacturer’s instructions. 
6.5.5 Vancouver Scar Scale  
Beginning when the burn wound has fully re-epithelialized, the Investigator or sub-Investigator will 
assess the appearance of the scar using the Vancouver Scar Scale. The scale and descriptions are found 
in Section 13.  
6.5.6 Subject Scar Assessment Scale  
Beginning when the burn wound has fully re-epithelialized, the subject (or caregiver) will assess the 
appearance of the scar using the Subject Scar Assessment Scale. The scale and descriptions are found in 
Section 13.  
NOTE: Data from the subject scar assessment scale will be recorded in the case report forms for 
subjects who are age 12 and older. 
6.6 SUBJECT COMPENSATION 
Subjects will be compensated $25.00 USD for their time at the confirmation of wound healing visit (last 
weekly visit) and upon completion of Visits 7 to 8. 


 
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7. STATISTICAL DESIGN  
7.1 
EVALUABILITY 
All subjects who receive study medication will be evaluable for the safety analysis. All subjects who are 
randomized to receive study medication will be evaluable for the intent-to-treat analysis.  
Unless specified otherwise, SPSS® Version 10.0 or higher will be utilized to perform the statistical 
analyses of efficacy and safety measures. 
Categorical variables will be summarized in general using frequencies and percentages, whereas 
continuous variables will be summarized in general using descriptive statistics of number of 
observations (n), mean, standard deviation (SD), minimum (Min), median, and maximum (Max). 
Hypothesis testing, unless otherwise indicated, will be performed at the 5% significance level. All P 
values will be rounded to four decimal places; P values less than 0.0001 will be presented as '<0.0001' in 
all tables. All group comparisons from analysis of variance (ANOVA) and/or analysis of covariance 
(ANCOVA) models will be based on Type III sums of squares. All confidence intervals will be two-
sided with 95% coverage. 
Missing or invalid data of efficacy assessments will be handled by individual scales or subscales on the 
basis of each individual assessment. Missing data for individual items will be assessed for each 
assessment of each scale and imputed with the mean score of the corresponding assessment and rounded 
up to the nearest integer if the number of items with missing data or invalid is less than or equal to 20% 
of total item number. Otherwise, the assessment score will be set to missing. 
Considering that a subject’s burn wound may be healed and/or a subject may discontinue from the study 
prior to the end of the study period, missing values at each weekly visit due to either burn wound healing 
or early termination or any other reasons will be imputed in this study prior to deriving the efficacy 
endpoints for evaluation, using the technique of last-observation carried forward (LOCF). By so doing, a 
burn wound that heals sooner will be given more weight for efficacy. 


 
Page 19 of 31 
 
7.1.1 Primary Efficacy 
The primary objectives of the study include the proportion of subjects with the burn wound healed after 
3 weeks of treatment, time (in weeks) to healing, and incidence of burn wound infection.,  
Both the proportion of subjects with burn wound healed after 3 weeks of treatment and the time to heal 
between the two treatment groups will be analyzed using ANOVA.  Also, the proportion of burn wounds 
healed at each of the 5 assessments (visit 2,3,4,5, and 6) between the two treatment groups will be 
analyzed through a mixed-effect ANOVA.The incidence of burn wound infection observed over the 
study will be compared between the two treatment groups, using a t-test. 
The analysis of the primary efficacy evaluations will be performed for the ITT population. 
7.1.2 Secondary Efficacy 
The secondary efficacy endpoint is to evaluate the effect of daily Collagenase Santyl ointment versus 
daily Bacitracin ointment on scar appearance at 90 days and at 180 days after the initiation of treatment. 
The secondary efficacy endpoint is defined as the VSS total score obtained at Visit 7 (Day 90) and at 
Visit 8 (Day 180). 
The treatment effect of Collagenase Santyl ointment versus Bacitracin ointment on the VSS total scores 
will be obtained at each of the two post-healing assessment time points, using analysis of variance 
(ANOVA) for the ITT population. The mixed-effect model will utilize SPSSPROC MIXED to perform 
the analysis and define treatment (Santyl vs. Bacitracin) and assessment time point (4 visits: Visits 5, 6, 
7 and 8) as well as their interaction as fixed effects, and subject as a random effect. The option of 
variance components will be used to define the covariance structure of the model. 
In addition, a model-based t-test comparisons between Santyl vs. Bacitracin will be performed for each 
of the 2 assessment time points (or visits).  
The null hypothesis states that there are no differences between the two treatments, with the alternative 
of non-zero differences. The type I error rate for rejecting a null hypothesis will be set at an alpha level 
of 0.05. 
Prior to conducting the analysis, those VSS total scores that are obtained at the early termination visit 
will be assigned to the next scheduled study visit. 
The analyses of the primary efficacy evaluations will also be performed for the PP population. 


 
Page 20 of 31 
 
 
7.1.3 Exploratory Efficacy 
Burn wound status (closed or open) at each study visit will be compared between the two treatments, 
using ANOVA for the combination groups of the burn wound perfusion and Fitzpatrick skin type. 
7.2 
SAFETY  
Safety variables include adverse events (AE). Adverse events will be coded using Medical Dictionary 
for Regulatory Activities (MedDRA) adverse event dictionary. Frequency of treatment emergent AE 
will be calculated for each body system, by preferred term, by treatment, for number of subjects and 
proportion reporting the event for the safety population. The severity of the AE and the relationship to 
study medication will be summarized for each body system and preferred term by treatment. 
Withdrawals, in general, and withdrawals due to AE will be summarized for each body system and 
preferred term by treatment. 
8. SAMPLE SIZE JUSTIFICATION 
A previous study of Santyl vs. white petrolatum in normal volunteers with dermatome wounds enrolled 
28 subjects, each of whom served as their own control (paired wounds, treated differently). At 9 months 
follow-up, the Santyl treated wounds had lower total scores on the Vancouver Scar Scale, suggesting the 
efficacy of Santyl ointment, although the difference between Santyl and its petrolatum vehicle was not 
significant (P = 0.09, Wilcoxon signed-rank test). 
 The current study uses a parallel-group design and non-uniform injuries on different individuals, which 
are more likely to lead to a larger variance as compared to the previous study. The injuries are non-
uniform and different in nature compared to the dermatome study. Assuming a moderate effect size of 
0.750 for the present study, the sample size of 80 (40 per group) will yield a statistical power of 
approximately 70% to detect a difference between the two treatment groups at the significance level of 
0.05 (2-sided). Based on a two-sample t-test, the current study is comparable in power to the described 
previous study. 


 
Page 21 of 31 
 
9. ADVERSE EVENTS 
9.1 
GENERAL INFORMATION 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. An 
adverse event can therefore be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to this medicinal product. 
Adverse drug reactions (ADR) are noxious and unintended responses to a medicinal product, meaning 
that a causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility. A reaction, in contrast to an event, is characterized by the fact that a causal relationship 
between the drug and the occurrence is suspected. 
Adverse Event CRF must be used to document all adverse events that occur during the course of the 
study. For each recorded event, the CRF must include the event’s onset and resolution date (if the event 
has resolved), the frequency and severity of the event, a summary of any action taken as a result of the 
event (both in regard to any treatment given and to any change in dosing with the test article), and an 
assessment of the event’s relationship to the test article. 
a Serious Adverse Events that are suspected to be related to the test article and are unexpected (not 
identified in the product-package insert), should be reported to IRB and to the manufacturer of the test 
article within 24 hrs of the investigator’s knowledge as described below in section 10.4 
9.2 
NON-SERIOUS ADVERSE EVENTS 
A non-serious adverse event is defined as a change from baseline (pre-treatment) in a subject's medical 
health that is not life-threatening, does not require hospitalization, does not prolong a current 
hospitalization, and is not disabling.  
9.3 
SERIOUS ADVERSE EVENTS 
A serious adverse event or reaction is any untoward medical occurrence that at any dose: 
• 
Results in death 


 
Page 22 of 31 
 
• 
Is life-threatening (NOTE: The term “life-threatening” in the definition of “serious” refers to an 
event/reaction in which the patient was at risk of death at the time of the event/reaction; it does 
not refer to an event/ reaction which hypothetically might have caused death if it were more 
severe) 
• 
Requires inpatient hospitalization or results in prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a medically important event or reaction 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered serious such as important medical events that might not be immediately life-threatening or 
result in death or hospitalization but might jeopardize the patient or might require intervention to prevent 
one of the other outcomes listed in the definition above. Examples of such events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse. 
9.4 
REPORTING OF SERIOUS ADVERSE EVENTS 
A Serious Adverse Event Form must be completed for all serious adverse events to the Institutional 
Review Board according to their requirements.  
9.5 
ADVERSE EVENT SEVERITY AND CAUSALITY ASSESSMENT 
Events should be classified as mild, moderate, or severe, regardless of whether or not the events are 
considered to be serious or non-serious. The classification should be based on the following definitions: 
• 
Mild – An event is mild if the subject is aware of, but can easily tolerate the sign or symptom 
• 
Moderate – An event is moderate if the sign or symptom results in discomfort significant 
enough to cause interference with the subject’s usual activities 
• 
Severe – An event is severe if the sign or symptom is incapacitating and results in the subject’s 
inability to work or engage in their usual activities 
In addition, the Principal Investigator will determine adverse event causality according to the following 
definitions and with due consideration to conditions and AE normally associated with the population 
under study: 


 
Page 23 of 31 
 
• 
Not Related – An event is considered to be not related to the use of the test article when the 
event is DEFINITELY UNRELATED or UNLIKELY to have any relationship to the use of the 
test article. 
• 
Related – An event is considered to be related to the use of the test article when there is a 
POSSIBLE, PROBABLE, or DEFINITE relationship between the adverse event and the use of 
the test article.  
For example, a single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens - Johnson syndrome) has a reasonable 
possibility of association with the test article. One or more occurrences of an event that is not commonly 
associated with drug exposure, but is otherwise uncommon in the population exposed to the test article, 
may have a reasonable possibility of association. Adverse events which are known to be common in the 
population under study would require additional evidence (e.g., strong temporal relationship, recurrence 
on re-challenge, unusual severity, and/or increasing frequency) before being considered possibly related. 
Adverse events which are known to occur frequently in the population defined by this protocol include: 
burn wound infection, pain and itch of the burn wound, and contact dermatitis. 
9.6 
FOLLOW-UP OF SUBJECTS WITH ADVERSE EVENTS 
For subjects who are experiencing ongoing unresolved adverse events at the time of their study 
completion or early discontinuation from the study, it is recommended that the Investigator schedule an 
appropriate follow-up visit in order to determine the outcome of the event.  
10. INVESTIGATOR OBLIGATIONS 
10.1 
THE PRINCIPAL INVESTIGATOR WILL COMPLY WITH CURRENT GOOD CLINICAL PRACTICE 
(GCP), AND WITH ALL APPLICABLE REGULATORY REQUIREMENTS. . 
11. REFERENCES 
 
(1)  Barrow RE, Herndon DN. History of Treatments of Burns. In: Herndon D, editor. Total Burn 
Care. Philadelphia: Saunders, 2007: 1-8. 
 
(2)  American Burn Association. Burn incidence and treatment in the US: 2007 fact sheet. 
http://www.ameriburn.org/resources_factsheet.php Accessed 14 Feb 2010. 2-14-2010.  
 
(3)  Edlich RF, Larkham N, O'Hanlan JT, et al. Modification of the American Burn Association 
injury severity grading system. JACEP 1978; 7(6):226-8. 


 
Page 24 of 31 
 
 
(4)  Boxer AM, Gottesman N, Bernstein H, Mandl I. Debridement of dermal ulcers and decubiti with 
collagenase. Geriatrics 1969; 24(7):75-86. 
 
(5)  Vrabec R, Moserova J, Konickova Z, et al. Clinical experience with enzymatic debridement of 
burned skin with the use of collagenase. J Hyg Epidemiol Microbiol Immunol 1974; 18(4):496-
8. 
 
(6)  Zimmerman WE. The importance of collagenase for the local treatment of major burns. In: 
Mandl I, editor. Collagenase. New York: Gordon & Breach, Science Publishers, 1972: 131-41. 
 
(7)  Soroff HS, Sasvary DH. Collagenase ointment and polymyxin B sulfate/bacitracin spray versus 
silver sulfadiazine cream in partial-thickness burns: a pilot study. J Burn Care Rehabil 1994; 
15(1):13-17. 
 
(8)  Hansbrough JF, Achauer B, Dawson J, et al. Wound healing in partial-thickness burn wounds 
treated with collagenase ointment versus silver sulfadiazine cream. J Burn Care Rehabil 1995; 
16(3 Pt 1):241-7. 
 
(9)  Frye KE, Luterman A. Decreased incidence of hypertrophic burn scar formation with the use of 
collagenase, an enzymatic debriding agent. Wounds 2005; 17(12):332-6.  
 (10)  Saarialho-Kere UK, Kovacs SO, Pentland AP, et al. Cell-matrix interactions modulate interstitial 
collagenase expression by human keratinocytes actively involved in wound healing. J Clin Invest 
1993; 92(6):2858-66. 
 (11)  Inoue M, Kratz G, Haegerstrand A, Stahle-Backdahl M. Collagenase expression is rapidly 
induced in wound-edge keratinocytes after acute injury in human skin, persists during healing, 
and stops at re-epithelialization. J Invest Dermatol 1995; 104(4):479-83. 
 (12)  Bister V, Makitalo L, Jeskanen L, Saarialho-Kere U. Expression of MMP-9, MMP-10 and TNF-
alpha and lack of epithelial MMP-1 and MMP-26 characterize pyoderma gangrenosum. J Cutan 
Pathol 2007; 34(12):889-98. 
 (13)  Riley KN, Herman IM. Collagenase promotes the cellular responses to injury and wound healing 
in vivo. J Burns Wounds 2005; 4:112-23. 
 (14)  O'Brien J, Lyons T, Monks J, et al. Alternatively Activated Macrophages and Collagen 
Remodeling Characterize the Postpartum Involuting Mammary Gland across Species. Am J 
Pathol 2010; 176(3):1241-55. 
 (15)  Payne WG, Salas RE, Ko F, et al. Enzymatic debriding agents are safe in wounds with high 
bacterial bioburdens and stimulate healing. Eplasty 2008; 8:e17. 
 (16)  Meier K, Nanney LB. Emerging new drugs for scar reduction. Expert Opin Emerg Drugs 2006; 
11(1):39-47. 


 
Page 25 of 31 
 
 (17)  Smack DP, Harrington AC, Dunn C, et al. Infection and allergy incidence in ambulatory surgery 
patients using white petrolatum vs bacitracin ointment. A randomized controlled trial. JAMA 
1996; 276(12):972-7. 
 (18)  Campbell RM, Perlis CS, Fisher E, Gloster HM, Jr. Gentamicin ointment versus petrolatum for 
management of auricular wounds. Dermatol Surg 2005; 31(6):664-9. 


 
Page 26 of 31 
 
12. STUDY PLAN 
Table 1-: Study Procedures by Visit 
 
 
Visit 1 
 
Visits 
 2-6 
 
Visits 
7-8 
 
Informed Consent 
X 
 
 
Medical 
History/Demographics 
X 
 
 
Concomitant Medications 
X 
X 
X 
Inclusion/Exclusion 
X 
 
 
Determine Fitzpatrick skin 
type  
X 
 
 
Determine burn depth (laser 
Doppler) 
X 
 
 
Pain and itch assessment 
X 
X 
X 
Randomize 
X 
 
 
Evaluate burn wound 
appearance 
X 
X 
 
Evaluate burn wound for 
closure 
X 
X* 
 
Apply daily treatment 
X 
X 
 
Photograph burn wound 
X 
X 
X 
Cutometer measurement 
 
 
X 
Subject scar assessment 
 
 
X 
Vancouver Scar Scale 
 
 
X 
Record Adverse Events 
X 
X 
X 
• 
If wound closed, subject does not return until Visit 7. 


 
Page 27 of 31 
 
13. APPENDICES 
13.1.1  
13.1.2 Fitzpatrick skin types 
Figure 13.1.1-1: Fitzpatrick Skin Type Chart 
 
Type 1  
Red & blonde hair, blue eyes, 
burns easily, never tans, 
freckles, very fair skin. 
High risk for skin cancer, may scar if slow 
to heal.  
Type 2  
Fair sandy/red hair, green or 
blue eyes, burns easily, tans 
with difficulty, some freckles.  
High risk for skin cancer, may pigment 
with trauma and may scar if slow to heal.  
Type 3  
Brown, fair, sandy hair; green, 
hazel, blue eyes. Slow to burn, 
will tan.  
High risk for all pigmented skin conditions; 
moderate risk for skin cancer; higher 
potential for scarring. 
Type 4  
Dark brown hair; green, hazel, 
brown eyes. Slow to burn--tans 
easily. 
High risk for trauma, heat & chemically 
caused pigmentation, and moderate risk for 
all other pigmented skin conditions. High 
risk for scarring. 
Type 5  
Dark and black hair; brown 
and dark brown eyes. May 
never burn. 
Very high risk for trauma, heat & 
chemically caused pigmentation, and lower 
risk for solar pigmented skin conditions. 
High risk for scarring (keloid). 
Type 6  
Black hair, dark brown eyes. 
May never burn. 
Very high risk for trauma, heat & 
chemically caused pigmentation, and lower 
risk for solar pigmented skin conditions. 
Very high risk for scarring (keloid). 
 
 
 


 
Page 28 of 31 
 
13.1.3 Burn Chart 
A replica of the following diagram will be used to depict the location and shape of the burn. It 
may be used as an aid to calculating BSA, if other methods are not available. (from Fenlon S , 
Nene S Contin Educ Anaesth Crit Care Pain 2007;7:76-80) 
Figure 13.1.2-1: Lund and Browder Chart 
 
 


 
Page 29 of 31 
 
13.1.4 Burn Wound Appearance 
Exudate amount 
 copious 
 large 
 moderate 
 small 
 scant 
 none 
Exudate type 
 foul purulent 
 fresh blood 
 green 
 sanguinous 
 serosanguinous 
 yellow 
Odor 
 none 
 mild 
 strong 
Presence of eschar 
 present 
 not present 
Presence of epithelial islands 
 present 
 not present 
Epithelialization of the burn wound 
expressed as a percent of the burn wound area re-epithelialized 
Burn wound closure 
 closed 
 open 
Peri-burn skin 
 cyanosis 
 ecchymosis 
 edema 
 erythema 
 intact 
 maceration 
 pallor 
 rash – if present, complete rash evaluation per Appendix 18.1.4. 
 
 


 
Page 30 of 31 
 
13.1.5 Rash Evaluation 
Periwound rash 
1  None 
2  Macular or multiforme  
3  Confluent erythema 
4  Papular or nodular 
5  Vesicular 
6  Pustular 
 
13.1.6 Subject Scar Assessment Scale 
No, not at all  
 
Yes, very much 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Was the scar painful during  
the last weeks? 
 
 
 
 
 
 
 
 
 
 
Was the scar itching during  
the last weeks? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Like normal skin  
Worst Difference 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Is the color of the scar  
different from your normal skin? 
 
 
 
 
 
 
 
 
 
 
Is the pliability of the scar  
different from your normal skin? 
 
 
 
 
 
 
 
 
 
 
Is the thickness of the scar  
different from your normal skin? 
 
 
 
 
 
 
 
 
 
 
Is the scar surface more  
uneven than your normal skin? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Best possible scar 
  
Worst possible scar 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
What is your general impression 
of the scar at this moment? 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 31 of 31 
 
13.1.7 Vancouver Scar Scale 
 
 
 
1. Vascularity 
Normal 
0 
 
Pink 
1 
 
Red 
2 
 
Purple 
3 
 
 
 
2. Pigmentation 
Normal 
0 
 
Hypopigmentation 
1 
 
Hyperpigmentation 
2 
 
 
 
3. Pliability 
Normal 
0 
 
Supple 
1 
 
Yielding 
2 
 
Firm 
3 
 
Ropes 
4 
 
Contracture 
5 
 
 
 
4. Height 
Flat 
0 
 
< 2 mm 
1 
 
2-5 mm 
2 
 
> 5 mm 
3