Clinical trial NCT02623829
Conditions: Post-operative Excessive Scarring
Keywords: scar prophylaxis Botulinum Toxin
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2015-12-01; Completion date: 2019-03-01
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Dermatological surgeons wear many hats to care for subjects with skin cancer. While their role in cancerous tissue removal results in superior cure rates, there is also a need for skilled excisional repair and effective wound healing regimens so the subject can heal with the least amount of scarring necessary. As such, numerous techniques have been developed for reducing the morbidity associated with excessive scarring. Various flaps and grafts allow the surgeon to approximate skin texture, thickness and adnexa with respect to the residual surrounding tissue. Optimal cosmetic and functional outcomes require close wound approximation with minimal static tension along the wound edge. In addition, there are post-operative wound care techniques that range from special dressings to cosmetic scar modification. To date, most surgical wounds are allowed to heal at least partially before scar revision or modulation is attempted.

Botulinum toxin presents a unique opportunity for surgeons to affect scar formation throughout the duration of the healing process. These effects are likely independent and adjunctive to any and all wound care techniques, and are primarily attributed to a reduction in dynamic tension on the wound edges. Most importantly, botulinum toxin's one time dosing requirements with respect to reduced scar formation precludes the variance inherent to standard wound care practices.

Therefore, it has been proposed that for selected subjects, botulinum toxin may be a safe, effective and reliable means for improved post-excisional repair outcomes. Botulinum toxin has been investigated as an inhibitor of excessive, post-excisional scar formation in plastic surgery and Otorhinolaryngology literature. However, these promising studies have yet to combine objective assessment measures of human scar formation in a randomized controlled trial. In addition, there are currently no formal studies of botulinum toxin as a prophylactic against excess scarring in the dermatological literature. Fortunately, Botulinum toxin dosing in the forehead for the purposes of inhibiting excessive scar formation is comparable to the amount given for cosmetic purposes, which is commonplace in dermatology and well-studied.

Detailed description:
This study will attempt to assess the efficacy of Botulinum toxin as a prophylactic treatment in post-excisional repairs for the purpose of preventing excess scar formation. The end points will be the evaluation of each scar using the Manchester Scar Scale.

All MSS and mMSS assessments will be performed in a standardized fashion. The mMSS assessments will be blinded and performed by board-certified dermatologists in the Department of Dermatology, Faculty Practice Associates, Icahn School of Medicine at Mount Sinai, New York City.

Arms: arm 1: 50 units of botulinum toxin diluted in 1ml of normal saline will be administered. The forehead will be injected with 12, evenly spaced and symmetrical aliquots of 0.05ml(2.5 units) and the glabella will be injected at the nasal root and the medial aspect of the corrugators with 0.1ml(5 units) each in addition to the lateral aspect of each corrugator with 0.05ml(2.5 units). The injections will be administered with a 30G needle perpendicular to the skin. arm 2: 1ml of normal saline will be injected with 12, evenly spaced and symmetrical aliquots of 0.05ml and the glabella will be injected at the nasal root and the medial aspect of the corrugators with 0.1ml each in addition to the lateral aspect of each corrugator with 0.05ml. The injections will be administered with a 30G needle perpendicular to the skin.
Interventions: intervention 1: Botulinum Toxin intervention 2: Saline
Intervention descriptions: intervention 1: 50 units of botulinum toxin diluted in 1ml of normal saline will be administered. intervention 2: 1ml of normal saline will be administered

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Title: Botulinum toxin is a promising prophylactic therapy for minimizing post-excisional scarring: A 
Double Blinded, Randomized Controlled Trial 
PI: Dr. Daniel Bernstein 
PI: Hooman Khorasani, MD 
NCT02623829 
Document Date:  7/9/2015 
 
 
 


 
 
Botulinum toxin is a promising prophylactic 
therapy for minimizing post-excisional scarring: 
A Double Blinded, Randomized Controlled Trial 
 
 
 
Investigators:  
Daniel Bernstein, MD 
 
Hooman Khorasani, MD 
 
Study Site:  
Mount Sinai School of Medicine 
 
 
Department of Dermatology 
 
 
5 East 98 Street, 5th Floor 
 
 
New York, NY 10029 
 
Financial Support:  
Protocol Version: 1, 7/9/2015 
 
 
 
 
 
 
 


 
 
 
 
 
Botulinum toxin is a promising prophylactic therapy for minimizing 
post-excisional scarring: A Double Blinded, Randomized Controlled 
Trial 
 
Introduction and Rationale: 
 
Dermatological surgeons wear many hats to care for subjects with skin cancer.  While their role 
in cancerous tissue removal results in superior cure rates, there is also a need for skilled 
excisional repair and effective wound healing regimens so the subject can heal with the least 
amount of scarring necessary.  As such, numerous techniques have been developed for 
reducing the morbidity associated with excessive scarring.  Various flaps and grafts allow the 
surgeon to approximate skin texture, thickness and adnexa with respect to the residual 
surrounding tissue.  However, for optimal cosmetic and functional outcome, specific suture 
techniques are often necessary to ensure close wound approximation while simultaneously 
minimizing static tension along the wound edge (1).  In addition, there are post-operative 
techniques for wound care that range from special dressings during the various stages of 
healing to cosmetic procedures for scar modification.  Unfortunately, once the operation is 
complete, there is little the surgeon can do to minimize adverse scar formation without impairing 
the healing process.  To date, most surgical wounds are allowed to heal at least partially before 
scar revision or modulation is attempted.   
 
Botulinum toxin presents a unique opportunity for surgeons to affect scar formation throughout 
the duration of the healing process.  These effects are likely independent and adjunctive to any 
and all wound care techniques, and are primarily attributed to a reduction in dynamic tension on 
the wound edges (1).  Most importantly, botulinum toxin’s one time dosing requirements with 
respect to reduced scar formation precludes the variance inherent to standard wound care 
practices. 
 
Therefore, it has been proposed that for selected subjects, botulinum toxin may be a safe, 
effective and reliable means for improved post-excisional repair outcomes (2).  Botulinum toxin 
has been investigated as an inhibitor of excessive, post-excisional scar formation in plastic 
surgery and Otorhinolaryngology literature (1-7).  However, these promising studies have yet to 
combine objective assessment measures of human scar formation in a randomized controlled 
trial.  In addition, there are currently no formal studies of botulinum toxin as a prophylactic 
against excess scarring in the dermatological literature.  Fortunately, Botulinum toxin dosing in 
the forehead for the purposes of inhibiting excessive scar formation is comparable to the 
amount given for cosmetic purposes (5), which is commonplace in dermatology and well-studied 
(6-8).   
 
 
 
Objective: 


 
 
 
This study will attempt to assess the efficacy of Botulinum toxin as a prophylactic treatment in 
post-excisional repairs for the purpose of preventing excess scar formation. The end points will 
be the evaluation of each scar using the Manchester Scar Scale.   
 
 
 
Description of Study: 
 
We plan to enroll 40 subjects in this study who are scheduled for forehead excisions on the day 
of enrollment. Each qualifying subject will undergo post-excisional injections into the forehead 
and glabella. Twenty will receive 1ml of normal saline and 20 will receive a total of 50 units of 
botulinum toxin diluted in 1ml of normal saline.  Both the subject and investigator will be blinded 
as to which site receives what.  After these injections, the subject will proceed as per the normal 
standard of care for their post-operative care.  Upon return for suture removal about a week later 
(as per normal standard of care), the subjects will all answer a brief questionnaire regarding any 
adverse events they may have had after the injections.  They will then be scheduled for their last 
and only additional clinical visit for this study, at 24 weeks.  Upon arrival for the final visit, the 
patient will again answer a brief questionnaire regarding any adverse events they may have had 
after the injections.  After this, the assessment of response will be made utilizing the Manchester 
Scar Scale (MSS) both clinically and in a modified version via standardized photographs taken of 
the scar.  The patient will then be discharged home, with their involvement in the study complete. 
 
Method of injection:  
Either 1ml of normal saline or 50 units of botulinum toxin diluted in 1ml of normal saline will be 
administered to a randomly assigned subject.  The procedure will be identical for either substance.  
The forehead will be injected with 12, evenly spaced and symmetrical aliquots of 0.05ml and the 
glabella will be injected at the nasal root and the medial aspect of the corrugators with 0.1ml each 
in addition to the lateral aspect of each corrugator with 0.05ml.  The injections will be administered 
with a 30G needle perpendicular to the skin.  The following diagram (labeled figure 1) depicts the 
injection pattern: 
 
Figure 1 
 
 
 
*Large red circles represent areas for injecting 5units of Botox or 0.1ml of normal saline 
*Small blue circles represent areas for injecting 2.5units of Botox or 0.05ml of normal saline 
 
 


 
 
 
Response Measures: 
The Manchester Scar Scale, a validated scale able to be used for linear surgical scars, will be 
applied in 2 ways (9-11).  These 2 scores will then be added to yield the overall scar 
assessment score for each scar at each visit.  Individual scores will be determined as follows: 
 
1) Manchester Scar Scale (MSS) 
The MSS will be used to clinically assess the scar of each subject at each visit with 
the following criteria clinical assessment sheet: 
 
 
 
 
The Visual Analog Scale is 
on a 10cm line with a zero 
signifying the worst 
possible outcome and 100 
representing the complete 
absence of noticeable 
scarring.  This is a global, 
subjective assessment that 
is combined with a more 
objective assessment 
based on scar color, 
reflectance of light, 
contour, distortion and 
texture.  A summation of 
the VAS score (rounded to 
the nearest cm) and the 
values assigned for each 
of the aforementioned 
assessment criteria will 
then be determined. 
 
2) 
Modified Manchester 
Scar Scale (mMSS) 
The mMSS will employ much of the MSS but will not include the assessment for 
texture since it will be applied to standardized photographs of each scar from each 
visit.  Photographs will be taken at a distance of 10cm and cropped to include the 
scar and surrounding 1cm of normal skin.  These photographs will then be assessed 
by a panel of Dermatologists at a later date.  The scores will then be averaged to 
yield the mMSS average score for each scar at each visit. 
 
 
 
 
 
Subject Selection: 
 


 
 
Inclusion Criteria 
 
1. English-speaking adults at least 18 years old. 
2. Subjects must be scheduled for an excision of forehead skin due to any etiology, with a 
simple linear closure planned as the most likely surgical repair. 
3. Subjects must be able to read, sign, and understand the informed consent. 
4. Subject is willing and able to participate in the study as an outpatient, making several visits 
to the study center during the treatment and follow-up periods and to comply with all study 
requirements including concomitant medication and other treatment restrictions. 
5. If subject is a female of childbearing potential she must have a negative urine pregnancy 
test result prior to study treatment initiation and must agree to use an approved method of 
birth control while enrolled in the study. 
 
 
Exclusion Criteria 
 
1. Subjects with an unstable medical condition as deemed by the clinical investigator, 
including review of the subject’s prior and current medications. 
2. Subjects with Myasthenia gravis, Lambert-Eaton Syndrome or other neuromuscular 
disorder. 
3. Subjects taking medications that may alter the function of neuromuscular junctions (i.e. 
aminoglycoside antibiotics) 
4. Women who are pregnant, lactating, or planning to become pregnant during the study 
period. 
5. Subjects who have a history of keloids. 
6. Known allergy to botulinum toxin. 
7. Subjects who are not able to be closed with a simple linear technique 
 
 
Informed Consent: 
 
Prior to entering the study, the investigator or designated assistant will explain to each subject 
the nature of the study, its purpose, procedures, expected duration, alternative therapy 
available, and the benefits and risks involved in study participation.  Subjects will be given the 
consent document, the opportunity to ask questions, and will be informed of their right to 
withdraw from the study at any time without prejudice.  After this explanation and before any 
study-specific procedures have been performed, the subject will voluntarily sign and date and 
informed consent form, including photographic consent.  Prior to participation in the study, the 
subject will receive a copy of the signed and dated written informed consent form.   
 
 
 
 
 
Study Methodologies: 
 


 
 
Visit 1 Screening/Baseline – Day 0 / Receive Injection 
 
The following pre-study screening procedures should be completed prior to randomization and 
Treatment Initiation: 
 
1. Obtain a signed and dated subject informed consent, including photographic 
authorization.  
2. Review inclusion and exclusion criteria. 
3. Collect demographic information including date of birth, sex, race, ethnicity, and 
underlying reason for excision. 
4. If applicable, perform urine pregnancy testing. 
5. After the excision is completed, the length of the defect will be recorded in addition to the 
number and type of sutures placed, final length of suture line and a photograph will be 
taken. 
6. The subject will be randomly assigned to receive normal saline with or without botulinum 
toxin, prepared by outside party (recorded separately) and handed to dispensing 
physician and neither injector nor subject will know which. 
7. Contents of syringe will be administered to forehead and glabella. 
8. Schedule week 2 visit.   
 
Visit 2 (Week 1 +/- 2 days, at suture removal as per normal standard of care) 
 
The following procedures will be performed at this visit: 
 
1. Review and record adverse events. 
2. Sutures will be removed and unidentifiable photographs will be taken of the forehead. 
3. Schedule final visit. 
 
Visit 3 (Week 24 +/- 2 days) 
 
The following procedures will be performed at this visit: 
 
1. Review and record adverse events. 
2. Subject will have their scar assessed clinically via the MSS and be photographed for 
later mMSS assessments. 
 
Note: any treatment-related AEs or LSRs that are ongoing will be followed to resolution or to the 
investigator’s satisfaction. 
 
Primary Endpoints 
1) Difference between treated and control MSS scores for each scar at 6 months 
2) Difference between treated and control average mMSS scores for each scar at 6 months 
3) Difference between treated and control aggregate scores for each scar at 6 months 
 
 


 
 
Lesion Assessment Guidelines: 
 
All MSS and mMSS assessments will be performed in a standardized fashion.  The mMSS 
assessments will be blinded and performed by board-certified dermatologists in the Department 
of Dermatology, Faculty Practice Associates, Icahn School of Medicine at Mount Sinai, New 
York City. 
 
 
Botulinum and Saline Injection Guidelines: 
 
50 units of Botulinum toxin will be injected into randomly assigned subjects.  The same 
procedure will be carried out for administration of the saline.   
 
 
Safety Evaluations: 
 
Urine Pregnancy Tests 
Females of childbearing potential will undergo a urine pregnancy test at Visit 1(Week 0).  If the 
pregnancy test is positive at Visit 1 the subject will not be permitted to enroll in the study and will 
not receive study drug.   
 
 
Adverse Reactions 
At each visit, the subjects will be assessed for any of the following possible AEs: 
-injection site pain 
-ecchymosis 
-eyelid/brow ptosis 
-systemic effects, including nausea, fatigue, malaise, flu-like symptoms, headache, runny nose, 
diplopia, dysarthria, generalized muscle weakness, asthenia, blurry vision, ptosis, dysphagia, 
dystonia, urinary incontinence, breathing difficulties, rash. 
 
 
Prior and Concomitant Medications: 
 
At the initial visit, prior and concomitant medications and therapies will be reviewed as may 
pertain to exclusion from the study. 
 
Restricted Medications/Treatments 
 
Restricted medications and treatments prior to the study initiation are those that the investigator 
feels may indicate that the subject has an unstable medical condition, as described in the 
exclusionary criteria. 
 
 
Subject Withdrawal or Discontinuation: 
 
Subjects may choose to withdraw from the study or may be withdrawn by the investigator at any 
time without prejudice to their future medical care.  Any subject who does not comply with the 
inclusion/exclusion criteria may be withdrawn from further participation in the study. 
 


 
 
Discontinuation Procedures: Any subject who wishes to discontinue prematurely from the 
study should return to the study center for an End of Study Visit. 
 
 
Adverse Event Definitions: 
 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject which is temporally related to protocol procedures, including administration of a 
pharmaceutical product at any dose, but which does not necessarily have a causal relationship 
with the treatment.  The term AE also applies to laboratory findings or results of other diagnostic 
procedures that are considered to be clinically relevant (e.g., that required unscheduled 
diagnostic procedures or treatment measures or result in withdrawal from the study).  Surgical 
procedures themselves are not adverse events; they are therapeutic measures for conditions 
that require surgery.  The condition for which the surgery is required is an adverse event, if it 
occurs or is detected during the study period.  Planned surgical measures permitted by the 
clinical study protocol and the condition(s) leading to these measures are not adverse events, if 
the condition(s) was (were) known before the start of study treatment.   
 
Adverse events will be recorded according to CTCAE guidelines.  
 
A serious adverse event (SAE) is any AE or adverse drug reaction that at any dose results in 
any of the following outcomes: 
- 
death 
- 
life-threatening adverse event 
- 
inpatient hospitalization or prolongation of existing hospitalization 
- 
persistent or significant disability/incapacity 
- 
congenital anomaly/birth defect 
 
An event may be considered serious when, based upon appropriate medical judgment, it 
jeopardizes the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
A life-threatening adverse event is any AE or adverse drug reaction that at any dose places the 
subject, in the view of the investigator, at immediate risk of death from the reaction as it 
occurred.  It does not include a reaction or event that, had it occurred in a more severe form, 
might have caused death. 
 
 
 
Materials and Supplies: 
 
Study Drug 
Botox botulinum toxin will be used for this study, a grant from Allergan to provide drug is 
pending. Normal saline will be used as the placebo. 
1cc Syringes and 30 G needles will be used. 
Gauze and alcohol swabs will be used to prepare the injection sites. 
 
 
Institutional Review Board: 
 


 
 
Prior to beginning this study, approval must be obtained from the Institutional Review Board at 
the Icahn School of Medicine at Mount Sinai.  
 
 
Data Analysis: 
 
Individual Manchester Scar Scale and modified Manchester Scar Scale scores will be summed 
and plotted in each group and the medians of each group will be assessed using the Wilcoxon 
Rank Sum Test to determine if the results are statistically significant.   
 
 
References: 
 
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