Clinical trial NCT01523275
Conditions: Laryngeal Stenosis Subglottic Stenosis Tracheal Stenosis
Keywords: mitomycin-C laryngotracheal stenosis subglottic stenosis tracheal stenosis endoscopic airway surgery
Sponsor: University of California, San Francisco
Start date: 2012-08-01; Completion date: 2018-02-01
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, prospective, double-blind, placebo-controlled clinical trial of the use of mitomycin-C topical application as an adjunctive treatment in the endoscopic surgical treatment of patients with laryngotracheal stenosis. We hypothesize that the use of mitomycin-C improves patient outcome in the endoscopic surgical treatment of laryngotracheal stenosis.

Detailed description:
Obstruction of the upper airway caused by laryngotracheal stenosis (LTS) often results in severe morbidity and even mortality. Treatment of LTS continues to present a challenge and a wide array of surgical techniques have been employed. Despite multiple endoscopic and/or open reconstructive procedures, patients often experience restenosis as a result of the abnormal wound-healing process that initially instigated the airway obstruction. The high rate of stenosis relapse has therefore motivated researchers to find new methods to modulate and control the wound-healing process of the airway. Although other adjuvant treatments such as steroids and antibiotics have been investigated in LTS, much attention in recent years has turned to the use of topical mitomycin-C (MMC). As a topical application, MMC has been shown to inhibit fibroblast proliferation in wound-healing processes. The use of MMC in the treatment of airway stenosis was first reported in 1998 and is now routinely used in the endoscopic management of LTS. However, despite numerous animal and human studies, the benefit of MMC in LTS patients remains questionable. While previously published retrospective data suggest that the addition of MMC improves outcome, there have been no prospective studies to directly address the efficacy of MMC in endoscopic LTS surgery. This study will be the first randomized, prospective, double-blind, placebo controlled clinical trial designed to investigate the efficacy of MMC as an adjunctive therapy to endoscopic surgical treatment in patients with LTS. In addition, the study will investigate the relationship between patient symptoms and objective pulmonary function measurements. Ultimately, the results of this study may influence the treatment and evaluation of patients with laryngotracheal stenosis.

Arms: arm 1: Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of MMC in the radial incisions. arm 2: Patients will undergo standard endoscopic surgical treatment for LTS involving CO2 laser radial incisions and balloon dilation, as well as topical application of isotonic saline in the radial incisions.
Interventions: intervention 1: Mitomycin -C intervention 2: Saline application
Intervention descriptions: intervention 1: Topical mitomycin-C at a dosage of 0.4mg/ml will be applied to cottonoid pledgets and placed into the radial incisions for 3 minutes. intervention 2: Isotonic saline will be applied to cottonoid pledgets and placed into the patient's radial incisions for 3 minutes as the placebo intervention.

Protocol documents:
Prot_SAP_000.pdf: 
A"Randomized"Study"of"Mitomycin3C"Application"in"the""
Endoscopic"Treatment"of"Patients"with"Laryngotracheal"Stenosis"
"
IRB"Study:"11307508"
IRB"Approval:"12/27/2018"""
NCT:"01523275"


A. Specific Aim 
 
Obstruction of the upper airway caused by laryngotracheal stenosis (LTS) often results in 
severe morbidity and even mortality.  Treatment of LTS continues to present a challenge 
and a wide array of surgical techniques have been employed.  Despite multiple 
endoscopic and/or open reconstructive procedures, patients often experience restenosis as 
a result of the abnormal wound-healing process that initially instigated the airway 
obstruction1,2.  The high rate of stenosis relapse has therefore motivated researchers to 
find new methods to modulate and control the wound-healing process of the airway.  
Although other adjuvant treatments such as steroids and antibiotics have been 
investigated in LTS3-5, much attention in recent years has turned to the use of topical 
mitomycin-C (MMC).  
 
As a topical application, MMC has been shown to inhibit fibroblast proliferation in 
wound-healing processes8 and is now routinely used in the endoscopic management of 
LTS.  In order to relieve the airway stenosis and immediately increase the airway 
diameter, patients undergo microdirect laryngoscopy or tracheoscopy with placement of 
relaxing radial incisions and mechanical balloon dilation.  Topical MMC is placed in the 
incisions with the intent to prevent or reduce the rate of restenosis.  However, despite 
numerous animal and human studies11-14, the benefit of MMC in LTS patients remains 
questionable. 
 
The goal of this research is to improve our understanding of LTS treatment by directly 
evaluating the effect of MMC as an adjunctive therapy to standard endoscopic surgical 
management of LTS.  We propose a prospective, randomized, double-blinded, placebo-
controlled study to assess the efficacy of MMC as an adjuvant therapy in the treatment of 
LTS.  A cohort of 60 LTS patients will be enrolled with the goal sample size set at 44 
subjects.  Subjects will be randomized into a MMC group or a placebo group.  All 
subjects will undergo standard endoscopic surgical treatment for their LTS.  Subjects in 
the MMC group will then undergo topical application of MMC placed into their 
incisions, while the placebo group will undergo saline application. We propose the 
following specific aim and hypotheses: 
 
Aim: To assess the efficacy of topical MMC as an adjunctive therapy to endoscopic 
surgical treatment in LTS patients. 
The primary outcome measure will be the interval to repeat surgical intervention.  
Secondary outcome measures will be the change in patient reported symptom scores, 
duration of symptom improvement, and peak inspiratory flow measurements. 
 
Analysis 1:  To determine changes seen with topical MMC therapy 
Hypothesis 1a: MMC group patients will have longer intervals to repeat surgery than the 
placebo group. 
Hypothesis 1b: MMC group patients and placebo group patients will have similar 
improvements in symptoms after surgical treatment for LTS. 
Hypothesis 1c: MMC group patients will have longer durations of symptom 
improvement when compared to placebo patients. 


Hypothesis 1d: MMC group patients and placebo group patients will have similar 
improvements in peak inspiratory flow measurements after surgical treatment for LTS. 
 
Analysis 2: To evaluate the association between patients’ subjective symptoms and 
pulmonary function testing measurements. 
Hypothesis 1a: There will be an association between patient reported symptoms and 
peak inspiratory flow measures. 
 
B. Background and Significance 
 
B.1 
Etiology of LTS and patient selection for endoscopic surgical management 
LTS in the current era is most commonly caused by mechanical trauma from prolonged 
intubation or tracheotomy.  Other etiologies include respiratory infections, external 
trauma, or inflammatory rheumatological disease, such as Wegener’s granulomatosis.  In 
many patients, no specific etiology is found and they are diagnosed with idiopathic LTS.  
Multiple studies have demonstrated an association between laryngopharyngeal reflux and 
LTS regardless of etiology and LPR may be implicated as the primary etiology in some 
cases.  An important consideration in the management of LTS is determining the degree 
of cartilage involvement. In a study published by Simpson et al., it was demonstrated that 
endoscopic management of LTS was most successful in stenoses that were not 
completely circumferential, less than 1.0cm in vertical height, and not associated with 
significant cartilaginous involvement.  Based on this early study and subsequent 
experience, LTS with cartilaginous involvement is not typically considered to be 
amenable to endoscopic surgical management with radial incisions and dilation. 
 
 
B.2 
Mitomycin-C is routinely used as an adjunctive therapy in the treatment of 
LTS with the intent to prevent scar reformation.  Discovered in 1956, MMC is an 
antimicrobial agent which has antimetabolite and antiproliferative properties6.  It is 
produced by Streptomyces caespitosus and acts as an akylating agent to inhibit DNA 
synthesis7.  As a topical application, MMC has been shown to inhibit fibroblast 
proliferation in wound-healing processes8.  The first clinical use of topical MMC 
occurred in 1963 by ophthomologists to reduce scar tissue formation in pterygium 
surgery with remarkable results9. The use of MMC in the treatment of airway stenosis 
was first reported in 199810 and is now routinely used in the endoscopic management of 
LTS.  
 
B.3  
The proposed research will provide prospective, randomized controlled data 
regarding the efficacy of MMC as an adjunctive therapy in the endoscopic surgical 
treatment of LTS.  With two exceptions, published clinical studies of MMC in LTS 
have been retrospective case series or cohort studies.  Most report positive outcomes, 
supporting the use of MMC as an adjuvant treatment15,16. Yet, in a prospective, 
randomized control trial of MMC in pediatric patients after open laryngotracheal 
reconstruction, outcomes were identical between the group who received MMC and the 
saline placebo group17.  The second exception is a randomized, prospective, double-blind, 
placebo controlled trial that examined the efficacy of two topical application of MMC 


given 3-6 weeks apart compared to a single topical application in endoscopic treatment of 
LTS18.  Although the results suggest that two applications reduced the restenosis rate for 
2 to 3 years, relapse rates at 5 years were the same between the two groups.  A recent 
literature review on the use of topical MMD as an adjunctive in airway surgery concluded 
that “heterogeneity within the clinic studies, the lack of controlled data, and the lack of 
significance in the pooled animal data suggest that the utility of MMC is still 
undetermined”19. 
 
B.4 
Measures of LTS treatment 
Interval to repeat surgery:  Endoscopic treatment of LTS with radial incisions and 
dilation results in significant improvement in the patient’s symptoms. However, the 
short-term improvement is often associated with long-term relapse.  Studies have 
reported a 40-70% recurrence rate over months to years (Smpson GT, Ann Otol Rhinol 
Laryngol 1982; 91:384-388., Duncavage JA Ann Otol Rhinol Laryngol  1985; 94:565-
569, Ossoff RH, Laryngoscope 1985; 95:1220-1223.).  The interval to repeat surgery has 
been selected as the primary outcome measure in this proposed study.  By using this 
continuous outcome measure on our study population with required regular follow up 
evaluation, both subjective outcomes such as patient symptoms and objective measures 
such as spirometry measurements and office examination of the airway diameter will be 
taken into consideration.  
Clinical COPD Questionnaire: The Clinical COPD Questionnaire is a 10-item 
psychophysical scale which was developed for patients with Chronic Obstructive 
Pulmonary Disease. The questionnaire requires the patients to rate respiratory symptoms, 
as well as functional and mental limitations related to their breathing.  Based on a study 
of 33 adult LTS patients, the CCQ was found to be valid and sensitive instrument for 
assessing symptom severity and levels of function and well-being in adult LTS patients 
(*Nouraei et al. ).  In the proposed study, the CCQ will be administered to the patients 
preoperatively and at every scheduled postoperative and subsequent follow up visit.  
Pulmonary Function Testing (PFTs):  Flow volume loops obtained in pulmonary 
function testing have long been used in the evaluation of dyspnea to differentiate between 
fixed and variable lesion and to differentiate between intrathoracic or extrathoracic 
obstruction.  As PFTs are non-invasive and easy to perform in the clinical setting, they 
provide useful information in the diagnosis and monitoring of LTS patients. Various 
indices have been proposed as sensitive measures for LTS, including PEF/PIF, 
MEF50/MIF50, among others ( Nouraei et al Laryngoscope 2007). In practice, it is 
difficult to accurately predict the degree of stenosis based on the spirometry results.  
However, many laryngologists consider a peak inspiratory flow (PIF) of less than 1.5 L 
per second to indicate a significant level of airway obstruction.  The proposed study will 
improve our understanding of the association between patient symptoms and objective 
pulmonary function testing measurements. 
 
C. 
Preliminary Study 
 
C.1 
Endoscopic Management of Adult Subglottic Stenosis Patients at the UCSF 
Voice and Swallowing Center.  In 2008, Drs. Roediger, Orloff, and Courey published a 
retrospective case series review of 15 consecutive adult subglottic stenosis patients 


treated over a 3 year period. All patients underwent microdirect subglottoscopy under jet 
ventilation, CO2 laser radial incisions through the stenotic segment, and topical MMC 
application in a concentration of 0.5mg/ml for 3 minutes. 28 total procedures were 
performed.  All subjects reported postoperative reduction in symptoms.  Six patients 
(40%) required only one surgical treatment for symptomatic relief during the study 
period, Nine patients (60%) required repeat surgery at an average interval of nine 
months20.  Relevance to proposed research: This works supports endoscopic 
management with laser radial incisions and topical MMC  application as an effective 
treatment for SGS. Due to the retrospective nature of this study and lack of a control 
group, the efficacy of the topical MMC application cannot be determined. It is possible 
that the results are due to the surgical treatment without an additional benefit from the 
MMC.  The proposed study will directly address whether the use of MMC is an effective 
adjunctive therapy. 
 
C.2 
Experience and Expertise in Surgical Treatment of LTS:  Presently at the 
UCSF Voice and Swallowing Center, LTS patients that are candidates for endoscopic 
surgical management are treated with CO2 laser radial incision, controlled balloon 
dilation, and given the option of topical MMC application. I have been performing these 
airway surgeries on my own patients since 2008. Since the completion of my residency 
training, I have performed XX endoscopic surgeries for the treatment of LTS.  All 
patients without cartilaginous involvement have had at least temporary relief from 
respiratory symptoms.  Most require repeat treatments consistent with the aforementioned 
published work from our center.  Relevance to proposed research:  I have the necessary 
expertise and experience to perform the surgical procedures in this study. 
 
D. 
Research Design and Methods 
 
 
D.1 
Overview of study design:  The overall goal in this study is to evaluate the effect 
of topical MMC therapy as an adjuvant to endoscopic surgical treatment in LTS patients.  
We plan to accomplish this by comparing a group of LTS patients who undergo 
endoscopic surgical management with the addition of MMC against a control group of 
LTS patients who undergo endoscopic surgical management without MMC in a 
prospective, placebo-controlled, double-blinded fashion. 
 
After eligibility is determined, LTS patients will undergo a clinical evaluation that 
includes a history and physical examination including videolaryngoscopy, clinical COPD 
questionnaire, and pulmonary function testing.  Prior to surgery, the patients will be 
randomized into one of two groups: 1) endoscopic surgical treatment with topical 
application of saline and 2) endoscopic surgical treatment with topical application of 
saline.  Both the patient and the physician will be blinded to the treatment group 
assignment.  Patients will be evaluated at regular post-operative intervals.  Symptom 
questionnaires and laryngoscopy will be performed at each office visit.  PFTs will be 
performed at 1 month and 6 months post-operatively.   Additional surgery will be 
performed as needed and group assignments will remain the same.  After the initial 6 


month post-operative period, if patients remain asymptomatic, office visits and PFTs will 
be performed at 6 month intervals until the completion of the 24 month study period. 
 
Figure 1. Schematic diagram of study 
 
 
 
 
LTS Patients 
Clinical evaluation, PFTs, and symptom questionnaire 
 
 
 
Randomization 
 
 
Group 1 
Direct laryngoscopy and bronchoscopy with 
laser radial incisions and balloon dilation 
Topical application of Mitomycin-C 
Group 2 
Direct laryngoscopy and bronchoscopy with 
laser radial incisions and balloon dilation 
Topical application of saline
 
Post-operative follow up visits at 1 week, 1 month, 3 months, and 6 months after surgery 
Complete symptom questionnaire and PFTs at each visit 
 
 
Follow up at 6 month intervals or more frequently as needed 
Additional surgery as needed, group assignment remains the same 
If no additional surgery needed, PFTs every 6 months 
 
 
 
 
D.2 
Study population:  Based on our sample size calculation (Section XX), we will 
enroll 60 subjects with LTS. 
 
Eligbility:  Patients with subglottic or tracheal stenosis will be considered for enrollment 
into the study based on the following: 
 
Inclusion criteria: 
•   
Age greater than or equal to 18 years 


•   
Patients with disease amenable to treatment with endoscopic CO2 laser radial 
incisions and balloon dilation  
 
Exclusion criteria: 
• 
Minors (age less than 18 years) and pregnant women 
• 
Patients with glottic and supraglottic stenosis 
• 
Patients with disease not amenable to treatment with endoscopic CO2 laser radial 
incisions and balloon dilation 
• 
Patients with cartilaginous subglottic or tracheal stenosis 
 
D.3  
Rationale for study design and study populations:  The proposed project is 
designed to be a prospective, randomized, placebo-controlled, double-blinded study to 
evaluate the effect of topical MMC as an adjuvant treatment to endoscopic surgical 
management in LTS.   Endoscopic surgical treatment including CO2 laser radial incisions 
and dilation has been demonstrated to be an effective treatment of LTS.  MMC is 
routinely used as an adjuvant therapy. However, the efficacy of MMC remains 
questionable.  Despite the presence of retrospective studies that have supported the use of 
MMC, there have been no prospective controlled studies directly addressing the efficacy 
of MMC in adult LTS patients.  Randomization of the patients into a MMC group or a 
placebo group should not expose them to additional or unnecessary risks, as in both 
groups the patients will be treated with the surgical standard of care. While the efficacy 
of MMC is unknown, the safety of topical MMC has been well-accepted.  Hueman and 
Simpson reported 4 complications that were believed to be caused by local toxicity of 
MMC out of 85 cases9. Complications were manifested by the presence of fibrinous 
debris at the operative site, resulting in airway restriction and need for airway 
intervention. The complication rate with the standard concentration was 2.8% (2/71), 
while the complication rate for the supersaturated concentration was 14% (2/14).  For this 
reason, we will use the standard concentration of 0.4mg/ml. Patients return for follow up 
1 week and 1 month postoperatively to evaluate for symptomatic and/or laryngoscopic 
improvement, as well as for adverse events. 
 
The study population is limited to adults LTS patients, excluding supraglottic and glottic 
level stenosis.  Soft tissue subglottic and tracheal stenosis is well treated with radial 
incisions and dilation, with the procedure being essentially identical for either diagnosis.  
The presentation and treatment of supraglottic and glottic level stenosis is more varied 
and direct comparisons between these groups and the more static sublgottic/tracheal 
stenoses would be less reliable.  Therefore, to eliminate variation in patient population 
and surgical treatment, we have decided to limit the study population to adult LTS 
patients. We have not excluded tracheotomized patients, as the presence or absence of the 
tracheotomy does not change our treatment of the stenotic region.  Patients are treated 
endoscopically with the intention to decannulate as soon as possible.  
 
D.4 Study procedures 
 
Subject recruitment and informed consent:  Patients seen at the UCSF Voice and 
Swallowing Center who meet the eligibility criteria for this study will be approached by 


Drs. Yung or Courey for enrollment. Drs. Yung or Courey will obtain written informed 
consent for the study 
 
Based on our experience in the past 12 months, we expect to enroll the 60 patients during 
a 2 year period.  Drs. Yung and Courey performed 40 endoscopic CO2 laser radial 
incisions with dilation in 2011, with similar numbers in the previous years.  Accounting 
for a 25% dropout, this should provide the calculated sample size of 44 subjects. 
 
Baseline visit:  Subjects will have a baseline visit from which demographic information, 
medical history, physical examination including videolaryngoscopy, and the clinical 
COPD questionnaire will be obtained. This visit will be performed at the UCSF Voice 
and Swallowing Center.  If the patient does not have a previous airway CT scan to 
document the absence of cartilaginous stenosis, we will obtain one prior to surgery. PFTs 
will be performed prior to surgery as well. 
 
Surgical procedure:  All patients will undergo a uniform surgical treatment.  General 
anesthesia with jet ventilation will be used unless the patient can be ventilated through a 
tracheotomy.  After the induction of general anesthesia, an initial survey of the larynx and 
pharynx will be performed with a monocular laryngoscope.  A subglottiscope will then be 
inserted into the larynx and suspended. Photodocumentation and measurements of the 
stenosis will be obtained.  The remainder of the surgery is performed with an operating 
microscope.  Using a CO2 laser with a pattern generator, radial incisions will be 
performed through the stenotic segment.  Incisions will be performed to reach the normal 
lumen of the adjacent trachea or larynx.  Using a balloon dilator, the stenotic segment 
will be dilated to the diameter of the normal tracheal lumen.  Cottonoids will be soaked in 
either MMC in a concentration of 0.4mg/ml or normal saline.  These are then applied to 
the incisions for 3 minutes.   
 
Post-operative visits:  Patients will return to the UCSF Voice and Swallowing Center for 
follow up visits at 1 week, 1 month, 3 months, and 6 months after surgery.  At each visit, 
videolaryngoscopy will be performed and the symptom questionnaire will be completed.  
PFTs will be obtained at 1 month and 6 months postoperatively.  Beyond 6 months, the 
patients will return for follow up every 6 months or sooner if needed. PFTs will be 
obtained every 6 months or prior to any additional surgical intervention. 
 
Additional surgery: Patients will undergo additional surgery as their symptoms and 
stenosis relapse.  They remain in their initial randomization for the entire 24 month study 
period and the surgeries are performed in the manner as described above. 
 
D.5  
Study measurements:  
 
Demographics: The patient’s age, gender, ethnicity, and race will be recorded. 
Medical history: A complete medical history will be obtained from each patient 
including medical comorbidities, current medications, social history, and family history. 
Physical examination: A complete head and neck exam will be performed at each office 
visit, including videolaryngoscopy. 


Interval to repeat surgery:  The time interval between the subject’s initial surgery and 
1st additional surgery will be recorded.   Additional intervals will be recorded as needed 
for all additional surgeries within the study period.   
Clinical COPD Questionnaire: The CCQ will be used to assess the patients’ respiratory 
symptoms and their effects on functional status and mood.  The total score (continuous 
variable) will be used as the outcome measure of interest. 
Duration of symptom improvement:  Symptom improvement will be assessed by 
comparing pre-operative CCQ scores with the 1st postoperative CCQ score. The duration 
of symptom improvement will be the duration of time where the improved scores remain 
stable.  The duration of symptom improvement may be a better outcome measure than 
interval to repeat surgery if a significant number of patients do not need repeat 
procedures during the study period. 
Pulmonary Function Testing (PFTs):  Flow volume loops and spirometry 
measurements will be obtained. Peak inspiratory flow (PIF) will be the main objective 
measurement used. However, additional data will be recorded for analysis, including 
PEF, FIV1, FEV1, FIVC, FVC, MIF50, MEF50. 
 
D.6 
Data quality and data management:  Data will be collected by Dr. Yung, Dr. 
Courey, or their staff during office evaluations.  Collected data will be recorded as a hard 
copy that will then be transferred to an electronic database format.  The data will be 
managed by Wendy Ma, the study coordinator. 
 
D.7 
Statistical analysis 
 
Analysis 1:  To determine changes seen with topical MMC therapy 
Rationale and approach: We hypothesize that the MMC group patients will have longer 
intervals to repeat surgery than the placebo group, as well as longer durations of 
symptom improvement when compared to placebo patients. Furthermore, we hypothesize 
that the two groups will have similar improvements in symptoms and similar 
improvements in peak inspiratory flow measurements after surgical treatment for LTS. 
Paired t-tests (within group), t-tests (between groups), and repeated measures techniques 
(particularly for duration of changes in symptoms) will be used to evaluate outcomes for 
the mitomycin-c and saline placebo groups. 
 
Analysis 2: To evaluate the association between patients’ subjective symptoms and 
pulmonary function testing measurements. 
Rationale and approach: We hypothesize that there will be an association between 
patient reported symptoms and peak inspiratory flow measures.  Linear regression will 
test the association between patient’s subjective symptoms and pulmonary function 
testing measurements. 
 
Sample size calculation: Sample size determination is based on the primary outcome, 
the time interval to repeat operation. Analysis of 44 subjects (22 in each arm) would 
provide 90% power to detect a difference in the time interval to reoperation of 6 months 
between the two treatment arms, at an alpha level of 0.05.  This difference of 6 months is 
clinically meaningful and is smaller than previous case series studies would suggest.  A 


sample size of 60 subjects will account for a potential 25% loss to follow up.  This 
sample size should be sufficient for examination of secondary outcomes, based on the 
limited data that are available. 
D.8 
Potential problems 
 
We are aware of two potential problems.  The interval to repeat surgery was selected as 
the primary outcome measurement based on the ease of definability and the notion that 
this outcome measurement would take into account both the patient’s symptoms as well 
as clinical exam findings.  However, if a large number of enrolled subjects do not require 
additional surgery during the 24 month study period, the interval to repeat surgery is a 
less relevant measure. In that case, a symptom-free interval or duration of symptom 
improvement may be a better outcome measure.  We will collect data on duration of 
symptom improvement and use this as the primary outcome measure if it appears more 
appropriate.  Although we expect to be able to enroll the necessary number of subjects 
within our current LTS patients and new referrals, it is possible that study accruement is 
slow.  In this situation, we may decide to publicize our clinical trial in order to recruit 
more subjects. 
 
D.9 
Timeline 
 
ALA Award would represent Year 1. 
 
Activity 
Year 1 
Year 2 
Year 3 
Year 4 
Enrollment of patients 
* 
* 
 
 
Study assessments 
* 
* 
* 
 
Data cleaning and statistical 
analysis 
 
 
* 
* 
Manuscript preparation and 
presentation of results 
 
 
* 
* 
 
E. 
Human Subjects 
 
E.1  
Risks to the subjects 
 
Human subjects involvement and characteristics: The patient sample for this research 
plan is adult patients with LTS seen in Dr. Yung and Dr. Courey’s practices at the UCSF 
Voice and Swallowing Center. Complete inclusion and exclusion criteria are outlined in 
Study Population, Section D.2. 
 
Sources of materials: Research material will be obtained from direct assessment of the 
patient, including medical history, physical examination, PFTs, and CCQ.   
 
Potential risks: The risks of physical examination including videolaryngoscopy are 
negligible.  The risks of pulmonary function testing are also negligible.  There have been 
few reported adverse events with topical MMC application.. In humans, multiple studies 
also document the absence of adverse effects with topical mitomycin. The standard 


dosage of 0.4mg/ml was used in most studies, with one author also including a 10mg/ml 
supersaturated concentration. Only 2 studies in the otolaryngology literature note possible 
complications from topical MMC use. Ubell et al. published a series of 50 patients who 
underwent 93 MMC applications. Only 1 suspected complication occurred in a patient 
with recurrent laryngeal amyloidosis who reported throat pain and dyspnea two weeks 
postoperatively. Diffuse laryngeal inflammation was noted and the patient ultimately 
required a tracheotomy. Although it is unclear whether MMC was directly responsible for 
this adverse event, the authors considered it a complication resulting in a complication 
rate of 1.1%.  Hueman and Simpson reported 4 complications that were believed to be 
caused by local toxicity of MMC out of 85 cases. Complications were manifested by the 
presence of fibrinous debris at the operative site, resulting in airway restriction and need 
for airway intervention. The complication rate with the standard concentration was 2.8% 
(2/71), while the complication rate for the supersaturated concentration was 14% (2/14). 
 For this reason, we will use the standard concentration of 0.4mg/ml. Patients return for 
follow up 1 week and 1 month postoperatively to evaluate for symptomatic and/or 
laryngoscopic improvement, as well as for adverse events. 
 
Additional risks of this study include the risk of randomization and the risk of radiation 
from the CT scan that is done as part of the pre-treatment/enrollment evaluation.  As an 
effect of the study randomization, subjects in one arm of the study, whether it is the 
MMC arm or the placebo arm, may have more side effects or receive treatment that may 
prove to be less effective than the other arm. The amount of radiation the subject is 
exposed to in a non-contrast neck CT scan is relatively small, but the risk of potential 
future harm can not be determined. 
 
E.2 
Adequacy of protection against risks 
 
Recruitment and informed consent:  Recruitment will not influence any treatment 
decisions.  Patients with LTS will be approached by either Dr. Yung or Dr. Courey 
regarding the study only after the decision to proceed with surgical treatment has been 
made.   Patients who decide not to enroll in the study will be offered standard LTS 
treatment and given the option of topical MMC. Informed consent will be obtained by 
either Dr. Yung or Dr. Courey, although certain aspects of the study may be explained in 
greater detail by Wendy Ma, the study coordinator. Emphasis will be placed on the 
independence of consent for this study and their surgical treatment, the ability to undergo 
treatment outside the study and that participation in the study will not affect their office 
evaluation and treatment.  Patients will receive a copy of the consent form and the 
Experimental Subject’s Bill of Rights. 
 
Protection against risk: Study patients will undergo topical application of MMC at the 
same concentration and the same application time as non-study patients. The standard 
concentration of 0.4mg/ml will be used.  Their airway symptoms will be monitored with 
close office follow up evaluations at one week and one month post-operatively. Patients 
will notify the UCSF Voice and Swallowing Center nursing staff or otolaryngologist of 
any adverse side effects they are experiencing.  Essentially, the symptom questionnaire is 
the only study component that standard non-study LTS patients do not undergo and as 


such, there is little if any additional risk that subjects will experience by agreeing to take 
part in this study.  In order to protect the privacy of research subjects, study personnel 
will follow all HIPAA regulations and maintain data on password-protected computers 
and/or secure networks.  Privacy in the research setting will include meeting in a private 
room for the consent discussion, conducting all office visits in a private examination 
room, using study ID numbers instead of names on data collection forms, storing all 
identifiers separately and securely from study data, and restricting access to research 
records. 
 
E.3  
Potential benefits of the proposed research to the subjects and others 
 
The proposed study will be the first randomized, prospective, double-blind, placebo 
controlled clinical trial of MMC as an adjunctive therapy to endoscopic surgical 
treatment in adult patients with LTS.  If this study shows that topical MMC therapy 
reduces the frequency of repeated airway surgeries for patient with LTS, society would 
benefit in terms of health care cost and resources. If this study shows that topical MMC 
therapy has no effect on the frequency of repeated surgeries, then future patients would 
not be offered MMC, therefore eliminating the cost of the medication as well as any 
potential adverse effects from the MMC.  In either instance, this study should advance 
our knowledge in the field, provide information regarding the use of MMC in LTS 
patients, and lead to improved treatment. 
 
 
12.3 
 
1. Goldenberg D, Esclamado R, Flint P, Cummings CW.  Surgical management of 
upper airway stenosis.  In: Cummings CW, Flint PW, Harker LA, Haughey BH, 
Richardson MA, Robbins KT, Schuller DE, Thomas JR, eds.  Cummings 
Otolaryngology Head & Neck Surgery.  Philadelphia, PA: Elsevier Mosby; 
2005:2103-2127. 
2. Simpson GT, Strong MS, Healy GB, Shapshay SM, Vaughan CW.  Predictive 
factors of success or failure in the endoscopic management of laryngeal and 
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