Clinical trial NCT02116608
Conditions: Granuloma Tracheostomy
Sponsor: University of Colorado, Denver
Start date: 2014-09-01; Completion date: 2019-09-05
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study plans to learn more about the different ways used to treat tracheostomy granulomas. Investigators want to see which standard of care method (steroid application, silver nitrate, or betadine) is more successful in treating tracheostomy granulomas.

Detailed description:
Upon joining the study patients will be assigned to one of the three treatment groups (steroid application, silver nitrate, and betadine). These three treatments are standard of care and patients would have been treated with one of them anyway. Patients will be followed for an observation period of six weeks with follow-up appointments, per standard of care, every two weeks (+/- 3 days) in order for a physician to evaluate if the treatment method is working. If during a follow-up visit, the physician determines the treatment method is not working, the follow-up period will end and participation in the study will be complete. In addition, if a patient is given a different form of treatment during the observation period, such as in the emergency department or through their primary care physician, the follow-up period will end and participation in the study will be complete.

Arms: arm 1: Apply locally as needed. arm 2: Arzol Silver Nitrate Applicators may be applied directly to mucous membranes and other moist surfaces. In the case of dry skin, the applicator tip should be dipped in water immediately before use. Apply carefully to the area to be treated. arm 3: Hydrocortisone butyrate cream, 1.0% should be applied to the affected area as a thin film two or three times daily depending on the severity of the condition.
Interventions: intervention 1: Betadine intervention 2: Silver Nitrate intervention 3: Hydrocortisone Butyrate Cream, 1.0%
Intervention descriptions: intervention 1: Apply locally as needed. intervention 2: Arzol Silver Nitrate Applicators may be applied directly to mucous membranes and other moist surfaces. In the case of dry skin, the applicator tip should be dipped in water immediately before use. Apply carefully to the area to be treated. intervention 3: Hydrocortisone butyrate cream, 1.0% should be applied to the affected area as a thin film two or three times daily depending on the severity of the condition.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Template 
Page 1 
CF-146, Effective 7/10/11 
 
w 
COMIRB Protocol 
 
 
COLORADO MULTIPLE INSTITUTIONAL REVIEW BOARD 
CAMPUS BOX F-490    TELEPHONE:  303-724-1055  Fax:  303-724-0990 
 
 
 
Protocol #: 13-2819 
Project Title: 
Treatment of tracheostomy granulomas 
 
 
 
Principal Investigator:  Jeremy Prager, MD 
Version Date: 12/07/2016 
 
I. Hypotheses and Specific Aims:   
 
Specific Aims: 
Examine standard of care by comparing the effectiveness of different treatments of 
tracheostomy granulomas: steroid application, silver nitrate, betadine.  
 
Hypotheses: 
We surveyed the thirteen attending doctors at Children's Hospital Colorado and 
the satellite clinic in Colorado Springs, CO regarding which method of treatment 
they deem as most successful.  The most commonly reported preferred method 
of treatment was silver nitrate (75%).  We hypothesize that treatment with steroid 
application or betadine may result in less frequent recurrence of tracheostomy 
granulomas compared to silver nitrate use.  
 
II. Background and Significance: 
 
The incidence of tracheostomy granulation tissue is between 10-80% of all tracheostomy tubes1,2,3 . 
Granulation tissue can cause bleeding, difficulty with tracheostomy tube changes, and respiratory 
distress if it occludes the end of the tracheostomy tube.  Reports of death due to obstruction from 
granulation tissue exist1. There is no significant data on the best course of treatment to prevent 
granulation tissue and to remove granulation tissue once it develops1,2.  The purpose of this study 
is to evaluate treatment of tracheostomy granulation tissue and determine if any significant 
difference in the frequency and extent of granulation tissue formation with different topical 
treatments.  Each treatment has minimal morbidity and side effects.  Granulation tissue is caused 
by fibroblasts, collagen and blood vessels formed in the proliferative phase of healing. Suggested 
causes of hypergranulation include prolonged inflammation from infection, foreign body irritation, 
external friction, and allergens.  Studies have shown that steroid treatment is effective in treating 
granulation tissue.  Silver nitrate works as chemical cautery by reacting with water in the blood and 
forming nitric acid4.  Anti-septic solutions, such as betadine, are known to be toxic for fibroblasts 
and also help with chronic low-grade infections, and therefore, are helpful in treatment of 
granulation tissue5. 
 
 
III. Preliminary Studies/Progress Report:  
 
To our knowledge, none of the faculty in the pediatric otolaryngology department at 
CHC has conducted any research studies the effectiveness of different treatments of 
tracheostomy granulomas. 
  
 
IV. Research Methods 
 
A. Outcome Measure(s):   
 


Protocol Template 
Page 2 
CF-146, Effective 7/10/11 
 
1. Success or failure of treatment method 
a. Definition of success: We are defining successful treatment of tracheostomy 
granulomas as a clinically significant decrease in the size of granuloma 
(greater than 50% improvement) over a six week observation period using the 
assigned treatment. 
b. Definition of failure: We are defining a treatment as a failure as if there is less 
than 50% reduction in size of tracheostomy granulomas at the conclusion of 
the six week observation period or if worsening occurs requiring alternative 
treatments.   
2. Categorical Improvement (Degree of Improvement) 
a. At each time point, the size of the granuloma will be measured and recorded. 
The percent circumference will also be measured 
b. The approximate percent decrease in the granuloma size will be determined to 
determine the category subject’s change in granuloma: 
i. Complete resolution: >90% improvement (Score = 4) 
ii. Improvement: 50  - 90% improvement (Score = 3) 
iii. Minimal improvement: < 50% improvement (Score = 2) 
iv. No improvement (Score = 1) 
v. Worsening (Score = 0) 
 
 
B. Description of Population to be Enrolled:   
The population to be enrolled in this study includes all Children’s Hospital Colorado patients, 31 
days to 18 years of age inclusive, who are being treated for a tracheostomy granuloma and 
consent to participating in the study.  We anticipate 45 patients will be needed for this pilot study to 
determine the effect size and variation in granuloma change. 
C. Study Design and Research Methods: 
 
The study will be a prospective comparison of three different treatment methods for patients with 
tracheostomy granulomas at Children’s Hospital Colorado. The current standards of care for 
tracheostomy granulomas that we will be examining include: steroid application, silver nitrate and 
betadine. Patients or parents will be consented or assented during the initial physician visit prior to 
any administration of treatment by the provider. The treatment method will be assigned starting at 
the time the patient is enrolled in the study.  
 
1. The three treatment methods (steroid application, silver nitrate, and betadine) will be 
assigned sequentially #1, #2, or #3.  (See below for description) 
2. Patients will be assigned a treatment method based on the sequential allocation done prior 
to enrollment. To reduce potential bias, the enrolling physicians will be unaware of the 
previous patient’s allocated treatment group.   
3. The treatment method for the patient given at the initial visit will be documented in Epic. 
During the six week observation period, the study team will collect follow-up data on the 
degree of improvement for each treatment method. Our primary time point will be 6 week 
follow up.  
4. Each patient will be followed for an observation period of six weeks, with follow-up 
appointments, per standard of care, every two weeks (+/- 3 days) in order for a physician 
to evaluate the degree of improvement for each treatment method.  If the investigator 
determines further follow-up is not necessary, per standard of care, the observation period 
will end. 
5. If during a follow-up visit, the physician determines the patient’s granuloma is worsening, 
the follow-up period will end and the patient’s participation in the study will be complete.  If 


Protocol Template 
Page 3 
CF-146, Effective 7/10/11 
 
other treatments are utilized, we will analyze with the intent to treat analysis based on the 
treatment the subject was received.   
6. In addition, if a patient is given a different form of treatment, such as in the emergency 
department or through a primary care physician, the follow-up period will end and the 
patient’s participation in the study will be complete. 
.   
Treatments: 
1) Silver nitrate – Silver nitrate will be applied to the tracheostomy site granuloma after 
enrollment. Parents will be instructed to keep the site dry for 14 hours.  Residual 
granuloma will be treated similarly at Follow up #1 and #2, but not at Follow up #3.   
2) Betadine solution will be used to topically treat the tracheostomy site BID for 2 weeks (until 
Follow up #1). If residual granuloma is present, an additional week will be recommended 
and this treatment duration recorded. 
3) Hydrocortisone 1% topical will be used to topically treat the tracheostomy site BID for 2 
weeks (until Follow up #1). If residual granuloma is present, an additional week will be 
recommended and this treatment duration recorded. 
 
 
 
 
 
 
 


Protocol Template 
Page 4 
CF-146, Effective 7/10/11 
 
  
 
 
 
Study Design Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sequential allocation of treatment methods (steroid application, silver nitrate, or betadine) 
Patient presents with tracheostomy granuloma 
Obtain consent/enroll patient in study 
Treatment #1 
Treatment #3 
Treatment #2 
Follow-up 
appointment #1 
Follow-up 
appointment #1 
Follow-up 
appointment #1 
Degree of 
improvement 
Degree of 
improvement 
Degree of 
improvement 
Follow-up 
appointment #2 
Follow-up 
appointment #2 
Follow-up 
appointment #2 
Degree of 
improvement 
Degree of 
improvement 
Degree of 
improvement 
Follow-up 
appointment #1 
Follow-up 
appointment #1 
Follow-up 
appointment #1 
Degree of 
improvement 
Degree of 
improvement 
Degree of 
improvement 


Protocol Template 
Page 5 
CF-146, Effective 7/10/11 
 
 
 
Definition of success: We are defining successful treatment of tracheostomy granulomas as a 
clinically significant decrease in the size of granuloma (greater than 50 percent reduction) over a 6 
week month period using the assigned treatment method.   
 
 
Definition of failure: We are defining a treatment as a failure if after 6 weeks of treatment there is 
less than 50% reduction in the size of tracheostomy granulomas.   
 
 
D. Description, Risks and Justification of Procedures and Data Collection Tools:  
 
These methods of treatment do not represent a deviation of the standard of care for tracheostomy 
granulomas and incur the standard amount of risk. 
 
The risks for administering steroid application include thinning of skin, local infection, and systemic 
absorption. Silver nitrate can cause superficial burning on normal tissue that is exposed. Betadine 
can cause skin irritation.  
 
    
E. Potential Scientific Problems:  
 
Potential scientific problems include the following: 
 
1. Inability to enroll the number of patients needed to obtain data pertaining the success or 
failure of the three methods of treatment 
2. Potential for bias in early failure between the 3 treatment arms. For example, it is possible 
that one treatment would work quickly and another would work slowly.  If we discontinue 
follow-up too early, we would bias towards the early treatment effect.  To minimize this risk 
we will continue to follow patients clinically with the treatment provided unless there is 
worsening of the granuloma that would require a change in treatment. There is the 
potential that this study is under powered.  There is no data on the treatment of 
tracheotomy site granulomas and therefore the mean and variance in the treatment effect 
may be different than that estimated in our power analysis below.  This study is powered to 
detect a clinically important difference and will additionally provide data to determine the 
sample size needed for future studies.  We feel this potential is reasonable given that this 
study is a pilot study. 
 
 
F. Data Analysis Plan:   
 
 Success and failure rates for each treatment method and the length of time between initial 
administration of the treatment and the determination of treatment success or failure will be utilized 
to compare the three standard of care treatment methods to better define and improve the current 
standard of care treatment of tracheostomy granulomas.   
 
All variable will be analyzed for distribution and cleaned.  For inconsistencies, we will refer back to 
the source data.  Data will be checked for normalcy and non-parametric tests will be utilized for 
non-normal data.  All analyses will utilize an alpha of 0.05 with two tails.  The study will utilize an 
intent to treat analysis where subjects are analyzed according to the treatment they were assigned 
to regardless of treatments they receive.   
 
 
 


Protocol Template 
Page 6 
CF-146, Effective 7/10/11 
 
Aim 1: Test for difference in treatment failure between the three treatment arms 
Hypothesis 1: At the primary time point (6 weeks), there will be a clinically important difference 
between the silver nitrate treatment and the topical treatments. 
 
Aim 2: Test for difference in categorical granuloma improvement in the three treatment arms 
Hypothesis 2: At the primary time point (6 weeks), there will be more categorical improvement in 
the silver nitrate treatment group compared to and the topical treatments. 
 
Aim 3: Describe the treatment effects of the three treatment arms including average number of 
treatments needed (silver nitrate), duration of topical medication administration (Betadine and 
Hydrocortisone, i.e. two weeks versus three weeks) 
Hypothesis 3: Descriptive aim, no specific hypothesis in this pilot study. 
 
Power Analysis: 
Power analysis is based on aim 2.  Because tracheotomy site granulomas have not 
been rigorously studied in the literature, the degree of improvement that will be found 
in the treatment groups is unclear.  We hypothesize that the standard deviation for 
this 5 point scale will be one unit of measure. We determined the power to detect a 
difference of one unit of measure between treatment groups (from partial response to 
resolution or from minimal improvement to improvement).  Assuming a sample size of 
15 and an alpha of 0.05, our study will have an 80% power to detect a 1.1 point 
difference in categorical granuloma improvement.  Table 1 below shows the power to 
detect differences between two treatment groups. 
 
Table 1: Power analysis for Aim 2 
Treatment A 
Treatment B 
% Diff 
Power 
mean 
mean 
  
  
3.4 
2.4 
42% 
78% 
3.4 
2.2 
55% 
91% 
3.4 
2.1 
62% 
94% 
3.5 
2.5 
40% 
78% 
3.6 
2.5 
44% 
85% 
3.7 
2.5 
48% 
90% 
 
The power to detect differences in treatment success (Aim 1) is shown in table 2. This 
study has an 80 percent power to detect a clinically important (50 percentage point) 
difference in treatment success between two treatment arms. 
 
Treatment A 
Treatment B 
Relative  
  
Success (%) 
Success (%) 
Risk* 
Power 
60% 
73% 
0.67 
12% 
53% 
73% 
0.57 
20% 
47% 
73% 
0.5 
30% 
40% 
73% 
0.44 
44% 
33% 
73% 
0.4 
60% 
27% 
73% 
0.36 
74% 
20% 
73% 
0.33 
87% 
*protective effect of treatment B 
 


Protocol Template 
Page 7 
CF-146, Effective 7/10/11 
 
G.  Summarize Knowledge to be Gained:   
 
Currently, there is no “gold” standard of care for the treatment of tracheostomy 
granulomas in children.  The knowledge gained by comparing the effectiveness of 
different treatments will better define and improve the current standard of care. The 
knowledge to be gained will expectantly benefit future patients by reducing the 
frequency of recurring tracheostomy granulomas as well as minimizing office visits 
with inconsistent forms of treatment.  This pilot study is powered to detect a clinically 
important difference in treatment effects with a modest sample size but additionally 
provide further estimates for sample sizes needed for future studies of this clinically 
important problem in pediatric otolaryngology.   
 
 
 H. References 
1. Yaremchuk, K. Regular tracheostomy tube changes to prevent formation of 
granulation tissue. The Laryngoscope 2003;113:1-20 
2. Chen C, Bent JP, Parikh SR. Powered debridement of suprastomal 
granulation tissue to facilitate pediatric tracheotomy decannulation. 
International Journal of Pediatric Otorhinolaryngology 2011;75:1558-1561 
3. Al Samri M et al. Tracheostomy in children: a population based experience 
over 17 years. Pediatric Pulmonology 2010;45:487-493. 
4. McShane Diana B and Jane S. Bellet. Treatment of Hypergranulation Tissue with High 
Potency Topical Corticosteroids in Children. Pediatric Dermatology Vol. 29 No. 5 675–678, 
2012 
5. Habif: Clinical Dermatology, 5th ed. Chap 27: Dermatologic Surgical Procedures