Clinical trial NCT02748070
Conditions: Chronic Rhinosinusitis Endoscopic Sinus Surgery Chronic Rhinosinusitis Without Polyps Oral Steroids
Sponsor: Stanford University
Start date: 2015-08-01; Completion date: 2019-07-15
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
While oral steroids have been shown to be effective in the management of patients with chronic rhinosinusitis with polyps, its role in treating chronic rhinosinusitis without polyps (CRSsNP) is ambiguous. Despite a lack of strong clinical evidence to suggest a benefit in this disease state, steroids are often prescribed as a component of post-operative care after sinus surgery for patients without polyps. Oral steroids carry with them significant adverse effects, and should be prescribed thoughtfully. The aims of this study are to determine if oral steroids in the peri-operative period improves patient outcomes in CRS without polyps.

Detailed description:

Arms: arm 1: Provided oral steroid and topical steroid arm 2: Provided oral placebo and topical steroid
Interventions: intervention 1: Prednisone intervention 2: Flonase
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
Perioperative Oral Steroids for Chronic 
Rhinosinusitis Without Polyps  
NCT02748070 
February 17, 2015 
Julia Noel, Principal Investigator 
Stanford University 
Stanford, California 94305 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
After patients with chronic rhinosinusitis (CRS) undergo sinus surgery, they are typically 
instructed to take oral steroids for several days to weeks. However, there is limited data to 
suggest this is a beneficial practice, and oral steroids have been shown to have significant and 
unpleasant side effects. This study will investigate whether there is truly evidence based utility to 
the use of steroids after sinus surgery 
 
b. 
Objectives 
Chronic rhinosinusitis is a disease that affects an estimated 13% of the adult population. Patients 
with this disease suffer from reduced quality of life, impaired sleep, fatigue, acute infections, and 
chronic pain. Healthcare expenditures for CRS are estimated at $8.6 billion annually, with the 
majority of costs arising from repetitive physician visits, emergency department encounters, and 
medications. Despite its prevalence, relatively little is understood about optimal medical therapy 
in the post-operative period. As described above, oral steroids are routinely prescribed after sinus 
surgery based on anecdotal data and expert opinion rather than convincing, randomized 
controlled data. The aim of conducting this study, therefore, is to to determine if oral steroids 
have a role in the peri-operative treatment of patients with CRS. This study would contribute a 
wealth of important data to the field of Rhinology and the management of CRS. The role of 
steroids in the peri-operative period would be further elucidated, providing randomized 
controlled data with which providers may make informed therapeutic decisions. In summary, the 
results of this study have significant potential to influence current practice and management 
guidelines. 
 
 


February 17, 2015 
 
Page 2 of 10 
c. 
Rationale for Research in Humans 
The purpose of the study is to test the efficacy of of a medication in individuals with CRS, which 
is not a disease known to be accurately duplicated in any other model. 
2. 
STUDY PROCEDURES 
a. 
Procedures 
Screening: Patients who have been recommended to undergo endoscopic sinus surgery by our 
department will be recruited for the study and informed of its purpose pre-operatively. SNOT22 
scores (a quality of life survey well established in Rhinology) and Lund-Kennedy endoscopic 
exam scores (an quantitative clinical assessment of disease severity) will be recorded in their 
medical records. This is the same protocol performed for all patients seen in our clinic regardless 
of their enrollment in the study. Randomization and Treatment Groups: The patients that wish to 
participate will be randomized into two treatment arms by our nurse practitioner based on a 
random number generator. They will receive one of the following post-operative regimens: 1) 
oral steroid (treatment) + steroid spray (treatment) 2) oral placebo (control) + steroid spray 
(treatment) These medications will be manufactured and packaged by an independent 
compounding pharmacy, and prescribed by our nurse practitioner at the preoperative visit. 
Patients will begin their therapy on the first post-operative day. All oral steroid regimens will be 
given in our institution's standard 12 days taper, while topical steroids will be delivered via a 
metered dose nasal spray bottle for two weeks. All study patients will receive identical 
perioperative antibiotic therapy. We do not anticipate these medications to be an inconvenience 
to study patients as all proposed interventions are not different from routine post-operative care. 
In addition, patients undergoing surgery will have already trialed these medications as part of 
their pre-operative medical therapy. Surgery: Routine endoscopic sinus surgery will be 
performed per our institution's standard protocol. In this step there will be no difference in 
treatment from those patients not enrolled in the study. Post-Operative Care: At this point, 
patients will begin therapies according to the treatment arm to which they have been randomized. 
Study patients will attend post-operative appointments at identical time points to non-study 
patients. These will take place at the following intervals: Post-operative visit 1: 1-2 weeks Post-
operative visit 2: 6-8 weeks Post-operative visit 3: 12-16 weeks Post-operative visit 4: 6 months 
Experimental therapy will finish after 2 weeks. At this visit, all patients will then be maintained 
on intranasal steroid spray and nasal saline irrigations, which is the commonly employed 
therapeutic standard. Thereafter, patients will, per standard protocol, be followed on an 
observational basis depending on the severity of symptoms and response to treatment. At each 
visit, as is done for all individuals, SNOT-22 and LundKennedy endoscopic exam scores will be 
repeated and recorded. 
 
b. 
Procedure Risks 
This study does not seek to evaluate a novel research procedure. Rather, we endeavor to 
determine if a procedure already in place nearly universally is, in fact, beneficial, as there is a 


February 17, 2015 
 
Page 3 of 10 
distinct lack of evidence of suggest so. Overall, we are investigating a procedural method that 
will have fewer side effects than the currently accepted practice. 
c. 
Use of Deception in the Study 
NA 
d. 
Use of Audio and Video Recordings 
NA 
e. 
Alternative Procedures or Courses of Treatment 
All reasonable alternatives are included as a treatment arm in this study. There is no standard of 
care that is being withheld from patients in any group. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
Yes, patients will stop all experimental therapies at the 2 week mark. They will then be placed on 
the typical post-operative regimen, which includes a nasal steroid spray and twice daily saline 
irrigations. They will continue to be followed in our clinic after the 4 week mark, and their 
therapies tailored to their current symptoms and the endoscopic appearance of the nasal cavity. 
g. 
Study Endpoint(s) 
Currently, our post-operative protocol dictates that patients will be seen in clinic at 1 week, 3 
weeks, and 6 weeks after surgery. We will only slightly alter this timeline for study patients. At 
the 2 week appointment, all experimental therapies will be completed. Patients will then be 
started on intranasal steroid sprays and saline irrigations so as not to deviate for an extended 
period from currently accepted practices. We will use the final scheduled appointment at 4 weeks 
after surgery as the official end point for comparison of treatment arms. Additionally, outcomes 
evaluated will be the symptom questionnaire and the endoscopic exam score at each visit. If, 
during the course of follow up, one regimen proves to be clearly superior to another, the study 
will be terminated and patients will receive the optimal therapy. By power analysis, we require 
50 patients to achieve statistical significance. If there is a clearly optimal therapy determined in 
these first 50 patients, we will end our research at that time. All patients will continue to be 
followed beyond 4 weeks depending on symptom severity and response to treatment 
 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
Currently, the preferred treatment regimen for patients with chronic rhinosinusitis (CRS) with 
and without polyps after endoscopic sinus surgery involves a nonstandardized combination of 
oral steroids and antibiotics. The European Position Paper on Rhinosinusitis and Nasal Polyps 
offers guidelines for surgeons in the appropriate therapies to improve patient symptoms based on 
data available in the literature to date. The use of oral steroids in CRS is associated with level IV 
evidence and a category C recommendation, indicating a lack of randomized controlled data to 


February 17, 2015 
 
Page 4 of 10 
support its use (1). Therefore, this almost universal current practice is perpetuated by anecdotal 
data and expert opinion. Furthermore, systemic steroids are associated with known significant 
side effects and potential drug interactions. These may be severe and include but are not limited 
to high blood pressure, hyperglycemia and diabetes, adrenal suppression, weight gain, glaucoma, 
osteoporosis, fluid retention, gastrointestinal bleeding, ulcers, and mood changes (2). Thus, oral 
steroids potentially pose a significant risk, have unproven benefit, and are not appropriate for 
repeated or longterm use – an unfortunate obstacle in treating a chronic disease. Recently, 
steroids dissolved in a saline irrigant have been increasingly used and proven to be effective in 
the routine management of CRS. Furthermore, several studies have suggested the utility and safe 
side effect profile of these medications; however, the data supporting their use as a perioperative 
treatment is distinctly lacking. While the data to support the utility of topical steroids in the 
treatment of CRS is evident, relatively few groups have explored topical steroid irrigations 
specifically as a peri-operative intervention. Fandino et al conducted a meta-analysis of 13 
randomized clinical trails and cohort studies examining the use of topical steroids delivered via 
drops, sprays, nebulizers, or irrigations for patients with CRS with nasal poylps who had 
previously undergone endoscopic sinus surgery. According to his analysis, intra-nasal 
corticosteroids had a significant beneficial effect on symptom scores and a reduction in polyp 
scores. Additionally, the use of INCS decreased the rate of polyp recurrence, and did not alter 
adrenocorticotropic hormones post-intervention, suggesting the intra-nasal delivery method to 
carry less risk than the oral version (3). Snidvongs et al conducted a study with 111 patients and 
reported significant improvement in symptom scores and endoscopy scores over those who did 
not receive postoperative topical steroids (4). Jang et al retrospectively evaluated 60 patients 
postsurgically who were treated with topical steroid deliveries and showed a significant decrease 
in quality of life and endoscopy scores after patients stopped their treatments (5). In summary, 
the data supporting the use of steroids in patients with CRS immediately after endoscopic sinus 
surgery is sparse. We, therefore, seek to more definitively elucidate the role and utility of steroid 
treatment in the peri-operative period. Furthermore, per our review of the literature, there has 
been no direct comparison of the traditional oral regimen to topical therapy (nasal spray). Could 
these be proven equally effective, topically delivered steroids may be considered as a 
replacement for systemic steroids. This would represent a significant shift and improvement in 
the current post-operative management of CRS. Patients would avoid the innumerable side 
effects of oral steroids, which are detailed above. Furthermore, while oral steroid usage is often 
limited by unwanted side effects, a topical regimen may be sustained over a prolonged period as 
a maintenance therapy if symptoms necessitate. 
 
b. 
Findings from Past Animal Experiments 
None 
 


February 17, 2015 
 
Page 5 of 10 
4. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
Prednisone 
Dosage: 
10-40mg daily 
Administration Route 
Oral 
New and different use? (Y/N) 
N 
Commercial Product 2 
Name: 
Flonase 
Dosage: 
50ug/spray 
Administration Route 
Nasal 
New and different use? (Y/N) 
N 
Commercial Product 3 
Name: 
NA 
Dosage: 
NA 
Administration Route 
NA 
New and different use? (Y/N) 
NA 
 
5. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
Based on a current rate of 12-15 endoscopic sinus surgeries weekly, as well as allowing for a 
significant percentage of patients who do not desire to participate in the study, we anticipate 
between 80 and 100 patients to enroll. The study will be conducted only at Stanford Hospitals 
and Clinics. Participants will be those with CRS with and without polyps who have been 
recommended and consented for endoscopic sinus surgery. These participants will be used 
because they suffer from the specific disease for which we endeavor to research alternative 
therapies 
 
b. 
Age, Gender, and Ethnic Background 
We will recruit patients >18 that are able to provide consent. There will be no gender or ethnic 
exclusions. 
c. 
Vulnerable Populations 
NA 
d. 
Rationale for Exclusion of Certain Populations 
Children will not be included in this study as it is not typical for endoscopic sinus surgery to be 
performed in this population. It is rare for them to develop the extent of disease that would 
require surgical intervention, and surgery, in fact, is often avoided as the sinuses have not fully 
developed in the pediatric population. Furthermore, they are unable to provide their own 
informed consent to participate in this trial. 
e. 
Stanford Populations 
NA 


February 17, 2015 
 
Page 6 of 10 
f. 
Healthy Volunteers 
NA 
g. 
Recruitment Details 
Recruitment will be invitation only from the patient population seen in our Rhinology clinics. 
Patients will first be evaluated by our providers. If, based on that evaluation, endoscopic sinus 
surgery is recommended to them and they meet inclusion criteria, they will then be informed of 
the study and its purpose and importance. After this has been discussed, patients will be invited 
to participate if they so choose. Our nurse practitioner performs all study introductions and 
obtains consent. If there are any questions, Rhinology providers are always available for 
consultation. We do not intend to advertise to nor recruit within the general public. There will be 
no recruitment materials. 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
Age > 18 Able to provide informed consent Chronic rhinosinusitis with or without nasal 
polyposis based on published diagnostic criteria Patients undergoing endoscopic sinus surgery 
ii. 
Exclusion Criteria 
Age  
Aspirin exacerbated respiratory disease 
Allergic fungal sinusitis 
Cystic fibrosis  
Immunosuppression  
Chronic steroid use  
Steroid use within 30 days prior to surgery 
 
i. 
Screening Procedures 
Screening will be performed during clinic visits. First, it must be determined if a patient is a 
surgical candidate, which is a decision based on establishing the diagnosis of chronic 
rhinosinusitis by published diagnostic criteria. Furthermore, patients with this diagnosis must 
have failed maximum medical therapy. At the pre-operative appointment, a complete routine 
history will be taken as is standard in our clinics. This will include information regarding past 
medical history, past surgical history, current medications, social history, family history, and 
allergies. This information is readily available to us as a part of the electronic medical record. 
Patients must also confirm accuracy by filling out a questionnaire prior to their first encounter. 
No qualifying laboratory values are necessary. 
j. 
Participation in Multiple Protocols 
We do not anticipate that participants will be enrolled in more than one study. However, we will 
be sure to inquire before enrolling patients if they are actively participating in another study. If 
so, and our interventions may interfere in any way, we will not continue with the enrollment 


February 17, 2015 
 
Page 7 of 10 
process. We do not anticipate difficulty in recruiting the required number of patients, and, 
therefore, will defer to studies in which patients are already enrolled. 
k. 
Payments to Participants 
NA 
l. 
Costs to Participants 
The participant will accrue identical costs to any patient being evaluated and treated for chronic 
rhinosinusitis, which will vary tremendously based on insurance policies. During the process, 
costs that may accumulate include: clinic appointments, prescribed medications, surgical 
intervention, specialty evaluation. No additional costs will be charged based on participation in 
this study. 
m. 
Planned Duration of the Study 
The study duration is anticipated to be 12 months. Time allotted for screening of the participant 
will depend heavily on the time that elapses between the initial patient encounter in clinic and the 
date for which surgery is scheduled. This may require 1-6 months, and occasionally longer. 
Active study participation will begin at the surgical date and end at the 4th post-operative visit. 
Organization and analysis of the data will require 2-4 weeks. 
6. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
NA 
ii. 
Investigational drugs 
NA 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
Oral Prednisone: The side effects of short courses of systemic steroids (<3 weeks) include 
stomach upset, weight gain, insomnia, hyperglycemia, hypokalemia, adrenal suppression, and 
mood changes. These can occur in up to 16% of patients, with stomach upset being the most 
common. These effects are all reversible after stopping the steroid. Topical Fluticasone: The side 
effects of topical steroids include dry throat, sore throat, nasal irritation, headache, nose bleeds. 
These are the more common side effects, the incidence of which is unknown. Rare and serious 
side effects include difficulty breathing, flu symptoms, and vision changes. Again, these 
typically improve after stopping the steroids. On very rare occasion, vision symptoms may be 
permanent. None of these interventions differ from those already being instituted by our staff. 
 
 
iv. 
Procedures 


February 17, 2015 
 
Page 8 of 10 
See the risks of the commercially available drugs - None of these interventions differ from those 
already being instituted by our staff. 
v. 
Radioisotopes/radiation-producing machines 
NA 
vi. 
Physical well-being 
NA 
vii. 
Psychological well-being 
NA 
viii. 
Economic well-being 
NA 
ix. 
Social well-being 
NA 
x. 
Overall evaluation of risk 
Low - innocuous procedures such as phlebotomy, urine or stool collection, no therapeutic agent, 
or safe therapeutic agent such as the use of an FDA approved drug or device. 
b. 
International Research Risk Procedures 
NA 
c. 
Procedures to Minimize Risk 
Medication administration will be monitored during the post-operative visits. Patients will begin 
their assigned therapy the day after surgery, and then will be seen 1, 2, and 4 weeks post-
operatively. Any side effects being encountered will be discussed at these visits, and specialty 
services available in a timely manner to address them if needed. Furthermore, patients have 24 
hour access to a physician in the department, and are, at any time, able to call with questions or 
concerns regarding their treatment.  
Identifiable patient information will be handled per institutional protocol. Unique login 
information is required for all persons wishing to access the electronic medical system. All 
communications with patient data are sent on a secured machine via an encrypted service that is 
password protected. 
 
d. 
Study Conclusion 
The study will officially terminate for each patient after the 4th post-operative visit.  
 
If a patient is experiencing an adverse outcome from surgery or from post-operative therapy, 
their participation in the study will be terminated early in the interest of well-being. In this event, 
patients will be promptly seen in subspecialty clinics (or by inpatient consultants if the patient is 


February 17, 2015 
 
Page 9 of 10 
admitted to the hospital) that may assist in managing these complications. Additionally, if a 
patient is having an emergency, they are able to contact one of our house staff 24 hrs per day for 
advice. As a last resort, our Emergency Department is available for expedited work up of major 
events.  
 
Finally, if it becomes clear after the first 50 patients have completed their interventional therapy 
that one therapy arm is drastically superior to others, and that patients are thus not receiving 
optimal care, the study will be terminated and therapies altered. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
Aggregate Data Analysis Reports Progress toward study endpoints AEs, SAEs, SUSARs 
ii. 
Person(s) responsible for Data and Safety Monitoring 
The Protocol Director will be responsible for Data and Safety Monitoring. 
iii. 
Frequency of DSMB meetings 
NA 
iv. 
Specific triggers or stopping rules 
Currently, our post-operative protocol dictates that patients will be seen in clinic at 1 week, 3 
weeks, and 6 weeks after surgery. We will only slightly alter this timeline for study patients. At 
the 2 week appointment, all experimental therapies will be completed. Patients will then be 
started on intranasal steroid sprays and saline irrigations so as not to deviate for an extended 
period from currently accepted practices. We will use the final scheduled appointment at 4 weeks 
after surgery as the official end point for comparison of treatment arms.  
 
Additionally, outcomes evaluated will be the symptom questionnaire and the endoscopic exam 
score at each visit. If, during the course of follow up, one regimen proves to be clearly superior 
to another, the study will be terminated and patients will receive the optimal therapy. By power 
analysis, we require 50 patients to achieve statistical significance. If there is a clearly optimal 
therapy determined in these first 50 patients, we will end our research at that time. All patients 
will continue to be followed beyond 4 weeks depending on symptom severity and response to 
treatment. 
 
v. 
DSMB Reporting 
NA 
vi. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
Y 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 


February 17, 2015 
 
Page 10 of 10 
N 
f. 
Risks to Special Populations 
NA 
7. 
BENEFITS 
The current standard of care in the management of CRS patients with and without nasal 
polyposis after endoscopic sinus surgery involves a non-standardized regimen of antibiotics and 
systemic steroids. However, the use of oral steroids in this period is based on anecdotal evidence 
and expert opinion (level IV evidence). Given the known risks of oral steroid use, it is important 
to definitively establish their utility and to investigate alternatives. Our study first seeks to more 
clearly define the role of steroids, both oral and topical, in the perioperative setting. Furthermore, 
we intend to establish topical steroids as a safer but equally effective therapy. This information 
will be invaluable to the field and practice of Rhinology. There is a great need for additional 
investigation to determine whether steroids truly have a beneficial role in post-operative CRS 
patients. We endeavor to provide randomized, controlled data on which clinicians may base their 
therapeutic decisions. In addition, the introduction of topical steroids into routine post-operative 
care would fundamentally change current clinical practices, and may even influence future 
guidelines. For patients, this may transform their post-operative care into one that is more easily 
tolerated with less detrimental effects on health. 
8. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health. 

SAP_001.pdf: 
 
Perioperative Oral Steroids for Chronic Rhinosinusitis  
Without Polyps  
Statistical Analysis Plan 
NCT02748070 
July 2, 2020 
Julia Noel, Principal Investigator 
Stanford University 
Stanford, California 94305 
 
 
The planned sample size was 75 patients. By power analysis, we required 50 patients to achieve 
statistical significance. We collected outcome measures of SNOT-22 and Lund-Kennedy 
endoscopy scores at the following time points: preoperative baseline, and postoperatively at 1 
week, 1 month, 3 months, and 6 months.  
 
All statistical analyses were performed using Stata 15 (Stata Statistical Software: Release 15; 
StataCorp LP, College Station, Texas). SNOT-22 total scores, SNOT-22 subdomain scores, 
Lund-Kennedy endoscopic scores, and adverse effects were compared between prednisone and 
placebo groups at each time point using t-tests.