Clinical trial NCT03362515
Conditions: Nasal Polyps
Sponsor: Thomas Jefferson University
Start date: 2017-12-01; Completion date: 2022-04-14
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Prior studies have suggested that topical furosemide may reduce the recurrence of sinonasal polyposis following sinus surgery. This project aims to further investigate that claim through a blinded randomized controlled clinical trial following patients who undergo functional sinus surgery for chronic rhinosinusitis with sinonasal polyposis by randomly assigning participants to receive topical furosemide versus placebo nasal spray for 2 months post operatively. Outcomes would be compared at 6 months through endoscopic grading scores using Lund Kennedy and Meltzer scores as well as Sino-Nasal Outcome Test (SNOT-22) scores to measure the rate and degree of recurrence and impact on symptoms in the treatment group versus placebo.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Furosemide intervention 2: Placebo
Intervention descriptions: intervention 1: furosemide intervention 2: placebo

Protocol documents:
Prot_SAP_000.pdf: 
Q2RESEARCH PROTOCOL TEMPLATE 
INVESTIGATOR INITIATED TREATMENT TRIALS 
 
Title of Project: Treatment of Post-Operative Sinonasal Polyposis with Topical 
Furosemide 
 
Principal Investigator: 
Mindy Rabinowitz, MD, Otolaryngology   
Co-Investigators:  
Gregory Epps MD, Otolaryngology; Marc Rosen, MD, 
Otolaryngology; Gurston Nyquist, MD, Otolaryngology;Jason 
Jerusik PharmD  
 
 
 
 
Abstract 
Prior studies have suggested that topical furosemide may reduce the recurrence 
of sinonasal polyposis following sinus surgery.1,2,3 This project aims to further 
investigate that claim through a blinded randomized controlled clinical trial 
following patients who undergo functional sinus surgery for chronic rhinosinusitis 
with sinonasal polyposis (CRSwP) by randomly assigning participants to receive 
topical furosemide versus placebo nasal irrigation for 6 weeks post operatively. 
Outcomes would be compared at 6 months through endoscopic grading scores 
using Lund Kennedy and Meltzer scores as well as Sino-Nasal Outcome Test 
(SNOT-22) scores to measure the rate and degree of recurrence and impact on 
symptoms in the treatment group versus placebo.  
 
A. Specific Aims 
State the hypothesis and specific aims.  List the long-term objectives and what 
the proposed research will accomplish.   
 
Hypothesis: Topical furosemide prevents the recurrence of sinonasal polyposis 
following endoscopic sinus surgery in CRSwP patients  
 
Through investigating this hypothesis, the group aims to provide evidence for 
treating CRSwP patients with a safe and effective medical therapy to prevent or 
reduce the recurrence of sinonasal polyposis after sinus surgery. If proven 
effective in the immediate post operative period, the research would lead to 
further research aimed at the long term effects of therapy in CRSwP patients to 
develop a protocol to prevent the recurrence of sinonasal polyps and potentially 
change the post-operative management of CRSwP patients.  
 
B.  Background and Significance 
Nasal polyposis is a common disease of the mucous membranes in the nose and 
the paranasal sinuses that develops as a reaction to a variety of stimuli including 
allergens and various microbes.4 They usually occur in chronic rhinosinusitis 
associated with allergy, inflammation, and submucosal edema.5 Nasal polyps are 
associated with nasal congestion, postnasal drip, runny nose, sneezing and 
olfactory disorder that greatly impact patient’s quality of life.6 Management of 
nasal polyposis in this patient population is extremely difficult and functional 
endoscopic sinus surgery remains a mainstay of treatment in those patients who 


have failed medical therapy. That said, there are high rates of recurrence after 
surgery.7 Recent studies have suggested that nasal furosemide may be effective 
in reducing the recurrence of polyps after sinus surgery by affecting inflammation 
and edema post operatively.1-3 However, evidence is limited and insufficient with 
further investigations required. This study aims to provide evidence for treating 
CRS patients with a safe and effective medical therapy to prevent or reduce the 
recurrence of sinonasal polyposis after sinus surgery and limit the morbidity of 
their recurrence in this group of patients as well as the limit the risks of 
corticosteroid steroid therapy used currently.  
 
 
 
 
C.  Preliminary Studies/Progress Report   
Provide an account of preliminary studies and/or information that establishes the 
experience and competence of the investigator to pursue the protocol. 
(suggested length less than ½ page) 
Our principal investigators, Drs. Mindy Rabinowitz, Marc Rosen and Gurston 
Nyquist have extensive experience and specialized training in treating patients 
with chronic sinusitis and nasal polyposis.  At this time, there is no standardized 
treatment for these patients and they often require multiple rounds of oral 
steroids which have associated side effects.  The goal of this study is to 
investigate whether or not the novel use of topical intranasal furosemide can help 
decrease the use of oral steroids for this population.  Collectively, we have the 
the equipment, expertise and knowledge-base to follow through with this study. 
 
 
 
D.  Research Design and Methods 
Describe the research design and procedures to be used (what, when, how) 
Include the duration of participation and early termination criteria.  Provide a flow 
diagram or timetable.  Procedures, situations, or materials that may be 
hazardous to personnel and the relevant precautions, should be outlined here. 
(suggested length not more than 2 pages) 
 
Through a blinded randomized controlled clinical trial, the recurrence rates of 
nasal polyps in patients with chronic rhinosinusitis with polyps who are 
undergoing sinus surgery will be compared through their response to therapy 
with topical furosemide versus placebo.  Eligible patients will be recruited through 
the Otolaryngology Department at Thomas Jefferson University Hospital. During 
pre-operative clinical visits, eligible patients will be selected and provided the 
option to participate in the study.  
 
Topical sinus medications have been administered via Mucosal Atomization 
Device (MAD) in the treatment of chronic rhinosinusitis.  Kanowitz et al studied 
the use of budesonide respules administered via MAD in refractory postoperative 


rhinosinusitis9.  A separate study found that medication administered via the 
MAD resulted in distribution to the maxillary sinus, ethmoid cavity, and frontal 
recess post endoscopic sinus surgery10.   
 
When administering furosemide via the MAD, a total daily dose used in a 
previous nasal spray trial of 300 mcg was utilized11.  Patients may administer 75 
mcg/0.3 ml to each nostril twice daily to result in the total daily dose of 300 mcg.  
The volume of 0.3 ml to each nostril is the volume recommended by the 
manufacturer for intranasal administration via the MAD nasal device.          
 
Performing nasal atomization with 150 mcg twice daily would results in a total 
exposure of 300 mcg of furosemide daily.  Following intranasal administration, a 
drug may enter systemic circulation through direct local absorption in the nasal 
mucosa or oral absorption of the swallowed medication12.  When administering 
intravenous furosemide it has a threshold dose.  No diuretic effect is evident at 
any dose lower than the threshold dose.  The threshold dose for intravenous 
furosemide is 10 mg in a population with normal renal function13.  Extrapolating 
this data, a 300 mcg exposure of furosemide should not result in diuresis.  A 
portion of the drug may also be cleared from the sinuses into the throat and 
swallowed, making it available for gastrointestinal absorption.  Furosemide oral 
solution has a bioavailability of 60%, of that from an intravenous injection of 
furosemide14.  Therefore swallowed medication should not result in therapeutic 
levels of furosemide.   
 
 
After obtaining consent, selected patients will be randomized into 2 groups using 
the balance block randomization method to either treatment group or placebo 
group and be scheduled for surgery. Balance block randomization involves the 
preparation of 4 sheets of paper, writing on 2 sheets “F” for “furosemide” and  on 
2 sheets “P” for “placebo”. The paper sheets will be pooled, placed in a 
container, and randomly drawn 1 at a time without replacement until all sheets 
were drawn. The paper sheets will then be placed back into the container and the 
selection process will be repeated until the sample size is reached. The study 
investigators will be blinded to the selection process and the randomization will 
be carried out by the clinical research nurse. A total of 100 patients will be 
enrolled in the study. 
 
Pre-operatively all patients will receive a 5 day course of 40 mg prednisone, at 
least one week of and intranasal steroid, and saline irrigation. During a 
preoperative clinical visit, the degree of sinonasal polyposis will be graded 
through the Lund Kennedy and Meltzer endoscopic scoring system as well as 
degree of symptoms through SNOT-22 scores. Also, a demonstration and 
instructional sheet for how to administer the nasal spray will be distributed at this 
time.  
 
Then, patients will undergo functional endoscopic surgery as scheduled. 


Immediately post-operatively, patients will begin a 6 week course of twice a day 
nasal spray If assigned to the treatment group they will receive 300 micrograms 
of furosemide daily. If assigned to the placebo group, they will receive saline. The 
clinical research nurse will distribute an unmarked bottle of nasal spray to the 
study patients either in a pre-operative clinical visit or in the recovery room on the 
day of surgery. Creation of the study drug will be done by AdvancedRx of 
Plymouth Meeting, Pa.  The department research nurse will store and distribute 
the study drug to the subjects.  Post-operatively, patients will also receive a 
40mg prednisone taper (40mg for 3 day, 30mg for 3 days, 20 mg for 3 days, 10 
mg for 3 days), nasal saline and a 5-day course of omnicef and at least a 6 week 
course of intranasal corticosteroid spray. Patients will be given a diary to record 
any doses that were missed.  
 
Patients taking aminoglycosides will be excluded from this trial as furosemide 
may increase the ototoxic potential of aminoglycosides.  Study subjects who 
require aminoglycoside use during the study treatment period will be instructed to 
discontinue taking the study drug and will be removed from the study. 
 
Post-operative visits will be scheduled at 1 week, 3 week, 2 month, 4 month and 
6 month intervals. The post-operative visits may be scheduled within 4 days of 
the scheduled interval. Post-operatively, the degree of nasal polyposis will again 
be graded through the Lund Kennedy and Meltzer endoscopic scoring system as 
well as degree of symptoms through SNOT-22 scores. These scores will be 
obtained at the 2, 4 and 6 month visit.   
The duration of participation for the study will be 6 months. Early termination 
criteria are serious adverse reactions, inability to recruit or adequately enroll an 
adequate number of patients, problems arise in the study medicine’s stability or 
manufacturing and new toxicological findings that affect the benefit-to-risk ratio.  
 
E.  Statistical Methods   
If not a pilot study, provide biostatistical design, power calculations determining 
the number of participants , and the proposed analysis. (suggested length: ½ 
page)  
 
Based on prior randomized controlled clinical trials, the study is powered to 
achieve at least 80% power. Based on the results published by Hashemian et 
al.1, Group sample sizes of 40 in ctrl and 40 in treat achieve 95% power to detect 
a difference of 38% vs. 79% using two-sided Fisher's Exact Test with significance 
level 5%. Also based on results published by Passali et al.2, group sample sizes 
of 47 in ctrl and 47 in treat achieve 80% power to detect a difference of 30% vs. 
6% using two-sided Fisher's Exact Test with significance level 5%.  
 
The primary outcomes will be compared through the independent t test for 
continuous variables and the Fischer exact test for nominal variables. All 
statistical analyses will be performed at a significance level of 0.05.  
 


F.  Gender/Minority/Pediatric Inclusion for Research 
All protocols must include documentation of the inclusion of women and 
minorities in the research protocol. If women and minorities are not to be 
included, provide rationale for exclusion. 
The study will include women and minorities. 
 
G.  Human Subjects 
1.  Provide number, age range, and health status of the subject population.  List 
criteria for inclusion or exclusion.  
100 patients, 18 to 65 years old, chronic rhinosinusitis with sinonasasl polyposis  
 
Inclusion Criteria:  
Patients with chronic rhinosinusitis and sinonasal polyposis who are candidates 
for functional endoscopic sinus surgery 
 
Exclusion Criteria:  
Hypersensitivity to furosemide or sulfonamides, pregnancy, history of tinnitus, 
history of sensorineural hearing loss, poorly controlled diabetes, current diuretic 
therapy, known electrolyte disorder, currently taking aminoglycosides, BUN and 
creatinine levels out of the normal range, history of renal disease, allergy to 
sulfonamides.   
 
2.  Identify sources of research material in the form of specimens, records or 
data.  
Patient medical record, physical exam findings (endoscopic scores), SNOT-22 
questionnaire,  
 
3.  Describe plans for recruitment and consent procedures to be followed. 
Patients will be recruited through clinical visits at the Department of 
Otolaryngology at Thomas Jefferson University Hospital. Informed consent will 
be obtained at those clinical visits. Potential subjects will be informed of the 
research and provided a copy of the consent at their office visit with the 
physician. Either the principal investigator, co-investigators, or the department’s 
research nurse will conduct the consent interview. At that time, one of the 
investigators will present the study to the subject.  The subject will be allowed to 
read the consent and ask questions.  The subject may also have the consent 
form read aloud to them.  The investigator conducting the consent interview will 
ensure that all sections of the consent form are reviewed with the subject. 
Subjects will be provided with as much time as they need to review the consent 
form.  If they do not want to sign at the time of this visit, they may bring the 
consent home with them and come back at a later time to sign. 
 
4.  Describe risks and assess likelihood and seriousness. 
Since the study involves the standard of care for CRSwP undergoing sinus 
surgery, the study’s risk are limited to the study drug, topical furosemide. As an 
FDA approved medicine, oral/intravenous furosemide has been shown to have 


the following risks: dehydration and fluid/electrolyte imbalance (hyponatremia, 
hypochloremic alkalosis, hypokalemia, hypomagnesemia or hypocalcemia): 
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle 
pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmia, 
or gastrointestinal disturbances such as nausea and vomiting). In addition 
furosemide has been shown to cause tinnitus and sensorineural hearing loss, 
dizziness, headache and blurred vision. Other reactions in decreasing order 
include hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, 
restlessness, urinary bladder spasm, thrombophlebitis and fever. Some 
hematologic and dermatologic reactions have also been reported. Patients 
allergic to sulfonamides may also be allergic to furosemide due to its 
incorporated sulfa moiety. That said, review of clinical trials of inhaled furosemide 
in acute and chronic asthma indicates that it does not induce significant side 
effects and no diuretic effect has been reported.8 In prior studies with topical 
nasal spray use, topical furosemide has be shown have a limited side effect 
profile including nasal irritation and constipation. It is unlikely that patients 
enrolled in the study will have side effects or adverse events based on prior 
studies and if they do the adverse effects will likely be minor. 
 
 
5.  Describe procedures for protecting against or minimizing potential risks. 
Patients will be screened closely using the inclusion/exclusion criteria involving 
health status and prior sensitivity reactions to furosemide or sulfonamides. Also, 
the patients will be followed closely for adverse reactions during the post-
operative period with visits at 1 week, 3 week, 2 month, 4 month and 6 month 
intervals. Any adverse effect will be documented and if serious appropriate 
intervention or discontinuation of study drug will be addressed.  
 
6.  Describe potential benefits and importance to the subjects and others. 
Topical furosemide nasal spray may limit the recurrence of nasal polyposis. If 
proven effective, it would provide support for a novel use of a well known and 
affordable drug to create a safe and effective medical therapy to limit the 
morbidity of recurrence of polyps and multiple surgical procedures as well as an 
alternative to harmful effects of current therapies involving chronic systemic and 
topic steroid use.  
  
 
 
7.  Discuss why risks are reasonable in relation to benefits.  
Given the minimal risks of topical furosemide, close follow up with monitoring and 
limited length of a 2-month treatment course in a 6 month study with the potential 
benefit of preventing the recurrence of nasal polyposis in this complicated subset 
of patients, the risks of the study are reasonable in relation to the benefits. If 
proven effective, this study may change the post-operative management of nasal 
polyposis and provide patients a safe and effective medical therapy to prevent 
and limit the morbidity of the recurrence of nasal polyps in chronic rhinosinusitis 
patients.  


 
 
H.  Data and Safety Monitoring Plan   
 
All protocols that pose greater than minimal risk must have a Data and Safety 
Monitoring Plan (see DHSP policy G 616 “Independent Monitoring of 
Investigator-Initiated Clinical Trials.” 
 
1.  Describe the Data and Safety Monitoring Plan (DSMP) 
a. reporting mechanisms for adverse events to the IRB, FDA, and NIH. 
Investigators will follow all guidelines for reporting to IRB. 
 
 
 
b. adverse event (AE) grading  
Adverse events will be graded by investigators using the CTCAE v.4. 
 
 
 
c. plan for unanticipated AE reporting 
Unanticipated adverse events will be reported to the IRB per the reporting 
guidelines. 
 
 
 
d. plan for annual reporting of AEs 
Annual reporting of AEs will be done at the time of continuing review. 
 
 
 
e. interim efficacy analysis where appropriate  
If not, just put n/a, no interim efficacy analysis will be done.  
 
2.  If applicable, describe the Data and Safety Monitoring Board (DSMB) that will 
be responsible for monitoring the study.  Indicate Chair, members, areas of 
expertise, frequency of meetings, distribution of reports. 
There is no DSMB for this study. 
 


I.  Literature Cited 
List only literature cited within the text. (suggested length:  no more than 12 references) 
 
    
 
 
 
Date   
5/10/2018 
 
 
Version 
6.0 
 
 
Research Protocol Template, 11/15/2010 
                                                 
1 Hashemian F, Ghorbanian MA, Hashemian F, Mortazavi SA, Sheikhi M, Jahanshahi J, 
Poorolajal J. Effect of Topical Furosemide on Rhinosinusal Polyposis Relapse After Endoscopic 
Sinus SurgeryA Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 
2016;142(11):1045-1049. doi:10.1001/jamaoto.2016.1249 
2 Passàli D, Bernstein JM, Passàli FM, Damiani V, Passàli GC, Bellussi L. Treatment of 
Recurrent Chronic Hyperplastic Sinusitis With Nasal Polyposis. Arch Otolaryngol Head Neck 
Surg. 2003;129(6):656-659. doi:10.1001/archotol.129.6.656 
3 Passàli D, Mezzedimi C, Passàli G, C, Bellussi L, Efficacy of Inhalation Form of Furosemide 
to Prevent Postsurgical Relapses of Rhinosinusal Polyposis. ORL 2000;62:307-310 
4 Michael A. DeMarcantonio, Joseph K. Han, Nasal Polyps: Pathogenesis and Treatment 
Implications, Otolaryngologic Clinics of North America, Volume 44, Issue 3, June 2011, Pages 
685-695, ISSN 0030-6665, http://doi.org/10.1016/j.otc.2011.03.005. 
5 Flint  PW, Bruce  HH, Lund  VJ,  et al.  Cummings Otolaryngology–Head & Neck Surgery. 6th 
ed. Philadelphia, PA: Mosby; 2015.  
6 P.S. Batra, L. Tong, M.J. Citardi Analysis of comorbidities and objective parameters in 
refractory chronic rhinosinusitis Laryngoscope, 123 (Suppl 7) (2013), pp. S1–S11 
7 Wynn, R. and Har-El, G. (2004), Recurrence Rates after Endoscopic Sinus Surgery for Massive 
Sinus Polyposis. The Laryngoscope, 114: 811–813. doi:10.1097/00005537-200405000-00004 
8 Niven AS, Argyros G (2003) Alternate treatments in asthma. Chest 123(4):1254–1265 
9. 
Kanowitz, S. J., Batra, P. S., & Citardi, M. J. (2008). Topical budesonide via mucosal atomization device in 
refractory postoperative chronic rhinosinusitis. Otolaryngology—Head and Neck Surgery, 139(1), 131-136 
10. 
Cannady, S. B., Batra, P. S., Citardi, M. J., & Lanza, D. C. (2005). Comparison of delivery of topical 
medications to the paranasal sinuses via “vertex-to-floor” position and atomizer spray after FESS. Otolaryngology—
Head and Neck Surgery, 133(5), 735-740.  
11. 
Hashemian, F., Ghorbanian, M. A., Hashemian, F., Mortazavi, S. A., Sheikhi, M., Jahanshahi, J., & 
Poorolajal, J. (2016). Effect of topical furosemide on rhinosinusal polyposis relapse after endoscopic sinus surgery: 
a randomized clinical trial. JAMA Otolaryngology–Head & Neck Surgery, 142(11), 1045-1049. 
12. 
Derendorf, H., & Meltzer, E. O. (2008). Molecular and clinical pharmacology of intranasal corticosteroids: 
clinical and therapeutic implications. Allergy, 63(10), 1292-1300. 
13. 
Oh, S. W., & Han, S. Y. (2015). Loop diuretics in clinical practice. Electrolytes & Blood Pressure, 13(1), 
17-21. 
14. 
Lasix(R) [package insert]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2011. 

ICF_001.pdf: