Clinical trial NCT02630472
Conditions: Rhinitis Sinusitis
Sponsor: University of Pennsylvania
Start date: 2015-10-01; Completion date: 2017-05-04
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the physiologic response of quinine-saline irrigations for acute exacerbation of uncomplicated chronic rhinosinusitis following endoscopic sinus surgery. Subjects who have previously had functional endoscopic sinus surgery with acute exacerbation of chronic rhinosinusitis will be randomized to either a quinine-saline or saline-placebo arm. The investigators will measure baseline and follow-up clinical and quality-of-life outcomes for both arms, and then compare the groups at the end of the study period. The investigators' hypothesis is that the participants in the quinine sulfate arm will perform better on all measures as compared to the control arm.

Detailed description:
Overall Objectives:

To evaluate the physiological differences between quinine-saline irrigations vs. saline-placebo irrigations for acute exacerbation of uncomplicated chronic rhinosinusitis following endoscopic sinus surgery. A secondary objective is to determine if the use of quinine is efficacious as an alternative therapy to treat bacterial rhinosinusitis.

Background:

Sinusitis is a common disorder accounting for an estimated 13 million physician office visits in the United States each year. The aggregated cost of sinusitis is approximately $8 billion annually, affecting an estimated 16% of the population in the United States. Despite multiple attempted treatments, including an estimated 550,000 surgeries per year, the disease continues to be a major health problem, both in expenditures and poor quality of life. Recent analysis of data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey from 2006 to 2010 showed that rhinosinusitis accounted for more outpatient antibiotic prescriptions in adults than any other diagnosis.

Chronic rhinosinusitis (CRS) represents a considerable subset of this population and accounts for a significant portion of expenditures and the vast majority of surgeries. It is defined as signs and symptoms of sinusitis lasting more than 12 weeks. Unlike the organisms responsible for acute rhinosinusitis, difficult to treat bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus and Stenotrophomonas multiformia are often offending pathogens in CRS. Their prevalence increases in those patients who have already had sinus surgery and continue to get recurring sinus infections. Staph aureus and gram-negative organisms have been shown to account for roughly 60% of infections in those patients who have previously undergone endoscopic sinus surgery. Due to increasing drug resistance as well as the potential for biofilm formation, there has been an increasing pressure from both patients and clinicians alike to develop alternative treatments to systemic antibiotics. One commonly used alternative in patients who have had previous sinus surgery is topical saline irrigation with and without other topical preparations. Topical irrigations have much greater paranasal sinus penetration in post surgical patients. Commonly used topical preparations include: saline alone or saline mixed with mupirocin, gentamicin, tobramycin, ceftazadine, betadine, manuka honey, baby shampoo, budesonide or mometasone.

The investigators have recently identified a novel arm of upper airway innate immunity mediated by bitter taste receptors. When a subset of airway bitter taste receptors are activated they stimulate the respiratory epithelium to generate nitric oxide, an important component of sinus innate immunity that increases mucociliary clearance as well as diffuses into the mucus where it is bactericidal. A topical therapy to activate these taste receptors may help the sinuses clear infections through this natural innate defense mechanism. While the investigators have identified multiple bitter compounds that stimulate this response, quinine piqued our interest as it activates multiple bitter taste receptors and has already been used in the human nose.

Arms: arm 1: Each study participant randomized into the experimental arm will receive 28 tubes with 1mg/ml (6 mls total) of quinine sulfate, as well as 28 3cc syringes with the mucosal atomizing devices. The solutions will be supplied in light-protected tubes. Patients will apply 3 mls of quinine sulfate to each nostril twice per day. Thus the patients will be exposed to a maximum of 12mls or 12.0 mg of quinine per day.

The Investigational Drug Service (IDS) will prepare and record the distribution of the irrigant. The Clinical Research Coordinator or Clinical Research Nurse will pick up the solutions and will demonstrate the application to the subject. The application of the solution is exactly the same as if the study subject were to irrigate with regular saline as part of their daily regimen for chronic rhinosinusitis. arm 2: The placebo arm will be spiked with Sucrose Octaacetate which has a bitter taste, but does not stimulate sinonasal nitric oxide production.

Each study participant will receive 28 tubes with 0.5mg/ml sucrose octaacetate, as well as 28 3cc syringes with the mucosal atomizing devices. The solutions will be supplied in light-protected tubes.

The placebo arm will mirror the experimental arm exactly, except for the treatment solution contained in the vials.
Interventions: intervention 1: Quinine Sulfate intervention 2: Placebo
Intervention descriptions: intervention 1: Our plan is to first study quinine against saline to determine efficacy and safety. The vast majority of patients with rhinosinusitis utilize low pressure / high volume (240mls) sinonasal lavage to cleanse the sinonasal cavity. The patients will be exposed to a maximum of 12mls or 12.0 mg of quinine. In standard tonic water, quinine is 8.3mg/100mls and thus an 8oz glass of Canada Dry tonic water has 19.6mg of quinine. Thus, the maximum systemic exposure in our study (assuming ingestion of the total nasal administration) is less than drinking one glass of tonic water / day. To put this in context, the therapeutic range of quinine to treat malaria is 10mg/kg true ileal digestibility (TID) (2100mg for a 70kg individual) nearly 200 X the dose the investigators are proposing. intervention 2: In order to blind the participants to which arm they have been randomized into, the placebo arm will contain saline solution spiked with 0.5 mg/ml sucrose octaacetate. This solution will produce a bitter flavor similar to the one produced by quinine. There is no evidence that sucrose octaacetate produces nitric oxide production in the sinonasal cavity, nor is there evidence that it has any side effects (it is used to wean babies off of pacifiers) so the investigators feel it is an effective and safe option for a placebo.

Protocol documents:
Prot_SAP_000.pdf: 
  
CONFIDENTIAL 
 
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CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
Protocol Title:  
 
 
 
 
Efficacy and Safety of Adjuvant Topical Irrigation in the 
Treatment of Acute Exacerbation of Chronic Rhinosinusitis 
Following Functional Endoscopic Sinus Surgery (FESS) 
Principal Investigator: 
 
 
 
 
 
 
Regulatory Sponsor: 
Nithin D. Adappa, M.D. 
Dept. of Otorhinolaryngology 
3400 Spruce St, Ravdin 5th Floor 
215-662-2360 
Nithin.Adappa@uphs.upenn.edu 
 
 
Bert W. O’Malley, Jr., M.D. 
Dept. of Otorhinolaryngology 
3400 Spruce St, Ravdin 5th floor 
215-349-5383 
Bert.OMalley@uphs.upenn.edu 
 
 
IRB Protocol Number: 
 
821731 
IND Number: 
128711 
ClinicalTrials.gov Number: 
02630472 
 
 
 
 
 
 
 
Initial version: 12/04/2014 
Amended: 
11/12/2015 
Amended: 
03/01/2016 
Amended:          05/24/2016 
Amended:  
06/30/2016 
Amended: 
09/27/2016 
Amended: 
02/08/2017 
Amended: 
05/11/2017 
Amended: 
07/11/2017 


Topical Irrigation Therapy for CRS 
 
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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1 
INTRODUCTION .................................................................................................................................. 2 
1.1 
BACKGROUND ................................................................................................................................ 2 
1.2 
INVESTIGATIONAL AGENT ................................................................................................................ 2 
1.3 
PRECLINICAL DATA ........................................................................................................................ 2 
1.4 
CLINICAL DATA TO DATE................................................................................................................. 3 
1.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................ 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 3 
3 
STUDY DESIGN ................................................................................................................................... 4 
3.1 
GENERAL DESIGN .......................................................................................................................... 4 
3.2 
PRIMARY STUDY ENDPOINTS .......................................................................................................... 4 
3.3 
SECONDARY STUDY ENDPOINTS ..................................................................................................... 5 
3.4 
PRIMARY SAFETY ENDPOINTS ......................................................................................................... 5 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................... 5 
4.1 
INCLUSION CRITERIA ...................................................................................................................... 5 
4.2 
EXCLUSION CRITERIA ..................................................................................................................... 5 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 5 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................. 6 
4.4.1 
When and How to Withdraw Subjects ..................................................................................... 6 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .......................................................... 6 
5 
STUDY DRUG ...................................................................................................................................... 6 
5.1 
DESCRIPTION ................................................................................................................................. 6 
5.2 
TREATMENT REGIMEN .................................................................................................................... 6 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................... 6 
5.4 
PREPARATION OF STUDY DRUG ...................................................................................................... 6 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................... 6 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................... 7 
5.7 
PACKAGING ................................................................................................................................... 7 
5.8 
BLINDING OF STUDY DRUG ............................................................................................................. 7 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................ 7 
5.9.1 
Receipt of Drug Supplies ......................................................................................................... 7 
5.9.2 
Storage .................................................................................................................................... 7 
5.9.3 
Dispensing of Study Drug ........................................................................................................ 7 
5.9.4 
Return or Destruction of Study Drug ....................................................................................... 7 
6 
STUDY PROCEDURES ....................................................................................................................... 7 
6.1 
VISIT 1 (WEEK 0) ............................................................................................................................ 8 
6.2 
VISIT 2 (WEEK 2) ............................................................................................................................ 8 
6.3 
VISIT 3 (WEEK 10) .......................................................................................................................... 8 
6.4 
SAMPLE SIZE DETERMINATION ........................................................................................................ 8 
6.5 
STATISTICAL METHODS .................................................................................................................. 8 
6.6 
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 9 
7 
SAFETY AND ADVERSE EVENTS ..................................................................................................... 9 
7.1 
DEFINITIONS .................................................................................................................................. 9 
7.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 10 
7.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 10 
7.3.1 
Investigator reporting: notifying the Penn IRB ....................................................................... 10 


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7.4 
UNBLINDING PROCEDURES ........................................................................................................... 11 
7.5 
STOPPING RULES ......................................................................................................................... 11 
7.6 
MEDICAL MONITORING ................................................................................................................. 11 
8 
DATA HANDLING AND RECORD KEEPING ................................................................................... 12 
8.1 
CONFIDENTIALITY ......................................................................................................................... 12 
8.2 
SOURCE DOCUMENTS .................................................................................................................. 12 
8.3 
CASE REPORT FORMS.................................................................................................................. 12 
8.4 
RECORDS RETENTION .................................................................................................................. 12 
9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 12 
9.1 
STUDY MONITORING PLAN ............................................................................................................ 12 
9.2 
AUDITING AND INSPECTING ........................................................................................................... 13 
10 
ETHICAL CONSIDERATIONS .......................................................................................................... 13 
11 
STUDY FINANCES ............................................................................................................................ 13 
11.1 
FUNDING SOURCE ........................................................................................................................ 13 
11.2 
CONFLICT OF INTEREST ................................................................................................................ 13 
11.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 13 
12 
PUBLICATION PLAN ........................................................................................................................ 13 
13 
REFERENCES ................................................................................................................................... 14 
 


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List of Abbreviations 
 
CRS  
 
Chronic Rhinosinusitis 
NO  
 
Nitric Oxide 
FESS  
Functional Endoscopic Sinus Surgery 
HUP 
 
Hospital of the University of Pennsylvania 
CRF 
 
Case Report Form 
AE 
 
Adverse Event 
SAE 
 
Serious Adverse Event 
IDS 
 
Investigational Drug Service 
 
 
 
 
 
 
 


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Study Summary 
 
Title 
Efficacy and Safety of Adjuvant Topical Irrigation in the Treatment of Acute 
Exacerbation of Chronic Rhinosinusitis Following Functional Endoscopic Sinus 
Surgery (FESS) 
Short Title 
Topical Irrigation Therapy for CRS 
Protocol Number 
821731 
Phase 
II 
Methodology 
Randomized, double-blinded, placebo-controlled clinical trial. 
Study Duration 
3 years for accrual and follow up (+1 year for data analysis) 
Study Center(s) 
Single-center: Dept. of Otorhinolaryngology at HUP 
Objectives 
To evaluate the physiological differences between quinine-saline vs sucrose 
octaacetate-placebo nasal irrigations in subjects with CRS (both with and 
without polyps) as well as allergic fungal sinusitis. 
Number of Subjects 
Number of subjects projected for the entire study: 100 
Diagnosis and Main 
Inclusion Criteria 
Chronic Rhinosinusitis post FESS 
Study Product, Dose, 
Route, Regimen 
Nasal instillation of quinine sulfate and saline solution using a 3cc syringe 
adopted with an atomizer.  
Duration of 
administration 
Total duration of drug product administration (including any open-label lead-in, 
if applicable) is twice/day for 28 days. 
Reference therapy 
Desroisers et al. (2001) findings showed that topical quinine in saline nasal 
solution was comparable, if not better to topical tobramycin (a commonly used 
antibiotic) for treatment of bacterial sinusitis.  
Statistical 
Methodology 
Longitudinal linear mixed-effects models to evaluate pre- and post-treatment 
continuous outcome scores. 
 


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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference 
on Harmonization guidelines), applicable government regulations and Institutional research policies and 
procedures.  
1.1 Background 
Sinusitis is a common disorder accounting for an estimated 13 million physician office visits in the United 
States each year1.  The aggregated cost of sinusitis is approximately $8 billion annually2, affecting an 
estimated 16% of the population in the United States1.  Despite multiple attempted treatments, including 
an estimated 550,000 surgeries per year3, the disease continues to be a major health problem, both in 
expenditures and poor quality of life.  Recent analysis of data from the National Ambulatory Medical Care 
Survey and the National Hospital Ambulatory Medical Care Survey from 2006 to 2010 showed that 
rhinosinusitis accounted for more outpatient antibiotic prescriptions in adults than any other diagnosis4. 
 
Chronic rhinosinusitis (CRS) represents a considerable subset of this population and accounts for a 
significant portion of expenditures and the vast majority of surgeries.  It is defined as signs and symptoms 
of sinusitis lasting more than 12 weeks5,6.  Unlike the organisms responsible for acute rhinosinusitis, 
difficult to treat bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus and 
Stenotrophomonas multiformia are often offending pathogens in CRS7. Their prevalence increases in 
those patients who have already had sinus surgery and continue to get recurring sinus infections.  Staph 
aureus and gram-negative organisms have been shown to account for roughly 60% of infections in those 
patients who have previously undergone endoscopic sinus surgery7.  
 
Due to increasing drug resistance as well as the potential for biofilm formation, there has been an 
increasing pressure from both patients and clinicians alike to develop alternative treatments to systemic 
antibiotics. One commonly used alternative in patients who have had previous sinus surgery is topical 
saline irrigation with and without other topical preparations. Topical irrigations have much greater 
paranasal sinus penetration in post surgical patients8. Commonly used topical preparations include: saline 
alone or saline mixed with mupirocin, gentamicin, tobramycin, ceftazadine, betadine, manuka honey, 
baby shampoo, budesonide or mometasone9.   
 
We have recently identified a novel arm of upper airway innate immunity mediated by bitter taste 
receptors10-15.  When a subset of airway bitter taste receptors is activated they stimulate the respiratory 
epithelium to generate nitric oxide, an important component of sinus innate immunity that increases 
mucociliary clearance as well as diffuses into the mucus where it is bactericidal.  A topical therapy to 
activate these taste receptors may help the sinuses clear infections through this natural innate defense 
mechanism.  While we have identified multiple bitter compounds that stimulate this response, quinine 
piqued our interest as it activates multiple bitter taste receptors and has already been used in the human 
nose.   
1.2 Investigational Agent 
Quinine sulfate (USP Grade) as well as Sucrose Octaacetate (USP Grade, from Spectrum 
Pharmaceuticals, Nenderson, NV).  Both are commonly used as agents to mimic a bitter taste in placebos 
at Penn IDS. 
1.3 Preclinical Data 
Using primary human sinonasal epithelial cells loaded with the intracellular dye DAF-FM we have 
screened multiple bitter tasting compounds12,13.  We have found that quinine stimulates robust NO 
production in a dose dependent manner that is mediated via T2Rs.  Sucrose Octaacetate (used to wean 
babies off pacifiers) does not stimulate sinonasal epithelial cells to produce NO. 
 


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Repetitive treatment (daily application) of Quinine (1mg/ml) to primary human sinonasal cultures does not 
demonstrate tachyphylaxis regarding NO production, nor demonstrates any cellular toxicity.   
1.4 Clinical Data to Date 
In a 2001 study by Desrosiers et al16, topical tobramycin was being evaluated for efficacy in medically 
recalcitrant bacterial sinusitis.  In order to blind the control group, quinine was added to saline to mimic 
the bitter taste of tobramycin.  Patients were treated with nasal solutions three times per day for 4 weeks.  
Interestingly, both treatment arms demonstrated clinical improvement, with the saline+quinine arm 
demonstrating comparable if not better efficacy to topical tobramycin with no adverse events reported in 
the study.  These findings were surprising and “unexplained” to the authors at the time.  We now believe 
that the quinine in their “control” group stimulated airway bitter taste receptors to stimulate sinonasal nitric 
oxide production to eradicate the infection.  We should also mention that tobramycin does not stimulate 
NO production in primary human sinonasal epithelial cells.  
 
Additionally, safety of quinine administration is further supported by a prior 1993 study that utilized 
quinine to determine compliance with nebulized tobramycin in the management of CF pseudomonas17.   
In this study the pharmacokinetics of inhaled tobramycin was evaluated.  To assess compliance with the 
protocol both the tobramycin and placebo arms were spiked with quinine (1mg/ml) and urine quinine 
concentrations were checked.  No adverse events were reported for the use of quinine in the airway. 
 
 
Thus, we propose to repeat the Desrosiers study, but to instead evaluate quinine as a therapeutic agent, 
not a placebo, and directly compare quinine to saline (spiked with Sucrose Octaacetate).  Truth be told, 
we stumbled onto the biologic effect of quinine in the search for a bitter compound to use in a randomized 
trial with another bitter compound.  Surprisingly, quinine stimulated a more robust NO response than our 
original compound of interest (phenylthiocarbamide).  Subsequently, we discovered the 2001 Desrosiers 
study that further supported the concept of quinine as a topical therapy for bacterial sinusitis.  
1.5 Dose Rationale and Risk/Benefits 
Our plan is to first study quinine against saline to determine efficacy and safety.  The vast majority of 
patients with rhinosinusitis utilize low pressure / high volume (240mls) sinonasal lavage to cleanse the 
sinonasal cavity9.  We propose to have the patients administer 6mls of quinine (1mg/ml) (same 
concentration that was used in the study mentioned above, which also activates NO production from 
human primary nasal cells in vitro) via a 3cc syringe with a mucosal atomizing device (MAD) on the tip.  
Patients will apply 3 mls to each nostril twice per day.  Thus the patients will be exposed to a maximum of 
12mls or 12.0 mg of quinine.  In standard tonic water, quinine is 8.3mg/100mls and thus an 8oz glass of 
Canada Dry tonic water has 19.6mg of quinine.  Thus, the maximum systemic exposure in our study 
(assuming ingestion of the total nasal administration) is less than drinking one glass of tonic water / day.  
To put this in context, the therapeutic range of quinine to treat malaria is 10mg/kg TID (2100mg for a 70kg 
individual) nearly 200 X the dose we are proposing.  
 
 
We propose to enroll only patients who have had prior functional endoscopic sinus surgery (FESS) for 
two reasons: (1) better access to the sinonasal cavity to obtain microbiologic samples before, during and 
after the trial, and (2) patients with a marsupialized sinonasal cavity are not at risk for developing intra-
orbital or intra-cranial complications from bacterial sinusitis, as a path of egress for the infection is widely 
patent into the nose.  
 
2 Study Objectives 
The overall objective of this study is to evaluate the efficacy of quinine nasal irrigations as a first line therapy 
for acute exacerbations of uncomplicated chronic rhinosinusitis following endoscopic sinus surgery.  
 
 
2.1  Primary Outcome Variable(s)   
 


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The primary outcomes variables are:  
• 
Pre- and post-treatment endoscopically guided sinonasal microbiologic cultures 
• 
Pre- and post-treatment nasal endoscopy scored with the Lund-Kennedy scoring system by a 
blinded investigator18. 
• 
Pre- and post-treatment quality of life questionnaires (22-item Sinonasal Outcomes Test [SNOT-
22]). 
• 
The necessity for rescue oral antibiotics for persistent infection. 
 
2.2.  Secondary Outcome Variable(s) 
The secondary outcomes variables are: 
• 
Pre- and post-treatment Sniffin’ Stick-12 (Burghart Instruments, Wedel, Germany) score. 
• 
Pre- and post-treatment CT scan scored with the Lund-MacKay CT scoring system 19  by a blinded 
investigator.  The CT scans at pre and post will only be done if clinically indicated by the physician. 
• 
Pre- and post-treatment microbiome analysis 
• 
Pre-treatment taste test to determine bitter taste sensitivity 
 
3 Study Design 
3.1 General Design 
• This is a Randomized, double-blinded, placebo-controlled protocol 
• The duration of subject participation is approximately 12 weeks 
o 
(Week 0) Screening/Baseline:  
 
Microbiome swab obtained 
 
Sniffin’ Stick-12 
 
Nasal Endoscopy (Lund-Kennedy Score) 
 
CT scan (Lund-MacKay CT Score) if clinically indicated. 
 
SNOT-22 survey 
 
Nasal Irrigation distributed (Week 0) 
4 week period of nasal irrigation administration (2 times a day)  
o 
(Week 4) 
 
Microbiome swab obtained 
 
Nasal Endoscopy (Lund-Kennedy Score) 
 
Sniffin’ Stick-12Microbiology/traditional swab*  
 
SNOT-22 survey 
o 
(Week 12) Return to clinic for assessment of durable changes:  
 
Microbiome swab obtained 
 
Sniffin’ Stick-12 
 
Microbiology/traditional swab* 
 
SNOT-22 survey 
 
CT scan (Lund-MacKay CT Score) if clinically indicated 
 
* Microbiology/traditional swabs are part of routine care if pus is evident during routine clinical nasal 
endoscopy. 
3.2 Primary Study Endpoints 
• Efficacy of quinine and saline irrigations compared to saline irrigations alone. 
• Changes in quality of life (SNOT-22 questionnaire) (both composite and subscale scores) 
• Nasal endoscopy (Lund-Kennedy Score) 
• Alterations in microbiology recovered (as determined by sinus microbiology culture) 
• Whether or not conventional antibiotics were needed to treat the infection during or following 
the irrigation trial (as prescribed as part of routine care) 


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3.3 Secondary Study Endpoints 
• Changes in olfaction as quantified with the Sniffin’ Stick-12 score [administered as part of 
research] 
• Pre and post treatment CT scan as scored by the Lund-MacKay CT scoring system 19.  These 
scores will only be available if CT scans are clinically indicated at the time of baseline and/or 12-
week post clinical visits. 
• Alterations in the Sinonasal microbiome (conducted as part of an ongoing research project) 
3.4 Primary Safety Endpoints 
• Tolerability (due to bitterness). 
 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1. Patients diagnosed with chronic rhinosinusitis, with and without polyps, as well as allergic fungal 
sinusitis 
2. Patients who have undergone Functional Endoscopic Sinus Surgery (FESS)  
3. Purulent drainage on nasal endoscopy  
4. Male or female subjects, 18 years of age or older 
5. Patients seen at the Dept. of Otorhinolaryngology clinic at HUP, a tertiary care clinic.  
4.2 Exclusion Criteria 
1. Pregnant women 
2. Immunocompromised patients 
3. Granulomatous diseases with rhinologic manifestations (Wegner’s, Sarcoid, Churg-Strauss) 
4. Primary ciliary dyskinesia  
4.3 Subject Recruitment and Screening 
All study personnel will be appropriately trained and certified according to their role in the study and 
duties, including HIPAA and CITI training.  
 
Subjects will be identified and approached as they present to clinic for their routine treatment for chronic 
rhinosinusitis. Subjects will be brought into a private clinical examination room where a clinical research 
nurse will explain the protocol in detail. Subjects will have the time to ask and have questions answered 
about the research prior to signing the consent form.  
 
Patients interested in enrolling in the study will be instructed on how to administer the solutions using a 
3cc syringe with an atomizer and have the opportunity to trial this technique with isotonic buffered saline 
under direct supervision of the treating physician or research coordinator.  Patients who feel that they can 
adequately self-administer the solution will be asked to participate in the study.  
 
Subjects who withdraw or are otherwise not interested in the protocol will have access to the ENT clinic 
for their regular care. They will be reminded that their care (and if applicable, employment, or student 
status at Penn) will in no way be affected by their decision to participate in the protocol or not. 
 
As per FDA recommendation, the first 10 patients enrolled into the study will be placed into the treatment 
arm, and will not be randomized. The purpose of this is to make sure that the treatment is efficacious 
enough to rationalize going forward with the trial.  This will not affect the ICF, as the patient will not be 
aware of this forced assignment into the treatment arm (i.e. they will still be blinded to their assignment). 


Topical Irrigation Therapy for CRS 
 
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4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subject may be withdrawn from the study prior to the expected completion of the protocol if the subject 
fails to adhere to protocol requirements, subject withdraws consent, or symptoms of acute rhinosinusitis 
exacerbation persist. Subjects will return to routine clinical care at that point.  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
Even though subjects may be prematurely withdrawn from the study, it is imperative to collect infection 
data (microbiology swabs) or symptomatic data. Such data is important to the integrity of the final study 
analysis since early withdrawal could be related to the tolerability profile or the ineffectiveness of the 
therapy.  If a subject withdraws consent to participate in the study, attempts should be made to obtain 
permission to follow up with the subject’s CRS for the duration of the 12-week follow-up period.  Subjects 
with incomplete/missing data will not be included in the analysis.  
 
 
5 Study Drug  
5.1 Description 
IDS will compound 0.9% buffered sterile NaCl for irrigation with USP grade quinine to a 1mg/ml 
concentration.  For the placebo arm, IDS will compound 0.9% sterile NaCl for irrigation with sucrose 
octaacetate (0.5mg/ml) to achieve the same degree of bitter taste as 1mg/ml concentration of quinine19. 
5.2 Treatment Regimen 
1 mg/ml concentration of quinine in saline solution will be given to participants to instill in each. Doses will 
be administered by use of an LMA® MAD NASAL™ Intranasal Mucosal Atomization Device with 3mL 
syringe and vial adapter (Teleflex Medical, Research Triangle Park NC; item # MAD140OS), which is 
patient-specific, or other comparable device.  If using a different device, the Sponsor will provide a 
statement confirming the devices’ comparability or equivalence.  Participants will do this twice per day for 
4 weeks. 
5.3 Method for Assigning Subjects to Treatment Groups 
Urn Randomization20 will be used to assign subjects to treatment groups.  Urn randomization is a type of 
adaptive biased-coin randomization, where the probability of being assigned to the treatment arm 
changes as the balance of participants in the treatment and placebo groups changes.  For example, when 
the first patient is added, assignment is based on simple randomization.  If that patient is assigned to the 
treatment arm, then the probability of the 2nd patient being assigned to the treatment arm is decreased by 
a probability p. As patients are recruited, the probability of being assigned to either arm adapts in 
response to the size of each arm at the time of recruitment. 
5.4 Preparation of Study Drug 
IDS will prepare and record the distribution of the irrigant. The Clinical Research Coordinator or Clinical 
Research Nurse will pick up the solutions and will demonstrate the application to the subject. The 
application of the solution is exactly the same as if the study subject were to irrigate with regular saline as 
part of their daily regimen for chronic rhinosinusitis. 
5.5 Subject Compliance Monitoring 
In general, these are highly motivated patients who are seeking alternative therapy for traditional 
antibiotics.  They have undergone surgical intervention (sometimes multiple surgeries). However, the 
measure of compliance will be determine by measuring the amount of solution remaining as the subjects 
return their irrigant bottles at the 4-week visit. 


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5.6 Prior and Concomitant Therapy 
The vast majority of our patients are typically using intranasal steroids. This is permitted during this trial.  
We will ask them not to use any conventional oral, or topically applied antibiotics.  If the patient feels that 
their infection is progressing, we would ask that they return to the clinic for evaluation at which time, the 
treating physician can decide to place them on standard antibiotic therapy. 
5.7 Packaging 
1 mg/ml concentration of quinine in saline solution will be given to participants to instill in each nostril.  
Product will be packaged in 90mL amber glass boston rounds, which have been autoclaved prior to use.  
A pharmaceutical press-in bottle adapter will be inserted into the neck and a child-resistant cap tightly 
placed onto the bottle.  Doses will be administered by use of an LMA® MAD NASAL™ Intranasal 
Mucosal Atomization Device with 3mL syringe and vial adapter (Teleflex Medical, Research Triangle Park 
NC; item # MAD140OS), which is patient-specific. Participants will do this twice per day for 4 weeks.  
Subjects will clean the mucosal atomization device after each use with an alcohol swab.   
 
Blinding of Study Drug 
The placebo arm will be spiked with Sucrose Octaacetate which has a bitter taste, but does not stimulate 
sinonasal NO production. 
5.8 Receiving, Storage, Dispensing and Return 
5.8.1 Receipt of Drug Supplies 
 
Upon receipt of the of the study supplies, an inventory must be performed and a receipt log filled out and 
signed by the person accepting the shipment.  It is important that the designated study staff counts and 
verifies that the delivery from IDS contains the necessary items for the protocol.   
5.8.2 Storage 
Solutions can be stored at room temperature in the light protected bottles they are supplied with. 
5.8.3 Dispensing of Study Drug 
IDS will record and dispense the quinine or placebo.  
5.8.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of solution provided, consumed, and 
solution remaining.  This reconciliation will be logged on the reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused irrigant.   
 
6 Study Procedures 
 
Clinical Care 
Research 
Baseline Visit  
(Week 0) 
SNOT-22 
Microbiome swab(s) 
CT Scan of Sinus (if clinically indicated) 
Sniffin’ Stick Test 
Nasal Endoscopy 
Given Saline OR Quinine Solution 
Sinus culture swab(s) 
Taste test 
Irrigate Sinus 2 Times Every Day for 4 Weeks 
4 Week Visit (+/- 7 days) SNOT-22 
Microbiome swab(s) 
Sinus culture swab(s) 
Sniffin’ Stick Test 
Nasal Endoscopy 
Return Unused Solution  


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12 Week Visit (+/- 14 
days) 
 
SNOT-22 
Microbiome swab(s) 
CT Scan of Sinus (if clinically indicated) 
Sniffin’ Stick Test 
Nasal Endoscopy 
 
Sinus culture swab(s) 
 
 
6.1 Visit 1 (week 0) 
Patients who consent to participate will be randomized to a treatment arm of quinine and saline (1mg/ml) 
or sucrose octaacetate (0.5mg/ml) in saline as dispensed by IDS. The study nurse coordinator will instruct 
the patient on how to administer the solution.  
 
Following the routine endoscopically guided sinus culture swab, an additional research microbiome swab 
will be obtained.  Patients will be asked to complete a routine Sinonasal Outcomes Test (SNOT-22) 
questionnaire as well as undergo a Sniffin’ Stick Test as part of the research. Additionally, as part of their 
initial clinical assessment, a nasal endoscopy will be performed and recorded. This will later be scored by 
a blinded clinical investigator.  If a CT scan of the sinuses is clinically indicated, then one will be 
performed.  Additionally, a taste test to determine bitter taste sensitivity will be administered.  This taste 
test is comprised of non-toxic solutions which are not swallowed by the patient. 
6.2 Visit 2 (week 4, +/- 7 days) 
Subject is asked to return to the clinic where they will be subjected to the same procedures at Visit 1.  
The clinical research nurse will measure and record the volume of nasal spray remaining in the stock 
bottle to determine compliance.  No CT scan will be performed at the 2nd visit. 
6.3 Visit 3 (week 12, +/- 14 days) 
Subject is asked to return to the clinic where they will be subjected to the same procedures at Visit 1.  A 
CT scan will only be performed if clinically indicated by the physician. 
6.4 Sample Size Determination 
There is no prior data to base a power calculation on.  This trial will utilize a total of 100 patients to help 
guide future studies with appropriate power.  In order to determine this sample size, we utilized a 
calculation that would ensure us that our confidence interval has a specified width.  A previous study 
sampled over 300 CRS patients and found pre- and post-surgical SNOT-22 scores to have a standard 
deviation of about 2021.  Based on this prior work, we estimate the required sample size to detect an 
effect with a precision of 10 (half the width of the desired 95% CI) to be 32 patients in each group.  We 
will therefore recruit a total of n=100 patients in order to provide a margin for error, early withdrawal, or 
non-compliance. 
6.5 Statistical Methods 
 
Data will be analyzed after 100 subjects have completed the study.  Descriptive demographic data will be 
compiled including mean and median age, adjuvant therapy use, use of oral antibiotics, and microbiome 
profile. Longitudinal linear mixed effects modeling will be used to examine the relationship between all 
outcome measures and treatment assignment, assuming that the distribution of the outcome measures 
follow a unimodal symmetric distribution and satisfies the assumptions for mixed effects modeling. Mixed 
effects modeling takes advantage of all available data (up to the point of loss to follow-up or withdrawal) 
and also can address missing data. As long as the level of missingness is not excessive and patterns of 
missingness are not detected, mixed effects modeling can use all available data.21-24  For all analyses, 
alpha will be set to 0.05 (two-sided). 
 
The Epidemiology Department may be consulted at the completion of the study to assist with data 
analysis. Only de-identified data will be provided. No PHI will be shared. 


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6.6 Subject Population(s) for Analysis 
All-randomized population:  Any subject randomized into the study, regardless of whether they received 
study drug, will be analyzed. 
 
7 Safety and Adverse Events 
7.1 Definitions 
 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in inpatient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is defined as the period from the initiation 
of any study procedures to the end of the study follow-up.   
 


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General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.   
 
7.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
7.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators must conform to the adverse event reporting timelines, formats and requirements of the 
various entities to which they are responsible, but at a minimum those events that must be reported are 
those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study irrigant was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study irrigant 
7.3.1 Investigator reporting: notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the Penn IRB. The 
University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related to study 
participation that are unforeseen and indicate that participants or others are at increased risk of harm.  
The Penn IRB will not acknowledge safety reports or bulk adverse event submissions that do not meet 
the criteria outlined below.  The Penn IRB requires researchers to submit reports of the following 
problems within 10 working days from the time the investigator becomes aware of the event: 
• Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) 
that occurs any time during or after the research study, which in the opinion of the principal 
investigator is: 


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Unexpected  
AND 
Related to the research procedures  
 
Reporting Process 
Unanticipated problems posing risks to subjects will be reported to the Penn IRB using the form: 
“Unanticipated Problems Posing Risks to Subjects or Others Including Reportable Adverse Events” or as 
a written report of the event (including a description of the event with information regarding its fulfillment 
of the above criteria, follow-up/resolution and need for revision to consent form and/or other study 
documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Other Reportable events: 
The following events are also reportable to the Penn IRB: 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased risk, or 
affects the rights or welfare of subjects. 
7.4 Unblinding Procedures 
This study will be unblinded upon completion. Once the lead investigator determines that the study 
recruitment is complete and ready for data analysis, he will provide IDS with a written request for study 
unblinding. IDS will then check allocation log for completion, sign and date the last entry, and provide the 
lead investigator the log of all study allocations.  
 
In the event that unblinding is required to make a clinical treatment decisions (ie: unexpected serious 
adverse events), an emergency unblinding request for that particular subject will be requested by the lead 
investigator to IDS.  
 
Unblinding will be required: 
– 
To make clinical treatment decisions when an unexpected serious adverse event occurs  
– 
During unmasked analysis in accordance with the study analysis plan 
– 
At the request of the IRB or Office of Clinical Research 
– 
At the conclusion of the study 
7.5 Stopping Rules  
The first 10 participants of the trial will be un-blinded to the attending physicians.  They will monitor the 
clinical efficacy of the treatment, and analyze outcome measures to determine whether or not the trial 
should proceed or be aborted.  The trial will continue if and only if no clinically significant adverse events 
are observed in the treatment and/or placebo arms. 
7.6 Medical Monitoring 
It is the responsibility of the Sponsor to oversee the safety of the study at his site.  This safety monitoring 
will include careful assessment and appropriate reporting of adverse events as noted above, as well as 
the construction and implementation of a site data and safety-monitoring plan (see section 10 Auditing, 
Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the number and type 
of serious adverse events. 


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8 Data Handling and Record Keeping 
8.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects who have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
Electronic data will be stored on an institutionally secured and managed drive and/or in the Research 
Electronic Data Capture system (REDCap).  Paper records will be stored in a locked cabinet in a secure 
location.  Only authorized study personnel will have access. 
8.2 Source Documents 
Original documents, and data records include: hospital records, clinical and office charts and procedural 
information, laboratory notes and results, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, and records kept at the pharmacy/IDS, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 
8.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
8.4 Records Retention 
Study documentation will be retained for 2 years after the last-study related subject visit. 
 
9 Study Monitoring, Auditing, and Inspecting 
9.1 Study Monitoring Plan 
The Investigator and Sponsor will allocate adequate time for monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to all the 
above noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 


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9.2 Auditing and Inspecting 
The Investigator will permit study-related monitoring, audits, and inspections by the Sponsor, EC/IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
10 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  See 
Attachment for a copy of the Subject Informed Consent Form.  This consent form will be submitted with 
the protocol for review and approval by the EC/IRB for the study.  The formal consent of a subject, using 
the EC/IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
 
11 Study Finances 
11.1 Funding Source 
Funded through departmental academic development funds 
11.2 Conflict of Interest 
N/A 
11.3 Subject Stipends or Payments 
Subjects will not be compensated for their participation.  
 
12 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided for the purposes of performing the study, will be published or passed on to any third 
party without the consent of the study PI (Nithin Adappa, MD).  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results and all data derived from the study. 
 


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13 References 
 
1 
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Fokkens, W. J. et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 
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Chronic rhinosinusitis. Laryngoscope, doi:10.1002/lary.24066 (2013). 
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Lee, R. J., Chen, B., Redding, K. M., Margolskee, R. F. & Cohen, N. A. Mouse nasal epithelial 
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Lee, R. J. & Cohen, N. A. The emerging role of the bitter taste receptor T2R38 in upper 
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Desrosiers, M. Y. & Salas-Prato, M. Treatment of chronic rhinosinusitis refractory to other 
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Ramsey, B. W. et al. Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N Engl J 
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Hopkins, C., Browne, J. P., Slack, R., Lund, V. & Brown, P. The Lund-Mackay staging system for 
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Delwiche, J. F., Buletic, Z. & Breslin, P. A. Covariation in individuals' sensitivities to bitter 
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24 
Zeger SL, Liang K-Y. Longitudinal data analysis for discrete and continuous outcomes. 
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