QSIND: Topical Irrigation Therapy for CRS
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Quinine Sulfate 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. |
Drug: Quinine Sulfate
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.
|
| Placebo Comparator: Placebo 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. |
Drug: Placebo
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.
|
Outcome Measures
Primary Outcome Measures
- Change in Microbiome Profile [Baseline, Week 2, and Week 10]
Pre and post treatment endoscopically-obtained sinonasal microbiologic cultures.
Secondary Outcome Measures
- Change in Lund-Kennedy Endoscope Score [Baseline, Week 2, and Week 10]
Pre and post treatment nasal endoscopy scored with a validated staging system for edema, -scored by an independent blind observer.
- Change in the 22-item Sinonasal Outcomes Test Score [Baseline, Week 2, and Week 10]
Pre and post treatment quality of life questionnaires (22-item Sinonasal Outcomes Test [SNOT-22]).
- Change in Sniffin' Stick-12 Score [Baseline, Week 2 and Week 10]
Change in olfactory sense from baseline to week 10 will be measured using the Sniffin' Stick-12 system. Patients will smell each "sniffing pen" and record the smell they detect. A score between 0-12 will indicate olfactory sense.
Other Outcome Measures
- Rescue Antibiotics [Week 2 and Week 10]
The necessity for rescue oral antibiotics for persistent infection.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Patients who have undergone Functional Endoscopic Sinus Surgery (FESS)
-
Purulent drainage on nasal endoscopy
-
Male or female subjects, 18 years of age or older
-
Patients seen at the Dept. of Otorhinolaryngology clinic at Hospital of the University of Pennsylvania (HUP), a tertiary care clinic
Exclusion Criteria:
-
Pregnant women
-
Immunocompromised patients
-
Granulomatous diseases with rhinologic manifestations (Wegner's, Sarcoid, Churg-Strauss)
-
Primary ciliary dyskinesia
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19104 |
Sponsors and Collaborators
- University of Pennsylvania
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.- 821731
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Quinine Sulfate | Placebo |
|---|---|---|
| Arm/Group Description | Each study participant randomized into the experimental arm will receive 28 tubes with 1mg/ml (6 mls) 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. Quinine Sulfate: Our plan is to first study quinine against saline to determine efficacy and safety. The vast majority of patients with rhinosinusitis utilize low pressure | 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 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. Placebo: 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 plac |
| Period Title: Overall Study | ||
| STARTED | 10 | 0 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 10 | 0 |
Baseline Characteristics
| Arm/Group Title | Quinine Sulfate | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Each participant in the experimental arm will receive 28 tubes with 1mg/ml (6 mls total) of quinine sulfate, as well as 28 3cc syringes with the atomizers. The solutions will be light-protected. Patients will apply 3 mls to each nostril twice per day. Patients will be exposed to 12.0 mg 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. The application of the solution is exactly the same as their daily regimen. Quinine Sulfate: Our plan is to first determine efficacy and safety. The patients will be exposed to a maximum of 12mls or 12.0 mg 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. The therapeutic range of quinine to treat malaria is nearly 200 X the dose proposed. | 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 in light-protected tubes. The placebo arm will mirror the experimental arm exactly, except for the treatment solution contained in the vials. Placebo: 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. | Total of all reporting groups |
| Overall Participants | 10 | 0 | 10 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
NaN
|
0
0%
|
| Between 18 and 65 years |
10
100%
|
0
NaN
|
10
100%
|
| >=65 years |
0
0%
|
0
NaN
|
0
0%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
6
60%
|
6
Infinity
|
|
| Male |
4
40%
|
4
Infinity
|
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
NaN
|
|
| Asian |
0
0%
|
0
NaN
|
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
NaN
|
|
| Black or African American |
0
0%
|
0
NaN
|
|
| White |
10
100%
|
10
Infinity
|
|
| More than one race |
0
0%
|
0
NaN
|
|
| Unknown or Not Reported |
0
0%
|
0
NaN
|
|
| Region of Enrollment (Count of Participants) | |||
| United States |
10
100%
|
10
Infinity
|
|
Outcome Measures
| Title | Change in Microbiome Profile |
|---|---|
| Description | Pre and post treatment endoscopically-obtained sinonasal microbiologic cultures. |
| Time Frame | Baseline, Week 2, and Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This study was terminated. Partial data was collected and is misleading due to mis-dosing. This outcome measure was not evaluated. |
| Arm/Group Title | Quinine Sulfate | Placebo |
|---|---|---|
| Arm/Group Description | 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 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. Placebo: 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. |
| Measure Participants | 0 | 0 |
| Title | Change in Lund-Kennedy Endoscope Score |
|---|---|
| Description | Pre and post treatment nasal endoscopy scored with a validated staging system for edema, -scored by an independent blind observer. |
| Time Frame | Baseline, Week 2, and Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This study was terminated. Partial data was collected and is misleading due to mis-dosing. This outcome was not measured. |
| Arm/Group Title | Quinine Sulfate | Placebo |
|---|---|---|
| Arm/Group Description | 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 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. Placebo: 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. |
| Measure Participants | 0 | 0 |
| Title | Change in the 22-item Sinonasal Outcomes Test Score |
|---|---|
| Description | Pre and post treatment quality of life questionnaires (22-item Sinonasal Outcomes Test [SNOT-22]). |
| Time Frame | Baseline, Week 2, and Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This study was terminated. Partial data was collected and is misleading due to mis-dosing. This outcome was not measured. |
| Arm/Group Title | Quinine Sulfate | Placebo |
|---|---|---|
| Arm/Group Description | 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 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. Placebo: 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. |
| Measure Participants | 0 | 0 |
| Title | Change in Sniffin' Stick-12 Score |
|---|---|
| Description | Change in olfactory sense from baseline to week 10 will be measured using the Sniffin' Stick-12 system. Patients will smell each "sniffing pen" and record the smell they detect. A score between 0-12 will indicate olfactory sense. |
| Time Frame | Baseline, Week 2 and Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This study was terminated. Partial data was collected and is misleading due to mis-dosing. This outcome was not measured. |
| Arm/Group Title | Quinine Sulfate | Placebo |
|---|---|---|
| Arm/Group Description | 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 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. Placebo: 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. |
| Measure Participants | 0 | 0 |
| Title | Rescue Antibiotics |
|---|---|
| Description | The necessity for rescue oral antibiotics for persistent infection. |
| Time Frame | Week 2 and Week 10 |
Outcome Measure Data
| Analysis Population Description |
|---|
| This study was terminated. Partial data was collected and is misleading due to mis-dosing. This outcome was not measured. |
| Arm/Group Title | Quinine Sulfate | Placebo |
|---|---|---|
| Arm/Group Description | 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 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. |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | 1 year (approximately) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | This was a very low risk trial. | |||
| Arm/Group Title | Quinine Sulfate | Placebo | ||
| Arm/Group Description | 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 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. Placebo: 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. | ||
All Cause Mortality |
||||
| Quinine Sulfate | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 0/0 (NaN) | ||
Serious Adverse Events |
||||
| Quinine Sulfate | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/10 (0%) | 0/0 (NaN) | ||
Other (Not Including Serious) Adverse Events |
||||
| Quinine Sulfate | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 7/10 (70%) | 0/0 (NaN) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Worsening of sinus symptoms | 7/10 (70%) | 7 | 7/0 (Infinity) | 7 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Nithin D. Adappa, Principal Investigator |
|---|---|
| Organization | UPenn |
| Phone | 215-662-2360 |
| Nithin.Adappa@uphs.upenn.edu |
- 821731