A Phase 4 interventional study of PL nasal spray and fluticasone furoate (FF) in Seasonal Allergic Rhinitis, sponsored by University of Chicago. Completed at 1 site in United States. Open to participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2013-07-17.
Sponsored by University of Chicago · Phase 4 and Interventional
People who have hayfever or allergic rhinitis often complain about eye symptoms associated with their nasal symptoms. How people with hayfever develop eye symptoms is not clear. The purpose of this study is to better understand the generation of eye symptoms in patients with allergic rhinitis. We have previously shown that placing the substance that subjects are allergic to in their nose causes both nose and eye symptoms. This can be explain by a parasympathetic neurogenic reflex from the nose to the eye. Such a reflex would readily explain the tearing and watery eye symptoms, but does not explain the itch. In this study, we are going to address one possible explanation for the itch; does an axonal neurogenic reflex stimulate mast cells in the eye to release histamine, which then causes the itch? We will do this by placing an antihistamine drop in the eye and challenge the nose with allergen. We will also attempt to demonstrate that mast activation isn't effected by blocking the initiating of the reflex with a nasal steroid, as done in our previous study, and showing that the addition of an antihistamine does not add to the reduction of symptoms.
We performed a randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study in 21 subjects with seasonal allergic rhinitis studied out of season. Healthy patients, between 18 and 50 years of age, came to the Nasal Physiology Laboratory at The University of Chicago for screening, where they completed an allergy questionnaire and underwent skin puncture testing for confirmation of allergy to grass or ragweed. Female subjects were given pregnancy tests. Patients who were eligible then underwent a screening nasal challenge with either grass or ragweed allergen depending on their skin test results and history. The study was approved by the Institutional Review Board at The University of Chicago and all of the patients gave written informed consent before entry.
After a 2-week washout period, after the screening challenge, 21 subjects who had positive screening challenge returned to the Nasal Physiology Laboratory where they were randomized to receive 1 week of one of four treatments:
Specifically, the PL eye drops used were lubricant eye drops with active ingredients of 0.3% glycerin and 1.0% propylene glycol and the PL nasal spray was provided by GlaxoSmithKline. Treatment with OLO consisted of 1 drop of 0.2% OLO in each eye daily and treatment of FF consisted of 2 puffs in each nostril daily, giving a total of 110 micrograms delivered in each nostril. After a week of each of the treatments, the subjects returned to the Nasal Physiology Laboratory to undergo a nasal challenge. The subjects then returned the next day while still receiving treatment for another nasal challenge to augment the nasal ocular reflex. Next, the patients had a 2-week washout period and then switched over to the next randomized treatment arm. This sequence was repeated until subjects completed all four arms of the trial.
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Exclusion Criteria:
Each subject received a total of 4 weeks of treatment (1 week per treatment with 2 week washout period between treatments) in the following order: * fluticasone furoate (FF) nasal spray and PL eye drops (FF/PL) * PL nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (PL/OLO), * FF nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (FF/OLO), and * placebo (PL) nasal spray and PL eye drops (PL/PL).
Drug: PL nasal spray · Drug: fluticasone furoate (FF) · Drug: PL eye drops · Drug: olopatadine (OLO)
Each subject received a total of 4 weeks of treatment (1 week per treatment with 2 week washout period between treatments) in the following order: * PL nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (PL/OLO), * FF nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (FF/OLO), * placebo (PL) nasal spray and PL eye drops (PL/PL), and * fluticasone furoate (FF) nasal spray and PL eye drops (FF/PL).
Drug: PL nasal spray · Drug: fluticasone furoate (FF) · Drug: PL eye drops · Drug: olopatadine (OLO)
Each subject received a total of 4 weeks of treatment (1 week per treatment with 2 week washout period between treatments) in the following order: * FF nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (FF/OLO), * placebo (PL) nasal spray and PL eye drops (PL/PL), * fluticasone furoate (FF) nasal spray and PL eye drops (FF/PL), and * PL nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (PL/OLO).
Drug: PL nasal spray · Drug: fluticasone furoate (FF) · Drug: PL eye drops · Drug: olopatadine (OLO)
Each subject received a total of 4 weeks of treatment (1 week per treatment with 2 week washout period between treatments) in the following order: * placebo (PL) nasal spray and PL eye drops (PL/PL), * fluticasone furoate (FF) nasal spray and PL eye drops (FF/PL), * PL nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (PL/OLO), and * FF nasal spray and olopatadine (OLO) 0.2% ophthalmic solution (FF/OLO).
Drug: PL nasal spray · Drug: fluticasone furoate (FF) · Drug: PL eye drops · Drug: olopatadine (OLO)
2 puffs of PL nasal spray (from GlaxoSmithKline) in each nostril once a day for 1 week
2 puffs of FF nasal spray in each nostril once a day for 1 week
Also known as: Veramyst
1 drop of placebo eye drops (lubricant eye drops with active ingredients 0.3% glycerin) in each eye once a day for 1 week
1 drop of OLO eye drops in each eye once a day for 1 week
Also known as: Olopatadine 0.2% ophthalmic solution
Total Eye Symptoms Score Difference
After treatment, each participant was subjected to a diluent (control) challenge in one eye and was asked to rate 2 eye symptoms (watery and itchy) according to the following scale: 0=none, 1=mild, 2=moderate, 3=severe. The participant was then exposed to 3 doses of an antigen challenge and was asked to similarly rate severity of watery and itchy eye symptoms after each dose. Diluent challenge scores were subtracted from the scores recorded after each dose. This process was repeated in the other eye. The outcome is the total of the score differences (i.e. score after each dose subtracted by diluent challenge score) summed across doses, symptoms (watery and itchy), and eyes (left and right). Thus, each participant's total score is an integer value ranging from -36 to 36.
Time frame: 50 minutes [duration of 3 nasal challenges and 2 washout periods]
Total Nasal Symptoms Score Difference
After treatment, each participant was subjected to a diluent (control) challenge in one nostril and was asked to rate nasal symptoms (congestion, rhinorrhea, and itchy nose/throat) according to the following scale: 0=none, 1=mild, 2=moderate, 3=severe. The participant was then exposed to 3 doses of an antigen challenge and was asked to similarly rate severity of nasal symptoms after each dose. Diluent challenge scores were subtracted from the scores recorded after each dose. This process was repeated in the other nostril. The outcome is the total number of score differences (i.e. score after each dose subtracted by diluent challenge score) summed across doses, symptoms (congestion, rhinorrhea, and itchy nose/throat), and nostrils (left and right). Thus, each participant's total score is an integer value ranging from -36 to 36.
Time frame: 50 minutes [duration of 3 nasal challenges and 2 washout periods]
Total Number of Sneezes
Time frame: 50 minutes [duration of 3 nasal challenges and 2 washout periods]
Change in Histamine Level (Across Nasal Challenges)
Histamines are simple chemical substances produced by immune system cells when reacting to an antigen in response to foreign invaders like germs and bacteria. Histamine in nasal lavages was measured using a histamine enzyme immunoassay kit market by SPI-BIo, Bertin Pharma (Montigny le Bretonneux, France). The limit of detection of the assay is 0.4 nM, and levels below the detection limit were arbitrarily assigned a value of 0.2 nM. Samples that yielded values above the upper detection limit of the assay were diluted and reassayed. For each patient, histamine levels recorded after the diluent challenge were subtracted from histamine levels recorded after each of the three nasal challenges. These differences were added across challenges, yielding the total change in histamine level reported in this outcome for each patient.
Time frame: 50 minutes [duration of 3 nasal challenges and 2 washout periods]
Change in Tryptase Level (Across Nasal Challenges)
Tryptase is an enzyme that is released, along with histamine and other chemicals, from mast cells when they are activated, often as part of an allergic immune response. Tryptase in nasal lavages was measured using the ImmunoCap tryptase assay, by Phadia (Uppsala, Sweden). The limit of detection of the assay is 1.0 ng/mL, and levels below this value were arbitrarily assigned a value of 0.5 ng/mL. For each patient, tryptase levels recorded after the diluent challenge were subtracted from tryptase levels recorded after each of the three nasal challenges. These differences were added across challenges, yielding the total change in tryptase level reported in this outcome for each patient.
Time frame: 50 minutes [duration of 3 nasal challenges and 2 washout periods]
Total Number of Eosinophils
The percentage of eosinophils among white blood cells was determined under light microscopy at 1000x magnification, and the total number of eosinophils in each lavage was then calculated. The specimens that had no eosinophils identified on differential counting despite adequate cells on the smear were assigned a number that corresponded to the lowest number of eosinophils on a slide where the number could be counted. That number was 33 total eosinophils.
Time frame: 50 minutes [duration of 3 nasal challenges and 2 washout periods]
Healthy patients age 18-50 completed an allergy questionnaire and underwent skin puncture testing for confirmation of allergy to grass or ragweed. Female subjects were given pregnancy tests. Patients who were eligible then underwent a screening nasal challenge with either grass or ragweed allergen depending on their skin test results and history.
| Milestone | FF/PL, PL/OLO, FF/OLO, PL/PL | PL/OLO, FF/OLO, PL/PL, FF/PL | FF/OLO, PL/PL, FF/PL, PL/OLO | PL/PL, FF/PL, PL/OLO, FF/OLO |
|---|---|---|---|---|
| Started | 6 | 5 | 5 | 5 |
| Completed | 6 | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 | 0 |
| Milestone | FF/PL, PL/OLO, FF/OLO, PL/PL | PL/OLO, FF/OLO, PL/PL, FF/PL | FF/OLO, PL/PL, FF/PL, PL/OLO | PL/PL, FF/PL, PL/OLO, FF/OLO |
|---|---|---|---|---|
| Started | 6 | 5 | 5 | 5 |
| Completed | 6 | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 | 0 |
| Milestone | FF/PL, PL/OLO, FF/OLO, PL/PL | PL/OLO, FF/OLO, PL/PL, FF/PL | FF/OLO, PL/PL, FF/PL, PL/OLO | PL/PL, FF/PL, PL/OLO, FF/OLO |
|---|---|---|---|---|
| Started | 6 | 5 | 5 | 5 |
| Completed | 6 | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 | 0 |
| Milestone | FF/PL, PL/OLO, FF/OLO, PL/PL | PL/OLO, FF/OLO, PL/PL, FF/PL | FF/OLO, PL/PL, FF/PL, PL/OLO | PL/PL, FF/PL, PL/OLO, FF/OLO |
|---|---|---|---|---|
| Started | 6 | 5 | 5 | 5 |
| Completed | 6 | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 | 0 |
| Milestone | FF/PL, PL/OLO, FF/OLO, PL/PL | PL/OLO, FF/OLO, PL/PL, FF/PL | FF/OLO, PL/PL, FF/PL, PL/OLO | PL/PL, FF/PL, PL/OLO, FF/OLO |
|---|---|---|---|---|
| Started | 6 | 5 | 5 | 5 |
| Completed | 6 | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 | 0 |
| Milestone | FF/PL, PL/OLO, FF/OLO, PL/PL | PL/OLO, FF/OLO, PL/PL, FF/PL | FF/OLO, PL/PL, FF/PL, PL/OLO | PL/PL, FF/PL, PL/OLO, FF/OLO |
|---|---|---|---|---|
| Started | 6 | 5 | 5 | 5 |
| Completed | 5 | 5 | 5 | 5 |
| Not completed | 1 | 0 | 0 | 0 |
| Withdrew: Physician decision | 1 | 0 | 0 | 0 |
| Milestone | FF/PL, PL/OLO, FF/OLO, PL/PL | PL/OLO, FF/OLO, PL/PL, FF/PL | FF/OLO, PL/PL, FF/PL, PL/OLO | PL/PL, FF/PL, PL/OLO, FF/OLO |
|---|---|---|---|---|
| Started | 5 | 5 | 5 | 5 |
| Completed | 5 | 5 | 5 | 5 |
| Not completed | 0 | 0 | 0 | 0 |
After treatment, each participant was subjected to a diluent (control) challenge in one eye and was asked to rate 2 eye symptoms (watery and itchy) according to the following scale: 0=none, 1=mild, 2=moderate, 3=severe. The participant was then exposed to 3 doses of an antigen challenge and was asked to similarly rate severity of watery and itchy eye symptoms after each dose. Diluent challenge scores were subtracted from the scores recorded after each dose. This process was repeated in the other eye. The outcome is the total of the score differences (i.e. score after each dose subtracted by diluent challenge score) summed across doses, symptoms (watery and itchy), and eyes (left and right). Thus, each participant's total score is an integer value ranging from -36 to 36.
| units on a scale | PL/PL | FF/PL | PL/OLO | FF/OLO |
|---|---|---|---|---|
| Total Eye Symptoms Score Difference | 6 (0 to 23) | 0 (-6 to 11) | 2.5 (0 to 26) | 1.5 (-9 to 16) |
After treatment, each participant was subjected to a diluent (control) challenge in one nostril and was asked to rate nasal symptoms (congestion, rhinorrhea, and itchy nose/throat) according to the following scale: 0=none, 1=mild, 2=moderate, 3=severe. The participant was then exposed to 3 doses of an antigen challenge and was asked to similarly rate severity of nasal symptoms after each dose. Diluent challenge scores were subtracted from the scores recorded after each dose. This process was repeated in the other nostril. The outcome is the total number of score differences (i.e. score after each dose subtracted by diluent challenge score) summed across doses, symptoms (congestion, rhinorrhea, and itchy nose/throat), and nostrils (left and right). Thus, each participant's total score is an integer value ranging from -36 to 36.
| units on a scale | PL/PL | FF/PL | PL/OLO | FF/OLO |
|---|---|---|---|---|
| Total Nasal Symptoms Score Difference | 17 (6 to 34) | 10 (3 to 31) | 9 (-2 to 35) | 9 (0 to 26) |
| sneezes | PL/PL | FF/PL | PL/OLO | FF/OLO |
|---|---|---|---|---|
| Total Number of Sneezes | 10 (0 to 36) | 2.5 (0 to 50) | 2.5 (0 to 49) | 1.0 (0 to 16) |
Histamines are simple chemical substances produced by immune system cells when reacting to an antigen in response to foreign invaders like germs and bacteria. Histamine in nasal lavages was measured using a histamine enzyme immunoassay kit market by SPI-BIo, Bertin Pharma (Montigny le Bretonneux, France). The limit of detection of the assay is 0.4 nM, and levels below the detection limit were arbitrarily assigned a value of 0.2 nM. Samples that yielded values above the upper detection limit of the assay were diluted and reassayed. For each patient, histamine levels recorded after the diluent challenge were subtracted from histamine levels recorded after each of the three nasal challenges. These differences were added across challenges, yielding the total change in histamine level reported in this outcome for each patient.
| nM | PL/PL | FF/PL | PL/OLO | FF/OLO |
|---|---|---|---|---|
| Change in Histamine Level (Across Nasal Challenges) | 5.9 (-2 to 203) | 0.3 (-91 to 209) | 11.4 (-9 to 435) | 3.4 (-34 to 250) |
Tryptase is an enzyme that is released, along with histamine and other chemicals, from mast cells when they are activated, often as part of an allergic immune response. Tryptase in nasal lavages was measured using the ImmunoCap tryptase assay, by Phadia (Uppsala, Sweden). The limit of detection of the assay is 1.0 ng/mL, and levels below this value were arbitrarily assigned a value of 0.5 ng/mL. For each patient, tryptase levels recorded after the diluent challenge were subtracted from tryptase levels recorded after each of the three nasal challenges. These differences were added across challenges, yielding the total change in tryptase level reported in this outcome for each patient.
| ng/mL | PL/PL | FF/PL | PL/OLO | FF/OLO |
|---|---|---|---|---|
| Change in Tryptase Level (Across Nasal Challenges) | 5 (0 to 527) | 0 (0 to 21) | 2 (0 to 140) | 0 (0 to 49) |
The percentage of eosinophils among white blood cells was determined under light microscopy at 1000x magnification, and the total number of eosinophils in each lavage was then calculated. The specimens that had no eosinophils identified on differential counting despite adequate cells on the smear were assigned a number that corresponded to the lowest number of eosinophils on a slide where the number could be counted. That number was 33 total eosinophils.
| eosinophils | PL/PL | FF/PL | PL/OLO | FF/OLO |
|---|---|---|---|---|
| Total Number of Eosinophils | 7883 (33 to 2246440) | 238 (33 to 604800) | 9606 (33 to 953250) | 311 (33 to 224000) |
Collected over 8 weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| PL/PL | — | 0/21 (0%) | 0/21 (0%) |
| FF/PL | — | 0/21 (0%) | 0/21 (0%) |
| PL/OLO | — | 0/21 (0%) | 0/21 (0%) |
| FF/OLO | — | 0/20 (0%) | 0/20 (0%) |
| Age Continuous(years) | Entire Study Population |
|---|---|
| Mean | 31.1 ± 6.89 |
| Sex: Female, Male(Participants) | Entire Study Population |
|---|---|
| Female | 7 |
| Male | 14 |
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University of Chicago