Allergic Rhinitis
Conditions
Brief summary
Dymista, a combined product containing the antihistamine azelastine and the intranasal steroid fluticasone, provides superior clinical efficacy to both fluticasone propionate and azelastine hydrochloride in the treatment of seasonal allergic rhinitis. The superiority of efficacy not only occurs at the initiation of treatment, but persists for its duration. The mechanism underlying the superior efficacy of Dymista is not known. This trial focuses on examining the effects of Dymista on the dynamics of the allergic response in man using nasal provocation with antigen. The investigators will study the relationship between symptoms, physiology, cells and mediators.
Detailed description
The main hypothesis for the trial is that Dymista affects multiple phases of the allergic response, which in sum are greater than the effects of fluticasone propionate or azelastine hydrochloride alone. Our objectives for this study are to demonstrate: 1. that the induction of allergic inflammation by nasal provocation with antigen causes a cellular infiltration, with subsequent release of inflammatory biomarkers that cause augmented responses to subsequent exposure to antigens. 2. that fluticasone prevents allergic inflammation from developing after antigen challenge and subsequently prevents the augmentation of the nasal response to nasal challenge with antigen. 3. that the azelastine in Dymista reduces the effects of released histamine To address these hypotheses we will perform a 3-way, randomized, placebo-controlled, and crossover trial. We will recruit 20 asymptomatic seasonal allergic rhinitis patients outside of the relevant season. The subjects will receive placebo, fluticasone propionate and Dymista. The nasal provocations will be separated by 2 weeks. Treatment will begin 15 minutes before nasal provocation with ragweed or grass antigen and the treatment will continue twice a day for 3 days. Nasal provocation will occur daily for three days to evaluate for priming (increased sensitization with repeated antigen exposure, which mimics seasonal disease where antigen exposure occurs in the setting of continued allergic inflammation). For outcome measures, we will monitor both nasal symptoms after nasal provocation as well as collect nasal lavage to evaluate effects on eosinophils and biomarkers of the immune response. In the nasal lavage, we will quantify the number of eosinophils (a marker of cellular recruitment) and measure the levels of histamine (a marker of basophil and mast cell activation), tryptase (a marker of mast cell activation), albumin (a marker of vascular permeability), lactoferrin (a marker of glandular activation) and ECP (a marker of eosinophil activation). Thus we expect to generate information on both clinical effects and physiologic differences between the treatments.
Interventions
DRUGPlacebo
Patients will be treated by placebo
DRUGFluticasone propionate
Patients will receive fluticasone nasal spray
DRUGFluticasone/Azelastine nasal spray
Patients will receive Dymista nasal spray
PROCEDURENasal Allergen Challenge
All subjects will receive a nasal challenge with allergen to mimick an allergic response and allow the investigation of the different drug effects on that response. Allergen extracts will be used as sprays into the nasal cavity. The extracts are approved by FDA for skin testing or desensitization therapy and an IND was obtained to allow intranasal administration
Sponsors
University of Chicago
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Males and females between 18 and 55 years of age. 2. History of grass and/or ragweed allergic rhinitis. 3. Positive skin test to grass and/or ragweed antigen. 4. Positive response to screening nasal challenge. 5. Off all anti-allergic medications for a minimum of 2 weeks.
Exclusion criteria
1. Physical signs or symptoms suggestive of renal, hepatic or cardiovascular disease. 2. Pregnant or lactating women. 3. Upper respiratory infection within 14 days of study start.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (albumin amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Sneezes After Allergen Challenge | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Our procedure used a diluent (sham) challenge followed by 2 allergen challenges. The final value is (the number of sneezes after 1st allergen exposure - number after sham) + (number of sneezes after 2nd exposure - sham amount). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Eosinophils | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (number of eosinophils in lavage after 1st allergen exposure - number after sham) + (number in lavage after 2nd exposure - sham number). |
| Histamine | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (histamine amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount). |
| Total Nasal Symptom Score | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Total nasal symptom Score = Sum of itchy, runny, sneezing, and congestion scores, each on scale 0-3 (0=no symptoms, 1=mild symptoms, 2=moderate symptoms, 3=severe symptoms). Thus, maximum=12, minimum=0, and higher score represents worse outcome. Measured in the 10 minute period after allergen challenge and normalized against symptoms experienced after sham challenge. |
| Eosinophil Cationic Protein (ECP) | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (ECP amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount). |
| Tryptase | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (tryptase amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount). |
| Change From Baseline Response in Lactoferrin Levels in Nasal Lavage Following Each Challenge | 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks. | Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (lactoferrin amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount). |
Countries
United States
Participant flow
Recruitment details
cross-over study
Participants by arm
| Arm | Count |
|---|---|
| Dymista/Placebo/Flonase Dymista:
Fluticasone/Azelastine nasal spray
Flonase: Fluticasone nasal spray
Placebo: nasal spray without active ingredient | 4 |
| Dymista/Flonase/Placebo Dymista:
Fluticasone/Azelastine nasal spray
Flonase: Fluticasone nasal spray
Placebo: nasal spray without active ingredient | 3 |
| Placebo/Dymista/Flonase Dymista:
Fluticasone/Azelastine nasal spray
Flonase: Fluticasone nasal spray
Placebo: nasal spray without active ingredient | 4 |
| Placebo/Flonase/Dymista Dymista:
Fluticasone/Azelastine nasal spray
Flonase: Fluticasone nasal spray
Placebo: nasal spray without active ingredient | 4 |
| Flonase/Dymista/Placebo Dymista:
Fluticasone/Azelastine nasal spray
Flonase: Fluticasone nasal spray
Placebo: nasal spray without active ingredient | 1 |
| Flonase/Placebo/Dymista Dymista:
Fluticasone/Azelastine nasal spray
Flonase: Fluticasone nasal spray
Placebo: nasal spray without active ingredient | 3 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Dymista/Flonase/Placebo | Placebo/Dymista/Flonase | Placebo/Flonase/Dymista | Flonase/Dymista/Placebo | Flonase/Placebo/Dymista | Dymista/Placebo/Flonase | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 4 Participants | 4 Participants | 1 Participants | 3 Participants | 4 Participants | 19 Participants |
| Age, Continuous | 29 years | 29 years | 27 years | 42 years | 36 years | 34.5 years | 34 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 4 participants | 1 participants | 3 participants | 4 participants | 19 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 0 / 19 | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 | 0 / 19 |
Outcome results
Primary
Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge
Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (albumin amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount).
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 2 | -41.87 ng/mL | Standard Error 59.22 |
| Placebo | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 1 | -33.61 ng/mL | Standard Error 53.03 |
| Placebo | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 3 | -106.68 ng/mL | Standard Error 46.08 |
| Fluticasone Propionate | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 2 | -29.70 ng/mL | Standard Error 72.14 |
| Fluticasone Propionate | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 1 | -82.2 ng/mL | Standard Error 54.22 |
| Fluticasone Propionate | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 3 | -78.73 ng/mL | Standard Error 58.44 |
| Dymista (Fluticasone/Azelastine) | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 1 | -185.85 ng/mL | Standard Error 158.04 |
| Dymista (Fluticasone/Azelastine) | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 3 | -69.50 ng/mL | Standard Error 35.49 |
| Dymista (Fluticasone/Azelastine) | Change From Baseline Response in Albumin Levels in Nasal Lavage Following Each Challenge | day 2 | -81.6 ng/mL | Standard Error 32.36 |
p-value: >0.05ANOVA
Secondary
Sneezes After Allergen Challenge
Our procedure used a diluent (sham) challenge followed by 2 allergen challenges. The final value is (the number of sneezes after 1st allergen exposure - number after sham) + (number of sneezes after 2nd exposure - sham amount).
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Sneezes After Allergen Challenge | day 3 | 9.0 Sneezes | Standard Error 2.5 |
| Placebo | Sneezes After Allergen Challenge | Day 2 | 9.3 Sneezes | Standard Error 2.6 |
| Placebo | Sneezes After Allergen Challenge | day 1 | 6.2 Sneezes | Standard Error 2.2 |
| Fluticasone Propionate | Sneezes After Allergen Challenge | day 3 | 7.1 Sneezes | Standard Error 2 |
| Fluticasone Propionate | Sneezes After Allergen Challenge | day 1 | 6.8 Sneezes | Standard Error 1.6 |
| Fluticasone Propionate | Sneezes After Allergen Challenge | Day 2 | 7.6 Sneezes | Standard Error 2.2 |
| Dymista (Fluticasone/Azelastine) | Sneezes After Allergen Challenge | day 3 | 2.1 Sneezes | Standard Error 0.9 |
| Dymista (Fluticasone/Azelastine) | Sneezes After Allergen Challenge | Day 2 | 2.0 Sneezes | Standard Error 0.9 |
| Dymista (Fluticasone/Azelastine) | Sneezes After Allergen Challenge | day 1 | 1.1 Sneezes | Standard Error 0.5 |
p-value: 0.001Friedman
p-value: 0.02Wilcoxon (Mann-Whitney)
p-value: 0.003Wilcoxon (Mann-Whitney)
p-value: 0.53Wilcoxon (Mann-Whitney)
Other Pre-specified
Change From Baseline Response in Lactoferrin Levels in Nasal Lavage Following Each Challenge
Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (lactoferrin amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount).
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
Population: There was one missing sample
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline Response in Lactoferrin Levels in Nasal Lavage Following Each Challenge | 131368 ng/mL | Standard Error 67483 |
| Fluticasone Propionate | Change From Baseline Response in Lactoferrin Levels in Nasal Lavage Following Each Challenge | 137539 ng/mL | Standard Error 40363 |
| Dymista (Fluticasone/Azelastine) | Change From Baseline Response in Lactoferrin Levels in Nasal Lavage Following Each Challenge | 31400 ng/mL | Standard Error 44982 |
p-value: 0.08Friedman's Test
Other Pre-specified
Eosinophil Cationic Protein (ECP)
Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (ECP amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount).
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Eosinophil Cationic Protein (ECP) | day 2 | 44.5 ng/mL | Standard Error 13.18 |
| Placebo | Eosinophil Cationic Protein (ECP) | day 1 | 47.08 ng/mL | Standard Error 14.67 |
| Placebo | Eosinophil Cationic Protein (ECP) | day 3 | 42.4 ng/mL | Standard Error 10.25 |
| Fluticasone Propionate | Eosinophil Cationic Protein (ECP) | day 2 | 36.13 ng/mL | Standard Error 11 |
| Fluticasone Propionate | Eosinophil Cationic Protein (ECP) | day 1 | 47.8 ng/mL | Standard Error 13.46 |
| Fluticasone Propionate | Eosinophil Cationic Protein (ECP) | day 3 | 37.91 ng/mL | Standard Error 10.77 |
| Dymista (Fluticasone/Azelastine) | Eosinophil Cationic Protein (ECP) | day 1 | 51.62 ng/mL | Standard Error 13.03 |
| Dymista (Fluticasone/Azelastine) | Eosinophil Cationic Protein (ECP) | day 3 | 53.33 ng/mL | Standard Error 16.14 |
| Dymista (Fluticasone/Azelastine) | Eosinophil Cationic Protein (ECP) | day 2 | 46.32 ng/mL | Standard Error 14.65 |
p-value: 0.85Friedman's Test
Other Pre-specified
Eosinophils
Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (number of eosinophils in lavage after 1st allergen exposure - number after sham) + (number in lavage after 2nd exposure - sham number).
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
Population: due technical difficulty in the staining, no data is available.
Other Pre-specified
Histamine
Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (histamine amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount).
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
Population: there were three missing samples
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Histamine | -0.97 ng/mL | Standard Error 1.2 |
| Fluticasone Propionate | Histamine | 10.3 ng/mL | Standard Error 7.6 |
| Dymista (Fluticasone/Azelastine) | Histamine | 12.3 ng/mL | Standard Error 9.8 |
p-value: 0.04Friedman's Test
Other Pre-specified
Total Nasal Symptom Score
Total nasal symptom Score = Sum of itchy, runny, sneezing, and congestion scores, each on scale 0-3 (0=no symptoms, 1=mild symptoms, 2=moderate symptoms, 3=severe symptoms). Thus, maximum=12, minimum=0, and higher score represents worse outcome. Measured in the 10 minute period after allergen challenge and normalized against symptoms experienced after sham challenge.
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Total Nasal Symptom Score | day 2 | 6.63 score on a scale | Standard Error 1.13 |
| Placebo | Total Nasal Symptom Score | day 1 | 6.26 score on a scale | Standard Error 0.85 |
| Placebo | Total Nasal Symptom Score | day 3 | 5.68 score on a scale | Standard Error 1.07 |
| Fluticasone Propionate | Total Nasal Symptom Score | day 2 | 6.44 score on a scale | Standard Error 0.91 |
| Fluticasone Propionate | Total Nasal Symptom Score | day 1 | 7.06 score on a scale | Standard Error 1.08 |
| Fluticasone Propionate | Total Nasal Symptom Score | day 3 | 5.67 score on a scale | Standard Error 0.89 |
| Dymista (Fluticasone/Azelastine) | Total Nasal Symptom Score | day 1 | 3.58 score on a scale | Standard Error 0.81 |
| Dymista (Fluticasone/Azelastine) | Total Nasal Symptom Score | day 3 | 4.22 score on a scale | Standard Error 0.88 |
| Dymista (Fluticasone/Azelastine) | Total Nasal Symptom Score | day 2 | 4.32 score on a scale | Standard Error 0.86 |
Comparison: We used Friedman test to compare the distribution of total nasal symptom scores among three treatment groups (Placebo, Fluticasone propionate, Dymista) in each of the three days (day 1, day 2, and day 3).p-value: 0.07Friedman's Test
Other Pre-specified
Tryptase
Our procedure used a diluent (sham) challenge followed by 2 allergen challenges where lavages are collected 10 minutes after each of these challenges. The final value is (tryptase amount in lavage after 1st allergen exposure - amount after sham) + (amount in lavage after 2nd exposure - sham amount).
Time frame: 3 rounds of 1 Nasal challenge every 3 days followed by 2 week washout periods in between. Total participation of 9 weeks.
Population: Data was missing for 3 subjects
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Tryptase | -0.08 ng/ml | Standard Error 0.28 |
| Fluticasone Propionate | Tryptase | -0.19 ng/ml | Standard Error 0.39 |
| Dymista (Fluticasone/Azelastine) | Tryptase | 0.12 ng/ml | Standard Error 0.26 |
p-value: >0.05Friedman's Test