Rhinitis, Allergic, Perennial and Seasonal
Conditions
Keywords
levocabastine fixed dose combination, Rhinitis, Allergic, Perennial and Seasonal, Allergic Rhinitis, fluticasone furoate
Brief summary
This study will be a randomised, double blind, placebo controlled, 3-way, incomplete block crossover study to evaluate the effect of single and repeat doses of levocabastine, FF, placebo and a FDC of FF/levocabastine administration in AR subjects. The total expected study duration for each individual participating in the study will be a maximum of up to 20 weeks (including the screening and follow-up). This will be a three period study and subjects will be assigned to a sequence of three treatments. There will be a wash-out period of 14-28 days between two treatment periods. The rational for this study is to demonstrate proof of concept with the FDC of FF and levocabastine compared with each of the components administered alone.
Interventions
DRUGFF/levocabastine
FF/levocabastine (25mcg/50 mcg) will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.
DRUGFF
FF (25mcg) will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.
DRUGlevocabastine
levocabastine (50mcg) will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.
DRUGPlacebo
Placebo will be supplied as intranasal aqueous microsuspension in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension. Two sprays in each nostril in the morning in a fasted state will be administered.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of AR, as determined by the presence of rhinitis symptoms that last for several months per year, for more than 1 year and are not attributed to infections or nasal abnormalities. * Subjects have a TNSS score of \>=6 during the screening allergen challenge chamber. * Subjects have a positive skin prick test (wheal \>=4 millimeter \[mm\]) for seasonal pollen at or within the 12 months preceding the screening visit. * Subjects have a positive radioallergosorbent test (RAST) (\>=class 2) for seasonal pollen at or within the 12 months preceding the screening visit. * There are no conditions or factors that would make the subject unlikely to be able to stay in the chamber for 5 hours. * Male/females between 18 and 65 years of age inclusive, at the time of signing the informed consent. * Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination and laboratory tests. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
, outside the reference range for the population being studied may be included only if the Investigator agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Body weight \>=50 kg and body mass index (BMI) within the range 19-30 kilogram per meter suare (kg/m\^2) (inclusive). * A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy \[for this definition, documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] \>40 milli international unit per milliliter (MIU/milliliter \[mL\]) and estradiol \<40 picogram per milliliter\[pg/mL\] (\<147 picomole per liter \[pmol/L\]) is confirmatory). Child-bearing potential with negative pregnancy test as determined by urine beta-human chorionic gonadotropin (β-hCG) test at screening or prior to dosing and; * Agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until 1 week post-last dose * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Subjects should be non-smokers, which for this study is defined as having smoked \<10 packs per year in their lifetime, and have not smoked in the 6 months prior to the screening visit. * alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). * Based on single or averaged corrected QT interval (QTc) values of triplicate electrocardiogram (ECGs) obtained over a brief recording period: Fridericia's QTC (QTcF) \<450 milliseconds (msec).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | Day 8 of each treatment period (up to 80 days) | The TNSS (score of 0-12) is defined as the sum of the symptom scores for the four individual components (nasal congestion, rhinorrhea, nasal itch, and sneezing, each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\]). TNSS was measured at the pre-allergen chamber challenge, and then every 15 minutes from 0 to 4 hours post start of the allergen chamber challenge. In the Environmental Exposure Chamber (EEC), aerosolized allergen was administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. Weighted mean TNSS was calculated by dividing the value of the area under the response time curve over the 0-4 hours (calculated by trapezoidal rule) by the time interval of available data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weighted Mean of the Magnitude of Symptom Relief on Total Nasal Symptom Score (TNSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | Day 1 of each treatment period (up to 80 days) | Magnitude of symptom relief was assessed by calculating change from pre-dose weighted mean TNSS (2-4h) post start of the allergen chamber challenge at Day 1. The pre-dose value was the maximum of the three pre-dose measurements (1h 15 minutes (min), 1h 30 min and 1h 45 min post start of the allergen chamber challenge). The TNSS (score of 0-12) is defined as the sum of the symptom scores for the four individual components (nasal congestion, rhinorrhea, nasal itch and sneezing, each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\]). |
| Weighted Mean of the Magnitude of Symptom Relief on Total Ocular Symptom Score (TOSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | Day 1 of each treatment period (up to 80 days) | Magnitude of symptom relief was assessed by calculating change from pre-dose weighted mean TOSS (2-4h) post start of the allergen chamber challenge at Day 1. The pre-dose value was the maximum of the three pre-dose measurements (1h 15 minutes (min), 1h 30 min and 1h 45 min post start of the allergen chamber challenge). The TOSS (score of 0-9) is defined as the sum of the symptom scores for the three individual components (red, itchy, and tearing eyes, each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\], average of two eyes). |
| Weighted Mean of the Total Ocular Symptom Score (TOSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | Day 8 of each treatment period (up to 80 days) | The TOSS (score of 0-9) is defined as the sum of the symptom scores for the three individual components (red, itchy, and tearing eyes , each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\], average of two eyes). TOSS was measured at the pre-allergen chamber challenge, and then every 15 minutes from 0 to 4 hours post start of the allergen chamber challenge. In the Environmental Exposure Chamber (EEC), aerosolized allergen was administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. Weighted mean TOSS was calculated by dividing the value of the area under the response time curve over the 0-4 hours (calculated by trapezoidal rule) by the time interval of available data. |
Countries
Austria
Participant flow
Pre-assignment details
Participants who met the eligibility criteria at Screening were randomized to 1 of 18 treatment sequences. The treatment phase was comprised of three 8-day treatment periods, each separated by a 14- to 28-day washout period.
Participants by arm
| Arm | Count |
|---|---|
| FF 100 μg, Levo 200 μg, FF 100 μg/Levo 200 μg, Placebo Participants received FF 100 µg, Levo 200 µg, FF 100 μg/Levo 200 μg and placebo once daily (OD) in the morning as 2 nasal sprays (FF: 25 µg per spray, Levo: 50 μg per spray, FF/Levo: 25 μg/50 μg per spray) into each nostril for 8 days each, in a crossover design. Treatment was given in one of 18 sequences in Periods 1, 2, and 3, (with a minimum of a 14-day washout period between treatments): BCD, BAC, BCA, DAC, DCB, CDB, ADC, CAD, DCA, ACB, BDC, CBA, CBD, ACD, CAB, CDA, ABC, DBC (A, FF 100 μg; B, Levo 200 μg; C, FF 100 μg/Levo 200 μg; D, placebo). On Day 1 and Day 8 of each treatment period, participants were subjected to an allergen challenge in a Vienna Challenge Chamber (VCC) for a 4-hour period, and the assessments were conducted 12-24 hours post-dose. All participants attended a follow-up visit of 14-28 days after their last dose, and the overall duration for participation in the study (screening to follow-up) was 20 weeks. | 71 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment Period 2 (8 Days) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Treatment Period 3 (8 Days) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | FF 100 μg, Levo 200 μg, FF 100 μg/Levo 200 μg, Placebo |
|---|---|
| Age, Continuous | 29.4 Years STANDARD_DEVIATION 8.91 |
| Gender Female | 36 Participants |
| Gender Male | 35 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 2 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 34 | 1 / 54 | 1 / 53 | 3 / 68 |
| serious Total, serious adverse events | 0 / 34 | 0 / 54 | 0 / 53 | 0 / 68 |
Outcome results
Primary
Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period
The TNSS (score of 0-12) is defined as the sum of the symptom scores for the four individual components (nasal congestion, rhinorrhea, nasal itch, and sneezing, each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\]). TNSS was measured at the pre-allergen chamber challenge, and then every 15 minutes from 0 to 4 hours post start of the allergen chamber challenge. In the Environmental Exposure Chamber (EEC), aerosolized allergen was administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. Weighted mean TNSS was calculated by dividing the value of the area under the response time curve over the 0-4 hours (calculated by trapezoidal rule) by the time interval of available data.
Time frame: Day 8 of each treatment period (up to 80 days)
Population: Pharmacodynamic (PD) Population: all participants in the All Subjects Population (defined as all participants who received at least one dose of investigational product) and who also provided data from at least one PD assessment. Only those participants contributing data at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 6.030 Scores on a scale |
| FF 100 μg | Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 4.189 Scores on a scale |
| Levo 200 μg | Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 4.500 Scores on a scale |
| FF 100 μg/Levo 200 μg | Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 1.933 Scores on a scale |
p-value: <0.000195% CI: [-2.895, -1.616]Mixed Model ANOVA
p-value: <0.000195% CI: [-3.208, -1.925]Mixed Model ANOVA
p-value: 0.000395% CI: [-2.342, -0.719]Mixed Model ANOVA
p-value: <0.000195% CI: [-2.654, -1.029]Mixed Model ANOVA
p-value: <0.000195% CI: [-4.857, -3.337]Mixed Model ANOVA
p-value: 0.369995% CI: [-0.994, 0.372]Mixed Model ANOVA
Secondary
Weighted Mean of the Magnitude of Symptom Relief on Total Nasal Symptom Score (TNSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period
Magnitude of symptom relief was assessed by calculating change from pre-dose weighted mean TNSS (2-4h) post start of the allergen chamber challenge at Day 1. The pre-dose value was the maximum of the three pre-dose measurements (1h 15 minutes (min), 1h 30 min and 1h 45 min post start of the allergen chamber challenge). The TNSS (score of 0-12) is defined as the sum of the symptom scores for the four individual components (nasal congestion, rhinorrhea, nasal itch and sneezing, each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\]).
Time frame: Day 1 of each treatment period (up to 80 days)
Population: PD Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Weighted Mean of the Magnitude of Symptom Relief on Total Nasal Symptom Score (TNSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -1.335 Scores on a scale |
| FF 100 μg | Weighted Mean of the Magnitude of Symptom Relief on Total Nasal Symptom Score (TNSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -0.904 Scores on a scale |
| Levo 200 μg | Weighted Mean of the Magnitude of Symptom Relief on Total Nasal Symptom Score (TNSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -2.588 Scores on a scale |
| FF 100 μg/Levo 200 μg | Weighted Mean of the Magnitude of Symptom Relief on Total Nasal Symptom Score (TNSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -2.267 Scores on a scale |
p-value: <0.000195% CI: [-1.853, -0.874]Mixed Model ANOVA
p-value: 0.197595% CI: [-0.169, 0.809]Mixed Model ANOVA
p-value: <0.000195% CI: [-1.87, -0.635]Mixed Model ANOVA
p-value: 0.164895% CI: [-0.179, 1.042]Mixed Model ANOVA
p-value: 0.001695% CI: [-1.506, -0.358]Mixed Model ANOVA
p-value: <0.000195% CI: [1.16, 2.208]Mixed Model ANOVA
Secondary
Weighted Mean of the Magnitude of Symptom Relief on Total Ocular Symptom Score (TOSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period
Magnitude of symptom relief was assessed by calculating change from pre-dose weighted mean TOSS (2-4h) post start of the allergen chamber challenge at Day 1. The pre-dose value was the maximum of the three pre-dose measurements (1h 15 minutes (min), 1h 30 min and 1h 45 min post start of the allergen chamber challenge). The TOSS (score of 0-9) is defined as the sum of the symptom scores for the three individual components (red, itchy, and tearing eyes, each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\], average of two eyes).
Time frame: Day 1 of each treatment period (up to 80 days)
Population: PD Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Weighted Mean of the Magnitude of Symptom Relief on Total Ocular Symptom Score (TOSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -0.097 Scores on a scale |
| FF 100 μg | Weighted Mean of the Magnitude of Symptom Relief on Total Ocular Symptom Score (TOSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -0.272 Scores on a scale |
| Levo 200 μg | Weighted Mean of the Magnitude of Symptom Relief on Total Ocular Symptom Score (TOSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -0.633 Scores on a scale |
| FF 100 μg/Levo 200 μg | Weighted Mean of the Magnitude of Symptom Relief on Total Ocular Symptom Score (TOSS) (2-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 1 of Each Treatment Period | -0.446 Scores on a scale |
p-value: 0.305295% CI: [-0.508, 0.16]Mixed Model ANOVA
p-value: 0.272595% CI: [-0.149, 0.523]Mixed Model ANOVA
p-value: 0.011895% CI: [-0.952, -0.12]Mixed Model ANOVA
p-value: 0.404995% CI: [-0.588, 0.239]Mixed Model ANOVA
p-value: 0.079395% CI: [-0.739, 0.041]Mixed Model ANOVA
p-value: 0.047895% CI: [0.004, 0.719]Mixed Model ANOVA
Secondary
Weighted Mean of the Total Ocular Symptom Score (TOSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period
The TOSS (score of 0-9) is defined as the sum of the symptom scores for the three individual components (red, itchy, and tearing eyes , each scored on 0-3 scale \[0=none, 1=mild, 2=moderate, 3=severe\], average of two eyes). TOSS was measured at the pre-allergen chamber challenge, and then every 15 minutes from 0 to 4 hours post start of the allergen chamber challenge. In the Environmental Exposure Chamber (EEC), aerosolized allergen was administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. Weighted mean TOSS was calculated by dividing the value of the area under the response time curve over the 0-4 hours (calculated by trapezoidal rule) by the time interval of available data.
Time frame: Day 8 of each treatment period (up to 80 days)
Population: PD Population. Only those participants contributing data at the indicated time points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Weighted Mean of the Total Ocular Symptom Score (TOSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 1.321 Scores on a scale |
| FF 100 μg | Weighted Mean of the Total Ocular Symptom Score (TOSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 0.761 Scores on a scale |
| Levo 200 μg | Weighted Mean of the Total Ocular Symptom Score (TOSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 0.621 Scores on a scale |
| FF 100 μg/Levo 200 μg | Weighted Mean of the Total Ocular Symptom Score (TOSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 of Each Treatment Period | 0.546 Scores on a scale |
p-value: 0.150295% CI: [-0.509, 0.079]Mixed Model ANOVA
p-value: 0.617795% CI: [-0.37, 0.221]Mixed Model ANOVA
p-value: 0.000495% CI: [-1.08, -0.322]Mixed Model ANOVA
p-value: 0.003595% CI: [-0.934, -0.187]Mixed Model ANOVA
p-value: <0.000195% CI: [-1.123, -0.428]Mixed Model ANOVA
p-value: 0.380795% CI: [-0.175, 0.456]Mixed Model ANOVA