Rhinitis, Allergic, Perennial and Seasonal
Conditions
Keywords
Allergic rhinitis, levocabastine, allergen challenge
Brief summary
This study will be a randomized, double blind, placebo controlled, 3-way cross over design in allergic rhinitis subjects. Subjects will receive repeat doses of intra-nasal levocabastine for 7 days in each period and the duration of the study will be about 13 weeks. An Environmental Exposure Chamber (EEC) will be used in this study. The primary objective of the study is to investigate the non-inferiority effect of 7 days treatment with levocabastine on nasal symptoms elicited by an EEC when administered once daily (QD) compared with twice daily (BID). Also study will be conducted to investigate the superiority of effect of 7 days treatment with levocabastine (QD and BID) on nasal symptoms elicited by an EEC in subjects compared to placebo.
Interventions
DRUGLevocabastine
Intranasal aqueous 50 mcg microsuspension of levocabastine supplied in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension
DRUGPlacebo
Intranasal aqueous 0 mcg microsuspension supplied in an amber glass bottle fitted with a white top actuated plastic metering atomising spray pump filled with a uniform white suspension
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 Allergic Rhinitis (AR), as determined by the presence of seasonal or perennial rhinitis symptoms 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 at the baseline screening allergen challenge. Total nasal symptom score is the sum of nasal congestion, rhinorrhoea, nasal itch and sneeze, each of which are scored on a scale from 0 to 3. * 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 4 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, laboratory tests and cardiac monitoring. 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 kilogram (kg) and body mass index (BMI) within the range 19 - 30 kg per meter square (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 (MlU/mL) and estradiol \<40 picogram (pg)/mL (\<147 picomol per liter \[pmol/L\]) is confirmatory); child-bearing potential with negative pregnancy test as determined by urine human chorionic gonadotropin (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 (ALP) and bilirubin \<=1.5 x 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 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 | Day 8 of each treatment period (up to 13 Weeks) | 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 Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | Day 8 of each treatment period (up to 13 Weeks) | TNSS contains symtom scores for the four individual components (nasal congestion \[NACG\], rhinorrhea \[RHSCR\], nasal itching \[NAITS\] and sneezing \[SNZS\]), each scored on a 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 is administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. The participants recorded their symptom scores on an e-diary. The mean score for each participant was calculated using the available diary data from the assessment periods, taking the average of non-missing data during the period. Weighted mean of the individual symptoms of theTNSS were 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
Canada
Participant flow
Pre-assignment details
Participants who met the eligibility criteria at Screening were randomized to 1 of 6 treatment sequences. The treatment phase was comprised of three 7-day treatment periods, each separated by a 14- to 20-day washout period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Levocabastine Participants received placebo/ Levo at a dose of 200 µg OD in the morning as 2 nasal sprays (50 µg per spray) into each nostril or 400 µg BID in the morning and evening as 2 nasal sprays (50 µg per spray) into each nostril for 7 days each, in a crossover design. Treatment was given in one of six sequences in Periods 1, 2, and 3, (14 to 20 day washout period between treatments): ABC, BCA, CAB, ACB, BAC, CBA (A, Levo 200µg; B, Levo 400µg: C, Placebo). On Day 8 of each treatment period (approximately 12 hours post dosing for treatment A and 24 hours post dosing for treatment B and C), participants entered the environmental exposure chamber (EEC) for a 4-hour period, and the assessments were conducted 12-24 hours post-dose. All participants attended a follow-up visit within 7 to 14 day after their final dose, and the overall duration for participation in the study (screening to follow-up) was 13 weeks. | 78 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (7 Days) | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period 1 (7 Days) | Protocol Violation | 1 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period 2 (7 Days) | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 |
| Treatment Period 2 (7 Days) | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period 2 (7 Days) | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo/Levocabastine |
|---|---|
| Age, Continuous | 42.3 Years STANDARD_DEVIATION 11.46 |
| Race/Ethnicity, Customized African American/African Heritage | 26 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 7 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 3 Participants |
| Race/Ethnicity, Customized Asian - Mixed Race | 1 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 3 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 3 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 35 Participants |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 75 | 3 / 76 | 5 / 74 |
| serious Total, serious adverse events | 0 / 75 | 0 / 76 | 0 / 74 |
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
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 13 Weeks)
Population: Per Protocol Population: all participants in the Intent-to-Treat Population (defined as all participants who were randomized and received \>= 1 dose of study medication) and not identified as full protocol deviators with respect to criteria that were considered to impact the primary efficacy analysis. Only those participants contributing data at the
| 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 | 5.190 Scores on a scale |
| Levocabastine 200µg OD | Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 | 4.071 Scores on a scale |
| Levocabastine 400µg BID | Weighted Mean of the Total Nasal Symptom Score (TNSS) (0-4) Hours (h) Post Start of Allergen Chamber Challenge on Day 8 | 3.840 Scores on a scale |
p-value: <0.000195% CI: [-1.943, -0.756]Mixed Model ANOVA
p-value: 0.000395% CI: [-1.712, -0.525]Mixed Model ANOVA
95% CI: [-0.361, 0.823]
Secondary
Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8
TNSS contains symtom scores for the four individual components (nasal congestion \[NACG\], rhinorrhea \[RHSCR\], nasal itching \[NAITS\] and sneezing \[SNZS\]), each scored on a 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 is administered in a sealed chamber to evaluate the efficacy of antihistamines/other treatments. The participants recorded their symptom scores on an e-diary. The mean score for each participant was calculated using the available diary data from the assessment periods, taking the average of non-missing data during the period. Weighted mean of the individual symptoms of theTNSS were 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 13 Weeks)
Population: ITT Population. Only those participants contributing data at the indicated time points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | NACG | 1.483 Scores on a scale |
| Placebo | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | RHSCR | 1.403 Scores on a scale |
| Placebo | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | NAITS | 1.257 Scores on a scale |
| Placebo | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | SNZS | 1.018 Scores on a scale |
| Levocabastine 200µg OD | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | SNZS | 0.647 Scores on a scale |
| Levocabastine 200µg OD | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | NACG | 1.217 Scores on a scale |
| Levocabastine 200µg OD | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | NAITS | 1.099 Scores on a scale |
| Levocabastine 200µg OD | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | RHSCR | 1.035 Scores on a scale |
| Levocabastine 400µg BID | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | SNZS | 0.529 Scores on a scale |
| Levocabastine 400µg BID | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | RHSCR | 1.004 Scores on a scale |
| Levocabastine 400µg BID | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | NAITS | 1.040 Scores on a scale |
| Levocabastine 400µg BID | Weighted Mean of the Symptom Scores for the Four Individual Components of the Total Nasal Symptom Score (TNSS) (Nasal Congestion, Rhinorrhea, Nasal Itching and Sneezing) (0-4) Hours Post Start of the Allergen Chamber Challenge on Day 8 | NACG | 1.226 Scores on a scale |