Rhinoconjunctivitis, Rhinitis, Conjunctivitis, Allergy
Conditions
Keywords
rhinoconjunctivitis, rhinitis, conjunctivitis, allergy, allergen, immunotherapy
Brief summary
The purpose of the study is to investigate the efficacy and safety of a grass sublingual tablet in children and adolescents with a history of grass-pollen induced rhinoconjunctivitis with or without asthma.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in participants aged 5 to \<18 years of either sex, and of any race with a history of grass pollen induced rhinoconjunctivitis with or without asthma. While receiving treatment, participants will receive either grass sublingual tablet or placebo. Open-label rescue medications for the rhinoconjunctivitis and asthma symptoms will be provided. Participants will visit the study site for at least 12 visits. A total of 10 allergic symptoms, 6 rhinoconjunctivitis and 4 lung symptoms, will be recorded daily on an electronic diary by the participant/parent/guardian. The start and end of the grass pollen season (GPS) was determined based on the regional grass pollen count, and lasted up to 162 days. For each region, the GPS is defined as the first day of 3 consecutive recorded days with a grass pollen count of ≥ 10 grains/m\^3, to the last day of the last occurrence of 3 consecutive recorded days with a grass pollen count ≥ 10 grains/m\^3, inclusively.
Interventions
DRUGPlacebo
Placebo sublingual tablet, once daily
BIOLOGICALSCH 697243
Grass sublingual tablet, once daily
DRUGLoratadine Syrup 1 mg/mL Rescue Treatment
Loratadine Syrup 1 mg/mL was dosed orally once daily at a dose of 5 mg for children aged 5 to \<6 years of age and at a dose of 10 mg for children aged 6 to \<18 years of age as rescue medication for symptoms of rhinoconjunctivitis among participants with a total symptom score ≥4.
Loratadine 10 mg RediTabs tablets were dosed orally once daily at a dose of 10 mg for children aged 6 to \<18 years of age as rescue medication for symptoms of rhinoconjunctivitis among participants with a total symptom score ≥4.
Olopatadine hydrochloride 0.1% ophthalmic solution was dosed intraocularly at a dose of 1 drop in each affected eye twice daily, in addition to loratadine, as rescue medication for participants with persistent eye symptoms due to rhinoconjunctivitis.
DRUGMometasone furoate 50 mcg Rescue Treatment
Mometasone furoate monohydrate nasal spray 50 mcg was dosed intranasally at a dose of one spray in each nostril once daily for participants aged 5 to \<12 years and a dose of 2 sprays in each nostril once daily for participants aged 12 to \<18 years as rescue medication for nasal symptoms of rhinoconjunctivitis among participants with a total symptom score of ≥4 despite loratadine and mometasone furoate nasal spray.
DRUGAlbuterol 108 mcg Rescue Treatment
Albuterol sulfate inhalation aerosol 108 mcg/inhalation was administered via inhalation at a dose of 2 inhalations every 4 to 6 hours as rescue medication among participants aged 5 to \<18 years with asthma symptoms .
DRUGFluticasone 44 mcg Rescue Treatment
Fluticasone propionate inhalation aerosol 44 mcg/inhalation was administered via inhalation at a dose of 2 inhalations twice daily among participants aged 12 to \<18 years up to a maximum dose of 10 inhalations twice daily, in combination with albuterol, among participants with ≥4 albuterol sulfate inhalations/day for 2 days as rescue medication for nocturnal asthma or shortness of breath.
Prednisone tablet 5 mg was administered orally at a dose of 1 mg/kg/day once daily up to a maximum of 50 mg/day on Day 1, and at a dose of 0.5 mg/kg/day once daily up to a maximum of 25 mg/day on Days 2, 3, 5, and 7 as rescue medication for asthma exacerbation at the discretion of the investigator.
Sponsors
ALK-Abelló A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Participant must be 5 to \<18 years of age, of either sex, and of any race. * Participant must have a clinical history of significant allergic rhinoconjunctivitis to grass (with or without asthma) diagnosed by a physician and have received treatment for their disease during the previous GPS. * Participant must have a positive skin prick test response (average wheal diameter \>=5 mm larger than the saline control after 15 to 20 minutes) to Phleum pratense at the Screening Visit. * Participant must have positive specific IgE against Phleum pratense (\>= IgE Class 2) at the Screening Visit. * Participant must have an FEV1 \>=70% of predicted value at the Screening Visit. * A participant's safety laboratory tests and vital signs conducted at the Screening Visit must be within normal limits or clinically acceptable to the investigator/sponsor. * A participant (and/or parent/guardian for subjects under the age of legal consent or who otherwise are unable to provide independent consent) must be willing to give written informed consent/assent and be able to adhere to dose and visit schedules. * Female participants of childbearing potential must be using a medically acceptable and adequate form of birth control. These include: * hormonal contraceptives as prescribed by a physician (oral, hormonal vaginal ring, hormonal implant or depot injectable); * medically prescribed intra-uterine device; * medically prescribed topically-applied transdermal contraceptive patch; * double-barrier method (eg, condom in combination with a spermicide); vasectomy and tubal ligation should each be considered as single barrier. * Female participants of childbearing potential should be counseled in the appropriate use of birth control while in the study. Female participants who are not currently sexually active must agree and consent to use one of the above-mentioned methods if they become sexually active while participating in the study. * Female participants of childbearing potential must have a negative urine pregnancy test at the Screening Visit in order to be considered eligible for enrollment.
Exclusion criteria
* Participant with a clinical history of symptomatic seasonal allergic rhinitis and/or asthma, having received regular medications due to another allergen during or potentially overlapping the GPS. * Participant with a clinical history of significant symptomatic perennial allergic rhinitis and/or asthma having received regular medication due to an allergen to which the participant is regularly exposed. * Participant with sufficient pre-seasonal data in the observational phase will not be eligible to continue in the treatment phase if the participant: 1) does not experience an increase in rhinoconjunctivitis symptom score of equal to or greater than 4 above the pre-seasonal average symptom score for at least 2 days, 2) does not use allergy rescue medication for at least 2 days, during the observational phase Year 1 2008 GPS. * Participant has received an immunosuppressive treatment within 3 months prior to the Screening Visit (except steroids for allergic and asthma symptoms). * Participant with a clinical history of severe asthma. * Participant with history of anaphylaxis with cardiorespiratory symptoms. * Participant with history of self-injectable epinephrine use. * Participant with a history of chronic urticaria and angioedema. * Participant with clinical history of chronic sinusitis during the 2 years prior to the Screening Visit. * Participant with current severe atopic dermatitis. * Female participants who are breast-feeding, pregnant, or intending to become pregnant. * Participant who has had previous treatment by immunotherapy with grass pollen allergen or any other allergen within the 5 years prior to the Screening Visit. * Participant with a known history of allergy, hypersensitivity or intolerance to the ingredients of the IMP (except for Phleum pratense), rescue medications, or self-injectable epinephrine. * Participant with any clinically significant condition or situation, other than the condition being studied that, in the opinion of the investigator, would interfere with the study evaluations or optimal participation in the study. Specific examples include but are not limited to hypertension being treated with beta blockers, coronary artery disease, arrhythmia, stroke, ocular conditions requiring topical beta blockers, any condition requiring the use of beta blockers. * Participant who has used any investigational drugs within 30 days of the Screening Visit. * Participant who is participating in any other clinical study. * Participant who is a family member of the investigational study staff conducting this study. * Participant who is unable to meet medication washout requirements as listed in the protocol. * Participant who is unlikely to be able to complete the trial, for any reason, or likely to travel for extended periods of time during the GPS, which in the opinion of the investigator will compromise the data. * Participant with a clinically significant abnormal vital sign or laboratory value that would preclude participation in the study. * A participant participating in this study may not participate in this same study at another investigational site. * A participant must not be randomized into this study more than once. * Participant who is unable to or will not comply with the use of self-injectable epinephrine. * Participants who may be at greater risk of developing adverse reactions after epinephrine administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participant Total Combined Symptom (TCS) Score Over the Entire Grass Pollen Season (GPS) | From the Start of the GPS to the End of the GPS | The TCS is the sum of the rhinoconjunctivitis daily symptom score (DSS) and rhinoconjunctivitis daily medication score (DMS) averaged over the entire GPS. The TCS ranged from 0 (no symptoms and no rescue medication use) to 54 (most severe symptoms and maximum use of rescue medication), with increasing score indicating a higher level of symptom severity. The DSS is composed of 6 rhinoconjunctivitis symptoms with scores from 0 (best) to 18 (worst), with increasing score indicating increased severity. The DMS is composed of a sum of the scores associated with rescue medication use per day. The range for the DMS was 0 (no rescue medication use) to 36 (maximum use of rescue medication), with a lower score indicating less use of rescue medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participant Average Rhinoconjunctivitis Daily Symptom Scores (DSS) Over the Entire GPS | Start of the GPS to the End of the GPS | The DSS is composed of six rhinoconjunctivitis symptoms which were recorded daily including runny nose, blocked nose, sneezing, itchy nose, gritty feeling/red/itchy, and watery eyes, and the symptoms were measured on a scale of 0 (no symptom) to 3 (severe symptoms). A higher score indicated a higher level of symptoms and the total daily score could range from 0 (best) to 18 (worst). |
| Participant Average Rhinoconjunctivitis Daily Medication Score (DMS) Over the Entire GPS | Start of the GPS to the End of the GPS | The DMS is composed of a sum of the scores associated with rescue medication use per day. Rescue medications were implemented when a participant had a symptom score \>= 4. Rescue medications for allergic rhinoconjunctivitis were to be utilized in a step-wise fashion: loratadine, olopatadine hydrochloride 0.1% opthalmic solution, mometasone, and prednisone, in that sequence. The score for the DMS ranged from 0 (no use of rescue medication) to 36 (maximum use of rescue medication). A lower medication score indicated less impact on symptoms and was suggestive of less use of rescue medication. |
| Participant Average Weekly Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) Total Score Over the Entire GPS | Start of the GPS to the End of the GPS | The RQLQ has 28 questions and focusses on 7 domains that may be significantly impaired in participants with seasonal allergic rhinoconjunctivitis: sleep impairment, non-nasal symptoms, practical problems, nasal symptoms, eye symptoms, activity limitations, and emotional difficulty. The RQLQ score is the mean of all 28 responses and the individual domain scores are the means of the items in those domains. RQLQ scores range from 0 (best) to 6 (worst), with a higher score indicating more significant impairment. |
Participant flow
Recruitment details
A total of 345 subjects were randomized at a total of 68 sites (58 sites from United States; 10 sites from Canada) to treatment assignment, and 344 subjects received at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| SCH 697243 SCH 697243 (Phleum pratense extract) administered sublingually once daily. | 175 |
| Placebo Matching placebo tablet administered sublingually once daily. | 169 |
| Total | 344 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 13 | 5 |
| Overall Study | Did Not Meet Protocol Eligibility | 1 | 1 |
| Overall Study | Lost to Follow-up | 4 | 0 |
| Overall Study | Protocol Violation | 5 | 14 |
| Overall Study | Randomized But Not Treated | 1 | 0 |
| Overall Study | Treatment Failure | 0 | 1 |
| Overall Study | Withdrawal by Subject | 10 | 8 |
Baseline characteristics
| Characteristic | SCH 697243 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 12.1 years STANDARD_DEVIATION 3 | 12.6 years STANDARD_DEVIATION 3 | 12.3 years STANDARD_DEVIATION 3 |
| Gender Female | 57 Participants | 64 Participants | 121 Participants |
| Gender Male | 118 Participants | 105 Participants | 223 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 141 / 176 | 121 / 169 |
| serious Total, serious adverse events | 0 / 176 | 4 / 169 |
Outcome results
Primary
Participant Total Combined Symptom (TCS) Score Over the Entire Grass Pollen Season (GPS)
The TCS is the sum of the rhinoconjunctivitis daily symptom score (DSS) and rhinoconjunctivitis daily medication score (DMS) averaged over the entire GPS. The TCS ranged from 0 (no symptoms and no rescue medication use) to 54 (most severe symptoms and maximum use of rescue medication), with increasing score indicating a higher level of symptom severity. The DSS is composed of 6 rhinoconjunctivitis symptoms with scores from 0 (best) to 18 (worst), with increasing score indicating increased severity. The DMS is composed of a sum of the scores associated with rescue medication use per day. The range for the DMS was 0 (no rescue medication use) to 36 (maximum use of rescue medication), with a lower score indicating less use of rescue medication.
Time frame: From the Start of the GPS to the End of the GPS
Population: The Full Analysis Set (FAS) population was comprised of all participants randomized with at least one post-treatment diary data entry.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 697243 | Participant Total Combined Symptom (TCS) Score Over the Entire Grass Pollen Season (GPS) | 4.62 Units on a Scale | Standard Error 0.52 |
| Placebo | Participant Total Combined Symptom (TCS) Score Over the Entire Grass Pollen Season (GPS) | 6.25 Units on a Scale | Standard Error 0.51 |
p-value: =0.00195% CI: [-2.6, -0.66]ANOVA
Secondary
Participant Average Rhinoconjunctivitis Daily Medication Score (DMS) Over the Entire GPS
The DMS is composed of a sum of the scores associated with rescue medication use per day. Rescue medications were implemented when a participant had a symptom score \>= 4. Rescue medications for allergic rhinoconjunctivitis were to be utilized in a step-wise fashion: loratadine, olopatadine hydrochloride 0.1% opthalmic solution, mometasone, and prednisone, in that sequence. The score for the DMS ranged from 0 (no use of rescue medication) to 36 (maximum use of rescue medication). A lower medication score indicated less impact on symptoms and was suggestive of less use of rescue medication.
Time frame: Start of the GPS to the End of the GPS
Population: The FAS population was comprised of all participants randomized with at least one post-treatment diary data entry.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 697243 | Participant Average Rhinoconjunctivitis Daily Medication Score (DMS) Over the Entire GPS | 0.91 Units on a Scale | Standard Error 0.25 |
| Placebo | Participant Average Rhinoconjunctivitis Daily Medication Score (DMS) Over the Entire GPS | 1.33 Units on a Scale | Standard Error 0.23 |
p-value: =0.06695% CI: [-0.88, 0.03]ANOVA
Secondary
Participant Average Rhinoconjunctivitis Daily Symptom Scores (DSS) Over the Entire GPS
The DSS is composed of six rhinoconjunctivitis symptoms which were recorded daily including runny nose, blocked nose, sneezing, itchy nose, gritty feeling/red/itchy, and watery eyes, and the symptoms were measured on a scale of 0 (no symptom) to 3 (severe symptoms). A higher score indicated a higher level of symptoms and the total daily score could range from 0 (best) to 18 (worst).
Time frame: Start of the GPS to the End of the GPS
Population: The FAS population was comprised of all participants with at least one post-treatment diary data entry.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 697243 | Participant Average Rhinoconjunctivitis Daily Symptom Scores (DSS) Over the Entire GPS | 3.71 Units on a Scale | Standard Error 0.4 |
| Placebo | Participant Average Rhinoconjunctivitis Daily Symptom Scores (DSS) Over the Entire GPS | 4.91 Units on a Scale | Standard Error 0.41 |
p-value: =0.00595% CI: [-1.95, -0.45]ANOVA
Secondary
Participant Average Weekly Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) Total Score Over the Entire GPS
The RQLQ has 28 questions and focusses on 7 domains that may be significantly impaired in participants with seasonal allergic rhinoconjunctivitis: sleep impairment, non-nasal symptoms, practical problems, nasal symptoms, eye symptoms, activity limitations, and emotional difficulty. The RQLQ score is the mean of all 28 responses and the individual domain scores are the means of the items in those domains. RQLQ scores range from 0 (best) to 6 (worst), with a higher score indicating more significant impairment.
Time frame: Start of the GPS to the End of the GPS
Population: The FAS population was comprised of all participants randomized with at least one post-treatment diary data entry for the rhinoconjunctivitis quality-of-life measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SCH 697243 | Participant Average Weekly Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) Total Score Over the Entire GPS | 1.45 Units on a Scale | Standard Error 0.11 |
| Placebo | Participant Average Weekly Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ) Total Score Over the Entire GPS | 1.77 Units on a Scale | Standard Error 0.12 |
p-value: =0.04295% CI: [-0.6, -0.03]ANOVA