A Study in Children and Adolescents With Birch Pollen-induced Rhinoconjunctivitis

ALK-Abelló A/S952 enrolled

Overview

This is a clinical study in children and adolescents (5-17 years) with allergy to pollen from birch (or related trees). It compares the tree SLIT-tablet with placebo in relieving rhinoconjunctivitis symptoms during the birch/tree pollen season based on the average allergic rhinoconjunctivitis daily total combined score. The study will also collect health-related quality of life information in the groups treated with the tree SLIT-tablet or with placebo during the pollen season. The trial medication used is already approved to treat allergic rhinitis caused by birch/tree pollen in adults in several countries?.

This is a phase III, parallel-group, double-blind, placebo-controlled study to evaluate efficacy and safety of the tree SLIT-tablet in children and adolescents (5-17 years) who have rhinoconjunctivitis (with or without asthma) induced by pollen from birch trees or by trees belonging to the birch homologous group. Approximately 1000 children and adolescents will be enrolled in the trial and will receive either the tree SLIT-tablet or placebo. The trial consists of 3 periods: a screening period, a treatment period, which includes pre-seasonal and co seasonal treatment, and a follow-up period. The duration is up to 13 months for each participant. The trial is conducted in several European countries and in Canada.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

952

Conditions

Allergy

Interventions

Tree SLIT-tabletDRUG

Sublingual allergy immunotherapy tablets

Placebo SLIT-tabletDRUG

Placebo

Eligibility

Sex: ALLMin age: 5 YearsMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male or female of any race/ethnicity aged ≥4 to \<18 years on the day informed consent is obtained from the parent/caregiver; the subject must be ≥5 to \<18 years old at the randomisation visit * A documented , physician diagnosed, clinically relevant history of moderate to severe AR/C induced by birch pollen (with or without asthma) despite having received treatment with symptom-relieving medication during at least 1 previous tree pollen season for ages 4 through 6 years at screening or at least 2 previous tree pollen seasons for ages 7 through 17 years at screening * Positive skin prick test (SPT) to Betula verrucosa at screening * Positive specific IgE to Bet v at screening * Presence of 1 or more of the following Allergic Rhinitis Impact on Asthma (ARIA) quality of life items due to AR/C during the previous BPS: 1. Sleep disturbance 2. Impairment of daily activities, leisure and/or sport 3. Impairment of school or work 4. Troublesome symptoms Exclusion Criteria: * A clinically relevant history of symptomatic seasonal AR/C caused by an allergen source, other than tree pollen from the birch homologous group, with a season overlapping the TPS * A clinically relevant history of symptomatic perennial AR/C caused by an allergen source such as animal hair and dander to which the subject is exposed during the TPS * Any clinical deterioration of asthma (i.e. asthma exacerbation) that resulted in emergency treatment, hospitalisation or treatment with systemic corticosteroids within 3 months prior to randomisation * Reduced lung function at randomisation defined as forced expiratory volume in 1 second (FEV1) \<70% of predicted value. For subjects with asthma, this is assessed on subject's usual asthma medication following at least a 6-hour wash-out of SABA. This criterion does not need to be fulfilled if the subject is \<7 years old, cannot perform reproducible FEV1 manoeuvres despite coaching and is not considered as having a diagnosis of asthma * Ongoing treatment with any allergy immunotherapy product * Severe chronic oral inflammation * A diagnosis of eosinophilic oesophagitis * A relevant history of systemic allergic reaction e.g. anaphylaxis with cardiorespiratory symptoms, generalised urticaria or severe facial angioedema that in the opinion of the investigator may constitute an increased safety concern * Immunosuppressive treatment (ATC code L04 or L01) within 3 months prior to the screening visit

Locations (80)

Outcomes

Primary Outcomes

Average Total Combined Score (TCS) During the Birch Pollen Season (BPS)

The primary endpoint of the trial was the average allergic rhinitis and/or conjunctivitis TCS during the BPS. The average TCS evaluates the treatment effect based on reduction in daily rhinoconjunctivitis symptoms and medication use (on a scale of 0-38). Higher scores indicate more severe symptoms and/or more medication use. The endpoint is calculated as the average score of all reported daily values during the BPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Secondary Outcomes

Average Total Combined Score (TCS) During the Tree Pollen Season (TPS)

Average TCS measured in the TPS. TPS includes hazel, alder, birch and oak pollen seasons. The average TCS evaluates the treatment effect based on reduction in daily rhinoconjunctivitis symptoms and medication use (on a scale of 0-38). Higher scores indicate more severe symptoms and/or more medication use. The endpoint is calculated as the average score of all reported daily values during the TPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the TPS (mean duration of approximately 11 weeks)

Average Daily Symptoms Score (DSS) During the Birch Pollen Season (BPS)

Average rhinoconjunctivitis DSS during the BPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis symptoms (on a scale of 0 to 18). Higher scores indicate more severe symptoms. The endpoint is calculated as the average score of all reported daily values during the BPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Data from ClinicalTrials.gov

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Allergy Center Vienna West

Vienna, Austria

Medical University of Vienna

Vienna, Austria

Practice Dr Jean-Benoit Martinot

Erpent, Namur, Belgium

Universitair Ziekenhuis Gent

Ghent, Oost-Vlandeeren, Belgium

UZ Leuven

Leuven, Vlaams Brabant, Belgium

CHU Sainte-Justine

Montreal, Quebec, Canada

Clinique specialisee en allergie de la capitale

Québec, Canada

Aarhus Universitetshospital, Astma, Allergi- og Lungeklinikken for Born

Aarhus, Denmark

Astma, Allergi- og Lungeklinik

Copenhagen, Denmark

Gentofte Hospital Allergy Clinic

Hellerup, Denmark

...and 70 more locations

Average Daily Symptoms Score (DSS) During the Tree Pollen Season (TPS)

Average rhinoconjunctivitis DSS during the TPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis symptoms (on a scale of 0 to 18). TPS includes hazel, alder, birch and oak pollen seasons. Higher scores indicate more severe symptoms. The endpoint is calculated as the average score of all reported daily values during the TPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the TPS (mean duration of approximately 11 weeks).

Average Daily Medication Score (DMS) During the Birch Pollen Season (BPS)

Average rhinoconjunctivitis DMS during the BPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis medication use (on a scale of 0 to 20). Higher scores indicate more medication use. The endpoint is calculated as the average score of all reported daily values during the BPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Average Daily Medication Score (DMS) During the Tree Pollen Season (TPS)

Average rhinoconjunctivitis DMS during the TPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis medication use (on a scale of 0 to 20). TPS includes hazel, alder, birch and oak pollen seasons. Higher scores indicate more medication use. The endpoint is calculated as the average score of all reported daily values during the TPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the TPS (mean duration of approximately 11 weeks)

Average Total Combined Score (TCS) During the Alder Hazel Pollen Season (AHPS)

Average TCS during the AHPS evaluates the treatment effect based on reduction in daily rhinoconjunctivitis symptoms and medication use (on a scale of 0-38). Higher scores indicate more severe symptoms and/or more medication use. The endpoint is calculated as the average score of all reported daily values during the AHPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the AHPS (mean duration of approximately 6-7 weeks)

Average Daily Symptoms Score (DSS) During the Alder Hazel Pollen Season (AHPS)

Average rhinoconjunctivitis DSS during the AHPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis symptoms (on a scale of 0 to 18). Higher scores indicate more severe symptoms. The endpoint is calculated as the average score of all reported daily values during the AHPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the AHPS (mean duration of approximately 6-7 weeks)

Average Daily Medication Score (DMS) During the Alder Hazel Pollen Season (AHPS)

Average rhinoconjunctivitis DMS during the AHPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis medication use (on a scale of 0 to 20). Higher scores indicate more medication use. The endpoint is calculated as the average score of all reported daily values during the AHPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the AHPS (mean duration of approximately 6-7 weeks)

Average Total Combined Score (TCS) During the Oak Pollen Season (OPS)

Average TCS measured in the OPS evaluates the treatment effect based on reduction in daily rhinoconjunctivitis symptoms and medication use (on a scale of 0-38). Higher scores indicate more severe symptoms and/or more medication use. The endpoint is calculated as the average score of all reported daily values during the OPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the OPS (mean duration of approximately 3 weeks)

Average Daily Symptoms Score (DSS) During the Oak Pollen Season (OPS)

Average rhinoconjunctivitis DSS during the OPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis symptoms (on a scale of 0 to 18). Higher scores indicate more severe symptoms. The endpoint is calculated as the average score of all reported daily values during the OPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the OPS (mean duration of approximately 3 weeks)

Average Daily Medication Score (DMS) During the Oak Pollen Season (OPS)

Average rhinoconjunctivitis DMS during the OPS evaluates the treatment effect based on the reduction in daily rhinoconjunctivitis medication use (on a scale of 0 to 20). Higher scores indicate more medication use. The endpoint is calculated as the average score of all reported daily values during the OPS. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the OPS (mean duration of approximately 3 weeks)

Number of Severe Days During the Birch Pollen Season (BPS)

The disease burden for participants was analyzed in terms of proportion of severe days. A severe day was a day with a daily symptom score (DSS) ≥6 and ≥2 moderate symptoms or 1 severe symptom. The DSS ranged from 0 to 18 and was the sum of the 6 allergic rhinoconjunctivitis symptom scores, each scored on a scale from 0 to 3 (0 = no symptoms, 1= mild symptoms, 2= moderate symptoms and 3 = severe symptoms). The proportion of severe days was the number of severe days divided by the number of days in the season.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Number of Severe Days During the Tree Pollen Season (TPS)

Time frame: During the TPS (mean duration of approximately 11 weeks)

Number of Well Days During the Birch Pollen Season (BPS)

A well day was defined as a day with no use of allergic rhinitis and/or conjunctivitis (AR/C) rescue medication (daily medication score =0) and daily symptom score ≤2. The proportion of well days was the number of well days divided by the number of days in the season.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Number of Well Days During the Tree Pollen Season (TPS)

Time frame: During the TPS (mean duration of approximately 11 weeks)

Number of Symptom-free Days During the Birch Pollen Season (BPS)

A a symptom-free day was defined as a day with no symptoms and with no use of rescue medication (Total Combined Score = 0). The proportion of symptom-free days was the number of symptom-free divided by the number of days in the season.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Number of Symptom-free Days During the Tree Pollen Season (TPS)

Time frame: During the TPS (mean duration of approximately 11 weeks)

Percentage of Patients Free of Symptoms and With no Use of Rescue Medication During the Birch Pollen Season (BPS)

A symptom-free day was defined as a day with no symptoms and with no use of rescue medication, i.e. total combined score (TCS) =0. Thus, the endpoint was categorized as a binary variable with a subject being a responder if he/she had no symptoms and had not used rescue medication during the season

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Percentage of Patients Free of Symptoms and With no Use of Rescue Medication During the Tree Pollen Season (TPS)

A symptom-free day was defined as a day with no symptoms and with no use of rescue medication, i.e. total combined score (TCS) = 0. Thus, the endpoint was categorized as a binary variable with a subject being a responder if he/she had no symptoms and had not used rescue medication during the tree pollen season.

Time frame: During the TPS (mean duration of approximately 11 weeks)

Average Total Combined Score (TCS) (EAACI Scoring) During Birch Pollen Season (BPS)

The TCS European Academy of Allergy and Clinical Immunology (EAACI) scoring was calculated using the medication score proposed by EAACI and was the sum of the DSS/6 and the daily EAACI medication score (DMSEAACI) (values 0,1,2), and thus ranged 0-5 with higher scores indicating more combined allergy symptoms and medication use. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Average Total Combined Score (TCS) (EAACI Scoring) During Tree Pollen Season (TPS)

Time frame: During the TPS (mean duration of approximately 11 weeks).

Average Weekly Overall Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) Score During the Birch Pollen Season (BPS) (12-17 Years Only)

The RQLQ measured the rhinoconjunctivitis quality of life. The RQLQ (for participants 12-17 years only) comprised 28 items, each scored on a 7-point scale ranging 0-6, with higher scores indicating worse quality of life. The overall RQLQ score was the mean of the 28 item scores. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Average Weekly Overall Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) Score During the Tree Pollen Season (TPS) (12-17 Years Only)

Time frame: During the TPS (mean duration of approximately 11 weeks)

Overall Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) Score During the Birch Pollen Season (BPS) (5-11 Years Only)

The PRQLQ measured the paediatric rhinoconjunctivitis quality of life. The PRQLQ consisted of 23 items, each scored on a 7-point scale ranging 0-6, with higher scores indicating worse quality of life. The overall PRQLQ score was the mean of the 23 item scores. The primary estimand for the endpoint was the trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: During the BPS (mean duration of approximately 3-4 weeks)

Treatment Satisfaction (TSQM-9)

Treatment satisfaction was measured using the 9-item treatment satisfaction questionnaire for medication (TSQM-9 questionnaire). After ending treatment, participants completed the TSQM-9 questionnaire which consisted of 9 items covering 3 domains. Each item was scored on a 5 point (ranging 1-5) or 7 point (ranging 1-7) scale. For each domain, item scores were summed and normalised to a 0-100 scale, with higher scores indicating better satisfaction.

Time frame: After ending treatment (after approximately 52 weeks of treatment)

Patient-rated Global Evaluation of Treatment Efficacy

The global evaluation measured patient treatment satisfaction. After ending treatment, participants were asked: 'Compared to your rhinitis and/or conjunctivitis symptoms in the previous birch/tree pollen season, how have you felt overall in this birch/tree pollen season?'. The endpoint was evaluated as a binary endpoint; answer options 'much better' and 'better' were categorised as improved (taking value 1), while answer options 'the same', 'worse', and 'much worse' were categorised as not improved (taking value 0). The primary estimand for the endpoint was he trial product estimand. The trial product estimand assesses the anticipated effect of the tree SLIT-tablet if it is taken as instructed.

Time frame: End of treatment (after approximately 52 weeks of treatment)

Change From Baseline in Birch Specific IgE

Birch specific IgE reflects the allergen-specific allergy immunotherapy-induced immune modulation

Time frame: From baseline (screening) to visit 4 (pre-TPS) (after approximately 19 weeks of treatment, on average) and from baseline (screening) to visit 6 (end of treatment) (after approximately 44 weeks of treatment, on average)

Change From Baseline in Birch Specific IgG4

Birch specific IgG4 reflects the allergen-specific allergy immunotherapy-induced immune modulation.

Change From Baseline in Birch Specific IgE-Blocking Factor (IgE-BF)

The IgE-blocking factor assesses the effect of serum components (including IgE-blocking antibodies known to be induced by allergy immunotherapy) competing with IgE for binding to allergen. IgE-blocking factor is calculated as 1-(S/T), where S is the amount of allergen-specific IgE bound to allergen in the (possible) presence of competing components, and where T is the total amount of allergen-specific IgE capable of binding to allergen when all competing antibodies/components have been washed off. IgE-blocking factor values closer to 0 indicate the presence of fewer IgE-blocking components and values closer to 1 indicate that more IgE is blocked from binding to the allergen.

Change From Baseline in Alder, Hazel and Oak Specific IgE

Change in alder, hazel and oak specific IgE reflects the allergen-specific allergy immunotherapy-induced immune modulation.

Change From Baseline in Alder, Hazel and Oak Specific IgG4

Change in alder, hazel and oak specific IgG4 reflects the allergen-specific allergy immunotherapy-induced immune modulation.

Change From Baseline in Alder and Hazel Specific IgE- Blocking Factor (IgE-BF)