Allergic Asthma Due to Dermatophagoides Farinae, Allergic Asthma Due to Dermatophagoides Pteronyssinus, Allergic Rhinitis Due to House Dust Mite
Conditions
Keywords
Allergic asthma, allergic rhinitis, HDM, pediatric
Brief summary
The trial aims to demonstrate efficacy of the House Dust Mite SLIT-tablet versus placebo as add-on treatment in children and adolescents (5-17 years) with House Dust Mite allergic asthma based on clinically relevant asthma worsening.
Detailed description
The trial aims to demonstrate efficacy of the HDM SLIT-tablet versus placebo as add-on treatment in children and adolescents (5-17 years) with HDM allergic asthma based on clinically relevant asthma exacerbations. Additionally, the trial will investigate if the treatment has an effect on asthma symptoms including nightly awakenings due to asthma, asthma medication use, asthma control, lung function, allergic rhinitis and allergic rhinoconjunctivitis. Finally, quality of life (QoL) for subjects and caregivers will be measured. The trial is a randomised, parallel-group, double-blind, placebo-controlled multi-national phase III trial conducted in Europe and North America. The treatment period will be approximately 2 years. Subjects will receive a written asthma action plan.
Interventions
BIOLOGICALHDM SLIT-tablet
Sublingual allergy immunotherapy tablet, for daily administration (1 tablet per day)
OTHERPlacebo
Placebo sublingual tablet, for daily administration (1 tablet per day)
Sponsors
ALK-Abelló A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
Parallel-group
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent * Male or female of any race/ethnicity aged 5-17 years * A female subject of childbearing potential must have a negative pregnancy test and be willing to practise appropriate contraceptive methods * A clinical history of HDM allergic asthma * Use of low daily dose of ICS plus LABA or medium/high daily dose of ICS with or without LABA for the control of asthma symptoms * A clinical history of asthma exacerbations in the past two years * One or more of the following within the past 4 weeks prior to randomisation: * Daytime asthma symptoms more than twice/week * Any nocturnal awakening due to asthma * SABA rescue medication needed for treatment of asthma symptoms * Any activity limitation due to asthma * Lung function measured by FEV1 ≥ 70% of predicted value or according to local requirements * Clinical history of HDM AR within the last year prior to randomisation * An average TCRS\>0 during the baseline period * Positive specific IgE (defined as ≥class 2, ≥0.70 kU/l) against D. pteronyssinus and/or D. farinae at screening * Positive SPT to D. pteronyssinus and/or D. farinae at screening * Subject willing and able to comply with trial protocol
Exclusion criteria
* Is sensitised and regularly exposed to animal dander, molds, and/or cockroach or other perennial allergen * Has experienced a life-threatening asthma attack * Within the last month before the randomisation visit (visit 3), has had an occurrence of any clinical deterioration of asthma that resulted in emergency treatment, hospitalisation, or treatment with systemic corticosteroids * Within the last 3 months before the randomisation visit (visit 3) while on high dose ICS treatment, has had an occurrence of any clinical deterioration of asthma that resulted in emergency treatment, hospitalisation, or treatment with systemic corticosteroids * Any SLIT or SCIT treatment with D. pteronyssinus or D. farinae within the previous 12 months * Ongoing treatment with any allergy immunotherapy product * Any clinically relevant condition or chronic disease incl. malignancy that in the opinion of the investigator would interfere with the trial evaluations or the safety of the subject * Has a diagnosis of eosinophilic oesophagitis * A relevant history of systemic allergic reactions * Ongoing treatment with OCS * Treatment with restricted and prohibited concomitant medication * Treatment with an investigational drug within 30 days/5 half-lives of the drug (which ever longest) prior to screening * A history of allergy, hypersensitivity or intolerance to any of the excipients or active substance of the IMP (except D. pteronyssinus and D. farinae) or to any excipient of the rescue medication provided in this trial * A business or personal relationship with trial staff or sponsor who is directly involved with the conduct of the trial * A history of alcohol or drug abuse * Has previously been randomised into this trial, is participating in this trial at another investigational site or is participating or planning to participate in any other clinical trial during the duration of this trial * Has a history or current evidence of any condition, treatment, laboratory values out of range or other circumstance that in the opinion of the investigator are clinically relevant and might expose the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject's participation for the full duration of the trial * Has a condition or treatment that increase the risk of the subject developing severe adverse reactions after adrenaline/epinephrine administration * Is unable to or will not comply with the use of adrenaline/epinephrine auto-injectors for countries where this is a regulatory requirement
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Clinically Relevant Asthma Exacerbations | Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period) | The primary endpoint of the trial was the annualized rate of clinically relevant asthma exacerbations calculated as the number of exacerbations per year per participant during the efficacy evaluation period of 20 months. A clinically relevant asthma exacerbation had to be medically confirmed and was defined as asthma worsening leading to at least 1 of the following criteria: * Doubling of ICS dose compared to background treatment * Systemic corticosteroids for treatment of asthma symptoms for at least 3 days * Emergency room visit due to asthma, requiring systemic corticosteroids * Hospitalization for more than 12 hours due to asthma, requiring treatment with systemic corticosteroids The outcome measure (by treatment group) is an adjusted annualized rate of clinically relevant asthma exacerbations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Days With Nocturnal Awakenings Due to Asthma Requiring SABA Rescue Medication | Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period) | The days with nocturnal awakenings due to asthma requiring SABA rescue medication were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months. The proportion of days with nocturnal awakenings due to asthma requiring SABA was presented on a range from 0 to 1 (1 indicating that all days in the eDiary period were with nocturnal awakenings due to asthma requiring SABA rescue medication). The efficacy assessment was based on data collected over the 20 months efficacy assessment period. The outcome measure (by treatment group) is an estimated proportion of days with nocturnal awakenings due to asthma requiring SABA rescue medication. |
| Proportions of Days With SABA Use | Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period) | The days with SABA use were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months. The proportion of days with SABA use was presented on a range from 0 to 1 (1 indicating that all days in the eDiary period were with SABA use). The efficacy assessment was based on data collected over the 20 months efficacy assessment period. The outcome measure (by treatment group) is an estimated proportion of days with SABA use. |
| Percentage Predicted FEV1 | Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period) | The outcome measure (by treatment) is an average of the percentage predicted FEV1 measured at visits 5 to 11 (every 4 months during the 20 months efficacy assessment period), analyzed using MMRM (mixed-effect model repeated measurement). FEV1 (forced expired volume in 1 second) is assessed by use of spirometry and is a measure for lung function. Percentage predicted FEV1 is derived from the predicted FEV1, which is the expected value of FEV1 for a person of a certain age, race, height and gender with healthy lungs. |
| Global Evaluation of Allergic Asthma as Having an Improved Outcome | Assessment done at the end of trial visit (after 24-30 months of treatment) | At the end of trial visit, the subject was asked, when compared to their asthma before IMP treatment, how they felt overall. Subjects who answered 'much better' or 'better' were categorized as having improved allergic asthma. At the end of trial visit, subjects had been treated for 24-30 months (including a 4-10 months treatment initiation and maintenance period). The outcome measure (by treatment) is an adjusted odds of experiencing improved allergic asthma. |
| Global Evaluation of Allergic Rhinitis as Having an Improved Outcome | Assessment done at the end of trial visit (after 24-30 months of treatment) | At the end of trial visit, the subject was asked, when compared to their rhinitis before IMP treatment, how they felt overall. Subjects who answered 'much better' or 'better' were categorized as having improved allergic rhinitis. At the end of trial visit, subjects had been treated for 24-30 months (including a 4-10 months treatment initiation and maintenance period). The outcome measure (by treatment) is an adjusted odds of experiencing improved allergic rhinitis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Allergic Rhinitis Symptoms | The efficacy assessment period for the endpoint started 4 months after treatment initiation and lasted until the end of the trial or discontinuation of treatment (up to 24-30 months of treatment). | Allergic rhinitis symptoms were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months, for up to 24-30 months. |
| Allergic Rhinitis Medication Use | The efficacy assessment period for the endpoint started 4 months after treatment initiation and lasted until the end of the trial or discontinuation of treatment (up to 24-30 months of treatment). | Allergic rhinitis medication use were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months, for up to 24-30 months. |
Countries
Bulgaria, France, Germany, Hungary, Poland, Russia, Spain, United Kingdom, United States
Participant flow
Recruitment details
The trial had randomized participants from 64 sites in 9 countries (Bulgaria, France, Germany, Hungary, Poland, Russia, Spain, United Kingdom, US).
Participants by arm
| Arm | Count |
|---|---|
| HDM SLIT-tablet (12 SQ-HDM) Participant's daily background asthma medication of low dose ICS plus LABA or medium/high dose ICS with or without LABA, reliever asthma medication of SABA as needed plus 1 daily HDM sublingual allergy immunotherapy tablet (12 SQ-HDM) | 270 |
| Placebo SLIT-tablet Participant's daily background asthma medication of low dose ICS plus LABA or medium/high dose ICS with or without LABA, reliever asthma medication of SABA as needed plus 1 daily placebo sublingual tablet | 263 |
| Total | 533 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Reason stated as 'Other' in CRF | 10 | 6 |
| Overall Study | Withdrawal by Subject | 12 | 11 |
Baseline characteristics
| Characteristic | Total | HDM SLIT-tablet (12 SQ-HDM) | Placebo SLIT-tablet |
|---|---|---|---|
| Age, Categorical <=18 years | 533 Participants | 270 Participants | 263 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 10.6 years STANDARD_DEVIATION 3.4 | 10.6 years STANDARD_DEVIATION 3.4 | 10.6 years STANDARD_DEVIATION 3.3 |
| Age, Customized Adolescents (12-17 years) | 217 Participants | 108 Participants | 109 Participants |
| Age, Customized Children (5-11 years) | 316 Participants | 162 Participants | 154 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 44 Participants | 19 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 462 Participants | 238 Participants | 224 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 27 Participants | 13 Participants | 14 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized Other | 8 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 513 Participants | 259 Participants | 254 Participants |
| Region Central (POL) | 291 Participants | 146 Participants | 145 Participants |
| Region East (BGR, HUN, RUS) | 140 Participants | 69 Participants | 71 Participants |
| Region West (DEU, ESP, FRA, GRB, USA) | 102 Participants | 55 Participants | 47 Participants |
| Region of Enrollment Bulgaria | 65 Participants | 32 Participants | 33 Participants |
| Region of Enrollment France | 25 Participants | 13 Participants | 12 Participants |
| Region of Enrollment Germany | 11 Participants | 6 Participants | 5 Participants |
| Region of Enrollment Hungary | 37 Participants | 18 Participants | 19 Participants |
| Region of Enrollment Poland | 291 Participants | 146 Participants | 145 Participants |
| Region of Enrollment Russia | 38 Participants | 19 Participants | 19 Participants |
| Region of Enrollment Spain | 36 Participants | 20 Participants | 16 Participants |
| Region of Enrollment United Kingdom | 4 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 26 Participants | 14 Participants | 12 Participants |
| Sex: Female, Male Female | 182 Participants | 88 Participants | 94 Participants |
| Sex: Female, Male Male | 351 Participants | 182 Participants | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 270 | 0 / 263 |
| other Total, other adverse events | 250 / 270 | 228 / 263 |
| serious Total, serious adverse events | 14 / 270 | 12 / 263 |
Outcome results
Primary
Annualized Rate of Clinically Relevant Asthma Exacerbations
The primary endpoint of the trial was the annualized rate of clinically relevant asthma exacerbations calculated as the number of exacerbations per year per participant during the efficacy evaluation period of 20 months. A clinically relevant asthma exacerbation had to be medically confirmed and was defined as asthma worsening leading to at least 1 of the following criteria: * Doubling of ICS dose compared to background treatment * Systemic corticosteroids for treatment of asthma symptoms for at least 3 days * Emergency room visit due to asthma, requiring systemic corticosteroids * Hospitalization for more than 12 hours due to asthma, requiring treatment with systemic corticosteroids The outcome measure (by treatment group) is an adjusted annualized rate of clinically relevant asthma exacerbations.
Time frame: Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period)
Population: Participant from the full analysis set with observations in the efficacy assessment period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HDM SLIT-tablet (12 SQ-HDM) | Annualized Rate of Clinically Relevant Asthma Exacerbations | 0.18 Exacerbations per year per participant |
| Placebo SLIT-tablet | Annualized Rate of Clinically Relevant Asthma Exacerbations | 0.21 Exacerbations per year per participant |
Comparison: The number of clinically relevant asthma exacerbations was analyzed using a negative binomial regression model with a log-link function and the logarithm of the time in years in the efficacy period as offset. The model included treatment, age group (\<12 years, \>=12 years) and region (west: DEU, ESP, FRA, GBR and USA; central: POL; east: BGR, HUN and RUS) as fixed factors. No missing data approach was applied.p-value: 0.541295% CI: [0.6, 1.31]Negative binomial regression
Secondary
Global Evaluation of Allergic Asthma as Having an Improved Outcome
At the end of trial visit, the subject was asked, when compared to their asthma before IMP treatment, how they felt overall. Subjects who answered 'much better' or 'better' were categorized as having improved allergic asthma. At the end of trial visit, subjects had been treated for 24-30 months (including a 4-10 months treatment initiation and maintenance period). The outcome measure (by treatment) is an adjusted odds of experiencing improved allergic asthma.
Time frame: Assessment done at the end of trial visit (after 24-30 months of treatment)
Population: Participants from the full analysis set with observations in the efficacy assessment period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HDM SLIT-tablet (12 SQ-HDM) | Global Evaluation of Allergic Asthma as Having an Improved Outcome | 14.66 Odds of improved allergic asthma |
| Placebo SLIT-tablet | Global Evaluation of Allergic Asthma as Having an Improved Outcome | 6.48 Odds of improved allergic asthma |
Comparison: The odds of having an improved outcome was analyzed using a generalized linear mixed model (GLMM) with a logit link function. The model included treatment, age group (\<12 years, \>=12 years) and region (west: DEU, ESP, FRA, GBR and USA; central: POL; east: BGR, HUN and RUS) as fixed factors. No missing data approach was applied.p-value: 0.004495% CI: [1.29, 3.96]Generalised linear mixed model
Secondary
Global Evaluation of Allergic Rhinitis as Having an Improved Outcome
At the end of trial visit, the subject was asked, when compared to their rhinitis before IMP treatment, how they felt overall. Subjects who answered 'much better' or 'better' were categorized as having improved allergic rhinitis. At the end of trial visit, subjects had been treated for 24-30 months (including a 4-10 months treatment initiation and maintenance period). The outcome measure (by treatment) is an adjusted odds of experiencing improved allergic rhinitis.
Time frame: Assessment done at the end of trial visit (after 24-30 months of treatment)
Population: Participants from the full analysis set with observations in the efficacy assessment period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HDM SLIT-tablet (12 SQ-HDM) | Global Evaluation of Allergic Rhinitis as Having an Improved Outcome | 8.29 Odds of improved allergic rhinitis |
| Placebo SLIT-tablet | Global Evaluation of Allergic Rhinitis as Having an Improved Outcome | 5.11 Odds of improved allergic rhinitis |
Comparison: The odds of having an improved outcome was analysed using a generalised linear mixed model (GLMM) with a logit link function. The model included treatment, age group (\<12 years, \>=12 years) and region (west: DEU, ESP, FRA, GBR and USA; central: POL; east: BGR, HUN and RUS) as fixed factors. No missing data approach was applied.p-value: 0.069895% CI: [0.96, 2.74]Generalised linear mixed model
Secondary
Percentage Predicted FEV1
The outcome measure (by treatment) is an average of the percentage predicted FEV1 measured at visits 5 to 11 (every 4 months during the 20 months efficacy assessment period), analyzed using MMRM (mixed-effect model repeated measurement). FEV1 (forced expired volume in 1 second) is assessed by use of spirometry and is a measure for lung function. Percentage predicted FEV1 is derived from the predicted FEV1, which is the expected value of FEV1 for a person of a certain age, race, height and gender with healthy lungs.
Time frame: Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period)
Population: Participants from the full analysis set with observations in the efficacy assessment period
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HDM SLIT-tablet (12 SQ-HDM) | Percentage Predicted FEV1 | 97.17 Percentage predicted FEV1 |
| Placebo SLIT-tablet | Percentage Predicted FEV1 | 97.05 Percentage predicted FEV1 |
Comparison: A 'mixed-effect model repeated measurement' model was analysed using treatment, visit, treatment\*visit, age group (\<12 years, \>=12 years) and region (west: DEU, ESP, FRA, GBR and USA; central: POL; east: BGR, HUN and RUS) as fixed factors. Baseline visit was included as a covariate. No missing data approach was applied.p-value: 0.882995% CI: [-1.47, 1.7]Mixed-effect model repeated measurement
Secondary
Proportion of Days With Nocturnal Awakenings Due to Asthma Requiring SABA Rescue Medication
The days with nocturnal awakenings due to asthma requiring SABA rescue medication were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months. The proportion of days with nocturnal awakenings due to asthma requiring SABA was presented on a range from 0 to 1 (1 indicating that all days in the eDiary period were with nocturnal awakenings due to asthma requiring SABA rescue medication). The efficacy assessment was based on data collected over the 20 months efficacy assessment period. The outcome measure (by treatment group) is an estimated proportion of days with nocturnal awakenings due to asthma requiring SABA rescue medication.
Time frame: Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period)
Population: Participants from the full analysis set with observations in the efficacy assessment period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HDM SLIT-tablet (12 SQ-HDM) | Proportion of Days With Nocturnal Awakenings Due to Asthma Requiring SABA Rescue Medication | 0.0147 Proportion of days with awakenings |
| Placebo SLIT-tablet | Proportion of Days With Nocturnal Awakenings Due to Asthma Requiring SABA Rescue Medication | 0.0190 Proportion of days with awakenings |
Comparison: A marginal logistic regression model with a generalized estimating approach was analyzed using treatment, visit, treatment\*visit, age group (\<12 years, \>=12 years) and region (west: DEU, ESP, FRA, GBR and USA; central: POL; east: BGR, HUN and RUS) as fixed factors. Baseline visit was included as a covariate. No missing data approach was applied.p-value: 0.415695% CI: [0.41, 1.44]Marginal logistic regression
Secondary
Proportions of Days With SABA Use
The days with SABA use were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months. The proportion of days with SABA use was presented on a range from 0 to 1 (1 indicating that all days in the eDiary period were with SABA use). The efficacy assessment was based on data collected over the 20 months efficacy assessment period. The outcome measure (by treatment group) is an estimated proportion of days with SABA use.
Time frame: Efficacy assessment period was 20 months (following a 4-10 months treatment initiation and maintenance period)
Population: Participants from the full analysis set with observations in the efficacy assessment period.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| HDM SLIT-tablet (12 SQ-HDM) | Proportions of Days With SABA Use | 0.0943 Proportion of days with SABA use |
| Placebo SLIT-tablet | Proportions of Days With SABA Use | 0.1094 Proportion of days with SABA use |
Comparison: A marginal logistic regression model with a generalized estimating approach was analyzed using treatment, visit, treatment\*visit, age group (\<12 years, \>=12 years) and region (west: DEU, ESP, FRA, GBR and USA; central: POL; east: BGR, HUN and RUS) as fixed factors. Baseline visit is included as a covariate. No missing data approach was applied.p-value: 0.414695% CI: [0.57, 1.26]Marginal logistic regression
Other Pre-specified
Allergic Rhinitis Medication Use
Allergic rhinitis medication use were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months, for up to 24-30 months.
Time frame: The efficacy assessment period for the endpoint started 4 months after treatment initiation and lasted until the end of the trial or discontinuation of treatment (up to 24-30 months of treatment).
Other Pre-specified
Allergic Rhinitis Symptoms
Allergic rhinitis symptoms were entered in an eDiary by the participant/caregiver in a 2-week period every 4 months, for up to 24-30 months.
Time frame: The efficacy assessment period for the endpoint started 4 months after treatment initiation and lasted until the end of the trial or discontinuation of treatment (up to 24-30 months of treatment).