Allergy
Conditions
Keywords
House dust mites, Sublingual immunotherapy, Allergy, Allergic asthma
Brief summary
This trial has been designed to evaluate the efficacy of specific immunotherapy with SLITone Dermatophagoides mix compared with placebo in subjects with house dust mite allergic asthma, based on asthma medication use during a period of 2 months with a high environmental exposure to mites (autumn 2008).
Detailed description
This trial was conducted as a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase III trial, assessing the efficacy of SLITone Dermatophagoides mix in adults (18-65 years). 5 centres in Spain participated. Subjects with house dust mite allergic asthma were randomised to receive either SLITone Dermatophagoides mix (active) or placebo treatment (1:1) for approximately 1 year. The trial duration was extended to 2 years. Administration was done sublingually (under the tongue) once daily preferably in the morning. A monodose container comprised the daily dose of 200 STU. Subjects were kept in asthma control during the entire trial (2 years). Except for during 2 evaluation periods of 2 months in autumn 2007 and autumn 2008, subjects used the medications prescribed by their physician. During the 2 evaluation periods of 2 months in autumn 2007 and autumn 2008, subjects used provided and standardised rhinoconjunctivitis and asthma medications. The asthma medication use was to reflect the subject's asthma status. This was done by treatment with a low maintenance dose of control medication supplemented with rescue medication as needed. Rhinoconjunctivitis medication during the 2 evaluation periods in autumn 2007 and autumn 2008; to standardise the medication used to relieve rhinoconjunctivitis symptoms, subjects were provided with the following free medications as needed: * Desloratadine tablet (5 mg per tablet; anti-histamine; Aerus®) * Budesonide nasal spray (64 µg per puff; inhaled corticosteroid) * Prednisone tablet (5 mg per tablet; oral corticosteroid) Subjects were instructed to use this medication instead of their usual medication during the 2 evaluation periods in autumn 2007 and autumn 2008, and to record the used medication and symptoms in the daily diary. Asthma medication during the evaluation period in autumn 2007; prior to the 2 months evaluation period in autumn 2007, the asthma control medication use was interrupted to obtain a medication-free period. Subjects were provided with the following free medications to standardise the treatment used to relieve asthma symptoms: * Salbutamol inhaler (200 µg per puff; a short acting β2-agonist; Ventilastin®). * Budesonide/formoterol inhaler (80/4.5 µg per inhalation; a combination of inhaled corticosteroids and long acting β2-agonist; Symbicort®). * Prednisone tablet (5 mg per tablet; oral corticosteroid). Subjects were instructed to use this medication instead of their usual medication during the evaluation period in autumn 2007 as follows: They were to use salbutamol inhaler as asthma rescue medication until they either: * needed more than 4 inhalations of salbutamol per day for 2 consecutive days * suffered from nocturnal asthma forcing them to wake up * suffered from exercise-induced dyspnoea doing ordinary tasks In these cases, subjects were to contact the investigator to determine the amount of budesonide/formoterol to use as daily asthma control medication. The budesonide/formoterol inhaler was thereafter to be used as rescue medication as needed instead of salbutamol. Prednisone could be used as a last option. Asthma medication during the evaluation period in autumn 2008: At the 2 months evaluation period in autumn 2008, subjects were maintained at a low dose of budesonide/formoterol (daily asthma control medication) and they used the budesonide/formoterol inhaler as rescue medication as needed. Prednisone could be used as a last option. Asthma medication used during the evaluation periods in autumn 2007 and autumn 2008 were recorded in a daily diary. One primary efficacy endpoint and 16 secondary efficacy endpoints were assessed; the result of the primary efficacy endpoint, 3 secondary endpoints and adverse event reportings are posted here. None of the other secondary endpoints demonstrated a difference between treatment groups.
Interventions
BIOLOGICALSLITone(TM) Dermatophagoides mix
Sublingual immunotherapy with SLITone Dermatophagoides mix (200 STU) once daily for 2 years
BIOLOGICALPlacebo
Sublingual immunotherapy once daily for 2 years
DRUGSalbutamol inhaler
200 µg per puff; a short acting beta2-agonist (please refer to the 'detailed description' for details on the use)
DRUGBudesonide/formoterol inhaler
80/4.5 µg per inhalation; a combination of inhaled corticosteroids and long acting beta2-agonist (please refer to the 'detailed description' for details on the use)
5 mg per tablet; oral corticosteroids (please refer to the 'detailed description' for details on the use)
DRUGDesloratadine tablet
5 mg per tablet: anti-histamine (please refer to the 'detailed description' for details on the use)
64 µg per puff; inhaled corticosteroid (please refer to the 'detailed description' for details on the use)
Sponsors
ALK-Abelló A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* A clinical history of house dust mite induced persistent mild to moderate. asthma, with or without concurrent rhinoconjunctivitis, of at least 1 year of evolution. * Demonstration of a positive specific serum IgE test to Dermatophagoides during the year prior to the screening visit (CAP Class 2 or higher or equivalent). * Positive Skin Prick Test response (wheal diameter ≥ 3 mm) to Dermatophagoides mix. * If pre-menopausal female of childbearing potential, the subject must test negative on standard urine pregnancy test. * Willingness to comply with this protocol.
Exclusion criteria
* FEV1 \< 70% of predicted value with appropriate medication. * Asthma controlled at randomization without need of inhaled corticosteroids or with a dose higher than 1000 µg/day of beclometasone or equivalent. * A clinical history of symptomatic perennial allergic asthma caused by allergens to which the subjects is regularly exposed (Alternaria, cat), other than house dust mites. * Chronic sinusitis. * Aspirin or sulfite intolerance. * Chronic obstructive pulmonary disease. * Current severe atopic dermatitis. * Severe asthma. * Use of an investigational drug within 30 days prior to screening. * Previous immunotherapy with house dust mite allergens for at least 2 years within the previous 10 years. * At randomisation, current symptoms of, or treatment for, upper respiratory tract infection, acute sinusitis, acute otitis media or other relevant infectious process (se-rous otitis media is not an exclusion criterion). * Physical examination with clinically relevant findings. * Any of the following underlying conditions known or suspected to be present: Cystic fibrosis, malignancy, insulin-dependent diabetes, malabsorption or malnutrition, renal or hepatic insufficiency, chronic infection, drug dependency or alco-holism, ischaemic heart disease or angina requiring current daily medication or with any evidence of disease making implementation of the protocol or interpretation of the protocol results difficult or jeopardising the safety of the subject (e.g. clinically significant cardiovascular, serious immunopathologic, immunodeficiency whether acquired or not, hepatic, neurologic, psychiatric, endocrine, or other ma-jor systemic disease). * Immunosuppressive treatment. * A mental condition rendering the subject unable to understand the nature, scope and possible consequences of the trial, and/or evidence of an uncooperative attitude. * Unlikely to be able to complete the trial. * Unwillingness to comply with trial protocol regimen for asthma and/or rhinoconjunctivitis medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2008 | 8 weeks | Scoring per inhalation/tablet: 1-2 inhalations twice daily of salbutamol (200 ug per inhalation), 2 scores; 1-2 inhalation twice daily of budesonide/formoterol 80 (4.5 ug per inhalation), 4 scores; 1 inhalation twice daily of budesonide/formoterol 160 (4.5 ug per inhalation), 8 scores; up to 10 tablets once daily of prednisone (5 mg), 1.6 scores. The total maximum daily scores were 40. The daily score for each medication step was calculated by multiplying the score per inhalation/tablet with the number of inhalations/tablets used (entered as units in the daily diary by the subject). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2007 | 8 weeks | Scoring per inhalation/tablet: 1-2 inhalations twice daily of salbutamol (200 ug per inhalation), 2 scores; 1-2 inhalation twice daily of budesonide/formoterol 80 (4.5 ug per inhalation), 4 scores; 1 inhalation twice daily of budesonide/formoterol 160 (4.5 ug per inhalation), 8 scores; up to 10 tablets once daily of prednisone (5 mg), 1.6 scores. The total maximum daily scores were 40. The daily score for each medication step was calculated by multiplying the score per inhalation/tablet with the number of inhalations/tablets used (entered as units in the daily diary by the subject). |
| Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008 | 8 weeks | The treatment efficacy was rated by subjects at the end of the evaluation period in autumn 2008. Subjects rated their asthma symptoms in comparison to previous autumn using the categories: much worse, worse, the same, better, or much better. The categories much better or better were grouped as improved. The categories the same, worse or much worse were grouped as not improved. |
| Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008 | 8 weeks | The treatment efficacy was rated by investigators at the end of the evaluation period in autumn 2008. Investigators rated the asthma symptoms in comparison to when subjects entered the trial, using the categories: much worse, worse, the same, better, or much better. The categories much better or better were grouped as improved. The categories the same, worse or much worse were grouped as not improved. |
| Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | 8 weeks | The treatment efficacy was rated by both subject and investigator at the end of the evaluation period in autumn 2007. Subjects rated their asthma symptoms in comparison to previous autumns and investigators rated the asthma symptoms in comparison to when subjects entered the trial, using the categories: much worse, worse, the same, better, or much better. The categories much better or better were grouped as improved. The categories the same, worse or much worse were grouped as not improved. |
Countries
Spain
Participant flow
Recruitment details
First subject first visit: 22 June 2006
Participants by arm
| Arm | Count |
|---|---|
| Active SLITone Dermatophagoides Mix | 63 |
| Placebo SLITone Placebo | 61 |
| Total | 124 |
Baseline characteristics
| Characteristic | Placebo | Active | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 61 Participants | 63 Participants | 124 Participants |
| Age Continuous | 30 years STANDARD_DEVIATION 9 | 32 years STANDARD_DEVIATION 8 | 31 years STANDARD_DEVIATION 8.6 |
| Region of Enrollment Spain | 61 participants | 63 participants | 124 participants |
| Sex: Female, Male Female | 39 Participants | 39 Participants | 78 Participants |
| Sex: Female, Male Male | 22 Participants | 24 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 63 | 21 / 61 |
| serious Total, serious adverse events | 2 / 63 | 2 / 61 |
Outcome results
Primary
Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2008
Scoring per inhalation/tablet: 1-2 inhalations twice daily of salbutamol (200 ug per inhalation), 2 scores; 1-2 inhalation twice daily of budesonide/formoterol 80 (4.5 ug per inhalation), 4 scores; 1 inhalation twice daily of budesonide/formoterol 160 (4.5 ug per inhalation), 8 scores; up to 10 tablets once daily of prednisone (5 mg), 1.6 scores. The total maximum daily scores were 40. The daily score for each medication step was calculated by multiplying the score per inhalation/tablet with the number of inhalations/tablets used (entered as units in the daily diary by the subject).
Time frame: 8 weeks
Population: Data were based on subjects from the Full Analysis Set (FAS; all randomised subjects following the ITT ICH principle) who had at least one record in the daily diary in the 2 months evaluation period in autumn 2008. All available data were used to their full extent, but no imputation of data was performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active | Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2008 | 4.4 Scores on a scale | Standard Deviation 5.9 |
| Placebo | Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2008 | 4.7 Scores on a scale | Standard Deviation 5.4 |
Comparison: The null hypothesis is the hypothesis of no difference and the alternative to the null hypothesis is the hypothesis of a difference.p-value: 0.85Linear mixed effect (LME) model
Secondary
Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2007
Scoring per inhalation/tablet: 1-2 inhalations twice daily of salbutamol (200 ug per inhalation), 2 scores; 1-2 inhalation twice daily of budesonide/formoterol 80 (4.5 ug per inhalation), 4 scores; 1 inhalation twice daily of budesonide/formoterol 160 (4.5 ug per inhalation), 8 scores; up to 10 tablets once daily of prednisone (5 mg), 1.6 scores. The total maximum daily scores were 40. The daily score for each medication step was calculated by multiplying the score per inhalation/tablet with the number of inhalations/tablets used (entered as units in the daily diary by the subject).
Time frame: 8 weeks
Population: Data were based on subjects from the Full Analysis Set (FAS; all randomised subjects following the ITT ICH principle) who had at least one record in the daily diary in the 2 months evaluation period in autumn 2007. All available data were used to their full extent, but no imputation of data was performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active | Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2007 | 4.1 Scores on a scale | Standard Deviation 5.1 |
| Placebo | Average Daily Asthma Medication Score During a 2-months Evaluation Period in Autumn 2007 | 3.6 Scores on a scale | Standard Deviation 3.9 |
Comparison: The null hypothesis is the hypothesis of no difference and the alternative to the null hypothesis is the hypothesis of a difference.p-value: 0.52Linear mixed effect (LME) model
Secondary
Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008
The treatment efficacy was rated by investigators at the end of the evaluation period in autumn 2008. Investigators rated the asthma symptoms in comparison to when subjects entered the trial, using the categories: much worse, worse, the same, better, or much better. The categories much better or better were grouped as improved. The categories the same, worse or much worse were grouped as not improved.
Time frame: 8 weeks
Population: All analyses were on all randomised participants (full analysis set) with data in 2008: All available data were used to their full extent, but no imputation of data was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active | Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008 | Investigator evaluation: Improved | 30 Participants |
| Active | Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008 | Investigator evaluation: Not improved | 7 Participants |
| Active | Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008 | Investigator evaluation: Missing data | 0 Participants |
| Placebo | Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008 | Investigator evaluation: Missing data | 0 Participants |
| Placebo | Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008 | Investigator evaluation: Improved | 24 Participants |
| Placebo | Global Evaluation of Efficacy by Investigator at the End of the Evaluation Period in Autumn 2008 | Investigator evaluation: Not improved | 17 Participants |
Comparison: The null hypothesis is the hypothesis of no difference and the alternative to the null hypothesis is the hypothesis of a difference.p-value: 0.0486Proportional odds regression
Secondary
Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007
The treatment efficacy was rated by both subject and investigator at the end of the evaluation period in autumn 2007. Subjects rated their asthma symptoms in comparison to previous autumns and investigators rated the asthma symptoms in comparison to when subjects entered the trial, using the categories: much worse, worse, the same, better, or much better. The categories much better or better were grouped as improved. The categories the same, worse or much worse were grouped as not improved.
Time frame: 8 weeks
Population: All analyses were on all randomised participants (full analysis set) with data in 2007: All available data were used to their full extent, but no imputation of data was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Subject evalution: Improved | 30 Participants |
| Active | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Subject evaluation: Not improved | 17 Participants |
| Active | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Investigator evaluation: Improved | 33 Participants |
| Active | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Investigator evaluation: Not improved | 14 Participants |
| Placebo | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Investigator evaluation: Not improved | 17 Participants |
| Placebo | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Subject evalution: Improved | 33 Participants |
| Placebo | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Investigator evaluation: Improved | 30 Participants |
| Placebo | Global Evaluation of Efficacy by Subject and Investigator at the End of the Evaluation Period in Autumn 2007 | Subject evaluation: Not improved | 14 Participants |
Comparison: The null hypothesis is the hypothesis of no difference and the alternative to the null hypothesis is the hypothesis of a difference.p-value: >0.05Proportional odds regression
Secondary
Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008
The treatment efficacy was rated by subjects at the end of the evaluation period in autumn 2008. Subjects rated their asthma symptoms in comparison to previous autumn using the categories: much worse, worse, the same, better, or much better. The categories much better or better were grouped as improved. The categories the same, worse or much worse were grouped as not improved.
Time frame: 8 weeks
Population: All analyses were on all randomised participants (full analysis set) with data in 2008: All available data were used to their full extent, but no imputation of data was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active | Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008 | Subject evaluation: Improved | 28 Participants |
| Active | Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008 | Subject evaluation: Not improved | 8 Participants |
| Active | Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008 | Subject evaluation: Missing data | 1 Participants |
| Placebo | Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008 | Subject evaluation: Improved | 28 Participants |
| Placebo | Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008 | Subject evaluation: Not improved | 13 Participants |
| Placebo | Global Evaluation of Efficacy by Subject at the End of The Evaluation Period in 2008 | Subject evaluation: Missing data | 0 Participants |
Comparison: The null hypothesis is the hypothesis of no difference and the alternative to the null hypothesis is the hypothesis of a difference.p-value: >0.05Proportional odds regression