Efficacy of SLITone in House Dust Mite Allergic Patients

A Randomised, Double-blind, Placebo-controlled Trial Assessing the Efficacy of SLITone in House Dust Mite Allergic Patients

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).

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.

200 µg per puff; a short acting beta2-agonist (please refer to the 'detailed description' for details on the use)

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)

64 µg per puff; inhaled corticosteroid (please refer to the 'detailed description' for details on the use)

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).

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).

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".

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

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".

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.