Efficacy and Safety Evaluation for the Treatment of HDM Induced Allergic Asthma and Rhinitis/Rhinoconjunctivitis

Study Overview
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Brief Summary
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Prospective, randomized, placebo-controlled, multicenter of 3 active treatment groups, compared to 1 placebo group, for the determination of the efficacy and safety of subcutaneous immunotherapy in patients with mild to moderate asthma and rhinitis/rhinoconjunctivitis (intermittent or persistent) allergic to Dermatophagoides pteronyssinus and/or Dermatophagoides farinae.

Detailed Description
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Prospective multicenter randomized double-dummy clinical trial of three active treatment groups compared to one placebo group. The principal objective of the clinical trial is the determination of the efficacy and safety of subcutaneous immunotherapy in patients with mild to moderate asthma and rhinitis/rhinoconjunctivitis (intermittent or persistent) allergic to Dermatophagoides pteronyssinus and/or Dermatophagoides farinae. The primary efficacy endpoint will be the symptom score and medication consumption required for the control of asthma and rhinitis/rhinoconjunctivitis symptoms. The study design consists of 3 active treatment groups and one placebo group. The trial population will include 400 subjects between the age of 12 and 60 years that will receive the treatment during 12 months.

Official Title
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Prospective, Randomised, DBPC, Double-dummy, Multicenter CT of Efficacy and Safety With IT in Patients With Controlled Mild to Moderate Allergic Asthma and Rhinitis/Rhinoconjunctivitis, Allergic to D. Pteronyssinus and/or D. Farinae.

Conditions
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House Dust Mite Allergy, Perennial Allergic Rhinitis, Allergic Rhinoconjunctivitis, Allergic Asthma

Intervention / Treatment
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* Biological: MM09 allergoid-mannan conjugates subcutaneous (3.000 UTm/mL)
* Biological: MM09 allergoid-mannan conjugates Sublingual (3.000 UTm/mL)
* Biological: MM09 allergoid-mannan conjugates Sublingual (9.000 UTm/mL)
* Biological: Placebo subcutaneous
* Biological: Placebo sublingual


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated Informed Consent Form (ICF). Female or male aged 12 to 60 years, both included. Confirmed clinical history of inhalation allergy (mild-moderate controlled intermittent or persistent asthma according to the definition of GEMA 5.0 and GINA 2020 and intermittent or persistent rhinitis / rhinoconjunctivitis according to the ARIA classification, caused by Dermatophagoides pteronyssinus and / or Dermatophagoides farinae). The asthma diagnosis will be valid up to 24 months prior to signing the informed consent. Positive skin prick test (wheal major diameter ≥ 5 mm) to a standardized allergen extract of Dermatophagoides pteronyssinus and/or Dermatophagoides farinae. Specific IgE against a complete extract of D. pteronyssinus and/or D. farinae or any of the molecular components of allergenic sources with a value ≥ 3.5 kU/L. Women of childbearing age must have a urine pregnancy test negative result before enrolling the study. Women of childbearing age must commit to using an adequate contraception method. Capable of complying with dosage regimen. Owning a smartphone to register symptoms and medication consumption. A negative skin prick test to other aeroallergens with specific IgE < 3.5 kU/L with no clinical relevance. Exclusion Criteria: Previous immunotherapy to any of the tested allergen during the last 5 years or any desensitization process in the last 2 years (ITO, milk, egg, ...) or currently receiving immunotherapy with any other allergen. Positive skin prick test to other aeroallergens, except for intermittent symptoms due to temporary exposition to dander. Those cases in which AIT would be a contraindication according to the criteria of European Allergy and Clinical Immunology Immunotherapy Subcommittee. Uncontrolled or severe asthma and/or FEV1 <70% despite pharmacological treatment by the time of enrolment. Intake of β-blockers. Use of immunosuppressive or biological drug. Unstable patients by the time of enrolment (acute exacerbation asthma, respiratory infection, fever, acute pruritus, etc). Patients who have suffered chronic urticaria during the last 2 years, severe anaphylaxis, or family history of angioedema. Having any contraindication for the use of adrenaline (hyperthyroidism, heart disease, high blood pressure). Other severe diseases not related to allergic asthma or rhinitis that could interfere in the study treatment or the follow-up (epilepsy, psychomotor agitation, diabetes, malformations, nephropathy) according to medical criteria. Autoimmune diseases (thyroiditis, lupus, etc.), tumoral diseases or immunodeficiencies. Participants that the investigator believes could not comply with the study protocol or have serious psychiatric disorders. Known allergy to any of the ingredients of the study medication except for mites. Lower respiratory tract diseases different from asthma as bronchiectasis or chronic obstructive pulmonary disease. Breast-feeding or pregnant women. Being immediate family of the investigator. Concurrent participation in other clinical trials or prior participation within 30 days prior to inclusion. History of serious systemic reactions, including food, Hymenoptera venom, medications, etc.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, placebo-controlled, double-blind, double-dummy, multi-center trial
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I: MM09 allergoid-mannan conjugates SC (3.000 UTm/mL) + sublingual placebo<br>Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 3,000 UTm/mL subcutaneous immunotherapy + sublingual placebo. Subcutaneous active treatment will be administered once a month for 12 months. Sublingual placebo will be administered daily (2 subsequent administrations) for 12 months. | Biological: MM09 allergoid-mannan conjugates subcutaneous (3.000 UTm/mL)<br>* Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 3.000 UTm/mL for subcutaneous administration.<br>Biological: Placebo sublingual<br>* The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.<br>|
| Experimental: Group II: MM09 allergoid-mannan conjugates SL (3.000 UTm/mL) + subcutaneous placebo<br>Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan sublingual immunotherapy at 3.000 UTm/mL + subcutaneous placebo. Sublingual active treatment will be administered daily (2 subsequent administrations) for 12 months. Subcutaneous placebo will be administered once a month for 12 months. | Biological: MM09 allergoid-mannan conjugates Sublingual (3.000 UTm/mL)<br>* Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 3.000 UTm/mL for sublingual administration.<br>Biological: Placebo subcutaneous<br>* The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.<br>|
| Experimental: Group III: MM09 allergoid-mannan conjugates SL (9.000 UTm/mL) + subcutaneous placebo<br>Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan sublingual immunotherapy at 9.000 UTm/mL + subcutaneous placebo. Sublingual active treatment will be administered daily (2 subsequent administrations) for 12 months. Subcutaneous placebo will be administered once a month for 12 months. | Biological: MM09 allergoid-mannan conjugates Sublingual (9.000 UTm/mL)<br>* Mixture of allergen extracts of Dermatophagoides pteronyssinus and Dermatophagoides farinae conjugated to mannan at 9.000 UTm/mL for sublingual administration.<br>Biological: Placebo subcutaneous<br>* The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.<br>|
| Placebo Comparator: Group IV: Placebo<br>Mixture of sublingual placebo + subcutaneous placebo. Sublingual placebo will be administered daily (2 subsequent administrations) for 12 months. Subcutaneous placebo will be administered once a month for 12 months | Biological: Placebo subcutaneous<br>* The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.<br>Biological: Placebo sublingual<br>* The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CSMS: Combined Symptoms and Medication Score | Evaluation of the number of symptoms and the consumption of medication necessary for the control of such symptoms in asthma and rhinitis / rhinoconjunctivitis of each subject during the trial, of the groups with each other and with respect to placebo. - The endpoint for each asthma and rhinitis / rhinoconjunctivitis symptom will be as follows: 0 = No symptoms; 1 = Mild; 2 = Moderate; 3 = Severe Total daily symptom score = 0-3 The asthma medication will be scored based on the therapeutic step in which drugs are included in the GEMA 5 guide. The rhinitis / rhinoconjunctivitis medication score: 0 = No medication; 1 = oral or topical (eyes or nose) non-sedative H1 antihistamines (H1A); 2 = intranasal corticosteroids (INS) with / without H1A; 3 = oral corticosteroids with/without (INS), with/without H1A Total daily medication score = 0-3 | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma symptom-free days | Number of days that subjects have no symptoms related to asthma | 12 months | 
| Rhinitis / rhinoconjunctivitis symptom-free days | Number of days that subjects have no symptom related to rhinitis / rhinoconjunctivitis. | 12 months | 
| Asthma medication-free days | Number of days that subjects need no medication for treatment of asthma. | 12 months | 
| Rhinitis / rhinoconjunctivitis medication-free days | Number of days that subjects need no medication for treatment of Rhinitis / rhinoconjunctivitis. | 12 months | 
| Respiratory function_FEV1 | Measurement of Forced Expiratory Volume in 1 Second (FEV1) % | Baseline, month 6, month 12 | 
| Respiratory function_PEF | Peak Expiratory Flow (PEF) [velocity] | Baseline, month 6, month 12 | 
| Asthmatic exacerbations | Time elapsed until the first appearance of asthmatic exacerbations, number, duration and severity. | 12 months | 
| Clinical benefit | Time to onset of clinical benefit | 12 months | 
| Immunological parameters | Analyses of total and specific IgE, specific IgE index / total IgE, specific IgG4 and Anti-Saccharomyces cerevisiae (ASCA) IgA&IgG. | 12 months | 
| Quality of life associated with asthma (AQLQ) | The quality of life associated with asthma will be measured using the Asthma Quality of Life Questionnaire (AQLQ). AQLQ consists of 32 items and 4 domains (limitations in activities, symptoms, emotional and environmental). Each item is scored from 1=no impairment to 7=severe impairment. | 12 months | 
| Quality of life associated with rhinoconjunctivitis (RQLQ) | The quality of life associated with rhinoconjunctivitis will be measured using the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). RQLQ it consists of 28 items (questions) and 7 domains (Activities, sleep, general symptoms, practical problems, nose symptoms, eye and emotional symptoms). The score of each item for all domains, except for the emotional one, ranges from 0=Nothing bothered me to 6=It has bothered me a lot. The emotional domain score ranges from 0=Never to 6=Always. | Baseline, month 6, month 12 | 
| Questionnaire for asthma control (ACQ) | Asthma control will be measured following the ACQ questionnaire. The ACQ questionnaire consists of 7 questions (ACQ-7) or 6 questions (ACQ-6). In questions 1-6, patients recall their experience during the last 7 days and answer using a scale of 7 points (from 0 = fully controlled to 6 = extremely poorly controlled). The seventh question, which refers to the% FEV1 of the reference value, must be completed by an employee of the site. The questionnaire score is the mean of the 7 responses (ACQ-7) or 6 responses (ACQ-6). The interpretation of the scores is as follows: Less than or equal to 0.75: Adequate control of asthma From 0.75 to 1.50: Partially controlled asthma More than 1.50: Inadequate asthma control | 12 months | 
| Visual Analogue Scale (VAS) | Visual Analogue Scale in which the subject has to indicate in a straight line of 10 cm how he/she feels regarding to his allergy symptoms. Being left side 0 = very bad and right side 10 = very well. VAS scale will also be completed by the investigator answering how he/she thinks that the patient feels. | 12 months | 
| Consumption of health resources | For each patient, the number of times that due to allergy symptoms has done the following will be counted: have visited the family doctor have made an unscheduled visit to the specialist has gone to the emergency room has been hospitalized have needed to contact the doctor by phone | 12 months | 
| Safety parameters | Global rate and severity of AE per administration and per subject | 12 months | 
| Number of Local Adverse Reactions | Local adverse reactions are those that appear at the site of the administration. They are classified into: Immediate (it appears during the first 30 minutes from the administration of investigational product) and Late (it appears after the first 30 minutes from the administration of investigational product) | 12 months | 
| Number of Systemic Adverse Reactions | Systemic adverse reactions are those that appear in other parts of the body other than the site of administration.Their severity will be classified following the indications proposed by the World Allergy Organization (WAO) in 2010. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rhinitis/ Rhinoconjunctivitis, Allergy, Immunotherapy, Mild to moderate asthma