Clinical Trial to Evaluate the Efficacy and Safety of Polymerized, Mannan-Conjugated Dermatophagoides Allergen Extract

Study Overview
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Brief Summary
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Prospective, randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of polymerized and mannan conjugated allergen extract of Dermatophagoides for the treatment of allergic rhinitis/rhinoconjunctivitis with or without asthma. The main objective of the clinical trial is to evaluate the clinical efficacy of the investigational medicinal product, administered sublingually, compared to placebo for the treatment of moderate-severe rhinitis/rhinoconjunctivitis with or without mild to moderate asthma and controlled using the Rhinitis/Rhinoconjunctivitis Combined Symptom and Medication Score (R-CSMS).

Detailed Description
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Allergen-specific immunotherapy (AIT) has been shown to be effective in relieving symptoms, reducing medication use, and improving quality of life in patients with respiratory allergies). This is thought to be due to the induction of a state of tolerance to specific allergens with long-lasting effects after discontinuation of treatment. And it is accepted that immunotherapy is the only available method for allergists to improve or cure, partially or definitely, an allergic process The study population of this clinical trial will comprise subjects allergic to mites (Dermatophagoides pteronyssinus and/or D. farinae) with symptoms of moderate-severe rhinitis/rhinoconjunctivitis with or without mild to severe controlled asthma, suitable to allergen immunotherapy. The primary efficacy endpoint will be the combined rhinitis/rhinoconjunctivitis symptom and medication score. Every single day from the beginning of the administration of the investigational drug (V2-VF), the subject will be asked to score and register his/her symptoms and record medication consumption in an electronic diary following the instructions of the application. This diary will provide the symptom score and medication consumption for each subject during the trial.

Official Title
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Prospective, Randomised, DBPC Clinical Trial to Evaluate the Efficacy and Safety of Polymerized and Mannan Conjugated Allergen Extract of Dermatophagoides for the Treatment of Allergic Rhinitis/Rhinoconjunctivitis With or Without Asthma

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

Intervention / Treatment
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* Biological: 3,000 MM09
* Biological: 9,000 MM09
* Other: Placebo sublingual


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form. Male or female, aged between 12 and 60 years, both included. Confirmed clinical history of inhalation allergy with moderate-severe rhinitis/rhinoconjunctivitis according to the ARIA classification with or without controlled mild-moderate intermittent or persistent asthma according to the definition of GEMA 5.0 y GINA caused by allergy to mites (D. pteronyssinus and/or D. farinae). The asthma diagnostic will be valid up to 24 months prior to signing the informed consent form. Combined Symptom and Medication Score for moderate to severe rhinitis/rhinoconjunctivitis (RCSMS) ≥ 1,8 out of 3. Positive skin prick test (wheal major diameter ≥ 5 mm) to a standardized allergen extract of Dermatophagoides pteronyssinus and/or Dermatophagoides farinae. The results will be valid up to 12 months prior to signing the informed consent form. Specific IgE against a complete extract of Dermatophagoides pteronyssinus and/or D. farinae or any the molecular components of allergenic sources with a value ≥ 3.5 kU/L. The results will be valid up to 12 months prior to signing the informed consent form. Subjects shall preferably be monosensitised to the study allergens. In case of subjects sensitised to other aeroallergens, only those with the following characteristics may be included in the study (results will be valid up to 12 months prior to signing the informed consent form): Subjects with a positive skin prick test to Blomia tropicalis and Lepidoglyphus destructor, whose wheal major diameter and specific IgE values do not exceed or equal the values for the study allergens. Subjects with a positive skin prick test for dander if they have occasional exposure and symptoms. Subjects with positive skin prick test to pollens, whose specific IgE values do not exceed or equal the values for the study allergens and who also do not have exacerbations during pollen season. The maximum specific IgE value to theses allergens is 17.5 kU/L. Subjects with negative skin prick test to mold. In case specific IgE determination have been performed, the result must be <0.35 kU/L. Women of childbearing age (since menarche) must present a negative urine pregnancy test at the time of trial enrollment. Women of childbearing age must commit to using and adequate contraception method. Subjects capable of complying with a dosage regimen. Subjects owning a smartphone to register symptoms and medication consumption. Exclusion Criteria: Subjects polysensitized to other aeroallergens with clinically relevant symptoms. Subjects who have received previous immunotherapy in the preceding 5 years to any of the tested allergens or a cross-reactive allergen or are currently receiving immunotherapy with any allergen. Patients in whom immunotherapy may be subject to an absolute general contraindication according to the criteria of the Immunotherapy Committee of the Spanish Society of Allergy and Clinical Immunology and the European Allergy and Clinical Immunology Immunotherapy Subcommittee may not be included. Subjects with uncontrolled severe asthma, and/or with FEV1 <80% of baseline despite adequate pharmacological treatment by the time of the enrolment. Subjects on treatment with ß-blockers. Subjects on treatment with immunosuppressive or biological drugs. Subjects who are unstable by the time of enrolment (respiratory infection, febrile process, acute pruritus, etc.). Subjects with chronic urticaria during the last 2 years, severe anaphylaxis or with hereditary angioedema history. Subjects with any pathology in which the administration of adrenaline is contraindicating (hyperthyroidism, hypertension, heart disease, etc.) according to the investigator discretion. Subjects with any other disease not related to moderate rhinoconjunctivitis or asthma, but potentially serious and that could interfere with treatment and follow-up (epilepsy, psychomotor disorders, diabetes, malformations, multi-surgery, nephropathy, etc.), according to the investigator discretion. Subjects with severe autoimmune disease (thyroiditis, lupus, etc.), tumour diseases or diagnosed with immunodeficiencies. Subject whose condition prevents him/her from offering cooperation and/or who presents severe psychiatric disorders, according to the investigator discretion. Subjects with known allergy to the other components of the investigational product other than allergen study. Subjects with lower airway diseases other than asthma such as emphysema or bronchiectasis. Pregnant or breastfeeding women. Subjects who are immediate family members of researchers. Concurrent participation in other clinical trials or previous participation within 30 days prior to inclusion. History of severe systemic reactions, including food, hymenoptera venom, etc. Subjects who have suffered a respiratory tract infection and/or asthma exacerbation within 4 weeks prior to screening. Subjects with a history of significant renal disease or chronic liver disease.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomised, double-blind, placebo-controlled clinical trial.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I: sublingual allergoid-mannan conjugates (MM09 at 3.000 UTm/mL)<br>Allergoid (Dermatophagoides pteronyssinus and Dermatophagoides farinae)-mannan conjugates (MM09) at 3.000 UTm/mL for sublingual immunotherapy. The dose is 2 sprays daily applied to the sublingual mucosa for 6 months. | Biological: 3,000 MM09<br>* Allergoid (Dermatophagoides pteronyssinus and Dermatophagoides farinae)-mannan conjugates (MM09) at 3.000 UTm/mL for sublingual immunotherapy.<br>|
| Experimental: Group II: sublingual allergoid-mannan conjugates (MM09 at 9.000 UTm/mL)<br>Allergoid (Dermatophagoides pteronyssinus and Dermatophagoides farinae)-mannan conjugates (MM09) at 9.000 UTm/mL for sublingual immunotherapy.. The dose is 2 sprays daily applied to the sublingual mucosa for 6 months. | Biological: 9,000 MM09<br>* Allergoid (Dermatophagoides pteronyssinus and Dermatophagoides farinae)-mannan conjugates (MM09) at 9.000 UTm/mL for sublingual immunotherapy.<br>|
| Placebo Comparator: Group III: sublingual placebo<br>The same solution, presentation, method of administration, frequency, and duration as the active treatment, but without active ingredients.The dose is 2 sprays daily applied to the sublingual mucosa for 6 months. | Other: 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 |
| --- | --- | --- |
| Rhinitis/rhinoconjunctivitis Combined Symptom and Medication Score (RCSMS) | Assessment of the number of rhinitis/rhinoconjunctivitis symptoms and medication consumption required to control these symptoms for each subject during the trial, for each group compared to the others, and compared to placebo. Rhinitis/Rhinoconjunctivitis Combined Symptom and Medication Score will be based on the work done by Pfaar et al. The score for each rhinitis/rhinoconjunctivitis symptom will be 0 = No symptoms; 1 = Mild; 2 = Moderate; 3 = Severe. Total daily symptom score = 0-3 The score for Rhinitis/rhinoconjunctivitis medication will be: 0 = No medication; 1 = Oral or topical (eye or nose) non-sedating 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 | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rhinitis/ Rhinoconjunctivitis Symptom Score (RSS) | Assessment of the number of rhinitis/rhinoconjunctivitis symptoms for each subject during the trial, for each group compared to the others, and compared to placebo. The score for each rhinitis/rhinoconjunctivitis symptom will be 0 = No symptoms; 1 = Mild; 2 = Moderate; 3 = Severe. Total daily symptom score = 0-3 | 6 months | 
| Rhinitis/Rhinoconjunctivitis Medication Score (RMS) | Evaluation of the medication consumption required to control the rhinitis/rhinoconjunctivitis symptoms for each subject during the trial, for each group compared to the others, and compared to placebo. The score for rhinitis/rhinoconjunctivitis medication will be: 0 = No medication; 1 = Oral or topical (eye or nose) non-sedating 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 | 6 months | 
| Asthma Combined Symptom and Medication Score (ACSMS) | Evaluation of the number of asthma symptoms and medication consumption required to control these symptoms for each subject during the trial, for each group compared to the others, and compared to placebo. The score for each asthma symptom will be: 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 the drugs are included in the Guía Española para el Manejo del Asma (GEMA) 5.0 and Global Initiative for Asthma (GINA) 2020 guidelines. The scoring method is detailed in the article entitled Combination of Allergic Asthma Symptom and Medication Scores in Allergen Immunotherapy Trials: A Proposal. Total daily medication score (ACSMS) = 0-3 | 6 months | 
| Asthma Symptom Score (ASS) | Assessment of the number of asthma symptoms of each subject during the trial, for each group compared to the others, and compared to placebo. The score for each asthma symptom will be: 0 = No symptoms; 1 = Mild; 2 = Moderate; 3 = Severe. Total daily symptom score (ASS) = 0-3 | 6 months | 
| Asthma Medication Score (AMS) | Evaluation of the medication consumption required to control the asthma symptoms for each subject during the trial, for each group compared to the others, and compared to placebo. The medication will be scored based on the therapeutic step in which the drugs are included in the GEMA 5.0 and GINA 2020 guidelines. Total daily medication score (AMS) = 0-3 | 6 months | 
| Asthma and Rhinitis/Rhinoconjunctivitis Symptom Score (ARSS) | Evaluation of the number of asthma and rhinitis/rhinoconjunctivitis symptoms of each subject during the trial, for each group compared to the others, and compared to placebo. The score for each and asthma rhinitis/rhinoconjunctivitis symptom will be 0 = No symptoms; 1 = Mild; 2 = Moderate; 3 = Severe. Total daily symptom score = 0-3 | 6 months | 
| Asthma and Rhinitis/Rhinoconjunctivitis Medication Score (ARMS) | Assessment of the number of medication consumption required to control asthma and rhinitis/rhinoconjunctivitis symptoms for each subject during the trial, for each group compared to the others, and compared to placebo. The score for rhinitis/rhinoconjunctivitis medication will be: 0 = No medication; 1 = Oral or topical (eye or nose) non-sedating H1 antihistamines (H1A); 2 = Intranasal corticosteroids (INS) with/without H1A; 3 = Oral corticosteroids with/without (INS), with/without H1A. The asthma medication will be scored based on the therapeutic step in which the drugs are included in the GEMA 5.0 and GINA 2020 guidelines. Total daily medication score (ARMS) = 0-3 | 6 months | 
| Asthma and Rhinitis/Rhinoconjunctivitis Combined Symptom and Medication Score (ARCSMS) | Evaluation of the number of asthma and rhinitis/rhinoconjunctivitis symptoms and medication consumption required to control these symptoms for each subject during the trial, for each group compared to the others, and compared to placebo. The score 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 score for rhinitis/rhinoconjunctivitis medication consumption will be: 0 = No medication; 1 = Oral or topical (eye or nose) non-sedating H1 antihistamines (H1A); 2 = Intranasal corticosteroids (INS) with/without H1A; 3 = Oral corticosteroids with/without (INS), with/without H1A. The score for the asthma medication will be based on the therapeutic step in which drugs are included in the GEMA 5 guide. Total daily medication score = 0-3 | 6 months | 
| Symptom free-days (rhinitis/rhinoconjunctivitis, asthma) | Number of days that the subjects have no symptom | 6 months | 
| Medication free days (rhinitis/rhinoconjunctivitis, asthma) | Number of days that the subjects need no medication | 6 months | 
| Asthma exacerbations | Time elapsed to first asthma exacerbation, number, duration and severity. | 4 months | 
| Clinical benefit | Elapsed time to clinical benefit | 6 months | 
| Respiratory function | Forced expiratory volume at one second (FEV1) and peak expiratory flow (PEF) will be measured to assess the degree of airflow obstruction. International consensus guidelines suggest that in asthma the measurements of FEV1 and PEF are equivalent when expressed as the per cent of predicted values. FEV1 of 80 to 100 percent is generally considered normal. FEV1 between 60 and 79 percent of predicted indicates a mild obstruction FEV1 between 40 and 59 percent indicates a moderate obstruction | 6 months | 
| Number of eosinophil | A blood sampling will be performed determine the number of eosinophils. | 6 months | 
| Immunological parameters in blood | A blood sampling will be performed determine Total immunoglobulin E (IgE) Specific IgE and immunoglobulin G4 (IgG4) Specific IgE/total IgE index Immunoglobulin A (IgA ) Immunoglobulin G (IgG) anti-Saccharomyces cerevisiae (ASCA)(4) | 6 months | 
| Immunological parameters in nasal mucosa. | A nasal sample will be taken using nasal swabs to determine the following immunological parameters: Total and specific IgA Total and specific IgG | Month 2 and month 7 | 
| Asthma Quality of Life Questionnaire (AQLQ) | Asthma Quality of Life Questionnaire (AQLQ) consists of 32 items and 4 domains (symptoms, activity limitations, emotional function and environmental stimuli). Each item is scored from 1 (no impairment) to 7 (severe impairment) | Month 2 and month 7 | 
| Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) | The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) consists of 28 items (questions) and 7 domains (Activities, Sleep, General symptoms, Practical problems, Nose symptoms, Eye symptoms and Emotional). The score of each item for all domains, except for the emotional domain, ranges from 0 (It did not bother me at all) to 6 (It bothered me a lot). The score for the emotional domain ranges from 0 (Never) to 6 (Always). | 6 months | 
| Asthma Control Questionnaire (ACQ 6) | The Asthma Control Questionnaire (ACQ-6) consists of 6 questions. In questions 1-6, subjects recall their experience over the past 7 days and respond using a 7-point scale from 0 (totally controlled) to 6 (extremely poorly controlled). The score of the questionnaire is the mean of the 6 answers (i.e., the sum of the 6 answers divided by 6). The interpretation of the scores is as follows: Less than or equal to 0.75: Adequate asthma control From 0.75 to 1.50: Partially controlled asthma Over 1.50: Inadequate asthma control | 4 months | 
| Asthma Control Questionnaire (ACQ 7) | The ACQ questionnaire consists of 7 questions (ACQ-7) 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) 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 | 6 months | 
| Visual Analogue Scales (VAS) | The visual analogue scale is a 10 cm straight line, where the left end means that the subject feels very bad, and the right end means that the subject feels very well. Throughout the trial, two VAS scale measurements will be used: Subject's VAS, where the participant marks a dot on the line that matches his or her health status with respect to allergy symptoms. Investigator's VAS, where the investigator must mark a dot on the line that matches the subject's health status with respect to allergy symptoms. | 7 months | 
| Consumption of health resources | For each subject, 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 | 7 months | 
| Security parameters | Global rate and severity of Adverse Events (AE) per administration and per subject | Month 2 and month 7 | 
| 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) | 6 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 according to World Allergy Organization, measured according to the following grades: 1: Symptoms or signs present in a system/organ (cutaneous, Upper respiratory tract, Conjunctival or Other) 2: Symptoms or signs of 2 or more organs systems listed in Grade 1 3: Lower airway disease: Mild bronchospasm and/or Gastrointestinal/Abdominal cramps and/or vomiting/diarrhoea/Other Uterine cramps/Any symptoms/signs from grade 1 would be included. 4: Lower airway: Severe bronchospasm not responding or worsening despite treatment and/or Upper airway/Laryngeal oedema with stridor /Any symptoms/signs from grades 1or 3 would be included. 5: Lower or upper airway: Respiratory failure and/or Cardiovascular /Collapse/hypotension and/or Loss of consciousness (vasovagal excluded)/Any symptoms/signs from grades 1,3, or 4 would be included. | 6 months | 
| Number of Adverse Reactions to any medication | Number of Adverse Reactions to any medication administered for the treatment of AE/AR | 7 months | 
| Treatment adherence | At each visit, a new bottle shall be provided to the subject and the previous bottle shall be collected. The amount remaining in each returned bottle shall be analysed to assess adherence to treatment. | 6 months | 
| Compliance of the electronic diary | All subjects included in the trial will download the ITK Diary Card app on their mobile phone, which will be used as the subject's electronic diary. Subjects will fill in their symptoms and medication intake. At each visit, the investigator should review the subject's electronic diary to ensure compliance. For the calculation of the main variable, only those subjects that have reported data corresponding to at least 40% of the days will be considered. Therefore, for subjects with less than 40% of the reported data, the main variable cannot be calculated. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allergy, Mites, Hypersensitivity, Rhinitis, Rhinoconjunctivitis