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

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

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

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

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

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

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

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

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

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

Number of days that the subjects have no symptom

Number of days that the subjects need no medication

Time elapsed to first asthma exacerbation, number, duration and severity.

Elapsed time to clinical benefit

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

A blood sampling will be performed determine the number of eosinophils.

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)

A nasal sample will be taken using nasal swabs to determine the following immunological parameters:

• Total and specific IgA
• Total and specific IgG

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")

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").

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

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

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.

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

Global rate and severity of Adverse Events (AE) per administration and per subject

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)

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.

Number of Adverse Reactions to any medication administered for the treatment of AE/AR

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.

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.