A Randomized, Double-Blind, Placebo-Controlled, Multi-Centre Study to Assess the Efficacy of PURETHAL Mites Mixture 50,000 AUeq/mL Subcutaneous Immunotherapy in Adult Subjects with Moderate to Severe Allergic Rhinitis/Rhinoconjunctivitis with or without Asthma Induced by House Dust Mite (HDM) Allergy

Prior treatment

• Any vaccination (including COVID-19) less than 1 week prior to screening, during screening and the up-dosing phase and the TCRS scoring periods.
• Any immunosuppressive treatment or anti-IgE therapy within the last 6 months prior to the first dosing of the trial drug and during the trial.
• Active COVID-19 infection at the time of screening or 2 weeks before.
• Use of prohibited medication and/or not able to discontinue medications that are prohibited during the specified trial periods.
• Nasal surgery and/or severe nasal or severe oral disease within 6 months prior to Screening.
• Alcohol, drug, or medication abuse within the past year and during the trial.
• Patients not adhering to the e-Diary procedure and/or procedure for Rescue Medication use during e-Diary phase.
• Uncontrolled asthma, as defined by any of the following: a. Asthma Control Test (ACT) ≤19, b. FEV1 ≤70% of predicted value, c. Emergency room visit for asthma attack/exacerbation within 6 months prior to screening, d. At least 1 hospitalization due to asthma within the last year, History of intubation/mechanical ventilation due to asthma, f. More than 2 courses of oral steroids used for treatment of asthma within the last 6 months prior to Screening, g. Daily use of inhaled corticosteroids >400mcg budesonide or equivalent.
• Previous treatment with AIT with HDM allergen or a cross-reacting allergen for more than 1 month at the maintenance level within the last 5 years. Initiation of HDM SCIT is acceptable, if treatment has been discontinued before reaching maintenance dose.
• AIT (subcutaneous, sublingual or oral) with other allergens than HDM within the last 3 months prior to screening or planned during the trial period.
• Participation in a clinical trial within the last 3 months prior to screening (e.g. new investigational drug or biological) or during the trial.

Other illness

• A clinically relevant history of symptomatic seasonal ARC and/or a positive SPT (mean wheal diameter ≥ 3 mm) caused by an allergen (including animal hair and dander), to which the subject is regularly exposed and/or exposure is overlapping with the e-Diary completion periods at Screening and at the end of treatment.
• Severe immune disorders (including autoimmune diseases) and/or diseases requiring immunosuppressive medication.
• Active malignancies or any malignant disease in the last 5 years.
• A chronic or acute disease that in the opinion of the investigator might place the subject at an additional risk, including but not limited to the following: cardiovascular insufficiency, any severe or unstable lung diseases, endocrine disorders, clinically significant renal or hepatic diseases, haematological disorders, severe atopic dermatitis, other relevant skin diseases (affecting SPT testing areas).
• Diseases with a contraindication for the use of adrenaline/epinephrine (e.g. hyperthyroidism, glaucoma).
• Moderate to severe nasal obstructive disease such as polyps, septum deviation.
• Clinically significant chronic sinusitis or ocular infection.
• Severe psychiatric, psychological, or neurological disorders.
• History of anaphylaxis with cardio-respiratory symptoms (food allergy, drugs or an idiopathic reaction).

Other

• Female subjects of childbearing potential who are pregnant or lactating.
• Any (expected) lack of cooperation or compliance upon the discretion of the investigator.
• Employees, 1st degree relatives, or partners of the investigator.
• Expected changes in average HDM exposure during the trial (e.g. new avoidance measures, relocation and holidays or trips lasting more than 10 days during the efficacy assessment period)
• Moderate and severe asthma (GINA 2022 treatment steps 3 - 5).

• Prior to screening, subjects need to have signed the current approved Informed Consent Form (ICF).
• Subjects need to have an average daily TNSS of at least 8 out of 12 points at baseline, determined according to the daily e-Diary entries during 2 weeks of baseline assessment. Subjects should have a minimum e-Diary entry compliance of 70% for which the average is calculated.
• Negative serum pregnancy test at screening for women of childbearing potential.
• Females of childbearing potential must be using 2 effective methods of contraception to prevent pregnancy and agree to continue to practice an acceptable method of contraception for the duration of participation in the trial..
• Male or female subjects age 18-65 years at the time of informed consent.
• Clinical history consistent with moderate-severe HDM allergic rhinitis (with or without asthma) according to the ARIA classification (Allergic Rhinitis and its Impact on Asthma) (Bousquet et al., 2008), for at least one year prior to the first dosing.
• Subjects should be able and willing to complete daily e-Diaries for a period of 4 weeks during the screening period, 1 week after maintenance visit 7, and for a period of 8 weeks at the end of treatment under the same living conditions.
• Forced Expiratory Volume 1 (FEV1) > 70% at Screening.
• If a subject is asthmatic, asthma must be controlled during the entire trial. (corresponding to GINA treatment steps 1 or 2). Subjects with seasonal allergy may be included, if they allow to control asthma only with short-acting beta2- agonists and/or dose inhaled corticosteroid (≤400mcg budesonide or equivalent) during TCRS scoring periods.
• Positive SPT to D. pter and/or D. far (mean wheal diameter ≥ 3 mm, negative control should be < 2 mm, histamine positive control should be ≥ 3 mm), assessed at Screening.
• Subjects with a positive NPT for D. pter extract at Screening (Lebel score ≥6 at 10,000 AU/mL, test should be postponed, if baseline score is ≥ 3 or if negative control score is > 3).
• Allergen specific serum IgE level for D. pter and/or D. far of > 0.7 U/mL, assessed at Screening.