A randomized, double-blind, placebo-controlled, double-dummy study to determine the safety/tolerability of a simultaneous subcutaneous treatment of BM41 and vitamin D 3 in patients with moderate to severe allergic rhinitis/ rhinoconjunctivitis caused by birch pollen

INTERVENTION: Product Name: BM41 160µg/ml Pharmaceutical Form: Suspension for injection Pharmaceutical form of the placebo: Suspension for injection Route of administration of the placebo: Subcutaneous use Trade Name: Zemplar Pharmaceutical Form: Solution for injection Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Subcutaneous use CONDITION: moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen (with or without concomitant mild to moderate persistent asthma) Therapeutic area: Body processes [G] ‐ Immune system processes [G12] PRIMARY OUTCOME: Main Objective: The primary objective is to demonstrate safety/tolerability of subcutaneous treatment with BM41 alone, VD3 alone and a simultaneous subcutaneous treatment with BM41 and VD3 in comparison to placebo in patients with moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen in a pre‐seasonal short‐term course of SCIT. Primary end point(s): The primary endpoint is the number of treatment‐related systemic reactions (classified in accordance with the WAO‐grading system) in the BM41/VD3 treatment group compared to BM41/Placebo2, VD3/Placebo1 and Placebo1/Placebo2 throughout the pre‐seasonal treatment course. This will be determined at every visit according to the reports of the patient. Secondary Objective: The secondary objectives include demonstration of clinical efficacy of SCIT with BM41, with BM41+VD3, and with VD3, all three compared to placebo. Efficacy will be analysed for the upper airways by TNPT and PNIF. Moreover, the clinical efficacy of SCIT with BM41, with BM41+VD3, and with VD3, is evaluated on birch seasonal allergic symptoms and medication use, by control of rhinitis symptoms, Health‐Related Quality of Life and “well‐days/severe days”, compared to placebo. ; The assessment of serological and cellular immunological changes induced by SCIT with BM41, BM41+VD3, and VD3, compared to placebo, the onset of clinical and immunological changes induced by SCIT with BM41 compared to BM41+VD3, the indentification of predictive and efficacy‐associated biomarkers by transcriptomics on nasal brushing, the assessment of the hypoallergenicity of BM41 and possible de‐novo sensitization to BM41 by tSPT. In a subset of patients, asthma control will be evaluated during birch pollen season. Timepoint(s) of evaluation of this end point: This will be determined at every visit according to the reports of the patient. SECONDARY OUTCOME: Secondary end point(s): 1) Reduction of upper airway response to allergen compared to baseline evaluation as assessed by a TNPT after the first maintenance shot.; 2) Improvement in nasal patency compared to baseline evaluation (Visit 1) as assessed by Peak Nasal Inspiratory Flow (PNIF) after TNPT after the first maintenance shot.; 3) Furthermore, clinical efficacy will be investigated by analyzing the reduction in a combined symptom and medication score (CSMS) in the BM41/VD3 treatment group compared to BM41/Placebo2, VD3/Placebo1 and Placebo1/Placebo2 as assessed during the birch pollen season. ; The following definition will be used to calculate the CSMS: ; CSMS = (daily) Symptom Score (dSS) + (daily) Medication Score (dMS) ; The dSS comprises of six individual symptom scores: four nasal symptoms (Itchy Nose, Sneezing, Runny Nose, Blocked Nose) and two ocular symptoms (Itchy/red eyes, Watery eyes), all daily scored (by patients in e‐diaries in the birch pollen season) on a scale from 0‐3. The dSS will be calculated as mean of all non‐missing daily SS during the birch pollen season (range 0‐18) divided by the number of individual symptoms (6 symptoms). As such the dSS has a range from 0‐3. ; The dMS is based on the following scores: 0 = no rescue medication, 1 = antihistamines (oral and topical), 2 = nasal corticosteroids, 3 = oral corticosteroids . The dMS will be scored as the average of the daily MS during the birch pollen season. As such, the dMS has a range from 0‐3. Therefore, the corresponding CSMS (dSS + dMS) has a range from 0‐6. ; 4) A self questionnaire for assessing the control of allergic rhinitis based on 5 standardized questions as being scored from 1 to 5 points (on a Likert‐scale) reporting the severity of AR over the previous 2 weeks. Averages of this ‘control‐score’ will be compared between the treatment groups.; 5) The “Mini‐Rhinoconjunctivitis Quality of Life Questionnaire (mini‐RQLQ)” will be assessed. This self‐administered questionnaire assesses (the disease specific) patients’ quality of life (QoL) . ; The m‐RQLQ comprises five domains (activity limitation, practical problems, nose symptoms, eye symptoms and non‐nose/eye symptoms) based on 14 standardized questions. The Quality of Life Total Score will be assessed based on subject's self‐filled Mini‐RQLQ. Averages of the m‐RQLQ will be compared between the treatment groups.; 6) Based on the dSS and the dMS, the percentage of ‘well days’ (=days with no intake of rescue mediation and a symptom score = 2) and ‘severe days’ (a symptom score of 3 for any of the rhinoconjunctivitis symptoms) will be compared between the treatment groups.; 7) Changes of serum specific immunoglobulin levels (total IgE, rBet v 1‐ and birch pollen‐specific IgG, rBet v 1‐ and birch pollen‐specific IgG4) (all centers) and cellular immunology (two centers) compared to baseline evaluation.; 8) Average of Asthma Control Score, obtained during the birch pollen season.; 9) Nasal brushing and analysis of basal nasal cells and nasal microbiom (two centers) will be compared between the treatment groups.; ; Timepoint(s) of evaluation of this end point: 1) Visit (V1),V6, V10 and at V12 (after grass/weed pollen seasons).; 2) V1,V6, V10 and a at V12 (after grass/weed pollen seasons).; 3) Patients will be asked to keep a daily e‐diary to collect the CSMS during the birch pollen season; 4) The standardized 5 questions will be assessed at baseline V1, during birch pollen‐season 2018 at V11 and at the end of the trial (V12).; 5) The mini‐RQLQ at baseline,during birch pollen‐season 2018 and at the end of the trial. The Quality of Life Total Score at baseline, during birch pollen‐season 2018 at V11 and at the end of the trial (V12).; 6) Daily Diary; 7) At V6, V10, V11 and V12 compared to baseline evaluation (V1).; 8) At V1, V11 and V12; 9) At V1, V6, V10 and V12; INCLUSION CRITERIA: 1. Signed informed consent 2. Age =18 = 65 years 3. Moderate to severe birch‐pollen‐induced AR/ARC of at least 2 years according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines (Appendix 1) with or without concomitant mild to moderate persistent asthma 4. FEV1>70% for patients with a history of asthma, FEV1>70% or PEF>80% for patients without a history of asthma 5. A positive SPT (mean wheal diameter = 3mm compared to negative control and negative control should be negative) for birch pollen assessed within 1 year before randomization 6. A positive TNPT for birch pollen at screening (Lebel score =6) Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 160 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range