A randomized, double-blind, placebo-controlled, study to determine the added value of vitamin D3 to treatment with subcutaneous immunotherapy in patients with moderate to severe allergic rhinitis/ rhinoconjunctivitis caused by birch pollen

INTERVENTION: 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: subcutaneous immunotherapy in allergic rhinitis (AR) patients with allergies to birchpollen Therapeutic area: Body processes [G] ‐ Immune system processes [G12] PRIMARY OUTCOME: Main Objective: The primary objective is the assessment of serological and cellular immunological changes and kinetics thereof induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen in a pre‐seasonal short‐term course of SCIT.; To this end, the primary outcome of the study is the IL‐10 production by PBMCs in response to allergen‐specific stimulation after 5 weeks of treatment with VD3 analogue Zemplar® compared to placebo (visit 7). ; Primary end point(s): The primary outcome of the study is the IL‐10 production by PBMCs in response to allergen‐specific stimulation after 5 weeks of treatment with VD3 analogue Zemplar® compared to placebo. Secondary Objective: Differences in the following parameters will be measured after (5 and) 11 weeks of treatment with SCIT +/‐ VD3:; ; • The IL‐10 production by PBMCs in response to allergen‐specific or polyclonal stimulation. ; • Cellular composition of PBMC (Th1,2,17,22, Tregs, B cells, and APCs.; • PBMC proliferatiskinon and cytokine production in response to allergen or polyclonal stimuli.; • Intracellular cytokines in response to PMA/ionomycin. ; • IgE, IgG and IgG4 responses in serum to birchpollen and Bet v 1.; • The functional blocking antibody capacity of IgG/IgG4. ; • Titrated SPT with birchpollen extract as a surrogate clinical marker of efficacy.; • Monitoring of epigenetic changes.; • Identification of predictive and efficacy‐associated biomarkers by transcriptomics on nasal brushing.; • Clinical efficacy by titrated nasal provocation test, peak nasal inspiratory flow, the combined symptom medication score (CSMS) and an electronic diary (e‐diary). ; Timepoint(s) of evaluation of this end point: 5 weeks of treatment SECONDARY OUTCOME: Secondary end point(s): • The IL‐10 production by PBMCs in response to allergen‐specific stimulation after 11 weeks of treatment with VD3 analogue Zemplar® compared to placebo. ; • The IL‐10 production by PBMCs in response to polyclonal stimulation after 5 and 11 weeks of treatment with VD3 analogue Zemplar® compared to placebo. ; • Determination of the difference between cellular composition of PBMC with respect to Th1, Th2, Th17, Th22, and Treg cells, B cells, and antigen‐presenting cells (APC) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.; • Determination of the difference between PBMC proliferation and cytokine production in response to allergen (Bet v 1) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.; • Determination of the difference between PBMC proliferation and cytokine production in response to polyclonal stimuli (aCD3/aCD28) induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.; • Determination of the difference between intracellular cytokine measurements in response to PMA/ionomycin induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.; • Determination of the changes in IgE, IgG and IgG4 antibody responses in serum to birch pollen and Bet v 1 induced by SCIT with VD3 compared to SCIT alone in patients with moderate to severe allergic rhinitis/rhino‐conjunctivitis caused by birch pollen after 5 and 11 weeks of treatment.; • Determination of changes in a so‐called IgE facilitated allergen‐binding assay (FAB) and in a rat basophilic leukemia cell (RBL)‐based histamine release test after 5 and 11 weeks of treatment, to monitor the functional blocking antibody capacity of induced IgG/IgG4 antibodies. ; • Evaluation of changes in a titrated skin prick test (SPT) with birch pollen extract after 5 and 11 weeks of treatment, as a surrogate clinical marker of efficacy.; • Monitoring of epigenetic changes after 5 and 11 weeks of treatment.; • The identification of predictive and efficacy‐associated biomarkers by transcriptomics on nasal brushing taken at after 5 and 11 weeks of treatment.; • Determination of a difference in clinical efficacy of SCIT with VD3 compared to SCIT alone, as analysed for the upper airways by titrated nasal provocation test (TNPT), including an objective read‐out i.e. peak nasal inspiratory flow (PNIF), after 5 and 11 weeks of treatment.; • Determination of a difference in clinical efficacy of SCIT with VD3 compared to SCIT alone, assessed by monitoring symptoms and medication in the birch pollen season with the combined symptom medication score (CSMS) of EAACI and the use of an electronic diary (e‐diary). In a subset of patients with allergic asthma, asthma control will be evaluated during birch pollen season.; Timepoint(s) of evaluation of this end point: 5 and 11 weeks of treatment 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, see manual) 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 ImmunoCAP (>0.7 kU/L) for birch pollen 7. A positive tNPT (for rules when a tNPT is positive see ref 40a) 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 40 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range