Efficacy and Safety of sublingual immunotherapy with Allergoid LAIS®Birch-Alder tablets for patients with tree pollen-induced allergic rhinoconjunctivitis

INTERVENTION: Product Name: LAIS Birch‐Alder tablets Product Code: LAIS Birch‐Alder tablets Pharmaceutical Form: Sublingual tablet INN or Proposed INN: LAIS Birch‐Alder tablets Other descriptive name: Chemically modified allergen extracts (monomeric allergoids) of tree pollen (Betula Pendula 50% and Alnus Incana 50%) Concentration unit: AgU antigen unit(s) Concentration type: equal Concentration number: 1000‐ Pharmaceutical form of the placebo: Sublingual tablet Route of administration of the placebo: Sublingual use CONDITION: Patients suffering from allergic rhinoconjunctivitis ; MedDRA version: 17.1 Level: LLT Classification code 10001728 Term: Allergic rhinoconjunctivitis System Organ Class: 100000004853 Therapeutic area: Body processes [G] ‐ Immune system processes [G12] INCLUSION CRITERIA: •Female or male patients aged 18–75 years with a history of at least two years of tree pollen induced allergic rhinitis and/or allergic rhinoconjunctivitis with or without seasonal controlled allergic asthma [From the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2012. Available from: http://www.ginasthma.org] •Clinical sensitization to tree pollen. Patients with sensitization to perennial allergens like mites, cats and dogs may be included, in the case that these sensitizations are not clinically relevant during the evaluation season •Positive clinical history of tree pollen, proven by: ‐the majority of clinical symptoms appearing during the appropriate season for tree, ‐specific IgE reactivity to tree pollen CAP‐radioallergoabsorbent test (CAP‐RAST) = 2 (0.70 kU/L) ‐positive screening Skin Prick Test (wheal diameter > 3 mm, negative control < 2 mm) ‐Positive response to conjunctival provocation test PRIMARY OUTCOME: Main Objective: The primary objective is to assess the efficacy of sublingual immunotherapy with the allergoid LAIS® Birch‐Alder tablets by the Total Combined Score (TCS) taking in account the Rhinoconjuncticitis Total Symptom Score (RTSS) of the six rhinoconjunctivitis symptoms (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes and the Total Rescue Medication Score (TRMS) for the peak of the birch pollen season. Primary end point(s): The primary objective is to assess the efficacy of sublingual immunotherapy with the allergoid LAIS® Birch‐Alder tablets by the Total Combined Score (TCS) taking in account the Rhinoconjuncticitis Total Symptom Score (RTSS) of the six rhinoconjunctivitis symptoms (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus and watery eyes and the Total Rescue Medication Score (TRMS) for the peak of the birch pollen season. Secondary Objective: o TCS: a) for the birch pollen season of 30 days and b) for the entire tree pollen season of 60 days; o Six individual symptom scores: a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days; o RTSS: a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days; o TRMS: a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days; o Asthma rescue medication for the tree pollen season of 60 days; o The mean improvement in the allergic severity S between baseline and visit V5; o The changes of the threshold allergen concentration for a positive response within conjunctival provocation test (CPT); o The “well days”; o Birch pollen specific IgG4; o A global evaluation; o Quality of Life; o The rhinitis symptom control ; • Safety of the treatment; Timepoint(s) of evaluation of this end point: 14 days of highest birch pollen count in each region, the peak period of the birch pollen season SECONDARY OUTCOME: Secondary end point(s): • To assess the efficacy of a sublingual immunotherapy with the allergoid LAIS® Birch‐Alder tablets related to; o The Total Combined Score (TCS): a) for the birch pollen season of 30 days and b) for the entire tree pollen season of 60 days (March to April); o Six individual symptom scores of the Rhinoconjunctivitis Total Symptom Score (RTSS): a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days (March to April); o The Rhinoconjunctivitis Total Symptom Score (RTSS): a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days (March to April); o The Total Rescue Medication Score (TRMS): a) for the peak birch pollen season of 14 days, b) for the birch pollen season of 30 days and c) for the entire tree pollen season of 60 days (March to April),; o The use of asthma rescue medication for the tree pollen season of 60 days (March to April); o The mean improvement in the allergic severity S between baseline and visit V5 within the conjunctival provocation test will be compared for both treatment groups. ; o The changes of the threshold allergen concentration for a positive response within conjunctival provocation test (CPT) will be compared for both treatment groups, according to the evaluation defined by Riechelmann H et al (2003) between baseline and visit V5.; o The “well days”, being defined as days of the entire tree pollen season with a maximum symptom score of 2 and no rescue medication use according to Dahl (2006) and Durham (2006); o Assessment of birch pollen specific IgG4; o A global evaluation carried out by the patient for the total tree pollen season; o To evaluate the Quality of Life by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ); o The rhinitis symptom control will be compared by RCAT between both treatment groups at the end of the tree pollen season; ; • To document the safety of the treatment by the physical examinations, the description of the adverse events (frequency, intensity, severity and duration of adverse events) and the safety laboratory data during the treatment with LAIS® Birch‐Alder tablets.; Timepoint(s) of evaluation of this end point: as specified in E.5.2