title: A randomized DBPC trial to determine the optimal effective and safe dose of a SLIT-birch pollen extract for the treatment of allergic rhinitis: results of a phase II study.
abstract: BACKGROUND
  Sublingual immunotherapy (SLIT) is a potential efficacious and safe treatment option for patients with respiratory, IgE-mediated allergic diseases. A combined tolerability, dose-finding study with a sublingual liquid birch pollen preparation (SB) was conducted.
  
  
  METHODS
  Two hundred and sixty-nine adults with birch-pollen-induced AR were randomized to placebo, SB: 3333, 10,000, 20,000 or 40,000 AUN/ml. Differences in symptom scores following a titrated nasal provocation test (TNPT) at baseline and after 5 months of treatment were determined. Safety, tolerability, birch-pollen-specific immunoglobulin levels and peak nasal inspiratory flow (PNIF) were also measured (all measures determined outside the birch pollen season).
  
  
  RESULTS
  In all treatment groups, an improvement in symptom scores after treatment compared to baseline was observed, with an additional stepwise improvement in the active groups compared to placebo, which was significant in high-dose groups (P = 0.008 and P < 0.001, respectively). For this primary endpoint, a significant linear dose-response curve was observed: the higher the dose, the better the improvement observed. Likewise, active treatment resulted in an increase in PNIF and serum IgG levels compared to placebo. The highest improvements were found in the 40,000 AUN/ml group. All active dosages resulted in more adverse reactions than placebo, which were mainly mild and well-controlled.
  
  
  CONCLUSIONS
  A multicentre trial evaluated the dose-response and tolerability of SB. All active treatment groups showed better responses than placebo for both primary and secondary parameters. The results indicate that, within the studied dose range, SB 40,000 AUN/ml is the most optimal effective and safe dose (ClinicalTrials.gov: NCT01639768).
authors.affiliation: Center for Rhinology and Allergology, Wiesbaden, Germany.|Department of Otorhinolaryngology, Head and Neck Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Pfaar
authors.affiliation: HAL Allergy BV, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: van Twuijver
authors.affiliation: HAL Allergy BV, Leiden, The Netherlands.
authors.forename: J D
authors.initials: JD
authors.lastname: Boot
authors.affiliation: HAL Allergy BV, Leiden, The Netherlands.
authors.forename: D J E
authors.initials: DJ
authors.lastname: Opstelten
authors.affiliation: Center for Rhinology and Allergology, Wiesbaden, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Klimek
authors.affiliation: Departments of Experimental Immunology and of Otorhinolaryngology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Ree
authors.affiliation: Department of Respiratory Medicine & Allergology, Institute for Clinical Science, Skane University Hospital, Lund, Sweden.|Departments of Clinical Pharmacy & Pharmacology and General Practice, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Z
authors.initials: Z
authors.lastname: Diamant
authors.affiliation: Dept. of Internal Medicine, Asthma and Allergy Medical University of Lodz, Lodz, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Kuna
authors.affiliation: Department of Allergology and Immunology, Medical Faculty in Plzen, Charles University Prague, Prague, Czech Republic.
authors.forename: P
authors.initials: P
authors.lastname: Panzner
mesh_terms: D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000276:immunology*; D029662:Betula / Q000009:adverse effects*; D003888:Desensitization, Immunologic / Q000379:methods; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D010936:Plant Extracts / Q000008:administration & dosage / Q000276:immunology*; D011058:Pollen / Q000009:adverse effects*; D006255:Rhinitis, Allergic, Seasonal / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D012882:Skin Tests; D063729:Sublingual Immunotherapy / Q000009:adverse effects / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000485:Allergens; D010936:Plant Extracts; D007073:Immunoglobulin E
keywords: allergen immunotherapy; birch pollen; dose finding; nasal provocation; sublingual immunotherapy