Article

Dahl R, Kapp A, Colombo G, et al. Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years

Department of Respiratory Diseases, Aarhus University Hospital, Aarhus, Denmark.
The Journal of allergy and clinical immunology (Impact Factor: 11.48). 03/2008; 121(2):512-518.e2. DOI: 10.1016/j.jaci.2007.10.039
Source: PubMed

ABSTRACT

This is an interim analysis of a randomized, double-blind, placebo-controlled phase III trial with 3 years of daily treatment with grass tablet immunotherapy (GRAZAX; ALK-Abelló A/S, Hørsholm, Denmark) or placebo, followed by 2 years of follow-up to assess the persistent efficacy.
We sought to evaluate the efficacy and safety of specific immunotherapy with grass allergen tablets compared with placebo after treatment covering 2 consecutive grass pollen seasons.
The interim analyses included 351 adult participants with moderate-to-severe allergic rhinoconjunctivitis caused by grass pollen. Participants were treated with active (n = 189) or placebo (n = 162) tablets for an average of 22 months. All participants were allowed to use symptomatic rescue medication.
The primary efficacy analysis showed highly significant mean reductions of 36% in rhinoconjunctivitis symptom score (P < .0001; median reduction, 44%) and 46% in rhinoconjunctivitis medication score (P < .0001; median reduction, 73%) in the active group relative to the placebo group. Mean rhinoconjunctivitis quality of life was 33% better (P < .0001; median, 40%). Clinical improvements were paralleled by significant changes in allergen-specific immunoglobulins. The treatment was well tolerated, and adverse events led to withdrawal in less than 1% of participants. There were no serious adverse events related to treatment.
Grass allergen tablet immunotherapy showed progressive immunologic changes and highly significant efficacy over 2 years of continued treatment.

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    • "Which mechanism is important in various different clinical conditions needs to be studied. Furthermore, though epicutaneous SIT is a clinically effective treatment, it has been shown that IgE-mediated allergen uptake by mucosal APCs may lead to better immunomodulation [43] [44]. "
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    ABSTRACT: Pollen grains are well established to be an important cause of respiratory allergy. Current pharmacologic therapies for allergic asthma do not cure the disease. Allergen specific immunotherapy is the only treatment method which re-directs the immune system away from allergic response leading to a long lasting effect. The mechanism by which immunotherapy achieves this goal is an area of active research world-wide. The present experimental study was designed to develop an experimental model of allergic lung inflammation based on a relevant human allergen, Alstonia scholaris pollen, and to establish the immunological and cellular features of specific allergen immunotherapy using this same pollen extract. Our results revealed that Alstonia scholaris pollen sensitization and challenge causes eosinophilic airway inflammation with mucin hypersecretion. This is associated with increased total IgE, increased expression of FcεRI on lung mast cells and increased levels of IL-4, IL-5 & IL-13 as confirmed by ELISA, in-situ immunofluorescence and FACS assay. Allergen specific immunotherapy reduced airway inflammation and also decreased total IgE level, FcεRI expression, IL-4, IL-5 & IL-13 levels. It was further noted that the reduction of these levels was more by intra-nasal route than by intra-peritoneal route. Thus we present a novel animal model of Alstonia scholaris pollen allergic disease and specific allergen immunotherapy which will pave the way towards the development of better treatment modalities.
    Full-text · Article · Jan 2016 · International immunopharmacology
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    • "When the trial was extended to further four years, 351 participants continued in the extension (189 active, 162 placebo). These participants were a representative subset of the population originally included in the trial [12]. Two hundred and thirty-eight participants (135 active, 103 placebo) completed the planned five-year trial duration. "
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    ABSTRACT: Background Grass allergen immunotherapy (AIT) reduces symptom severity in seasonal allergic rhinoconjunctivitis (ARC) but its impact on general health-related utility has not been characterised for the purposes of economic evaluation. The aim of this study was to model the preferred measure of utility, EQ-5D index, from symptom severity and estimate incremental quality adjusted life years (QALYs) associated with SQ-standardised grass immunotherapy tablet (GRAZAX®, 75,000 SQ-T/2,800 BAU, ALK, Denmark). Methods Data were analysed from five consecutive pollen seasons in a randomised placebo controlled trial of GRAZAX®. Binomial and Gaussian mixed effects modelling related weekly EQ-5D index score to daily symptom and medication scores (DSS & DMS respectively). In turn, daily EQ-5D index was estimated from ARC symptoms and medication use. Results DSS and DMS were the principal predictors of ‘perfect’ health (EQ-5D = 1.000; binomial) and ‘imperfect’ health (EQ-5D < 1.000; Gaussian). Each unit increase in DSS and DMS reduced the odds of ‘perfect’ health (EQ-5D = 1.000) by 27% and 16% respectively, and reduced ‘imperfect’ health by 0.17 and 0.13, respectively. Gender remained the only other significant main fixed effect (Male odds ratio [OR] = 1.82). Incremental estimated EQ-5D index utility for GRAZAX® was observed from day -30 to day +70 of the pooled pollen season; mean daily utility for GRAZAX® = 0.938 units (95%CI 0.932-0.943) vs. 0.914 (0.907-0.921) for placebo, an incremental difference of 0.0238 (p < 0.001). This translates into an incremental 0.0324 Quality Adjusted Life Years over the five year study period. Conclusions ARC symptoms and medication use are the main predictors of EQ-5D index. The incremental QALYs observed for GRAZAX® may not fully describe the health benefits of this treatment, suggesting that economic modelling may be conservative.
    Full-text · Article · Jun 2014 · Health and Quality of Life Outcomes
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    • "Increased risk with placebo Increased risk with immunotherapy Overall (I 2 = 0.0%, P = 0.572) Nelson, 2011 Frew, 2006 Horak, 2009 ID Drachenberg, 2001 Didier, 2007 Dubuske, 2011 Dahl, 2006a Halken, 2010 Dahl, 2008 Durham, 2010 Bufe, 2009 Didier, 2011 Pfaar, 2012 Durham, 2006 Corrigan, 2005 Frew, 2006 Didier, 2011 Dahl, 2006 Zenner, 1997 Blaiss, 2011 Didier, 2007 Study 2.64 (1.88, 3.72) 1.45 (0.60, 3.54) 8.12 (1.09, 60.37) 0.49 (0.05, 5.20) ES (95% CI) 2.96 (0.12, 71.68) 13.08 (0.74, 230.27) 6.50 (1.47, 28.66) 2.01 (0.87, 4.64) 3.50 (0.74, 16.55) 0.43 (0.04, 4.68) 0.81 (0.05, 12.86) 2.02 (0.38, 10.81) 6.35 (1.90, 21.23) 0.89 (0.17, 4.72) 3.43 (0.72, 16.25) 1.00 (0.02, 49.77) 2.97 (0.31, 28.10) 5.64 (1.67, 19.08) 3.83 (0.20, 72.29) 2.74 (0.11, 65.42) 2.51 (0.91, 6.89) 16.58 (0.97, 284.79) 100.00 14.66 2.89 2.08 Weight 1.15 1.42 5.29 16.73 4.82 2.04 1.53 4.13 7.99 4.18 4.81 0.76 2.31 7.84 1.35 1.16 11.43 1.44 % 2.64 (1.88, 3.72) 1.45 (0.60, 3.54) 8.12 (1.09, 60.37) 0.49 (0.05, 5.20) ES (95% CI) 2.96 (0.12, 71.68) 13.08 (0.74, 230.27) 6.50 (1.47, 28.66) 2.01 (0.87, 4.64) 3.50 (0.74, 16.55) 0.43 (0.04, 4.68) 0.81 (0.05, 12.86) 2.02 (0.38, 10.81) 6.35 (1.90, 21.23) 0.89 (0.17, 4.72) 3.43 (0.72, 16.25) 1.00 (0.02, 49.77) 2.97 (0.31, 28.10) 5.64 (1.67, 19.08) 3.83 (0.20, 72.29) 2.74 (0.11, 65.42) 2.51 (0.91, 6.89) 16.58 (0.97, 284.79) 100.00 14.66 2.89 2.08 Weight 1.15 1.42 5.29 16.73 4.82 2.04 1.53 4.13 7.99 4.18 4.81 0.76 2.31 7.84 1.35 1.16 11.43 1.44 % 1 0.25 0.5 1 2.5 20 Oralair Grazax SCIT Figure 5 "
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    ABSTRACT: The standard of preventive care for poorly controlled seasonal allergic rhinitis (AR) is subcutaneous immunotherapy (SCIT) with allergen extracts, administered in a physician's office. As an alternative to SCIT, sublingual immunotherapy (SLIT) is now an option for patients with seasonal AR. Oralair™, a SLIT tablet containing freeze-dried allergen extracts of five grasses [cocksfoot (Dactylis glomerata), meadow grass (Poa pratensis), rye grass (Lolium perenne), sweet vernal grass (Anthoxanthum odoratum) and timothy grass (Phleum pratense)], and Grazax™, a SLIT tablet containing a standardized extract of grass pollen allergen from timothy grass (P pratenase), are two such agents currently available in many countries. However, head-to-head comparative data are not available. In this study, an indirect comparison on efficacy, safety and cost was undertaken between Oralair™, Grazax™ and SCIT. A systematic review was conducted for double-blind placebo-controlled randomized trials evaluating Oralair™, Grazax™ or SCIT in patients with grass-induced seasonal AR. Using placebo as the common control, an indirect statistical comparison between treatments was performed using meta regression analysis with active drug as the primary independent variable. An economic analysis, which included both direct and indirect costs for the Canadian setting, was also undertaken. Overall, 20 placebo-controlled trials met the study inclusion criteria. The indirect analysis suggested improved efficacy with Oralair™ over SCIT [standardized mean difference (SMD) in AR symptom control = -0.21; P = 0.007] and Grazax™ (SMD = -0.18; P = 0.018). In addition, there were no significant differences in the risk of discontinuation due to adverse events between therapies. Oralair™ was associated with cost savings against year-round SCIT ($2471), seasonal SCIT ($948) and Grazax™ ($1168) during the first year of therapy. Oralair™ has at least non-inferior efficacy and comparable safety against SCIT and Grazax™ at a lower annual cost.
    Full-text · Article · Jan 2014 · Journal of Evaluation in Clinical Practice
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