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


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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    • "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.
    Health and Quality of Life Outcomes 06/2014; 12(1):99. DOI:10.1186/1477-7525-12-99 · 2.12 Impact Factor
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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.
    Journal of Evaluation in Clinical Practice 01/2014; 20(3). DOI:10.1111/jep.12112 · 1.08 Impact Factor
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    • "Administering a short four-week therapy with a grass allergen extract together with an MPL adjuvant showed that specific IgG and IgG4 levels increased only slightly in year one of SIT, but which became highly significant in year two [86]. A progressive immunological change as indicated by the significant induction of non-IgE competitive antibodies was also observed in year two of treatment with a sublingual tablet for grass pollen allergy whose clinical efficacy comparable to the benefits of year one [87]. In a three-year long-term SIT study in grass allergic patients with both rhinoconjunctivitis and asthma the asthma symptoms had completely cleared after 3 years with a general progression in clinical effect over the years. "
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    ABSTRACT: Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.
    04/2012; 2(article 8):8. DOI:10.1186/2045-7022-2-8
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