Efficacy and safety of 5-grass pollen sublingual immunotherapy tablets in patients with different clinical profiles of allergic rhinoconjunctivitis (original) (raw)
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The safety of sublingual immunotherapy with one or multiple pollen allergens in children
Allergy, 2008
Sublingual immunotherapy (SLIT) is now recognized as a viable alternative to the classical injection route (1, 2) and it is currently used in everyday clinical practice in several European Countries. In addition to the well-demonstrated clinical efficacy (3), one of the distinguishing features of SLIT is its good safety profile, which has been repeatedly confirmed in both clinical trials (4) and postmarketing surveys (5-7). In this regard, it is well recognized from the literature that systemic and/or severe side-effects are exceptional, and these side-effects usually do not differ between placebo and treated groups (8). Nonetheless, it is true that all clinical trials were performed with a single allergen extract and so was performed in the postmarketing surveys. This is because of the fact that, at least in Europe, there is the tendency to prescribe immunotherapy for one allergen, which is recognized as the responsible for the disease (9). On the contrary, the vast majority of patients are polysensitized (10) and different allergens can cause their symptoms, so that a vaccination with multiple allergens is often required and justified. Of note, the administration of multiple allergens is a common practice in the USA and other countries (11). Very recently, concerns of the safety of SLIT when different allergens are given together have been raised, based on isolated case reports (12, 13). Certainly, this aspect becomes one of primary relevance in children who are, in principle, the ideal candidates to SLIT, especially based on safety considerations. In other words, it is essential to know if in children the administration of more than one allergen may increase the occurrence of adverse events. For this reason, we compared in a postmarketing survey, by means of proper diary cards, the rate of sideeffects in paediatric patients receiving SLIT either with single or multiple allergens. Methods Consecutive paediatric patients with respiratory allergy due to pollens, seen in the period 2004-2007 receiving SLIT for multiple allergens and matched patients treated with one single allergen were followed-up in this postmarketing survey. Inclusion criteria were those for prescribing SLIT according to guidelines (2). In particular, SLIT was given to those children suffering from respiratory allergy Background: Since the majority of allergic patients are polysensitized, it is often necessary to prescribe immunotherapy with multiple allergens. It is crucial to know if the administration of multiple allergens with sublingual immunotherapy (SLIT) increases the risk of side-effects in children. Methods: Consecutive children with respiratory allergy because of pollens, receiving SLIT for multiple or single allergens were followed-up in a postmarketing survey. Inclusion criteria were those for prescribing SLIT according to guidelines. Parents recorded in a diary card the side-effects (eye symptoms, rhinitis/ear itching, asthma, oral itching/swelling, nausea, vomiting, abdominal pain, diarrhoea, urticaria, angioedema and anaphylaxis). The side-effects were graded as mild, moderate and severe. Results: Four hundred and thirty-three children (285 male, age range 3-18 years) receiving SLIT were surveyed. Of them, 179 received a single extract, and 254 multiple allergens. The total number of doses given was 40 169 (17 143 with single allergen). Overall, 178 episodes were reported. Of them, 76 occurred with the single allergen (42.46% patients, 4.43/1000 doses) and 102 (40.3% patients, 4.42/1000 doses) with multiple allergens (P = NS). 165 episodes (92.5%) were mild and self-resolving and were equally distributed in the two groups. In 13 cases, the events were judged of moderate severity and medical advice was required. Three patients discontinued SLIT, despite the local side-effects being mild. No emergency treatment was required at all. Conclusion: The use of multiple allergens for SLIT does not increase the rate of side-effects in children.
Allergy, 2004
Several well-controlled studies proved clinical benefit of specific immunotherapy (SIT) for therapy of intermittent or seasonal (1) allergic rhinitis (SAR) to pollen, so that SIT became part of the standard treatment guidelines (2, 3). Moreover, it is generally accepted that SIT decreases the risk for subsequent development of asthma and/or bronchial hyperresponsiveness in children with SAR (4, 5), although its inhibitory effect on sensitization with secondary allergen is a matter of debate (6). Still, several important issues limit the general use of SIT. First, specific allergen has to be applied at steadily increasing doses (7), so that the effects of SIT may be incomplete during the first pollen season (5, 8). Secondly, most patients undergoing SIT still have incomplete control of their symptoms and are in need of additional, symptomatic medication. And thirdly, application of specific allergen to previously sensitized patients always bears the risk of anaphylactic side-effects (2). Therefore, in order to allow broader application of SIT, additional antiallergic drugs are required that limit the risks of side-effects and cover the patients until full effects of SIT are accomplished.
JAMA Internal Medicine, 2015
IMPORTANCE Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014. OBJECTIVE To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen. DATA SOURCES Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists. STUDY SELECTION Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo. DATA EXTRACTION AND SYNTHESIS Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird. MAIN OUTCOMES AND MEASURES The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported. RESULTS Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, −0.28; 95% CI, −0.37 to −0.19; P < .001) and in the medication score (SMD, −0.24; 95% CI, −0.31 to −0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine. CONCLUSIONS AND RELEVANCE Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.
Journal of Allergy and Clinical Immunology, 2009
Background: The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. Objective: We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. Methods: Patients with grass pollen-induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. Results: In the intention-to-treat population (n 5 89) a significant treatment effect was achieved after the first month (P 5 .0042) and second month (P 5 .0203) and was maintained through to the fourth month (P 5 .0007). In the active group the ARTSS (means 6 SDs) decreased at each challenge: week 1, 7.40 6 2.682; month 1, 5.89 6 2.431; month 2, 5.09 6 2.088; and month 4, 4.85 6 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergenspecific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. Conclusions: In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.
Clinical Therapeutics, 2011
The summary of product characteristics of the grass allergy immunotherapy tablet (AIT) (Phleum pratense grass pollen allergen extract) states that clinical effect may be observed in the first pollen season of treatment, if treatment is initiated ≥2 months (8 weeks) before the start of the grass pollen season. However, because patients with grass allergy may first present to physicians during the season, immediate treatment initiation (ie, in-season initiation) may increase treatment compliance and reduce the risk for disease progression compared with asking patients to return before the next pollen season to initiate treatment. This “in-season approach” may offer more patients the potentially beneficial treatment option of specific immunotherapy. However, to date, the immunomodulatory effects and tolerability of in-season treatment initiation is unknown.The aim of this study was to assess the immunologic effects and tolerability of in-season initiation of treatment with the grass AIT.This multicenter, randomized, double-blind, placebo-controlled trial was carried out in Germany and Austria. Adults with grass pollen allergy (positive skin-prick test and specific grass-pollen immunoglobulin [Ig] E) and grass pollen–induced moderate to severe persistent rhinoconjunctivitis were enrolled. Patients were randomly assigned to receive once-daily grass AIT or placebo, starting during the 2008 grass pollen season and continuing for 8 to 10 weeks. The primary end point was change from baseline in IgE-blocking factor (serum components competing with IgE for allergen binding). Secondary end points included changes from baseline in specific IgE and IgG4 and measures of tolerability (assessed mainly by adverse events [AEs]). Blood samples for immunologic assessment were obtained by the investigators at baseline and after treatment. All AEs observed by the investigator and/or reported by the patient were recorded throughout the trial and follow-up.A total of 276 patients were enrolled and formed the full analysis set (mean age, 35 years; 55% men, 45% women; 99% white; mean weight, 76 kg; history of asthma, 41%; mean duration of grass allergy, 15.1 years). No major differences in medical history were found between the grass AIT group (n = 219) and the placebo group (n = 57). The change from baseline in mean concentration of IgE-blocking factor was significantly greater with grass AIT compared with placebo (+0.14 vs +0.05; P < 0.0001). The changes from baseline in specific IgE and specific IgG4 concentrations were significantly greater with AIT compared with placebo (IgE, +0.59 vs +0.21 log kU/L; IgG4, +0.18 vs +0.04 log relative units; both, P < 0.0001). At least 1 AE was reported in 58% of patients in the AIT group and in 40% of patients in the placebo group. Most AEs considered related to AIT were mild or moderate events in the mouth, throat, and/or ears (eg, oral pruritus). Four serious AEs were reported in the AIT group (sinusitis, road traffic accident, salmonellosis, meniscus lesion), but all were considered unlikely to be related to treatment. Three percent of the grass AIT group and 2% of the placebo group were withdrawn from the trial due to an AE.In-season initiation of grass AIT was associated with an immunomodulatory response in terms of induction of IgE-blocking factor, specific IgE, and specific IgG4. In-season initiation of grass AIT was generally well tolerated in this group of adults with moderate to severe grass pollen–induced rhinoconjunctivitis. These findings are consistent with those related to the preseasonal initiation of AIT therapy. ClinicalTrials.gov identifier: NCT00773240.
Journal of Allergy and Clinical Immunology, 2010
Background: Sustained and disease-modifying effects of sublingual immunotherapy have never before been confirmed in a large-scale randomized, double-blind, placebo-controlled trial. Objective: We sought to investigate sustained efficacy 1 year after a 3-year period of daily treatment with the SQ-standardized grass allergy immunotherapy tablet Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU; ALK-Abelló, Hørsholm, Denmark). Methods: A randomized, double-blind, placebo-controlled, phase III trial including adults with a history of moderateto-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications. The analysis set comprised 257 subjects at the follow-up. Efficacy end points were rhinoconjunctivitis symptom and medication scores, quality of life, and percentages of symptom and medication free days. Immunologic end points included grass pollen-specific serum IgG4 and IgE-blocking factor. Safety was assessed based on adverse events. Results: Significant improvements in efficacy were consistently shown during 3 years' treatment. One year after treatment, the active group showed sustained reductions in mean rhinoconjunctivitis symptom scores (26%, P < .001) and medication scores (29%, P 5 .022) when compared with placebo. This level was similar to the efficacy observed during the 3-year treatment period. The differences in percentages of symptom-and medication-free days were significant during and 1 year after treatment. The active group also reported sustained and significant improvements in quality of life. Sustained clinical benefit was accompanied by immunologic changes. No safety issues were identified. Conclusion: Three years of treatment with the SQ-standardized grass allergy immunotherapy tablet resulted in consistent clinical improvement and accompanying immunologic changes that were sustained 1 year after treatment, which is indicative of disease modification and associated long-term benefits. (J Allergy Clin Immunol 2010;125:131-38.)
Pediatric Allergy and Immunology, 2011
Sublingual immunotherapy (SLIT) is currently accepted as a safe and effective treatment for respiratory allergy in adults and children. The proofs of efficacy and safety SLIT come from more than 60 randomized placebo controlled trials, several meta-analyses, and numerous post-marketing surveys (for review see 1). In addition, SLIT has been shown capable of conferring a long-term protection and may have a preventative effect on development of asthma (2). Nonetheless, there are several practical aspects of SLIT that still need to be better addressed, including, the optimal maintenance dose, clearly identified only for grass (2), the compliance (3), and the treatment regimen to choose, especially in the case of pollen allergies. In fact, effective pre-seasonal, precoseasonal, and continuous regimens have been proposed in various trials (4). On the other hand, continuous treatments entail certain inconveniences for patients who have symptoms only during the pollen season, and in addition would represent a not negligible economic burden. In this regard, no direct comparison between continuous and seasonal regimen has been carried out so far. Based on this, we designed a clinical trial to compare the efficacy (and safety) of continuous vs. coseasonal SLIT, in children with grass pollen Abstract Background: Pre-seasonal, pre-coseasonal and continuous regimens of immunotherapy have been proposed, but their efficacy was never compared. This phase IV open study was designed to compare the clinical efficacy of a continuous and a coseasonal sublingual immunotherapy (SLIT) for grass allergy over 3 years. Methods: Children with rhinitis/asthma because of grass were randomized to SLIT given continuously (all year long) or coseasonally. The treatment started in October 2005 in the continuous SLIT group and in March 2006 in the coseasonal group Diary cards for clinical symptoms (from 0 = none to 3 = severe), and drug intake were recorded form March to June in 2005 (baseline), 2006 2007, and 2008. Specific IgE and IgG4 were evaluated every year.