Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial

BACKGROUND: Sublingual treatment of grass pollen induced rhinoconjunctivitis might provide easier access to specific immunotherapy (SIT) and minimize the risk of serious adverse events (AEs) compared to subcutaneous SIT. AIM OF THE STUDY: To identify a safe dose range for once-daily administration of a grass allergen tablet in participants with grass pollen induced seasonal rhinoconjunctivitis. METHODS: A randomized, double blind, placebo-controlled Phase I trial was conducted outside the grass pollen season. Seven dosage groups [25,000, 75,000, 150,000, 300,000, 500,000, 750,000, or 1,000,000 standardized quality tablet (SQ-T)], consisting of 12 participants randomized either to active treatment or placebo (3 : 1) daily for 28 days, commenced treatment in a staggered manner at intervals of approximately 1 week to allow for intermittent safety reviews. RESULTS: The grass allergen tablet did not cause any serious, systemic or significant (leading to withdrawal) AEs. The overall incidence of AEs was 74% (1,013 events); all of mild or moderate intensity and most considered treatment-related. The most frequently reported treatment-related AEs, including irritation of the throat, and itching sensations in the mouth and ears, increased with dose. These were primarily mild in intensity, started shortly after medication intake and lasted for minutes to a few hours maximum. Objective oral findings were also dose-dependent. No clinically significant observations were found in safety laboratory, vital signs and 12-lead ECG. CONCLUSIONS: A sublingual grass allergen tablet in doses up to 1,000,000 SQ-T daily caused no serious or systemic AEs displaying a safety profile that allows further investigation as once-daily self-medication.     

Efficacy and safety of specific immunotherapy with a high-dose sublingual grass pollen preparation: a double-blind, placebo-controlled trial.

BACKGROUND: Sublingual immunotherapy (SLIT) is increasingly being used for the treatment of allergic rhinitis, but there are conflicting study results demonstrating clinically relevant efficacy. OBJECTIVE: To show clinical efficacy and safety of a new high-dose grass pollen preparation for SLIT. METHODS: In a 2-year, double-blind, placebo-controlled trial, 185 subjects with rhinitis or rhinoconjunctivitis, with or without asthma, were treated with a recently developed, high-dose, 6-grass pollen mixture for SLIT once daily. RESULTS: The primary end point, a combined symptom-medication score, showed almost no change in the placebo group during a 42-day evaluation period in the grass pollen season from 2003 to 2005, whereas active treatment was associated with a significant and clinically relevant improvement (full analysis set, P = .01; main data set, P = .002). The effect was irrespective of asthma diagnosis. Allergen-specific IgE showed no difference in both groups, and specific IgG4 and IgG1 increased with active treatment in the first and second study years compared with placebo, clearly indicating the immunogenic effect of the active treatment. The SLIT was well tolerated. No serious adverse drug reactions occurred. CONCLUSIONS: High-dose, sublingual, specific immunotherapy with an extract of a 6-grass pollen mixture showed a significant and clinically relevant improvement in subjects with grass pollen-associated rhinitis or rhinoconjunctivitis, with or without asthma. The treatment with the sublingual solution was well tolerated.     

Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial

BACKGROUND: Previous studies suggest that sublingual immunotherapy (SLIT) represents a safer alternative to injection immunotherapy but equivalent efficacy is yet to be confirmed. OBJECTIVE: To evaluate the efficacy and safety of SLIT in grass pollen-induced seasonal rhinoconjunctivitis. METHODS: A randomized, placebo-controlled trial in 56 adults over 18 months. Outcome measures included diary scores of seasonal symptoms and medication use, overall assessments, conjunctival and intradermal provocation tests and serum antibody measurements. To investigate possible mechanisms, sublingual biopsies were taken for measurement of local T cells, antigen-presenting cells and IL-12 mRNA expression. RESULTS: There were no significant differences between the immunotherapy (IT) and placebo groups for diary symptom scores (P = 0.48) or rescue medication (P = 0.19). The patients' overall assessment of hayfever severity compared with previous years showed a highly significant improvement in favour of the IT group (P < 0.02). After treatment the late skin response was smaller (P = 0.003) and the ratio of serum allergen-specific IgG4/IgE was higher (P = 0.05) in the IT group. Both of these variables correlated with the clinical response to SLIT. There were no differences between groups in either the sublingual epithelium or lamina propria for numbers of CD3+ cells (epithelium: P = 0.9, lamina propria: P = 0.2), CD1a+ cells (P = 0.3, P = 0.25), CD68+ cells (P = 0.9, P = 1.0) or IL-12 mRNA+ cells (P = 0.6, P = 0.4). Local side-effects were minor and there were no serious treatment-related adverse events. CONCLUSION: Grass pollen sublingual immunotherapy was well tolerated. Although there was no significant change in diary scores, the improvement in overall assessments, which correlated with inhibition of the late skin response and increases in serum IgG4 : IgE ratio, indicates the need for larger, dose-ranging studies.     

Efficacy and safety of sublingual immunotherapy.

OBJECTIVE: To review the available published data concerning the use of sublingual immunotherapy (SLIT) in respiratory allergy to primarily evaluate the clinical efficacy and safety of the treatment and to secondarily consider the mechanisms of action and any unresolved questions. DATA SOURCES: Articles in the medical literature (starting from 1986 up to November 2003) derived from searching the MEDLINE database with the keywords sublingual immunotherapy, respiratory allergy, asthma, and rhinitis. Sources included review articles, randomized controlled clinical trials, postmarketing surveillance studies, and relevant reports from meeting proceedings. STUDY SELECTION: Articles concerning safety, efficacy, and mechanisms of SLIT published in English-language, peer-reviewed journals. RESULTS: SLIT proved effective and safe in adults and children. As with traditional subcutaneous immunotherapy, SLIT has long-lasting efficacy and a preventive effect on new sensitizations. CONCLUSION: SLIT is a viable alternative to subcutaneous immunotherapy. Its use in pediatric patients seems to be particularly promising.     

Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis

BACKGROUND: Allergen immunotherapy (desensitization) by injection is effective for seasonal allergic rhinitis and has been shown to induce long-term disease remission. The sublingual route also has potential, although definitive evidence from large randomized controlled trials has been lacking. OBJECTIVE: The aim was to confirm the efficacy of a rapidly dissolving grass allergen tablet (GRAZAX, ALK-Abelló, H?rsholm, Denmark) compared with placebo in patients with seasonal rhinoconjunctivitis. METHODS: A longitudinal, double-blind, placebo-controlled, parallel-group study that included 51 centers from 8 countries. Subjects were randomized (1:1) to receive a grass allergen tablet or placebo once daily. A total of 634 subjects with a history of grass pollen-induced rhinoconjunctivitis for at least 2 years and confirmation of IgE sensitivity (positive skin prick test and serum-specific IgE) were included in the study. Subjects commenced treatment at least 16 weeks before the grass pollen season, and treatment was continued throughout the entire season. RESULTS: The primary efficacy analysis showed a reduction of 30% in rhinoconjunctivitis symptom score (P < .0001) and a reduction of 38% in rhinoconjunctivitis medication score (P < .0001) compared with placebo. Side effects mainly comprised mild itching and swelling in the mouth that was in general well tolerated and led to treatment withdrawal in less than 4% of participants. There were no serious local side effects and no severe systemic adverse events. CONCLUSION: Sublingual immunotherapy with grass allergen tablets was effective in grass pollen-induced rhinoconjunctivitis. The tablet was well tolerated with minor local side effects. CLINICAL IMPLICATIONS: The grass allergen tablet represents a safe alternative to injection immunotherapy suitable for home use.     

Efficacy and safety of sublingual immunotherapy in children

Allergen immunotherapy (AIT) is currently the only available disease-modifying and aetiological treatment of IgE-mediated diseases. Sublingual allergen immunotherapy (SLIT) constitutes the preferred route of administration of AIT for respiratory allergies in Europe. Recently it has also been approved in the US. Further applications are currently under evaluation, such as IgE-mediated food allergy and IgE-mediated atopic dermatitis. The SLIT safety profile is overall favourable, although local adverse events, usually mild, are described. Most of the meta-analyses confirmed the efficacy of SLIT in reducing symptoms and medication intake in children with allergic diseases. AIT, as an immune-modulating treatment, can modify the natural history of the allergic diseases: reduction of the risk of development of asthma and bronchial hyperreactivity in patients with allergic rhinitis, and reduction of the onset of new sensitizations. A great interest is now devoted to the preventive effects of AIT and, consequently, to the optimal time of initiation.     

Efficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollen

Background Although sublingual immunotherapy (SLIT) has been used with increasing frequency, the data on the efficacy of SLIT in pediatric asthma are limited.
Aim The aim of our study was to evaluate the efficacy and the safety of high-dose SLIT given pre-seasonally and co-seasonally in an ultra-rush scheme in children with bronchial asthma allergic to grass pollen.
Methods Fifty children with asthma, aged 6–17, sensitive to grass pollen, participated in the 2-year prospective, randomized, double-blind, placebo-controlled trial, to investigate the efficacy and safety of SLIT (Staloral 300 IR, Stallergenes SA, 25 μg major allergens) as a standardized extract of five grass pollen with ultra-rush induction.
Results SLIT significantly improved asthma symptom scores (41% vs. placebo group), reduced nasal symptoms (25% vs. placebo group) and the use of rescue medications (10% vs. placebo group), improved forced expiratory volume in 1 s, but had no effect on ocular symptoms, nasal hyper-reactivity, peak expiratory flow and forced expiratory volume between 25% and 75% of vital capacity. Serum levels of immunoglobulin E and IgG4 did not change after SLIT. After the second season of SLIT, an improvement in bronchial hyperresponsiveness was observed; however, compared with placebo, this effect was not significant. Among all subjects in SLIT group, predominantly local reactions have been recorded in 59% of subjects in the first year of treatment and in 35% in the second.
Conclusions Our study indicated that high-dose ultra-rush, co-seasonal SLIT given for 2 years, was safe and reduced a multiple symptom–medication score.     

Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis

BACKGROUND: Specific immunotherapy is the only treatment modality that has the potential to alter the natural course of allergic diseases. Sublingual immunotherapy has been developed to facilitate access to this form of treatment and to minimize serious adverse events. OBJECTIVE: To investigate the efficacy and safety of sublingual grass allergen tablets in seasonal allergic rhinoconjunctivitis. METHODS: A multinational, multicenter, randomized, placebo-controlled trial conducted during 2002 and 2003. Fifty-five centers in 8 countries included 855 participants age 18 to 65 years who gave a history of grass pollen-induced allergic rhinoconjunctivitis and had a positive skin prick test and elevated serum allergen-specific IgE to Phleum pratense. Participants were randomized to 2500, 25,000, or 75,000 SQ-T grass allergen tablets (GRAZAX; ALK-Abelló, H?rsholm, Denmark) or placebo for sublingual administration once daily. Mean duration of treatment was 18 weeks. RESULTS: Average rhinoconjunctivitis scores during the season showed moderate reductions of symptoms (16%) and medication use (28%) for the grass allergen tablet 75,000 SQ-T (P = .0710; P = .0470) compared with placebo. Significantly better rhinoconjunctivitis quality of life scores (P = .006) and an increased number of well days (P = .041) were also observed. Efficacy was increased in the subgroup of patients who completed the recommended preseasonal treatment of at least 8 weeks before the grass pollen season (symptoms, 21%, P = .0020; and medication use, 29%, P = .0120). No safety concerns were observed. CONCLUSION: This study confirms dose-dependent efficacy of the grass allergen tablet. Although further studies are required, the greater tolerability of the tablet may permit immunotherapy to be available to a much broader group of patients with impaired quality of life caused by grass pollen allergy. CLINICAL IMPLICATIONS: For patients with grass pollen allergy, sublingual immunotherapy is well tolerated and can reduce symptoms and improve quality of life.     

Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy

1. Download high-res image (227KB)
2. Download full-size image

     

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults

BackgroundRagweed is an important cause of allergic rhinitis with or without conjunctivitis (AR/C) in North America and elsewhere. Allergen immunotherapy enabling safe patient self-administration is considered an unmet clinical need. Allergy immunotherapy tablet (AIT) treatment has shown promising efficacy and safety for grass allergy but has not been assessed for ragweed allergy.ObjectiveTo evaluate efficacy and safety of 2 short ragweed AIT doses in patients with AR/C.MethodsAdults with ragweed pollen–induced AR/C were randomized 1:1:1 to daily ragweed AIT (6 or 12 Amb a 1 units) or placebo before, throughout, and after ragweed season (approximately 52 weeks). Patients could use predefined allergy rescue medications in season. Efficacy end points included peak and entire season total combined score (TCS) and its components daily symptom score (DSS), and daily medication score (DMS). Safety assessments included adverse events.ResultsA total of 565 patients were randomized. During peak season, the 6– and 12–Amb a 1 unit ragweed AIT doses showed 21% (?1.76 score) and 27% (?2.24 score) improvement in TCS vs placebo (P < .05). The 6– and 12–Amb a 1 unit AIT doses significantly improved DSS and DMS vs placebo (P < .05). Peak and entire season efficacy were comparable. The 12–Amb a 1 unit AIT dose reduced peak-season TCS vs placebo by 21% and 25% in subgroups with and without local application-site reactions, respectively. Most treatment-related adverse events were mild, oral reactions; no systemic allergic reactions were reported. One patient in the 6–Amb a 1 unit group received epinephrine at an emergency facility for sensation of localized pharyngeal edema.ConclusionIn this trial, ragweed AIT was effective and well tolerated in ragweed-allergic North American adults.Trial Registrationclinicaltrials.gov Identifier: NCT00783198.     

Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial

BACKGROUND: Grass pollen immunotherapy significantly reduces hay fever symptoms and medication requirements. Effects on seasonal asthma are less clear, and concerns over safety persist. OBJECTIVE: The goal of this study was to assess the effects of grass pollen immunotherapy on symptoms, bronchial hyperresponsiveness, and quality of life in seasonal rhinitis and asthma. METHODS: Forty-four patients with severe summer hay fever (of whom 36 reported seasonal chest symptoms and 28 had seasonal bronchial hyperresponsiveness) participated in a randomized, double-blind, placebo-controlled, parallel group study. After symptom monitoring for one summer, participants received injections of a depot grass pollen vaccine (n = 22) or matched placebo injections (n = 22) in a rapid updosing cluster regimen for 4 weeks, followed by monthly injections for 2 years. Outcome measures included hay fever symptoms and medication use, health-related quality of life, and measurements of nonspecific bronchial responsiveness. RESULTS: Significant reductions were observed in the immunotherapy group compared with the placebo group in hay fever symptoms (49%, 15%; P =.01), medication scores (80%, 18%; P =.007), and seasonal chest symptoms (90%, 11%; P <.05). Impairment of overall quality of life (mean score of 7 domains) during the pollen season was less in the immunotherapy group than in the placebo group (median difference [95% CI], 0.8 [0.18-1.5]; P =.02). During the pollen season there was no change in airway methacholine PC(20) (provocation concentration producing a 20% fall in FEV(1)) in the immunotherapy-treated group (P =.5), compared with an almost 3 doubling-dose decrease in the placebo-treated group (P =.01, between-group difference). There were no significant local or systemic side effects during the study. CONCLUSION: Grass pollen immunotherapy improves quality of life in seasonal allergic rhinitis and reduces seasonal asthma symptoms and bronchial hyperresponsiveness.     

A double-blind, placebo-controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract

Fifty-eight patients with well-documented history of seasonal rhinoconjunctivitis caused by grass pollens were allocated randomly on a double-blind basis to receive either sublingual therapy with a solution of purified, standardized allergen preparation (Stallergenes) or a matched placebo for 17 weeks. The assessment of the effect of oral immunotherapy, done with drops of five-grass allergen extract, was on the clinical symptoms and on the medication score of the authorized rescue treatments. The actively treated patients had significantly (P<0.05 to P<0.01) fewer symptoms of rhinitis (sneezing and rhinorrhea) and of conjunctivitis (redness and tears) during the pollen season than the placebo group. Consumption of nasal solution of sodium cromoglycate and of betamethasone and dexchlorpheniramine was significantly less in the desensitized group (P<0.01). Side-effects were negligible. This study concludes that perlingual immunotherapy with grass pollen extract in grass-pollen-sensitive seasonal hay fever and conjunctivitis patients is effective, easy to perform, inexpensive, and safe.     

Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study

BACKGROUND: Sublingual immunotherapy (SLIT) has been proved to be effective in allergic rhinitis and asthma, but there are few data on its preventive effects, especially in children. OBJECTIVE: To evaluate the clinical and preventive effects of SLIT in children by assessing onset of persistent asthma and new sensitizations, clinical symptoms, and bronchial hyperreactivity. METHODS: A total of 216 children with allergic rhinitis, with or without intermittent asthma, were evaluated and then randomized to receive drugs alone or drugs plus SLIT openly for 3 years. The clinical score was assessed yearly during allergen exposure. Pulmonary function testing, methacholine challenge, and skin prick testing were performed at the beginning and end of the study. RESULTS: One hundred forty-four children received SLIT and 72 received drugs only. Dropouts were 9.7% in the SLIT group and 8.3% in the controls. New sensitizations appeared in 34.8% of controls and in 3.1% of SLIT patients (odds ratio, 16.85; 95% confidence interval, 5.73-49.13). Mild persistent asthma was less frequent in SLIT patients (odds ratio, 0.04; 95% confidence interval, 0.01-0.17). There was a significant decrease in clinical scores in the SLIT group vs the control group since the first year. The number of children with a positive methacholine challenge result decreased significantly after 3 years only in the SLIT group. Adherence was 80% or higher in 73.8% of patients. Only 1 patient reported systemic itching. CONCLUSIONS: In everyday clinical practice, SLIT reduced the onset of new sensitizations and mild persistent asthma and decreased bronchial hyperreactivity in children with respiratory allergy.     

Relevance of a 5-grass sublingual tablet for immunotherapy of patients with grass pollen allergy in North America

Grass pollen allergy is common and clinically consequential in North America. While it is frequently treated with subcutaneous or sublingual immunotherapy, debate remains regarding whether allergen immunotherapy is best carried out using a single representative or multiple cross-reactive allergen(s). Patients are commonly exposed to pollens from multiple allergenic grass species belonging to the Pooideæ subfamily. Beyond the known IgE cross-reactivity, considerable molecular heterogeneity exists with respect to allergen content among grass species, with further evidence that these molecular variants can be detected by the patients’ immune system. These observations provide a compelling scientific rationale for the use of mixed pollen allergen extracts to broaden the allergen repertoire, with the aim of reorienting inappropriate immune responses in allergic patients.     

Clinical, functional, and immunologic effects of sublingual immunotherapy in birch pollinosis: a 3-year randomized controlled study

BACKGROUND: Sublingual immunotherapy (SLIT) has been proved effective in allergic rhinitis, but there are few studies assessing its effects on inflammation and on the lower airways. OBJECTIVE: We sought to evaluate at the same time the effects of SLIT on rhinitis symptoms, nasal inflammation, and lower airways function in patients with birch pollinosis. METHODS: Adult patients with rhinitis and asthma monosensitized to birch were evaluated during a run-in pollen season and then randomized to receive openly either drugs alone or drugs plus SLIT and reevaluated in the subsequent 4 pollen seasons. Rhinitis symptoms and consumption of bronchodilators were assessed by means of diary card. A nasal smear for eosinophil count was carried out in and out of pollen seasons, and pulmonary function tests with methacholine challenge were performed at each season. RESULTS: Of 79 enrolled patients, 27 dropped out, with a significantly higher rate of dropouts in the control group. There was a decrease in symptoms and bronchodilator use in the SLIT group versus the control group, becoming significant at the second and third pollen seasons, respectively ( P < .01 at all times). Nasal eosinophils decreased significantly in the active group, starting from the third pollen season ( P < .01). In the SLIT group a significant increase in FEV 1 , specific airways conductance, and maximal expiratory flow at 25% of forced vital capacity was seen starting from the second year and was associated with an increase in the methacholine threshold dose ( P < .01). The differences were significant also at the intragroup comparison over time. CONCLUSION: SLIT achieved a significant clinical benefit in birch pollinosis, reduced the eosinophil infiltration in nasal mucosa, and significantly improved pulmonary function during the pollen seasons.