Grass Allergy Immunotherapy Tablet Research Articles

Design and Recruitment for the GAP Trial, Investigating the Preventive Effect on Asthma Development of an SQ-Standardized Grass Allergy Immunotherapy Tablet in Children with Grass Pollen–Induced Allergic Rhinoconjunctivitis

Background Allergic rhinoconjunctivitis is a risk factor for asthma development. Treating the underlying allergy may represent an attractive method of asthma prevention. No regulatory guidance exists in this area, and, to our knowledge, no clinical investigations meeting modern regulatory standards have been published. Objective The objective of this publication is to describe the rationale behind the design of and report on the recruitment for the ongoing pediatric Grazax Asthma Prevention (GAP) trial. Methods The trial was designed for assessment of the preventive effect of an SQ-standardized grass allergy immunotherapy tablet (AIT) on asthma development, both during treatment and after the end of treatment. (The standardized quality [SQ] procedure is a standardization procedure comprising 3 components: total potency, major allergen content, and assessment of extract complexity.) The trial design was discussed with several European Competent Authorities. Results The GAP trial is a multinational, parallel-group, double-blind, placebo-controlled randomized trial. Main eligibility criteria were age of 5 to 12 years, grass pollen–induced allergic rhinoconjunctivitis, no asthma, and no overlapping symptomatic allergies. The children have been randomized 1:1 to receive the grass AIT or placebo once daily for 3 years, followed by a blinded observational period of 2 years. Asthma is assessed by the investigators according to specific diagnostic criteria, used at screening visits before randomization to exclude children with existing asthma, and evaluated at least half-yearly during the trial. Seven months of screening resulted in 812 randomized children at 101 centers in 11 countries. Conclusions To our knowledge, the GAP trial represents the first double-blind, placebo-controlled randomized trial to assess the preventive effect of allergen-specific immunotherapy on asthma development. A total of 812 children were successfully recruited into the trial. EudraCT number: 2009-011235-12.

Immunologic Effects and Tolerability Profile of In-Season Initiation of a Standardized-Quality Grass Allergy Immunotherapy Tablet: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial in Adults with Grass Pollen–Induced Rhinoconjunctivitis

Background 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. Objective The aim of this study was to assess the immunologic effects and tolerability of in-season initiation of treatment with the grass AIT. Methods 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 IgG 4 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. Results 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 IgG 4 concentrations were significantly greater with AIT compared with placebo (IgE, +0.59 vs +0.21 log kU/L; IgG 4, +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. Conclusions In-season initiation of grass AIT was associated with an immunomodulatory response in terms of induction of IgE-blocking factor, specific IgE, and specific IgG 4. 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.

Effect of AIT in children including potential to prevent the development of asthma

Allergy specific immunotherapy may alter the natural course of allergic disease. Thus, it is of significant importance, particularly in paediatric populations. Four studies using the grass allergy immunotherapy tablet (AIT) for allergic rhinoconjunctivitis in children showed good clinical outcomes and good safety profiles. Allergic rhinoconjunctivitis often precedes asthma, and treatment with specific immunotherapy has the potential to reduce the development of asthma in children suffering from rhinoconjunctivitis. Since Grazax® AIT has been shown to induce disease modification the prevention of asthma might be hypothesised. The GAP (Grazax® Asthma Prevention) trial is investigating the asthma preventive effect of standardised grass AIT in grass allergic children with rhinoconjunctivitis without asthma. The trial is a 5-year, multicentre, multinational, randomised, double-blind, placebo-controlled, prospective trial for children aged 5-12 years. In a few years, the results will show if grass AIT with Grazax® can prevent the development of asthma in children suffering from allergic rhinoconjunctivitis.

Sustained effects of grass pollen AIT

To cite this article: Durham SR, on behalf of the GT‐08 investigators. Sustained effects of grass pollen AIT. Allergy 2011; 66 (Suppl. 95): 50–52.AbstractWe report the sustained efficacy of the SQ‐standardized grass allergy immunotherapy tablet Grazax® (Phleum pratense 75 000 SQ‐T/2,800 BAU, ALK, Denmark) from a 5‐year randomized, double‐blind, placebo‐controlled phase III trial. Adults with moderate‐to‐severe grass pollen allergy inadequately controlled by symptomatic medications were followed for 2 years after the completion of 3 years of treatment. The active group demonstrated a 31% reduction in median rhinoconjunctivitis symptom score over the season compared with placebo. Individual symptom scores favoured active treatment. Combined symptom and medication scores demonstrated a 33% reduction in medians with active treatment. Persistent clinical efficacy was accompanied by prolonged increases in allergen‐specific IgG4 antibodies and IgE‐blocking factor, confirming clinical and immunological tolerance for at least 2 years after the treatment completion. No safety issues were identified during follow‐up.

Single-Species Grass Pollen Extracts and Mixtures of Extracts From Multiple Phylogenetically Related Grass Species Activate Allergic Patients' Basophils to the Same Degree

RATIONALE: The necessity of complete identity between the sensitizing allergens and allergens used for immunotherapy has been debated. We have previously demonstrated that the effect of individual Derp2 isoforms on basophil activation is minimal, given a polyclonal IgE response (Christensen et al Journal of Immunology (2010) 184, 4966). Similarly, we here demonstrate that extracts of single-pollen and mixes of multiple grass species, respectively, activate basophils from grass-pollen allergic individuals to the same extent. METHODS: Blood basophils from grass allergic donors or basophils sensitized with IgE from grass allergic donors were incubated with either Phleum pratense, a 5-grass (Dac glo, Fes pra, Lol per, Phl pra, Sec cer) or 7-grass mix (Dac glo, Fes pra, Lol per, Phl pra, Poa pra, Arr ela, Sec cer). Activation was measured by flow cytometry. Also, alum-formulated vaccines in the form of Phleum pratense alone or grass mixes were compared in basophil activation assays. RESULTS: No differences in the ability of the single-species Phleum pratense extract and the 5- or 7-grass mixes to activate basophils from individual allergic donors were seen. Comparable responses were maintained after formulation of Phleum pratense and 5- and 7- species grass mixes with ALOH. CONCLUSIONS: Identical responses to single-species and multiple-species extract mixes in basophil activation assays indicate that in allergic individuals antibody responses to epitopes that are shared between different related grass species dominate over species-specific epitopes and -isoforms. This is in agreement with the confirmed clinically efficacy of single-species (Phleum pratense) grass pollen vaccines, both in subcutaneous and Allergy Immunotherapy Tablet regimens.

Efficacy of Timothy Grass Allergy Immunotherapy Tablet During Peak Grass Pollen Season in North American Children and Adolescents

Efficacy of Timothy Grass Allergy Immunotherapy Tablet During Peak Grass Pollen Season in North American Children and Adolescents

Efficacy of Timothy Grass Allergy Immunotherapy Tablet During Peak Grass Pollen Season in North American Adults

RATIONALE: Patients with allergic rhinoconjunctivitis (ARC) may need symptom relief most during peak grass pollen season (pGPS). Timothy grass allergy immunotherapy tablet (grass AIT) pGPS efficacy was assessed in a randomized, double-blind study of North American adults with ARC with/without asthma.METHODS: 438 subjects received once-daily 2800 BAU-standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, ∼15μg Phl p 5) a median of 16 weeks before and throughout GPS. pGPS was defined as the 15-consecutive-day period with the highest moving average pollen count. Daily symptom score (DSS), daily medication score (DMS), total combined score (TCS= DSS+DMS), and Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) score were assessed. Adverse events were monitored for safety.RESULTS: 85% of subjects were multisensitized. Mean pollen counts (grains/m3/d) were: GPS=27, pGPS=48. During pGPS, observed changes in TCS, DSS, DMS, and RQLQ[S] for grass AIT subjects vs placebo were: 21% (P=0.01), 21% (P=0.003), 22% (P=0.21), and 27% (P=0.01). During entire GPS, observed changes in TCS, DSS, DMS, and RQLQ[S] for grass AIT subjects vs placebo were: 20% (P=0.005), 18% (P=0.02), 26% (P=0.08), and 17% (P=0.02). Grass AIT treatment was well-tolerated, with no systemic allergic reactions, anaphylactic shocks, or respiratory compromise reported.CONCLUSIONS: The effectiveness of Timothy grass AIT during pGPS, when pollen counts are highest and symptoms may be most severe, is comparable with or improved over that of the entire GPS. Grass AIT may provide a safe and effective new modality for treating patients with Timothy (and other cross-reactive Festucoideae) grass pollen-induced ARC. RATIONALE: Patients with allergic rhinoconjunctivitis (ARC) may need symptom relief most during peak grass pollen season (pGPS). Timothy grass allergy immunotherapy tablet (grass AIT) pGPS efficacy was assessed in a randomized, double-blind study of North American adults with ARC with/without asthma. METHODS: 438 subjects received once-daily 2800 BAU-standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, ∼15μg Phl p 5) a median of 16 weeks before and throughout GPS. pGPS was defined as the 15-consecutive-day period with the highest moving average pollen count. Daily symptom score (DSS), daily medication score (DMS), total combined score (TCS= DSS+DMS), and Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) score were assessed. Adverse events were monitored for safety. RESULTS: 85% of subjects were multisensitized. Mean pollen counts (grains/m3/d) were: GPS=27, pGPS=48. During pGPS, observed changes in TCS, DSS, DMS, and RQLQ[S] for grass AIT subjects vs placebo were: 21% (P=0.01), 21% (P=0.003), 22% (P=0.21), and 27% (P=0.01). During entire GPS, observed changes in TCS, DSS, DMS, and RQLQ[S] for grass AIT subjects vs placebo were: 20% (P=0.005), 18% (P=0.02), 26% (P=0.08), and 17% (P=0.02). Grass AIT treatment was well-tolerated, with no systemic allergic reactions, anaphylactic shocks, or respiratory compromise reported. CONCLUSIONS: The effectiveness of Timothy grass AIT during pGPS, when pollen counts are highest and symptoms may be most severe, is comparable with or improved over that of the entire GPS. Grass AIT may provide a safe and effective new modality for treating patients with Timothy (and other cross-reactive Festucoideae) grass pollen-induced ARC.

Lower Respiratory-Related Events in Adults and Children With Allergic Rhinoconjunctivitis Receiving Timothy Grass Allergy Immunotherapy Tablet

Lower Respiratory-Related Events in Adults and Children With Allergic Rhinoconjunctivitis Receiving Timothy Grass Allergy Immunotherapy Tablet

Safety of a Short Ragweed Allergy Immunotherapy Tablet in Adults With Ragweed-Induced Allergic Rhinoconjunctivitis and Asthma

FEBRUARY 2011 AB48 Abstracts S A T U R D A Y 173 Efficacy of Timothy Grass Allergy Immunotherapy Tablet During Peak Grass Pollen Season in North American Children and Adolescents J. Maloney, D. Skoner, H. Nolte, S. Gawchik, M. Blaiss; Merck Research Laboratories, Kenilworth, NJ, Drexel University College of Medicine, Philadelphia, PA, Asthma and Allergy Associates, Upland, PA, University of Tennessee Health Science Center, Memphis, TN. RATIONALE: Children with allergic rhinoconjunctivitis (ARC) may experience discomfort and activity limitations, especially during peak grass pollen season (pGPS) when symptoms are the most severe. Efficacy of Timothy grass allergy immunotherapy tablets (grass AIT) during pGPS was evaluated in a randomized, double-blind efficacy/safety trial in North American children/adolescents. METHODS: 344 subjects (5-17y) with grass pollen-induced ARC with/ without asthma received once-daily 2800 BAU-standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, ;15mg Phl p 5) or placebo amedian of 16 weeks before and duringGPS 2009. pGPSwas defined as the 15-consecutive-day period with the highest moving average pollen count. The daily symptom score (DSS), daily medication score (DMS), total combined score (TCS5sum of DSS andDMS), and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores (pediatric and adolescent) were assessed. Safetywasmonitored through adverse event (AE) reporting. RESULTS: 89% of subjects were multisensitized. Mean pollen counts (grains/m/d) were: GPS528, pGPS548. Relative to placebo, improvements in TCS, DSS, DMS, and RQLQ with grass AIT were numerically greater during pGPS (31%, P _5 years with Timothy (and other cross-reactive Festucoideae) grass pollen-induced ARC with safe, effective symptom relief.

Effect of Timothy Grass Allergy Immunotherapy Tablet on Allergic Rhinoconjunctivitis Eye Symptoms in North American Adults and Children

RATIONALE: In patients with allergic rhinoconjunctivitis (ARC), itchy and/or watery eyes are common and bothersome. The effect of Timothy grass allergy immunotherapy tablet (grass AIT) treatment on eye symptoms was assessed in 2 randomized, double-blind, clinical trials designed to evaluate grass AIT efficacy/safety in North American adults, children, and adolescents with grass pollen-induced ARC with/without asthma.

Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults

Immunotherapy for allergic rhinoconjunctivitis (ARC) in North America is generally administered subcutaneously, but alternative formulations might be safer and more convenient. Trials of sublingual formulations in North America are needed to confirm European efficacy and safety data. We sought to investigate the efficacy and safety of timothy grass allergy immunotherapy tablet (AIT) treatment in North American subjects with ARC. Four hundred thirty-nine adults with grass pollen-induced ARC with or without asthma were randomized to once-daily 2,800 bioequivalent allergen units of standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 standardized quality tablet, containing approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). The primary end point was the average total combined score of the daily symptom score and the daily medication score during the GPS. Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) scores, Phl p 5-specific IgG4 levels, and IgE-blocking factor levels were additional end points. Adverse events (AEs) were monitored for safety. Relative to placebo, grass AIT treatment improved total combined scores by 20% (P = .005), daily symptom scores by 18% (P = .02), and RQLQ(S) scores by 17% (P = .02). Daily medication scores were improved by 26% and trended toward significance (P = .08). Phl p 5-specific IgG4 and IgE-blocking factor levels were higher after grass AIT treatment compared with those after placebo at the end of the GPS (P < .001). Grass AIT treatment was safe and well tolerated. The majority of AEs were transient mild local reactions with no investigator-diagnosed grass AIT-related serious AEs or reports of anaphylactic shock/respiratory compromise. In the grass AIT group, 1 subject received epinephrine after experiencing a possible grade 1 systemic reaction (local site reactions, chest discomfort, and rash). Timothy grass AIT treatment (cross-reactive with related Pooideae grasses) was demonstrated to be effective, generally safe, and well tolerated in North American adults with grass pollen-induced ARC.

Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents

Allergy immunotherapy tablet (AIT) treatment might be a safe and convenient form of specific immunotherapy but it has not been investigated in North American children and adolescents. We sought to investigate the efficacy and safety of timothy grass AIT treatment in North American children/adolescents with grass pollen-induced allergic rhinoconjunctivitis (ARC) with or without asthma. Three hundred forty-five subjects (5-17 years old) were randomized to once-daily grass AIT treatment (2,800 bioequivalent allergen units, 75,000 standardized quality tablet, approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). Treatment continued through the GPS. Daily symptoms and allergy rescue medication use were recorded. The primary end point was the total combined score (TCS) of the daily symptom score (DSS) and daily medication score (DMS) for the entire GPS. DSS, DMS, Rhinoconjunctivitis Quality of Life Questionnaire score, and Phl p 5-specific IgG4 and IgE-blocking factor levels were secondary end points. Safety was assessed through adverse events. Eighty-nine percent of subjects were multisensitized. TCS, DSS, DMS, and Rhinoconjunctivitis Quality of Life Questionnaire score versus placebo improved 26% (P = .001), 25% (P = .005), 81% (P = .006), and 18% (P = .04). Phl p 5-specific IgG4 and IgE-blocking factor levels were significantly higher at the peak and end of the GPS (P < .001). Treatment was well tolerated. Adverse events were generally mild and transient. Although no investigator-assessed systemic allergic reactions were reported, 1 grass AIT-treated subject experienced an event indicating a systemic reaction (lip angioedema, dysphagia, and cough). Use of once-daily timothy grass AIT treatment effectively treats timothy grass (cross-reactive with Festucoideae grasses) pollen-induced ARC in North American children 5 years and older. Given its convenient administration, lack of dose build-up requirement, safety profile, and efficacy, AIT treatment might become an important addition to the North American ARC treatment armamentarium.

Days with severe symptoms: an additional efficacy endpoint in immunotherapy trials

In immunotherapy trials, primary and secondary endpoints often focus on average symptom and medication scores during the pollen season or on days with low symptoms and low medication use. Thus, there is a need for endpoints describing the treatment effect on the most troublesome days in the pollen season. A possible additional efficacy endpoint, days with severe symptoms during the pollen season, was investigated using data from a multicentre, double-blind, randomized, placebo-controlled trial of the SQ-standardized grass allergy immunotherapy tablet (AIT) (Grazax, Phleum pratense, 75,000 SQ-T/2,800 BAU, ALK, Hørsholm, Denmark). The trial included 634 subjects (N(Grass AIT) = 316; N(Placebo) = 318) with grass pollen-induced rhinoconjunctivitis. Six different definitions of a day with severe symptoms were suggested. The number of days with severe symptoms was analysed and odds ratios were calculated. The number and percentage of days with severe symptoms differed between definitions, but overall the analysis of days with severe symptoms showed consistent results (odds ratios: 2.0-3.4) for the different definitions. All definitions showed a reduced risk of having days with severe symptoms in the grass AIT group when compared to the placebo group. Days with severe symptoms during the pollen season is a relevant additional efficacy endpoint, which can be used in immunotherapy trials to support the clinical interpretation of commonly used efficacy endpoints.

Sustained effect of SQ‐standardized grass allergy immunotherapy tablet on rhinoconjunctivitis quality of life

The prevalence of allergic rhinoconjunctivitis has increased significantly over the past decades with grass pollen being a common trigger. The impact of allergy on patient's quality of life is substantial. To investigate the sustained effect on quality of life during the grass pollen season 1 year after 3 years of treatment with the SQ-standardized grass allergy immunotherapy tablet (AIT), Graza (Phleum pratense 75,000 SQ-T/2800 BAU; ALK, Denmark). The trial was a randomized, parallel-group, double-blind, placebo-controlled trial in adult subjects with a history of moderate-severe grass pollen induced rhinoconjunctivitis inadequately controlled by symptomatic medications. Subjects received 3 years of grass AIT (n = 157) or placebo (n = 126), followed by 1 year of follow-up. Quality of life assessments were based on the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ(S)); completed weekly during the entire grass pollen season. During follow-up, the overall RQLQ(S) score for the entire grass pollen season was significantly improved in the active group (relative difference to placebo: 23%, P = 0.004). The improvement was higher during the peak pollen season (28%, P = 0.001). The treatment effect of grass AIT during the follow-up year and the previous three treatment years was similar. Improvements were found in all seven RQLQ(S) domains. The RQLQ(S) as a function of the weekly average pollen counts showed a clear separation between the treatment groups (P < 0.001). In subjects inadequately controlled by symptomatic medications, grass AIT provided sustained and clinically relevant improvements in rhinoconjunctivitis quality of life compared to placebo. The effect increased with increasing grass pollen exposure.

Efficacy and Safety of Grass Allergy Immunotherapy Tablet (AIT) in a North American Pediatric Population

Efficacy and Safety of Grass Allergy Immunotherapy Tablet (AIT) in a North American Pediatric Population

Long-term clinical efficacy in grass pollen–induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet

Sustained and disease-modifying effects of sublingual immunotherapy have never before been confirmed in a large-scale randomized, double-blind, placebo-controlled trial. 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). A randomized, double-blind, placebo-controlled, phase III trial including adults with a history of moderate-to-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. 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 = .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. 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.