SQ-standardized Grass Allergy Immunotherapy Tablet Research Articles

Economic evaluation of SQ-standardized grass allergy immunotherapy tablet (Grazax(®)) in children.

BackgroundGrass pollen-induced rhinoconjunctivitis is a common allergic respiratory disorder affecting over 20% of the UK population in terms of quality of life and sleep, work, and school patterns. The SQ-standardized grass allergy immunotherapy tablet (AIT) has been demonstrated as a disease-modifying treatment which gives a sustained effect even after completion of a treatment course. The objective of this study was to provide an economic assessment of whether treatment with the SQ-standardized grass AIT, Grazax® (Phleum pratense) in combination with symptomatic medications is preferable to the standard of care using symptomatic medications only. The analysis was performed for children with grass pollen-induced rhinoconjunctivitis, with or without concomitant asthma, in the UK.MethodsThe model evaluated the two treatment regimens in a cohort of 1,000 children from a payer’s perspective. Treatment was modeled in terms of management of symptoms, impact on resource use, and development of allergic asthma. The analysis modeled the use of SQ-standardized grass AIT and the sustained effects of treatment over a 9-year time horizon (ie, 3 years of treatment, with modeled long-term benefits). Data inputs were drawn from a recent clinical trial, published studies, and databases.ResultsSQ-standardized grass AIT improves patient outcomes, generating an incremental cost per quality-adjusted life year gained of £12,168. This is below commonly accepted thresholds in the UK.ConclusionThe resulting incremental cost per QALY falls below commonly accepted willingness to pay thresholds. Therefore, the SQ-standardized grass AIT is a cost-effective option for the treatment of grass pollen-induced rhinoconjunctivitis in the UK pediatric population.

Efficacy and safety of the SQ‐standardized grass allergy immunotherapy tablet in mono‐ and polysensitized subjects

The efficacy of single-allergen-specific immunotherapy in polysensitized subjects is a matter of debate. We therefore performed a post hoc analysis of pooled data from six randomized, double-blind, placebo-controlled trials (N = 1871) comparing the efficacy and safety of the SQ-standardized grass allergy immunotherapy tablet (AIT), Grazax (Phleum pratense 75 000 SQ-T/2800 BAU, ALK, Denmark), in mono- and polysensitized subjects. A statistically significant reduction in the mean total combined symptom/medication score (TCS) of 27% was demonstrated in actively treated subjects compared with placebo (P < 0.0001). This was not dependent on sensitization status (P = 0.5772), suggesting a similar treatment effect in mono- and polysensitized subjects (i.e. reductions of the TCSs of 28% and 26%, respectively, both P < 0.0001). Finally, a comparable and favourable safety profile of grass AIT was demonstrated in the two subgroups. Thus, no difference in efficacy and safety of single-allergen grass AIT was observed between mono- and polysensitized subjects.

Budget impact analysis of two immunotherapy products for treatment of grass pollen-induced allergic rhinoconjunctivitis

BackgroundGrass pollen-induced allergic rhinoconjunctivitis constitutes a large burden for society. Up to 20% of European and United States (US) populations suffer from respiratory allergies, including grass pollen-induced allergic rhinoconjunctivitis. The majority of patients are treated with symptomatic medications; however, a large proportion remains uncontrolled despite use of such treatments. Specific immunotherapy is the only treatment documented to target the underlying cause of the disease, leading to a sustained effect after completion of treatment. The aim of this study was to compare the economic consequences of treating patients suffering from allergic rhinoconjunctivitis with either a grass allergy immunotherapy tablet (AIT) or subcutaneous immunotherapy (SCIT).MethodsA budget impact analysis was applied comparing SQ-standardized grass AIT (Grazax®; Phleum pratense, 75,000 SQ-T/2,800 BAU; ALK, Denmark) with SCIT (Alutard®; P. pratense, 100,000 SQ-U/mL; ALK, Denmark). Budget impact analysis included health care utilization measured in physical units based on systematic literature reviews, guidelines, and expert opinions, as well as valuation in unit costs based on drug tariffs, physician fees, and wage statistics. Budget impact analysis was conducted from a Danish health care perspective.ResultsTreating patients suffering from allergic rhinoconjunctivitis with grass AIT instead of grass SCIT resulted in a total reduction in treatment costs of €1291 per patient during a treatment course. This cost saving implies that approximately 40% more patients could be treated with grass AIT per year without influencing the cost of treatment.ConclusionBudget impact analysis showed that grass AIT is a cost-saving alternative to SCIT when treating patients with grass pollen-induced allergic rhinoconjunctivitis.

Safety and Tolerability of an SQ-Standardized GRAss ALlergy Immunotherapy Tablet (GRAZAX®) in a Real-Life Setting for Three Consecutive Seasons – The GRAAL Trial

GRAZAX(®) (Phleum Pratense, 75,000 SQ-T/2,800 BAU, ALK, Denmark), an SQ-standardized grass allergy sublingual immunotherapy tablet for the desensitization of grass pollen-induced rhinoconjunctivitis, has been developed to facilitate patient access to specific immunotherapy (SIT), while minimizing the risk of serious treatment-related adverse events. As a minimum duration of 3 years is recommended for SIT treatment, the GRAAL trial aimed to assess the safety profile of GRAZAX(®) in real-world conditions during long-term treatment of patients with grass pollen-induced allergic rhinoconjunctivitis (ARC). A multicentre, prospective, open-label, observational trial was conducted over three consecutive grass pollen seasons from November 2007 to October 2010 in France. A total of 130 physicians included 628 patients with previously documented ARC. Patients received one tablet daily (no up-titration) for at least 4 months before the expected start of the pollen season (pre-season), which was then maintained throughout the entire season (co-season). The primary endpoint was safety and tolerability (immediate, i.e. each year at first tablet administration, and long-term) after pre- and co-seasonal exposure to GRAZAX(®). Patients were treated for an average of 5.5 months per year. After administration of the first tablet, immediate tolerable reactions (defined as benign, local, of short duration [<30 minutes] and not requiring any symptomatic treatment) were experienced by 54.6%, 38.4% and 33.6% of the patients during the first, second and third years of treatment, respectively. Immediate intolerable reactions (required study discontinuation, symptomatic medication or lasted >30 minutes) occurred in 14 patients (2.2%) during GRAZAX(®) initiation, and one patient (0.3%) at treatment reintroduction during the second year. Adverse events considered to be related to GRAZAX(®) were reported by 46.2%, 14.4% and 1.8% of patients, during the first, second and third years of treatment, respectively. The most frequently reported adverse events were mild-to-moderate local events (at the oral and pharyngeal mucosa levels). These symptoms mainly occurred within the first month of treatment initiation and subsequent tablet reintroduction. Daily administration of GRAZAX(®) for three consecutive years was generally safe and well tolerated. An improvement in the incidence of adverse events related to treatment was observed at reintroduction of GRAZAX(®) and during the course of treatment. http://clinicaltrials.gov (NCT01433510).

Treatment of seasonal allergic rhinoconjunctivitis with a once-daily SQ-standardized grass allergy immunotherapy tablet

Objectives:Specific immunotherapy with the grass allergy immunotherapy tablet (AIT) has been developed as an effective, well tolerated, and convenient treatment for grass pollen induced seasonal allergic rhinoconjunctivitis (ARC). Six phase II/III randomized, placebo-controlled trials with the duration of a single grass pollen season of treatment using the SQ-standardized grass AIT, Grazax (Phleum pratense, 75,000 SQ-T/2,800 BAU, ALK, Denmark), have been published previously. This review compares results from these trials.Methods:As outcome measures and methods of assessing them were similar across the trials, we have summarized the main efficacy findings (Total Combined Score [TCS], average daily rhinoconjunctivitis symptom and medication scores, percentage of well days, quality of life scores) during a single season of treatment with grass AIT in adults and children with seasonal ARC.Results:The results of the European and North American trials were similar. Compared with the placebo group, who received symptomatic medications only, treatment with grass AIT resulted in fewer rhinoconjunctivitis symptoms, a lower intake of symptomatic medication, better patient self-rated quality of life and a greater percentage of well days during the entire grass pollen season. The data indicate that grass AIT treatment is equally effective in adults and children; the measured effect varies with pollen exposure, but is comparable across regions and continents, with a consistent difference compared with placebo in TCS that was above 20% for all trials. Local adverse events were experienced by the majority of patients. These reactions were generally mild to moderate in severity and transient in duration. Systemic adverse events were rare.Conclusions:This review confirms SQ-standardized grass AIT as a suitable therapeutic option for seasonal use in patients aged 5 years or older with grass pollen induced ARC.

SQ-standardized sublingual grass immunotherapy: Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial

The main aim of specific immunotherapy is sustained effect due to changes in the immune system that can be demonstrated only in long-term trials. To investigate sustained efficacy and disease modification in a 5-year double-blind, placebo-controlled trial, including 2 years of blinded follow-up after completion of a 3-year period of treatment, with the SQ-standardized grass allergy immunotherapy tablet, Grazax (Phleum pratense 75,000 SQ-T/2,800 BAU,(∗) ALK, Denmark) orplacebo. A randomized, double-blind, placebo-controlled, multinational, phase III trial included adults with a history of moderate-to-severe grass pollen-induced allergic rhinoconjunctivitis, with or without asthma, inadequately controlled by symptomatic medications. Two hundred thirty-eight participants completed the trial. End points included rhinoconjunctivitis symptom and medication scores, combined scores, asthma symptom and medication scores, quality of life, days with severe symptoms, immunologic end points, and safety parameters. The mean rhinoconjunctivitis daily symptom score was reduced by 25% to 36% (P ≤ .004) in the grass allergy immunotherapy tablet group compared with the placebo group over the 5 grass pollen seasons covered by the trial. The rhinoconjunctivitis DMS was reduced by 20% to 45% (P ≤ .022 for seasons 1-4; P= .114 for season 5), and the weighted rhinoconjunctivitis combined score was reduced by 27% to 41% (P ≤ .003) in favor of active treatment. The percentage of days with severe symptoms during the peak grass pollen exposure was in all seasons lower in the active group than in the placebo group, with relative differences of 49% to 63% (P ≤ .0001). Efficacy was supported by long-lasting significant effects on the allergen-specific antibody response. No safety issues were identified. The results confirm disease modification by SQ-standardized grass allergy immunotherapy tablet in addition to effective symptomatic treatment of allergic rhinoconjunctivitis.

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.

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.

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.