How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: An ARIA-GA2LEN statement

University Hospital, Hôpital Arnaud de Villeneuve, Montpellier, France.
Allergy (Impact Factor: 6.03). 06/2011; 66(6):765-74. DOI: 10.1111/j.1398-9995.2011.02590.x
Source: PubMed


To cite this article: Bousquet J, Schünemann HJ, Bousquet PJ, Bachert C, Canonica GW, Casale TB, Demoly P, Durham S, Carlsen K-H, Malling H-J, Passalacqua G, Simons FER, Anto J, Baena-Cagnani CE, Bergmann K-C, Bieber T, Briggs AH, Brozek J, Calderon MA, Dahl R, Devillier P, Gerth van Wijk R, Howarth P, Larenas D, Papadopoulos NG, Schmid-Grendelmeier P, Zuberbier T. How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA2LEN statement. Allergy 2011; 66: 765–774.
Specific immunotherapy (SIT) is one of the treatments for allergic rhinitis. However, for allergists, nonspecialists, regulators, payers, and patients, there remain gaps in understanding the evaluation of randomized controlled trials (RCTs). Although treating the same diseases, RCTs in SIT and pharmacotherapy should be considered separately for several reasons, as developed in this study. These include the severity and persistence of allergic rhinitis in the patients enrolled in the study, the problem of the placebo, allergen exposure (in particular pollen and mite), the analysis and reporting of the study, the level of symptoms of placebo-treated patients, the clinical relevance of the efficacy of SIT, the need for a validated combined symptom–medication score, the differences between children and adults and pharmacoeconomic analyses. This statement reviews issues raised by the interpretation of RCTs in sublingual immunotherapy. It is not possible to directly extrapolate the rules or parameters used in medication RCTs to SIT. It also provides some suggestions for the research that will be needed. Interestingly, some of the research questions can be approached with the available data obtained from large RCTs.

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    • "Compared with trials for symptomatic AR/C treatments, the design and execution of immunotherapy clinical trials is complex. In pharmacotherapy studies, subjects with AR/C are typically enrolled once their symptoms have reached a predefined level of severity, and the ability of the target agent to reduce symptoms can be observed within hours to days of initiation [6]. In trials of immunotherapy for seasonal allergies, treatment is initiated weeks or months prior to the onset of pollen season and the associated symptoms, to allow the treatment to modulate the immune system before the season starts [7]. "
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    ABSTRACT: Design and execution of immunotherapy trials for seasonal allergies may be complicated by numerous factors including variable allergy testing methods, pollen levels, and timing and intensity of other seasonal allergens. We evaluated grass allergy immunotherapy tablet (AIT) treatment in North American adults with grass pollen-induced allergic rhinitis with or without conjunctivitis (AR/C), with/without asthma. Subjects age 18–65 with clinical history of grass pollen–induced AR/C, with/without asthma were randomized 1:1 to once-daily 2800 BAU Timothy grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, containing approximately 15 μg of Phl p 5) or placebo. The AR/C symptom and medication scores were recorded daily. The primary end point was the average AR/C daily symptom score (DSS) during the entire grass pollen season (GPS). Ranked key secondary end points were Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, daily medication score (DMS), and percentage of well days, all over entire GPS. Safety was monitored through adverse event reporting. Efficacy analysis included 289 subjects. Over the entire GPS, mean DSS was 6% lower with AIT versus placebo (5.69 vs. 6.06), but this difference was not statistically significant (p = 0.3475) despite significantly higher immunological response in the grass AIT group. No significant between-group differences were seen for key secondary end points. In general, DSS was high before GPS began and no clear relationship between DSS and grass pollen counts was seen during GPS. In post hoc analysis of subjects with pre-seasonal DSS ≤3, mean DSS and DMS were both significantly lower with grass AIT versus placebo (27%; p = 0.0327 and 68%; p = 0.0060, respectively). In this subgroup a relationship between DSS and grass pollen counts was observed. Grass AIT was generally well tolerated, with no events of anaphylactic shock or respiratory compromise. In this trial, 2800 BAU grass AIT did not demonstrate significant symptom improvement versus placebo. Lack of relationship between pollen count and symptom score in the study population, and post hoc findings among subjects with low pre-seasonal symptoms, suggest that the symptoms reported in this study were not primarily reflective of the effects of grass pollen exposure. Trial registration NCT00421655
    Journal of Negative Results in BioMedicine 06/2013; 12(1):10. DOI:10.1186/1477-5751-12-10 · 1.47 Impact Factor
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    Allergy 06/2011; 66(6):709-12. DOI:10.1111/j.1398-9995.2011.02595.x · 6.03 Impact Factor
  • H Ott · A Bufe · H F Merk ·
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    ABSTRACT: Allergic rhinitis (AR) is a common disease affecting 7-17% of children and adolescents who may suffer from a significantly impaired quality of life. For 100 years subcutaneous immunotherapy (SCIT) has been used to treat AR. If patients are chosen carefully, a clinically relevant reduction of seasonal symptoms and medication use can be achieved by SCIT. Serious adverse events are rarely encountered during adequately performed and monitored SCIT. Sublingual immunotherapy (SLIT) may be used as a less painful therapeutic alternative in children if the administration of SCIT is impossible. Recent controlled trials have shown that SLIT performed over one pollen season also ameliorates seasonal symptoms and reduces the need for concomitant medication. Local reactions are frequently encountered during SLIT whereas systemic and life-threatening adverse events under correctly performed SLIT have not been reported so far.
    Der Hautarzt 08/2011; 62(9):671-6. · 0.56 Impact Factor
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