Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper.

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.

Mind the gaps: Clinical trial concepts to address unanswered questions in aeroallergen immunotherapy-An NIAID/AHRQ Workshop.

The Agency for Healthcare Research and Quality and the National Institute of Allergy and Infectious Diseases organized a workshop to develop trial concepts that could improve the use and effectiveness of aeroallergen immunotherapy (AAIT). Expert groups were formed to accomplish the following tasks: (1) propose a study design to compare the effectiveness and safety of subcutaneous versus sublingual AAIT; (2) propose a study design to compare the effectiveness and safety of AAIT by using 1 or a few allergens versus all or most allergens to which a patient is sensitized; (3) propose a study design to determine whether AAIT can alter the progression of childhood allergic airways disease; and (4) propose a study design to determine the optimal dose and duration of AAIT to achieve maximal effectiveness with acceptable safety. Study designs were presented by the workgroups, extensively discussed at the workshop, and revised for this report. The proposed trials would be of long duration and require large highly characterized patient populations. Scientific caveats and feasibility matters are discussed. These concepts are intended to help the development of clinical trials that can address some of the major questions related to the practice of AAIT for the management and prevention of allergic airways disease.

Treatment effect of sublingual immunotherapy tablets and pharmacotherapies for seasonal and perennial allergic rhinitis: Pooled analyses.

BACKGROUND: Data comparing the treatment effect of allergy immunotherapy and pharmacotherapy are lacking. OBJECTIVE: We sought to indirectly compare the treatment effect of sublingual immunotherapy (SLIT)-tablets with pharmacotherapy for seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). METHODS: Pooled data from randomized, double-blind, placebo-controlled trials for the clinical development programs of selected allergic rhinitis treatments were evaluated. Total nasal symptom scores (TNSSs) relative to placebo were compared. Subjects scored symptoms daily during entire pollen seasons in 6 timothy grass SLIT-tablet trials (n = 3094) and 2 ragweed SLIT-tablet trials (n = 658) and during the last 8 weeks of treatment in 2 house dust mite (HDM) SLIT-tablet trials (n = 1768). Subjects scored symptoms daily in 7 montelukast (10 mg, n = 6799), 9 desloratadine (5 mg, n = 4455), and 8 mometasone furoate nasal spray (MFNS; 200 µg daily, n = 2140) SAR or PAR trials. SLIT-tablet trials allowed rescue medication use, whereas most pharmacotherapy trials did not. A fixed-effect meta-analysis method estimated differences in on-treatment average TNSSs. RESULTS: In grass and ragweed SLIT-tablet trials, overall improvement in TNSSs relative to placebo was 16.3% and 17.1%, respectively. In HDM SLIT-tablet trials, TNSS overall improvement relative to placebo was 16.1%. In the montelukast, desloratadine, and MFNS trials, TNSS overall improvement relative to placebo was 5.4%, 8.5%, and 22.2%, respectively, for SAR trials, and 3.7%, 4.8%, and 11.2%, respectively, for PAR trials. CONCLUSIONS: Although comparisons were limited by study design heterogeneity and use of rescue medications in SLIT-tablet trials, effects on nasal symptoms with timothy grass and ragweed SLIT-tablets were nearly as great as with MFNS and numerically greater than with montelukast and desloratadine for SAR. HDM SLIT-tablet effects were numerically greater than all pharmacotherapies for PAR. SLIT-tablets offer the additional benefit of long-term efficacy.

Randomized, double-blind, placebo-controlled trial of standardized ragweed sublingual-liquid immunotherapy for allergic rhinoconjunctivitis.

BACKGROUND: Sublingual immunotherapy with liquid extracts provides an appealing alternative to subcutaneous immunotherapy for the treatment of allergic rhinoconjunctivitis (ARC), but a lack of robust evidence has deterred its use in North America. OBJECTIVE: To determine the efficacy and tolerability of standardized glycerinated short ragweed sublingual allergen immunotherapy liquid (RW-SAIL) extract in subjects with ragweed-related ARC. METHODS: This phase 3, randomized, placebo-controlled trial was conducted in North America. Subjects (age range, 18-55 years) with or without asthma were selected based on ARC symptom severity and erythema skin prick reaction to short ragweed. Subjects self-administered the maximum tolerated dose of RW-SAIL (n = 218) or placebo (n = 211) daily beginning approximately 8 to 16 weeks before and through the end of the ragweed pollen season. The primary end point was subject-assessed total combined daily rhinoconjunctivitis symptom and medication scores (TCS). RESULTS: During the entire season, there was a 43% decrease in TCS in subjects treated with RW-SAIL compared with placebo. Similar decreases were observed in TCS between the 2 groups during peak season (42%) and in daily symptom scores during the entire (42%) and peak (41%) seasons. The occurrence of adverse events was similar between the treatment groups; most were mild in severity. Treatment-related oromucosal local application site reactions occurred early and were transient and self-limited. No anaphylaxis occurred. CONCLUSIONS: This is the first successful North American confirmatory phase 3 clinical trial to demonstrate the safety and efficacy of a sublingual standardized ragweed allergen immunotherapy liquid extract for the treatment of ARC.

Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults.

BACKGROUND: In North America and Europe, millions of patients experience symptoms of allergic rhinitis with or without conjunctivitis (AR/C) on exposure to ragweed pollen. The disease burden can be significant, with most patients relying on symptomatic medications without disease-modifying potential. However, novel sublingual immunomodulatory treatment options may potentially play an important role if efficacy and side effect profiles allow the convenience of self-administration. OBJECTIVES: This study evaluated an allergy immunotherapy tablet (AIT; SCH 39641/MK-3641) for treatment of ragweed-induced AR/C in the first large randomized, double-blind multinational trial of this therapeutic modality for ragweed allergy. METHODS: Adults (n = 784) with short ragweed-induced AR/C were randomly assigned to approximately 52 weeks of daily self-administered ragweed AIT of 1.5, 6, or 12 units of Ambrosia artemisiifolia major allergen 1 (Amb a 1-U) or placebo. Subjects could use as-needed allergy rescue medication. Symptoms and medications were recorded daily. The primary efficacy end point was total combined daily symptom/medication score (TCS) during peak ragweed season. Safety was monitored through adverse event diaries maintained through study duration. RESULTS: During peak ragweed season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 9% (-0.76; P = .22), 19% (-1.58; P = .01), and 24% (-2.04; P = .002) compared with placebo. During the entire season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 12% (-0.88; P = .09), 18% (-1.28; P = .01), and 27% (-1.92; P < .001) compared with placebo. Treatment was well tolerated; no systemic allergic reactions occurred. CONCLUSIONS: In this trial, ragweed AIT of 12 Amb a 1-U was effective and tolerable with a safety profile that permitted daily self-administration of ragweed allergen immunotherapy.

Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE.

BACKGROUND: Previous trials have demonstrated the efficacy, safety, and optimal dosage of the 5-grass pollen sublingual tablet for adults and children with grass pollen-induced allergic rhinoconjunctivitis. OBJECTIVES: We sought to evaluate the efficacy and safety of 300 index of reactivity (IR) 5-grass pollen sublingual tablet in US adults. METHODS: Adults with grass pollen allergy and Rhinoconjunctivitis Total Symptom Scores of 12 or greater (scale, 0-18) during the previous grass pollen season were randomized in a double-blind, placebo-controlled study to receive 300IR 5-grass pollen sublingual tablet or placebo starting 4 months before and continuing through the pollen season. The primary efficacy end point was the daily Combined Score (CS; scale, 0-3), which integrates symptoms and rescue medication use. RESULTS: Four hundred seventy-three participants were randomized. The mean daily CS over the pollen period was significantly lower in the active treatment group versus the placebo group (least-squares mean difference: -0.13; 95% CI, -0.19 to -0.06; P = .0003; relative reduction: 28.2%; 95% CI, 13.0% to 43.4%). In placebo-treated participants, the daily CS least-squares mean was 0.32 in the subgroup with baseline timothy grass-specific serum IgE of less than 0.1 kU/L (n = 23) and 0.46 in those with baseline timothy grass-specific serum IgE of 0.1 kU/L or greater (n = 204). The most frequent reported adverse events were oral pruritus, throat irritation, and nasopharyngitis. There were no reports of anaphylaxis, and no actively treated participant received epinephrine. CONCLUSION: In US adults with grass pollen-induced allergic rhinoconjunctivitis, preseasonal and coseasonal treatment with 300IR 5-grass pollen sublingual tablet demonstrated clinically meaningful efficacy, especially in study subjects with measurable timothy grass-specific serum IgE. Use of 300IR 5-grass pollen sublingual tablet was safe and well tolerated. A requirement for a measurable level of allergen-specific serum IgE should be considered in future studies in this field.

One Hundred Ten Years of Allergen Immunotherapy: A Broad Look Into the Future.

Allergen immunotherapy (AIT) is the only disease-modifying treatment option for patients with type 1-mediated allergic diseases such as allergic rhinitis/rhinoconjunctivitis with/without allergic asthma. Although many innovations have been developed since the first clinical report of Noon et al in 1911, the improvement of clinical efficacy and tolerability of this treatment is still an important unmet need. Hence, much progress has been made in the characterization of the cell types, cytokines, and intracellular signaling events involved in the development, maintenance, and regulation of allergic reactions, and also in the understanding of the mechanisms of tolerance induction in AIT. This comprehensive review aims to summarize the current innovative approaches in AIT, but also gives an outlook on promising candidates of the future. On the basis of an extensive literature review, integrating a clinical point of view, this article focuses on recent and future innovations regarding biologicals, allergen-derived peptides, recombinant allergens, "Toll"-like receptor agonists and other adjuvants, and novel application routes being developed for future AIT.

Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.

BACKGROUND: Conjugating immunostimulatory sequences of DNA to specific allergens offers a new approach to allergen immunotherapy that reduces acute allergic responses. METHODS: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of a vaccine consisting of Amb a 1, a ragweed-pollen antigen, conjugated to a phosphorothioate oligodeoxyribonucleotide immunostimulatory sequence of DNA (AIC) in 25 adults who were allergic to ragweed. Patients received six weekly injections of the AIC or placebo vaccine before the first ragweed season and were monitored during the next two ragweed seasons. RESULTS: There was no pattern of vaccine-associated systemic reactions or clinically significant laboratory abnormalities. AIC did not alter the primary end point, the vascular permeability response (measured by the albumin level in nasal-lavage fluid) to nasal provocation. During the first ragweed season, the AIC group had better peak-season rhinitis scores on the visual-analogue scale (P=0.006), peak-season daily nasal symptom diary scores (P=0.02), and midseason overall quality-of-life scores (P=0.05) than the placebo group. AIC induced a transient increase in Amb a 1-specific IgG antibody but suppressed the seasonal increase in Amb a 1-specific IgE antibody. A reduction in the number of interleukin-4-positive basophils in AIC-treated patients correlated with lower rhinitis visual-analogue scores (r=0.49, P=0.03). Clinical benefits of AIC were again observed in the subsequent ragweed season, with improvements over placebo in peak-season rhinitis visual-analogue scores (P=0.02) and peak-season daily nasal symptom diary scores (P=0.02). The seasonal specific IgE antibody response was again suppressed, with no significant change in IgE antibody titer during the ragweed season (P=0.19). CONCLUSIONS: In this pilot study, a 6-week regimen of the AIC vaccine appeared to offer long-term clinical efficacy in the treatment of ragweed allergic rhinitis. (ClinicalTrials.gov number, NCT00346086 [ClinicalTrials.gov] .).

Coseasonal Initiation of Allergen Immunotherapy: A Systematic Review.

BACKGROUND: It is unclear whether allergen immunotherapy (AIT) can be safely initiated during the pollen season (coseasonal initiation [CSI]) because of a potential increased risk of systemic allergic reactions. OBJECTIVE: To systematically review publications reporting the safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) CSI to validate or invalidate the perception of increased safety risk. METHODS: PubMed, EMBASE, Ovid, Literatura Latino Americana em Ciências da Saúde (LILACS), and Cochrane Library databases were searched without limits for studies of any design reporting SCIT or SLIT CSI for pollen allergen. Congress abstracts were included. RESULTS: Nineteen eligible studies were identified: 8 SCIT (n = 947 subjects total; n = 340 double-blind placebo-controlled [DBPC]) and 11 SLIT (n = 2668 subjects total; n = 565 DBPC). Study characteristics and safety reporting were heterogeneous. No epinephrine administrations were reported. Discontinuation frequencies were 6% or less and 10% or less with SCIT and SLIT CSI, respectively. In SCIT studies, systemic allergic reaction frequency was 0% to 7% with "up to peak season" or CSI, 0% to 6% with "after peak season" or out-of-season initiation, and 0% to 7% with placebo. In SCIT studies, serious treatment-related adverse event (AE) frequency with CSI ranged from 0% to 2%; few severe AEs were reported. In SLIT studies, systemic allergic reaction frequency ranged from 0% to 4% with CSI, 0% with out-of-season initiation, and 0% to 2% with placebo. Overall, 2 serious treatment-related AEs with SLIT CSI were reported. Severe AE frequency in SLIT studies ranged from 0% to 8% with CSI, 0% to 12% with out-of-season initiation, and 0% to 8% with placebo. CONCLUSIONS: No increase in AEs of concern was observed with SCIT or SLIT CSI; however, additional data with standardized regimens and doses are needed.

Treatment options for initial maintenance therapy of persistent asthma: a review of inhaled corticosteroids and leukotriene receptor antagonists.

Inhaled corticosteroids (ICSs) are recognized as the cornerstone of asthma therapy. They are considered to be the most effective anti-inflammatory medication currently available for the treatment of persistent asthma, regardless of its severity. Leukotriene receptor antagonists (LTRAs) are also used as initial maintenance therapy in patients whose asthma is uncontrolled by bronchodilators alone. There are now sufficient data available to allow a comparison of the relative effectiveness and cost-effectiveness of LTRAs and ICSs as initial maintenance therapy. The consensus from the studies reviewed in this article demonstrates that ICSs are more effective than LTRAs as initial maintenance therapy. In particular, studies on fluticasone propionate have shown that it was more effective than LTRAs in clinical outcomes: producing greater improvements in lung function and asthma control; as measured by either forced expiratory volume in 1 second (FEV1) or peak expiratory flow (PEF); by a greater reduction in daytime and night-time asthma symptoms; and short-acting beta2-agonist use. This superiority was also seen when patients were switched from an LTRA to fluticasone propionate. Similar findings have been demonstrated with beclomethasone dipropionate (BDP), showing that, in adults, this inhaled steroid also had a greater effect on pulmonary function and symptom scores than did LTRAs. Quality of life assessments showed that fluticasone propionate achieved improvements that were deemed to be clinically meaningful; these changes were significantly greater than those achieved with LTRAs. However, questionnaire-based patient preference studies comparing BDP with LTRAs showed that children and adolescents generally preferred an LTRA to BDP. A number of comparative analyses showed that inhaled fluticasone propionate is more cost-effective than either montelukast or zafirlukast; these analyses used cost per symptom-free day and cost per successfully treated patient as outcome measures, from the perspective of a third-party payer. In general, these results were supported by resource utilisation studies in real-world settings. Asthma treatment guidelines (e.g. GINA, 2002) recommend combination therapy with ICSs and a long-acting beta2-agonist as initial maintenance therapy if the disease is of sufficient severity. Studies that assessed the effectiveness, cost-effectiveness, and quality of life achieved with a salmeterol fluticasone propionate combination as initial maintenance therapy also showed it to be superior to LTRAs. In conclusion, in terms of efficacy and quality of life, fluticasone propionate is more effective than LTRAs as initial maintenance therapy and is associated with significantly lower healthcare costs and less frequent use of healthcare resources than LTRAs. There is also evidence to suggest that initial maintenance therapy with the combination of an inhaled steroid plus a long-acting beta-agonist bronchodilator may be a more effective option for the management of persistent asthma than treatment with a single-controller agent alone (ICS or LTRA).

Immunotherapy of Allergic Disorders: Traditional and Novel Approaches.

For approaches to the immunotherapy of allergic respiratory diseases now under study at Johns Hopkins are reviewed. Traditional high dose parenteral immunization with mixtures of allergens corresponding to patients' allergic sensitivities is being evaluated in the long-term management of allergic asthma in children. Oral desensitization employing doses of short ragweed extract 100 fold higher than for parenteral therapy has been proven safe and efficacious and is now being modified to render it practicable. Intradermal injections of autologous IgG immune complexes with D. pteronyssinus antigens has been reported to improve symptoms and reduce IgE synthesis; a trial to replicate these findings is underway. Immunization with immunodominant peptides from Fel d. I is also under development as a novel immunoregulatory intervention with potential clinical application.

Progress in the development of new methods of immunotherapy: potential application of immunostimulatory DNA-conjugated to allergens for treatment of allergic respiratory conditions.

Allergen immunotherapy was first introduced in the early part of the twentieth century. It is widely practiced despite having specific limitations. Considerable effort has been devoted to developing new modified allergens that, compared with conventional allergen immunotherapy, improve efficacy, decrease the time required to achieve effect, reduce inconvenience, and enhance safety. Increased understanding of allergic respiratory inflammation has led to the development of therapeutic modalities that potentially arrest the disease process in asthma or allergic rhinitis. This paper addresses an adjuvant approach in which highly active immunostimulatory phosphorothioate oligodeoxyribonucleotide sequence (i.e. immunostimulatory DNA) are conjugated to the principal allergenic moiety of a relevant aeroallergen. We have recently completed the first human safety studies in patients with allergic rhinitis with Amb a 1-immuno-stimulatory oligonucleotide conjugate (AIC) --a novel therapeutic vaccine comprised of Amb a 1, the principal allergenic protein of ragweed, conjugated specific immunostimulatory oligonucleotides (ISS). The results demonstrate that AIC was several hundred-fold less reactive than a standardized ragweed extract when evaluated by quantitative intradermal skin titration methodology. Furthermore, AIC reduced histamine release from basophils to a similar degree. The DNA vaccine induced IgG antibody production in treated patients. AIC compared with standardized aqueous ragwood exhibited fewer local reactions on skin testing, a finding that suggests that AIC offers the potential for an improved safety profile for immunotherapy. Additional trials to further evaluate the safety, immunologic effect, and therapeutic efficacy of AIC for ragwood-induced allergic rhinitis and asthma are ongoing.

IFN-alpha inhibits IL-3 priming of human basophil cytokine secretion but not leukotriene C4 and histamine release.

BACKGROUND: Innate immune responses play a critical role in determining the course of acquired immunity, including that associated with allergic disease. Type I interferons, which are generated early in these reactions, are important soluble factors that prime for TH1-like activity. OBJECTIVE: Because human basophils secrete IL-4 and IL-13 in response to both IgE-dependent and IgE-independent stimuli, we tested whether IFN-alpha, a major type I IFN, affects the production of these TH2 cytokines and/or mediator release from these cells. METHODS: Basophils isolated from blood were treated with IFN-alpha in the presence and absence of IL-3 priming before stimulating through the IgE receptor to release histamine, leukotriene C4, and IL-4. Effects of IFN-alpha on IL-3-mediated IL-13 secretion and basophil survival were also tested. IFN-alpha receptor expression was determined by RT-PCR. RESULTS: IFN-alpha specifically inhibited the effects IL-3 has on basophil cytokine secretion. Enhanced secretion of IL-4 resulting from IL-3 priming was significantly inhibited in cells concurrently cultured with IFN-alpha. This effect was specific for cytokine generation, because histamine and leukotriene C4 were unaffected. Furthermore, IFN-alpha blocked IL-13 secretion directly induced by IL-3. Although IFN-beta also possessed some inhibitory activity, IFN-gamma (a type II IFN) had no effect on basophil cytokine secretion. Basophils constitutively expressed mRNA for the type I IFN receptor, and IFN-alpha did not affect basophil viability with regard to inhibition of cytokine secretion. CONCLUSIONS: These results support the belief that early innate immune responses resulting in IFN-alpha production negatively regulate allergic responses by also inhibiting priming of basophil cytokine release.

A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered- dose inhalers.

BACKGROUND: With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation. OBJECTIVE: In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED(50), the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations. METHODS: On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 microg by using specially manufactured MDI canisters. FEV(1) was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV(1) was measured after each methacholine dose until a 20 % decrease in FEV(1) (PD(20)) was achieved. RESULTS: Mean PD(20) values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD(20) values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 microg) of albuterol MDI were within the sensitive region of the dose- response curve. The mean estimated ED(50) value on the basis of nonlinear mixed effect modeling was 119.2 microg (range, 33.3-337.1 microg), with an intersubject percentage coefficient of variation of 69.0 %. CONCLUSIONS: The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products.