René Zieglmayer

Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber

BACKGROUND The efficacy and safety of a 5-grass-pollen sublingual immunotherapy (SLIT) tablet (Stallergènes SA, Antony, France) have been evaluated in clinical studies during the pollen season. The allergen challenge chamber (ACC) has been developed as a pharmacodynamic assessment tool to control the environmental allergens and to avoid all problems associated with unpredictable pollen seasons. OBJECTIVE We sought to evaluate the onset of action and efficacy of 300-IR (index of reactivity) SLIT tablets by using an ACC. METHODS Patients with grass pollen-induced rhinoconjunctivitis were randomized into the active or placebo groups. A standardized allergen challenge with grass pollen and symptom evaluation every 15 minutes was performed at baseline, 1 week, and 1, 2, and 4 months of treatment. The primary end point was the average rhinoconjunctivitis total symptom score (ARTSS). Allergen-specific basophil activation, T-cell proliferation, and plasmatic IgE and IgG responses were assessed before and after treatment. RESULTS In the intention-to-treat population (n = 89) a significant treatment effect was achieved after the first month (P = .0042) and second month (P = .0203) and was maintained through to the fourth month (P = .0007). In the active group the ARTSS (means +/- SDs) decreased at each challenge: week 1, 7.40 +/- 2.682; month 1, 5.89 +/- 2.431; month 2, 5.09 +/- 2.088; and month 4, 4.85 +/- 1.999. An improvement (vs placebo) of 29.3% for the mean ARTSS (median, 33.3%) was observed at end point. Furthermore, the induction of grass pollen allergen-specific IgGs was associated with clinical response. The most frequent adverse reactions were local: oral pruritus, ear pruritus, and throat irritation. CONCLUSIONS In this ACC study the 300-IR 5-grass-pollen SLIT tablets had a significant effect on rhinoconjunctivitis symptoms (vs placebo) from the first month of treatment onward.

Azelastine nasal spray and desloratadine tablets in pollen-induced seasonal allergic rhinitis: a pharmacodynamic study of onset of action and efficacy

ABSTRACT Objective: To assess the efficacy and onset of action of azelastine nasal spray and desloratadine tablets in patients with allergen-induced seasonal allergic rhinitis (SAR). Research design and methods: 46 adult patients with a history of SAR were exposed to a controlled grass pollen concentration for 6 h in the Vienna Challenge Chamber (VCC) in each treatment period according to a randomised, double-blind (double-dummy), three-period, three-sequence crossover design (wash-out period of 12 days). Single doses of study medication (one puff nasal spray into each nostril of azelastine, 0.28 mg, or placebo before swallowing one encapsulated tablet of desloratadine, 5 mg) were administered 2 h after the start of the allergen challenge. Results of subjective and objective assessments were recorded throughout the challenge. Results: Efficacy of azelastine nasal spray was significantly superior compared to desloratadine tablets ( p = 0.005) and placebo ( p < 0.001). Desloratadine was significantly better than placebo ( p < 0.001). Decrease both in Major Nasal Symptom Score (MNSS) and in Total Nasal Symptom Score (TNSS) was fastest after azelastine treatment. Improvement of nasal symptom severity was most pronounced after azelastine treatment for all nasal symptoms including nasal congestion. Onset of action was 15 min for azelastine compared to 150 min for desloratadine. Both active preparations were safe and well tolerated. Conclusions: This study confirms the usefulness of azelastine nasal spray for the symptomatic treatment of seasonal allergic rhinitis. Concerning onset of action in particular, the results favour the topical treatment over systemic therapy.

Effects of rupatadine vs placebo on allergen-induced symptoms in patients exposed to aeroallergens in the Vienna Challenge Chamber

BACKGROUND Rupatadine is a novel compound with potent dual antihistamine and platelet-activating factor antagonist activities and no sedative effects. OBJECTIVE To evaluate the efficacy of rupatadine, 10 mg once daily, and placebo on allergen-induced symptoms (including nasal congestion), nasal airflow, nasal secretion, and subjective tolerability in response to grass pollen in a controlled allergen-exposure chamber. METHODS In a randomized, double-blind, placebo-controlled, crossover trial, 45 patients with a history of seasonal allergic rhinitis received rupatadine or placebo every morning for 8 days in 2 different periods separated by a 14-day washout interval. On day 8 of each crossover period, patients underwent a 6-hour allergen exposure in the Vienna Challenge Chamber, where a constant and homogeneous concentration of aeroallergens was maintained. Subjective and objective assessments were performed online during the exposure. RESULTS Subjective single and composite nasal and nonnasal symptoms were consistently less severe with rupatadine use than with placebo use starting from the first evaluation at 15 minutes to the end of the 6-hour Vienna Challenge Chamber challenge, with the most significant effects seen for nasal rhinorrhea, nasal itching, sneezing attacks, and total nasal symptoms (P < .001 for all). All the other symptoms (including nasal congestion, P < or = .005) were also significantly reduced with active treatment compared with placebo use. Mean secretion weights and overall feeling of complaint were significantly lower with rupatadine therapy than with placebo use (P < or = .001). Overall, rupatadine treatment was well tolerated. CONCLUSION Rupatadine treatment is effective and well tolerated in patients with allergen-induced symptoms exposed to aeroallergens in a controlled exposure chamber.

A direct comparison of the efficacy of antihistamines in SAR and PAR: randomised, placebo-controlled studies with levocetirizine and loratadine using an environmental exposure unit - the Vienna Challenge Chamber (VCC).

SUMMARY Objective: The Vienna Challenge Chamber (VCC) is an established method for the controlled exposure of patients to specific allergens, used to make valid comparisons between antihistamines. The aim of the two placebo-controlled, randomised studies reported here was to compare the efficacy and safety of levocetirizine 5 mg od and loratadine 10 mg od in subjects suffering from seasonal allergic rhinitis (SAR) or perennial allergic rhinitis (PAR). Subjects and methods: During each study period, SAR and PAR subjects were exposed to grass pollen or house-dust mite allergens, respectively for 6 h on 2 consecutive days in the VCC. Each day, medications were administered 2 h after the start of the challenge; with a washout of at least 5 days between each period. The main criterion for evaluation of efficacy was the major symptom complex (MSC) for SAR and the complex symptom score (CSS) for PAR. Results: The pattern of patients’ response was similar in SAR and PAR. Both levocetirizine and loratadine were superior to placebo in alleviating SAR and PAR symptoms at all time intervals evaluated during the two study days. Levocetirizine decreased the mean MSC score significantly more than loratadine at all time intervals in SAR subjects, with the most marked difference observed on day 2 ( p = 0.002). In PAR patients, although with borderline significance ( p = 0.08), levocetirizine decreased the mean CSS more than loratadine. Levocetirizine appeared to have a faster onset of action than loratadine in SAR (45 min versus 1 h 15 min) and PAR (1 h versus 1 h 30 min). However, these apparent differences were not tested for statistical significance. Both medications were well tolerated and no treatment-related adverse events were reported. This level of antihistamine efficacy was maintained regardless of whether the subjects’ rhinitis was seasonal or perennial. Conclusion: This study demonstrated that levocetirizine is superior to loratadine in improving symptoms in SAR and that there is a similar trend in PAR.

Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy

Background We have developed a recombinant B cell epitope-based vaccine (BM32) for allergen-specific immunotherapy (AIT) of grass pollen allergy. The vaccine contains recombinant fusion proteins consisting of allergen-derived peptides and the hepatitis B surface protein domain preS as immunological carrier. Methods We conducted a randomized, double-blind, placebo-controlled AIT study to determine safety, clinical efficacy and immunological mechanism of three subcutaneous injections of three BM32 doses adsorbed to aluminum hydroxide versus aluminum hydroxide (placebo) applied monthly to grass pollen allergic patients (n = 70). Primary efficacy endpoint was the difference in total nasal symptom score (TNSS) through grass pollen chamber exposure before treatment and 4 weeks after the last injection. Secondary clinical endpoints were total ocular symptom score (TOSS) and allergen-specific skin response evaluated by titrated skin prick testing (SPT) at the same time points. Treatment-related side effects were evaluated as safety endpoints. Changes in allergen-specific antibody, cellular and cytokine responses were measured in patients before and after treatment. Results Sixty-eight patients completed the trial. TNSS significantly decreased with mean changes of − 1.41 (BM32/20 μg) (P = 0.03) and − 1.34 (BM32/40 μg) (P = 0.003) whereas mean changes in the BM32/10 μg and placebo group were not significant. TOSS and SPT reactions showed a dose-dependent decrease. No systemic immediate type side effects were observed. Only few grade 1 systemic late phase reactions occurred in BM32 treated patients. The number of local injection site reactions was similar in actively and placebo-treated patients. BM32 induced highly significant allergen-specific IgG responses (P < 0.0001) but no allergen-specific IgE. Allergen-induced basophil activation was reduced in BM32 treated patients and addition of therapy-induced IgG significantly suppressed T cell activation (P = 0.0063). Conclusion The B cell epitope-based recombinant grass pollen allergy vaccine BM32 is well tolerated and few doses are sufficient to suppress immediate allergic reactions as well as allergen-specific T cell responses via a selective induction of allergen-specific IgG antibodies. (ClinicalTrials.gov number, NCT01445002.)

Changes in basophil activation during grass‐pollen sublingual immunotherapy do not correlate with clinical efficacy

To cite this article: Van Overtvelt L, Baron‐Bodo V, Horiot S, Moussu H, Ricarte C, Horak F, Zieglmayer P, Zieglmayer R, Montagut A, Galvain S, de Beaumont O, Le Gall M, Moingeon P. Changes in basophil activation during grass‐pollen sublingual immunotherapy do not correlate with clinical efficacy. Allergy 2011; 66: 1530–1537.

A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber.

BACKGROUND Studies on the efficacy of phenylephrine in the treatment of nasal congestion have yielded inconsistent results, notwithstanding its approval for this indication. OBJECTIVE To evaluate and compare the decongestant effect of a single dose of phenylephrine to placebo and pseudoephedrine in patients with seasonal allergic rhinitis. METHODS This randomized, placebo-controlled, 3-way crossover study evaluated patient-scored nasal congestion, peak nasal inspiratory flow, and rhinomanometry at more than 6 hours in 39 grass-sensitive patients exposed to grass pollen in the Vienna Challenge Chamber. Patients were dosed with immediate-release formulations of phenylephrine, 12 mg, pseudoephedrine, 60 mg, as a control, or placebo. RESULTS Phenylephrine was not significantly different from placebo in the primary end point, mean change in nasal congestion score at more than 6 hours (P = .56), whereas pseudoephedrine was significantly more effective than both placebo (P < .01) and phenylephrine (P = .01). Phase 1 results showed a difference between phenylephrine and placebo that was 64% of the difference between pseudoephedrine and placebo, substantially greater than the 17% difference observed for all phases. Carryover bias due to patient recall of the pseudoephedrine effect may have influenced these results. Rhinomanometry and peak nasal inspiratory flow results were consistent with these data. Neither phenylephrine nor pseudoephedrine had an effect on the nonnasal symptoms. No adverse events were reported in this study. CONCLUSIONS During a 6-hour observation period, a single dose of pseudoephedrine but not phenylephrine resulted in significant improvement in measures of nasal congestion. Neither phenylephrine nor pseudoephedrine had an effect on nonnasal symptoms.

Fluticasone furoate versus placebo in symptoms of grass-pollen allergic rhinitis induced by exposure in the Vienna Challenge Chamber

ABSTRACT Objective: The Vienna Challenge Chamber (VCC) offers a controlled and controllable paradigm in which to reproducibly evaluate the efficacy of anti-allergic treatment. The aim of this study was to assess the efficacy of the novel intranasal corticosteroid fluticasone furoate (FF) in the VCC. Methods: The single-centre, randomised, double-blind, placebo-controlled, two-period crossover study was conducted in 59 adult males with grass pollen allergic rhinitis (AR). Patients received either Fluticasone furoate 200 mcg once-daily, or placebo intranasally for 8 days. AR symptoms were induced during 4-hour allergen challenges with grass pollen in the VCC at the end of each 8-day treatment period. A first challenge was conducted at 1–5 hours post-dose, followed by a second challenge at 22–26 hours post-dose. The primary endpoint was total nasal symptom score (TNSS; sum of itch, sneeze, rhinorrhoea, obstruction symptoms assessed on a categorical scale of 0–3) weighted mean over 2–5 hours post-dose. Secondary endpoints included: TNSS weighted mean over 23–26 hours post-dose and global symptom score, eye symptom score, nasal secretions and nasal airflow weighted means over 2–5 and 23–26 hours post-dose. Results: Fluticasone furoate showed consistent attenuation of AR symptoms in both the early and late challenges. Compared with placebo, weighted mean of TNSS was reduced on average by 4.14 point-scores at 2–5 hours post-dose and 3.63 point scores at 23–26 hours post-dose. These positive effects were also seen across all secondary endpoints. Conclusion: An 8-day treatment course of intranasal FF 200 mcg given once-daily statistically significantly reduced symptoms of AR including associated eye symptoms. Statistical significance was declared where the relevant two-sided 95 % confidence interval did not contain zero. This positive effect was sustained over 24 hours suggesting that fluticasone furoate could be efficacious as a once daily steroid.

The effects of a TRPV1 antagonist, SB-705498, in the treatment of seasonal allergic rhinitis.

BACKGROUND Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 μg (FP), FP 200 μg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Onset and duration of action of ketotifen 0.025% and emedastine 0.05% in seasonal allergic conjunctivitis : efficacy after repeated pollen challenges in the vienna challenge chamber.

AbstractObjective: To compare the efficacy, onset and duration of action, and the safety of ketotifen fumarate 0.025% ophthalmic solution and emedastine difumarate 0.05% ophthalmic solution in subjects with seasonal allergic conjunctivitis (SAC) induced by allergen exposure, using the Vienna Challenge Chamber model. Design and setting: This was a double-masked, randomised, comparative, crossover study conducted at an allergy outpatient clinic in Austria. Study participants: Subjects with an allergy to grass pollen were exposed to the allergen in a pollen chamber for 4 hours, followed by a 3-hour break and then a second exposure for 3 hours. Interventions: Study participants were randomised to a treatment sequence (ketotifen followed by emedastine or emedastine followed by ketotifen), receiving 1 drop per eye of ketotifen or emedastine 2 hours after the initial allergen exposure in the pollen chamber. Outcomes: Individual and composite ocular, individual and composite nasal, and total (ocular + nasal) symptom complex scores were determined by repeated exposure to allergen 0–2 hours and 5–8 hours after dosing. Onset of action was defined as the time to the first observation of a 20% reduction from baseline in the composite ocular symptom score. Results: All 37 subjects enrolled completed the study. The median time to onset of action was 15 minutes for ketotifen and 30 minutes for emedastine. This difference was significant using the generalised linear model (p = 0.048), but not for the log-rank test analysis. In the initial 2 hours post dose, ketotifen provided significantly greater relief of both composite ocular symptoms (p = 0.026) and total symptom complex (p = 0.014). Both medications were effective in reducing symptoms 5 to 8 hours after dosing. No adverse events were reported for either treatment. Conclusions: In the Vienna Challenge Chamber model, ketotifen and emedastine both effectively alleviated ocular symptoms of SAC after single-dose administration. Ketotifen had a faster onset of action and provided better symptom relief than emedastine during the first 2 hours after dosing. The rapid onset of action and symptom control make ketotifen a valuable treatment for SAC.