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Keywords:

  • allergy;
  • blocked nose;
  • grass pollen;
  • rhinoconjunctivitis;
  • sublingual immunotherapy;
  • tablet-based

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Background:  Symptoms of allergic rhinitis have a considerable impact on the quality of life of the sufferer. Sneezing, runny nose, blocked nose and headache are some of the most common symptoms of allergic rhinitis, which affects work, home and social life for many patients. Sublingual immunotherapy has shown to induce a protective immune response and provide sustained symptom prevention for allergic patients.

Aims of the trial:  The overall aims were to investigate the efficacy and safety of a sublingual grass allergen tablet (Grazax® 75 000 SQ-T; ALK-Abelló A/S, Denmark). Reported here are the effects of Grazax on individual eye and nasal symptoms.

Methods:  The trial was a double-blind placebo-controlled trial including 634 participants with significant rhinoconjunctivitis because of grass pollen. Participants were randomized 1 : 1 to Grazax (a fast dissolving, once daily immunotherapy tablet for home administration) or placebo and received treatment for at least 16 weeks prior to and continuing during the grass pollen season of 2005. Four nasal symptoms and two eye symptoms were scored on a scale from 0 (no symptoms) to 3 (severe symptoms) every day during the entire grass pollen season. Nasal symptoms included runny nose, blocked nose, sneezing and itchy nose; eye symptoms included gritty feeling/red/itchy eyes and watery eyes.

Results:  Consistent and highly significant reductions in individual eye and nasal symptoms (from 22 to 44%) were observed following treatment with Grazax as compared with placebo (< 0.0001).

Conclusions:  Grazax has effects on multiple allergic symptoms, including nasal blockage, and is an effective treatment of rhinoconjunctivitis, thereby reducing the need for topical anti-allergic drugs.

An estimated 45 million people in Europe suffer from grass allergy (1). Although trivial for some, symptoms of allergic rhinitis may have a considerable impact on the quality of life of the sufferer. In a survey involving 260 allergic patients, sneezing, runny nose, blocked nose, headache, itchy and watery eyes and itchy nose were the most common symptoms of allergic rhinitis (2). The symptoms were reported to affect work (29% of cases), home (34%) and social life (30%), and symptoms were well-controlled only in 34% of patients with seasonal allergic rhinitis (2). These figures are supported by a practice-based community study in UK (3).

In trials of antihistamines and their effect on seasonal rhinoconjunctivitis symptoms, the total symptom score typically includes four individual scores: sneezing; rhinorrhea; itchy nose, palate or throat; and itchy, watery or red eyes, while nasal blockage is scored separately (4–6). A common trend is that while total symptom scores were significantly reduced after antihistamine treatment, this treatment was generally not or only moderately effective in relieving nasal blockage during natural pollen exposure (5, 7, 8). In contrast, intranasal corticosteroids are more effective than antihistamines and may also relieve nasal obstruction (9). In a recent meta-analysis of treatments for allergic rhinitis, the effect sizes for antihistamines (7%), leukotriene receptor antagonists (5%) and intranasal corticosteroids (12%) were modest as compared with placebo (10).

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

In a recent large double-blind placebo-controlled trial of the sublingual grass allergen tablet (Grazax® 75 000 SQ-T; ALK-Abelló A/S, Denmark) (11), the effect of sublingual immunotherapy on individual eye and nasal symptoms was analysed. The trial included 634 participants with significant rhinoconjunctivitis due to grass pollen. They were randomized 1 : 1 to Grazax (a fast dissolving, once daily immunotherapy tablet for home administration) or placebo and received treatment for at least 16 weeks prior to and continuing during the grass pollen season of 2005 [primary results published in (11)]. The average overall rhinoconjunctivitis symptom score was derived from individual symptom scores for four nasal symptoms and two eye symptoms during the entire grass pollen season. Nasal symptoms included runny nose, blocked nose, sneezing and itchy nose; eye symptoms included gritty feeling/red/itchy eyes and watery eyes. Each symptom was scored on a scale from 0 (no symptoms) to 3 (severe symptoms) on a daily basis during the grass pollen season and presented as an average for each participant on each day. Independent rhinoconjunctivitis medication scores were derived based on the use of trial rescue medication (Desloratadine tablets, Budesonide nasal spray, Prednisone tablets) [published in (11)].

Comparison of the two treatment groups was performed by analysis of variance with the efficacy endpoint as response variable, treatment group as a fixed effect, and pollen region as random effect. Each treatment group was adjusted for different error variation. The calculated P-values were as a result of the multiplicity issue as compared with a Bonferroni adjusted significance level (0.006) to keep the overall probability of type I error less than 5%.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

A total of 634 subjects were randomized and included in the present analysis. Grass pollen counts were obtained from 33 pollen stations in the participating countries. The grass pollen season lasted on average 57.8 days (range: 16–86 days). The average daily rhinoconjunctivitis symptom scores were presented separately as nasal and eye symptoms (Table 1). For both symptoms, the score for the actively treated group was lower than in the placebo group. A further separation of the nasal symptoms into four individual symptoms showed consistently lower symptom score for each symptom in the Grazax group as compared with placebo (Fig. 1A). A separation of the eye symptoms into two individual symptoms also showed consistently lower symptom score for each symptom in the immunotherapy group as compared with placebo (Fig. 1B). The percentage reductions relative to placebo ranged from 22 to 44% and were in all cases statistically highly significant (< 0.0001) (Table 1).

Table 1.   Effect of sublingual immunotherapy with Grazax on seasonal nose and eye symptoms
 Score in subjects receiving Grazax n = 316Score in subjects receiving placebo n = 318 Difference (%) 95% CIP-value
  1. CI, confidence interval; %, per cent difference in the Grazax group as compared with placebo. Average daily symptom scores were calculated from diary data during the entire pollen season. The comparison of the two treatment groups was performed by use of anova with average symptom score as response variable and treatment group as a fixed effect and pollen region as a random effect as well as adjusting for different error variation for each treatment group. As a result of Bonferroni adjustment for multiple comparisons, the significance level was 0.006.

Nose symptoms1.692.32−0.63 (−27%)−0.86; −0.41<0.0001
Runny nose0.420.56−0.15 (−26%)−0.21; −0.08<0.0001
Blocked nose0.360.53−0.17 (−32%)−0.24; −0.10<0.0001
Sneezing0.510.66−0.15 (−22%)−0.21; −0.08<0.0001
Itchy nose0.400.57−0.17 (−30%)−0.24; −0.11<0.0001
Eye symptoms0.651.03−0.37 (−36%)−0.49; −0.25<0.0001
Gritty eyes0.440.64−0.21 (−32%)−0.28; −0.14<0.0001
Watery eyes0.220.38−0.17 (−44%)−0.22; −0.11<0.0001
image

Figure 1.  Reductions in rhinoconjunctivitis symptoms and use of medication after treatment with Grazax previous to and during one grass pollen season. (A) Nasal and eye symptom scores; four nasal symptoms and two eye symptoms were scored on a scale from 0 (no symptoms) to 3 (severe symptoms) each day during the entire grass pollen season. The score presented is the sum of individual nasal and eye symptoms calculated as an average for each participant on each day. **: the P-value for the difference between Grazax and placebo is <0.0001. (B) The total number of participants (n) with use of rescue medication [also published in (11)].

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On top of the reduction in symptom scores, the participants in the Grazax group also used significantly less rescue medication as compared with placebo [reduction of total symptom score 38%, < 0.0001; see (11)]. The total number of participants who use different types of rescue medication is shown in Fig. 1B. The reduced score was mainly because of fewer participants using Desloratadine tablets and Budesonide nasal spray in the immunotherapy group as compared with placebo.

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Grazax is the first allergy tablet to address the underlying cause of grass pollen allergy. The tablet has been investigated in a large clinical programme involving more than 2400 grass pollen allergic patients (11–16). All trials have shown consistent results in terms of safety and efficacy.

The current analysis of separate eye and nasal symptoms, which included correction for multiple comparisons, gave consistent and highly statistically significant results. The observed effect sizes for Grazax over placebo compare favourably with those observed in recent placebo-controlled trials with the antihistamines Cetirizine (10 mg), Levocetirizine (5.0 mg) and Fexofenadine (120 or 180 mg) which showed effect sizes of 12–26% as compared with placebo (4–6, 8). However, while the symptom scores for antihistamines in most trials did not include nasal blockage, Grazax has proven to reduce this symptom by 32%. Furthermore, antihistamines only reduce symptoms with relapse within days when discontinued. There appears to be a contribution of H1, H2 and H3 receptors to histamine-induced nasal blockage in normal human subjects, which may explain why single antihistamines have a limited effect on relieving nasal blockage (17).

The decrease in rhinoconjunctivitis symptom scores for Grazax-treated patients that occurred in parallel with a marked reduction in their requirement for rescue medication provides additional evidence for the efficacy of sublingual immunotherapy over and above usual pharmacotherapy for rhinitis.

The quality of life of the patients is an important component of the efficacy of hay fever medication. When asked the participants in this trial how they felt overall in the treatment season as compared with previous seasons, 49% more than in the immunotherapy group relative to the placebo group responded that they felt better or much better (11), which implies that their quality of life in the treatment season was better than previously.

Whether sublingual immunotherapy, like subcutaneous immunotherapy (18), has the potential to produce long-term remission is currently being investigated in a prolonged and double-blinded, placebo-controlled extension of the current trial over a 5-year period.

In conclusion, Grazax has effects on multiple allergic symptoms, including nasal blockage, and is effective in the treatment of rhinoconjunctivitis, thereby reducing the need for topical anti-allergic drugs.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The trial was sponsored by ALK-Abelló A/S, Denmark. We thank the GT-08 study group and participating investigators (W. Aberer, M. Andersson, J. Arnved, M. Augustin, V. Backer, C. Baumgarten, A. Bentley, C. Bindslev-Jensen, G. Cadario, M. Calderon, R. Cantone, L. -O. Cardell, T. Chivato, G. Colombo, R. Dahl, S. R. Durham, W. Emminger, P. Ewan, A. Fay, M. Fernández Rivas, W. J. Fokkens, A. Frew, L. Frølund, G. Gazzola, M. Grove, J. Hald, H. Harving, B. Hauswald, W. Heppt, A. Huissoon, A. P. H. Jansen, A. Kapp, J. Kleine-Tebbe, P. Lange, B. Lassen Brandelev, G. Marcer, C. Martinez Cócera, J. G. R. de Monchy, C. M. G. Nieuwhof, N. Novak, R. J. Powell, R. K. Rajakulasingam, S. Rak, G. Rasp, H. Riechelmann, N. Reider, G. Scadding, G. Senna, F. W. J. M. Smeenk, A. Stewart, M. Worm and O. Zetterström).

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
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