300IR 5-Grass pollen sublingual tablet offers relief from nasal symptoms in patients with allergic rhinitis Elie Serrano, M.D.,1 Hans Ulrich Wahn, M.D.,2 Alain Didier, M.D.,3 and Claus Bachert, M.D.4

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ABSTRACT

Background: 300IR 5-grass pollen sublingual immunotherapy tablets have been approved for the treatment of allergic rhinitis (AR) with or without conjunctivitis in adults and children ⬎5 years with grass pollen allergy. This study was designed to review data on nasal symptoms with 300IR 5-grass pollen sublingual tablets in adults and children. Methods: We reviewed data from four double-blind, placebo-controlled, randomized clinical trials. Two groups of patients who received a daily dose of either placebo or 300IR 5-grass pollen sublingual tablets starting 4 months before the expected start of the pollen season and continuing through the season were compared (analysis of covariance) for scores of sneezing, rhinorrhea, nasal pruritus, nasal congestion, total nasal symptom score (TNSS), and adult Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores. Results: Data for 266 children (one pediatric trial) and 1036 adults (three trials) were analyzed. Compared with the placebo groups, mean TNSS in the 300IR groups was lower by 22% in children and 19 –36% in adults. Among the four nasal symptoms, the lowest scores relative to placebo were for nasal congestion in children (31%) and adults (43%). Mean adult RQLQ scores were 21–31% lower in the 300IR group than in the placebo group. Conclusion: Allergen immunotherapy with 300IR 5-grass pollen sublingual tablets was consistently associated with AR symptom relief in adults and children and provided a clinically meaningful improvement in quality of life. (Am J Rhinol Allergy 28, 471–476, 2014; doi: 10.2500/ajra.2014.28.4112)

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easonal allergic rhinitis (AR) is a noninfectious, inflammatory condition of the upper respiratory tract that results from an immune response to allergens. Seasonal AR occurs in response to certain seasonal inhaled allergens (e.g., grass, tree, and weed pollens) to which the individual has become sensitized.1–3 In a survey performed in Belgium, France, Germany, Italy, Spain and the United Kingdom, the average prevalence of adults with clinically confirmed AR to any type of allergen was 23% (range, 17% in Italy to 29% in Belgium).3 According to the International Study of Asthma and Allergies in Childhood, the overall worldwide prevalence of rhinoconjunctivitis symptoms, other than those due to viral causes, was 14.6% in 13- to 14-year-old children and 8.5% in 6- to 7-year-old children.4 Furthermore, AR is associated with the development or aggravation of a number of comorbidities including asthma, sinusitis, upper respiratory tract infections, otitis media with effusion, and nasal polyposis, which further affect the patients’ quality of life.4–10 The symptoms of AR include nasal congestion, rhinorrhea, sneezing, postnasal drip, and nasal pruritus.4 These nasal symptoms are often accompanied by ocular pruritus, tearing, or grittiness.4,10 In clinical trials of pollen-induced AR, the most frequently scored nasal symptoms are sneezing, rhinorrhea, pruritus, and congestion, yielding a four-component total nasal symptom score (TNSS) that is clinically relevant. According to the Allergic Rhinitis and its Impact on Asthma guidelines,5,6,9 treatment of AR includes the elimination or avoidance of the offending allergens whenever possible, patient education, and the initiation of appropriate pharmacotherapy (symptomatic medications)

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Ear, Nose and Throat Department, Larrey Hospital, Toulouse, France, 2Charite/ Virchow-Klinikum, Berlin Children’s Hospital, Berlin, Germany, 3Department of Pneumology, Larrey Hospital, Toulouse, France, and 4Upper Airway Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, Ghent, Belgium The manuscript was developed with medical writing support, which was funded by Stallergenes. E Serrano and HU Wahn are consultants for Stallergenes. A Didier received honorariums from Stallergenes. C Bachert has conflicts of interest to declare pertaining to this article Address correspondence to Elie Serrano, M.D., De´partement d’Otorhinolaryngologie, Hoˆpital Larrey, 24 chemin de Pouvourville, TSA 30030, F-31059 Toulouse, France E-mail address: [email protected] Published online September 2, 2014 Copyright © 2014, OceanSide Publications, Inc., U.S.A.

and/or allergen immunotherapy (AIT). Guideline-recommended symptomatic medications include oral and intranasal H1-antihistamines, intranasal corticosteroids, oral and intranasal decongestants, intranasal anticholinergics, intranasal cromolyn, and leukotriene receptor antagonists.6 Allergic Rhinitis and its Impact on Asthma guidelines also state that AIT may be considered for the treatment of adults and children with moderate-to-severe pollen-induced rhinitis, whether accompanied by asthma or not, for those who do not want to receive constant or long-term pharmacotherapy and in those in whom pharmacotherapy induces undesirable side effects or for whom pharmacotherapy is ineffective.5,6 The choice of appropriate therapy for a given AR patient requires the physician to consider the disease’s impact on quality of life, sleep, school/work performance, and health economic factors.5,6,9,10 At present, AIT is the only treatment for AR that is capable of modifying the course of the underlying disease and, thus, potentially preventing the progression from rhinitis to asthma.11,12 AIT consists of regular, progressive exposure to the causal allergen, which is usually administered subcutaneously in a clinic or sublingually with tablets or drops self-administered at home. In Europe, the first report of the successful application of grass pollen extract for AIT appeared in 1911.13 Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are the most widely prescribed AIT regimens. SCIT is associated with more local or systemic side effects than SLIT,14 and, according to Cox and colleagues, “the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time, and is of higher convenience for the patients.”15 Systematic reviews have shown that SLIT significantly reduces symptom scores and medication use in AR.16–18 Many robust clinical trials have shown the beneficial effect of SLIT tablets on pollen-induced AR symptoms right from the first treatment season.19–33 A recent review found that SLIT tablets for grass pollen AR provide the specialist physician with the strongest evidence for drawing reliable conclusions.34 The 300IR 5-grass pollen sublingual tablet (Oralair; Stallergenes S.A., Antony, France) has been developed as a treatment for grass pollen–induced rhinoconjunctivitis and has been marketed since 2008. The tablet contains a standardized mixture of equal amounts of pollen extracts from five grasses (orchard grass/cocksfoot, Dactylis glomerata; Kentucky bluegrass/meadow grass, Poa pratensis; perennial rye grass, Lolium perenne; sweet vernal grass, Anthoxanthum odoratum; timothy grass, Phleum pratense).35 The dose of allergens is measured as an index of reactivity (IR), where 100IR is the amount of a solution of

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5-grass pollen extract that causes a wheal ⱖ7 mm in diameter (geometric mean) in skin-prick tests in 30 sensitized individuals. Clinical trials have been conducted with different doses (100IR, 300IR, and 500IR) and dosing regimens. The currently recommended treatment regimen with the 5-grass pollen sublingual tablet comprises an initiation treatment (including a 3-day dose escalation), with the first dose taken under medical supervision, and a continuation treatment with a 300IR daily dose (major allergen content, 25 ␮g of Phl p5, the major allergen of timothy grass), taken at home. Treatment is initiated 4 months before the expected start of the pollen season and is continued throughout the season. In a long-term study, the 300IR 5-grass pollen sublingual tablet was found to be effective over three consecutive treatment seasons and the following treatment-free season.30,33 Clinical trials of the 300IR 5-grass pollen sublingual tablet have been conducted over the last 10 years in Europe and North America. The primary efficacy outcome measurements were based on selfassessment of six individual rhinoconjunctivitis symptom scores (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus, and watery eyes) and, in some trials, the use or influence of rescue medication.22–24,26–31,33 Here, we specifically review data on four nasal symptoms (sneezing, rhinorrhea, nasal pruritus, and nasal congestion) and the adult allergic Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score36 from four phase III natural field trials that were conducted between 2004 and 2011 in adult and pediatric patients from Europe, Russia, Canada, and the United States.22,26,29–31,33

lowed by a treatment-free follow-up period in eight European countries, Canada, and Russia.30,33 4. U.S. study (NCT00955825): A study confirming the efficacy of the 300IR dose versus placebo in the United States in adults conducted over a single pollen season.31 In the present analysis, the placebo and 300IR groups from the aforementioned studies were selected for comparison of relief from rhinitis symptoms after treatment over one pollen season, starting from 4 months before the expected start of the pollen season. From the long-term study, only data from the 3rd year were included because the primary efficacy calculations were based on the outcomes for this year.

The main inclusion criteria for subjects participating in these four trials were as follows: a history of at least 1 year of grass pollen– induced allergic rhinoconjunctivitis (with or without mild or moderate asthma), a retrospective self-assessment of symptom severity in the previous year of ⬎12 (on a scale of 0–18), a positive skin-prick test to the 5-grass pollen extract mixture or timothy grass, and timothy grass–specific IgE ⱖ 0.7 kU/L (except in the U.S. study, where serum IgE levels were measured but did not constitute an inclusion criterion). Both monosensitized patients (sensitized only to 5-grass pollen extract) and polysensitized patients (sensitized to allergens other than 5-grass pollen, provided that this sensitization was unlikely to influence the AR symptoms during the treatment period) were included in the studies.

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METHODS Study Design The four studies with 300IR 5-grass pollen sublingual tablets reviewed here were natural field, phase III, placebo-controlled, randomized clinical trials in which the subjects and all trial personnel were blinded to the treatment being administered.22,26,29–31,33 The following is the list of studies with the respective ClinicalTrials.gov registration number in chronological order (Table 1):

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1. European study (NCT0036764): A dose-ranging study (500IR, 300IR, and 100IR versus placebo) in an adult population conducted over a single pollen season in 10 European countries.22 2. Pediatric study (NCT00409409): A study testing the 300IR dose versus placebo in a pediatric population (age range, 5–17 years) conducted over a single pollen season in five European countries.26,29 3. Long-term study (NCT00418379): A study evaluating the sustained efficacy and posttreatment effect of 300IR versus placebo in adults conducted over three consecutive pollen seasons fol-

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Patient Selection

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Study Treatment and Rescue Medication The treatment arms selected from the four studies for this analysis were the 300IR and placebo groups in which treatment was initiated ⬃4 months before the expected start of the grass pollen period and continued for its duration. One tablet of the assigned treatment (300IR 5-grass pollen tablet or placebo) was taken sublingually at the same time every day, from the randomization visit to the end of the treatment period. Patients were instructed to leave the tablet under the tongue until it had completely dissolved before swallowing. Rescue medications (oral and eye drop antihistamines and nasal corticosteroids) were supplied and were to be used for the management of severe or intolerable allergic rhinoconjunctivitis symptoms according to a prespecified regimen. The investigators were allowed to provide oral corticosteroids only if symptoms remained uncontrolled with other rescue medications.

Table 1 300IR 5-grass pollen sublingual tablet phase III studies* Study

European study19§ Pediatric study23,26 Long-term study20,27¶ U.S. study28

Year

2004–2005 2006–2007 2006–2011 2008–2009

No. of Patients Randomized All Groups

300IR

Placebo

628 278 633 473

155 139 207 233

156 139 219 240

Age Range (yr)

Duration of SAR (yr)# mean ⴞ SD

Polysensitized Patients# n (%)

18–45 5–17 18–50 18–65

12.2 ⫾ 7.98 4.69 ⫾ 2.52 13.8 ⫾ 9.07 22.9 ⫾ 12.78

339 (54.0) 163 (58.6) 382 (60.3) 369 (78.0)

*The four studies reviewed here were conducted under different settings. Patients started the assigned treatment 4 mo before the expected start of the pollen season and continued through the season. #At baseline, all randomized patients. §This study included two additional treatment arms (100IR and 500IR doses). ¶This study involved discontinuous treatment (pre- and coseasonal treatments and a treatment-free period between seasons) for 3 consecutive years, followed by 2 yr of treatment-free follow-up. It also included another treatment arm (300IR dose starting 2 mo before the expected start of the pollen season). The number of patients randomized in the 1st year is given. SAR ⫽ seasonal allergic rhinitis; IR ⫽ index of reactivity.

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Efficacy Outcome Measures

Table 2 Primary efficacy results of 300IR 5-grass pollen sublingual tablet phase III trials

Various outcome measures were used in the four studies. Patients were asked to score each of their AR symptoms daily as 0 ⫽ absent, 1 ⫽ mild, 2 ⫽ moderate, or 3 ⫽ severe. The four-component TNSS (range, 0–12) was the total of the four individual scores for sneezing, rhinorrhea, nasal pruritus, and nasal congestion. The Rhinoconjunctivitis Total Symptom Score (RTSS; range, 0–18) was the sum of the six individual symptom scores (sneezing, rhinorrhea, nasal pruritus, nasal congestion, ocular pruritus, and watery eyes). The rescue medication score (range, 0–3) was scored according to the medication taken as follows: 0 ⫽ no medication taken, 1 ⫽ antihistamine, 2 ⫽ nasal corticosteroid, and 3 ⫽ oral corticosteroid. In cases where the patient took two or more different rescue medications on the same day, the higher score was recorded. The average adjusted symptom score used in the long-term study corresponds to the RTSS adjusted for rescue medication use and averaged over the pollen period.37 The daily combined score (scale, 0–3) used in the U.S. study equally weights symptoms and rescue medication use.31 The adult allergic rhinoconjunctivitis-related quality of life questionnaire RQLQ consisted of 28 questions divided into seven domains: activity limitations, sleep problems, nonnose/eye symptoms, practical problems, nasal symptoms, ocular symptoms, and emotional function.36 The lower the RQLQ score, the better the quality of life. Adult patients were asked to complete the RQLQ at a visit expected to be in the middle of the pollen season.

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Design of the Studies and Patient Distribution The design and settings of the four phase III clinical studies are described briefly in Table 1. A total of 278 children and 1734 adults were randomized in these studies. The population evaluated hereafter for efficacy comprised 266 children (of whom 135 received placebo and 131 received the 300IR dose) and 1036 adults (of whom 541 received placebo and 495 received the 300IR dose). The demographic characteristics were similar between the two respective treatment groups in each study. The primary efficacy criterion was the RTSS in the adult and pediatric studies. In the long-term and the U.S. studies, RTSS and rescue medication use were both taken into account in the primary efficacy criteria (Table 2). In the four studies, the relative LS mean differences in the primary efficacy outcome between the 300IR group

Relative LS Mean Difference for 300IR vs Placebo

European study19 Pediatric study23,26 Long-term study20,277 U.S. study28

Average RTSS* Average RTSS* AAdSS# Daily CS

⫺28% ⫺26% ⫺35% ⫺28%

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and the respective placebo group ranged from ⫺26% (average RTSS in the pediatric study) to⫺35% in the third treatment period of the long-term study (average adjusted symptom score; Table 2).

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RESULTS

Primary Efficacy Variable

Efficacy analyses were performed using an ANCOVA (European study, Pediatric study and Long-term study) or a repeated measures linear mixed model (U.S. study) for the respective full analysis sets (FAS). *The average RTSS was calculated for the entire pollen period. #Data for the third pollen period. RTSS ⫽ rhinoconjunctivitis total symptom score; AAdSS ⫽ average adjusted symptom score (daily RTSS adjusted for use of rescue medication and averaged over the pollen period); CS ⫽ combined score (combines RTSS and rescue medication score); ANCOVA ⫽ analysis of covariance; LS ⫽ least square; IR ⫽ index of reactivity.

Statistical Methods Statistical analyses were performed using SAS software (SAS Institute, Inc., Cary, NC). In all four studies, the full analysis set consisted of all patients who had received at least one dose of the assigned treatment and had recorded at least one symptom evaluation while on treatment. In all four studies, daily rhinitis symptom scores were averaged over the pollen period and the average rhinitis symptom scores were analyzed using analysis of covariance, with treatment as the main effect and pooled center, age, gender, sensitization status, and asthma status as covariates. Daily TNSS was analyzed using a repeated measures linear mixed model, with treatment and count of valid TNSSs as fixed effects, subject as a random effect, and age, gender, pooled center, sensitization status, and asthma status as covariates (fixed effects). The RQLQ scores of adult patients corresponding to the midpollen season (adult and U.S. studies) or last available measurement in year 3 (long-term study) were compared for the full analysis set using analysis of covariance, with treatment as main effect and pooled center, age, gender, sensitization status, asthma status, and baseline RQLQ as covariates. Least squares (LS) mean values were calculated for the two groups. A value of p ⬍ 0.05 was considered a statistically significant difference.

Study

Individual Rhinitis Symptom Scores The average scores for the four rhinitis symptoms (sneezing, rhinorrhea, nasal pruritus, and nasal congestion) over the pollen period for the 300IR group and the corresponding placebo group were analyzed for the four studies (Fig. 1). The highest difference in LS mean scores relative to placebo was for nasal congestion in children (⫺31%; p ⫽ 0.0017), as well as in adults in two studies, the European study (⫺38%; p ⫽ 0.0002) and the long-term study (⫺43%; p ⫽ 0.0001).

Total Nasal Symptoms Score In each study, the sum of the four daily individual nasal symptom scores (i.e., the TNSS) was compared between the 300IR group and the placebo group (Table 3). The relative LS means difference in the TNSS in the 300IR group relative to the placebo group was ⫺22% in children and ranged from ⫺19 to ⫺36% in adults. The highest relative reduction in TNSS (36%) was seen in the long-term study after 3 years of discontinuous treatment.

Quality of Life The RQLQ was self-evaluated by adult patients (not in the pediatric study). The overall RQLQ scores (mean for all seven domains) in the 300IR and placebo groups are shown in Fig. 2. As observed for the comparison of nasal symptom scores, the greatest relative LS means difference in the RQLQ scores in the 300IR group (versus the placebo group) was seen in the third pollen period of the long-term study (⫺31%).

DISCUSSION The four clinical trials reviewed here differed in their individual design and setting, but had in common the two arms analyzed, placebo, and 300IR daily dose started 4 months preseason and continued through the season. Although other treatment arms with different doses or regimens were also included in some of these studies, our analysis focused on the results from patients in treatment arms who received 300IR once daily, in natural field trials where treatment was begun 4 months before the estimated start of the pollen season, this being the approved dose and regimen.22 This treatment regimen with 300IR 5-grass pollen sublingual tablets was found to be safe and

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Nasal congestion

LS mean SE

**

-38%

0.8

**

0.89

-43%

0.6

0.75

0.65 0.56

0.4

-25%

1.0

-17%

0.81

0.76

*

*

* -31%

1.0

Rhinorrhea

1.2

LS mean SE

1.2

0.94 0.8

0.77

0.79 0.65

0.62

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0.51

0.4

0.47

-18%

-32%

0.76

0.70

0.6

*

**

-20%

0.37

0.2

0.2

0.0

0.0

1.2

Pediatric Long-term U.S. study study study

Sneezing

* -20%

LS mean SE

1.01

*

-21%

0.92 0.81

* -17% 0.87

0.85 0.78

0.6

0.73

0.62

0.2

0.2

Placebo

European Pediatric study study

300IR

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0.68

0.58

T

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Long-term U.S. study study

0.68

0.62 0.52

0

European Pediatric study study

-35%

-15% 0.59

0.4

**

0.84

0.6

0.4

0.0

** -29%

1 0.8

Long-term U.S. study study

Nasal pruritus

1.2

-8%

1.0 0.8

European Pediatric study study

LS mean SE

European study

0.44

Long-term U.S. study study

Figure 1. Individual rhinitis symptom scores. In the four clinical studies, daily scores (range, 0–3) for each of the four nasal symptoms (sneezing, rhinorrhea, nasal pruritus, and nasal congestion) were recorded by patients receiving a daily sublingual tablet of either placebo or 300IR and averaged over the pollen period. For the long-term study, data for the 3rd year of treatment are given. Values plotted are least squares (LS) means ⫾ SEs for the full analysis set in the two treatment groups for the pollen period (*p ⬍ 0.05; **p ⬍ 0.001). Number of patients analyzed: European study, placebo, 148, and 300IR, 136; pediatric study, placebo, 135, and 300IR, 131; long-term study, placebo, 165, and 300IR, 149; U.S. study, placebo, 228 and 300IR, 208.

Table 3 Daily TNSS from phase III trials of 300IR 5-grass pollen sublingual tablet Study

Treatment

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European study19

Pediatric study23,26

Long-term study20,27* U.S. study28

300IR Placebo 300IR Placebo 300IR Placebo 300IR Placebo

n

136 148 131 135 149 165 208 228

LS Mean (SE)

2.53 (0.22) 3.51 (0.22) 1.98 (0.22) 2.54 (0.22) 1.64 (0.22) 2.57 (0.21) 2.42 (0.22) 2.97 (0.21)

Difference in LS Mean vs Placebo

Relative LS Means Difference

Point Estimate

(95% CI)

p Value

⫺0.97

(⫺1.47; ⫺0.48)

0.0001

⫺27.7%

⫺0.56

(⫺1.05; ⫺0.07)

0.0250

⫺22.1%

⫺0.92

(⫺1.39; ⫺0.45)

0.0001

⫺36.0%

⫺0.55

(⫺1.00; ⫺0.11)

0.0155

⫺18.6%

TNSS was calculated as the sum of the four daily rhinitis symptom scores and analyzed during the pollen period using a repeated measures linear mixed model (n ⫽ number of patients evaluated). *Data for the 3rd year of treatment (primary time point); the other three studies were conducted over a single pollen season. LS ⫽ least squares; TNSS ⫽ total nasal symptom score; IR ⫽ index of reactivity; SE ⫽ standard error; CI ⫽ confidence interval.

effective in adults and children; sensitization status and presence of asthma did not impact the results.22,24,26,29–31,33 The most beneficial treatment effects were seen in the long-term study with discontinuous treatment (⬃5 months of treatment per year) over three pollen seasons. The quality-of-life outcomes were consistent with those of symptom severity scores. Patient surveys in Europe and the United States have found that nasal congestion is frequently the most troublesome symptom of allergic rhinoconjunctivitis,38–41 followed by red, itchy eyes.41 Conges-

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tion significantly worsens a patient’s quality of life because it contributes to poor sleep quality and daytime lethargy, which in turn affect the ability to concentrate at school or work, poor productivity, and impaired social and physical functioning.42,43 In the present analysis, treatment with 300IR 5-grass pollen sublingual tablets was seen to relieve nasal symptoms (versus placebo), notably nasal congestion, and this was reflected in an improved quality of life. Efficacy analyses in this type of clinical trial are impacted by seasonal and geographical variations in pollen counts. The trials

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Although antihistamines and nasal corticosteroids are the first-line treatment for seasonal AR and have a rapid onset-of-action, these symptomatic medications only control symptoms for some hours or days at best. In contrast to AIT, antihistamines, nasal corticosteroids, and systemic corticosteroids do not have a disease-modifying effect. There is robust evidence for clinical efficacy of SCIT and SLIT for ⱖ1 year after treatment discontinuation.30,33,48 Moreover, in a real-life study of patients with grass pollen AR and concomitant mild asthma performed in Germany, Karagiannis et al. showed that mean asthma symptom scores decreased significantly (p ⬍ 0.001) by 60 and 70% during grass pollen seasons 1 and 2 compared with the proceeding grass pollen season, thus confirming the disease-modifying effect of SLIT.49 In conclusion, the robust, well-powered clinical trials reviewed here provide strong evidence in support of the routine clinical use of 300IR 5-grass pollen sublingual tablets for the treatment of grass pollen–induced rhinitis with or without conjunctivitis in adults and children. The data reviewed here reveal that administration of these tablets (starting 4 months before the expected start of the pollen season and continuing through the season) resulted in clinically meaningful relief from rhinitis symptoms and an improvement in the patients’ quality of life.

2.0

*

1.8

*

1.6

**

-21%

-31%

LS mean SE

1.4 1.2 1.0

1.39

-21% 1.58

1.36 1.25

1.10

Y P

0.94

0.8 0.6 0.4 0.2 0.0

European study Long-term study Placebo

U.S. study

300IR

Figure 2. Allergic rhinoconjunctivitis–related quality-of-life scores. In the three clinical studies that included adult patients, allergic rhinoconjunctivitis–related quality-of-life questionnaire scores (range, 0–6, mean score for the seven domains) were recorded by patients receiving a daily sublingual tablet of either placebo or 300IR. Values plotted are the lease squares (LS) means ⫾ SEs for the full analysis set in the two treatment groups* (p ⬍ 0.05; **p ⬍ 0.001). Number of patients analyzed: European study, placebo, 144, and 300IR, 128); long-term study, placebo, 151, and 300IR, 138; U.S. study, placebo, 223, and 300IR, 207.

The authors thank Laurence Ambroisine for providing the data and performing the analyses, Anuradha Alahari and David Fraser for medical writing, and Newmed Publishing for editorial services.

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REFERENCES 1.

reviewed here included three single-season studies and one long-term study (over three pollen seasons) and were conducted in different regions of the world in adults and children. It is noteworthy that all four studies were characterized by a considerable placebo effect, which is often encountered in studies in which efficacy assessments are based on patient-reported outcomes. One of the reasons for the placebo effect is that a large proportion of included patients may not be sufficiently symptomatic through the study period. In studies of seasonal allergies, patients are recruited before the start of the allergy season and are selected based on a retrospective, potentially biased self-assessment of the severity of their AR symptoms from the previous year. Thus, in the data presented here (Table 3, and Figs. 1 and 2), the LS mean values for the TNSS (range, 0–12) and the RQLQ (range, 0–6) were rather low. In the placebo group, the LS mean for TNSS varied between 2.54 and 3.51, and that for the RQLQ scores varied between 1.36 and 1.58. However, despite the differences in design and setting of the four studies reviewed here and the aforementioned study limitations, 300IR 5-grass pollen sublingual tablet treatment was seen to be consistently efficacious in terms of overall allergic rhinoconjunctivitis symptoms (data previously reported), as well as in terms of rhinitis symptoms and rhinitisrelated quality of life. A recent review of studies with 300IR 5-grass pollen sublingual tablets indicated the efficacy and safety of 4-month pre- and coseasonal treatment.44 Another recent review of six phase II/III placebocontrolled, randomized studies of grass allergy SLIT tablets formulated from a timothy grass extract alone concluded that the treatment was similarly effective in adults and children.45 However, Chabre et al.46 reported that a 5-grass pollen mixture is more suitable for specific immunotherapy because it contains a broader repertoire of IgE epitopes to which patients are sensitized and will optimally reeducate the immune system. This view was supported by Archila et al. who showed that not all Pooideae grass epitopes with sequence homology are cross-reactive. These authors also recommended using a mixture of pollens for immunotherapy to reorient existing Th2 responses against a broader spectrum of T-cell epitopes.47

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ACKNOWLEDGMENTS

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3. 4.

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6.

7.

8.

9.

10.

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November–December 2014, Vol. 28, No. 6

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