Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults

Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults Harold S. Nelson, MD,a Hendrik Nolte, MD, PhD,b,c Peter Creticos, MD,d Jennifer Maloney, MD,b,e Jiangming Wu, PhD,b and David I. Bernstein, MDf Denver, Colo, Kenilworth, NJ, Copenhagen, Denmark, Baltimore, Md, New York, NY, and Cincinnati, Ohio Background: Immunotherapy for allergic rhinoconjunctivitis (ARC) in North America is generally administered subcutaneously, but alternative formulations might be safer and more convenient. Trials of sublingual formulations in North America are needed to confirm European efficacy and safety data. Objective: We sought to investigate the efficacy and safety of timothy grass allergy immunotherapy tablet (AIT) treatment in North American subjects with ARC. Methods: Four hundred thirty-nine adults with grass pollen– induced ARC with or without asthma were randomized to oncedaily 2,800 bioequivalent allergen units of standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 standardized quality tablet, containing approximately 15 mg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). The primary end point was the average total combined score of the daily symptom score and the daily medication score during the GPS. Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) scores, Phl p 5–specific IgG4 levels, and IgE-blocking factor levels were additional end points. Adverse events (AEs) were monitored for safety. Results: Relative to placebo, grass AIT treatment improved total combined scores by 20% (P 5 .005), daily symptom scores by 18% (P 5 .02), and RQLQ(S) scores by 17% (P 5 .02). Daily medication scores were improved by 26% and trended toward significance (P 5 .08). Phl p 5–specific IgG4 and IgE-blocking factor levels were higher after grass AIT treatment compared with those after placebo at the end of the GPS (P < .001). Grass AIT treatment was safe and well tolerated. The majority of AEs From athe Department of Medicine, Division of Allergy and Immunology, National Jewish Health, Denver; bMerck Research Laboratories, Kenilworth; cthe Respiratory Research Unit, Bispebjerg Copenhagen University Hospital, Copenhagen; dthe Division of Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore; ethe Department of Pediatrics, Mount Sinai School of Medicine, New York; and fthe Department of Medicine, Division of Allergy and Immunology, University of Cincinnati. Supported by Merck & Co. Disclosure of potential conflict of interest: H. S. Nelson has consulted for Genentech/ Novartis, Merck, Sepracor, Forest Labs, Pfizer, Planet Biopharmaceuticals, GlaxoSmithKline, AstraZeneca, Abbott Laboratories, DBV Technologies, and Vectura and has received research support from ALK-Abello. P. Creticos has consulted for Greer Labs, Schering-Plough, Sanofi-Aventis, and Stallergenes; has received research support from Merck/Schering-Plough, Greer Labs, GlaxoSmithKline, and Stallergenes; and is a member of the American Academy of Allergy, Asthma & Immunology (AAAAI) Immunotherapy Committee. H. Nolte is an employee of Merck. J. Maloney is an employee of Merck. J. Wu is an employee of Merck D. I. Bernstein has served on advisory boards for ALK America and Merck; has received research support from Merck; and is a member of the AAAAI Immunotherapy Committee. Received for publication August 13, 2010; revised October 22, 2010; accepted for publication November 22, 2010. Reprint requests: Harold S. Nelson, MD, National Jewish Health, 1400 Jackson St, Room B104, Denver, CO. E-mail: [email protected]. 0091-6749/$36.00 Ó 2010 American Academy of Allergy, Asthma & Immunology doi:10.1016/j.jaci.2010.11.035

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were transient mild local reactions with no investigatordiagnosed grass AIT–related serious AEs or reports of anaphylactic shock/respiratory compromise. In the grass AIT group, 1 subject received epinephrine after experiencing a possible grade 1 systemic reaction (local site reactions, chest discomfort, and rash). Conclusions: Timothy grass AIT treatment (cross-reactive with related Pooideae grasses) was demonstrated to be effective, generally safe, and well tolerated in North American adults with grass pollen–induced ARC. (J Allergy Clin Immunol 2011;127:72-80.) Key words: Allergy immunotherapy tablet, allergic rhinoconjunctivitis, specific immunotherapy, grass pollen, sublingual immunotherapy

A 2006 survey conducted in the United States revealed that approximately 30 million adults have allergic rhinoconjunctivitis (ARC).1 For many of these persons, grass pollen is a cause of their ARC symptoms. In some regions of the United States, it is estimated that 50% to 70% of subjects with ARC are sensitive to grass allergens.2,3 The symptoms of ARC can have a pronounced negative effect on patients’ health-related quality of life by affecting sleep quality, work performance, and social activities.4 The effect of these symptoms was documented in the Allergies in America survey in which 64% of patients reported frequently (29%) or sometimes (36%) feeling miserable during the allergy season.4 Options to treat ARC include over-the-counter and prescription medications; however, these medications only treat symptoms and do not have long-term benefits. Specific allergen immunotherapy is an option recommended in treatment guidelines as a firstline therapy for ARC and is the only treatment option that alters the disease.5 In North America administration of immunotherapy has been predominantly subcutaneous. However, safety concerns related to the risk of near-fatal or fatal anaphylaxis, in combination with the inconvenience of frequent injections, make subcutaneous immunotherapy undesirable for many subjects.6-9 Sublingual administration has become a popular delivery method of immunotherapy in Europe. The efficacy of sublingual immunotherapy has been demonstrated in European trials and confirmed in meta-analyses of trials in children and adults.10,11 In some studies immunotherapy (both subcutaneous and sublingual) has been shown to reduce the development of other sensitivities and the progression of ARC to asthma.12-15 Furthermore, immunotherapy has disease-modifying potential. When therapy is discontinued, the treatment effect persists.16,17 Although the benefits of sublingual immunotherapy have been well established in European populations, it is unknown whether the results of European trials can be applied to North American populations because of differences in sensitization patterns and the distribution of pollinating plants. Trials in North America are required to confirm the efficacy of sublingual immunotherapy for subjects with ARC who live in this region. There are only a

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Abbreviations used AE: Adverse event AIT: Allergy immunotherapy tablet ARC: Allergic rhinoconjunctivitis BAU: Bioequivalent allergen units DMS: Daily medication score DSS: Daily symptom score GPS: Grass pollen season RQLQ(S): Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities SQ-T: Standardized quality tablet TCS: Total combined score

limited number of immunotherapy studies in North America using sublingual administration. Reports from only 4 trials in the United States have been published, and all 4 investigated sublingual drops.18-21 In Europe multiple studies have shown the safety and efficacy of timothy grass allergy immunotherapy tablet (AIT) treatment22-25 and 5-grass extract tablets.26 Timothy grass (Phleum pratense), a member of the Pooideae subfamily, demonstrates distinct cross-reactivity with other Pooideae members, such as rye (Lolium species), meadow fescue (Festuca species), bluegrass/June (Poa species), orchard/cocksfoot (Dactylis species), sweet vernal (Anthoxanthum species), and redtop/bent/velvet (Agrostis species), and is partially cross-reactive with Johnson grass, all of which are major aeroallergens in North America.27,28 However, no study has reported the efficacy of grass tablet treatment in a North American population. The objective of this study was to investigate the efficacy and safety of daily administration of grass AIT treatment in subjects with ARC with or without asthma in North America.

METHODS Study design This was a phase III, double-blind, randomized, placebo-controlled, parallel-group multicenter study conducted between March 2008 and September 2009 in North America. By region, 7 sites were in Canada, 9 sites were in the mid-Atlantic region, 12 sites were in the north central region, 1 site was in the northeast, 6 sites were in the south, and 16 sites were in the west. The study was conducted in compliance with Good Clinical Practice guidelines. The protocol was approved by institutional review boards for each center. All subjects provided written informed consent before any study activity. The study consisted of 2 periods (Fig 1). The first stage of the study was an observational period conducted before and during the 2008 grass pollen season (GPS). The purpose of the observational period was to recruit subjects and ensure appropriate grass pollen–induced ARC symptoms before the start of investigational medication. The second stage was the treatment period conducted during the 2009 GPS. Subjects were added after the 2008 GPS to meet the targeted sample size and were required to have had a history of significant symptoms and treatment for their ARC during the previous GPS. These criteria, combined with the objective diagnostic measures, ensured a homogeneous population of subjects recruited during the observational and treatment years. Subjects were randomized to active therapy or placebo during the treatment period.

Treatment Qualified subjects were randomized 1:1 to once-daily 2,800 bioequivalent allergen units (BAU) of standardized timothy grass AIT treatment (oral lyophilisate, P pratense, 75,000 standardized quality tablet [SQ-T], containing approximately 15 mg of Phl p 5; Schering-Plough Corp, Kenilworth, NJ) or placebo with no build-up dosing administered sublingually for approximately

16 weeks before the anticipated start of the GPS and continuing throughout the 2009 GPS. Subjects were randomized by using a computer-generated randomization schedule in blocks of appropriate size. Randomization was conducted by an external randomization group using an interactive voice-response system and was stratified by study site and the asthmatic status of the subject. Double blinding (subject and investigator) was established by use of a matching placebo tablet. Blinding was maintained until the database was locked. The first 3 daily doses of study medication were administered at the study site, and the subject was required to remain at the site for 30 minutes after administration to monitor for any adverse events (AEs). Subsequent treatments were self-administered by the subject once daily at home. Site personnel contacted each subject by telephone for the first 4 days of at-home treatment to inquire about any reactions related to study treatment. Self-injectable epinephrine was supplied to all subjects as a rescue medication for use in the event of a significant systemic allergic reaction.

Study subjects Subjects included in the study (both the observational and treatment years, unless otherwise noted) were 18 to 65 years of age with a physician-diagnosed history of grass pollen–induced ARC with or without asthma and had received treatment for their ARC during the previous GPS. At screening, subjects were required to meet the following criteria: a positive skin prick test response to P pratense defined as a wheal diameter of 5 mm or larger than that elicited by the saline control (standardized timothy grass extract 100,000 BAU/mL, 5 mL [ALK-Abello, Hørsholm, Denmark] administered to the inner forearm with a DuoTip [Lincoln Diagnostics, Decatur, Ill]; positive control, Histatrol Histamine Positive Control 1.0 mg/mL, 5-mL [ALK-Abello, Hørsholm, _0.7 kU/L; measured by Denmark]), a positive P pratense–specific IgE level (> using the ImmunoCAP assay, Phadia AB, Portage, Mich), and an FEV1 of 70% or greater of predicted value. For those subjects who participated in the observational period, an increase in rhinoconjunctivitis symptom score of 4 or greater (maximum possible score, 18) above the preseasonal average score for at least 2 days or symptomatic medication use for at least 2 days during the observational period was also required to continue into the treatment period of the trial. Reasons for exclusion from the trial included a history of symptomatic seasonal or perennial ARC, asthma, or both to an allergen other than the northern grasses that required medication during or potentially overlapping the GPS, immunotherapy within the previous 5 years, a history of severe asthma, chronic urticaria/angioedema, chronic sinusitis, or current severe atopic dermatitis. Although Bermuda grass sensitivity was not specifically assessed (to exclude subjects with this allergy), most of the study sites (approximately 90%) were not located in the southern regions in which Bermuda grass is known to pollinate.

GPS Pollen counts (grass, tree, and ragweed) were to be obtained for each site an average of 5 days per week and recorded. The start of the GPS was defined as the first of 3 consecutive days with a pollen count of 10 grains/m3 or greater. The end of the GPS was defined as the last day of the last occurrence of 3 consecutive days with a pollen count of 10 grains/m3 or greater. The peak GPS was defined as the period of 15 consecutive days with the highest average among all possible 15 consecutive-day averages across the GPS.

Assessments The primary end point of the study was the total combined score (TCS), which is a sum of the rhinoconjunctivitis daily symptom score (DSS) and daily medication score (DMS) averaged over the entire GPS. Key secondary end points were the average DSS over the entire GPS, the average DMS over the entire GPS, and the average weekly score on the Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) during the GPS. Rhinoconjunctivitis and asthma symptom scores were recorded once daily in an electronic diary from the time of randomization through the end of the GPS. The DSS comprises 6 rhinoconjunctivitis symptoms (runny nose, blocked nose, sneezing, itchy nose, gritty feeling/red/itchy eyes, and watery eyes) and 4 asthma symptoms (cough, wheeze, chest tightness/shortness of breath, and exercise-induced symptoms) measured as follows: 0, no symptoms; 1, mild

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FIG 1. Study design. SQ-T, Standardized quality tablet.

FIG 2. Subject disposition. *These subjects met eligibility criteria for entry into the treatment year of the trial but, because of personal choice, decided not to commit to the additional study period.

symptoms; 2, moderate symptoms; or 3, severe symptoms. Open-label rhinoconjunctivitis and asthma medication (for subjects with asthma) were provided approximately 2 weeks before the start of the GPS to be used in a step-up sequence if needed once the start of the GPS had been confirmed. Subjects were instructed to record their use of rescue medications in the electronic diary. The rhinoconjunctivitis DMS was composed of the sum of scores for antihistamine, ocular antihistamine, nasal corticosteroid, and oral steroid use (see Table E1 in this article’s Online Repository at www.jacionline. org). For the treatment period, the RQLQ(S) was completed at visit 2 (randomization) and weekly during the GPS; the average weekly score was calculated. The RQLQ(S) is a validated instrument specifically focused on domains that might be significantly impaired in subjects with seasonal ARC.29 A higher score indicates more significant impairment. Other additional end points were the levels of Phl p 5–specific IgG4 and IgE-blocking antibodies. Blood samples were collected at screening, peak GPS, and 1 week after the GPS and analyzed by means of immunoassay (ADVIA Centaur Specific IgE 2-step assay with ADVIA Centaur Specific IgE

[Simultan], Siemens Healthcare Diagnostics, Deerfield, Ill; ImmunoCAP IgG4 assay, Phadia AB, Portage, Mich). as previously described.22

Safety Safety was assessed through spontaneously reported AEs that were recorded in a paper diary. AEs were graded by the investigators as mild (easily tolerated), moderate (some discomfort, possible intervention), severe (incapacitating or significantly affects clinical status and requires intervention), or life-threatening (immediate risk of death).

Statistics Assuming a 25% dropout rate, 450 subjects in the observational phase and 340 subjects in the treatment phase allowed for a 1.63-point difference from placebo (23% based on a placebo mean of 7.07 points) in TCS to be detected with 88% power at a 5% level of significance (2-sided test). The differences

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between the grass AIT and placebo groups for TCSs, DSSs, DMSs, and RQLQ (S) scores for the entire GPS were evaluated by using a linear effect model, with asthma status, study site, and treatment group as fixed effects. The Hochberg test was used to control for type 1 error for the key secondary end points of DSS, DMS, and RQLQ(S) score during the GPS. An adjusted P value is presented for the key secondary end points, and therefore a P value of less than .05 for any of the primary or key secondary end points is considered statistically significant. P values presented for the percentage differences are the P values for the mean score differences. All analyses were conducted based on all randomized subjects who had at least 1 posttreatment diary data entry available for analysis (ie, the intent-to-treat population). Safety analyses were conducted on all subjects who received at least 1 dose of treatment. There was no imputation of missing data. The software used for statistical analysis was SAS version 9.1 (SAS Institute, Inc, Cary, NC) in UNIX.

RESULTS Demographics and baseline characteristics A total of 439 subjects were randomized, 189 who participated in the observational period and 250 who participated as new subjects; 438 received at least 1 dose of treatment (Fig 2). The intent-to-treat population included 184 subjects in the grass AIT group and 207 subjects in the placebo group. The demographic and baseline characteristics of the subjects are presented in Table I and were similar to those of subjects in the observational period (data not shown). The majority of subjects were white (84%), and the mean age was 35.9 years. Asthma as a coexisting condition was well represented in both groups (grass AIT group, 21%; placebo group, 26%). Mean timothy grass skin prick test wheal sizes were large (grass AIT group, 11.8 mm; placebo group, 11.5 mm), as were the wheal sizes in response to histamine (grass AIT group, 6.3 mm; placebo group, 6.2 mm). In both treatment groups 85% of the subjects were multisensitized. GPS The 2009 GPS had a mean duration of 53 days for the grass AIT group and 52 days for the placebo group. The weighted mean grass pollen count for the GPS was 26.8 grains/m3 (SD, 18.3 grains/m3). The mean peak season grass pollen count was 48.0 grains/m3 (SD, 22.0 grains/m3). At the start of the GPS, tree pollen levels averaged approximately 300 grains/m3 but decreased to less than 60 grains/m3 over the first half of the GPS (Fig 3). No significant effect of tree pollen was noted on symptom and medication scores. Subjects were allowed to participate in the trial regardless of other sensitivities as long as the relevant season did not overlap with the GPS. Symptom, medication, and RQLQ(S) scores Grass AIT treatment resulted in improvements relative to placebo during the GPS for all the primary (TCS) and key secondary end points (DSS, DMS, and RQLQ[S] score; Table II). The increase in TCS paralleled mean pollen counts over the entire course of the GPS (Fig 3). Separation in TCSs between the grass AIT and placebo groups was observed beginning approximately 10 days before the official start of the protocol-defined GPS coincident with low levels of grass pollen. There was a 20% improvement in mean TCS for the grass AIT group relative to the placebo group during the entire GPS (P 5.005, Fig 4). Mean DSS was also significantly improved by grass AIT treatment (18%, P 5.02) relative to those seen after placebo treatment during the GPS (Fig 4).

TABLE I. Demographics and baseline characteristics

Sex, no. (%) Women Race, no. (%) White Black Age (y) Mean Range Subjects with asthma (%) Sensitive to non–grass allergens, no. (%) Mites Tree pollen Weeds Cat/dog Mold/herbs Grass sensitivity Mean (SD) histamine wheal diameter (mm) Mean (SD) P pratense wheal diameter (mm) Specific IgE (kU/L [SD]) Preseason score* (SE) TCS DSS DMS 

Grass AIT group (n 5 213)

Placebo group (n 5 225)

109 (51)

112 (50)

182 (85) 21 (10)

187 (83) 21 (9)

35.9 18-63 21 85 77 (36) 117 (55) 141 (66) 95 (45) 51 (24)

35.9 18-61 26 85 78 (35) 111 (49) 143 (64) 100 (44) 57 (25)

6.3 (3.1) 11.8 (4.4) 15.9 (21.6)

6.2 (3.7) 11.5 (4.6) 17.2 (21.3)

3.3 (0.3) 3.1 (0.3) 0.2 (0.0)

3.6 (0.3) 3.5 (0.3) 0.2 (0.1)

*Adjusted mean scores.  Rescue medication was provided approximately 2 weeks before the start of the GPS and was not to be used until the season started. However, some subjects recorded use.

Symptomatic medication use was low overall in both groups, but the mean DMS was improved 26%, with a trend toward statistical significance (P 5 .08) in subjects treated with grass AIT relative to placebo (Fig 4). Grass AIT significantly improved nasal symptoms (runny nose, blocked nose, sneezing, and itchy nose combined) and ocular symptoms (itchy eyes and watery eyes combined) by 15% and 26% relative to placebo (P 5 .02 and P < .001, respectively; Table II). Overall, the individual nasal and ocular symptoms (uncombined) were significantly improved by grass AIT _ .04 vs placebo), with the exception of blocked nose treatment (P < (P 5 .13). The RQLQ(S) total score was significantly improved (17%, P 5 .02) by grass AIT treatment relative to placebo (Fig 4). Improvements in TCS, DSS, DMS, and RQLQ(S) score during the peak season were similar to those during the entire GPS.

Effects on asthma For the entire study population, there was a 24% improvement in total asthma symptom scores for the grass AIT group relative to the placebo group (P 5 .04). The symptom score was 0.84 in the grass AIT group and 1.10 in the placebo group (Table II). There was a 22% improvement in asthma symptoms for the active group during the peak season relative to the placebo group (P 5 .07). In general, there was a limited need for asthma rescue medications. However, the mean asthma DMS for the grass AIT treatment group was 46% lower compared with that seen in the placebo group (P 5 .01). Fewer subjects receiving grass AIT treatment required treatment for worsening of asthma, which was defined as needing 4 or more inhalations of short-acting b2-agonist per day at any point during the treatment period, compared with subjects in the placebo group (2 subjects receiving grass AIT treatment and 13 subjects receiving placebo, respectively). In

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FIG 3. TCS and pollen counts over time. Pollen counts were weighted by the number of subjects exposed. The box indicates the 3-day period that qualified as the beginning of the GPS.

TABLE II. Adjusted scores during the GPS*

TCS Mean (SE) Median DSS Mean (SE) Median DMS Mean (SE) Median Ocular symptoms Mean (SE) Median Nasal symptoms Mean (SE) Median RQLQ(S) scoreà Mean (SE) Median Asthma symptoms, mean (SE) Total Coughing Wheezing Chest tightness/shortness of breath Exercise induced

Grass AIT group (n 5 208)y

Placebo group (n 5 225)y

5.08 (0.4) 4.62

6.39 (0.4) 6.13

.005

21.31

22.22 to 20.40

3.83 (0.3) 3.43

4.69 (0.3) 4.52

.02§

20.86

21.46 to 20.26

1.25 (0.2) 0.26

1.7 (0.2) 0.50

.08§

20.45

20.96 to 0.06

1.07 (0.1) 0.82

1.46 (0.1) 1.29

<.001

20.38

20.61 to 20.16

2.76 (0.2) 2.47

3.24 (0.2) 3.14

.023

20.48

20.89 to 20.07

1.30 (0.1) 1.01

1.57 (0.1) 1.45

.02§

20.27

20.48 to 20.05

0.84 0.32 0.17 0.16 0.18

1.10 0.33 0.25 0.26 0.25

.04 .81 .03 .005 .04

20.26 20.01 20.08 20.10 20.07

20.51 20.10 20.15 20.18 20.14

(0.1) (0.04) (0.03) (0.03) (0.02)

P value

(0.1) (0.04) (0.03) (0.03) (0.03)

Difference

95% CI for difference

to to to to to

20.01 0.08 20.01 20.03 0.00

*Scores were adjusted by using the ANOVA model, with treatment and site as a factor in the analysis.  Number of subjects included in analysis (intent-to-treat population): grass AIT group, n 5 184; placebo group, n 5 207. àGrass AIT group, n 5 172; placebo group, n 5 197. §P values adjusted with the Benjamini and Hochberg method.

addition, a low but comparable number of subjects in each treatment group required the initiation of inhaled corticosteroids for asthma treatment during the GPS (6 subjects receiving grass AIT treatment and 5 subjects receiving placebo).

Immunologic measures Phl p 5–specific IgG4 and IgE-blocking factor levels in the grass AIT group increased over time after initiation of treatment, whereas the corresponding levels in the placebo group remained

constant (see Fig E1 in this article’s Online Repository at www. jacionline.org). The mean log10 IgG4 level at the end of the season was 20.29 compared with 20.72 for the placebo group (P < .001). The mean IgE-blocking factor level at the end of the season was 0.11 compared with 20.05 for the placebo group (P < .001).

Safety Grass AIT treatment was safe and well tolerated overall. There were no events of anaphylactic shock or respiratory compromise.

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FIG 4. Improvements in TCS, DSS, DMS, and RQLQ(S) scores after grass AIT treatment. *P 5 .005,  P 5 .02, and àP 5 .08 versus placebo.

No new safety signals were detected. Of the 438 treated subjects, 76.9% experienced an AE (82.6% in the grass AIT group and 71.6% in the placebo group). Treatment-related AEs were experienced by 72.8% of subjects in the grass AIT group and 27.6% of subjects in the placebo group. Table III lists the AEs with an incidence of 5% or greater. Discontinuations due to AEs were infrequent with both grass AIT treatment (n 5 11/213 [5.2%]) and placebo (n 5 8/225 [3.5%]). The day of onset for local application-site reactions ranged from 1 to 8 days after treatment initiation, and the median number of days on which these events were reported to occur ranged from 1 to 7 days (Table IV). Most (98%) treatment-related AEs were mild to moderate in severity both in the grass AIT group (mild, 112/155; moderate, 40/155) and in the placebo group (mild, 52/62; moderate, 9/62). The most common treatment-related AEs reported in the grass AIT group were local application-site reactions (oral pruritus, 35%; throat irritation, 29%; ear pruritus, 20%; oral paresthesia, 14%; mouth edema, 8%; and mouth inflammation [recorded as ‘‘stomatitis’’ but generally referring to mild erythema and not ulcerations or infections], 8%; Table III). Urticaria was reported by 7 subjects; 6 of these events were considered treatment related, but most were in the placebo group (placebo, n 5 5), and none resulted in study discontinuation. Only 1 event of pruritus led to study discontinuation (grass AIT group). No subjects reported angioedema. Treatment-related local mouth edema was reported by 18 subjects (grass AIT group, n 5 17; placebo group, n 5 1), and treatmentrelated lip edema was reported by 5 subjects (grass AIT group, n 5 4; placebo group, n 5 1). Four asthma events were reported during the treatment period, 2 from subjects in the grass AIT group and 2 from subjects in the placebo group. Only 1 of these asthma events was considered treatment related (grass AIT group; day 53 of treatment), and this event was assessed as moderate in severity. There were 7 subjects reporting serious AEs during the trial, with only 1 event assessed as possibly treatment related (abdominal pain). This one serious treatment-related AE was in a subject in the placebo group. Two subjects were administered epinephrine. One of these subjects was in the grass AIT group and experienced local application-site symptoms (dysphagia, uvular edema, and pharyngeal edema) along with a flush/macular rash and chest discomfort within minutes of the first dose on day 1 of treatment. There was no wheezing or respiratory distress, and vital signs remained stable without hypotension. The subject was treated on site with antihistamine, epinephrine, and prednisone; the event resolved, and the subject was released from the

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investigator’s site after 1 hour. The event was rated as mild by the investigator, and although it was not considered by the investigator to be a systemic allergic reaction, according to World Allergy Organization guidelines30 this event would be considered a grade 1 systemic reaction. The second subject was in the placebo group. On day 4, the subject administered self-injectable epinephrine in response to a non–treatment-related anxiety attack. Both of these subjects were discontinued from the trial. A study sponsor–initiated search was conducted for AEs that constituted criteria considered highly likely for the diagnosis of a systemic allergic reaction to comprehensively assess the potential for such reactions.31 There was 1 subject in the placebo group who had diarrhea and urticaria on day 2 of treatment. The subject remained in the trial.

DISCUSSION This is the first clinical trial to report the efficacy and safety of timothy grass AIT treatment in a North American adult population. Grass AIT treatment significantly improved TCS, DSS, and RQLQ (S) scores relative to placebo, despite the fact that the majority of subjects were multisensitized to aeroallergens, including tree pollen, weeds, and house dust mites, and other timothy grass– related grass pollens. Furthermore, these results are consistent with the efficacy demonstrated in European trials of grass AIT treatment.22-25 The safety profile was also consistent with data from European trials.22-25 In this study it is noteworthy that there were no grass AIT–related serious AEs, life-threatening events, or anaphylactic shock events. Importantly, the design of the trial was consistent with recommendations by Casale et al32 for producing highquality evidence of sublingual immunotherapy’s efficacy. The TCS was the primary end point of this study, which allowed for adjustment of symptom scores based on symptomatic medication use, an end point suggested by the World Allergy Organization and consistent with guidance issued by the European regulatory agency.5,33 The minimum important difference has yet to be established for TCS; however, the improvements in TCS were equal to the 20% difference relative to placebo that has been suggested as a clinically important difference for sublingual immunotherapy.5 The improvements in DSS (18%) and DMS (26%) demonstrated in the current trial were comparable with those seen in another randomized, placebo-controlled grass AIT treatment trial conducted in Europe and Canada25 in which subjects who received 75,000 SQ-T (2800 BAU) grass AIT treatment for at least 8 weeks before the season had a 21% improvement in DSS and a 29% improvement in DMS. In the first year of a European trial reported by Dahl et al,24 subjects received grass AIT treatment for at least 16 weeks before the GPS and reported an improvement of 30% in DSS and 38% in DMS relative to placebo. Variability of results among trials can be partly attributed to the severity and length of the GPS. In the study by Dahl et al, the GPS lasted longer (mean, 57.8 days), and grass pollen counts were much higher (a peak of approximately 125 grains/ m3) compared with the GPS in the current study (mean, 52 days; peak grass pollen count, 48.0 grains/m3). A GPS that was longer, more robust, or both might have resulted in higher symptom scores and use of rescue medication in the placebo group, increasing potential treatment differences between the grass AIT– and placebo-treated groups. Nevertheless, despite a weak pollen season, the results in this study were significant both statistically and clinically.

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TABLE III. AEs experienced by 5% or more of all treated subjects Treatment emergent AEs, no. (%)

Grass AIT group (n 5 213)

Oral pruritus Throat irritation Ear pruritus Oral paresthesia Mouth edema Stomatitis* Pharyngeal edema URTI Nasopharyngitis Headache Eye pruritus Swollen tongue Pruritus Dyspepsia Oropharyngeal pain

75 63 42 29 17 16 14 38 17 15 11 11 11 11 10

Treatment related

Placebo group (n 5 225)

(35.2) (29.6) (19.7) (13.6) (8.0) (7.5) (6.6) (17.8) (8.0) (7.0) (5.2) (5.2) (5.2) (5.2) (4.7)

7 11 3 5 1 1 25 29 16 8 6 3 12

Grass AIT group (n 5 213)

(3.1) (4.9) (1.3) (2.2) (0.4) (0.4) 0 (11.1) (12.9) (7.1) (3.6) 0 (2.7) (1.3) (5.3)

Placebo group (n 5 225)

75 62 42 29 17 16 14 1

(35.2) (29.1) (19.7) (13.6) (8.0) (7.5) (6.6) (0.5)

7 11 3 5 1 1

(3.1) (4.9) (1.3) (2.2) (0.4) (0.4) 0 1 (0.4)

7 9 10 10 6 4

(3.3) (4.2) (4.7) (4.7) (2.8) (1.9)

3 7 0 4 0 4

(1.3) (3.1) (0.0) (1.8) (0.0) (1.8)

URTI, Upper respiratory tract infection. *Indicates mild erythema and not ulcerations or infection.

TABLE IV. Time to onset and number of days reported for local application-site AEs Time to onset (d) Grass AIT group (n 5 213)

No. of days reported Placebo group (n 5 225)

Grass AIT group (n 5 213)

Placebo group (n 5 225)

AE

No.

Median

Range

No.

Median

Range

Median

Range

Median

Range

Oral pruritus Mouth edema Throat irritation Pharyngeal edema Stomatitis* Ear pruritus Oral paresthesia

75 17 63 14 16 42 29

1 8 1 2.5 2 1 1

1-135 1-36 1-58 1-36 1-65 1-8 1-6

7 1 11 — 1 3 5

2 2 1 — 6 2 1

1-140 2 1-78 — 6 1-26 1-1

6 4 4 1 3 2.5 7

1-217 1-158 1-170 1-22 2-241 1-224 1-241

2 1 2 — 1 1 2

1-27 1 1-5 — 1 1 1-6

*Indicates mild erythema and not ulcerations or infection.

It would be of interest to compare the efficacy of grass AIT treatment with similar trials of subcutaneous grass pollen immunotherapy. However, there are very few randomized, placebocontrolled, double-blind trials for comparison. The only wellcontrolled trial that fits these criteria was conducted by Frew et al,34 who reported a relative DSS improvement of 29% for high-dose allergen and 22% for low-dose allergen. However, these symptom improvements are still not directly comparable with those in the current study because the study by Frew et al also included lung symptoms in the DSS. No well-controlled subcutaneous grass pollen allergen study has provided combined symptom and medication score results. In the current study asthma symptom scores were improved by grass AIT treatment. These results agree with those published in 3 meta-analyses of previous studies35-37 that concluded that immunotherapy improved asthma symptoms; however, this study was not powered to determine differences in asthma outcomes. For subcutaneous immunotherapy, asthma is a risk factor for serious systemic reactions.8,9,38 There were no serious or severe treatment-related asthmatic events in the current study, although 21% of the grass AIT-treated subjects had asthma. It is important to note that only subjects whose asthma was well controlled were enrolled in the trial. More studies are needed to evaluate the safety of grass AIT treatment in asthmatic subjects.

Overall, grass AIT treatment was generally safe and well tolerated. The AEs reported were typical for sublingual administration of allergen and were similar to those reported in European trials, with mainly mild and moderate local application-site reactions.24,39 The typical pattern of these reactions was onset within a few days of treatment initiation and persistence for 1 to 2 days, followed by spontaneous resolution with no need for intervention. The duration of each type of event was not systematically measured in this study, but observations suggest the AEs were transient, which is consistent with a previous study with grass AIT treatment reporting that each episode lasts only minutes or a few hours at most.39 ‘‘Stomatitis’’ was one of the commonly reported AEs in this trial; these events were not generally infections or ulcerations in the mouth but rather usually described as redness or erythema in the mouth. One of the safety concerns with subcutaneous immunotherapy is the risk of systemic allergic reactions.8,9,40 In this study there were no events of anaphylactic shock or respiratory compromise. Epinephrine was administered to 2 subjects (by the investigator after the first grass AIT dose in 1 subject and self-administered in a placebo-treated subject). The subject in the grass AIT group who received epinephrine after experiencing chest discomfort and rash in addition to local application-site reactions might have had a grade 1 systemic reaction according to the World Allergy

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Organization grading system for subcutaneous immunotherapy.30 The event occurred on day 1 in a health care environment, the reaction resolved with standard intervention, and the subject was discontinued from the study. Nonetheless, it is important for not only the treating medical personnel but also the patient to recognize the signs/symptoms of a systemic reaction to treat appropriately and avoid a potentially serious outcome. Some of the AEs reported, namely pruritus and urticaria, might be indicative of a systemic reaction; however, such events occurred in both treatment groups, resolved without progression, and rarely led to treatment discontinuation. Overall, this trial confirmed an acceptable safety profile of grass AIT treatment in a North American population with no new safety signals compared with the European experience, which to date includes 5 major clinical trials involving 1106 subjects treated with grass AIT (dose range 2500–500,000 SQ-T [93–18,666 BAU]). In these trials there have been no reports of anaphylactic shock and only 1 treatment-related serious AE (uvula edema, 25,000 SQ-T [933 BAU] dose, no treatment was required and the subject did not discontinue from the study).22-25,39 In conclusion, this trial indicates the efficacy of timothy grass AIT treatment (timothy grass is cross-reactive with rye, meadow fescue, bluegrass, cocksfoot, sweet vernal, and redtop and partially cross-reactive with Johnson grass) in multisensitized North American subjects. The treatment was generally well tolerated, with no reports of respiratory compromise or anaphylactic shock. Grass AIT treatment might provide a new convenient treatment modality for North American patients with timothy grass– and related grass pollen–induced ARC. Medical writing and editorial assistance was provided by Erin P. Scott, PhD, of Complete Publication Solutions, LLC. This assistance was funded by Merck & Co.

Clinical implications: Patients with timothy grass–and other related grass–induced ARC in North America can be treated safely and effectively with timothy grass AIT treatment. REFERENCES 1. Blaiss MS. Allergic rhinoconjunctivitis: burden of disease. Allergy Asthma Proc 2007;28:393-7. 2. Galant S, Berger W, Gillman S, Goldsobel A, Incaudo G, Kanter L, et al. Prevalence of sensitization to aeroallergens in California patients with respiratory allergy. Allergy Skin Test Project Team. Ann Allergy Asthma Immunol 1998;81:203-10. 3. Wu LY, Steidle GM, Meador MA, Fosso CK, McDowell LJ, Shin RB, et al. Effect of tree and grass pollens and fungal spores on spring allergic rhinitis: a comparative study. Ann Allergy Asthma Immunol 1999;83:137-43. 4. Nathan RA. The burden of allergic rhinitis. Allergy Asthma Proc 2007;28:3-9. 5. Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, et al. Sub-lingual immunotherapy: World Allergy Organization position paper 2009. Allergy 2009;64(suppl 91):1-59. 6. Nelson HS. Allergen immunotherapy: where is it now? J Allergy Clin Immunol 2007;119:769-79. 7. Canonica GW, Passalacqua G. Noninjection routes for immunotherapy. J Allergy Clin Immunol 2003;111:437-49. 8. Bernstein DI, Wanner M, Borish L, Liss GM. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990-2001. J Allergy Clin Immunol 2004; 113:1129-36. 9. Amin HS, Liss GM, Bernstein DI. Evaluation of near-fatal reactions to allergen immunotherapy injections. J Allergy Clin Immunol 2006;117:169-75. 10. Penagos M, Compalati E, Tarantini F, Baena-Cagnani R, Huerta J, Passalacqua G, et al. Efficacy of sublingual immunotherapy in the treatment of allergic rhinitis in pediatric patients 3 to 18 years of age: a meta-analysis of randomized, placebocontrolled, double-blind trials. Ann Allergy Asthma Immunol 2006;97:141-8. 11. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 2005;60:4-12.

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12. Novembre E, Galli E, Landi F, Caffarelli C, Pifferi M, De Marco E, et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J Allergy Clin Immunol 2004;114:851-7. 13. Acquistapace F, Agostinis F, Castella V, Kantar A, Novembre E, Perrone MR, et al. Efficacy of sublingual specific immunotherapy in intermittent and persistent allergic rhinitis in children: an observational case-control study on 171 patients. The EFESO-children multicenter trial. Pediatr Allergy Immunol 2009;20:660-4. 14. Marogna M, Tomassetti D, Bernasconi A, Colombo F, Massolo A, Businco AD, et al. Preventive effects of sublingual immunotherapy in childhood: an open randomized controlled study. Ann Allergy Asthma Immunol 2008;101:206-11. 15. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, Host A, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007;62:943-8. 16. Durham SR, Emminger W, Kapp A, Colombo G, de Monchy JG, Rak S, et al. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J Allergy Clin Immunol 2010;125:131-8, e1-7. 17. Durham SR, Walker SM, Varga EM, Jacobson MR, O’Brien F, Noble W, et al. Longterm clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468-75. 18. Nelson HS, Oppenheimer J, Vatsia GA, Buchmeier A. A double-blind, placebocontrolled evaluation of sublingual immunotherapy with standardized cat extract. J Allergy Clin Immunol 1993;92:229-36. 19. Skoner D, Gentile D, Bush R, Fasano MB, McLaughlin A, Esch RE. Sublingual immunotherapy in patients with allergic rhinoconjunctivitis caused by ragweed pollen. J Allergy Clin Immunol 2010;125:660-6, e1-6. 20. Esch RE, Bush RK, Peden D, Lockey RF. Sublingual-oral administration of standardized allergenic extracts: phase 1 safety and dosing results. Ann Allergy Asthma Immunol 2008;100:475-81. 21. Amar SM, Harbeck RJ, Sills M, Silveira LJ, O’Brien H, Nelson HS. Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. J Allergy Clin Immunol 2009;124:150-6, e1-5. 22. Bufe A, Eberle P, Franke-Beckmann E, Funck J, Kimmig M, Klimek L, et al. Safety and efficacy in children of an SQ-standardized grass allergen tablet for sublingual immunotherapy. J Allergy Clin Immunol 2009;123:167-73, e7. 23. Calderon M, Essendrop M. Specific immunotherapy with high dose SO standardized grass allergen tablets was safe and well tolerated. J Investig Allergol Clin Immunol 2006;16:338-44. 24. Dahl R, Kapp A, Colombo G, de Monchy JG, Rak S, Emminger W, et al. Efficacy and safety of sublingual immunotherapy with grass allergen tablets for seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;118:434-40. 25. Durham SR, Yang WH, Pedersen MR, Johansen N, Rak S. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:802-9. 26. Didier A, Malling HJ, Worm M, Horak F, Jager S, Montagut A, et al. Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. J Allergy Clin Immunol 2007;120:1338-45. 27. Martin BG, Mansfield LE, Nelson HS. Cross-allergenicity among the grasses. Ann Allergy 1985;54:99-104. 28. White JF, Bernstein DI. Key pollen allergens in North America. Ann Allergy Asthma Immunol 2003;91:425-36, 92. 29. Juniper EF, Thompson AK, Ferrie PJ, Roberts JN. Validation of the standardized version of the Rhinoconjunctivitis Quality of Life Questionnaire. J Allergy Clin Immunol 1999;104:364-9. 30. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: the World Allergy Organization subcutaneous immunotherapy systemic reaction grading system. J Allergy Clin Immunol 2010;125:569-74, 574.e1-574.e7. 31. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117: 391-7. 32. Casale TB, Canonica GW, Bousquet J, Cox L, Lockey R, Nelson HS, et al. Recommendations for appropriate sublingual immunotherapy clinical trials. J Allergy Clin Immunol 2009;124:665-70. 33. Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases. London: European Medicines Agency; 2009. 34. Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006;117:319-25. 35. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003;(4):CD001186. 36. Calamita Z, Saconato H, Pela AB, Atallah AN. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006;61:1162-72.

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37. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies. Clin Ther 2000;22:329-41. 38. Cox L. Allergen immunotherapy and asthma: efficacy, safety, and other considerations. Allergy Asthma Proc 2008;29:580-9.

39. Kleine-Tebbe J, Ribel M, Herold DA. Safety of a SQ-standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo-controlled trial. Allergy 2006;61:181-4. 40. Bernstein DI, Epstein T, Murphy-Berendts K, Liss GM. Surveillance of systemic reactions to subcutaneous immunotherapy injections: year 1 outcomes of the ACAAI and AAAAI collaborative study. Ann Allergy Asthma Immunol 2010;104:530-5.

ALLERGY ARCHIVES ROSE POLLEN Dr A. W. Frankland describes the changing nomenclature of seasonal rhinitis.

Razi

In 1960 Dr Freeman was asked about making a rose pollen extract for testing patients since it was available commercially. He stated that it was perfume and not pollen that might cause symptoms in someone who already had hay fever symptoms due to grass pollen. This person sees the roses blooming at the same time the grass pollen is in the air, and they blame what they can see, not what they cannot see. Indeed summer hay fever due to grass pollen was called “rose fever” in the past. The first description of summer hay fever called “rose fever” was about 1000 years ago by Razi.1 The large rose called “peace” was grown and, when the rose when fully blossoming and with a subtle scent, the antlers were cut off with scissors and these were floated in chloroform, dried, and then extracted with buffered water solution. The open rose certainly had been contaminated with grass pollens. Even a 1% contamination would give a positive skin test and a nasal provocation test in someone who is grass pollen allergic.

William Dunbar

It is reported that Leonardo Botello of the University of Pavia, described in detail in 1533 what became known as “rose-fever,” but it was recognised even before then because Cardinal Olivieri, who died in 1511, made guards outside his palace send away any visitor who brought bunches of roses.2 Bostock of London, in 1828, describes his seasonal symptoms affecting the eyes and chest.3 Blackley, in 1873, also notes that Dr Cornay from Switzerland prefers “de foin” (of hay) to that of “d’été” (of summer).4 Dunbar,5 who had proved that grass pollen was the cause of his seasonal symptoms, tried to explain the word “fever” because people had thought the complaint an infectious disease and were influenced at the time by Pasteur’s publications. This explanation of the word “fever” seems unlikely as Razi (865-925) writes that if the symptoms were very severe the temperature rises. John Bostock writing in 1828 objects to the word “hay fever” as his complaint was not due to “hay” but he makes no mention of fever.3 Blackley having proved his seasonal symptoms were due to grass pollen, states that the terminology of hay fever, used by the laity, was wrong in that the symptoms were not due to hay. He makes no reference to the term “fever.” Finally, rose pollen has now been described as causing urticaria of the hands, conjunctivitis, rhinitis and occupational asthma in 6.2% of rose water production workers, whoser only allergic reaction was to Rosa rugosa.6

1. Hau FB. The English translation by Jawadf on Razi’s thesis on Rose Allergy. Pakistan J. Otolaryngology 1986;2:20-5. 2. Footnotes on allergy. Harper DS (ed). Uppsala, Sweden: 1980. 3. Bostock JM. Of catarrhus aestivus. Med Chir Trans 1828;14:437. 4. Blackley CH. Experimental researches on the causes and nature of catarrhus aestivus (hay fever or hay-asthma). London: Balliere, Tindall and Cox; 1873. 5. Dunbar WPJ. The present state of our knowledge of hayfever Hygiene 1913;13:105-48. 6. Demir AU, Karakaya G, Kalyoncu AF. Allergy symptoms and IgE immune response to rose: an occupational and environmental disease. Allergy 2002;57:936-9.

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FIG E1. Change from baseline in adjusted mean antibody levels for Phl p 5–specific IgG4 (A) and IgE-blocking factor (B). *P < .001 versus placebo.

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TABLE E1. Scoring of rescue medication use Step

Rescue medication

Rhinoconjunctivitis 1 Loratadine tablet: 10 mg, 1 tablet QD 1b Olopatadine hydrochloride 0.1% ophthalmic solution: 1 drop in the affected eye BID 2 Mometasone furoate monohydrate nasal spray: 50 mg, 2 sprays in each nostril QD 3 Prednisone tablet: 5 mg (day 1, 1 mg/kg/d, maximum of 50 mg/d) 3 Prednisone tablet: 5 mg (day 21, 0.5 mg/kg/d, maximum of 25 mg/d) Maximum daily rhinoconjunctivitis medication score Asthma A Albuterol sulfate HFA inhalation aerosol: 108 mg/inhalation, 2 inhalations every 4-6 h as needed  B Fluticasone propionate HFA inhalation aerosol: 44 mg/inhalation, 2 inhalations BID (maximum of 10 inhalations BID)à C Prednisone tablet: 5 mg (day 1, 1 mg/kg/d, maximum of 50 mg/d) C Prednisone tablet: 5 mg (day 21, 0.5 mg/kg/d, maximum of 25 mg/d) Maximum daily asthma medication score Maximum combined medication score

Score/dose unit

6 (per tablet) 1.5 (per drop) 2 (per spray) 1.6 (per tablet) 1.6 3 2 (per tablet)

2 (per inhalation) 1 (per inhalation) 1.6 (per tablet) 1.6 3 2 (per tablet)

BID, Twice daily; HFA, hydrofluoroalkane; QD, once daily. *Prednisone use was counted in the rhinoconjunctivitis or asthma score depending on the symptoms and was counted only once in the combined score.  Labeled strength of 108 mg per inhalation (equivalent to 90 mg of albuterol base) in the United States and salbutamol sulfate (100 mg) in Canada. àLabeled strength of 44 mg per inhalation in the United States and 50 mg per inhalation in Canada.

Maximum daily score

6 6 8 16* 16* 36 8 8 16* 16* 32 52*