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In AIT, multiyear administration regimens (Figure 1) can be dichotomized as continuous (i.e. year-round) or discontinuous (i.e. with
a treatment-free period each year).

Figure 1. AIT regimens for seasonal allergic rhinitis.

Setting aside the allergen build-up phase (during which administration of the maintenance
dose of allergen is achieved over a number of weeks, days or even hours, depending
on whether conventional, rush or ultra-rush protocols are applied), SCIT is generally
administered via a continuous, year-round maintenance regimen in which injections
performed in a medically supervised setting at regular intervals (typically every
4 to 6 weeks for aeroallergen extracts) for several years and thus over several pollen
periods (Figure 1) 22]). Injections with longer time intervals have not been tested in DBPC RCTs. The literature
data suggest that the risk of a severe adverse reaction to pollen SCIT is exacerbated
during the corresponding peak pollen period 40]. For example, Lockey et al.’s analysis of data collected between 1945 and 1973 found
that 41% of the recorded SCIT-related deaths had occurred during the pollen period
41]. Hence, the latest US practice parameter for AIT confirms historical practice and
suggests that maintenance dose levels may be reduced (and certainly not increased)
during periods when the patient is naturally exposed to high levels of the disease-inducing
allergen 22],42],43] (Figure 1).

Despite the proven efficacy of SCIT, a number of safety and ease-of-use concerns remain.
Indeed, SLIT has advantages in terms of safety and convenience (especially in children)
20],21],44]. Although pre-seasonal-only, co-seasonal-only and perennial regimens have all been
evaluated for SLIT formulations, a pre- and co-seasonal regimen is most commonly used
(Figure 1). A 2009 review of pollen SLIT administration regimens (mostly involving drop formulations)
45] listed three studies with a pre-seasonal-only regimen (e.g. 46]), three with a co-seasonal-only regimen (e.g. 47],48]), eight with a continuous or partially post-seasonal regimen (e.g. 49]) and 27 with a pre- and co-seasonal regimen. Historically, pollen SLIT drops have
been administered daily, every other day or three times a week. In pollen-induced
AR, continuous or post-seasonal administration is challenging because patients will
not perceive the benefit of SLIT after the pollen period has ended (i.e. when their
symptoms have disappeared). Longer periods of medication are associated with poorer
compliance and thus a lower likelihood of effectiveness 50],51].

Conversely, pre- and co-seasonal regimens also have limitations. Trials of a five-grass
pollen SLIT tablet formulation have shown that 2 months of pre-seasonal treatment
(followed by co-seasonal treatment) is less effective than 4 months of pre-seasonal
treatment 52],53]. Similarly, a trial of a single-grass pollen SLIT tablet formulation found that the
magnitude of the reductions in rhinoconjunctivitis symptom and medication scores increased
with the duration of preseasonal treatment (4 months appeared to be optimal) 54]. Hence, a patient with a pollen allergy following a pre- and co-seasonal regimen
from one year to another must remember to obtain medication and initiate treatment
long enough ahead of the pollen season. This particular problem (persistence of treatment)
is avoided if a year-round regimen is strictly adhered to. In a study in Germany,
the prescription renewal rate (a proxy for treatment persistence) for SLIT or subcutaneous
immunotherapy formulations were higher (at 55%–71%) than those reported elsewhere
for conventional medications 55].

A large body of evidence attests to the safety and efficacy of pre- and co-seasonal
regimens for pollen SLIT drops when administered for one season or several consecutive
seasons. Recently, Worm et al. performed a robust, two-season, DBPC RCT of pre- and
co-seasonal treatment with a 300 index of reactivity (IR) birch pollen sublingual
solution in 574 adult immunotherapy-naïve patients with birch-pollen-induced allergic
rhinoconjunctivitis at 56 investigating centres in 11 European countries 56]. The treatment started 4 months before the expected pollen period. At the start of
the study, 68% of the patients were polysensitized, 20% had mild-to-moderate asthma
and 54% had oral allergy syndrome. The primary efficacy endpoint over the second birch
pollen period) was found to be significantly lower (p??0.0001) in the active SLIT
group (relative difference vs. placebo: 30.6%; difference in the least-squares (LS)
means: ?2.04 [95% confidence interval: ?2.69; ?1.40]). A 19.0% difference was also
seen for active SLIT in the first pollen period. The average medication score was
significantly lower in the 300 IR SLIT group in both seasons, with relative LS mean
differences of ?29.3% and ?41.9%, respectively (p??0.0001 for both). Active treatment
was associated with a better Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ)
score in the first and second pollen periods, with relative LS mean differences of
?23.1% and ?34.5%, respectively. Treatment-emergent adverse events (TEAEs) were no
more frequent in the 300 IR SLIT group than in the placebo group and were less frequent
in the second season (respectively 70.7% and 64.0% of patients affected in season
1, and 46.8% and 48.6% p in season 2. This decrease over time was also observed for
common, local adverse events (AEs) such as oral pruritus (24.7% of patients affected
in season 1 and 8.3% affected in season 2 in the SLIT group; 3.8% and 0.8% in the
placebo group, respectively. The treatment’s efficacy and the frequency of TEAEs did
not appear to depend on the presence or absence of oral allergy syndrome 56].

In a multicentre, DBPC, randomized phase III trial, Wahn et al. 57] randomized 207 children aged between 4 and 12 with grass pollen AR/rhinoconjunctivitis
with or without bronchial asthma into an active treatment group (SLIT with an aqueous
six-grass pollen extract) and a placebo group. A pre- and co-seasonal regimen was
applied. The primary efficacy end point was the comparison of the change of the area
under the curve for the symptom–medication score, starting from the baseline season
to the first grass pollen season after the initiation of treatment. The values were
-212.5 and -97.8 in the active SLIT group and the placebo groups, respectively (p??0.004),
evidencing a significantly greater reduction in severity in the active SLIT group.
In terms of safety, 75.9% of the patients in the active SLIT treatment group experienced
at least one AE (compared with 32.7% of the patients in the placebo group) but no
treatment-related severe AEs were recorded. However, only one pollen period was studied;
the effect of treatment discontinuation and resumption could not therefore be assessed.

Although most studies of pre- and co-seasonal SLIT regimens have dealt with grass
and birch pollen formulations, other pollens have been studied. For example, pre-
and co-seasonal SLIT with a standardized aqueous ragweed pollen extract was studied
by Creticos et al. 58] A total of 429 patients were randomized (active SLIT: n?=?218; placebo: n?=?211)
into a multicentre, DBPC, randomized, phase III trial in North America. The treatments
were administered between April 2011 (i.e. at least 4 months before the start of the
ragweed pollen period in October) and November 2011 (the end of the period). The primary
efficacy end point was the average daily rhinoconjunctivitis symptom-medication score
over the course of the ragweed pollen season; the value in the SLIT group (0.82?±?1.64)
was significantly lower than in the 1.44?±?2.40 in the placebo group (p??0.001).
Again, only one pollen period was studied and the effect of treatment discontinuation
and resumption was not assessed.

Although DBPC RCTs remain the gold standard for evaluating investigational products,
“real-life” studies are essential for completing effectiveness and safety under “real-life”
conditions in the target patient population. To this end, Hadler et al. performed
an open, prospective, non-interventional study in Germany evaluating the 300 IR birch
pollen SLIT solution in 716 polyallergic and monoallergic patients (mean?±?SD age:
38?±?16; age range 3-87) over two pollen seasons 59]. A pre- and co-seasonal regimen was applied. The patients’ symptoms were scored on
a hybrid scale that took account of disease severity and frequency for rhinitis alone,
conjunctivitis alone and rhinoconjunctivitis. The mean rhinitis score in the birch
season prior to the study was 4.83. This value fell to 3.17 in the first pollen season
and 2.31 (a 52% reduction, p??0.001) in the second pollen season. The mean conjunctivitis
score fell from 3.74 to 2.1 and then 1.69 (a 55% reduction, p??0.001). Lastly, the
mean rhinoconjunctivitis score fell from 3.76 to 2.29 and then 1.76 (a 53% reduction,
p??0.001). In a subgroup analysis, the 300 IR pollen SLIT solution appeared to be
similarly effective in mono-allergic and polyallergic patients and in those with an
intra-seasonal start to treatment. The percentage of patients requiring symptomatic
medication was also significantly lower (p??0.001) during the first and second pollen
season (59% and 48%, respectively, compared with 81% before the study. Both mono-allergic
and poly-allergic patients gained clinical relief. The 300 IR birch pollen SLIT solution
was well tolerated, and 97% of the patients evaluated tolerability as “good” or “very
good”. Ninety percent of the patients did not report an adverse event during the two
treatment seasons 59]. In clinical practice, the majority of patients receiving sublingual immunotherapy
with allergen-specific 300 IR SLIT solution are satisfied with treatment 60], and compliance and prescription renewal rates are relatively high 55],61].

Taken as a whole, these “real-life” findings for 300 IR birch pollen SLIT solution
confirmed the results of the DBPC RCTs.

The third main type of AIT formulation is the SLIT tablet. Two tablet formulations
of grass pollen SLIT (a single-grass tablet 36],37] and a five-grass pollen tablet 38],39]) have been approved to date for an indication of grass-pollen-induced AR (with or
without conjunctivitis) in adults and children. According to the respective summaries
of product characteristics and the pivotal DBPC RCTs, a 75,000 standardized quality
tablet (SQ-T) single-grass SLIT tablet 36],37] is approved for administration with a continuous, year-round regimen (starting before
the first pollen season; Figure 1), whereas a 300 IR five-grass SLIT tablet 38],39] is approved for administration with a discontinuous pre-and co-seasonal regimen (i.e.
starting four months before the expected start of the pollen season and finishing
at the end of the pollen season; Figure 1). Hence, the total treatment duration per year is between 5 and 7 months (depending
on the duration of the pollen season) and the onset of action (in an allergen challenge
chamber study) was found to occur after one month of treatment 62].

Over the last 10 years, the safety and/or efficacy of pre-seasonal and co-seasonal
treatment with a novel, 300 IR five-grass-pollen SLIT tablet has been unambiguously
demonstrated in a series of pre- and post-marketing clinical trials in adult and paediatric
populations 39]. Worldwide, a total of 2,512 study participants have been randomized to receive either
the five-grass-pollen SLIT tablet (n?=?1,514) or a placebo (n?=?998) 39]. Furthermore, the 300 IR five-grass-pollen SLIT tablet was proven to be similarly
effective in several clinical profiles (monosensitized patients, polysensitized patients,
patients with high symptom scores and patients with high skin sensitivity) 63]. After the pivotal, single-season Phase II/III DBPC RCT in which the dose of 300
IR was selected for further investigation and registration 64], the 300 IR five-grass-pollen SLIT tablet’s sustained efficacy and efficacy after
discontinuation of treatment was investigated by Didier et al. in a 5-year DBPC RCT
in adults with AR at centres in the European Union and Canada 39],52],53]. In fact, the European Medicines Agency currently requires AIT preparations to have
(i) efficacy in the first season after the start of treatment, (ii) a proven, sustained
clinical effect (defined as the maintenance of significant and clinically relevant
efficacy during two to three treatment years) and (iii) long-term efficacy (defined
as sustained significant and clinically relevant efficacy in post-treatment years,
i.e. a disease-modifying effect) 65].

Hence, Didier et al. investigated three seasons of pre-seasonal and co-seasonal treatment
with a 300 IR five-grass-pollen SLIT tablet in adult patients (aged 18 to 50) with
a history of seasonal AR to grass pollen for more than two pollen seasons and continued
to monitor the patients for a further two treatment-free seasons 39],52],53],66]. A total of 633 patients were randomized into one of three groups: (i) 300 IR grass
pollen SLIT tablet, with active treatment starting 4 months (the 4 M group) before
the expected start of the pollen season followed by co-seasonal treatment; (ii) 300
IR grass pollen SLIT tablet, with first a placebo taken for 2 months (starting 4 months
before the expected start of the pollen season, to maintain the blinding), followed
by 2 months of active treatment (the 2 M group) and then co-seasonal active treatment,
and lastly (iii) placebo treatment starting 4 months before the expected start of
the pollen season, followed by co-seasonal treatment. These discontinuous treatments
were administered for three pollen seasons (years 1 to 3). After the end of the third
treatment season, patients were monitored over the following two treatment-free pollen
season (years 4 and 5). Of the 633 randomized patients, 457 completed year 3 and 435
contributed to the (post-treatment) efficacy analyses in year 4. The study’s primary
efficacy end-point was a symptom score over the third pollen period. Secondary endpoints
included the six individual rhinoconjunctivitis symptom scores (sneezing, rhinorrhoea,
nasal pruritus, nasal congestion, ocular pruritus and watery eyes), the average medication
score and the RQLQ score. In year 4, the symptom scores in the two active treatment
groups were similarly and significantly lower than in the placebo group, and significant
efficacy was determined in year 5 66]. In a subsequent post hoc analysis, the mean LS daily combined score was found to be 28.1% lower in the 300
IR tablet group than the placebo group p?=?0.0478), thus demonstrating long-term efficacy
and a disease-modifying effect of the 300 IR five-grass-pollen SLIT tablet. The difference
in LS means between the 4 M group and the 2 M group was not statistically significant.
The 300 IR five-grass-pollen SLIT tablet’s safety profile over the entire study period
was consistent with previous reports, with generally mild, transient, local AEs 39],52],53],67]. Over the first three treatment seasons, the incidence and severity of TEAEs decreased
from one year to the next in all three treatment groups. In the first treatment season,
the most frequently reported TEAEs were oral pruritus (30% and 11.4% in the active
and placebo groups, respectively), throat irritation (15% and 3.7%, respectively),
and mouth oedema (6% and 1.4%, respectively). During the first treatment year (but
not the second and the third treatment year), the number of discontinuations due to
TEAEs was higher in patients treated with the 300 IR formulation (7.2% in the two
active groups and 1.4% in the placebo group). During the fourth year of study, the
incidence of treatment-emergent AEs was similar in the 300 IR (4 M), 300 IR (2 M)
and placebo groups, with values of 31.7%, 34.8% and 35.9%, respectively. Importantly,
exacerbation of asthma was not an issue, and the one case in the 300 IR (4 M) and
the two cases in the placebo group were not judged to be related to the study treatment
52],53].

Following on from the above-mentioned DBPC RCTs, a number of post-marketing studies
in Europe have confirmed the 300 IR five-grass-pollen SLIT tablet’s safety and/or
efficacy when a pre- and co-seasonal regimen is used in actual clinical practice.
In Germany, the OPTIMAL multicentre, prospective, open-label, non-interventional study
assessed the tolerability and effectiveness of two consecutive years of a pre- and
co-seasonal treatment regimen with the 300 IR five-grass-pollen SLIT tablet in a total
of 1,482 adult and paediatric patients (including 248 children aged from 4 to 11 and
201 adolescents aged from 12 to 17) 68]. Compared with the baseline season, the mean rhinoconjunctivitis scores were significantly
lower in the two treatment seasons (by 51% and 64%, respectively; p??0.001). Importantly,
the asthma symptom score for the 522 patients with comorbid mild asthma was also significantly
lower in the two treatment seasons (by 60% and 70%, respectively for year 1 and 2,
respectively; p??0.001). When considering the children alone, the mean rhinoconjunctivitis
score fell from 4.1 in the baseline season to 1.93 after the first season and 1.39
after the second. For the adolescent subgroup, the corresponding values were 4.05,
1.97 and 1.39. The mean rhinoconjunctivitis score fell in both mono-allergic and polyallergic
subjects, confirming the DBPC RCT results. For example, the respective baseline, year
1 and year 2 rhinoconjunctivitis score were 4.05, 1.95 and 1.29 in mono-allergic children
and 4.09, 1.94 and 1.46 in polyallergic children 68].

A similar multicentre, open-label, observational, cross-sectional, single-season study
of pre- and co-seasonal treatment with a 300 IR five-grass-pollen SLIT tablet has
been carried out in Spain 69]. A total of 226 adult patients (mean age: 33.9?±?11.5) were included in the study.
Fifty-five percent had mild asthma and 92% of patients had persistent moderate-severe
AR (according to the Allergic Rhinitis and its Impact on Asthma criteria 1],2]). Following pre- and co-seasonal treatment with the 300 IR five-grass-pollen SLIT
tablet, the percentage of patients with moderate-severe AR was 30%. Symptomatic medication
use also fell; the percentages of patients using oral H1-antihistamines and ICSs decreased
from 92% and 77%, respectively, at baseline to 62% and 28%, respectively, at the end
of the treatment period 69].