Pediatric Allergy and Immunology

ORIGINAL ARTICLE Upper airways & sit

Efficacy of MP-AzeFlu in children with seasonal allergic

rhinitis: Importance of paediatric symptom assessment
William Berger1,2, Eli O. Meltzer3, Niran Amar4, Adam T. Fox5, Jocelyne Just6,7, Antonella Muraro8,
Antonio Nieto9, Erkka Valovirta10, Magnus Wickman11,12 & Jean Bousquet13,14,15,16
1
Division of Basic Clinical Immunology, School of Medicine, University of California, Irvine, CA, USA; 2Allergy and Asthma Associates, Mission
Viejo, CA, USA; 3Allergy and Asthma Medical Group and Research Center, San Diego, CA, USA; 4Allergy & Asthma Research Institute, Waco,
TX, USA; 5King’s College London, MRC & Asthma UK centre in Allergic Mechanisms of Asthma, Division of Asthma, Allergy and Lung Biology,
Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 6Allergology Department, Centre de l’Asthme et des Allergies, Ho ^pital d’Enfants
Armand-Trousseau (APHP) -APHP, Paris, France; 7Sorbonne Universite s, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis
d’Epidemiologie et de Sante  Publique, Equipe EPAR, Paris, France; 8Department of Mother and Child Health, Padua General University Hospital,
Padua, Italy; 9Pediatric Allergy and Pneumology Unit, Children’s Hospital La Fe, Valencia, Spain; 10Department of Lung Diseases & Clinical
Allergology, University of Turku & Terveystalo Allergy Clinic, Turku, Finland; 11National Institute of Environmental Medicine, Karolinska Institutet,
Stockholm, Sweden; 12Department of Pediatrics, Sachs’ Children’s Hospital, Stockholm, Sweden; 13University Hospital, Montpellier, France;
14
MACVIA-LR, Contre les Maladies Chronique pour un Vieillissement Actif en Languedoc Roussilon, European Innovation Partnership on Active
and Healthy Aging Reference Site, Montpellier, France; 15INSERM, VIMA: Ageing and chronic diseases. Epidemiological and public health
approaches, U1168, Paris, France; 16UVSQ UMR-S1168, Universite Versailles St-Quentin-en-Yvelines, Versailles, France

To cite this article: Berger W, Meltzer EO, Amar N, Fox AT, Just J, Muraro A, Nieto A, Valovirta E, Wickman M, Bousquet J. Efficacy of MP-AzeFlu in children with
seasonal allergic rhinitis: Importance of paediatric symptom assessment. Pediatr Allergy Immunol 2016: 27: 126–133.

Keywords Abstract
azelastine; assessment; children; dymista;
fluticasone propionate; MP-AzeFlu; seasonal
Background: This study aimed to assess the efficacy of MP-AzeFlu (a novel intranasal
allergic rhinitis formulation of azelastine hydrochloride and fluticasone propionate in a single spray)
in children with seasonal allergic rhinitis (SAR) and explore the importance of child
Correspondence symptom severity assessment in paediatric allergic rhinitis (AR) trials.
William E. Berger, Allergy and Asthma Methods: A total of 348 children (4–11 years) with moderate/severe SAR were
Associates of Southern California, Mission randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial.
Viejo, CA 92691, USA Efficacy was assessed by changes from baseline in reflective total nasal symptom score
Tel.: +1 949 364 2900 (rTNSS), reflective total ocular symptom score (rTOSS) and individual symptom
Fax: +1 949 365 0117 scores over 14 days (children 6–11 years; n = 304), recorded by either children or
E-mail: weberger@uci.edu caregivers. To determine whether a by-proxy effect existed, efficacy outcomes were
assessed according to degree of child/caregiver rating. Moreover, total Paediatric
Accepted for publication 17 December 2015 Rhinitis Quality of Life Questionnaire (PRQLQ) score was compared between the
groups.
DOI:10.1111/pai.12540 Results: A statistically superior, clinically relevant efficacy signal of MP-AzeFlu versus
placebo was apparent for PRQLQ overall score (diff: 0.29, 95% CI 0.55, 0.03;
p = 0.027), but not for rTNSS (diff: 0.80; 95% CI: 1.75; 0.15; p = 0.099). However,
as the extent of children’s self-rating increased, so too did the treatment difference
between MP-AzeFlu and placebo; MP-AzeFlu provided significantly better relief than
placebo for rTNSS (p = 0.002), rTOSS (p = 0.009) and each individual nasal and
ocular symptom assessed (except rhinorrhoea; p = 0.064) when children mostly rated
their own symptoms.
Conclusions: MP-AzeFlu is an effective treatment for AR in childhood. Caregivers are
less able than children to accurately assess response to treatment with available tools.
A simple paediatric-specific tool to assess efficacy in AR trials in children is needed.

Allergic rhinitis (AR) occurs in 8.3% of children aged is far-reaching, negatively affecting children’s overall physical
6–7 years, rising to 14.6% in older children (those aged and emotional health, daily activities, quality of sleep and
13–14 years) (1). Its impact is routinely underestimated, but productivity at school (2). Due to this high burden of disease,

126 Pediatric Allergy and Immunology 27 (2016) 126–133 ª 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Berger et al. Efficacy of MP-AzeFlu in paediatric SAR

there is an ethical duty to ensure provision of effective paediatric symptom severity assessment when assessing efficacy
pharmacotherapy by conducting and reporting good quality in paediatric AR trials.
efficacy and safety trials in children with AR. To that end,
applications for new medicinal products in the EU (since 2007)
and the United States (since 2003 according to the Pediatric Methods
Research Equity Act) must include the results of studies
Study design and hypothesis
conducted in the paediatric population, in compliance with an
agreed paediatric investigation plan (3). This was a randomized, double-blind, multicentre (35 investi-
Intranasal corticosteroids (INS) are widely used to treat AR gational sites in the United States) placebo-controlled, parallel-
in children. Their efficacy is well established in both adults and group, 14-day trial, carried out in children (aged 4 to <12 years
adolescents with seasonal allergic rhinitis (SAR) (4, 5), but old) with moderate/severe SAR (July 2013 to February 2014).
inconsistent effects have been observed in school children (6), Ethics approval was obtained from Chesapeake Research
without a clear dose–response relationship (6–8). Indeed, a Review Inc, Columbia MD. Informed consent (from caregiver)
Cochrane review concluded that the evidence for the effective- and paediatric informed consent (from children 7 years of age
ness of INS for the treatment of intermittent and persistent AR and older) were obtained prior to initiation of any study-
in children is ‘weak and unreliable’, and the reduction in related procedure. The study was conducted in accordance with
symptom severity as assessed in these trials could not be good clinical practice.
confirmed with the data provided (6). Difficulties associated Symptom severity was assessed using changes from baseline
with analysing data from paediatric AR trials include the high in rTNSS, reflective total ocular symptom score (rTOSS),
placebo effect in randomized controlled trials (RCTs) in all reflective total of 7 symptom scores (rT7SS) and individual
groups, and the smaller effect size traditionally observed in symptom scores and could be recorded by either children or
children as compared to adults (4, 7). caregivers. Quality of life (QoL) was assessed using the
Furthermore, there are few specific instruments to assess the PRQLQ and was completed by physicians and children, but
efficacy of anti-allergic treatments in children. The Paediatric without input from caregivers. To determine whether a
Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ) by-proxy effect existed, overall and individual nasal and ocular
has been developed specifically for children (9), but has been symptom scores were assessed according to degree of child/
used in relatively few RCTs (10, 11). In paediatric AR trials, caregiver rating. Moreover, PRQLQ was also compared
efficacy is still assessed using end-points originally designed for between the two groups.
adult use (i.e. reflective total nasal and ocular symptom scores).
The extensiveness, complexity and subjective nature of these
Participants
scores leads to them often being recorded by caregivers rather
than by children themselves. However, comparisons of the Inclusion criteria and exclusion criteria are presented in the
results between children and caregiver assessments have not Data S1. Briefly, male and female children ≥4 to <12 years of
been made to validate this approach. An allergic rhinitis and its age (at screening visit) with a history of SAR and positive skin
impact on asthma (ARIA)-GA2LEN article proposed that prick test showing hypersensitivity to prevailing pollen were
paediatricians and methodologists should analyse current enrolled. Participants were required to have a rTNSS ≥6 and
RCTs in 5- to 11-year-old children to make a comparison reflective congestion score ≥2 on the first day of placebo lead-
between adolescent/adult and children studies (pharmacologic in.
and immunotherapy) (12).
MP-AzeFlu (Dymista, Meda, Solna, Sweden) comprises
Interventions and timing
an intranasal antihistamine (azelastine hydrochloride (AZE))
an INS (fluticasone propionate (FP)) and a novel formula- The study comprised a 3–7 days, single-blind, placebo lead-in
tion delivered in a single spray. Its efficacy and safety is well period and a 14-day treatment period, with 3 study visits on
established in adults and adolescents with SAR (13, 14) and days 1, 8 (1 day) and at end of trial (Day 15 + 3 days). On
those with chronic rhinitis (i.e. perennial AR (PAR) or non- Day 1, eligible children were randomized in a 1:1 ratio to
allergic rhinitis) (15, 16), providing faster and more complete treatment with either MP-AzeFlu nasal spray or placebo, both
symptom control than monotherapy with an intranasal administered as 1 spray/nostril bid, separated by approxi-
antihistamine or INS. MP-AzeFlu has recently been mately 12 h (total daily dose of AZE: 548 lg, FP: 200 lg).
approved for paediatric use in the United States by the Children or their caregivers recorded nasal and ocular symp-
Food and Drug Agency (FDA). Interestingly, although the tom scores in an eDiary twice daily prior to dosing with study
FDA acknowledged that the reflective total nasal symptom medication. Children >6 years old also completed the PRQLQ
score (rTNSS) remains the gold standard primary end-point at the investigator site on Day 8 and Day 15.
in AR trials, the challenges of caregiver-reported assessment
were noted.
Efficacy variables
As part of a pivotal phase III study assessing the efficacy and
safety of MP-AzeFlu in 6- to 11-year-old children with SAR The primary end-point was change from baseline in morning
(NCT01915823), different outcomes for efficacy were analysed and evening rTNSS (max score: 24) over the 14-day treatment
in-depth to provide new insights into the importance of period in children aged 6 to 11 years. Secondary efficacy

Pediatric Allergy and Immunology 27 (2016) 126–133 ª 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd. 127
Efficacy of MP-AzeFlu in paediatric SAR Berger et al.

end-points included change from baseline in rTOSS (max score Table 1 Child demographic and baseline characteristics in those
18), rT7SS (i.e. rTNSS + rTOSS; max score; 42), and individual children aged ≥6 to <12
nasal and ocular symptoms (each scored 0 to 3; AM and PM)
MP-AzeFlu Placebo
over the entire double-blind period in the same age group
Characteristic (n = 152) (n = 152)
(Data S1). Daily change from baseline in rTNSS, rTOSS and
rT7SS were also assessed secondarily. Change in the PRQLQ Age, years, 9.0  1.6 9.0  1.6
total score was assessed from baseline to days 8 and 15. ≥6 years to <9 years 59 (38.8) 60 (39.5)
≥9 years to <12 years 93 (61.2) 92 (60.5)
Gender
Safety variables
Male 86 (56.6) 80 (52.6)
Safety end-points included child/caregiver-reported adverse Race
events (AE; by incidence, type and severity – see Data S1), Black/African American 43 (28.3) 39 (25.7)
focused nasal examination and vital signs measurements. White 100 (65.8) 107 (70.4)
Other or mixed 9 (5.9) 6 (3.9)
Duration of SAR, years 6.1  2.6 6.2  2.4
Sample size, randomization and blinding rTNSS (AM + PM) 18.4  3.5 18.0  3.2
rTOSS (AM + PM) 9.9  4.5 9.5  4.7
Details are provided in the Data S1 text.
Total PRQLQ score 2.6  1.2 2.7  1.2

Statistical analyses Values are presented as mean  standard deviation or n (%).

SAR, seasonal allergic rhinitis; rTNSS, reflective total nasal symptom
Children were randomized and stratified by age group (i.e. 4– score; rTOSS, reflective total ocular symptom score; PRQLQ,
5 years, 6–8 years, and 9–11 years). As pre-specified in the Paediatric Rhinitis Quality of Life Questionnaire.
protocol, data from 6- to 11-year-olds were analysed using
inference statistics. Data from 4- to 5-year-olds were consid-
ered as exploratory only and summarized using descriptive (Fig. 1). By Day 15, MP-AzeFlu-treated children experienced a
statistics. Primary and secondary end-points, including statistically superior and clinically relevant improvement in
PRQLQ for children aged 6 to 11 years were assessed using a their QoL ( 0.95) compared with placebo-treated children
repeated-measures analysis of covariance (ANCOVA) model with ( 0.65; diff 0.29; 95% CI 0.55, 0.03; p = 0.027) (Fig. 1).
treatment day (for PRQLQ: visit), treatment group and age MP-AzeFlu also provided greater improvement than placebo
group as fixed effects and baseline as a covariate. p-values in each of the domain scores of the PRQLQ, reaching
≤0.05 were judged to be significant. Primary and secondary significance by Day 15 for the activity limitation (diff 0.43;
end-points were also analysed post hoc according to degree of 95% CI 0.73, 0.12; p = 0.007) and nose symptoms (diff:
child assessment (details provided in the results section). A 0.35; 95% CI 0.69, 0.02; p = 0.036) domains (Figure S2).
change from baseline in morning and evening rTNSS of at least
50% was considered and defined as a substantial response and Overall nasal symptoms (children aged 6–11 years)
analysed by Kaplan–Meier estimates and log-rank tests.
There was no statistically significant difference between
MP-AzeFlu and placebo (ITT population) for overall change
Results from baseline in rTNSS (AM + PM). Children treated with
MP-AzeFlu experienced a 3.70 pt reduction from baseline
Children
A total of 348 children were randomized. Children aged ≥4 to
<6 years old (n = 44) were excluded from the efficacy analyses
as pre-specified in the statistical analysis plan and agreed with
the FDA. Efficacy is presented for the pre-defined pivotal
group only (6–11 years; n = 152 in each group in the intent-to-
treat (ITT) population). Children’s disposition is provided in
the Data S1 (Figure S1). Discontinuation rate was very low
(n = 2 in each group). Baseline characteristics were similar in
the MP-AzeFlu and placebo groups (Table 1).

Child-reported quality of life (children aged 6–11 years)

Figure 1 Least square (LS) mean change from baseline in Paediatric
A superior efficacy signal of MP-AzeFlu versus placebo was Rhinitis Quality of Life Questionnaire (PRQLQ) total score following
apparent in the QoL outcome. By Day 8, treatment with treatment with MP-AzeFlu (n = 152) or placebo (n = 152), both 1
MP-AzeFlu induced the clinically relevant improvement in spray/nostril bid, for 14 days in children aged ≥6 to 11 years with
PRQLQ overall score (17) of 0.62, which was not the case for moderate/severe seasonal allergic rhinitis. *Diff: 0.29; 95% CI
placebo ( 0.45; diff: 0.17; 95% CI 0.38, 0.04; p = 0.118) 0.55, 0.03; p = 0.027.

128 Pediatric Allergy and Immunology 27 (2016) 126–133 ª 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.
Berger et al. Efficacy of MP-AzeFlu in paediatric SAR

compared to 2.90 in the placebo group (diff: 0.80; 95% poor compliance with rTNSS recording in the diary (i.e.
CI: 1.75; 0.15; p = 0.099) (Table 2). However, statistical <9 days rTNSS data for days 2–14).
significance over placebo was noted for sneezing (diff 0.32;
95% CI: 0.59, 0.04; p = 0.025) and approached signifi-
Efficacy outcome (children vs. caregiver sensitivity analysis)
cance for eye watering (diff: 0.26; 95% CI 0.52, 0.0002;
p = 0.051) (Table S1). Furthermore, older children (i.e. those Since PRQLQ was assessed by children themselves at the
aged ≥9 and <12 years) treated with MP-AzeFlu (n = 93) investigational site, whereas rTNSS was assessed by either
experienced a 3.75 change from baseline in their overall children or their caregivers, it was hypothesized that lack of
rTNSS compared with 2.62 point reduction in the placebo statistical significance in the primary efficacy end-point (i.e.
group (n = 92) (diff: 1.13; 95% CI: 2.21, 0.05; change from baseline in overall rTNSS [AM + PM]) was a
p = 0.040). Similarly, those in the per protocol population consequence of rater assessment bias rather than lack of
(PPP) who received MP-AzeFlu (n = 128) experienced a efficacy. Further evidence to support that hypothesis is the
3.99 pt reduction from baseline in rTNSS compared to statistically significant difference between treatments in overall
2.78 pt reduction observed in placebo children (n = 136), a rTNSS change from baseline observed in older children (aged
difference of 1.21 (95% CI 2.24, 0.13; p = 0.022). ≥9 to <12 years) who more likely assessed their own symptoms.
Exclusions from the PPP were primarily due to poor dosing A rater sensitivity analysis was conducted to test this
compliance (i.e. <70% compliance on days 1–14) or due to hypothesis. Distribution of degree of child assessment is

Table 2 Comparison of the efficacy of 14 days treatment with MP-AzeFlu or placebo (both 1 spray/nostril bid) in children aged 6 to 11 years
with moderate/severe SAR in the ITT population and according to degree of child self-rating

Child self-rating <10% 10% ≤child self-rating Child self-rating >90%

All children (n = 304) (n = 157) ≤90% (n = 65) (n = 82)

MP-AzeFlu MP-AzeFlu MP-AzeFlu MP-AzeFlu

End-point - placebo p-value - placebo p-value - placebo p-value - placebo p-value

rTNSS 0.80 0.099 0.29 0.6722 1.14 0.2281 2.18 0.0020

rTOSS 0.53 0.143 0.19 0.6862 0.48 0.4713 1.34 0.0090
rT7SS 1.34 0.093 0.49 0.6662 2.05 0.1951 3.41 0.0036
Nasal congestion 0.13 0.318 0.03 0.8589 0.08 0.7328 0.45 0.0174
Nasal Itch 0.20 0.140 0.19 0.2702 0.17 0.5109 0.54 0.0039
Rhinorrhoea 0.09 0.505 0.01 0.9705 0.26 0.2876 0.37 0.0640
Sneezing 0.32 0.025 0.04 0.7982 0.31 0.2092 0.93 <0.0001
Ocular itch 0.19 0.172 0.08 0.6053 0.12 0.6320 0.60 0.0008
Ocular watering 0.26 0.051 0.18 0.2400 0.00 0.9835 0.51 0.0098
Ocular redness 0.11 0.389 0.04 0.7791 0.35 0.0771 0.38 0.0355

Data shown in bold with shading: statistically significant superiority of MP-AzeFlu versus placebo.
Child self-rating <10%: child assessment <10% of time (i.e. mostly caregiver); 10% ≤child self-rating ≤90%: child assessment ≥10% but ≤90%
of the time (i.e. mixture of child and caregiver assessment); Child self-rating >90%: child assessment >90% of time (i.e. mostly children).
ITT, intent to treat; rTNSS, reflective total nasal symptom score; rTOSS, reflective total ocular symptom score; rT7SS, reflective total of 7
symptom scores; SAR, seasonal allergic rhinitis.

Figure 2 Distribution of child

symptom severity assessment
rating.

Pediatric Allergy and Immunology 27 (2016) 126–133 ª 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd. 129
Efficacy of MP-AzeFlu in paediatric SAR Berger et al.

shown in Fig. 2. Three groups were identified: (i) child outcome assessed. Conversely, in the group which comprised
assessment <10% of time (i.e. mostly caregiver; n = 157); (ii) >90% child self-rating (n = 82), children treated with MP-
child assessment ≥10% but ≤90% of the time (i.e. mixture of AzeFlu experienced significantly better relief than those
child and caregiver assessment; n = 65); and (iii) child treated with placebo from their overall nasal symptoms
assessment >90% of time (i.e. mostly children; n = 82). This (TNSS; p = 0.002), their overall ocular symptoms (TOSS;
sensitivity analysis revealed greater treatment difference p = 0.009), overall T7SS (p = 0.0036), and from each indi-
between MP-AzeFlu and placebo with increasing degree of vidual nasal and ocular symptoms assessed (with the
child self-rating (Table 2). As the extent of child self-rating exception of rhinorrhoea p = 0.064) (Table 2). Daily change
increased, so too did the treatment difference between from baseline in rTNSS (AM + PM) according to degree of
MP-AzeFlu and placebo. In the group which comprised self-rating is shown in Fig. 3a–c. A similar pattern of
<10% child self-rating (n = 157), no significant difference increasing effect with increasing degree of child rating was
was noted between MP-AzeFlu and placebo for any efficacy observed for the ≥50% response data (Fig. 4a–c). Baseline

Figure 3 Least square (LS) mean

change from baseline in reflective
total nasal symptom score (rTNSS;
AM + PM) per day according to
degree of child self-rating following
treatment with MP-AzeFlu or
placebo, both 1 spray/nostril bid,
for 14 days in children aged 6 to
11 years with moderate/severe
SAR. *p ≤ 0.040 vs. placebo.

130 Pediatric Allergy and Immunology 27 (2016) 126–133 ª 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.
Berger et al. Efficacy of MP-AzeFlu in paediatric SAR

characteristics of children in each subgroup are shown in incidence in the MP-AzeFlu (n = 6; 3.5%) and placebo groups
Table S2. (n = 5; 3.4%). All of these TRAE were considered by
investigators to be ‘mild’ in severity. The percentage of
children with TEAEs leading to discontinuation was the same
Safety
in each group: 1 child (0.6%) per group. No serious adverse
All children (i.e. 4–11 years; n = 348) were included in the events were reported.
safety analysis. Twenty-eight children (16.2%) in the MP- Neither MP-AzeFlu nor placebo was associated with any
AzeFlu-group and 23 children (13.1%) in the placebo group significant focused nasal examination finding. The proportion
reported at least one treatment emergent adverse event of children with moderate or severe mucosal oedema or nasal
(TEAE). Of these, 15 (8.7%) and 6 (3.4%) were considered discharge decreased over time. Slight improvements in mucosal
to be treatment-related adverse events (TRAE) in the MP- erythema were evidenced among the MP-AzeFlu-treated
AzeFlu and placebo groups, respectively. The most common children. There were no clinically relevant abnormal vital sign
TRAE in the MP-AzeFlu group was dysgeusia (n = 7; 4.0% vs. measurements from baseline to end of the study in either
n = 0 in the placebo group). Epistaxis occurred with similar treatment group.

Figure 4 Time to achieve ≥50%

change from baseline in reflective
total nasal symptom score (rTNSS)
according to degree of child self-
rating in children aged 6 to
11 years with moderate/severe
SAR. MP-AzeFlu versus placebo
for <10% child self-rating:
p = 0.36; ≥10% to ≤90% child self-
rating: p = 0.69; >90% child self-
rating: p = 0.0065.

Pediatric Allergy and Immunology 27 (2016) 126–133 ª 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd. 131
Efficacy of MP-AzeFlu in paediatric SAR Berger et al.

resonates with children, describes the burden of their disease in

Discussion
a way that is understandable to them and more importantly
AR carries a high symptomatic and societal burden for represents the views of children themselves (being completed at
sufferers, but especially so for children who experience signif- the investigational site without the presence of caregivers).
icant negative impact on their QoL, daily functionality, sleep However, the complexity of the PRQLQ, the fact that it
quality and productivity (2, 18). More effective pharmacolog- collects reflective data for the past 7 days and that it must be
ical interventions would reduce this burden. MP-AzeFlu filled in during clinic visits makes it an unsuitable tool for
provides twice the overall nasal and ocular symptom relief as everyday use. MP-AzeFlu also reduced children’s overall nasal
an INS and more complete rapid symptom control in both symptom burden to a greater degree than placebo, but this did
adults and adolescents (13–15). The results of this study not reach statistical significance for the ITT population, most
confirm its efficacy in children, with an effect size (when likely compromised due to the fact that caregivers rated
children rate their own symptoms) comparable to that seen in symptom severity for children by proxy.
adult studies (13), providing the evidence needed to achieve Superiority over placebo was achieved, however, for older
approval for paediatric use in the United States. However, children (those >9 years), and in the PPP as well as for the
assessment of efficacy was confounded by factors particular to more ‘objective’ symptoms of sneezing (which can be heard)
paediatric AR trials, most notably, the practice of caregiver by- and eye watering (which can be seen). However, the more
proxy assessment of children’s symptom severity. The results ‘hidden’ symptoms (such as congestion) proved more difficult
presented here show that children’s and caregivers’ symptom for caregivers to accurately assess. This substantially reduced
assessments cannot be assumed to be the same, and emphasize the study sensitivity; caregivers underestimated the MP-AzeFlu
the importance of using paediatric-generated data when response and overestimated the placebo response. However,
possible. when children rated their own symptoms MP-AzeFlu provided
This study is important as for the first time the efficacy of significantly better symptom relief for all nasal and ocular
MP-AzeFlu has been shown in children with SAR. It included a efficacy parameters assessed (with the exception of rhinor-
large paediatric population, with a representative cross section rhoea, which approached statistical significance).
of ages (4–5 years (n = 44), 6–8 years (n = 119) and 9–11 years The same lower treatment effect and confounder has been
(n = 185)) and evaluated efficacy in three ways ((i) QoL, (ii) reported in other paediatric trials (24–26). For example, Danell
symptom score reduction (both nasal and ocular) and (iii) time and colleagues showed that children (with asthma, rhinitis or
to achieve a clinically relevant response). However, although eczema) reported more symptoms than their parents, concluding
QoL was assessed using a paediatric-specific and validated tool that symptoms of allergic disease should be reported by children
(i.e. by PRQLQ), symptom relief was assessed by rTNSS (which themselves, from the age of 11 years (24). Poor agreement
is not validated in either adults or children). Future paediatric between children and parents for asthma drug use has also been
AR trials would benefit from the inclusion of a paediatric- noted (25). Finally, a recently published ARIA-GALEN state-
specific and validated symptom severity assessment tool, such ment recognized that the efficacy of sublingual immunotherapy
as a simple visual analogue scale (VAS). Such a VAS has been (SLIT) for AR observed in RCTs may be less in children than in
used in other AR trials (19), correlates well with rhinitis QoL adults (12), possibly due in part to lack of a paediatric-specific
questionnaire scores and rTNSS (20) and is sensitive enough to assessment tool. Indeed, when using an easy overall efficacy
discriminate according to severity (21) and effectiveness of assessment tool (e.g. a 4-point symptom severity rating scale
pharmacological interventions (22). The generalizability of from 0 (no symptoms) to 3 (severe symptoms)), MP-AzeFlu
these data is an inherent limitation of all RCTs (23) since provided significantly greater AR symptom relief than FP in
inclusion and exclusion criteria must be in agreement with FDA children aged ≥6–12 years with AR (27).
and EMA guidelines. In conclusion, MP-AzeFlu is an effective treatment option
In the present study, children treated with MP-AzeFlu for AR in childhood. Caregivers are less able than children to
experienced a clinically relevant and statistically significant accurately assess response to treatment (at least with available
improvement in their QoL compared with those children tools). A simple and paediatric-specific tool to assess efficacy in
treated with placebo by Day 15. Impact on QoL clearly AR trials in children is urgently needed.

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Supporting Information (n = 152), both 1 spray/nostril bid in children aged ≥6 to 11 years with
moderate/severe seasonal allergic rhinitis.
Additional Supporting Information may be found in the online version of Table S1. rTNSS, rTOSS, rT7SS and individual nasal and ocular symptom
this article: scores at baseline and change from baseline following 14 days treatment
Data S1. Online supplement. with either MP-Aze-Flu or placebo in children (aged 6–11 yrs) with
Figure S1. Child disposition. moderate/severe SAR.
Figure S2. Least square (LS) mean change from baseline in Individual Table S2. Child demographic and baseline characteristics by child self-rating
Paediatric Rhinitis Quality of Life Questionnaire (PRQLQ) domain scores group in those children aged 6 to 11 years.
following 15 days treatment with MP-AzeFlu (n = 152) or placebo

Pediatric Allergy and Immunology 27 (2016) 126–133 ª 2016 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd. 133