the same site as the high-affi nity receptor for IgE.
The monoclonal antibody complexes with free IgE
block the binding of IgE to the cell membrane high-
affi nity receptor for IgE of mast cells and basophiles
and inhibit cell activation and mediator release. 1,2
Omalizumab is a treatment option limited to patients
with elevated serum levels of IgE (30-700 IU/mL).
Its current indication is for adolescents and adults
with moderate to severe (United States) or severe
malizumab is a recombinant humanized mono-
clonal anti-IgE antibody that recognizes IgE at
(Europe) allergic asthma who remain uncontrolled
after treatment with a high dose of corticosteroids
plus long-acting b -agonists. 3,4 These patients are at a
high risk of suffering severe exacerbations and death 5,6
and have the greatest medical need with associated
economic cost. 7 Oral corticosteroids are effective in
some of these patients with severe asthma but they are
associated with signifi cant side effects.
Several reviews have analyzed the effi cacy and
safety of omalizumab on the basis of studies that used
different manners of administration (IV, subcutaneous,
Background: Omalizumab is a humanized monoclonal anti-IgE for the treatment of severe aller-
gic asthma. Because omalizumab targets an immune system molecule, there has been particular
interest in the drug’s safety.
Methods: To establish the effi cacy and safety of subcutaneous omalizumab as add-on therapy to
corticosteroids, a systematic review of placebo-controlled studies was performed. Primary out-
comes were reduction of steroid use and asthma exacerbations. Secondary outcome measures
included lung function, rescue medication use, asthma symptoms, health-related quality of life,
and adverse effects.
Results: Eight trials (3,429 participants) fulfi lled the selection criteria. At the end of the steroid-
reduction phase, patients taking omalizumab were more likely to be able to withdraw from corti-
costeroids completely compared with those taking placebo (relative risk [RR] 5 1.80; 95% CI,
1.42-2.28; P 5 .00001). Omalizumab patients showed a decreased risk of asthma exacerbations at
the end of the stable (RR 5 0.57; 95% CI, 0.48-0.66; P 5 .0001) and adjustable-steroid phases
(RR 5 0.55; 95% CI, 0.47-0.64; P 5 .0001); post-hoc analysis suggests this effect was independent
of duration of treatment, age, severity of asthma, and risk of bias. The frequency of serious
adverse effects was similar in the omalizumab (3.8%) and placebo (5.3%) groups. However, injec-
tion site reactions were more frequent in the omalizumab patients (19.9% vs 13.2%). There were
no indications of increased risk of hypersensitivity reactions, cardiovascular effects, or malig-
Conclusions: Data indicate that the effi cacy of add-on omalizumab in patients with moderate-to-
severe allergic asthma is accompanied by an acceptable safety profi le. CHEST 2011; 139(1):28–35
Abbreviations: AQLQ 5 Asthma Quality of Life Questionnaire; BDP 5 beclomethasone dipropionate; FDA 5 US Food
and Drug Administration; NNTB 5 number needed to treat for benefi t; NNTH 5 number needed to treat for harm;
PEF 5 peak expiratory fl ow; RR 5 relative risk; WMD 5 weighted mean difference
Effi cacy and Safety of Subcutaneous
Omalizumab vs Placebo as Add-on Therapy
to Corticosteroids for Children and Adults
A Systematic Review
Gustavo J. Rodrigo , MD ; Hugo Neffen , MD ; and José A. Castro-Rodriguez , MD , PhD
CHEST / 139 / 1 / JANUARY, 2011 29
Data Abstraction and Assessment of Risk of Bias
This systematic review was performed according to the PRISMA
guidelines. 16 From full text, the authors independently assessed
all studies for inclusion based on the predefi ned criteria. After
obtaining full reports about potentially relevant trials, they assessed
eligibility. The authors, G. J. R. and J. A. C.-R., were involved in
all stages of study selection, data extraction, and risk of bias assess-
ment. The last was assessed using the Cochrane fi ve risk of bias
domains tool. 17 Disagreements were resolved by group consensus.
In the case of multiple published or unpublished reports, data
from the most recent version were extracted.
Binary outcomes were pooled using common relative risks
(RRs) and 95% CIs. If pooled effect estimates were signifi cantly
different between groups, we calculated the number needed to
treat for benefi t (NNTB) or for harm (NNTH). For continuous
outcomes, the standardized mean difference or weighted mean
difference (WMD) was calculated. Heterogeneity was measured
by the I 2 test 18 ( , 40% might be unimportant, 40%-60% might
be moderate, and 60%-100% might be substantial). 19 Because
selected studies differed in the mixes of participants and interven-
tions, a random-effects meta-analysis was performed to address
this variation across studies in all outcomes. 20 The publication bias
of primary outcomes was evaluated by visual inspection of funnel
plots. 21 A predefi ned sensitivity analysis of the primary outcome
(ie, number of patients with at least one asthma exacerbation) was
conducted on the basis of the risk of bias (low vs high). Addition-
ally, as an a priori subgroup analysis, we explored the infl uence of
the age of patients (children vs adolescents and adults), asthma
severity (moderate to severe vs severe), and length of treatment
( , 24 weeks vs ? 24 weeks). Subgroups were compared using the
interaction test. 22 P ? .05 (2-tailed test) was considered signifi cant.
Meta-analysis was performed with Review Manager 5.0.23 software
(The Cochrane Collaboration, 2010; The Nordic Cochrane Centre;
Eight studies 11,12,23-28 met the inclusion criteria and
were selected for analysis (a total of 3,429 patients,
1,883 receiving omalizumab and 1,546 placebo) ( Fig 1 ).
Cumulative exposure (patient-years) was 1,080 for
omalizumab and 823 for placebo. The mean baseline
IgE serum level was 273 IU/mL (range 179-470 IU/mL).
Omalizumab was given in all studies at doses of
0.016 mg/kg/international units/mL every 2 to 4 weeks
( Table 1 ). After a run-in phase, omalizumab was admin-
istered as adjunctive therapy to inhaled or oral corticos-
teroids for 12 to 28 weeks (stable-steroid phase),
followed in fi ve studies 11,23-26 by a steroid-reduction
phase for 8 to 28 additional weeks, during which
attempts were made to reduce or withdraw corticos-
teroids use (inhaled or oral beclomethasone dipropi-
onate [BDP], 12,23-25,28 fl uticasone propionate, 11,26 or
budesonide 27 ). There was no difference in mean dose of
inhaled corticosteroids at baseline (expressed as BDP
equivalent values) between omalizumab (1,221 m g/d) and
placebo (1,217 m g/d) groups ( P 5 .99) ( Table 1 ). Six
studies included adolescents and adults only, 12,23,25-28 and
or inhaled), therapies (with or without corticoster-
oids), and allergic diseases (asthma or rhinitis). 8,9
However, omalizumab is available for subcutaneous
administration only. 10 Also, new randomized placebo-
controlled trials performed in adolescents/adults
and children have been published. 11,12 Additionally,
European regulatory authorities have approved its
use in children aged 6 to 11 years, 13 whereas the
US Food and Drug Administration (FDA) has not
and claims this is because of a cardiovascular safety
issue. 14 Therefore, it seems reasonable to explore
the effi cacy and safety of subcutaneous omalizumab
vs placebo as add-on therapy to corticosteroids in
patients with moderate to severe persistent allergic
Materials and Methods
Search and Selection Criteria
We identifi ed studies from MEDLINE, EMBASE (January
1980-April 2010), and Cochrane Controlled Trials Register
(CENTRAL) (fi rst quarter 2010) databases using the following
medical subject headings, full text, and keywords: “anti-IgE” or
“anti-immunoglobulin E” or “anti-IgE antibody” or “omalizumab”
or “rhuMAb-E25” or “Xolair” and “asthma.” Also, we performed
a search of relevant files from the Novartis (http://www.
novartisclinicaltrials.com) and FDA (www.fda.gov) databases.
Trials published solely in abstract form were excluded. The specifi c
inclusion criteria were as follows: (1) children (aged ? 12 years)
and adolescents/adults (aged . 12 years) with allergic asthma;
(2) subcutaneous omalizumab therapy at any dose vs placebo as
add-on therapy to corticosteroids; (3) patients possibly taking
other treatment as long as they were the same in each arm;
(4) randomized (parallel group) placebo-controlled trials without
language restriction; and (5) primary outcomes: reduction of ste-
roid use (inhaled, oral, or both) from baseline, and asthma exac-
erbations (as defi ned by hospital admissions, ED visits, increase
in rescue medication, or use of corticosteroids). Secondary out-
come measures were lung function (FEV 1 or peak expiratory
fl ow [PEF]), rescue medication use, asthma symptoms, health-
related quality of life, and adverse effects. A serious adverse
event was defi ned as any untoward medical occurrence that
sometimes resulted in death, was life-threatening, required
inpatient hospitalization, or resulted in persistent or signifi cant
Manuscript received May 8, 2010; revision accepted July 16, 2010.
Affi liations: From the Departamento de Emergencia (Dr Rodrigo),
Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay;
Unidad de Medicina Respiratoria (Dr Neffen), Hospital de Niños
“O. Allassia,” Santa Fe, Argentina; and the School of Medicine
(Dr Castro-Rodriguez), Pontifi cia Universidad Católica de Chile,
Correspondence to: Gustavo J. Rodrigo, MD, Departamento
de Emergencia, Hospital Central de las Fuerzas Armadas, Av. 8 de
Octubre 3020, Montevideo 11600, Uruguay; e-mail: gurodrig@
© 2011 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians ( http://www.chestpubs.org/
placebo group) (WMD 5 2 0.19, 95% CI, 2 0.23 to 0.14;
I 2 5 0%), 11,12,23-28 and hospitalizations due to asthma exac-
erbation were in favor of omalizumab (1.7% vs 4.8%)
(RR 5 0.44, 95% CI, 0.23-0.83; I 2 5 15%; NNTB 5 33,
95% CI, 22-69). 12,23-25,28
Although fi ve studies 11,23-26 presented a steroid-
reduction phase, only four 23-26 reported data with
regard to withdrawal or reduction of steroid dose.
Their analysis showed that those treated with omali-
zumab were more likely to be able to withdraw
their corticosteroids completely compared with those
treated with placebo (41.8% vs 21.%) (RR 5 1.80,
95% CI, 1.42-2.28; I 2 5 54%; NNTB 5 5, 95% CI, 4-6).
A moderate degree of heterogeneity was observed
but this was all explained by the mild severity of
asthma of the pediatric study. 24 Patients treated with
omalizumab 23-26 were more likely to be able to reduce
their corticosteroid dose by . 50% (76% vs 56.0%)
(RR 5 1.34, 95% CI, 1.23-1.46; I 2 5 26%; NNTB 5 5,
95% CI, 4-6). Finally, based on data from three stud-
ies, 23,25,26 the mean difference in steroid use (BDP
equivalent) between omalizumab and placebo at the
end of the steroid-reduction phase was 2 141 m g/d
(95% CI, 2 61.4 to 2 220.9; I 2 5 67%; P 5 .0005).
Data from the fi ve studies with a steroid-reduction
phase of treatment 11,23-26 showed reductions in the
number of patients with at least one asthma exacer-
bation (17.2% in the omalizumab group vs 30.9%
in the placebo group) (RR 5 0.55, 95% CI, 0.47-0.64;
I 2 5 0%; NNTB 5 8, 95% CI, 6-10) in the mean asthma
exacerbations per patient (WMD 5 2 0.36, 95% CI,
2 0.54 to 0.19; I 2 5 77%), and in the frequency of hos-
pitalizations due to asthma exacerbations (RR 5 0.14,
95% CI, 0.03-0.66; I 2 5 0%) in favor of omalizumab.
Patients treated with subcutaneous omalizumab
showed greater reductions in the use of rescue medi-
cation ( 2 0.5 puffs/d) and asthma symptom score at
the end of the stable phase compared with those tak-
ing placebo ( Table 4 ). Although there was no signifi -
cant difference in fi nal pulmonary function (FEV 1 or
PEF), omalizumab patients showed a small but sig-
nifi cant increase in morning PEF (12 L/min). Addi-
tionally, omalizumab patients presented a statistically
signifi cantly improvement in overall Asthma Quality
of Life Questionnaire (AQLQ) responses. The sig-
nifi cant decreased use of rescue medication persisted
in the steroid-reduction phase.
There was no difference in the number of with-
drawals due to adverse events between omalizumab-
treated (1.3%) and placebo-treated patients (1.5%)
( Table 4 ). The number of patients reporting any
two also included pediatric participants. 11,24 Subjects with
allergic asthma (patients demonstrated a positive skin
prick test and a serum total IgE level of 30-1,300 IU/mL)
were recruited in seven studies, 11,12,23-26,28 and one study
included patients with coexisting allergic asthma and
rhinitis. 27 Patients with moderate asthma were recruited
in one study, 24 with moderate to severe asthma in fi ve
studies, 11,12,23,25,27 and with severe asthma in two stud-
ies. 26,28 All trials were sponsored by the pharmaceuti-
cal industry. Regarding the risk of bias, only one study
met all fi ve accepted criteria ( Table 2 ). 12
During the stable phase, the asthma exacerbation
rate (per 100 patient-years) was 37.6 in the omalizumab
group and 69.9 in the placebo group (RR 5 0.57,
95% CI, 0.48-0.66; NNTB 5 10, 95% CI, 7-13) ( Fig 2 ).
A visual inspection of the funnel plot did not reveal
any asymmetry, suggesting the absence of publica-
tion bias. The predefi ned post hoc subgroup analy-
sis showed that factors such as duration of treat-
ment, age of patients, severity of asthma, and risk
of bias did not infl uence the effect size ( Table 3 ).
There were signifi cantly fewer asthma exacerbations
per patient (0.41 in the omalizumab group vs 0.77 in the
Figure 1. Flowchart for identifi cation of usable studies. ICS 5 inhaled
CHEST / 139 / 1 / JANUARY, 2011 31
two episodes (one in each group); the second study, 28
one episode (in the omalizumab group) (0.33% in the
omalizumab group and 0.24% in the placebo group,
P 5 .94). Malignant neoplasms were reported in two
studies 11,25 (one in each group). Cardiovascular adverse
effects were recorded in two studies, 25,27 two in the
fi rst and one in the last, all in the placebo group.
Finally, one study 23 reported one death due to car-
diac arrest in a subject receiving placebo.
This is a more extensive systematic review per-
formed exclusively to explore the effi cacy and safety
of subcutaneous omalizumab as add-on therapy to
corticosteroids in schoolchildren, adolescents, and
adults with moderate to severe persistent allergic
adverse effect was similar between groups. Serious
adverse effects were reported by 3.8% of patients
receiving omalizumab and 5.3% of patients in the
placebo group ( P 5 .14). The overall prevalence of
suspected treatment-related adverse effects was sig-
nifi cantly higher in the omalizumab group (5.0%) than
in the placebo group (3.2%) (NNTH 5 56, 95% CI,
28-975). This was mainly because of an increased
prevalence of injection site reactions (erythema,
pruritus, swelling, pain, or induration) in the omali-
zumab group compared with the placebo group (19.9%
vs 13.2%; P 5 .002; NNTH 5 14, 95% CI, 10-24).
The frequency of adverse effects suggesting hyper-
sensitivity reactions (such as anaphylactic reactions
or urticaria) was low. Urticaria occurred infre-
quently (omalizumab 2.5% and placebo 2.1%). Two
studies reported anaphylactic reactions: the fi rst study, 11
Table 1— Characteristics of Included Studies
Age, y, Mean
(Baseline % Predicted
FEV 1 Mean)
Mean Baseline IgE
m g /d O/P Intervention
et al 23
525 (41) 39 (12-75)M-S (68) 179570/568 O S/C (0.016 mg /kg IgE [international units/mL]
every 2-4 wk or placebo). Initial phase
of the trial was a stable-steroid phase of
16 wk duration, followed by a 12-wk
steroid reduction phase.
O S/C (0.016 mg/kg/IgE [international units/mL]
every 4 wk, depending on body weight
vs placebo). Four-phase study: 6-10-wk run-in
phase, 16-wk steroid-stable phase, 16-wk
steroid-reduction phase, and 12-wk follow-up.
O S/C (0.016 mg/kg per international units/mL
vs placebo every 2-4 wk). 7-d screening
period, 8-wk run-in phase, and 28-wk drug
add-on treatment phase .
O S/C (0.016 mg/kg/IgE [international units/mL]
every 2-4 wk, depending on participant’s
body weight). Run-in phase lasted 4-6 wk
with stabilization on ICS, followed by a
stable-steroid phase (16 wk) and a steroid-
reduction phase (12 wk).
O S/C ( ? 0.016 mg/kg/IgE [international
units/mL] vs placebo every 2-4 wk over 28-wk
period). Run-in phase was 4-6 wk with
stabilization of ICS. Stable BDP dose (fi rst
16 wk) and reduction phases of BDP (8 wk).
O S/C (0.016 mg/kg/IgE [international units/mL]
every 4 wk vs placebo). A 4-wk run-in phase
(participants switched to BUD equivalent
Turbuhaler [AstraZeneca; Södertälje,
Sweden]), dose was kept stable for at
least 4 wk prior to study entry). Study
duration: 28 wk.
O S/C (0.016 mg/kg/IgE [international units/mL]
every 2-4 wk according to the patient’s body
weight vs placebo). Study duration: 12 wk.
O S/C (75-350 mg every 2-4 wk over a period
of 52 wk [24-wk fi xed-steroid phase followed
by a 28-wk adjustable-steroid phase]).
et al 26
246 (39) 41 (12-75)S (65) 2662,737/2,750
et al 28
482 (33) 43 (12-79) S (61)193 2,359/2,301
et al 24
334 (69) 9.4 (5-12)M (84)335 284/267
et al 25
546 (49)40 (12-76) M-S (70)214 769/772
et al 27
405 (45) 38 (12-74)M-S (78)30-1300842/901
et al 12
315 (46)49 (20-75)M-S (75) 2531,175/1,163
et al 11
576 (68)8.6 (6-12) M-S (86)470 1,036/1,018
BDP 5 beclomethasone dipropionate; BUD 5 budesonide; ICS 5 inhaled corticosteroids; M 5 moderate; O 5 omalizumab; P 5 placebo; S 5 severe;
S/C 5 subcutaneous .
treated with omalizumab showed a small but signifi cant
increase in morning PEF. Furthermore, an improve-
ment in overall AQLQ responses was seen in those
treated with omalizumab. However, these improve-
ments must be interpreted as clinically nonsignifi cant
because they did not reach the minimal important dif-
ference of each outcome ( 2 0.81 for rescue medication,
2 0.31 for asthma symptoms, 18.8 L/min for PEF, and
0.5 for AQLQ). 29,30 Finally, the decreased use of rescue
medication persisted and was even higher in the
steroid-reduction phase in the omalizumab group. The
results of this study support the indication given in
international guidelines 3,4 for the use of omalizumab
in children, adolescents, and adults with moderate
to severe allergic asthma who remain uncontrolled
after treatment with a high-dose of corticosteroids
plus long-acting b -agonists.
Regarding safety, omalizumab-associated adverse
events did not differ from those from placebo, except
for drug-related adverse effects. Omalizumab patients
presented a similar number of serious adverse effects
as did placebo patients. Hypersensitivity reactions
including anaphylaxis showed a low prevalence. The
fi ndings are similar to those from a recent review
of the safety and tolerability of omalizumab based
on three databases of patients who had received
medication in the omalizumab development program
( . 7,500 patients with asthma, rhinitis, or related
conditions). 10 It showed that omalizumab exhibited
a good safety and tolerability profi le that was main-
tained for up to 4 years (4.2% prevalence of serious
adverse effects in the omalizumab group and 3.8% in
the placebo group, and 1.3% for urticaria in both
groups). Finally, that review reported a prevalence of
anaphylaxis in the all-controlled studies population
of 0.14% in omalizumab patients and 0.07% in the
placebo group. Additionally, no increased risk of malig-
nant neoplasia was found. A postmarketing safety
database analysis based on estimated exposure of
57,300 patients (3 years) reported 124 cases of
anaphylaxis (0.2%) attributed to omalizumab. 31 Two
asthma. Asthmatics treated with omalizumab during
a steroid-reduction phase increased the likelihood of
greater steroid reduction. Thus, omalizumab-treated
patients were more likely to be able to withdraw their
corticosteroids completely or to reduce their corti-
costeroid dose by . 50% (the NNTB was 5, indi-
cating that one of every fi ve patients treated with
omalizumab obtained this benefi t). Also, the reduction
in daily inhaled dose following treatment with omali-
zumab was modest but signifi cant. Moreover, omali-
zumab therapy was associated with fewer asthma
exacerbations at the end of the stable-steroid phase,
compared with placebo (NNTB 5 10) and also at the
end of the adjustable-steroid phase (NNTB 5 8). The
result was unaffected by duration of treatment, age of
patients, severity of asthma, or level of bias risk.
Additionally, we found that patients treated with
omalizumab showed reductions in the use of rescue
medication and asthma symptom score at the end of
the stable-steroid phase. Although there was no sig-
nifi cant difference in pulmonary function, patients
Table 2— Risk of Bias of the Eligible Studies
et al 23
et al 26
et al 28
et al 24
et al 25
et al 27
et al 12
et al 11
NoNo Yes YesYes
NoNo YesYes Yes
No No YesYesYes
No No Yes Yes Yes
No No Yes Yes Yes
Yes Yes Yes Yes Yes
YesNo Yes Yes Yes
Figure 2. Pooled relative risk for the number of patients with at least one asthma exacerbation (with
95% CI) of eligible studies comparing omalizumab with placebo at the end of the stable-steroid phase.
M-H 5 Mantel-Haenszel.
CHEST / 139 / 1 / JANUARY, 2011 33
priate sequence generation, and only one ade-
quately concealed allocation. Regarding consistency,
the meta-analysis of the majority of outcomes did
not show evidence of statistical heterogeneity. Only
two trials recruited pediatric participants. Although
the results from these two trials were similar to those
reported for adults and adolescents, there is a need for
further studies in an exclusively pediatric population.
In conclusion, this meta-analysis shows that in school-
aged children, adolescents, and adults with moderate-
to-severe persistent allergic asthma, subcutaneous injec-
tion of omalizumab (0.016 mg/kg/international units/mL
every 2 to 4 weeks depending on body weight) was supe-
rior to placebo in preventing asthma exacerbation at
the end of the stable-steroid phase and in the adjust-
able-steroid phase. The magnitude of the NNTBs sug-
gests a clinically worthwhile benefi t.
In addition, asthmatics treated with omalizumab were
more likely to be able to withdraw their corticosteroids
malignant neoplasms were reported during our
study (one in each group): a medulloblastoma in the
placebo group 11 and a squamous cell carcinoma of
the face in the omalizumab group. 25
Recently, the FDA raised concerns about the car-
diovascular safety of omalizumab. 14 Data from an
epidemiologic study (EXCELS) suggested more car-
diovascular and cerebrovascular adverse effects in
patients using omalizumab compared with a group
not given the drug. 32 Our review found four cases of
cardiovascular adverse effects (angina pectoris and
tachyarrhythmia, 25 and atrial fi brillation, 27 all in the
placebo group). Finally, one study reported one death
due to cardiac arrest in a subject receiving placebo. 23
As a result, there were no indications of an increase
of cardiovascular risk; however, studies included in
this review were of limited span (1 year) as compared
with the epidemiologic study, which will span 5 years
This study met most of the methodologic criteria
suggested for systematic reviews. 16 The analysis of
the main outcome was based on data from all studies.
However, of eight studies, only two reported an appro-
Table 3— Sensitivity Analysis of the Number of Patients With At Least One Asthma Exacerbation at the End of the
Stable-Steroid Phase (Omalizumab vs Placebo)
Subgroup ComparisonRR (95% CI) Interactive Test, RR (95% CI) P Value
Risk of bias (low 11,12 vs high 23-28 )
Duration of study ( , 24 wk 12,23-26 vs ? 24 wk 11,27,28 )
Asthma severity (moderate-severe 11,12,23-25,27 vs severe 26,28 )
Age of patients (adolescents and adults 12,23,25-28 vs children 11,24 )
0.46 (0.34-0.62) vs 0.61 (0.51-0.72)
0.56 (0.43-0.72) vs 0.59 (0.47-0.74)
0.55 (0.45-0,66) vs 0.68 (0.49-0.94)
0.58 (0.48-0.71) vs 0.55 (0.39-0.77)
RR 5 relative risk.
Table 4— Analysis of Secondary Outcomes (Omalizumab vs Placebo)
Outcome No. Omalizumb vs PlaceboMeasure (95% CI) P ValueI 2 , %
Rescue medication (stable phase), 11,23,25-27
Final pulmonary function (FEV 1 or PEF)
(stable phase) 23-26, a
Change from baseline in morning PEF
(stable phase), 12,23,27 L/m
Asthma symptom score (stable phase) 11,23,25-27
Change in AQLQ score (stable phase) 23,25-28
Rescue medication (steroid-reduction
phase), 23,25-26 puffs/d
Prematurely discontinued patients 11-12,23-28
Withdrawals due to adverse events 11-12,23-28
Any adverse effect 11-12,23-28
Serious adverse effects 11-12,23-28
Treatment-related adverse effects 11-12,24,27-28
Injection site reactions 12,23-28
Anaphylactic reactions 11,28
2,285 2.27 vs 2.76 a
WMD 5 2 0.52 ( 2 0.79 to 0.25)
1,651 3.82 vs 3.63 ab
SMD 5 0.07 ( 2 0.03 to 017) ab
1,245 15.0 vs 3.05 a
WMD 5 11.8 (8.1-15.5)
1.53 vs 1.71 a
0.37 vs 0.06 a
2.27 vs 2.76 a
WMD 5 2 0.30 ( 2 0.40 to 0.20)
WMD 5 0.33 (0.28-0.37)
WMD 5 2 0.73 ( 2 1.04 to 0.42)
9.6% vs 12.5%
1.3% vs 1.5%
84.9% vs 82.4%
3.8% vs 5.3%
5.0% vs 3.2%
2.5% vs 2.1%
19.9% vs 13.2%
0.33% vs 0.24%
RR 5 0.69 (0.50-0.97)
RR 5 0.97 (0.43-2.20)
RR 5 1.01 (0.97-1.05)
RR 5 0.75 (0.52-1.10)
RR 5 1.61 (1.05-2.47)
RR 5 1.11 (0.53-2.32)
RR 5 1.43 (1.15-1.79)
RR 5 1.08 (0.13-8.74)
AQLQ 5 Asthma Quality of Life Questionnaire; PEF 5 peak expiratory fl ow; SMD 5 standardized mean difference; WMD 5 weighted mean
difference. See Table 3 for expansion of other abbreviation.
a Mean value.
b Expressed in SD units.
10 . Xolair [omalizumab] full prescribing information. July 2008 .
http://www.xolair.com/prescribing_information.html . Accessed
March 29, 2010.
11 . Lanier B , Bridges T , Kulus M , Taylor AF , Berhane I , Vidaurre
CF . Omalizumab for the treatment of exacerbations in chil-
dren with inadequately controlled allergic (IgE-mediated)
asthma . J Allergy Clin Immunol . 2009 ; 124 ( 6 ): 1210 - 1216 .
12 . Ohta K , Miyamoto T , Amagasaki T , Yamamoto M ; 1304 Study
Group . Effi cacy and safety of omalizumab in an Asian popula-
tion with moderate-to-severe persistent asthma . Respirology .
2009 ; 14 ( 8 ): 1156 - 1165 .
13 . European Medicines Agency . Assessment report for Xolair.
Xolair-H-606-II-18-AR.pdf . Accessed March 26, 2010.
14 . Federal Drug Administration advisory for omalizumab .
forHeathcareProfessionals/ucm172218.htm . Accessed January 8,
15 . International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use. Clinical safety data management: defi nitions and standards
for expedited reporting. http://www.ich.org/LOB/media/
MEDIA436.pdf . Accessed January 10, 2010.
16 . Liberati A , Altman DG , Tetzlaff J , et al . The PRISMA state-
ment for reporting systematic reviews and meta-analyses of
studies that evaluate health care interventions: explanation
and elaboration . Ann Intern Med . 2009 ; 151 ( 4 ): W65-W94 .
17 . Centre for Reviews and Dissemination . Systematic reviews:
CRD’s guidance for undertaking reviews in health care.
www.york.ac.uk/inst/crd/systematic_reviews_book.htm . Accessed
January 4, 2010.
18 . Higgins JPT , Thompson SG , Deeks JJ , Altman DG . Measuring
inconsistency in meta-analyses . BMJ . 2003 ; 327 ( 7414 ): 557 - 560 .
19 . Higgins JPT , Green S , eds. Cochrane handbook for systematic
reviews of interventions, version 5.0.0 (updated February
2008). The Cochrane Collaboration; 2008 . http://www.cochrane-
handbook.org . Accessed January 5, 2010.
20 . Borenstein M , Hedges LV , Higgins JPT , Rothstein HR . Intro-
duction to Meta-analysis . Chichester, England: John Wiley &
Songs, Ltd ; 2009 .
21 . Egger M , Davey Smith G , Schneider M , Minder C . Bias
in meta-analysis detected by a simple, graphical test . BMJ .
1997 ; 315 ( 7109 ): 629 - 634 .
22 . Altman DG , Bland JM . Interaction revisited: the difference
between two estimates . BMJ . 2003 ; 326 ( 7382 ): 219 .
23 . Busse W , Corren J , Lanier BQ , et al . Omalizumab, anti-IgE
recombinant humanized monoclonal antibody, for the treat-
ment of severe allergic asthma . J Allergy Clin Immunol . 2001 ;
108 ( 2 ): 184 - 190 .
24 . Milgrom H , Berger W , Nayak A , et al . Treatment of childhood
asthma with anti-immunoglobulin E antibody (omalizumab) .
Pediatrics . 2001 ; 108 ( 2 ): E36 .
25 . Solèr M , Matz J , Townley R , et al . The anti-IgE antibody
omalizumab reduces exacerbations and steroid requirement
in allergic asthmatics . Eur Respir J . 2001 ; 18 ( 2 ): 254 - 261 .
26 . Holgate ST , Chuchalin AG , Hébert J , et al ; Omalizumab 011
International Study Group . Effi cacy and safety of a recombi-
nant anti-immunoglobulin E antibody (omalizumab) in severe
allergic asthma . Clin Exp Allergy . 2004 ; 34 ( 4 ): 632 - 638 .
27 . Vignola AM , Humbert M , Bousquet J , et al . Effi cacy and tol-
erability of anti-immunoglobulin E therapy with omalizumab
in patients with concomitant allergic asthma and persistent
allergic rhinitis: SOLAR . Allergy . 2004 ; 59 ( 7 ): 709 - 717 .
28 . Humbert M , Beasley R , Ayres J , et al . Benefi ts of omalizumab
as add-on therapy in patients with severe persistent asthma
who are inadequately controlled despite best available therapy
completely compared with those treated with placebo.
No significant adverse effects were seen among
patients taking omalizumab in studies shorter than
1 year . Longer clinical trials will be required for
full evaluation of the long-term effi cacy and safety of
Author contributions: Dr Rodrigo: contributed to the study
concept and design, and the acquisition, analysis, and interpreta-
tion of data; drafting of the submitted article and critical revision
for important intellectual content; and fi nal approval of the ver-
sion to be published.
Dr Neffen: contributed to the study concept and design and inter-
pretation of data; critical revision of the article for important intel-
lectual content; and fi nal approval of the version to be published.
Dr Castro-Rodriguez: contributed to the study concept and design
and interpretation of data; critical revision of the article for impor-
tant intellectual content; and fi nal approval of the version to be
Financial/nonfi nancial disclosures: The authors have reported
to CHEST the following conflicts of interest: Dr Rodrigo has
participated as a lecturer and speaker in scientific meetings
and courses under the sponsorship of Boehringer Ingelheim,
Glaxo SmithKline, AstraZeneca, Dr. Esteve SA, and Merck Sharp &
Dome. Dr Neffen has participated as a lecturer and speaker
in scientifi c meetings and courses under the sponsorship of Schering
Plough, GlaxoSmithKline, Novartis, and AstraZeneca. Dr Castro-
Rodriguez has participated as a lecturer and speaker in scientifi c
meetings and courses under the sponsorship of Merck Sharp &
Dohme, GlaxoSmithKline, and Grunenthal.
1 . Shields RL , Whether WR , Zioncheck K , et al . Inhibition of
allergic reactions with antibodies to IgE . Int Arch Allergy
Immunol . 1995 ; 107 ( 1-3 ): 308 - 312 .
2 . Barnes PJ . Anti-IgE therapy in asthma: rationale and thera-
peutic potential . Int Arch Allergy Immunol . 2000 ; 123 ( 3 ):
196 - 204 .
3 . National Asthma Education and Prevention Program . Expert
Panel Report 3 (EPR-3): guidelines for the diagnosis and
management of asthma-summary report 2007 . J Allergy Clin
Immunol . 2007 ; 120 ( 5 )( Suppl ): S94 - S138 .
4 . Global Initiative for Asthma. Global Strategy for Asthma
Management and Prevention: Revised 2009 . http://www.
ginasthma.com. Accessed April 8, 2010.
5 . Tough SC , Hessel PA , Ruff M , Green FH , Mitchell I , Butt JC .
Features that distinguish those who die from asthma from
community controls with asthma . J Asthma . 1998 ; 35 ( 8 ):
657 - 665 .
6 . Turner MO , Noertjojo K , Vedal S , Bai T , Crump S , Fitzgerald JM .
Risk factors for near-fatal asthma. A case-control study in
hospitalized patients with asthma . Am J Respir Crit Care Med .
1998 ; 157 ( 6 Pt 1 ): 1804 - 1809 .
7 . Wenzel SE , Busse WW ; National Heart, Lung, and Blood
Institute’s Severe Asthma Research Program . Severe asthma:
lessons from the severe asthma research program . J Allergy
Clin Immunol . 2007 ; 119 ( 1 ): 14 - 21 . , quiz 22-23.
8 . Walker S , Monteil M , Phelan K , Lasserson TJ , Walters EH .
Anti-IgE for chronic asthma in adults and children . Cochrane
Database Syst Rev . 2006 ; ( 2 ) CD003559 .
9 . Corren J , Casale TB , Lanier B , Buhl R , Holgate S , Jimenez P .
Safety and tolerability of omalizumab . Clin Exp Allergy .
2009 ; 39 ( 6 ): 788 - 797 .
CHEST / 139 / 1 / JANUARY, 2011 35
(GINA 2002 step 4 treatment): INNOVATE . Allergy . 2005 ;
60 ( 3 ): 309 - 316 .
29 . Santanello NC , Zhang J , Seidenberg B , Reiss TF , Barber BL .
What are minimal important changes for asthma measures in
a clinical trial? Eur Respir J . 1999 ; 14 ( 1 ): 23 - 27 .
30 . Juniper EF , Guyatt GH , Willan A , Griffi th LE . Determining
a minimal important change in a disease-specifi c Quality of
Life Questionnaire . J Clin Epidemiol . 1994 ; 47 ( 1 ): 81 - 87 .
31 . Limb SL , Starke PR , Lee CE , Chowdhury BA . Delayed
onset and protracted progression of anaphylaxis after omali-
zumab administration in patients with asthma . J Allergy Clin
Immunol . 2007 ; 120 ( 6 ): 1378 - 1381 .
32 . American Thoracic Society . 104th International Conference.
San Diego, CA. 2009 . Abstracts. Publication page: A613. http://
www.abstracts2view.com/ats08/view.php?nu 5 ATS08L_1129 .
Accessed January 25, 2010.
DOI 10.1378/chest.10-1194 Download full-text
; Prepublished online August 5, 2010; 2011;139; 28-35Chest
Gustavo J. Rodrigo, Hugo Neffen and José A. Castro-Rodriguez
Asthma : A Systematic Review
Add-on Therapy to Corticosteroids for Children and Adults With
Efficacy and Safety of Subcutaneous Omalizumab vs Placebo as
January 3, 2011 This information is current as of
Updated Information and services can be found at:
Updated Information & Services
This article cites 22 articles, 6 of which can be accessed free at:
found online at:
Information about reproducing this article in parts (figures, tables) or in its entirety can be
Permissions & Licensing
Information about ordering reprints can be found online:
"Services" link to the right of the online article.
Receive free e-mail alerts when new articles cite this article. To sign up, select the
PowerPoint slide format. See any online figure for directions.
articles can be downloaded for teaching purposes inCHEST Figures that appear in
Images in PowerPoint format