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Original Research: ASTHMA |

Efficacy and Safety of Subcutaneous Omalizumab vs Placebo as Add-on Therapy to Corticosteroids for Children and Adults With Asthma: A Systematic Review FREE TO VIEW

Gustavo J. Rodrigo, MD; Hugo Neffen, MD; José A. Castro-Rodriguez, MD, PhD
Author and Funding Information

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), Pontificia Universidad Católica de Chile, Santiago, 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@adinet.com.uy


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(1):28-35. doi:10.1378/chest.10-1194
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Background:  Omalizumab is a humanized monoclonal anti-IgE for the treatment of severe allergic asthma. Because omalizumab targets an immune system molecule, there has been particular interest in the drug’s safety.

Methods:  To establish the efficacy and safety of subcutaneous omalizumab as add-on therapy to corticosteroids, a systematic review of placebo-controlled studies was performed. Primary outcomes 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) fulfilled the selection criteria. At the end of the steroid-reduction phase, patients taking omalizumab were more likely to be able to withdraw from corticosteroids completely compared with those taking placebo (relative risk [RR] = 1.80; 95% CI, 1.42-2.28; P = .00001). Omalizumab patients showed a decreased risk of asthma exacerbations at the end of the stable (RR = 0.57; 95% CI, 0.48-0.66; P = .0001) and adjustable-steroid phases (RR = 0.55; 95% CI, 0.47-0.64; P = .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, injection 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 malignant neoplasms.

Conclusions:  Data indicate that the efficacy of add-on omalizumab in patients with moderate-to-severe allergic asthma is accompanied by an acceptable safety profile.

Figures in this Article

Omalizumab is a recombinant humanized monoclonal anti-IgE antibody that recognizes IgE at the same site as the high-affinity receptor for IgE. The monoclonal antibody complexes with free IgE block the binding of IgE to the cell membrane high-affinity 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 (Europe) allergic asthma who remain uncontrolled after treatment with a high dose of corticosteroids plus long-acting β-agonists.3,4 These patients are at a high risk of suffering severe exacerbations and death5,6 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 significant side effects.

Several reviews have analyzed the efficacy and safety of omalizumab on the basis of studies that used different manners of administration (IV, subcutaneous, or inhaled), therapies (with or without corticosteroids), 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 efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids in patients with moderate to severe persistent allergic asthma.

Search and Selection Criteria

We identified studies from MEDLINE, EMBASE (January 1980-April 2010), and Cochrane Controlled Trials Register (CENTRAL) (first 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 specific 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 steroid use (inhaled, oral, or both) from baseline, and asthma exacerbations (as defined by hospital admissions, ED visits, increase in rescue medication, or use of corticosteroids). Secondary outcome measures were lung function (FEV1 or peak expiratory flow [PEF]), rescue medication use, asthma symptoms, health-related quality of life, and adverse effects. A serious adverse event was defined as any untoward medical occurrence that sometimes resulted in death, was life-threatening, required inpatient hospitalization, or resulted in persistent or significant disability/incapacity.15

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 predefined 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 assessment. The last was assessed using the Cochrane five 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.

Data Analysis

Binary outcomes were pooled using common relative risks (RRs) and 95% CIs. If pooled effect estimates were significantly different between groups, we calculated the number needed to treat for benefit (NNTB) or for harm (NNTH). For continuous outcomes, the standardized mean difference or weighted mean difference (WMD) was calculated. Heterogeneity was measured by the I2 test18 (< 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 interventions, 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 predefined 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). Additionally, as an a priori subgroup analysis, we explored the influence 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.22P ≤ .05 (2-tailed test) was considered significant. Meta-analysis was performed with Review Manager 5.0.23 software (The Cochrane Collaboration, 2010; The Nordic Cochrane Centre; Copenhagen, Denmark).

Eight studies11,12,23-28 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 administered as adjunctive therapy to inhaled or oral corticosteroids for 12 to 28 weeks (stable-steroid phase), followed in five studies11,23-26 by a steroid-reduction phase for 8 to 28 additional weeks, during which attempts were made to reduce or withdraw corticosteroids use (inhaled or oral beclomethasone dipropionate [BDP],12,23-25,28 fluticasone propionate,11,26 or budesonide27). There was no difference in mean dose of inhaled corticosteroids at baseline (expressed as BDP equivalent values) between omalizumab (1,221 μg/d) and placebo (1,217 μg/d) groups (P = .99) (Table 1). Six studies included adolescents and adults only,12,23,25-28 and 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 five studies,11,12,23,25,27 and with severe asthma in two studies.26,28 All trials were sponsored by the pharmaceutical industry. Regarding the risk of bias, only one study met all five accepted criteria (Table 2).12

Figure Jump LinkFigure 1. Flowchart for identification of usable studies. ICS = inhaled corticosteroids.Grahic Jump Location
Table Graphic Jump Location
Table 1 —Characteristics of Included Studies

BDP = beclomethasone dipropionate; BUD = budesonide; ICS = inhaled corticosteroids; M = moderate; O = omalizumab; P = placebo; S = severe; S/C = subcutaneous.

Table Graphic Jump Location
Table 2 —Risk of Bias of the Eligible Studies
Primary Outcomes

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 = 0.57, 95% CI, 0.48-0.66; NNTB = 10, 95% CI, 7-13) (Fig 2). A visual inspection of the funnel plot did not reveal any asymmetry, suggesting the absence of publication bias. The predefined post hoc subgroup analysis showed that factors such as duration of treatment, age of patients, severity of asthma, and risk of bias did not influence the effect size (Table 3). There were significantly fewer asthma exacerbations per patient (0.41 in the omalizumab group vs 0.77 in the placebo group) (WMD = −0.19, 95% CI, −0.23 to 0.14; I2 = 0%),11,12,23-28 and hospitalizations due to asthma exacerbation were in favor of omalizumab (1.7% vs 4.8%) (RR = 0.44, 95% CI, 0.23-0.83; I2 = 15%; NNTB = 33, 95% CI, 22-69).12,23-25,28

Figure Jump LinkFigure 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 = Mantel-Haenszel.Grahic Jump Location
Table Graphic Jump Location
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)

RR = relative risk.

Although five studies11,23-26 presented a steroid-reduction phase, only four23-26 reported data with regard to withdrawal or reduction of steroid dose. Their analysis showed that those treated with omalizumab were more likely to be able to withdraw their corticosteroids completely compared with those treated with placebo (41.8% vs 21.%) (RR = 1.80, 95% CI, 1.42-2.28; I2 = 54%; NNTB = 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 omalizumab23-26 were more likely to be able to reduce their corticosteroid dose by > 50% (76% vs 56.0%) (RR = 1.34, 95% CI, 1.23-1.46; I2 = 26%; NNTB = 5, 95% CI, 4-6). Finally, based on data from three studies,23,25,26 the mean difference in steroid use (BDP equivalent) between omalizumab and placebo at the end of the steroid-reduction phase was −141 μg/d (95% CI, −61.4 to −220.9; I2 = 67%; P = .0005).

Data from the five studies with a steroid-reduction phase of treatment11,23-26 showed reductions in the number of patients with at least one asthma exacerbation (17.2% in the omalizumab group vs 30.9% in the placebo group) (RR = 0.55, 95% CI, 0.47-0.64; I2 = 0%; NNTB = 8, 95% CI, 6-10) in the mean asthma exacerbations per patient (WMD = −0.36, 95% CI, −0.54 to 0.19; I2 = 77%), and in the frequency of hospitalizations due to asthma exacerbations (RR = 0.14, 95% CI, 0.03-0.66; I2 = 0%) in favor of omalizumab.

Secondary Outcomes

Patients treated with subcutaneous omalizumab showed greater reductions in the use of rescue medication (−0.5 puffs/d) and asthma symptom score at the end of the stable phase compared with those taking placebo (Table 4). Although there was no significant difference in final pulmonary function (FEV1 or PEF), omalizumab patients showed a small but significant increase in morning PEF (12 L/min). Additionally, omalizumab patients presented a statistically significantly improvement in overall Asthma Quality of Life Questionnaire (AQLQ) responses. The significant decreased use of rescue medication persisted in the steroid-reduction phase.

Table Graphic Jump Location
Table 4 —Analysis of Secondary Outcomes (Omalizumab vs Placebo)

AQLQ = Asthma Quality of Life Questionnaire; PEF = peak expiratory flow; SMD = standardized mean difference; WMD = weighted mean difference. See Table 3 for expansion of other abbreviation.

a 

Mean value.

b 

Expressed in SD units.

Safety

There was no difference in the number of withdrawals due to adverse events between omalizumab-treated (1.3%) and placebo-treated patients (1.5%) (Table 4). The number of patients reporting any 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 = .14). The overall prevalence of suspected treatment-related adverse effects was significantly higher in the omalizumab group (5.0%) than in the placebo group (3.2%) (NNTH = 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 omalizumab group compared with the placebo group (19.9% vs 13.2%; P = .002; NNTH = 14, 95% CI, 10-24). The frequency of adverse effects suggesting hypersensitivity reactions (such as anaphylactic reactions or urticaria) was low. Urticaria occurred infrequently (omalizumab 2.5% and placebo 2.1%). Two studies reported anaphylactic reactions: the first study,11 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 = .94). Malignant neoplasms were reported in two studies11,25 (one in each group). Cardiovascular adverse effects were recorded in two studies,25,27 two in the first and one in the last, all in the placebo group. Finally, one study23 reported one death due to cardiac arrest in a subject receiving placebo.

This is a more extensive systematic review performed exclusively to explore the efficacy and safety of subcutaneous omalizumab as add-on therapy to corticosteroids in schoolchildren, adolescents, and adults with moderate to severe persistent allergic 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 corticosteroid dose by > 50% (the NNTB was 5, indicating that one of every five patients treated with omalizumab obtained this benefit). Also, the reduction in daily inhaled dose following treatment with omalizumab was modest but significant. Moreover, omalizumab therapy was associated with fewer asthma exacerbations at the end of the stable-steroid phase, compared with placebo (NNTB = 10) and also at the end of the adjustable-steroid phase (NNTB = 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 significant difference in pulmonary function, patients treated with omalizumab showed a small but significant increase in morning PEF. Furthermore, an improvement in overall AQLQ responses was seen in those treated with omalizumab. However, these improvements must be interpreted as clinically nonsignificant because they did not reach the minimal important difference of each outcome (−0.81 for rescue medication, −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 guidelines3,4 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 β-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 findings 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 profile that was maintained 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 malignant 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 malignant neoplasms were reported during our study (one in each group): a medulloblastoma in the placebo group11 and a squamous cell carcinoma of the face in the omalizumab group.25

Recently, the FDA raised concerns about the cardiovascular safety of omalizumab.14 Data from an epidemiologic study (EXCELS) suggested more cardiovascular 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 fibrillation,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 when complete.

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 appropriate sequence generation, and only one adequately 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 injection of omalizumab (0.016 mg/kg/international units/mL every 2 to 4 weeks depending on body weight) was superior to placebo in preventing asthma exacerbation at the end of the stable-steroid phase and in the adjustable-steroid phase. The magnitude of the NNTBs suggests a clinically worthwhile benefit.

In addition, asthmatics treated with omalizumab were more likely to be able to withdraw their corticosteroids 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 efficacy and safety of omalizumab.

Author contributions:Dr Rodrigo: contributed to the study concept and design, and the acquisition, analysis, and interpretation of data; drafting of the submitted article and critical revision for important intellectual content; and final approval of the version to be published.

Dr Neffen: contributed to the study concept and design and interpretation of data; critical revision of the article for important intellectual content; and final 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 important intellectual content; and final approval of the version to be published.

Financial/nonfinancial 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, GlaxoSmithKline, AstraZeneca, Dr. Esteve SA, and Merck Sharp & Dome. Dr Neffen has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Schering Plough, GlaxoSmithKline, Novartis, and AstraZeneca. Dr Castro-Rodriguez has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Merck Sharp & Dohme, GlaxoSmithKline, and Grunenthal.

AQLQ

Asthma Quality of Life Questionnaire

BDP

beclomethasone dipropionate

FDA

US Food and Drug Administration

NNTB

number needed to treat for benefit

NNTH

number needed to treat for harm

PEF

peak expiratory flow

RR

relative risk

WMD

weighted mean difference

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Figures

Figure Jump LinkFigure 1. Flowchart for identification of usable studies. ICS = inhaled corticosteroids.Grahic Jump Location
Figure Jump LinkFigure 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 = Mantel-Haenszel.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Characteristics of Included Studies

BDP = beclomethasone dipropionate; BUD = budesonide; ICS = inhaled corticosteroids; M = moderate; O = omalizumab; P = placebo; S = severe; S/C = subcutaneous.

Table Graphic Jump Location
Table 2 —Risk of Bias of the Eligible Studies
Table Graphic Jump Location
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)

RR = relative risk.

Table Graphic Jump Location
Table 4 —Analysis of Secondary Outcomes (Omalizumab vs Placebo)

AQLQ = Asthma Quality of Life Questionnaire; PEF = peak expiratory flow; SMD = standardized mean difference; WMD = weighted mean difference. See Table 3 for expansion of other abbreviation.

a 

Mean value.

b 

Expressed in SD units.

References

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Barnes PJ. Anti-IgE therapy in asthma: rationale and therapeutic potential. Int Arch Allergy Immunol. 2000;1233:196-204. [CrossRef] [PubMed]
 
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