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Hanania NA, et al. "Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy: A Randomized Trial". Annals of Internal Medicine. 2011. 154(9):573-582.

Clinical Question

In patients with uncontrolled severe allergic asthma on inhaled corticosteroids and long-acting beta agonists, does omalizumab reduce asthma exacerbations?

Bottom Line

Omalizumab reduces asthma exacerbations in patients with uncontrolled severe allergic asthma on inhaled corticosteroids and long-acting beta agonists.

Major Points

Omalizumab is an anti-IgE monoclonal antibody that has been shown to reduce asthma exacerbations and use of inhaled corticosteroids (ICS) and rescue medications in patients ≥12 years with moderate- to severe- persistent asthma uncontrolled on ICS [1]. Omalizumab is approved by the FDA in patients with asthma uncontrolled on ICS, but the role of omalizumab as an adjunct to both high-dose ICS and long-acting beta agonists (LABAs) for severe asthma[2] was unclear.

The 2011 EXTRA study randomized 848 patients with uncontrolled asthma on ICS and LABAs to omalizumab or placebo. At 48 weeks, omalizumab was associated with fewer exacerbations than placebo (0.66 vs. 0.88 per patient; P=0.006) with no difference in adverse events. Of note, this trial did not allow modifications in controller medications so the intervention was not evaluated as a replacement for other treatment, including long-term systemic corticosteroids. The 2011 ICATA study[3] demonstrated a similar outcome in patients 6-20 years with persistent allergic asthma in the inner city.

The use of omalizumab is limited by the high cost. Economic analyses preceding publication of EXTRA found the medication to be cost effective only if patients were admitted ≥5 times or ≥20 days annually [4] and that the cost for every QALY gained was $821,000.[5]


NHLBI EPR-3 Diagnosis and Management of Asthma (2007)[2]

  • Consider omalizumab for patients ≥12 years with allergies for treatment steps 5 and 6 in addition to the preferred treatment
  • Step 5 preferred treatment: High-dose inhaled corticosteroids and long-acting beta agonist
  • Step 6 preferred treatment: High-dose inhaled corticosteroids, long acting beta agonist, and oral corticosteroid


  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=848
    • Omalizumab (n=427)
    • Placebo (n=421)
  • Setting: 197 centers in the US and Canada
  • Enrollment: Not stated
  • Follow-up: 48 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Asthma exacerbations, defined as worsening symptoms requiring systemic corticosteroids for ≥3 days or increase of prednisone 20 mg daily for OCS users.


Inclusion Criteria

  • Age 12-75 years with severe allergic asthma for ≥1 year
  • Therapy with high-dose ICS, LABAs (salmeterol or formoterol), and/or oral corticosteroids (OCS)
  • Uncontrolled asthma defined as:
    • ≥1 weekly nighttime wakening from symptoms
    • Use of rescue medications for daytime symptoms ≥2 days weekly in prior 4 weeks
    • ≥1 asthma exacerbation in prior year requiring systemic corticosteroid use
  • Allergy to perennial allergen in prior 12 months
  • 40-80% predicted FEV1
  • IgE 30-700 IU/mL
  • Weight 30-150 kg

Exclusion Criteria

  • Asthma exacerbation requiring OCS in prior 30 days or intubation in prior year
  • Non-asthma active lung disease
  • Therapy with omalizumab in prior year
  • Elevated IgE for non-allergy
  • ≥10 pack year history of smoking

Baseline Characteristics

  • Age: 44.5 years
  • Female: 65.8%
  • Race: 74.4% white, 20.8% black
  • BMI 31.8 kg/m2
  • FEV1: 65% predicted
  • IgE level: 177 IU/mL
  • Duration of disease: 23.8 years
  • Exacerbations requiring systemic corticosteroids in prior year: 2
  • Total Asthma Symptom Severity (TASS) score: 3.9
  • Asthma Quality of Life Questionnaire (AQLQ) score: 4.0
  • FeNO level: 28.9 ppb
  • Medications:
    • OCS: 17.0%
    • Other controllers except OCS: 46.5%
    • No additional controllers: 36.6%
    • Rescue inhalers: 4 puffs daily


  • 2-4 week run-in without dose adjustment of previous medications followed by randomization to one of two groups:
    • Omalizumab at 0.008 mg/kg/IgE q2 weeks or 0.016 mg/kg/IgE q4 weeks
    • Placebo
  • ICS at equivalent dosing to fluticasone ≥500 mcg inhaled BID and LABA use
  • No modifications of dosing of controller medications was permitted, including omalizumab, ICS, LABAs, or OCS
  • Systemic corticosteroids were administered as needed for acute asthma exacerbations
  • Albuterol was used as needed
  • Use of one controller medication permitted, including montelukast, zafirlukast, zileuton, antiocholinergics, cromolyn, nedocromil, immunotherapies, theophyline, and OCS


Comparisons are omalizumab vs. placebo at 48 weeks.

Primary Outcome

Asthma exacerbations per patient
0.66 vs. 0.88 (RR 0.75; 95% CI 0.61-0.92; P=0.006)

Secondary Outcomes

Difference in change in TASS score
Out of 9, higher indicating worse symptoms.
Omalizumab better: -0.26 (95% CI -0.42 to -0.10)
Difference in change of AQLQ score
Out of 7, higher indicating worse quality of life.
Omalizumab better: +0.29 points (95% CI 0.15 to 0.43)
Difference in change in FeNO
In a subgroup of 394 patients.
Omalizumab better: -4.24 ppb (CI -7.29 to -1.19)
Difference in change of albuterol use
Omalizumab better: -0.27 puff/day (95% CI -0.49 to -0.04)

Adverse Events

Any adverse event
80.4% vs. 79.5% (NS)
Serious adverse events
9.3% vs. 10.5% (NS)


  • Likely too small to detect anaphylaxis as an adverse event
  • Too small to power subgroup analyses
  • No evaluation of steroid-sparing or other modifications of medications
  • Clinical significance for FeNO is not clear in this field
  • Only modest clinical effect[6]
  • High drop-out rate[6]
  • No assessment for GERD or noncompliance[6]
  • High cost for treatment[6]
  • Of note, the WJC editors found that the related ClinicalTrials.gov trial details include patients with moderate or severe asthma though this publication only includes patients with severe asthma[7]


Genentech and Novartis Pharmaceuticals, manufacturers of Xolair, brand name of omalizumab.

Further Reading

  1. Busse W, et al. "Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma." Journal of Allergy and Clinical Immunology. 2001;108(2):184-190.
  2. 2.0 2.1 National Heart, Lung, and Blood Institute Education and Prevention Program. "Full report of the Expert Panel." NHLBI website. Accessed 2013-09-25.
  3. Busse WW et al. "Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children." The New England Journal of Medicine. 2011;364:1005-1015.
  4. Oba, Y and Salzman, GA. "Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate-to-severe allergic asthma." Journal of Allergy and Clinical Immunology(2004)114:2;265-269.
  5. Wu, AC et al. "Cost-effectiveness of omalizumab in adults with severe asthma: Results from the Asthma Policy Model". Journal of Allergy and Clinical Immunology (2007)120:5;1146–1152.
  6. 6.0 6.1 6.2 6.3 Chandra D, et al. "Beyond the blue: What fellows are reading in other journals. MUC5B and pulmonary fibrosis, omalizumab for severe allergic asthma, and intersitial lung abnormalities in smokers with emphysema." American Journal of Respiratory and Critical Care Medicine. 2012;185(9):1021-1022.
  7. ClinicalTrials.gov. "A Study of Omalizumab (Xolair) in Subjects With Moderate to Severe Persistent Asthma (EXTRA)." Last updated 2012-02-08. Accessed 2013-10-09.