Nicola A. Hanania, MD, MS; Oral Alpan, MD; Daniel L. Hamilos, MD; John J. Condemi, MD; Irmarie Reyes-Rivera, PhD; Jin Zhu, PhD; Karin E. Rosen, MD, PhD; Mark D. Eisner, MD, MPH; Dennis A. Wong, MD; William Busse, MD
Acknowledgment: The authors thank Shilpa Lalchandani, PhD, of Embryon, for her writing assistance.
Financial Support: By Genentech and Novartis Pharmaceuticals.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-1852.
Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Dr. Reyes-Rivera (e-mail, email@example.com).
Requests for Single Reprints: Mark D. Eisner, MD, MPH, Associate Group Medical Director, Product Development, Inflammation & Respiratory, Genentech, 1 DNA Way, South San Francisco, CA 94080-4990; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Hanania: Baylor College of Medicine, One Baylor Plaza, BCM621, Houston, TX 77030.
Dr. Alpan: O & O Alpan, LLC, Section on Immunopathogenesis, 5511 Oakmont Avenue, Bethesda, MD 20817-3527.
Dr. Hamilos: Massachusetts General Hospital–Rheumatology, 55 Fruit Street, Bulfinch 422, Boston, MA 02114.
Dr. Condemi: Allergy Asthma Immunology of Rochester, Brighton, 300 Meridian Centre, Suite 300, Rochester, NY 14618.
Drs. Reyes-Rivera, Zhu, Rosen, Eisner, and Wong: Genentech, 1 DNA Way, South San Francisco, CA 94080-4990.
Dr. Busse: K4/910 CSC, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Mail Code 998, Madison, WI 53792.
Author Contributions: Conception and design: I. Reyes-Rivera, M.D. Eisner, A. Wong.
Analysis and interpretation of the data: N.A. Hanania. O. Alpan, I. Reyes-Rivera, J. Zhu, K.E. Rosen, A. Wong.
Drafting of the article: N.A. Hanania, I. Reyes-Rivera, K.E. Rosen, M.D. Eisner, A. Wong, W. Busse.
Critical revision of the article for important intellectual content: N.A. Hanania, O. Alpan, D.L. Hamilos, J.J. Condemi, I. Reyes-Rivera, K.E. Rosen, M.D. Eisner, A. Wong.
Final approval of the article: N.A. Hanania, D.L. Hamilos, J.J. Condemi, I. Reyes-Rivera, K.E. Rosen, M.D. Eisner, A. Wong, W. Busse.
Provision of study materials or patients: O. Alpan, D.L. Hamilos, J.J. Condemi, A. Wong.
Statistical expertise: I. Reyes-Rivera, J. Zhu, M.D. Eisner, A. Wong.
Obtaining of funding: A. Wong.
Administrative, technical, or logistic support: A. Wong.
Collection and assembly of data: D.L. Hamilos, I. Reyes-Rivera, K.E. Rosen, A. Wong.
Inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) are recommended in patients with asthma that is not well-controlled; however, many patients continue to have inadequately controlled asthma despite this therapy.
To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs, with or without additional controller therapy.
Prospective, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00314574)
193 investigational sites in the United States and 4 sites in Canada.
850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs, with or without other controllers.
Omalizumab (n = 427) or placebo (n = 423) was added to existing medication regimens for 48 weeks.
The primary end point was the rate of protocol-defined exacerbations over the study period. Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol, mean total asthma symptom score, and mean overall score on the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Safety end points included the frequency and severity of treatment-emergent adverse events.
During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (−0.27 puff/d [CI, −0.49 to −0.04 puff/d]), and decreased mean asthma symptom score (−0.26 [CI, −0.42 to −0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively.
The results are limited by early patient discontinuation (20.8%). The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup.
In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy.
Genentech and Novartis Pharmaceuticals.
It has not been clearly established whether omalizumab, a recombinant humanized monoclonal antibody to IgE, is beneficial in patients with severe asthma and persistent symptoms despite therapy with both high-dose inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs).
In this double-blind, placebo-controlled, randomized trial, patients with severe asthma who received omalizumab in addition to ongoing ICS and LABAs had fewer asthma exacerbations, reduced rescue inhaler use, and improved symptom and quality-of-life scores over 48 weeks.
Although no difference in the incidence of adverse events was seen, the study may have been too small to detect rare but important safety events, such as anaphylaxis.
Omalizumab may be beneficial in the treatment of severe asthma with persistent symptoms despite therapy with high-dose ICS and LABAs.
Appendix Table 1. Definitions of Adverse Events of Special Interest
Study flow diagram.
The proportion of patients remaining in the study through week 24 was 88.5% in the omalizumab group and 86.7% in the placebo group.
Appendix Table 2. Reasons for Discontinuations, by Interval
Table 1. Baseline Demographic and Clinical Characteristics
Table 2. Protocol-Defined Asthma Exacerbations Over the 48-Week Treatment Period
Kaplan–Meier estimates of time to first protocol-defined asthma exacerbation.
The P value based on a Cox proportional model for the difference of time to exacerbation between the 2 treatment groups was 0.008.
Treatment effect estimates for overall AQLQ(S) score, by visit.
Data shown are estimated means (except for baseline values) from a mixed-effects model that included treatment group, time, and baseline AQLQ(S) score. The treatment effect did not vary over time on the basis of the lack of observed time-by-treatment interaction. AQLQ(S) = standardized version of the Asthma Quality of Life Questionnaire.
Rescue medication puffs and total asthma symptom score over 48 weeks.
Data shown are means of observed data, with the number of patients included at each visit given below the horizontal axis. Daytime, nocturnal, and morning scores at each visit were calculated as the mean of available data for the last 28 days before each visit. Top. Rescue medication puffs per day over 48 weeks. Bottom. Total asthma symptom score plotted over 48 weeks.
Appendix Table 3. Secondary Efficacy End Points: Protocol-Specified Analysis of Covariance With Last Observation Carried Forward
FeNO marker of persistent lung inflammation in a subgroup of 394 patients.
Data shown are estimated means (except for baseline values) from a mixed-effects model. The treatment effect did not vary over time on the basis of the lack of observed time-by-treatment interaction. FeNO = fractional exhaled nitric oxide.
Table 3. Summary of Safety and Tolerability (Safety Population)
Appendix Table 4. Participants With Treatment-Emergent Adverse Events, by System Organ Class (Safety-Evaluable Population)
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Verdugo Hills Hospital
May 11, 2011
No major improvement with omalizumab
The conclusions drawn by the authors do not seem to fit the data presented in the articles. The benefits of treatment with omalizumab were small and not clinically significant. The primary end point was the number of exacerbations and the authors say it was reduced by 25% in the treatment group as compared to the placebo group. However if we look at the number of patients who had exacerbation during the study period of 48 weeks there was hardly any difference between the two groups. There were 427 patients in the treatment group and of these 152 patients had exacerbations, in the placebo group the figures were 421 and 179. So we can say that in placebo group 27 additional patients had exacerbations. That is about a 6% decrease. The number of patients is so small that a few patients having multiple exacerbations in the placebo group can change the total numbers of exacerbations significantly. The improvement in AQLQ, inhaler use and asthma scores were not dramatic.
The main point I would like to bring out is that the data does not show any big improvement in the treatment group. If you analyze the data a dozen different ways you can come up with some statistically significant figures. However these figures can be misleading, if we ignore the whole picture.
Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy: A Randomized Trial. Ann Intern Med. 2011;154:573–582. doi: https://doi.org/10.7326/0003-4819-154-9-201105030-00002
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Published: Ann Intern Med. 2011;154(9):573-582.
Asthma, Pulmonary/Critical Care.
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