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Add-on omalizumab improves day-to-day symptoms in inadequately controlled severe persistent allergic asthma

  1. M. Humbert1,
  2. W. Berger2,
  3. G. Rapatz3,
  4. F. Turk4

Article first published online: 18 MAR 2008

DOI: 10.1111/j.1398-9995.2008.01654.x

Issue

Allergy

Allergy

Volume 63, Issue 5, pages 592–596, May 2008

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How to Cite

Humbert, M., Berger, W., Rapatz, G. and Turk, F. (2008), Add-on omalizumab improves day-to-day symptoms in inadequately controlled severe persistent allergic asthma. Allergy, 63: 592–596. doi: 10.1111/j.1398-9995.2008.01654.x

Author Information

  1. 1

    Université Paris-Sud 11, Service de Pneumologie, Hôpital Antoine Béclère, Clamart, France

  2. 2

    Allergy and Asthma Associates, Mission Viejo, CA, USA

  3. 3

    Novartis Pharma AG, Basel, Switzerland

  4. 4

    Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

*Prof. M. Humbert Service de Pneumologie et Réanimation Respiratoire Hôpital Antoine Béclère Assistance Publique Hôpitaux de Paris Université Paris-Sud 11 157, rue de la Porte de Trivaux 92140 Clamart France

Publication History

  1. Issue published online: 18 MAR 2008
  2. Article first published online: 18 MAR 2008
  3. Accepted for publication 20 December 2007

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Keywords:

  • allergic asthma;
  • asthma;
  • omalizumab;
  • quality of life;
  • symptoms

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Background:  Omalizumab is efficacious in the treatment of moderate-to-severe and severe persistent allergic (immunoglobulin E-mediated) asthma, reducing exacerbations, emergency visits and improving quality of life (QoL). However, as exacerbations are relatively infrequent, assessment of efficacy on day-to-day symptoms is warranted.

Aims:  To investigate the effect of add-on omalizumab on day-to-day symptoms, and how they correlate with QoL in severe persistent asthma.

Methods:  The correlation between asthma symptom scores and QoL [Asthma Quality of Life Questionnaire (AQLQ)] was assessed. Symptom-free days (total symptom score = 0) and symptom-controlled days (definition 1: total symptom score ≤1; and definition 2: morning peak expiratory flow ≥90% of baseline, daytime asthma score ≤1 and night-time asthma score = 0) were compared between the omalizumab-treated group, omalizumab responders and placebo.

Results:  Four hundred and nineteen patients (omalizumab, n = 209; placebo, n = 210) were included in the efficacy analyses, and 61% (118/195) of patients with response data were classified as responders. Total symptom score strongly correlated with AQLQ overall and symptom scores and individual domains. AQLQ overall score correlated well with symptom scores. Responders had significantly more symptom-free days than the omalizumab-treated and placebo groups (45.8%, 37.2% and 22.6% respectively), and more symptom-controlled days (definition 1: 56.1%, 47.9% and 35.3%, respectively, and definition 2: 50.8%, 43.9% and 28.0%, respectively).

Conclusions:  In patients with inadequately controlled severe persistent asthma, day-to-day symptoms correlate well with QoL. Add-on omalizumab significantly improves day-to-day symptoms compared with placebo. Further improvement in responders confirms the physician’s assessment as a response measure.

Severe asthma is associated with a high risk of asthma-related hospitalization and mortality (1, 2) and significantly impairs patients’ quality of life (QoL) (3). The economic burden of asthma is the greatest in patients with inadequately controlled severe persistent asthma (4). Although treatments are available for severe persistent asthma, many patients remain inadequately controlled. For example, the INSPIRE study reported that 52% of patients were classified by the Asthma Control Questionnaire as having uncontrolled asthma and 74% of patients used short-acting β2-agonists daily despite regular maintenance therapy with inhaled corticosteroids (ICS) or ICS plus a long-acting β2-agonist (LABA) (5).

Adding omalizumab, an anti-immunoglobulin (Ig) E antibody, to standard asthma therapies (ICS with or without an LABA and additional controller medications as needed) has proven efficacy in the treatment of severe persistent allergic (IgE-mediated) asthma, reducing exacerbations, emergency visits for asthma and improving QoL (6).

Analyses of clinical trial data (6) and pooled data (7–11) have found the physician’s overall assessment – a composite measure including patient interview, review of medical notes, spirometry and symptom diaries, rescue medication use and peak expiratory flow (PEF) – to be the most meaningful measure of response to omalizumab therapy (12). Graded in a five-level evaluation of asthma control (complete control; marked improvement in control; discernible but limited control; no appreciable change; worsening in control), those with marked improvement or complete control are defined as responders (12). In this responder group, clinical outcomes were further improved compared with the overall omalizumab-treated population (12). In order to target those patients who will benefit most from omalizumab, thereby minimizing unnecessary drug exposure and healthcare costs, the omalizumab European Union (EU) label states that treatment response should be assessed at 16 weeks by the physician and treatment discontinued in those judged not to respond.

Asthma exacerbations and exacerbation-related healthcare resource use are strong indicators of lack of asthma control, but can occur relatively infrequently in many patients. Day-to-day asthma symptoms are also of major relevance to patients, and therefore may be useful in demonstrating the efficacy of a given treatment.

The aims of this study were to investigate the correlation between day-to-day asthma symptoms and asthma-related QoL, and to evaluate the effect of add-on omalizumab on day-to-day control of asthma symptoms in patients with severe persistent asthma. Results in omalizumab responders were also examined.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Study design

This post hoc analysis was conducted on efficacy results of a large, randomized, double-blind, placebo-controlled trial (INNOVATE study) (5). All patients included in the INNOVATE study had symptoms that remained inadequately controlled despite Global Initiative for Asthma (GINA) 2002 step 4 therapy (high-dose ICS plus a LABA with additional controller medication as necessary) (13). All patients received omalizumab or placebo in addition to their current asthma therapy for 28 weeks. Omalizumab was administered subcutaneously for every 2 or 4 weeks according to the patients’ body weight and baseline IgE levels. Further details of the INNOVATE study had been reported previously (5).

Data analysis

Correlation between day-to-day asthma symptoms and QoL at baseline

The Asthma Quality of Life Questionnaire (AQLQ) is a broad measure of patient-related outcomes, and a correlation between this and asthma symptom scores may indicate the importance of asthma symptoms in the disease burden of asthma experienced by patients. Questions in the AQLQ relate to the previous 2 weeks. Therefore average asthma symptom scores (night, day, morning and total) over the 2 weeks prior to randomization (weeks −2 to 0) were determined so that they related to the same time period. The correlation between average asthma symptom scores and AQLQ scores (overall and individual domains) taken at baseline was then assessed using Pearson’s correlation coefficients. The assessment was performed on baseline data pooled from all treatment groups in order to show any correlation irrespective of treatment.

Symptom-free days and symptom-controlled days

Between-group data for symptom-free and symptom-controlled days were compared in the omalizumab-treated group, omalizumab-responder subgroup (as judged by the physician’s overall assessment) and the placebo group.

Symptom-free days were defined as a total symptom score of 0 (no symptoms) during the day that measurements were taken. The total symptom score is the sum of the daytime (range 0–4), night-time (range 0–4) and morning (range 0–1) scores, with a score of 0 signifying no symptoms (9).

Symptom-controlled days were defined as follows: definition 1: minor symptoms (total symptom score ≤1); and definition 2: a day on which the morning PEF rate was ≥90% of baseline, daytime asthma score was ≤1 and night-time asthma score was 0.

Symptom-free and symptom-controlled days were determined at 2-weekly intervals from baseline (taken as being the first 2 intervals recorded, i.e. weeks −4 to −2 and weeks −2 to 0) to endpoint (weeks 26–28). The percentage of symptom-free days (total symptom score of 0) and symptom-controlled days were compared at the last observed interval (weeks 26–28) between treatment groups using chi-square test.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Baseline demographics and clinical characteristics

The baseline demographics and clinical characteristics of the omalizumab-treated group, omalizumab-responder subgroup and placebo group were similar and are shown in Table 1. Of the 419 patients (omalizumab n = 209; placebo n = 210) included in efficacy analyses of the INNOVATE study (18), response data (i.e. responder or non-responder) were available for 396 patients (omalizumab n = 195; placebo n = 201), and of the omalizumab-treated patients, 61% (118/195) were classified as responders using the physician’s overall assessment.

Table 1.   Baseline demographics and clinical characteristics
 Placebo (n = 210)Omalizumab-treated population (n = 209)Omalizumab responder population (n = 118)

  1. FEV1, forced expiratory volume in 1 s; AQLQ, Asthma Quality of Life Questionnaire; IgE, immunoglobulin E; ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; OCS, oral corticosteroids; SD,standard deviation.

  2. *Beclometasone dipropionate (BDP) equivalent.

  3. †To be maintained unchanged throughout the treatment phase of the study.

Age (years), mean (SD)43.3 (13.49)43.4 (13.29)44.1 (13.58)
Sex, n (%)
 Male72 (34.3)68 (32.5)40 (33.9)
 Female138 (65.7)141 (67.5)78 (66.1)
Race, n (%)
 Caucasian164 (78.1)163 (78.0)93 (78.8)
 Black14 (6.7)14 (6.7)6 (5.1)
 Oriental3 (1.4)2 (1.0)1 (0.8)
 Other29 (13.8)30 (14.4)18 (15.3)
Weight (kg), mean (SD)79.2 (17.48)81.2 (19.75)78.7 (18.14)
Smoking history, n (%)
 Never smoked162 (77.1)157 (75.1)85 (72.0)
 Ex-smoker48 (22.9)52 (24.9)33 (28.0)
FEV1 (% of predicted), mean (SD)61.6 (13.83)61.0 (14.42)63.5 (13.73)
Reversibility (%), mean (SD)24.5 (23.27)28.9 (23.27)27.2 (20.85)
AQLQ overall score, mean (SD)3.9 (1.12)3.9 (1.05)3.8 (0.98)
Serum total IgE (IU/ml), mean (SD) 189.6 (153.14)197.6 (145.18)222 (153.11)
Duration of allergic asthma (years), mean (SD)22.7 (14.72)23.3 (15.23)23.2 (14.82)
ICS dose* (μg/day), mean (SD)2300.9 (978.3)2359.1 (1210.2)2232.9 (1049.5)
Patients at baseline receiving, n (%)†
 ICS plus LABA210 (100)209 (100)118 (100)
 Anti-leukotrienes72 (34.3)74 (35.4)43 (36.4)
 Theophyllines51 (24.3)64 (30.6)38 (32.2)
 Maintenance OCS42 (20.0)49 (23.4)23 (19.5)
 Oral β2-agonists3 (1.4)1 (0.5)0 (0)

Correlation between day-to-day symptoms and QoL

Average total symptom score was strongly correlated with AQLQ overall score (r = −0.503) and AQLQ symptoms score (r = −0.601) and also correlated with each individual AQLQ domain score (Table 2). Of the components of average total asthma symptom score, daytime symptom score (r = −0.517) was the most strongly correlated with AQLQ overall score followed by night-time symptom score (r = −0.508) and morning symptom score (r = −0.368).

Table 2.   Correlation between Asthma Quality of Life Questionnaire (AQLQ) overall score and individual domain scores with day-to-day asthma symptoms
Variabler
AQLQ overall scoreAQLQ symptoms scoreAQLQ activities scoreAQLQ emotions scoreAQLQ environment score
Average morning symptom score−0.368−0.469−0.227−0.273−0.207
Average day symptom score−0.517−0.598−0.411−0.366−0.285
Average night symptom score−0.508−0.602−0.377−0.374−0.281
Average total symptom score−0.503−0.601−0.379−0.345−0.291

Symptom-free days and symptom-controlled days

The percentage of symptom-free days for the last observed interval (weeks 26–28) was significantly (P < 0.001) greater in the omalizumab-responder subgroup (45.8%) than in the omalizumab-treated group (37.2%) and placebo group (22.6%, Fig. 1A). Significant (P < 0.001) improvements were observed for total, morning, daytime and night-time symptoms (Fig. 1B–D). Graphical comparisons of the number of symptom-free days (symptom score = 0) from baseline to weeks 26–28 are shown alongside symptom-free morning, daytime and night-time periods (Fig. 1A–D).

Figure 1.  Total symptom-free days (A), morning period (B), daytime period (C) and night-time period (D) from baseline to the last observed interval (weeks 26–28).

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image

Graphical comparisons of the number of symptom-controlled days (definitions 1 and 2) are shown in Fig. 2A,B respectively. The percentage of symptom-controlled days (definitions 1 and 2) was significantly (P < 0.001) greater in omalizumab-responder subgroup (definition 1: 56.1%, definition 2: 50.8%) than in the omalizumab-treated group (definition 1: 47.9%, definition 2: 43.9%) and placebo group (definition 1: 35.3%, definition 2: 28.0%, Fig. 2A,B).

Figure 2.  Symptom-controlled days for definition 1 (A) and definition 2 (B) from baseline to the last observed interval (weeks 26–28).

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image

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Our results show a correlation between day-to-day asthma symptom scores (morning, day, night and total) and the AQLQ across all domains in patients with inadequately controlled severe persistent allergic asthma despite GINA 2002 step 4 therapy. Day, night and total asthma symptom scores were strongly correlated with AQLQ overall and symptoms domains, particularly daytime symptoms. This confirms that day-to-day asthma symptom scores provide a measure of asthma control that is highly relevant to patients, and are an important component of assessments of asthma control in addition to asthma exacerbations (14). Indeed, the characteristics listed in the GINA 2006 guidelines indicating controlled asthma include the absence of daytime and nocturnal symptoms (15).

Baseline clinical characteristics, AQLQ score and additional controller medication usage were similar in all groups. All patients had inadequately controlled severe persistent asthma, high medication use and healthcare utilization, and had experienced continuing uncontrolled asthma symptoms despite GINA 2002 step 4 therapy (13). The similar baseline clinical characteristics between the omalizumab-treated group and the omalizumab-responder subgroup provide further evidence of the difficulty in predicting which patients might achieve the greatest benefit with omalizumab, and the value of assessing response after 16 weeks of treatment.

Our results show that add-on omalizumab significantly increases the number of symptom-free days, symptom-controlled days and improves day-to-day symptoms compared with add-on placebo in patients with inadequately controlled severe persistent allergic asthma despite GINA 2002 step 4 therapy. The assessment of the effectiveness of omalizumab in patients who respond to omalizumab therapy was an important feature of this study. In the omalizumab-responder population, further improvements were seen over the omalizumab-treated population in all outcomes. Assessment of this subgroup may reflect treatment outcomes seen in clinical practice after omalizumab therapy is continued only in those judged by a physician to have responded to omalizumab after 16 weeks of treatment, as stated in the EU label.

In conclusion, day-to-day asthma symptoms correlate well with improved QoL and provide an important additional simple measure of asthma control. Add-on omalizumab improves day-to-day symptoms in patients with inadequately controlled severe persistent allergic asthma. This study also illustrates the value of assessing treatment response to omalizumab after 16 weeks.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The authors were assisted in the preparation of this text by professional medical writer, Thomas McMurray (ACUMED); this study was funded by Novartis Pharma AG.

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  • 1
    Guite HF, Dundas R, Burney PGJ. Risk factors for death from asthma, chronic obstructive pulmonary disease, and cardiovascular disease after a hospital admission for asthma. Thorax 1999;54:301–307.
  • 2
    Dolan CM, Fraher KE, Bleecker ER, Borish L, Chipps B, Hayden ML et al. Design and baseline characteristics of the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study: a large cohort of patients with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol 2004;92:32–39.
  • 3
    Juniper EF, Wisniewski ME, Cox FM, Emmett AH, Nielsen KE, O’Byrne PM. Relationship between quality of life and clinical status in asthma: a factor analysis. Eur Respir J 2004;23:287–291.
  • 4
    Turk F, Kay S, Higgins V. The economic and human impact of poor control in patients with severe persistent allergic asthma: results from a multinational study. Thorax 2005;60(Suppl. II):P21.
  • 5
    Partridge MR, Van Der MT, Myrseth SE, Busse WW. Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med 2006;6:13.
  • 6
    Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005;60:309–316.
    Direct Link:
  • 7
    Vignola AM, Humbert M, Bousquet J, Boulet LP, Hedgecock S, Blogg M et al. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with concomitant allergic asthma and persistent allergic rhinitis (SOLAR). Allergy 2004;59:709–717.
    Direct Link:
  • 8
    Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 2001;108:184–190.
  • 9
    Solèr M, Matz J, Townley R, Buhl R, O’Brien J, Fox H et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001;18:254–261 [Erratum in: Eur Respir J 2001;18:739–740].
  • 10
    Holgate ST, Chuchalin AG, Hébert J, Lötvall J, Persson GB, Chung KF et al. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy 2004;34:632–638.
    Direct Link:
  • 11
    Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S et al. The effect of treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency medical visits in patients with severe persistent asthma. Allergy 2005;60:302–308.
    Direct Link:
  • 12
    Bousquet J, Rabe K, Humbert M, Chung KF, Berger W, Fox H et al. Predicting and evaluating response to omalizumab in patients with severe allergic asthma. Respir Med 2007;10:1483–1492.
  • 13
    Global Initiative for Asthma. Global strategy for asthma management and prevention. NIH Publication No 02-3659 (issued January 1995, revised 2002, 2005, 2006, 2007). National Institutes of Health/National Heart, Lung, and Blood Institute. http://www.nhlbi.nih.gov. Available at http://www.ginastham.org; accessed 8 February 2008.
  • 14
    Humbert M, Holgate S, Boulet L-P, Bousquet J. Asthma control or severity: that is the question. Allergy 2007;62:95–101.
    Direct Link:
  • 15
    Global Initiative for Asthma. Global strategy for asthma management and prevention. Revised 2006. Available at http://www.ginasthma.org; accessed 8 February 2008.
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