Omalizumab in Patients With Moderate to Severe Persistent Allergic Asthma Not Adequately Controlled Despite GINA (2009) Step 4 Therapy

A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits LS Mean of change from baseline in mean morning PEF is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates.

A Peak Expiratory Flow (PEF) meter was distributed to patients at Visit 1, to be used to measure PEF twice-daily as directed. During the Screening and Treatment Periods, PEF was measured in the morning and evening every day. the morning PEF was performed within 15 minutes after waking, and the evening PEF approximately 12 hours later. Patients were encouraged to perform morning and evening PEF measurements before the use of any LABA or rescue medication. The highest of 3 values was recorded as the daily personal best. The personal best was used to calculate the mean morning PEF and mean evening PEF value collected between assessment Visits. LS Mean of change from baseline in mean morning PEF is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline mean morning PEF as covariates.

Spirometry was used at defined time points throughout the study to assess the clinical status of patients and to capture the following variables: forced expiratory volume in one second (FEV1), FEV1 percent predicted, forced vital capacity (FVC) and the FEV1/FVC ratio. During the Screening assessment, spirometry was performed pre- and post-bronchodilator administration to assess reversibility. During the treatment period (including prerandomization assessments on Day 1), spirometry was performed after withholding bronchodilators. The results of spirometry were required to meet the ATS/ERS criteria for acceptability and repeatability. Acceptability criteria were applied before repeatability was determined. LS Mean of change from baseline in % predicted FEV1 is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, center grouping, smoking status, and baseline % predicted FEV1 as covariates.

The standardized version of the Asthma Quality of Life Questionnaire (AQLQs)), was used to assess the patients' asthma-related quality of life. There are 32 questions in the AQLQ and they are in 4 domains (symptoms, activity limitation, emotional function and environmental exposure). Each question was answered on a 7 point scale (1-totally limited/problems all the time, 7-not at all limited/no problems). The overall AQLQ score is the mean of all 32 responses, and the individual domain scores are the means of the items in those domains (a minimum domain / overall score of 1 = Severely impaired whereas a maximum domain / overall score of 7 = not impaired at all). A positive change from baseline score indicates improvement.

The standardized version of the Asthma Quality of Life Questionnaire (AQLQs)), was used to assess the patients' asthma-related quality of life. There are 32 questions in the AQLQ and they are in 4 domains (symptoms, activity limitation, emotional function and environmental exposure). Each question was answered on a 7 point scale (1-totally limited/problems all the time, 7-not at all limited/no problems). The overall AQLQ score is the mean of all 32 responses, and the individual domain scores are the means of the items in those domains (a minimum domain / overall score of 1 = Severely impaired whereas a maximum domain / overall score of 7 = not impaired at all). A positive change from baseline score indicates improvement.

The Asthma Control Questionnaire (ACQ) is a questionnaire consisting of 7 questions assessing symptoms, airway caliber and rescue β2-agonist use. One value representing overall asthma control on that occasion was calculated. Decrease in scores of 0.5 or higher between ACQ assessments are considered clinically meaningful. The ACQ was completed by the patient at the Investigator's site at Visit 2 (Week 1, pre-dose), Visit 6 (after completion of 16 weeks of treatment) and at the End of Study/Early Termination visit. LS Mean of change from baseline in ACQ score is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, center grouping, smoking status, and baseline ACQ score as covariates. Score 0= totally controlled, 6= extremely poorly controlled

The Asthma Control Questionnaire (ACQ) is a questionnaire consisting of 7 questions assessing symptoms, airway caliber and rescue β2-agonist use. One value representing overall asthma control on that occasion was calculated. Decrease in scores of 0.5 or higher between ACQ assessments are considered clinically meaningful. The ACQ was completed by the patient at the Investigator's site at Visit 2 (Week 1, pre-dose), Visit 6 (after completion of 16 weeks of treatment) and at the End of Study/Early Termination visit. Only patients with no more than 1 item missing are included, and the missing item was imputed by interpolation

Total asthma symptom score was derived for each day as the total of the morning (scale 0-1), daytime (scale 0-4) and nocturnal (scale 0-4) scores with a max score of 9. The mean score across the 28 days prior to the week 24 assessment visit was used to calculate a change from baseline. Analysis of total asthma symptom score was performed using ANCOVA model and Van-Elteren test. LS Mean of change from baseline in mean asthma symptom score is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, smoking status, center grouping, and baseline mean asthma symptom scores as covariates. Decrease of score on change from baseline means improvement of asthma symptom control.

The global evaluation of treatment effectiveness (GETE) is an assessment of asthma symptom control and overall response to asthma treatment. The evaluation was performed by both investigator and patient, each using the same 5 point scale. The GETE scale ranges were as follows: excellent, good, moderate, poor and worsening. A good or excellent response on the 5 point scale indicated that a patient had responded to treatment. 1=excellent 2=good 3=moderate 4=poor 5= worsening. Responder is defined as the patient who achieved an excellent or good response. Non-responder isdefined as the patient who achieved a moderate or poor or worsening response.

Analysis of rescue medication use followed a similar method to that employed for total asthma symptom score. The mean number of puffs across the 28 days prior to the Week 24 assessment visit was used to calculate a change from baseline. LS Mean of change from baseline in mean number of puffs of asthma rescue medication is calculated with the ANCOVA model using treatment, stratification group, dosing schedule, gender, smoking status, center grouping, and baseline mean number of puffs of asthma rescue medication as covariates.