Asthma
Conditions
Keywords
Persistent Asthma, EXTRA, Xolair, Difficult Breathing
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of subcutaneously administered Xolair as add-on therapy for the treatment of subjects aged 12-75 years old diagnosed with moderate to severe asthma who are inadequately controlled with high-dose inhaled corticosteroids (ICS)+ long-acting beta-agonists (LABA) with or without additional controller therapy.
Interventions
Omalizumab (Xolair) was administered by subcutaneous (SC) injection every 2 or 4 weeks. Xolair was supplied as a sterile, white, preservative-free, lyophilized powder in single-use vials that were reconstituted with Sterile Water for Injection (SWFI), USP.
DRUGplacebo
Placebo was administered by subcutaneous (SC) injection every 2 or 4 weeks. Placebo contained the same ingredients as the lyophilized formulation of Xolair,excluding omalizumab.
DRUGcorticosteroids
Minimum dose of 500 µg of fluticasone dry-powder inhaler or its equivalent ex-valve dose twice a day.
DRUGlong-acting beta-agonists
50 µg salmeterol twice daily or 12 µg formoterol twice daily.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Signed Informed Consent Form and an informed assent, if applicable * Be between the ages of 12 to 75 years * Have had a history of moderate to severe asthma for at least one year prior to screening * Have had treatment with a stable regimen of of salmeterol 50 µg twice a day (BID) or formoterol 12 µg BID for at least 8 weeks prior to screening * Have had treatment with a stable regimen of high-dose inhaled corticosteroids (ICS) for at least 8 weeks prior to screening * Have inadequately controlled asthma * Have had at least one asthma exacerbation requiring systemic corticosteroid rescue in the 12 months prior to the screening visit while receiving treatment with high-dose ICS * Have less than 10 pack-years smoking history * Have a positive skin test for or a positive, in vitro response to one relevant perennial aeroallergen documented within the 12 months prior to screening * If a subject has not had a positive skin test or in vitro reactivity in the 12 months prior to screening, the subject must demonstrate a positive response to at least one relevant perennial aeroallergen in a skin or in vitro test prior to randomization * Female subjects of childbearing potential must use an effective method of contraception from screening through their duration of participation in the study * For the collection of additional blood samples for future research (optional), provide signed consent and an informed assent, if applicable.
Exclusion criteria
* Have had an asthma exacerbation requiring intubation within 12 months prior to screening * Have active lung disease other than asthma * Have had an asthma exacerbation requiring treatment with the addition of systemic (oral or intravenous) corticosteroids or an increase in systemic corticosteroids within 30 days prior to screening * Require chronic immunosuppressive therapy including cyclosporine, methotrexate, etc. * Have significant medical illness other than asthma * Have taken methotrexate, gold salts, cyclosporine, or macrolide antibiotics, within 3 months prior to screening * Have taken other investigational drugs within 30 days prior to screening * Have been treated with Xolair within the 12 months prior to screening * Have a history of drug or alcohol abuse that, in the judgment of the investigator, may put the subject at risk for being unable to participate fully in the study for the duration of the study * Have elevated serum IgE levels for reasons other than allergy * Are pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Asthma Exacerbations Over the 48 Week Treatment Period | 48 weeks | A protocol-defined asthma exacerbation was defined as worsening of asthma symptoms requiring treatment with systemic corticosteroids for 3 or more days; for patients receiving long-term oral corticosteroids, an exacerbation was a 20 mg or more increase in average daily dose of oral prednisone (or a similar dose of another systemic corticosteroid). The rate of protocol-defined asthma exacerbations, normalized by subject-time at risk and computed over the 48 week treatment period in each treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Asthma Symptom Scores | Baseline and Week 48 | Change from baseline to week 48 in Total Asthma Symptom Score (TASS), which included a nocturnal asthma score (0 to 4 scale), morning asthma symptoms (yes or no), and a daytime asthma symptom score (0 to 4 scale, total score range 0 to 9, higher TASS scores represent worse symptoms; breathlessness, tightness in chest, wheezing and cough. Score achieved by week 48 minus baseline. |
| Change From Baseline in the Number of Puffs Per Day of Beta Agonist Rescue Medication | Baseline and Week 48 | Change from baseline to week 48 in mean puffs per day of albuterol. Puffs per day was achieved by week 48 minus baseline. |
| Change From Baseline in Overall Asthma-related Quality of Life | Baseline and Week 48 | Change from baseline to week 48 in overall asthma-specific health-related quality of life, as measured by the standardized version of the Asthma Quality of Life Questionnaire (AQLQ\[S\]) score. The AQLQ(S) consists of 4 domains (activity limitations, symptoms, emotional function, and environmental stimuli), with a total of 32 items; the overall score is the mean of these 32 items on a scale of 1 to 7 (1 = severe impairment, 7 = no impairment). Overall outcome achieved by mean visit minus baseline. |
| Number of Participants Assessed for Frequency and Severity of Treatment-emergent Adverse Events | Week 48 | This outcome is represented in the adverse event section of the database. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo subcutaneous dose minimum of 0.008 mg/kg/IgE (IU/mL) every 2 weeks or a minimum of 0.016 mg/kg/IgE (IU/mL) every 4 weeks for 48 weeks.
Participants maintained their high-dose inhaled corticosteroid (minimum of 500 µg of fluticasone dry powder inhaler twice a day or its ex-valve equivalent) and Long-Acting Beta-Agonist dose (either 50 µg salmeterol twice daily or 12 µg formoterol twice daily) throughout the study.
Participants were permitted to use albuterol as rescue medicine throughout the study. | 421 |
| Xolair Omalizumab (Xolair) subcutaneous dose minimum of 0.008 mg/kg/IgE (IU/mL) every 2 weeks or a minimum of 0.016 mg/kg/IgE (IU/mL) every 4 weeks for 48 weeks.
Participants maintained their high-dose inhaled corticosteroid (minimum of 500 µg of fluticasone dry powder inhaler twice a day or its ex-valve equivalent) and Long-Acting Beta-Agonist dose (either 50 µg salmeterol twice daily or 12 µg formoterol twice daily) throughout the study.
Participants were permitted to use albuterol as rescue medicine throughout the study. | 427 |
| Total | 848 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 16 |
| Overall Study | Data unknown at database lock | 0 | 1 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Lost to Follow-up | 19 | 25 |
| Overall Study | Physician Decision | 22 | 15 |
| Overall Study | Pregnancy | 6 | 4 |
| Overall Study | Withdrawal by Subject | 33 | 22 |
Baseline characteristics
| Characteristic | Placebo | Xolair | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 16 Participants | 23 Participants | 39 Participants |
| Age, Categorical >=65 years | 29 Participants | 25 Participants | 54 Participants |
| Age, Categorical Between 18 and 65 years | 376 Participants | 379 Participants | 755 Participants |
| Age Continuous | 45.3 years STANDARD_DEVIATION 13.9 | 43.7 years STANDARD_DEVIATION 14.3 | 44.5 years STANDARD_DEVIATION 14.1 |
| Sex: Female, Male Female | 295 Participants | 262 Participants | 557 Participants |
| Sex: Female, Male Male | 126 Participants | 165 Participants | 291 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 339 / 420 | 329 / 428 |
| serious Total, serious adverse events | 44 / 420 | 40 / 428 |
Outcome results
Primary
Rate of Asthma Exacerbations Over the 48 Week Treatment Period
A protocol-defined asthma exacerbation was defined as worsening of asthma symptoms requiring treatment with systemic corticosteroids for 3 or more days; for patients receiving long-term oral corticosteroids, an exacerbation was a 20 mg or more increase in average daily dose of oral prednisone (or a similar dose of another systemic corticosteroid). The rate of protocol-defined asthma exacerbations, normalized by subject-time at risk and computed over the 48 week treatment period in each treatment group.
Time frame: 48 weeks
Population: Modified Intent-to-Treat population included all randomized patients who received at least 1 dose of study drug (Xolair or placebo).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Rate of Asthma Exacerbations Over the 48 Week Treatment Period | 0.88 exacerbation/patient-week |
| Xolair | Rate of Asthma Exacerbations Over the 48 Week Treatment Period | 0.66 exacerbation/patient-week |
Secondary
Change From Baseline in Overall Asthma-related Quality of Life
Change from baseline to week 48 in overall asthma-specific health-related quality of life, as measured by the standardized version of the Asthma Quality of Life Questionnaire (AQLQ\[S\]) score. The AQLQ(S) consists of 4 domains (activity limitations, symptoms, emotional function, and environmental stimuli), with a total of 32 items; the overall score is the mean of these 32 items on a scale of 1 to 7 (1 = severe impairment, 7 = no impairment). Overall outcome achieved by mean visit minus baseline.
Time frame: Baseline and Week 48
Population: Modified Intent-to-Treat population included all randomized patients who received at least 1 dose of study drug (Xolair or placebo). Five patients were missing baseline values and were excluded from the analyses. The Last Observation Carried Forward was used to impute missing values at week 48 for patients who discontinued the study early.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Overall Asthma-related Quality of Life | 0.96 score on a scale | Standard Deviation 1.26 |
| Xolair | Change From Baseline in Overall Asthma-related Quality of Life | 1.16 score on a scale | Standard Deviation 1.22 |
Secondary
Change From Baseline in the Number of Puffs Per Day of Beta Agonist Rescue Medication
Change from baseline to week 48 in mean puffs per day of albuterol. Puffs per day was achieved by week 48 minus baseline.
Time frame: Baseline and Week 48
Population: Modified Intent-to-Treat population included all randomized patients who received at least 1 dose of study drug (Xolair or placebo). Five patients were missing baseline values and were excluded from the analyses. The Last Observation Carried Forward was used to impute missing values at week 48 for patients who discontinued the study early.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Number of Puffs Per Day of Beta Agonist Rescue Medication | -1.35 puffs per day | Standard Deviation 2.69 |
| Xolair | Change From Baseline in the Number of Puffs Per Day of Beta Agonist Rescue Medication | -1.57 puffs per day | Standard Deviation 2.58 |
Secondary
Change From Baseline in Total Asthma Symptom Scores
Change from baseline to week 48 in Total Asthma Symptom Score (TASS), which included a nocturnal asthma score (0 to 4 scale), morning asthma symptoms (yes or no), and a daytime asthma symptom score (0 to 4 scale, total score range 0 to 9, higher TASS scores represent worse symptoms; breathlessness, tightness in chest, wheezing and cough. Score achieved by week 48 minus baseline.
Time frame: Baseline and Week 48
Population: Modified Intent-to-Treat population included all randomized patients who received at least 1 dose of study drug. Ten patients were missing baseline values and were excluded from the analyses. The Last Observation Carried Forward was used to impute missing values at week 48 for patients who discontinued the study early.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Total Asthma Symptom Scores | -1.36 score on a scale | Standard Deviation 1.87 |
| Xolair | Change From Baseline in Total Asthma Symptom Scores | -1.61 score on a scale | Standard Deviation 1.85 |
Secondary
Number of Participants Assessed for Frequency and Severity of Treatment-emergent Adverse Events
This outcome is represented in the adverse event section of the database.
Time frame: Week 48
Population: Safety Population: The safety-evaluable population comprised 848 patients (428 Xolair group and 420 placebo group). Patients in the safety-evaluable population were analyzed according to the actual treatment received. One subject was assigned to receive placebo but inadvertently received at least one dose of xolair during the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Assessed for Frequency and Severity of Treatment-emergent Adverse Events | 420 participants |
| Xolair | Number of Participants Assessed for Frequency and Severity of Treatment-emergent Adverse Events | 428 participants |