Asthma
Conditions
Keywords
allergic, asthma, atopic, omalizumab, immunoglobulin E, IgE, anti-IgE
Brief summary
A substance called immunoglobulin E (IgE), which is naturally produced by our body, has a key role in generating asthma attacks. In patients with allergies, there is an exaggerated production of IgE in response to specific substances such as pollens. Omalizumab is a new drug that inactivates IgE. This study tested the safety and efficacy of omalizumab against asthma attacks in children with allergic asthma.
Detailed description
This study was designed to provide one year efficacy and safety data for subcutaneous (SC) omalizumab, compared to placebo in children (6 to \< 12 years) with moderate to severe persistent asthma who have inadequate asthma control despite treatment according to National Heart, Lung and Blood Institute (NHLBI) step 3 or 4 (at least medium dose inhaled corticosteroids with or without other controller asthma medications).
Interventions
DRUGOmalizumab
The omalizumab dose administered, based on the patient's body weight and total serum IgE level at Screening, and the number of injections and injection volume was determined from the dosing tables in the protocol. Omalizumab 75 to 375 mg was administered subcutaneous (SC) every 2 or 4 weeks depending on the dose.
DRUGPlacebo
Placebo was administered subcutaneous (SC) every 2 or 4 weeks depending on the dosing schedule in the protocol.
DRUGFluticasone
Patients entered the study using their current formulation of any inhaled steroid (proprietary drug and device) ≥ 200 μg/day equivalent of fluticasone administered with a dry-powder inhaler.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
* Parent or legal guardian was informed of the study procedures and medications and gave written informed consent. * Outpatient males and females aged 6 - \< 12 years on study entry, with body weight between 20 and 150 kg. * Total serum IgE level ≥ 30 to ≤ 1300 IU. * Diagnosis of allergic asthma ≥ 1 year duration, according to American Thoracic Society (ATS) criteria, and a screening history consistent with clinical features of moderate or severe persistent asthma according to National Heart Lung and Blood Institute (NHLBI) guidelines. * Positive prick skin test to at least one perennial allergen, documented within the past 2 years or taken at Screening. A radioallergosorbent test (RAST) could have been performed for patients with a borderline skin prick test result after consultation with Novartis clinical personnel. * Patients with ≥ 12% increase in forced expiratory volume in 1 second (FEV1) over starting value within 30 minutes of taking up to 4 puffs (4x100 µg) salbutamol (albuterol) or nebulized salbutamol up to 5 mg (or equivalent of alternative B2-agonist) documented within the past year, at screening, during the run-in period, or prior to randomization. Patients were not to take their long acting B2-agonist (LABA) medication within 12 hours of reversibility testing. * Clinical features of moderate or severe persistent asthma (at least step 3) despite therapy at step 3 or 4 (at least medium dose inhaled corticosteroid (ICS) - fluticasone dry-powder inhaler (DPI) ≥ 200 mg/day or equivalent with or without other controller medications). * Documented history of experiencing asthma exacerbations and demonstrated inadequate symptom control during the last 4 weeks of run-in despite receiving an equivalent dose of fluticasone DPI ≥ 200 mg/day total daily ex-valve dose.
Exclusion criteria
* Patients who received systemic corticosteroids for reasons other than asthma, beta-adrenergic antagonists by any route, anticholinergics within 24 hours of Screening, methotrexate, gold salts, cyclosporin or troleandomycin, or had received desensitization therapy with less than 3 months of stable maintenance doses prior to Screening. * Patients with a history of food or drug related severe anaphylactoid or anaphylactic reaction, a history of allergy to antibiotics, with aspirin or other non-steroidal anti-inflammatory drugs (NSAID)-related asthma (unless the NSAID could be avoided), with active lung disease or acute sinusitis/chest infection, elevated serum IgE levels for other reasons, presence/history of a clinically significant uncontrolled systemic disease, cancer, abnormal, electrocardiogram (ECG) in the previous month, or platelets ≤ 100 x 109/L or clinically significant laboratory abnormalities at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Clinically Significant Asthma Exacerbations Per Patient in the 24-week Fixed-dose Steroid Treatment Period | Baseline to end of the fixed-dose steroid treatment period (Week 24) | A clinically significant asthma exacerbation was defined as a worsening of asthma symptoms, as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose and/or treatment with systemic rescue corticosteroids for at least 3 days. The exacerbations rate per patient was derived using Poisson model adjusted by time at risk and the following covariates: country, exacerbation history, and dose schedule. A patient's person-days at risk was taken as the total amount of time (in days) he/she spent in the 24-week fixed-dose steroid treatment period. |
| Percentage of Participants With at Least 1 Adverse Event | Baseline to end of the study (Week 68) | See Adverse Events module for details. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Nocturnal Asthma Symptom Score From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | Baseline to the end (last 4 weeks) of the 24-week fixed-dose steroid treatment period | Nocturnal asthma symptom was measured daily on a scale of 0 to 4 in response to the question How did you sleep last night?, with 0 as the best response and 4 as the worst response. The mean of the last 4 weeks of the 24-week fixed-dose steroid treatment period was calculated; for patients who discontinued prematurely, the mean of the last 28 days before discontinuation was calculated. A negative change in mean score indicated improvement. |
| Rate of Clinically Significant Asthma Exacerbations Per Patient in the 52-week Treatment Period | Baseline to end of the treatment period (Week 52) | A clinically significant asthma exacerbation was defined as a worsening of asthma symptoms, as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose and/or treatment with systemic rescue corticosteroids for at least 3 days. The exacerbations rate per patient was derived using Poisson model adjusted by time at risk and the following covariates: country, exacerbation history, and dose schedule. A patient's person-days at risk was taken as the total amount of time (in days) he/she spent in the 52-week treatment period. |
| Change in Mean Daily Number of Puffs of Asthma Rescue Medication From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | Baseline to the end (last 4 weeks) of the 24-week fixed-dose steroid treatment period | Patients were instructed to record the number of puffs of rescue medication they took twice daily in a diary. The mean daily number of puffs during the last 4 weeks of the 24-week fixed-dose steroid treatment period was calculated; for patients who discontinued prematurely, the mean of the last 28 days before discontinuation was calculated. A negative change in mean daily number of puffs indicated reduced use of rescue medication. |
| Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Baseline to the end of the 24-week fixed-dose steroid treatment period (Week 24) | PAQLQ measures functional problems that are most troublesome to children with asthma. PAQLQ has 23 questions in 3 domains (activity limitation=5, emotional function=8, symptoms=10). Patients responded to each question on a 7-point Likert scale. Overall PAQLQ score is mean of 23 questions; each domain score is mean of questions in that domain. Minimum possible value is 1 (maximum impairment); maximum possible value is 7 (no impairment). Positive change indicated improvement. The analysis included country, baseline PAQLQ value, and dosing schedule (2-weekly/4-weekly) as factors and covariates. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Omalizumab Participants received omalizumab administered by subcutaneous injection every 2 or 4 weeks for a duration of 52 weeks. The omalizumab dose was based on the patient's body weight and total serum IgE level at Screening. The first 24 weeks of the treatment period was a fixed steroid phase where the steroid dose was maintained constant; in the following 28 weeks the steroid dose was adjustable, depending on the patient's condition. Following the 52-week treatment period, patients were followed up for an additional 16 weeks. | 421 |
| Placebo Placebo was administered by subcutaneous injection every 2 or 4 weeks depending on the dosing schedule in the protocol for a total of 52 weeks. The first 24 weeks of the treatment period was a fixed steroid phase where the steroid dose was maintained constant; in the following 28 weeks the steroid dose was adjustable, depending on the patient's condition. Following the 52-week treatment period, patients were followed up for an additional 16 weeks. | 207 |
| Total | 628 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 22 | 11 |
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 12 | 5 |
| Overall Study | Protocol Violation | 8 | 6 |
| Overall Study | Subject no longer requires study drug | 3 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 1 | 2 |
| Overall Study | Withdrawal by Subject | 21 | 7 |
Baseline characteristics
| Characteristic | Omalizumab | Total | Placebo |
|---|---|---|---|
| Age Continuous | 8.7 years STANDARD_DEVIATION 1.7 | 8.6 years STANDARD_DEVIATION 1.7 | 8.4 years STANDARD_DEVIATION 1.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 69 Participants | 99 Participants | 30 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 103 Participants | 150 Participants | 47 Participants |
| Race (NIH/OMB) White | 249 Participants | 377 Participants | 128 Participants |
| Sex: Female, Male Female | 134 Participants | 203 Participants | 69 Participants |
| Sex: Female, Male Male | 287 Participants | 425 Participants | 138 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 374 / 421 | 194 / 207 |
| serious Total, serious adverse events | 27 / 421 | 26 / 207 |
Outcome results
Primary
Percentage of Participants With at Least 1 Adverse Event
See Adverse Events module for details.
Time frame: Baseline to end of the study (Week 68)
Population: Safety population: All patients who received any study drug and had at least 1 post-baseline safety assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omalizumab | Percentage of Participants With at Least 1 Adverse Event | 90.3 Percentage of participants |
| Placebo | Percentage of Participants With at Least 1 Adverse Event | 93.7 Percentage of participants |
Primary
Rate of Clinically Significant Asthma Exacerbations Per Patient in the 24-week Fixed-dose Steroid Treatment Period
A clinically significant asthma exacerbation was defined as a worsening of asthma symptoms, as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose and/or treatment with systemic rescue corticosteroids for at least 3 days. The exacerbations rate per patient was derived using Poisson model adjusted by time at risk and the following covariates: country, exacerbation history, and dose schedule. A patient's person-days at risk was taken as the total amount of time (in days) he/she spent in the 24-week fixed-dose steroid treatment period.
Time frame: Baseline to end of the fixed-dose steroid treatment period (Week 24)
Population: Modified intent-to-treat population: All patients who were randomized, excluding patients from 2 sites due to Good Clinical Practice non-compliance. Excluded patients were replaced with patients at other sites to maintain statistical power.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Omalizumab | Rate of Clinically Significant Asthma Exacerbations Per Patient in the 24-week Fixed-dose Steroid Treatment Period | 0.45 Exacerbations per patient per 24-weeks |
| Placebo | Rate of Clinically Significant Asthma Exacerbations Per Patient in the 24-week Fixed-dose Steroid Treatment Period | 0.64 Exacerbations per patient per 24-weeks |
Secondary
Change in Mean Daily Number of Puffs of Asthma Rescue Medication From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period
Patients were instructed to record the number of puffs of rescue medication they took twice daily in a diary. The mean daily number of puffs during the last 4 weeks of the 24-week fixed-dose steroid treatment period was calculated; for patients who discontinued prematurely, the mean of the last 28 days before discontinuation was calculated. A negative change in mean daily number of puffs indicated reduced use of rescue medication.
Time frame: Baseline to the end (last 4 weeks) of the 24-week fixed-dose steroid treatment period
Population: Modified intent-to-treat population: All patients who were randomized, excluding patients from 2 sites due to Good Clinical Practice non-compliance. Excluded patients were replaced with patients at other sites to maintain statistical power.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omalizumab | Change in Mean Daily Number of Puffs of Asthma Rescue Medication From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | -1.3 Puffs | Standard Deviation 2.84 |
| Placebo | Change in Mean Daily Number of Puffs of Asthma Rescue Medication From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | -1.0 Puffs | Standard Deviation 2.5 |
Secondary
Change in Mean Nocturnal Asthma Symptom Score From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period
Nocturnal asthma symptom was measured daily on a scale of 0 to 4 in response to the question How did you sleep last night?, with 0 as the best response and 4 as the worst response. The mean of the last 4 weeks of the 24-week fixed-dose steroid treatment period was calculated; for patients who discontinued prematurely, the mean of the last 28 days before discontinuation was calculated. A negative change in mean score indicated improvement.
Time frame: Baseline to the end (last 4 weeks) of the 24-week fixed-dose steroid treatment period
Population: Modified intent-to-treat population: All patients who were randomized, excluding patients from 2 sites due to Good Clinical Practice non-compliance. Excluded patients were replaced with patients at other sites to maintain statistical power.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Omalizumab | Change in Mean Nocturnal Asthma Symptom Score From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | -0.63 Units on a scale | Standard Deviation 0.72 |
| Placebo | Change in Mean Nocturnal Asthma Symptom Score From Baseline to the End (Last 4 Weeks) of the 24-week Fixed-dose Steroid Treatment Period | -0.50 Units on a scale | Standard Deviation 0.71 |
Secondary
Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24)
PAQLQ measures functional problems that are most troublesome to children with asthma. PAQLQ has 23 questions in 3 domains (activity limitation=5, emotional function=8, symptoms=10). Patients responded to each question on a 7-point Likert scale. Overall PAQLQ score is mean of 23 questions; each domain score is mean of questions in that domain. Minimum possible value is 1 (maximum impairment); maximum possible value is 7 (no impairment). Positive change indicated improvement. The analysis included country, baseline PAQLQ value, and dosing schedule (2-weekly/4-weekly) as factors and covariates.
Time frame: Baseline to the end of the 24-week fixed-dose steroid treatment period (Week 24)
Population: Modified intent-to-treat population: All patients who were randomized, excluding patients from 2 sites due to Good Clinical Practice non-compliance. Excluded patients were replaced with patients at other sites to maintain statistical power.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Omalizumab | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Activity limitation | 0.85 Units on a scale |
| Omalizumab | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Emotional function | 0.89 Units on a scale |
| Omalizumab | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Symptoms | 0.99 Units on a scale |
| Omalizumab | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Overall (total) | 0.92 Units on a scale |
| Placebo | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Overall (total) | 0.89 Units on a scale |
| Placebo | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Activity limitation | 0.76 Units on a scale |
| Placebo | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Symptoms | 0.93 Units on a scale |
| Placebo | Change in Pediatric Asthma Quality of Life Questionnaire (Standardized) [PAQLQ(S)] Scores From Baseline to the End of the 24-week Fixed-dose Steroid Treatment Period (Week 24) | Emotional function | 0.91 Units on a scale |
Secondary
Rate of Clinically Significant Asthma Exacerbations Per Patient in the 52-week Treatment Period
A clinically significant asthma exacerbation was defined as a worsening of asthma symptoms, as judged clinically by the investigator, requiring doubling of the baseline inhaled corticosteroid dose and/or treatment with systemic rescue corticosteroids for at least 3 days. The exacerbations rate per patient was derived using Poisson model adjusted by time at risk and the following covariates: country, exacerbation history, and dose schedule. A patient's person-days at risk was taken as the total amount of time (in days) he/she spent in the 52-week treatment period.
Time frame: Baseline to end of the treatment period (Week 52)
Population: Modified intent-to-treat population: All patients who were randomized, excluding patients from 2 sites due to Good Clinical Practice non-compliance. Excluded patients were replaced with patients at other sites to maintain statistical power.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Omalizumab | Rate of Clinically Significant Asthma Exacerbations Per Patient in the 52-week Treatment Period | 0.78 Exacerbations per patient per year |
| Placebo | Rate of Clinically Significant Asthma Exacerbations Per Patient in the 52-week Treatment Period | 1.36 Exacerbations per patient per year |