Allergic Asthma
Conditions
Keywords
Allergic Asthma, IgE, immunotherapy, omalizumab
Brief summary
This study is designed to investigate the use of omalizumab as a pretreatment for patients with persistent allergic asthma who are candidates for allergen immunotherapy (ie, allergy shots) and will test the hypothesis that omalizumab may reduce the rate of systemic reactions to immunotherapy in patients with persistent allergic asthma.
Interventions
DRUGPlacebo
Doses of placebo were administered subcutaneously every 2 to 4 weeks according to the US product label, depending on the patient's body weight and baseline serum IgE.
DRUGOmalizumab
Doses of omalizumab were administered subcutaneously every 2 to 4 weeks according to the US product label, depending on the patient's body weight and baseline serum IgE.
DRUGImmunotherapy
Customized allergen extracts were prepared centrally for each patient based on his/her specific skin test results. Four vials containing dilutions of the patient's extract were provided. Investigators initiated dosing according to the protocol for the cluster dosing titration regimen, beginning with vial #4 (the most dilute) and progressing to vial #1, which was the most concentrated or maintenance solution. Each dose was administered subcutaneously into the deltoid region as a single injection. During study visits that required multiple IT injections, each injection was to be given at least 30 minutes apart. During weeks that required multiple visits for IT injections, each visit was to be separated by at least 48 hours.
Sponsors
Genentech, Inc.
Tanox
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
Patients were eligible for inclusion if they met all of the following criteria: Informed Consent * Patients who were informed of the study procedures and medications and provided their written informed consent Demographics * Male or female * Any race * Ages 18 - 55 years * Body weight \>=20 kg and \<=150 kg * Total serum IgE concentration \>=30 and \<=700 IU/mL at Visit 0 Disease Definitions/Medications * History of at least moderate persistent allergic asthma (consistent with Global Initiative for Asthma \[GINA\] guidelines of \>=1 year in duration * On a stable asthma treatment regimen including inhaled corticosteroids for the preceding 4 weeks * An FEV1 while withholding short-acting beta-agonists for at least 6 hours and long-acting beta-agonists for at least 12 hours, of \>=75% of the predicted value at Visit 0 * Evidence of reversible airway obstruction, as defined by an increase in FEV1 of \>=12% between 20 to 30 minutes after 4 puffs (or less at the discretion of the investigator) of inhaled short-acting beta-agonist administration at Visit 0 or within the preceding year * Documented sensitivity to perennial aeroallergens, as evidenced by a positive skin test (wheal \>=5mm greater than saline control) to at least 1 of 3 perennial aeroallergens (house dust mite, cat, or dog) at Visit 0 or within the preceding year * Average PEFR variability \<=20% (calculated as \[(PM PEF - AM PEF)/(PM PEF + AM PEF)/2 x 100) during the 2-week screening period * Pre-specified level of nocturnal asthma symptoms (i.e., a mean nocturnal asthma score of \>0 and \<=0.5) and a mean combined clinical symptom score (nocturnal, morning, and daytime) of \>0 and \<=3 during the screening period * Non-smoker for at least 1 year prior to Visit 1, with a smoking history of no more than 10 pack-years (i.e., 1 pack \[20 cigarettes\] per day for 10 years) * Judged to be in good physical and mental health (except for his/her asthma), based on medical history, physical examination, and routine laboratory data, and appeared to be able to successfully complete this trial
Exclusion criteria
Patients were to be excluded from participation if they met any of the following criteria: Pulmonary * History of intubation for asthma * Asthma exacerbation requiring treatment with systemic steroids within the preceding 3 months * Asthma exacerbation requiring treatment in an emergency department or a hospital admission in the preceding 6 months * Upper respiratory tract infection or sinusitis within the preceding 4 weeks * History of an anaphylactic allergic reaction (except to stinging insects, foods, or drugs other than omalizumab) * History of treatment with immunotherapy to any allergen within past 3 years * History of aspirin or non steroidal anti-inflammatory drug (NSAID)-related asthma; patients could have been included in NSAIDs use was avoided for the duration of the study General Medical * History of or current malignancy * Any clinically significant uncontrolled systemic disease or a history of such disease (e.g., infectious, hematologic, renal, hepatic, endocrinologic, gastrointestinal, or cardiovascular disease) within the previous 3 months * Clinically significant laboratory abnormalities at Visit 1 * Platelet levels \<=130 x 10 9/L at visit 1 * Women of childbearing potential who were not practicing a medically approved contraception method (e.g., oral, subcutaneous, mechanical, or surgical contraception), as well as women who were pregnant or nursing * History of hypersensitivity to any ingredients, including excipients (sucrose, histidine, or polysorbate 20) of the study medication or drugs related to omalizumab (e.g., monoclonal anti-bodies or polyclonal gammaglobulin) * Severe medical condition(s) that, in the view of the investigator, prohibited participation in the study * Previous treatment with omalizumab within 1 year of screening * Considered by the investigator to be potentially unreliable or who may not have reliably attended study visits * History of drug or alcohol abuse Procedural * Unable to perform acceptable, reproducible spirometry, or PEFR measurements * Unable or unwilling to comply with the study procedures as determined during the screening phase, including adequate completion of the diary Medications Patient took the following medications before Visit 0. These medications were not permitted during the trial unless otherwise specified: * Oral, intravenous, intramuscular, or intra-articular corticosteroids within 4 weeks * Beta-adrenergic antagonists (including ocular preparations) within 1 week * Antihistamines within 1 week; after skin testing was completed (Visit 0), antihistamines could be used as needed for the remainder of the study * Intravenous gammaglobulin or immunosuppressants within 4 weeks * Tricyclic antidepressants within 1 week * Investigational drugs within 4 weeks
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Systemic Allergic Reactions (SAR) to Specific Immunotherapy (SIT) | 26 Weeks | The number of participants with Systemic Allergic Reactions (SAR) to Specific Immunotherapy (SIT). A SAR was captured and recorded as an outcome, not as adverse events (AEs) or SAEs. The primary analysis time point was the end of Period 4 (maintenance immunotherapy). Participants were observed for 1 hour after each immunotherapy (IT) injection visit. Allergic reactions were graded on a 4-point scale from Grade 1 to Grade 4. Grade 1: Skin symptoms, Grade 2: Gastrointestinal symptoms, Grade 3: Respiratory symptoms and Grade 4: Cardiovascular symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of First Systemic Allergic Reaction (SAR) | 26 Weeks | Systemic reactions associated with immunotherapy (IT), defined as occurring within 1 hour following injection of SIT, were graded on a four-point scale: Grade 1: Skin symptoms (generalized urticaria, itching, or erythema), Grade 2: Gastrointestinal symptoms (stomach pain, nausea, or vomiting), Grade 3: Respiratory symptoms (clinically significant nasal symptoms and/or dyspnea, wheezing, persistent cough, etc.), Grade 4: Cardiovascular symptoms (cyanosis, hypotension, collapse, arrhythmias, or angina pectoris). |
| Number of Participants Who Achieved Target Maintenance Specific Immunotherapy (SIT) Dose | 16 Weeks | Achievement of target maintenance IT dose is defined as answering 'Yes' to the question, 'Was the target maintenance SIT dose achieved?' on Visit 13, Week 16. |
| Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | Up to 26 Weeks | During period 3, a cluster dosing protocol was utilized to initiate the allergen immunotherapy (IT). Participants received escalating doses of IT according to a cluster dosing titration regimen. Visits 5 through 13 were cluster visits for this study. The number of visits needed for completion of the cluster SIT dosing regimen was defined as the number of planned visits plus the number of unplanned visits needed to reach maintenance IT dose. |
| Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | Up to 26 Weeks | Epinephrine for injection, antihistamines, corticosteroids for injection, inhaled beta-agonists, and oral corticosteroids, as well as other drugs used for managing acute allergic reactions to SIT, were available during all study visits. One dose of rescue medication for SAR reactions was equivalent to 1 entry of the CRF page 'concomitant medications/significant non-drug therapies associated with immunotherapy' in response to the question 'Was this medication given in response to a SAR?' |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo The dose of placebo was determined according to the omalizumab US product label using a dosing table nomogram that ensures patients receive at least 0.016 mg/kg/IgE (IU/ml) per 4 weeks. The study drug was administered by subcutaneous injection every 2 or 4 weeks according to the dosing table nomogram. | 136 |
| Omalizumab The dose of omalizumab was determined according to the omalizumab US product label using a dosing table nomogram that ensures patients receive at least 0.016 mg/kg/IgE (IU/ml) per 4 weeks. The study drug was administered by subcutaneous injection every 2 or 4 weeks according to the dosing table nomogram. | 139 |
| Total | 275 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 2 | 1 |
| Overall Study | Adverse Event | 13 | 7 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Protocol Violation | 2 | 3 |
| Overall Study | Unsatisfactory therapeutic effect | 21 | 8 |
| Overall Study | Withdrawal by Subject | 12 | 15 |
Baseline characteristics
| Characteristic | Placebo | Omalizumab | Total |
|---|---|---|---|
| Age, Continuous | 38.2 years STANDARD_DEVIATION 10.02 | 38.2 years STANDARD_DEVIATION 9.89 | 38.2 years STANDARD_DEVIATION 9.93 |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 11 participants | 17 participants | 28 participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 13 participants | 3 participants | 16 participants |
| Race/Ethnicity, Customized White | 112 participants | 118 participants | 230 participants |
| Sex: Female, Male Female | 99 Participants | 88 Participants | 187 Participants |
| Sex: Female, Male Male | 37 Participants | 51 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 88 / 139 | 91 / 136 |
| serious Total, serious adverse events | 4 / 139 | 3 / 136 |
Outcome results
Primary
Number of Participants With Systemic Allergic Reactions (SAR) to Specific Immunotherapy (SIT)
The number of participants with Systemic Allergic Reactions (SAR) to Specific Immunotherapy (SIT). A SAR was captured and recorded as an outcome, not as adverse events (AEs) or SAEs. The primary analysis time point was the end of Period 4 (maintenance immunotherapy). Participants were observed for 1 hour after each immunotherapy (IT) injection visit. Allergic reactions were graded on a 4-point scale from Grade 1 to Grade 4. Grade 1: Skin symptoms, Grade 2: Gastrointestinal symptoms, Grade 3: Respiratory symptoms and Grade 4: Cardiovascular symptoms.
Time frame: 26 Weeks
Population: Efficacy Population: Consisted of all randomized patients who completed the omalizumab or placebo treatment period and received at least one dose of immunotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Systemic Allergic Reactions (SAR) to Specific Immunotherapy (SIT) | 32 participants |
| Omalizumab | Number of Participants With Systemic Allergic Reactions (SAR) to Specific Immunotherapy (SIT) | 17 participants |
| All Patients | Number of Participants With Systemic Allergic Reactions (SAR) to Specific Immunotherapy (SIT) | 49 participants |
Secondary
Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT)
Epinephrine for injection, antihistamines, corticosteroids for injection, inhaled beta-agonists, and oral corticosteroids, as well as other drugs used for managing acute allergic reactions to SIT, were available during all study visits. One dose of rescue medication for SAR reactions was equivalent to 1 entry of the CRF page 'concomitant medications/significant non-drug therapies associated with immunotherapy' in response to the question 'Was this medication given in response to a SAR?'
Time frame: Up to 26 Weeks
Population: Efficacy population: Consisted of all randomized participants who completed the omalizumab or placebo treatment period, received at least one dose of immunotherapy and received rescue therapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 0 doses | 2 participants |
| Placebo | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 1 dose | 10 participants |
| Placebo | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 2 doses | 5 participants |
| Placebo | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 3 doses | 4 participants |
| Placebo | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 4 doses | 5 participants |
| Placebo | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: >= 5 doses | 6 participants |
| Omalizumab | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: >= 5 doses | 1 participants |
| Omalizumab | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 0 doses | 4 participants |
| Omalizumab | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 3 doses | 4 participants |
| Omalizumab | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 4 doses | 2 participants |
| Omalizumab | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 1 dose | 3 participants |
| Omalizumab | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 2 doses | 3 participants |
| All Patients | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 1 dose | 13 participants |
| All Patients | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 2 doses | 8 participants |
| All Patients | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: >= 5 doses | 7 participants |
| All Patients | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 3 doses | 8 participants |
| All Patients | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 0 doses | 6 participants |
| All Patients | Number of Participants Requiring 0 to >=5 Doses of Rescue Medications for Systemic Allergic Reactions (SARs) to Specific Immunotherapy (SIT) | All rescue medications: 4 doses | 7 participants |
Secondary
Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen
During period 3, a cluster dosing protocol was utilized to initiate the allergen immunotherapy (IT). Participants received escalating doses of IT according to a cluster dosing titration regimen. Visits 5 through 13 were cluster visits for this study. The number of visits needed for completion of the cluster SIT dosing regimen was defined as the number of planned visits plus the number of unplanned visits needed to reach maintenance IT dose.
Time frame: Up to 26 Weeks
Population: Efficacy population: Consisted of all randomized patients who completed the omalizumab or placebo treatment period and received at least one dose of immunotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 11 Visits | 0 participants |
| Placebo | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 10 Visits | 0 participants |
| Placebo | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 8 Visits | 87 participants |
| Placebo | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 9 Visits | 35 participants |
| Placebo | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 12-20 Visits | 0 participants |
| Omalizumab | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 10 Visits | 0 participants |
| Omalizumab | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 8 Visits | 110 participants |
| Omalizumab | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 9 Visits | 15 participants |
| Omalizumab | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 11 Visits | 1 participants |
| Omalizumab | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 12-20 Visits | 0 participants |
| All Patients | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 12-20 Visits | 0 participants |
| All Patients | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 11 Visits | 1 participants |
| All Patients | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 8 Visits | 197 participants |
| All Patients | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 10 Visits | 0 participants |
| All Patients | Number of Participants Requiring 8 to 20 Visits to Complete Cluster Specific Immunotherapy (SIT) Dosing Regimen | 9 Visits | 50 participants |
Secondary
Number of Participants Who Achieved Target Maintenance Specific Immunotherapy (SIT) Dose
Achievement of target maintenance IT dose is defined as answering 'Yes' to the question, 'Was the target maintenance SIT dose achieved?' on Visit 13, Week 16.
Time frame: 16 Weeks
Population: Efficacy population: Consisted of all randomized patients who completed the omalizumab or placebo treatment period and received at least one dose of immunotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Who Achieved Target Maintenance Specific Immunotherapy (SIT) Dose | 88 participants |
| Omalizumab | Number of Participants Who Achieved Target Maintenance Specific Immunotherapy (SIT) Dose | 110 participants |
| All Patients | Number of Participants Who Achieved Target Maintenance Specific Immunotherapy (SIT) Dose | 198 participants |
Secondary
Severity of First Systemic Allergic Reaction (SAR)
Systemic reactions associated with immunotherapy (IT), defined as occurring within 1 hour following injection of SIT, were graded on a four-point scale: Grade 1: Skin symptoms (generalized urticaria, itching, or erythema), Grade 2: Gastrointestinal symptoms (stomach pain, nausea, or vomiting), Grade 3: Respiratory symptoms (clinically significant nasal symptoms and/or dyspnea, wheezing, persistent cough, etc.), Grade 4: Cardiovascular symptoms (cyanosis, hypotension, collapse, arrhythmias, or angina pectoris).
Time frame: 26 Weeks
Population: Efficacy population: Consisted of all randomized patients who completed the omalizumab or placebo treatment period and received at least one dose of immunotherapy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Severity of First Systemic Allergic Reaction (SAR) | Grade 4 (cardiovascular symptoms) | 2 participants |
| Placebo | Severity of First Systemic Allergic Reaction (SAR) | Grade 3 (respiratory symptoms) | 24 participants |
| Placebo | Severity of First Systemic Allergic Reaction (SAR) | Grade 1 (skin symptoms) | 6 participants |
| Placebo | Severity of First Systemic Allergic Reaction (SAR) | Grade 2 (gastrointestinal symptoms) | 0 participants |
| Placebo | Severity of First Systemic Allergic Reaction (SAR) | No systemic allergy | 0 participants |
| Omalizumab | Severity of First Systemic Allergic Reaction (SAR) | Grade 3 (respiratory symptoms) | 6 participants |
| Omalizumab | Severity of First Systemic Allergic Reaction (SAR) | Grade 1 (skin symptoms) | 7 participants |
| Omalizumab | Severity of First Systemic Allergic Reaction (SAR) | Grade 2 (gastrointestinal symptoms) | 2 participants |
| Omalizumab | Severity of First Systemic Allergic Reaction (SAR) | Grade 4 (cardiovascular symptoms) | 2 participants |
| Omalizumab | Severity of First Systemic Allergic Reaction (SAR) | No systemic allergy | 0 participants |
| All Patients | Severity of First Systemic Allergic Reaction (SAR) | No systemic allergy | 0 participants |
| All Patients | Severity of First Systemic Allergic Reaction (SAR) | Grade 4 (cardiovascular symptoms) | 4 participants |
| All Patients | Severity of First Systemic Allergic Reaction (SAR) | Grade 1 (skin symptoms) | 13 participants |
| All Patients | Severity of First Systemic Allergic Reaction (SAR) | Grade 3 (respiratory symptoms) | 30 participants |
| All Patients | Severity of First Systemic Allergic Reaction (SAR) | Grade 2 (gastrointestinal symptoms) | 2 participants |