Allergic Asthma
Conditions
Keywords
Asthma, adults, anti-immunoglobulin E ( IgE), omalizumab, airway inflammation, airway remodeling, allergy
Brief summary
This study aims to investigate the effect of omalizumab on the number of tissue eosinophils and other markers of airway inflammation and remodeling, including thickness of the lamina reticularis, in moderate to severe asthmatics with persistent symptoms and evidence of airway inflammation despite treatment with inhaled corticosteroids and long acting beta-agonists. This study will also investigate the correlation between systemic and pulmonary inflammation, and the correlation between clinical outcomes and changes within the tissue, to assist in the future identification of patients with tissue eosinophilia and their response to treatment, without the need for invasive bronchoscopy.
Interventions
DRUGomalizumab at a dose of 0.016mg/kg/IU/mL
DRUGPlacebo
Sponsors
Genentech, Inc.
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients 18-75 years of age with moderate to severe persistent allergic asthma receiving a high dose inhaled corticosteroid (≥800µg per day BDP or equivalent) and a regular long acting beta-agonist for at least 3 months prior to screening * With a body weight between 20 and 150kg and a serum total IgE level of 30 to 700 IU/mL * With ≥2% eosinophilia in induced sputum at screening * With post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥60% predicted * With a positive skin prick test (diameter of wheal ≥ 3 mm) or RAST test to at least one perennial aero-allergen (eg. dust mite, cat/dog dander, cockroaches), documented within the past 2 years or demonstrated at Visit 1, to which the patient will be exposed on a regular basis (most days) for the duration of the study.
Exclusion criteria
* Patients who've had an asthma exacerbation during the 4 weeks prior to randomization * Current smokers, stopped smoking within the last 12 months or have a smoking history of \>10 pack years * History of severe allergy to food or drugs * Previous treatment with omalizumab * Any patient considered to be unsuitable to bronchoscopy, according to the judgment of the investigator Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Subepithelial Eosinophils at the End of Week 78 (End of Treatment) | Baseline, at end of week 78 | The primary variable of change from baseline in total epithelia eosinophils at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sub-epithelial Cell Count of Mast Cells Following 78 Weeks Treatment, as Assessed Biopsy Samples | Baseline, at end of week 78 | The variable of change from baseline in Sub-epithelial cell count of mast cells at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator. |
| Change From Baseline in Sub-epithelial CD4+ T-lymphocytes Following 78 Weeks Treatment, as Assessed Biopsy Samples | Baseline, at end of week 78 | The variable of change from baseline in Sub-epithelial CD4+ T-lymphocytes at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator. |
| Change From Baseline in Thickness of the Lamina Reticularis Following 78 Weeks Treatment, as Assessed Biopsy Samples | Baseline, at end of week 78 | The variable of change from baseline in thickness of the lamina reticularis at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator. |
| Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy | 78 weeks | — |
Countries
Canada, France, Germany, Netherlands, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Omalizumab Omalizumab was supplied as lyophilized, sterile powder in a single use, 5 ml vial that was designed to deliver 150 mg of omalizumab for subcutaneous (SQ) administration upon reconstitution with 1.4 ml sterile water for injection. The dose administered was individualized for each patient based on the patient's body weight and total serum Immunoglobulin E (IgE) level at Visit 1 and the number of injections and injection volume was determined using protocol-specified dosing tables. Omalizumab 75 to 375 mg was administered SQ every 2 or 4 weeks depending on the dose for the 78 weeks duration of double-blinded treatment. | 23 |
| Placebo Omalizumab matching placebo was supplied as lyophilized, sterile powder in a single-use, 5 ml vial that was designed to deliver omalizumab matching placebo for subcutaneous (SQ) administration upon reconstitution with 1.4 ml sterile water for injection. The number of injections and injection volume was individualized for each patient based on the patient's body weight and total serum Immunoglobulin E (IgE) level at Visit 1 and was determined using protocol-specified dosing tables. Placebo was administered SQ every 2 or 4 weeks for the 78 weeks duration of double-blinded treatment. | 12 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adminstrative Problem | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Omalizumab | Placebo | Total |
|---|---|---|---|
| Age Continuous | 43.7 Years STANDARD_DEVIATION 9.66 | 41.8 Years STANDARD_DEVIATION 10.43 | 43.1 Years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 13 Participants | 6 Participants | 19 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 23 | 12 / 13 |
| serious Total, serious adverse events | 1 / 23 | 0 / 13 |
Outcome results
Primary
Change From Baseline in Total Subepithelial Eosinophils at the End of Week 78 (End of Treatment)
The primary variable of change from baseline in total epithelia eosinophils at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator.
Time frame: Baseline, at end of week 78
Population: Intent-to-treat (ITT) population: The ITT population consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization. Patients with both baseline and af end of week 78 data in each category have been reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omalizumab | Change From Baseline in Total Subepithelial Eosinophils at the End of Week 78 (End of Treatment) | Responder (n= 9, 3) | -5.807 cells/mm^2 | Standard Deviation 13.921 |
| Omalizumab | Change From Baseline in Total Subepithelial Eosinophils at the End of Week 78 (End of Treatment) | Non-responder (n = 8, 8) | 1.555 cells/mm^2 | Standard Deviation 11.065 |
| Placebo | Change From Baseline in Total Subepithelial Eosinophils at the End of Week 78 (End of Treatment) | Responder (n= 9, 3) | -5.890 cells/mm^2 | Standard Deviation 9.128 |
| Placebo | Change From Baseline in Total Subepithelial Eosinophils at the End of Week 78 (End of Treatment) | Non-responder (n = 8, 8) | -5.626 cells/mm^2 | Standard Deviation 15.816 |
Secondary
Change From Baseline in Sub-epithelial CD4+ T-lymphocytes Following 78 Weeks Treatment, as Assessed Biopsy Samples
The variable of change from baseline in Sub-epithelial CD4+ T-lymphocytes at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator.
Time frame: Baseline, at end of week 78
Population: Intent-to-treat (ITT) population: The ITT population consisted of all randomized patients. Patients with both baseline and end of treatment (at the end of week 78) data were only included for the analysis under each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omalizumab | Change From Baseline in Sub-epithelial CD4+ T-lymphocytes Following 78 Weeks Treatment, as Assessed Biopsy Samples | Responder (n= 9, 3) | -5.820 cells/mm^2 | Standard Deviation 12.49 |
| Omalizumab | Change From Baseline in Sub-epithelial CD4+ T-lymphocytes Following 78 Weeks Treatment, as Assessed Biopsy Samples | Non-responder (n= 8, 8) | -4.719 cells/mm^2 | Standard Deviation 11.021 |
| Placebo | Change From Baseline in Sub-epithelial CD4+ T-lymphocytes Following 78 Weeks Treatment, as Assessed Biopsy Samples | Responder (n= 9, 3) | -2.693 cells/mm^2 | Standard Deviation 8.117 |
| Placebo | Change From Baseline in Sub-epithelial CD4+ T-lymphocytes Following 78 Weeks Treatment, as Assessed Biopsy Samples | Non-responder (n= 8, 8) | -7.320 cells/mm^2 | Standard Deviation 13.95 |
Secondary
Change From Baseline in Sub-epithelial Cell Count of Mast Cells Following 78 Weeks Treatment, as Assessed Biopsy Samples
The variable of change from baseline in Sub-epithelial cell count of mast cells at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator.
Time frame: Baseline, at end of week 78
Population: Intent-to-treat (ITT) population: The ITT population consisted of all randomized patients. Patients with both baseline and end of treatment (at the end of week 78) data were only included for the analysis under each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omalizumab | Change From Baseline in Sub-epithelial Cell Count of Mast Cells Following 78 Weeks Treatment, as Assessed Biopsy Samples | Responder (n= 9, 3) | -1.392 cells/mm^2 | Standard Deviation 13.123 |
| Omalizumab | Change From Baseline in Sub-epithelial Cell Count of Mast Cells Following 78 Weeks Treatment, as Assessed Biopsy Samples | Non-responder (n= 8, 8) | 10.140 cells/mm^2 | Standard Deviation 10.266 |
| Placebo | Change From Baseline in Sub-epithelial Cell Count of Mast Cells Following 78 Weeks Treatment, as Assessed Biopsy Samples | Responder (n= 9, 3) | 5.840 cells/mm^2 | Standard Deviation 19.809 |
| Placebo | Change From Baseline in Sub-epithelial Cell Count of Mast Cells Following 78 Weeks Treatment, as Assessed Biopsy Samples | Non-responder (n= 8, 8) | 1.114 cells/mm^2 | Standard Deviation 18.397 |
Secondary
Change From Baseline in Thickness of the Lamina Reticularis Following 78 Weeks Treatment, as Assessed Biopsy Samples
The variable of change from baseline in thickness of the lamina reticularis at end of Week 78 was analyzed on sub-population such as responders and non-responders. Responders are defined as all patients having a Global Evaluation of Treatment Effectiveness (GETE) outcome of excellent or good where as non-responders are with GETE outcome of poor, moderate or worsening. GETE categories are excellent, good, moderate, poor, worsening, and missing as determined by the investigator.
Time frame: Baseline, at end of week 78
Population: Intent-to-treat (ITT) population: The ITT population consisted of all randomized patients. Patients with both baseline and end of treatment (at the end of week 78) data were only included for the analysis under each category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Omalizumab | Change From Baseline in Thickness of the Lamina Reticularis Following 78 Weeks Treatment, as Assessed Biopsy Samples | Responder (n= 8, 3) | -1.300 micrometer(µm) | Standard Deviation 2.926 |
| Omalizumab | Change From Baseline in Thickness of the Lamina Reticularis Following 78 Weeks Treatment, as Assessed Biopsy Samples | Non-responder (n= 8, 8) | 0.098 micrometer(µm) | Standard Deviation 2.276 |
| Placebo | Change From Baseline in Thickness of the Lamina Reticularis Following 78 Weeks Treatment, as Assessed Biopsy Samples | Responder (n= 8, 3) | -1.603 micrometer(µm) | Standard Deviation 0.258 |
| Placebo | Change From Baseline in Thickness of the Lamina Reticularis Following 78 Weeks Treatment, as Assessed Biopsy Samples | Non-responder (n= 8, 8) | -0.659 micrometer(µm) | Standard Deviation 2.288 |
Secondary
Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy
Time frame: 78 weeks
Population: The safety population consisted of all patients in the intent to treat (ITT) population that received at least one dose of study drug and had at least one post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Omalizumab | Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy | Death | 0 Participants |
| Omalizumab | Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy | At least one adverse event | 19 Participants |
| Omalizumab | Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy | At least one serious adverse event | 1 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy | At least one adverse event | 12 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy | At least one serious adverse event | 0 Participants |
| Placebo | Number of Participants With Adverse Events, Serious Adverse Events and Death as an Assessment of Safety and Tolerability of 78 Weeks Therapy | Death | 0 Participants |