Asthma, Bronchial Diseases, Hypersensitivity, Hypersensitivity, Immediate, Immune System Diseases, Lung Diseases, Lung Diseases, Obstructive, Respiratory Hypersensitivity, Respiratory Tract Diseases
Conditions
Keywords
Asthma, Uncontrolled asthma, Severe uncontrolled asthma
Brief summary
A phase 2, multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the effect of tezepelumab on airway inflammation in adults with inadequately controlled asthma.
Detailed description
This is a multicentre, randomized, double-blind, placebo-controlled, parallel group study to evaluate the effect of tezepelumab on airway inflammation in adults with inadequately controlled moderate-to-severe asthma, taking inhaled corticosteroids and at least one additional asthma controller. Approximately 110 subjects will be randomized globally. Subjects will receive tezepelumab, or placebo, administered via subcutaneous injection at the study site, over a 28-week treatment period. Although, due to the Covid-19 pandemic this may be an extended time frame for some subject visits. The study also includes a post-treatment follow-up period of 12 weeks.
Interventions
BIOLOGICALTezepelumab
Tezepelumab subcutaneous injection
OTHERPlacebo
Placebo subcutaneous injection
Sponsors
Amgen
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double-blind
Intervention model description
Subjects will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Principal Inclusion Criteria: * Subject must be 18 to 75 years of age. * Documented physician-diagnosed asthma for at least 12 months. * Subjects who have received a physician- prescribed asthma controller medication with medium or high dose ICS for at least 12 months; must be stable for at least 3 months prior to screening visit. * At least one additional maintenance asthma controller medication is required according to standard practice of care and must be documented for at least 3 months. * At enrolment, the subject must have a predicted normal value for the morning pre-bronchodilator FEV1\>50% and more than 1L. * Evidence of asthma as documented by reversibility of FEV1 ≥12% and ≥200 mL in the previous 12 months prior to screening, or during the screening period prior to randomization. * ACQ-6 score ≥ 1.5 during the screening period prior to randomization. Principal
Exclusion criteria
* Any clinically important pulmonary disease other than asthma. * History of cancer. * Hospitalization or required OCS for asthma exacerbation within 6 weeks of enrolment or \>3 exacerbations requiring OCS or hospitalization in the year prior to visit 1 or who had been intubated or admitted to ICU for asthma exacerbation in the year prior to enrolment. * History of a clinically significant infection, including upper (URTI) or lower respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral medications finalized \<2 weeks before visit 1 or during the run-in period. * Current smokers or subjects with smoking history ≥10 pack-yrs, including e-cigarettes. Former smokers with a smoking history of \<10 pack-yrs must have stopped for at least 6 months prior to visit 1, including e-cigarette use. * History of chronic alcohol or drug abuse within 12 months prior to visit 1. * Tuberculosis requiring treatment within 12 months prior to visit 1. * History of known immunodeficiency disorder including a positive HIV test at visit 1, or the subject is taking antiretroviral medications as determined by medical history and/or subject's verbal report. * History of anaphylaxis or documented immune complex disease (type III hypersensitivity reactions) following any biologic therapy Subject randomized in a previous Tezepelumab study or in a current study with another investigational product. * Pregnant, breastfeeding or lactating women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). | The change from baseline to end of treatment (EOT) expressed as a ratio i.e. (EOT/baseline) in numbers of each of the airway submucosal inflammatory cells, determined by microscopic evaluation of bronchoscopic biopsies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reticular Basement Membrane (RBM) Thickness Ratio Change From Baseline to EOT. | First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). | The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in RBM thickness, determined by microscopic evaluation of bronchoscopic biopsies. |
| Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT. | First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic). | The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in % airway epithelial, determined by microscopic evaluation of bronchoscopic biopsies. |
Countries
Canada, Denmark, Germany, United Kingdom, United States
Participant flow
Recruitment details
116 subjects randomized to Tezepelumab 210 mg Q4W or Placebo in 1:1 treatment allocation. All randomized subjects were treated.
Pre-assignment details
The study randomized subjects across the spectrum of T2 status. Randomization was stratified by screening blood eosinophil level (\<150 , 150 - \<300, \>=300 cells/µL).
Participants by arm
| Arm | Count |
|---|---|
| Teze 210 mg Q4W Tezepelumab subcutaneous injection | 59 |
| Placebo Placebo subcutaneous injection | 57 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Other | 1 | 0 |
Baseline characteristics
| Characteristic | Teze 210 mg Q4W | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 8 Participants | 16 Participants |
| Age, Categorical Between 18 and 65 years | 51 Participants | 49 Participants | 100 Participants |
| Age, Continuous | 50.4 Years STANDARD_DEVIATION 12.7 | 50.4 Years STANDARD_DEVIATION 13.9 | 50.4 Years STANDARD_DEVIATION 13.2 |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 59 Participants | 57 Participants | 116 Participants |
| Race/Ethnicity, Customized Other (includes Native Hawaiian or Other Pacific Islander and American Indian or Alaska Native) | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 54 Participants | 55 Participants | 109 Participants |
| Sex: Female, Male Female | 39 Participants | 26 Participants | 65 Participants |
| Sex: Female, Male Male | 20 Participants | 31 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 59 |
| other Total, other adverse events | 45 / 57 | 48 / 59 |
| serious Total, serious adverse events | 7 / 57 | 3 / 59 |
Outcome results
Primary
Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT.
The change from baseline to end of treatment (EOT) expressed as a ratio i.e. (EOT/baseline) in numbers of each of the airway submucosal inflammatory cells, determined by microscopic evaluation of bronchoscopic biopsies.
Time frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Population: Number of Participants Analyzed are all subjects randomized to study treatment who completed at least 20 weeks of study treatment and had an EOT visit not greater than 8 weeks after date of last dose of IP. In order to be included in analysis, the participants also had to have a non-missing baseline as well as a non-missing EOT assessment for the respective variable.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Teze 210 mg Q4W | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Eosinophils | 0.11 Ratio |
| Teze 210 mg Q4W | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Neutrophils | 1.11 Ratio |
| Teze 210 mg Q4W | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | T cells CD3+ | 0.91 Ratio |
| Teze 210 mg Q4W | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | T cells CD4+ | 0.96 Ratio |
| Teze 210 mg Q4W | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Mast cells Tryptase+ | 0.84 Ratio |
| Teze 210 mg Q4W | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Mast cells Chymase+ | 1.07 Ratio |
| Placebo | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Mast cells Tryptase+ | 1.01 Ratio |
| Placebo | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Eosinophils | 0.75 Ratio |
| Placebo | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | T cells CD4+ | 0.81 Ratio |
| Placebo | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Neutrophils | 0.81 Ratio |
| Placebo | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | Mast cells Chymase+ | 0.90 Ratio |
| Placebo | Airway Submucosal Inflammatory Cells Ratio Change From Baseline to EOT. | T cells CD3+ | 0.81 Ratio |
p-value: <0.00190% CI: [0.06, 0.35]ANCOVA
p-value: 0.10690% CI: [0.99, 1.86]ANCOVA
p-value: 0.38990% CI: [0.9, 1.4]ANCOVA
p-value: 0.21690% CI: [0.94, 1.48]ANCOVA
p-value: 0.2690% CI: [0.64, 1.09]ANCOVA
p-value: 0.54690% CI: [0.74, 1.92]ANCOVA
Secondary
Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT.
The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in % airway epithelial, determined by microscopic evaluation of bronchoscopic biopsies.
Time frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Population: Number of Participants Analyzed are all subjects randomized to study treatment who completed at least 20 weeks of study treatment and had an EOT visit not greater than 8 weeks after date of last dose of IP. In order to be included in analysis, the participants also had to have a non-missing baseline as well as a non-missing EOT assessment for the respective variable.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Teze 210 mg Q4W | Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT. | Intact epithelium | 0.87 Ratio |
| Teze 210 mg Q4W | Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT. | Damaged epithelium | 1.01 Ratio |
| Teze 210 mg Q4W | Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT. | Denuded epithelium | 1.05 Ratio |
| Placebo | Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT. | Intact epithelium | 0.84 Ratio |
| Placebo | Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT. | Damaged epithelium | 0.95 Ratio |
| Placebo | Percent (%) Airway Epithelial Integrity Ratio Change From Baseline to EOT. | Denuded epithelium | 1.34 Ratio |
Secondary
Reticular Basement Membrane (RBM) Thickness Ratio Change From Baseline to EOT.
The change from baseline to EOT expressed as a ratio i.e. (EOT/baseline) in RBM thickness, determined by microscopic evaluation of bronchoscopic biopsies.
Time frame: First dose of investigational product to end of treatment (EOT) at Week 28 (or up to Week 48 due to COVID19 pandemic).
Population: All subjects randomised to study treatment who completed at least 20 weeks of study treatment and had a baseline assessment and an EOT assessment not greater than 8 weeks after date of last dose of IP.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Teze 210 mg Q4W | Reticular Basement Membrane (RBM) Thickness Ratio Change From Baseline to EOT. | 0.87 Ratio |
| Placebo | Reticular Basement Membrane (RBM) Thickness Ratio Change From Baseline to EOT. | 0.90 Ratio |