Asthma
Conditions
Keywords
Amgen, AMG 157, Asthma
Brief summary
The purpose of this study is to assess the late and early asthmatic response after an allergen inhalation challenge in adults with mild atopic asthma after receiving multiple doses of tezepelumab (AMG 157), as well as the safety, tolerability, immunogenicity, and pharmacokinetics of multiple doses of tezepelumab in adults with mild atopic asthma.
Interventions
DRUGPlacebo
Administered in a 1-hour intravenous infusion
BIOLOGICALTezepelumab
Administered in a 1-hour intravenous infusion
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male or female subjects with history of mild atopic asthma between 18 and 60 years-of-age * Body mass index (BMI) between 18 and 35 kg/m\^2 * Normal or clinically acceptable physical examination (PE), clinical laboratory values, and electrocardiogram (ECG); clinically acceptable PE includes history of mild atopic asthma * Used only inhaled short-acting β2-agonists infrequently to treat asthma * No current exposure to allergens to which subject experiences asthmatic responses * No other lung disease, exacerbations of asthma or lower respiratory tract infections for at least 6 weeks prior to screening * Positive skin prick test to common aeroallergens at screening * Additional inclusion criteria apply
Exclusion criteria
* History or evidence of a clinically significant disorder (including psychiatric), condition or disease that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion; * History or current medical conditions that are contraindicated for methacholine challenge, such as myocardial infarction or stroke within previous 3 months, known cardiac disease, uncontrolled hypertension and aortic or cerebral aneurysm * Evidence of active or suspected bacterial, viral, fungal or parasitic infections within past 6 weeks * Subject has know type I/II diabetes * History of residential exposure to tuberculosis or has a positive purified protein derivative (PPD) or QuantiFERON test within 4 weeks before randomization * Subject who has history of malignancy of any type within 5 years prior to enrollment * Subjects tested positive for drugs/alcohol or nicotine use at screening * Subjects tested positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Percentage Decrease in Forced Expiratory Volume in 1 Second (FEV1) at 3 to 7 Hours Post Allergen Challenge | Days 42 and 84 at pre-allergen challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post allergen challenge | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction (measured by a fall in FEV1). FEV1 was measured prior to the challenge and between 3 to 7 hours post allergen challenge to assess late asthmatic response (LAR). The percent change in FEV1 from pre-challenge was calculated to each time point between 3 to 7 hours post challenge. The maximum percent decrease in FEV1 from pre-allergen challenge is the percent change in FEV1 representing the largest percentage decrease (or minimum percentage increase) from pre-allergen challenge FEV1 during late (3-7 hour) asthmatic response time frame. |
| Time-Adjusted Area Under the Curve for the Percent Decrease From Pre-Allergen Challenge in Forced Expiratory Volume in 1 Second (FEV1) From 3 to 7 Hours Post Allergen Challenge | Days 42 and 84 at pre-challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post challenge | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post challenge to assess late asthmatic response (LAR). The percent change in FEV1 from pre-challenge was calculated to each time point between 3 to 7 hours post challenge. The area under the curve for the percent change at each time point was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Days 29, 57, 85, 113, and 169 | All study samples (tezepelumab and placebo) were tested using an electrochemiluminescence (ECL) based immunoassay to detect and confirm the presence of antibodies capable of binding to tezepelumab. Samples identified as positive in the immunoassay were tested in a receptor-binding ECL-based assay to detect neutralizing or inhibitory effects toward tezepelumab. The number of participants with positive anti-tezepelumab binding antibodies / neutralizing antibodies at any time post-baseline with a negative or no result at baseline is reported. |
| Maximum Percentage Decrease in FEV1 From 0 to 2 Hours Post Allergen Challenge | Days 42 and 84 at pre-allergen challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post allergen challenge | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The maximum percent decrease in FEV1 from pre-allergen challenge is the percent change in FEV1 representing the largest percentage decrease (or minimum percentage increase) from pre-allergen challenge FEV1 during early (0-2 hour) asthmatic response time frame. |
| Time-Adjusted AUC for the Percent Decrease From Pre-Allergen Challenge in FEV1 From 0 to 2 Hours Post Allergen Challenge | Days 42 and 84 at pre-challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post challenge | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The percent change in FEV1 from pre-allergen challenge was calculated to each time point between 0 to 2 hours post challenge. The area under the curve for the percent change at each time point was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated. |
| Minimum FEV1 From 0 to 2 Hours Post Allergen Challenge | Days 42 and 84 at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post allergen challenge | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The minimum FEV1 post onset of the allergen challenge for EAR is defined as the smallest value of FEV1 measured during 0 to 2 hours post allergen challenge. |
| Time-Adjusted AUC for FEV1 From 0 to 2 Hours Post Allergen Challenge | Days 42 and 84 at pre-challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post challenge | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The area under the curve for the FEV1 between 0 to 2 hours post allergen challenge was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated. |
| Minimum FEV1 From 3 to 7 Hours Post Allergen Challenge | Days 42 and 84 at 180, 240, 300, 360, and 420 minutes (3-7 hours) post allergen challenge | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post challenge to assess late asthmatic response (LAR). The minimum FEV1 post allergen challenge for LAR is defined as the smallest value of FEV1 measured during 3 to 7 hours post allergen challenge. |
| Time-Adjusted AUC for FEV1 From 3 to 7 Hours Post Allergen Challenge | Days 42 and 84 at pre-challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post challenge. | Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post allergen challenge to assess late asthmatic response (LAR). The area under the curve for the FEV1 between 3 to 7 hours post allergen challenge was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated. |
| Number of Participants With Adverse Events | Up to 169 days | A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: * fatal, * life-threatening, * requires in-patient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * congenital anomaly/birth defect, and/or * other medically important serious event. The severity of each adverse event was graded by the Investigator as mild, moderate, severe, life-threatening, or fatal according to the Common Terminology Criteria for Adverse Events (Version 4). |
| Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | The PK parameter Tmax was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL. |
| Minimum Observed Serum Concentration (Cmin) of Tezepelumab | First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | The PK parameter Cmin was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL. |
| Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose: Day 1 at predose and 1 and 4 hours postdose and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, and 85. | The PK parameter AUCtau was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The dosing interval (tau) was 28 days. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL. |
| Accumulation Ratio Based on AUCtau | First dose: Day 1 at predose and 1 and 4 hours postdose and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, and 85. | Accumulation ratio (AR) based on AUCtau was calculated as AUCtau after last dose / AUCtau after first dose. |
| Accumulation Ratio Based on Cmax | First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | Accumulation ratio based on Cmax calculated as Cmax after last dose / Cmax after first dose. |
| Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) After Last Dose for Tezepelumab | Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | The PK parameter AUCinf was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL. |
| Terminal Half-life (t1/2z) of Tezepelumab After Last Dose | Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | The PK parameter t1/2,z was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL. |
| Maximum Observed Serum Concentration (Cmax) of Tezepelumab | First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | The PK parameter Cmax was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL. |
| Number of Participants With Grade ≥ 3 Laboratory Values | Up to 169 days | Laboratory toxicities were graded according to the Common Terminology Criteria for Adverse Events (Version 4) on a scale from grade 1 (mild) to 5 (death). |
Countries
Canada
Participant flow
Recruitment details
This proof-of-concept, randomized, double-blind, placebo-controlled study was conducted at 5 centers in Canada.
Pre-assignment details
Participants were randomly assigned in a 1:1 ratio to receive tezepelumab or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo administered by intravenous infusion on study days 1, 29, and 57. | 15 |
| Tezepelumab 700 mg Participants received 700 mg tezepelumab administered by intravenous infusion on study days 1, 29, and 57. | 16 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Moved Away | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Tezepelumab 700 mg | Total |
|---|---|---|---|
| Age, Continuous | 31.5 years STANDARD_DEVIATION 11.2 | 30.8 years STANDARD_DEVIATION 10.9 | 31.1 years STANDARD_DEVIATION 10.9 |
| Forced Expiratory Volume in 1 Second (FEV1) | 3.335 liters STANDARD_DEVIATION 0.753 | 3.358 liters STANDARD_DEVIATION 0.865 | 3.346 liters STANDARD_DEVIATION 0.799 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 6 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 15 | 15 / 16 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 |
Outcome results
Primary
Maximum Percentage Decrease in Forced Expiratory Volume in 1 Second (FEV1) at 3 to 7 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction (measured by a fall in FEV1). FEV1 was measured prior to the challenge and between 3 to 7 hours post allergen challenge to assess late asthmatic response (LAR). The percent change in FEV1 from pre-challenge was calculated to each time point between 3 to 7 hours post challenge. The maximum percent decrease in FEV1 from pre-allergen challenge is the percent change in FEV1 representing the largest percentage decrease (or minimum percentage increase) from pre-allergen challenge FEV1 during late (3-7 hour) asthmatic response time frame.
Time frame: Days 42 and 84 at pre-allergen challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post allergen challenge
Population: Participants who received at least 1 dose of study drug with available data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Percentage Decrease in Forced Expiratory Volume in 1 Second (FEV1) at 3 to 7 Hours Post Allergen Challenge | Day 42 | -20.645 percent change | Standard Deviation 11.554 |
| Placebo | Maximum Percentage Decrease in Forced Expiratory Volume in 1 Second (FEV1) at 3 to 7 Hours Post Allergen Challenge | Day 84 | -19.366 percent change | Standard Deviation 14.686 |
| Tezepelumab 700 mg | Maximum Percentage Decrease in Forced Expiratory Volume in 1 Second (FEV1) at 3 to 7 Hours Post Allergen Challenge | Day 42 | -16.949 percent change | Standard Deviation 14.209 |
| Tezepelumab 700 mg | Maximum Percentage Decrease in Forced Expiratory Volume in 1 Second (FEV1) at 3 to 7 Hours Post Allergen Challenge | Day 84 | -12.064 percent change | Standard Deviation 9.131 |
Comparison: Treatment difference in late asthmatic response at day 42 was evaluated using a repeated-measures analysis of covariance (ANCOVA) that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0995% CI: [-1.3, 16.6]ANCOVA
Comparison: Treatment difference in late asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0295% CI: [1.59, 18.23]ANCOVA
Primary
Time-Adjusted Area Under the Curve for the Percent Decrease From Pre-Allergen Challenge in Forced Expiratory Volume in 1 Second (FEV1) From 3 to 7 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post challenge to assess late asthmatic response (LAR). The percent change in FEV1 from pre-challenge was calculated to each time point between 3 to 7 hours post challenge. The area under the curve for the percent change at each time point was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.
Time frame: Days 42 and 84 at pre-challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post challenge
Population: Participants who received at least 1 dose of study drug and with available AUC data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time-Adjusted Area Under the Curve for the Percent Decrease From Pre-Allergen Challenge in Forced Expiratory Volume in 1 Second (FEV1) From 3 to 7 Hours Post Allergen Challenge | Day 42 | 12.062 percent change | Standard Deviation 8.231 |
| Placebo | Time-Adjusted Area Under the Curve for the Percent Decrease From Pre-Allergen Challenge in Forced Expiratory Volume in 1 Second (FEV1) From 3 to 7 Hours Post Allergen Challenge | Day 84 | 11.864 percent change | Standard Deviation 9.482 |
| Tezepelumab 700 mg | Time-Adjusted Area Under the Curve for the Percent Decrease From Pre-Allergen Challenge in Forced Expiratory Volume in 1 Second (FEV1) From 3 to 7 Hours Post Allergen Challenge | Day 42 | 9.321 percent change | Standard Deviation 10.787 |
| Tezepelumab 700 mg | Time-Adjusted Area Under the Curve for the Percent Decrease From Pre-Allergen Challenge in Forced Expiratory Volume in 1 Second (FEV1) From 3 to 7 Hours Post Allergen Challenge | Day 84 | 7.569 percent change | Standard Deviation 7.069 |
Comparison: Treatment difference in late asthmatic response at day 42 was evaluated using a repeated-measures analysis of covariance (ANCOVA) that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.1195% CI: [-9.8, 1.1]ANCOVA
Comparison: Treatment difference in late asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0795% CI: [-9.71, 0.39]ANCOVA
Secondary
Accumulation Ratio Based on AUCtau
Accumulation ratio (AR) based on AUCtau was calculated as AUCtau after last dose / AUCtau after first dose.
Time frame: First dose: Day 1 at predose and 1 and 4 hours postdose and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, and 85.
Population: The PK parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after first dose and after last dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Accumulation Ratio Based on AUCtau | 1.64 ratio | Standard Deviation 0.25 |
Secondary
Accumulation Ratio Based on Cmax
Accumulation ratio based on Cmax calculated as Cmax after last dose / Cmax after first dose.
Time frame: First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169.
Population: The PK parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after first dose and after last dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Accumulation Ratio Based on Cmax | 1.31 ratio | Standard Deviation 0.25 |
Secondary
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) After Last Dose for Tezepelumab
The PK parameter AUCinf was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Time frame: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169.
Population: The PK parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after last dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) After Last Dose for Tezepelumab | 8620 day*μg/mL | Standard Deviation 2440 |
Secondary
Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab
The PK parameter AUCtau was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The dosing interval (tau) was 28 days. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Time frame: First dose: Day 1 at predose and 1 and 4 hours postdose and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, and 85.
Population: The PK parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after first dose and after last dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | First dose | 2730 day*μg/mL | Standard Deviation 700 |
| Placebo | Area Under the Concentration-time Curve Over the Dosing Interval (AUCtau) for Tezepelumab | Last dose | 4420 day*μg/mL | Standard Deviation 1250 |
Secondary
Maximum Observed Serum Concentration (Cmax) of Tezepelumab
The PK parameter Cmax was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Time frame: First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169.
Population: The pharmacokinetic (PK) parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after first dose and after last dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Serum Concentration (Cmax) of Tezepelumab | First dose | 262 μg/mL | Standard Deviation 73 |
| Placebo | Maximum Observed Serum Concentration (Cmax) of Tezepelumab | Last dose | 325 μg/mL | Standard Deviation 81 |
Secondary
Maximum Percentage Decrease in FEV1 From 0 to 2 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The maximum percent decrease in FEV1 from pre-allergen challenge is the percent change in FEV1 representing the largest percentage decrease (or minimum percentage increase) from pre-allergen challenge FEV1 during early (0-2 hour) asthmatic response time frame.
Time frame: Days 42 and 84 at pre-allergen challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post allergen challenge
Population: Participants who received at least 1 dose of study drug with available data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Percentage Decrease in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | -33.296 percent change | Standard Deviation 10.084 |
| Placebo | Maximum Percentage Decrease in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | -33.160 percent change | Standard Deviation 15.28 |
| Tezepelumab 700 mg | Maximum Percentage Decrease in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | -22.501 percent change | Standard Deviation 15.001 |
| Tezepelumab 700 mg | Maximum Percentage Decrease in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | -20.990 percent change | Standard Deviation 13.393 |
Comparison: Treatment difference in early asthmatic response at day 42 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0595% CI: [0.01, 17.13]ANCOVA
Comparison: Treatment difference in early asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0695% CI: [-0.46, 21]ANCOVA
Secondary
Minimum FEV1 From 0 to 2 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The minimum FEV1 post onset of the allergen challenge for EAR is defined as the smallest value of FEV1 measured during 0 to 2 hours post allergen challenge.
Time frame: Days 42 and 84 at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post allergen challenge
Population: Participants who received at least 1 dose of study drug with available data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Minimum FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | 2.211 liters | Standard Deviation 0.589 |
| Placebo | Minimum FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | 2.184 liters | Standard Deviation 0.72 |
| Tezepelumab 700 mg | Minimum FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | 2.682 liters | Standard Deviation 0.839 |
| Tezepelumab 700 mg | Minimum FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | 2.774 liters | Standard Deviation 0.826 |
Comparison: Treatment difference in early asthmatic response at day 42 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0595% CI: [-0.01, 0.68]ANCOVA
Comparison: Treatment difference in early asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0895% CI: [-0.06, 0.84]ANCOVA
Secondary
Minimum FEV1 From 3 to 7 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post challenge to assess late asthmatic response (LAR). The minimum FEV1 post allergen challenge for LAR is defined as the smallest value of FEV1 measured during 3 to 7 hours post allergen challenge.
Time frame: Days 42 and 84 at 180, 240, 300, 360, and 420 minutes (3-7 hours) post allergen challenge
Population: Participants who received at least 1 dose of study drug with available data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Minimum FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 84 | 2.627 liters | Standard Deviation 0.864 |
| Placebo | Minimum FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 42 | 2.659 liters | Standard Deviation 0.778 |
| Tezepelumab 700 mg | Minimum FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 42 | 2.943 liters | Standard Deviation 1.036 |
| Tezepelumab 700 mg | Minimum FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 84 | 3.097 liters | Standard Deviation 0.827 |
Comparison: Treatment difference in late asthmatic response at day 42 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0195% CI: [0.12, 0.7]ANCOVA
Comparison: Treatment difference in late asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0195% CI: [0.11, 0.72]ANCOVA
Secondary
Minimum Observed Serum Concentration (Cmin) of Tezepelumab
The PK parameter Cmin was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Time frame: First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169.
Population: The PK parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after first dose and after last dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Minimum Observed Serum Concentration (Cmin) of Tezepelumab | First dose | 60.7 μg/mL | Standard Deviation 20.8 |
| Placebo | Minimum Observed Serum Concentration (Cmin) of Tezepelumab | Last dose | 17.7 μg/mL | Standard Deviation 13.4 |
Secondary
Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment
All study samples (tezepelumab and placebo) were tested using an electrochemiluminescence (ECL) based immunoassay to detect and confirm the presence of antibodies capable of binding to tezepelumab. Samples identified as positive in the immunoassay were tested in a receptor-binding ECL-based assay to detect neutralizing or inhibitory effects toward tezepelumab. The number of participants with positive anti-tezepelumab binding antibodies / neutralizing antibodies at any time post-baseline with a negative or no result at baseline is reported.
Time frame: Days 29, 57, 85, 113, and 169
Population: Participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 1 Participants |
| Placebo | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
| Tezepelumab 700 mg | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab binding antibodies | 0 Participants |
| Tezepelumab 700 mg | Number of Participants Who Developed Anti-tezepelumab Antibodies After Initiation of Treatment | Anti-tezepelumab neutralizing antibodies | 0 Participants |
Secondary
Number of Participants With Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: * fatal, * life-threatening, * requires in-patient hospitalization or prolongation of existing hospitalization, * results in persistent or significant disability/incapacity, * congenital anomaly/birth defect, and/or * other medically important serious event. The severity of each adverse event was graded by the Investigator as mild, moderate, severe, life-threatening, or fatal according to the Common Terminology Criteria for Adverse Events (Version 4).
Time frame: Up to 169 days
Population: Participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events | Any adverse event | 12 Participants |
| Placebo | Number of Participants With Adverse Events | Serious adverse event | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Leading to discontinuation of study drug | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Leading to discontinuation from study | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Severe adverse events | 1 Participants |
| Placebo | Number of Participants With Adverse Events | Life-threatening adverse events | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Treatment-related adverse events | 3 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Treatment-related adverse events | 4 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Any adverse event | 15 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Severe adverse events | 0 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Serious adverse event | 0 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Leading to discontinuation of study drug | 2 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Life-threatening adverse events | 0 Participants |
| Tezepelumab 700 mg | Number of Participants With Adverse Events | Leading to discontinuation from study | 1 Participants |
Secondary
Number of Participants With Grade ≥ 3 Laboratory Values
Laboratory toxicities were graded according to the Common Terminology Criteria for Adverse Events (Version 4) on a scale from grade 1 (mild) to 5 (death).
Time frame: Up to 169 days
Population: Participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Grade ≥ 3 Laboratory Values | Any Grade ≥ 3 Laboratory Toxicity | 2 Participants |
| Placebo | Number of Participants With Grade ≥ 3 Laboratory Values | Increased creatine kinase | 2 Participants |
| Placebo | Number of Participants With Grade ≥ 3 Laboratory Values | Decreased lymphocytes | 0 Participants |
| Tezepelumab 700 mg | Number of Participants With Grade ≥ 3 Laboratory Values | Decreased lymphocytes | 1 Participants |
| Tezepelumab 700 mg | Number of Participants With Grade ≥ 3 Laboratory Values | Any Grade ≥ 3 Laboratory Toxicity | 2 Participants |
| Tezepelumab 700 mg | Number of Participants With Grade ≥ 3 Laboratory Values | Increased creatine kinase | 1 Participants |
Secondary
Terminal Half-life (t1/2z) of Tezepelumab After Last Dose
The PK parameter t1/2,z was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Time frame: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169.
Population: The PK parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after last dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Terminal Half-life (t1/2z) of Tezepelumab After Last Dose | 28.0 days | Standard Deviation 4.2 |
Secondary
Time-Adjusted AUC for FEV1 From 0 to 2 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The area under the curve for the FEV1 between 0 to 2 hours post allergen challenge was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.
Time frame: Days 42 and 84 at pre-challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post challenge
Population: Participants who received at least 1 dose of study drug and with available AUC data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time-Adjusted AUC for FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | 2.709 liters | Standard Deviation 0.695 |
| Placebo | Time-Adjusted AUC for FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | 2.607 liters | Standard Deviation 0.681 |
| Tezepelumab 700 mg | Time-Adjusted AUC for FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | 3.076 liters | Standard Deviation 0.844 |
| Tezepelumab 700 mg | Time-Adjusted AUC for FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | 3.120 liters | Standard Deviation 0.856 |
Comparison: Treatment difference in early asthmatic response at day 42 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0395% CI: [0.03, 0.53]ANCOVA
Comparison: Treatment difference in early asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0695% CI: [-0.01, 0.66]ANCOVA
Secondary
Time-Adjusted AUC for FEV1 From 3 to 7 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 3 to 7 hours post allergen challenge to assess late asthmatic response (LAR). The area under the curve for the FEV1 between 3 to 7 hours post allergen challenge was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.
Time frame: Days 42 and 84 at pre-challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post challenge.
Population: Participants who received at least 1 dose of study drug and with available AUC data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time-Adjusted AUC for FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 42 | 2.940 liters | Standard Deviation 0.781 |
| Placebo | Time-Adjusted AUC for FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 84 | 2.853 liters | Standard Deviation 0.78 |
| Tezepelumab 700 mg | Time-Adjusted AUC for FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 42 | 3.188 liters | Standard Deviation 0.994 |
| Tezepelumab 700 mg | Time-Adjusted AUC for FEV1 From 3 to 7 Hours Post Allergen Challenge | Day 84 | 3.252 liters | Standard Deviation 0.831 |
Comparison: Treatment difference in late asthmatic response at day 42 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0295% CI: [0.04, 0.45]ANCOVA
Comparison: Treatment difference in late asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.1595% CI: [-0.07, 0.44]ANCOVA
Secondary
Time-Adjusted AUC for the Percent Decrease From Pre-Allergen Challenge in FEV1 From 0 to 2 Hours Post Allergen Challenge
Participants underwent allergen inhalation challenge on study days 42 and 84 to induce airway bronchoconstriction. FEV1 was measured prior to the challenge and between 0 to 2 hours post challenge to assess early asthmatic response (EAR). The percent change in FEV1 from pre-allergen challenge was calculated to each time point between 0 to 2 hours post challenge. The area under the curve for the percent change at each time point was calculated using the linear trapezoidal rule, then time adjusted by dividing by the length of time over which the AUC was calculated.
Time frame: Days 42 and 84 at pre-challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post challenge
Population: Participants who received at least 1 dose of study drug and with available AUC data on each day.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Time-Adjusted AUC for the Percent Decrease From Pre-Allergen Challenge in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | 18.592 percent change | Standard Deviation 8.432 |
| Placebo | Time-Adjusted AUC for the Percent Decrease From Pre-Allergen Challenge in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | 20.179 percent change | Standard Deviation 10.973 |
| Tezepelumab 700 mg | Time-Adjusted AUC for the Percent Decrease From Pre-Allergen Challenge in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 42 | 11.284 percent change | Standard Deviation 11.509 |
| Tezepelumab 700 mg | Time-Adjusted AUC for the Percent Decrease From Pre-Allergen Challenge in FEV1 From 0 to 2 Hours Post Allergen Challenge | Day 84 | 11.297 percent change | Standard Deviation 10.708 |
Comparison: Treatment difference in early asthmatic response at day 42 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0395% CI: [-11.56, -0.6]ANCOVA
Comparison: Treatment difference in early asthmatic response at day 84 was evaluated using a repeated-measures ANCOVA that included study treatment and study visit as independent variables, treatment by study visit as an interaction term, and the corresponding baseline value (as measured 14 days before the first dose of a study drug) as a model covariate.p-value: 0.0395% CI: [-14.22, -0.66]ANCOVA
Secondary
Time of Maximum Observed Concentration (Tmax) of Tezepelumab
The PK parameter Tmax was estimated based on the serum concentrations of tezepelumab using noncompartmental methods. The concentration of tezepelumab in human serum was measured using a validated ELISA. The lower limit of quantification of the assay was 10 ng/mL.
Time frame: First dose: Day 1 at predose and 1 and 4 hours postdose, and days 4, 8, 15, and 29 (predose); Last dose: Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169.
Population: The PK parameter analysis set includes participants for whom pharmacokinetic parameter estimates could be derived after first dose and after last dose.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | First dose | 2.1 hours |
| Placebo | Time of Maximum Observed Concentration (Tmax) of Tezepelumab | Last dose | 2.0 hours |