Double-blind, Multiple Dose Study of Tezepelumab (AMG 157) in Adults With Mild Atopic Asthma

Study Overview
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Brief Summary
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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.

Official Title
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Randomized, Double-Blind, Placebo-Controlled, Parallel Design, Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 157 in Subjects With Mild Atopic Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo
* Biological: Tezepelumab


Participation Criteria
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Eligibility Criteria
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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 exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo to tezepelumab administered by intravenous infusion on study days 1, 29, and 57. | Drug: Placebo<br>* Administered in a 1-hour intravenous infusion<br>|
| Experimental: Tezepelumab 700 mg<br>Participants received 700 mg tezepelumab administered by intravenous infusion on study days 1, 29, and 57. | Biological: Tezepelumab<br>* Administered in a 1-hour intravenous infusion<br>* Other names: Tezspire;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Days 42 and 84 at pre-allergen challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post allergen challenge | 
| 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. | Days 42 and 84 at pre-challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post challenge | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 169 days | 
| 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). | Up to 169 days | 
| 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. | Days 29, 57, 85, 113, and 169 | 
| 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. | 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 | 
| 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. | Days 42 and 84 at pre-challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post challenge | 
| 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. | Days 42 and 84 at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post allergen challenge | 
| 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. | Days 42 and 84 at pre-challenge and at 10, 20, 30, 45, 60, 90, and 120 minutes (0-2 hours) post challenge | 
| 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. | Days 42 and 84 at 180, 240, 300, 360, and 420 minutes (3-7 hours) post allergen challenge | 
| 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. | Days 42 and 84 at pre-challenge and at 180, 240, 300, 360, and 420 minutes (3-7 hours) post challenge. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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. | 
| 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. | 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 Based on AUCtau | Accumulation ratio (AR) based on AUCtau was calculated as AUCtau after last dose / AUCtau after first dose. | 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 Based on Cmax | Accumulation ratio based on Cmax calculated as Cmax after last dose / Cmax after first dose. | 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. | 
| 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. | Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | 
| 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. | Day 57 predose, 1 and 4 hours postdose, and at days 60, 64, 71, 83, 84, 85, 113, and 169. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Amgen, AMG 157