Study to Evaluate Tezepelumab in Adults With Severe Uncontrolled Asthma

Study Overview
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Brief Summary
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A Regional, Multicentre, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults with Severe Uncontrolled Asthma

Detailed Description
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This is a regional, multicentre, randomized, double-blind, placebo controlled, parallel group, phase 3 study designed to evaluate the efficacy and safety of 210 mg Q4W (SC) of tezepelumab in adults with severe, uncontrolled asthma on medium to high-dose ICS and at least one additional asthma controller medication with or without OCS. Approximately 396 participants will be randomized regionally (China/non-China). Participants will receive tezepelumab, or placebo, administered via subcutaneous injection at the study site, over a 52-week treatment period. The study also includes a post-treatment follow-up period of 12 weeks

Official Title
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A Regional, Multicentre, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults With Severe Uncontrolled Asthma

Conditions
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Asthma

Intervention / Treatment
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* Biological: Experimental: Tezepelumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age. 18-80 Documented physician-diagnosed asthma for at least 12 months Participants who have received a physician-prescribed asthma controller medication with medium or high dose ICS for at least 6 months. Documented treatment with a total daily dose of either medium or high dose ICS (≥ 500 µg fluticasone propionate dry powder formulation equivalent total daily dose) for at least 3 months. 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. Morning pre-BD FEV1 <80% predicted normal Evidence of asthma as documented by either: Documented historical reversibility of FEV1 ≥12% and ≥200 mL in the previous 12 months OR Post-BD (albuterol/salbutamol) reversibility of FEV1 ≥12% and ≥200 mL during screening. Documented history of at least 2 asthma exacerbation events within 12 months, and at least one of the exacerbations should occur during the treatment of medium-to-high dose ICS. ACQ-6 score ≥1.5 at screening and on day of randomization Exclusion Criteria: Pulmonary disease other than asthma. History of cancer. History of a clinically significant infection. Current smokers or participants with smoking history ≥10 pack-yrs. History of chronic alcohol or drug abuse within 12 months. Hepatitis B, C or HIV. Pregnant or breastfeeding. History of anaphylaxis following any biologic therapy. participant randomized in the current study or previous tezepelumab studies.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Interventional Model Description: Participants will be randomized in a 1:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezepelumab<br>Tezepelumab: Tezepelumab subcutaneous injection | Biological: Experimental: Tezepelumab<br>* Tezepelumab subcutaneous injection<br>* Other names: Tezepelumab;|
| Placebo Comparator: Placebo<br>Placebo: Placebo subcutaneous injection | Other: Placebo<br>* Placebo subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized asthma exacerbation rate (AERR) | The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 52 weeks. | Randomization to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pre-dose/pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1) | Mean change from baseline in FEV1 as compared to placebo at Week 52. FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration. | Randomization, Week 52 | 
| Change from baseline in Standardized Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(S)+12) total score | Mean change from baseline in AQLQ(S)+12 as compared to placebo at Week 52. The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by asthma participants. The total score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). | Randomization， Week 52 | 
| Change from baseline in Asthma Control Questionnaire-6 (ACQ-6) Score | Mean change from baseline in ACQ-6 as compared to placebo at Week 52. The ACQ-6 captures asthma symptoms and short-acting β2-agonist use via subject-report. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 score is the mean of the responses. | Randomization, Week 52 | 
| Change from baseline in weekly mean daily Asthma Symptom Diary score | Mean change from baseline in Asthma Symptom Diary score as compared to placebo at Week 52. The Asthma Symptom Diary comprises of 10 items (5 items in the morning; 5 items in the evening). Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the daily diary. A daily ASD score is the mean of the 10 items. Responses for all 10 items are required to calculate the daily ASD score; otherwise, it is treated as missing. For the 7-day average asthma symptom score, scoring is done with no imputation using the mean of at least 4 of the 7 daily ASD scores as a mean weekly item score. The 7-day average ASD score ranges from 0 to 4. | Randomization, Week 52 | 
| Time to first asthma exacerbation | Time to the first occurrence of asthma exacerbation post randomization, presented as number of participants with at least one asthma exacerbation reported in the eCRF | Randomization to Week 52 | 
| Change from baseline in fractional exhaled nitric oxide | Mean change from baseline in FENO (ppb) at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers | Randomization, Week 52 | 
| Change from baseline in weekly mean rescue medication use | Mean change from baseline in weekly mean rescue medication use at Week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on other asthma control metrics. The number of rescue medication inhalations (puffs) and nebulizer treatments taken will be recorded by the participant in the Asthma Symptom Diary twice daily (i.e., in the morning and evening). Each timepoint is calculated as weekly means based on daily diary data. | Randomization, Week 52 | 
| Number of participants with asthma specific resource utilization (e.g.,eg, unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) | Number of participants with asthma specific resource utilization (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 52 weeks. | Randomization to Week 52 | 
| Serum trough concentrations | Serum trough concentrations (pre-dose samples) at each scheduled visit to evaluate the pharmacokinetics (PK) of tezepelumab | Baseline to Week 64 | 
| European Quality of Life - 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) score | Mean change from baseline in EQ-5D-5L at week 52. EQ-5D-5L has two sections. The first section assesses five dimensions (mobility, self-care, usual activity, pain/discomfort, and anxiety/depression). Patients rate each of these items from no problem, slight problem moderate problem, severe problem and unable. A composite health index is defined by combining the levels for each dimension. The second section measures self-rated (global) health status using a vertically oriented visual analogue scale where 100 represents the best possible health state and 0 represents the worst possible health state. EQ-5D-5L assesses health status in terms of a single index value or health utility score. It allows weighting by the patient of particular health states and the generation of patient utilities. Overall scores range from 0 to 1,with lower scores representing a higher level of dysfunction. | Randomization, Week 52 | 
| Change from baseline in peripheral blood eosinophils | Mean change from baseline in blood eosinophil counts at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers. | Randomization, Week 52 | 
| Change from baseline in total serum IgE | Mean change from baseline in IgE at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers. | Randomization, Week 52 | 
| Change from baseline in weekly mean morning and evening peak expiratory flow (PEF) | Mean change from baseline in weekly mean morning and evening peak expiratory flow (PEF) at Week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on other asthma control metrics. Home PEF testing will be performed by the participant in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Each timepoint is calculated as weekly means. | Randomization, Week 52 | 
| Change from baseline in weekly mean number of night time awakenings | Mean change from baseline in weekly mean number of night time awakenings at Week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on other asthma control metrics. Each timepoint is calculated as weekly mean number of awakenings due to asthma based on daily diary data. Weekly mean number of night time awakenings is defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data and multiplied by 100%. | Randomization, Week 52 | 
| Immunogenicity anti-drug antibodies | Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post baseline assessments (with >=16 weeks between the first and the last positive) or positive at last post baseline assessment. Transiently positive is defined as having at least one post baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Treatment boosted ADA defined as baseline positive ADA that was boosted to a 4 fold or higher level following treatment. Treatment emergent ADA defined as sum of treatment induced ADA and treatment boosted ADA. | Baseline to Week 64 | 
| Proportion of participants who did not experience an asthma exacerbation | Percentage of participants who did not experience an asthma exacerbation as compared to placebo at Week 52 | Week 52 | 
| Annualized rate of exacerbations associated with emergency room (ER) visit or hospitalizations | Annualized rate of exacerbations associated with ER visit or hospitalization as compared to placebo over 52 weeks | Randomization to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Uncontrolled Asthma, Severe Uncontrolled Asthma