Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma

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

Detailed Description
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This is a multicentre, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma on medium to high-dose ICS and at least one additional asthma controller medication with or without OCS. Approximately 1060 subjects will be randomized globally. Subjects 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 Multicentre, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Adults and Adolescents With Severe Uncontrolled Asthma (NAVIGATOR)

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. 12-80 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. 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 (<90% for subjects 12-17 yrs) 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. 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 subjects with smoking history ≥10 pack-years and subjects using vaping products, including electronic cigarettes. 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. Subject randomized in the current study or previous tezepelumab studies.

Ages Eligible for Study
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Minimum Age: 12 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: Subjects 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 |
| --- | --- | --- |
| Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma | The annual exacerbation rate is based on unadjudicated exacerbations reported by the investigator in the eCRF. The analysis is based on the primary population (Full Analysis Set) | From randomisation to Study Week 52. | 
| Annual Asthma Exacerbation Rate in Adult and Adolescent Patients With Uncontrolled Asthma in Subjects With Baseline Eosinophils < 300 Cells/uL | The annual exacerbation rate is based on unadjudicated exacerbations reported by the investigator in the eCRF. This analysis is based on subjects with baseline eosinophils < 300 cells/uL | From randomisation to Study Week 52. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline at Week 52 in Pre-dose/Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in 1 Second (FEV1) (L) (Key Secondary Endpoint) | 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. | From randomisation to Study Week 52 | 
| Mean Change From Baseline at Week 52 in Standardized Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) Total Score (Key Secondary Endpoint) | 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 subjects. 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). | From randomisation to Study Week 52 | 
| Mean Change From Baseline at Week 52 in Asthma Control Questionnaire-6(ACQ-6) (Key Secondary Endpoint) | 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. | From randomisation to Study Week 52 | 
| Mean Change From Baseline at Week 52 in Asthma Symptom Diary (Key Secondary Endpoint) | Mean change from baseline at Week 52 in Asthma Symptom Diary. 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, where 0 indicates no asthma symptoms. | From randomisation to Study Week 52 | 
| Time to First Asthma Exacerbation | Time to first occurrence of asthma exacerbation post-randomisation, presented as number of subjects with at least one asthma exacerbation as reported by the investigator in the eCRF. | From randomisation to Study Week 52 | 
| Mean Change From Baseline at Week 52 in Clinic Fractional Exhaled Nitric Oxide (FeNO) (Ppb) | Mean change from baseline at Study Week 52 in FeNO (ppb) measured at site | From randomisation to Study Week 52 | 
| Mean Change From Baseline in Daily Rescue Medication Use (Weekly Means) at Week 52 | Daily rescue medication use is defined as: Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of daytime inhaler puffs + 2 x [number of day nebulizer times]. Weekly means are calculated using at least 4 of 7 days of daily rescue medication use. | From randomisation to Study Week 52 | 
| Mean Change From Baseline in Work Productivity Loss Due to Asthma at Week 52 | WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Work productivity loss is derived by sum of percentage of missed work due to asthma and product of percentage of actual working hours times degree of asthma affecting work productivity while working. Percentage of missed work due to asthma is calculated by number of hours missed work due to asthma divided by total number of hours missed work plus number of hours actually worked. | From randomisation to Study Week 52 | 
| Mean Change From Baseline in Class Productivity Loss Due to Asthma at Week 52 | WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Class productivity loss is derived by sum of percentage of missed class hours due to asthma and product of percentage of actual hours in class times degree of asthma affecting productivity while in class. Percentage of missed hours in class due to asthma is calculated by number of hours in class missed due to asthma divided by total number of hours in class missed plus number of hours actually in class. | From randomisation to Study Week 52 | 
| Activity Impairment at Week 52 | WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Activity impairment is the degree health affected regular activities (other than work or class) rated from 0 to 10, with 0 meaning no effect, divided by 10, and then expressed as a percentage. | From randomisation to Study Week 52 | 
| Pharmacokinetics of Tezepelumab | Mean serum trough PK concentrations taken pre-dose at each visit | Pre-dose samples at Baseline, Week 4, Week 12, Week 24, Week 36, Week 52, Week 64 | 
| Mean Change From Baseline at Week 52 in EQ-5D-5L VAS | Mean change from baseline at Study Week 52 in EQ-5D-5L VAS. EQ-5D-5L visual analogue scale (VAS) allows subjects to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state. | At Study Week 52 | 
| Clinicians Global Impression of Change at Week 52 | CGIC (Clinical global impression of change) is an overall evaluation of response to treatment, conducted by investigator using 7-point rating scale, ranging from 1 (very much improved), to 7 (very much worse) | From randomisation to Study Week 52 | 
| Patients Global Impression of Change at Week 52 | PGIC (Patient global impression of change) is an overall evaluation of response to treatment, conducted by the patient using 7-point rating scale, ranging from 1 (very much improved), to 7 (very much worse). | From randomisation to Study Week 52 | 
| Patients Global Impression of Severity at Week 52 | PGI-S (Patient global impression of severity) is an overall evaluation of patient's perception of overall symptom severity using a 6-point rating scale, ranging from 0 = No symptoms, 1=Very mild symptoms, 2=Mild symptoms, 3=Moderate symptoms, 4=Severe symptoms, 5=Very severe symptoms | At Study Week 52 | 
| Mean Change From Baseline at Week 52 in Blood Eosinophils (Cells/uL) | Mean change from baseline at Study Week 52 in blood eosinophils (cells/uL) | From randomisation to Study Week 52 | 
| Mean Change From Baseline at Week 52 in Total Serum IgE (IU/mL) | Mean change from baseline at Study Week 52 in total serum IgE (IU/mL) | From randomisation to Study Week 52 | 
| Number of Participants With Asthma Specific Healthcare Utilization Over 52 Weeks | Number of participants with asthma specific healthcare utilizations (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 52 weeks | From randomisation to Study Week 52 | 
| Mean Change From Baseline in Home Based Morning Peak Expiratory Flow (PEF) at Week 52 (Weekly Means) | Mean change from baseline in home based morning PEF (L/min) at Study Week 52. Home PEF testing will be performed by the subject in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Weekly means are calculated using at least 4 of the 7 days of PEF data. | From randomisation to Study Week 52 | 
| Mean Change From Baseline in Home Based Evening Peak Expiratory Flow (PEF) at Week 52 (Weekly Means) | Mean change from baseline in home based evening PEF (L/min) at Study Week 52. Home PEF testing will be performed by the subject in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Weekly means are calculated using at least 4 of the 7 days of PEF data. | From randomisation to Study Week 52 | 
| Mean Change From Baseline in Night Time Awakenings (Weekly Means) at Week 52 | Mean change from baseline in night time awakenings due to asthma at Study Week 52. Night-time awakenings percentage defined as number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data and multiplied by 100%. At least 4 out of 7 days of data is required to calculate a weekly mean. | From randomisation to Study Week 52 | 
| Immunogenecity of Tezepelumab | 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, and from time of first dose at Week 0 to end of study at Week 64. | 
| Proportion of Subjects Who Had no Asthma Exacerbations | The proportion of subjects who have no exacerbations is presented as the percentage of subjects with no exacerbations. This is defined as subjects who meet both the following criteria: (1) completed the 52 week treatment period and (2) did not report an exacerbation during this period. | From randomisation to Study Week 52 | 
| Annual Asthma Exacerbation Rate Resulting in Emergency Room Visit or Hospitalisation | The annualized exacerbation rate is based on exacerbations reported by the investigator that are associated with an emergency room visit, urgent care visit, or a hospitalization (where urgent care visit was captured as an emergency room visit on the eCRF) | From randomisation to Study Week 52 | 
| Proportion of Subjects With at Least One Asthma Exacerbation Associated With Emergency Room Visit or Hospitalisation | Proportion of subjects with at least one asthma exacerbation associated with emergency room visit or hospitalisation as recorded by the investigator in the CRF. This is presented as percentage of subjects with at least one asthma exacerbation associated with emergency room visit or hospitalisation. | From randomisation to Study Week 52 | 
| Proportion of Subjects Who Had no Asthma Exacerbations Associated With Emergency Room or Hospitalisation | The proportion of subjects with no exacerbations is presented as percentage of subjects who meet both the following criteria: (1) completed the 52 week treatment period and (2) did not report an exacerbation associated with emergency room or hospitalisation during this period. | From randomisation to Study 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