Tezepelumab Efficacy and Safety in Reducing Oral Corticosteroid Use in Adults With Oral Corticosteroid Dependent Asthma

Study Overview
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Brief Summary
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A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled 28-week Phase 3 Efficacy and Safety Study of Tezepelumab in Reducing Oral Corticosteroid Use in Adults with Oral Corticosteroid Dependent Asthma

Detailed Description
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This is a multicentre, randomised, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma treated with maintenance OCS in combination with high dose inhaled corticosteroids (ICS) and long-acting β2 agonists (LABA), with or without other asthma controller therapies. Approximately 207 subjects will be randomized globally. Subjects will receive tezepelumab, or placebo, administered via subcutaneous injection using the accessorized pre-filled syringe (APFS), over a 28-week treatment period. The study also includes a post-treatment follow-up period of 12 weeks.

Official Title
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A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled 28-week Phase 3 Efficacy and Safety Study of Tezepelumab in Reducing Oral Corticosteroid Use in Adults With Oral Corticosteroid Dependent Asthma (SUNRISE)

Conditions
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Asthma

Intervention / Treatment
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* Biological: Tezepelumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Main inclusion criteria: Participant must be 18 to 80 years of age. Documented physician-diagnosed asthma for at least 12 months prior to Visit 1. Participants must have received a physician-prescribed medium- or high-dose ICS for at least 12 months prior to Visit 1. Participants must have received physician prescribed LABA and high dose ICS for at least 3 months prior to Visit 1. Additional maintenance asthma controller medications are allowed. The use of these medications must be documented for at least 3 months prior to Visit 1. Participants must have received OCS for the treatment of asthma for at least 6 months prior to Visit 1 and on a stable dose of between ≥7.5 to ≤ 30 mg (prednisone or prednisolone) daily or daily equivalent for at least 1 month prior to Visit 1. Morning pre- bronchodilator (BD) FEV1 must be < 80% predicted normal at Visit 1 or Visit 2. a) Post-BD responsiveness test result: FEV1 ≥12% and ≥200 mL documented either in the previous 60 months prior to or at Visit 1 or at Visit 2 or at Visit 3; OR b)Airway hyperresponsiveness (methacholine: provocative concentration that causes a positive reaction [PC20] of <8 mg/mL) documented in the 60 months prior to Visit 1. Blood eosinophils at Visit 1 ≥150 cells/μL or documented EOS ≥300 cells/μL within 12 months prior to Visit 1. Participants must have a history of at least 1 asthma exacerbation event within 24 months prior to Visit 1. Participants must have received the optimised OCS dose for at least 2 weeks prior to randomisation. Other inclusion criteria per protocol apply. Main exclusion criteria Any clinically important pulmonary disease other than asthma. Any disorder that is not stable in the opinion of the Investigator and could: a. Affect the safety of the participant throughout the study; b. Influence the findings of the study or the interpretation; c. Impede the participant's ability to complete the entire duration of study. History of cancer: a. Participants who have had basal cell carcinoma, localised squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible to participate in the study provided that curative therapy was completed at least 12 months prior to Visit 1; b. Participants who have had other malignancies are eligible provided that curative therapy was completed at least 5 years prior to Visit 1. Asthma exacerbation, requiring use of systemic corticosteroids or increase in the maintenance dose of OCS finalized within 30 days prior to Visit 1. Clinically significant infection requiring treatment with systemic antibiotics or antiviral medications finalized < 2 weeks before Visit 1 or during the run-in period. Participants with evidence of active COVID-19 infection during run-in period and optimisation. A helminth infection diagnosed within 6 months prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy. A participant who is on SABA maintenance treatment within 30 days prior to Visit 1. Current smokers or participants with smoking history ≥ 10 pack-years and participants using vaping products, including electronic cigarettes. Former smokers with a smoking history of <10 pack years and users of vaping or e-cigarette products must have stopped for at least 6 months prior to Visit 1 to be eligible. Receipt of any marketed or investigational biologic agent within 4 months or 5 half-lives (whichever is longer) prior to Visit 1 or receipt of any investigational non-biologic agent within 30 days or 5 half-lives (whichever is longer) prior to Visit 1. COVID-19 vaccination within 28 days prior to randomisation. Tuberculosis requiring treatment within the 12 months prior to Visit 1. During the optimisation period, asthma control reached at an OCS dose of <7.5 mg or >30 mg and/or 3 consecutive dose reductions after which asthma control was still obtained. Other exclusion criteria per protocol apply.

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: Subjects will be randomized in a 2:1 ratio to either tezepelumab or matching placebo both administered subcutaneously.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tezepelumab<br>Tezepelumab subcutaneous injection, in an accessorised pre-filled syringe. | Biological: Tezepelumab<br>* Tezepelumab subcutaneous injection<br>|
| Placebo Comparator: Placebo<br>Placebo subcutaneous injection, in an accessorised pre-filled syringe. | 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 |
| --- | --- | --- |
| Categorised percent reduction from baseline in the daily maintenance OCS dose at Week 28 whilst maintaining asthma control. | Categorised percent reduction from baseline at Week 28. Percent change from baseline is defined as {final dose-baseline dose)/baseline dose}*100%, and the categories of percent change from baseline in daily OCS dose are defined as: ≥90% to ≤100% reduction, ≥75% to <90% reduction, ≥50% to <75% reduction, >0% to <50% reduction, and, no change or any increase. | Baseline to Week 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1) at Week 28 | Change from baseline in pre-BD FEV1 at Week 28. FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration. | Baseline to Week 28 | 
| Proportion of subjects with 100% reduction from baseline in daily OCS dose at Week 28 | Proportion of subjects with 100% reduction from baseline in daily OCS dose at Week 28. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100%. | Baseline to Week 28 | 
| Proportion of subjects with daily OCS dose ≤5 mg at Week 28 | Proportion of subjects with daily OCS dose ≤5 mg at Week 28. | Week 28 | 
| Proportion of subjects with ≥50% reduction from baseline in daily OCS dose at Week 28 | Proportion of subjects with ≥50% reduction from baseline in daily OCS dose at Week 28. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100%. | Baseline to Week 28 | 
| Annualised asthma exacerbation rate (AAER) over 28 weeks | The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 28 weeks. | Baseline to Week 28 | 
| Time to first asthma exacerbation | Time to first asthma exacerbation. | Baseline to Week 28 | 
| Change from baseline in Asthma Control Questionnaire 6 (ACQ-6) score at Week 28 | Change from baseline in ACQ-6 as compared to placebo at Week 28. 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. | Baseline to Week 28 | 
| Change from baseline in weekly mean home peak expiratory flow (PEF) (morning and evening) at Week 28 | Change from baseline in weekly mean morning and evening peak expiratory flow (PEF) as compared to placebo at Week 28. 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. Each timepoint is calculated as weekly. | Baseline to Week 28 | 
| Change from baseline in Standardized Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s)+12) total score at Week 28 | Change from baseline in AQLQ(S)+12 as compared to placebo at Week 28. 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). | Baseline to Week 28 | 
| Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Score at Week 28 | Change from baseline in SGRQ as compared to placebo at Week 28. The questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual's respiratory condition. The total score indicates the impact of disease on overall health status. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible health status and 0 indicates the best possible health status. | Baseline to Week 28 | 
| Change from baseline in fractional exhaled nitric oxide (FeNO) at Week 28 | Change from baseline in fractional exhaled nitric oxide (FeNO) at Week 28. | Baseline to Week 28 | 
| Change from baseline in peripheral blood eosinophils at Week 28 | Change from baseline in blood eosinophil counts at Week 28. | Baseline to Week 28 | 
| Change from baseline in total serum immunoglobulin E (IgE) at Week 28 | Change from baseline in total serum IgE at Week 28. | Baseline to Week 28 | 
| PK: Serum trough concentrations at Week 0, 12 and 28 | Pharmacokinetics samples are collected at baseline and at Week 12 prior to study intervention administration, and at Week 28 (End of Treatment visit). | Baseline, Week 12 and Week 28 | 
| Immunogenicity: Incidence of anti-drug antibodies (ADA) at Week 0, 12, 28, and 40 | Immunogenicity samples are collected at baseline and at Week 12 prior to study intervention administration, at Week 28 (End of Treatment visit) and at Week 40 (Follow-up visit). 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 40 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Severe Asthma, Oral Corticosteroid Dependent Asthma, Tezepelumab, Phase 3 Study, Reducing Oral Corticosteroid