Study to Evaluate Tezepelumab in Adults With Severe Uncontrolled Asthma

Phase 3

Completed

Conditions: Asthma

Interventions: Other: Placebo

Registration Number: NCT03927157

Lead Sponsor: AstraZeneca

Brief Summary: 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: 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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 405

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo: Placebo subcutaneous injection

Primary Outcome Measures

Name	Time	Method
Annual Asthma Exacerbation Rate (AERR)	Randomization to Week 52	The annual exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 52 weeks

Secondary Outcome Measures

Name	Time	Method
Mean Change From Baseline in Pre-dose/Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in 1 Second (FEV1) at Week 52	Randomization to Week 52	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.
Mean Change From Baseline in Weekly Mean Daily Asthma Symptom Diary Score at Week 52	Randomization to Week 52	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. A higher value indicates a worse outcome. 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.
Mean Change From Baseline in Asthma Control Questionnaire-6 (ACQ-6) Score at Week 52	Randomization to Week 52	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.
Time to First Asthma Exacerbation	Randomization to Week 52	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
Mean Change From Baseline in Fractional Exhaled Nitric Oxide at Week 52	Randomization to Week 52	Mean change from baseline in FENO (ppb) at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers
Number of Participants With Asthma Specific Resource Utilization Over 52 Weeks	Randomization to Week 52	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.
Pharmacokinetics of Tezepelumab	Baseline, Week 24, Week 52, Week 64	Mean serum trough PK concentrations taken pre-dose at each scheduled visit to evaluate the pharmacokinetics (PK) of tezepelumab
Mean Change From Baseline in EQ-5D-5L VAS Score at Week 52	At Week 52	Mean change from baseline in EQ-5D-5L VAS at week 52. EQ-5D-5L visual analogue scale (VAS) allows participants to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state.
Mean Change From Baseline in Blood Eosinophils (Cells/uL) at Week 52	Randomization to Week 52	Mean change from baseline in blood eosinophil counts at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers.
Mean Change From Baseline in Total Serum IgE (IU/mL) at Week 52	Randomization to Week 52	Mean change from baseline in IgE at week 52 to assess the effect of 210 mg of tezepelumab SC Q4W on biomarkers.
Mean Change From Baseline in Night Time Awakenings (Percentage) at Week 52	Randomization to Week 52	Mean change from baseline in night time awakenings due to asthma at Week 52. Night time awakenings percentage is defined as number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with available data and multiplied by 100%. At least 4 out of 7 days of data is required to calculate a weekly mean.
Immunogenicity of Tezepelumab	Baseline to Week 64	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.
Mean Change From Baseline in Daily Rescue Medication Use (Weekly Means) at Week 52	Randomization to 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.
Mean Change From Baseline in Home Based Morning Peak Expiratory Flow (PEF) at Week 52	Randomization to Week 52	Mean change from baseline in home based morning PEF (L/min) at Week 52. Home PEF testing was performed by participant 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.
Mean Change From Baseline in Home Based Evening Peak Expiratory Flow (PEF) at Week 52	Randomization to Week 52	Mean change from baseline in home based evening PEF (L/min) at Week 52. Home PEF testing was performed by participant 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.
Annual Asthma Exacerbation Rate Resulting in Emergency Room Visit or Hospitalization	Randomization to Week 52	The annual 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).
Proportion of Participants Who Had no Asthma Exacerbations	Randomization to Week 52	The proportion of participants who had no asthma exacerbations is presented as the percentage of participants with no exacerbations. This is defined as participants who meet both the following criteria: (1) completed the 52 week treatment period and (2) did not report an exacerbation during this period.
Mean Change From Baseline in Standardized Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) Total Score at Week 52	Randomization to Week 52	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).