A Phase 2 Placebo-Controlled, Randomized, Double Blind, Adaptive Dose Trial of the Safety and Efficacy of Inhaled AZD1419 in Adults With Eosinophilic, Moderate to Severe Asthma
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- AstraZeneca
- Enrollment
- 81
- Locations
- 1
- Primary Endpoint
- Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis
Study Overview
Brief Summary
Ph2a study planned to be run at approximately 16-18 sites in 4 EU countries (Denmark, Hungary, Poland and Sweden) enrolling approximately 170 patients to ensure 70 randomized patients with eosinophilic, moderate to severe asthma. The patients will receive 13 once weekly inhaled doses of the study drug. Treatment is initiated on top of their ICS/LABA controller medication, which is then tapered down and withdrawn during a period of 3 weeks and during the last 3 weeks of treatment the study drug is given as monotherapy. SABA is used as reliever medication during the whole study period. Primary endpoint is Loss of asthma control. When the endpoint is met, patients will resume their ICS/LABA, will be followed for an additional 4 weeks and will thereafter discontinue the study.
Detailed Description
Ph2a study planned to be run in approximately 16-18 sites in 4 EU countries (Denmark, Hungary, Poland and Sweden) enrolling approximately 170 patients to ensure 70 randomized patients with eosinophilic, moderate to severe asthma.
The study has a withdrawal design.The patients will receive 13 once weekly inhaled doses of the study drug (AZD1419 or placebo). Treatment is initiated with 6 doses of the study drug on top of their ICS/LABA controller medication. Prior to the 7th dose of the study drug the LABA is withdrawn. The following 3 doses are given when ICS is tapered down. Dose 7 is given on top of 100% of their ICS, dose 8 is given on top of 50% of the ICS dose, which is then tapered down to 25% the following week and withdrawn completely prior to dose 10 of the study drug. During the last 3 weeks of treatment (ie last 4 doses), the study drug is given as monotherapy. SABA is used as reliever medication during the whole study period. Primary endpoint is Loss of asthma control, defined as any of the following criteria: a) An increase of ACQ-5 to 1.5 or more b) A reduction of 30% or more in morning peak expiratory flow (PEF) from baseline on 2 consecutive days c) At least six additional reliever inhalations of SABA in a 24-hour period relative to baseline on 2 consecutive days and d) An exacerbation requiring systemic corticosteroids
When the endpoint is met, patients will resume their regular ICS/LABA controller medication and will be followed for an additional 4 weeks, when they do an Early Discontinuation (ED) Visit and will thereafter leave the study. For patients not loosing their asthma control, the full Observational period is up to week 52, when they will do an End of Treatment Visit (EOT). Study procedures are the same on ED and EOT Visits.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 99 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male and female patients 18 years and above
- •Physician-diagnosed asthma requiring treatment with ICS and a long-acting beta agonist (LABA). Patients must have taken ICS plus LABA controller medication for at least 3 months prior to screening
- •Pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% predicted
- •Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception
- •Male patients must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) from the first dose of the IMP and until 1 month after the last dose of the IMP to prevent pregnancy in a partner
- •Blood eosinophil levels ≥ 250 cells/μL at screening OR a history of blood eosinophil levels ≥ 250 cells/μL at any time in the preceding 2 years AND blood eosinophil levels ≥ 150 cells /μL at screening. The eosinophilia must be believed to be due to asthma and not have other known causes, e.g. helminth infection
- •ACQ-5 score ≤1.5 at screening
- •ACQ-5 score ≤0.75 at randomization
- •Documentation of any of the following within 5 years prior to Visit 1:
- •Proof of post-bronchodilator reversibility in FEV1 of ≥12% and ≥200 mL
- •Proof of a positive response to a methacholine or histamine challenge (a decrease in FEV1 by 20% [PC20] at ≤8 mg/mL)
- •Proof of positive response to mannitol challenge (a decrease in FEV1 by 15% [PD15] at ≤635 mg or a >10% decrease in FEV1 between consecutive doses)
- •Proof of diurnal variability in PEF >20% over the course of 24 hours in at least 4 out of 7 consecutive days If historical documentation is not available, proof of reversibility or a positive response to a methacholine, histamine or mannitol challenge or diurnal variation must be demonstrated according to above and documented during Visit 1
Exclusion Criteria
- •Clinically significant lung disease other than asthma (eg, chronic obstructive pulmonary disease, cystic fibrosis, allergic bronchopulmonary aspergillosis, active tuberculosis).
- •History of autoimmune disease including but not limited to Wegener's granulomatosis, system lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, autoimmune thrombocytopenia, primary biliary cirrhosis or any other autoimmune disease considered clinically relevant by the investigator
- •Ongoing allergen immunotherapy or plans to begin such therapy during the study period
- •DLco ≤ 60% of the lower limit of normal
- •Breast feeding, pregnancy or intention to become pregnant during the course of the study
- •Changes in chest X-ray suggesting clinically significant parenchymal disease other than asthma
Arms & Interventions
AZD1419
Dose adaption of AZD1419, 4 mg or 8 mg or 1 mg based on occurence of AE's
Intervention: AZD1419 (Drug)
Placebo
Matching placebo
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis
Time Frame: Baseline (Week 0) up to Week 52
LOAC was defined as any of the following: * Increase of asthma control questionnaire-5 (ACQ-5) to ≥ 1.5. * ≥ 30% reduction in morning peak expiratory flow (PEF) from baseline on 2 consecutive days. * ≥ 6 additional reliever inhalations of short-acting β agonist (SABA) in a 24-hour period relative to baseline on 2 consecutive days. * Exacerbation requiring systemic corticosteroids as decided by Investigator. Time to LOAC was calculated as start date of first LOAC - date of randomization + 1. Start date of LOAC was latest date that 1 of the 4 criteria were satisfied immediately prior to the exacerbation start date, provided no more than 7 days between LOAC and exacerbation start date. Time to LOAC was displayed using a Kaplan-Meier plot and the outcome measure is presented as number of participants with events. Cox regression analysis was used to compare treatments.
Secondary Outcomes
- Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis(Baseline (Week 0) up to Week 52)
- Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks(Baseline (Week 0) up to Week 52)
- LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks(Baseline (Week 0) up to Week 52)
- Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52(Baseline (Week 0) up to Week 52)
- Percentage of Participants Using Reliever Medication up to Week 52(Baseline (Week 0) up to Week 52)
- LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks(Baseline (Week 0) up to Week 52)
- LS Mean Total PEF (Weekly) Over 52 Weeks(Baseline (Week 0) up to Week 52)
- LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks(Baseline (Week 0) up to Week 52)