Clinical trial NCT02898662: AZD1419 Ph2a Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: inhaled
TLR9 agonist
withdrawal design
loss of control
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2016-09-13
Enrollment: 81
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 Treatment is initiated on top of their ICS/LABA controller medication, which is then tapered down and withdrawn during a period of 3 weeks and during the last 3 weeks of treatment the study drug is given as monotherapy.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 Prior to the 7th dose of the study drug the LABA is withdrawn.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of their ICS, dose 8 is given on top of 50% of the ICS dose, which is then tapered down to 25% the following week and withdrawn completely prior to dose 10 of the study drug.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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Events for Time to Loss of Asthma Control (LOAC) up to Week 52 - Cox Regression Analysis
timeFrame: Baseline (Week 0) up to Week 52
Secondary outcomes:
measure: Number of Participants Experiencing LOAC up to Week 52 - Generalized Estimating Equation Analysis
timeFrame: Baseline (Week 0) up to Week 52
measure: Least Squares (LS) Mean ACQ-5 Score Over 52 Weeks
timeFrame: Baseline (Week 0) up to Week 52
measure: LS Mean Asthma Daily Diary Score (Weekly Total) Over 52 Weeks
timeFrame: Baseline (Week 0) up to Week 52
measure: Number of Participants With Events for Time to Moderate Or Severe Exacerbation up to Week 52
timeFrame: Baseline (Week 0) up to Week 52
measure: Percentage of Participants Using Reliever Medication up to Week 52
timeFrame: Baseline (Week 0) up to Week 52
measure: LS Mean Pre- and Post-Bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) Over 52 Weeks
timeFrame: Baseline (Week 0) up to Week 52
measure: LS Mean Total PEF (Weekly) Over 52 Weeks
timeFrame: Baseline (Week 0) up to Week 52
measure: LS Mean Fractional Exhaled Nitric Oxide (FeNO) (Weekly) Over 52 Weeks
timeFrame: Baseline (Week 0) up to Week 52
Other outcomes:
Locations:
city: Hvidovre
country: Denmark
facility: Research Site
city: København NV
country: Denmark
facility: Research Site
city: Naestved
country: Denmark
facility: Research Site
city: Odense C
country: Denmark
facility: Research Site
city: Balassagyarmat
country: Hungary
facility: Research Site
city: Edelény
country: Hungary
facility: Research Site
city: Farkasgyepü
country: Hungary
facility: Research Site
city: Miskolc
country: Hungary
facility: Research Site
city: Törökbálint
country: Hungary
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Lubin
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Linköping
country: Sweden
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
Study officials:
References: