Clinical trial NCT03622112: A Study to Assess the Efficacy and Safety of Multiple Dose Levels of AZD7594 Administered Once Daily by Inhalation in Asthmatic Subjects
Official title: A Phase 2b Randomised, Double Blind, Placebo-Controlled, Parallel Arm, Multi-Centre Study to Assess Efficacy and Safety of Multiple Dose Levels of AZD7594 DPI Given Once Daily for Twelve Weeks, Compared to Placebo, in Asthmatics Symptomatic on Low Dose ICS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: Inhaled non-steroidal glucocorticoid receptor modulator
Asthma
Inhaled corticosteroids.
Glucocorticoid receptor (GA) agonists.
Chronic obstructive pulmonary disease.
Short-acting B2 agonist.
Fluticasone furoate.
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2018-08-09
Enrollment: 808
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will assess the efficacy and safety of multiple dose levels of AZD7594 administered once daily (QD) by inhalation in a 12-week treatment period on asthma subjects. The activity will be assessed by comparing AZD7594 to placebo. The comparison between active comparator (FF) and placebo will be used for bench marking. The efficacy is assessed by the evaluation of change in trough forced expiratory volume in 1 second (FEV1). The aim is to develop AZD7594 as a once daily inhaled non-steroidal selective GR modulator (SGRM), which may ultimately lead to better disease control of both chronic obstructive pulmonary disease (COPD) and asthma through improved efficacy and compliance. The overall rationale for developing a once daily AZD7594 in a dry powder inhaler (DPI) is to provide a safe and effective future treatment option for both asthma and COPD subjects.

Detailed description: This is a randomised, placebo-controlled, double-blind multi center (8 countries: Europe, United States \[US\], South Africa, and Japan) study conducted on 714 subjects (102 subject per arm) with asthma symptomatic on low dose inhaled corticosteroids (ICS). The study consists of 3 periods:

* Run-in period (21-28 days; visits 1 to 3)
* Treatment period (12-week; Visits 4 to 7)
* Follow-up (1-week; visit 8).

The Run-in period consist of 3 visits: Screening visit (1), reversibility visit (2) and randomization visit (3). All subjects will sign an informed consent form (ICF) prior to participating in any study-specific procedures. Subjects found to be eligible at Visit 1 (Screening Visit) will discontinue all asthma medications and switch to low dose budesonide (200 μg twice a day \[BID\] in Europe and 180 μg BID in US) and rescue medication will be taken as needed. Subjects on long-acting beta agonist (LABA), fixed dose combination ICS/LABA treatment or a long-acting muscarinic antagonist (LAMA) will return for Visit 2 between 2 to 7 days after Visit 1 to have a sufficient wash-out time of their asthma medications. If reversibility criteria are met at Visit 2, subjects will proceed to Visit 3 (Randomization will occur within 21 to 28 days of Visit 1). At Visit 3, subjects who remain symptomatic while on low dose budesonide will be randomized in an overall ratio of 1:1:1:1:1:1:1 to one of 7 possible treatments and will receive inhalation powder via oral route:

* AZD7594 DPI 55μg \[nominal strength\]/50 μg \[delivered dose\] (QD)
* AZD7594 DPI 99 μg/90 μg QD
* AZD7594 DPI 198 μg/180 μg QD
* AZD7594 DPI 396 μg/360 μg QD
* AZD7594 DPI 792 μg/720 μg QD
* Placebo for AZD7594 QD
* FF 100 μg QD (open-label) The follow-up will be done by telephone contact within 7 to 10 days after Visit 7 or last investigational product (IP) intake.

The total duration of the study will be between 113 to 135 days for each individual subject and is planned to run approximately 12 months (it should not exceed 18 months).

Eligibility criteria: Inclusion criteria

1. Provision of informed consent prior to any study-specific procedures 2. Men and women 18 to 85 years of age, inclusive, with body mass index (BMI)≤35 3. Subjects need to be non-smokers or ex-smokers (have quit e cigarettes or other inhaled tobacco products ≥6 months before Visit 1) with a total smoking history of less than 10 pack-years (not applicable for e cigarettes) 4. Documented clinical diagnosis of asthma for ≥6 months before Visit 1 5. Subjects on stable medium to high dose ICS (equivalent of budesonide \>400 μg/day) or low to medium dose ICS/LABA for at least 4 weeks prior to screening (Visit 1) (Appendix A, GINA, 2018) 6. Subjects must demonstrate reversibility to inhaled bronchodilators at Visit 2 (a ≥12% and ≥200 mL improvement in FEV1 after administration of a 4 puffs of salbutamol/albuterol) 7. Pre-bronchodilator FEV1 at Visit 3 between 40% and 90% predicted at either -45 or -15 minutes pre-dose 8. At Visit 3, subjects need to be symptomatic on low dose ICS as evidenced by combined daily asthma mean symptom score of \>1 over the previous 7 days or SABA use on ≥3 of the last 7 days during the Run-in Period 9. Demonstrate the ability to use the study inhalation device properly 10. Subject able to perform acceptable pulmonary function testing for FEV1 according to American Thoracic Society/European Respiratory Society (ATS/ERS) acceptability criteria 11. Subject is willing and able to follow study procedures and restrictions. Women of child bearing potential (WOCBP) should be stable on their chosen method of highly effective birth control for a minimum of 3 months prior to Visit 1, and willing to use that for the entire duration of the study (from the time they sign the informed consent), and for 1 month after the last dose of IP 12. For optional inclusion in the Gx component of the study, subjects must provide separate informed consent for the genomic sampling and analysis Exclusion criteria

1. Known or suspected hypersensitivity to any of the IPs, including budesonide, or excipients, including lactose
2. Systemic steroid use within the 6 weeks before Visit 1
3. Concomitant chronic respiratory disease (including current sleep apnea)
4. History or clinical suspicion of any clinically relevant or active disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study, or any other safety concerns in the opinion of the Investigator
5. Use of prohibited medications that cannot be stopped during the entire period of the study (starting Visit 1).
6. Subjects with \<80% eDiary compliance during Run in Period at Visit 3
7. ACQ-5 of ≥3 at Visit 1, Visit 2, or Visit 3
8. Daily rescue use of SABA ≥12 puffs for ≥3 consecutive days at any time during Run-in Period, before randomisation
9. Any clinically important abnormalities in rhythm, conduction or morphology of the digital ECG at rest and any abnormalities in the digital ECG (at Visit 1 or Visit 3) that, as considered by the Investigator, may interfere with the interpretation of QT interval corrected (QTc) interval changes
10. Prolonged QT interval corrected using Fridericia's formula (QTcF) ≥450 msec based on ECG at Visit 1 or Visit 3; or family history of long QT syndrome
11. PR (PQ) interval prolongation (\>240 msec), intermittent second or third degree atrial-ventricular (AV) block or AV dissociation at Visit 1 or Visit 3
12. Subjects with implantable cardiac defibrillator and subjects with sustained symptomatic ventricular and/or atrial tachyarrhythmia
13. Subjects with unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society Class II, or a myocardial infarction or stroke within 6 months before Visit 1
14. History of hospitalisation within 12 months before Visit 1 caused by heart failure or a diagnosis of heart failure higher than New York Heart Association Class II
15. Subjects who are positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) at Visit 1
16. Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1
17. Suspected poor capability to follow instructions of the study, as judged by the Investigator
18. Previous participation or prior screen failure in the current study, or participation in any other research study within 1 month prior to Visit 1
19. Subject under treatment with biologicals such as monoclonal antibodies or chimeric biomolecules including omalizumab, mepolizumab, and reslizumab within 6 months or 5 half-lives before Visit 1, whichever is longer
20. Subject treated with any investigational drug within 30 days (or 5 half-lives, whichever is longer) prior to Visit 1
21. Positive drug screening result that cannot be justified by subject's medical history and its relevant treatment (over-the-counter product or a valid prescription), or history of or current alcohol or drug abuse (including marijuana and marijuana-containing valid prescriptions), as judged by the Investigator
22. Planned in-patient surgery, major dental procedure or hospitalisation during the study
23. Pregnant woman or lactating woman
24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, contract research organisation staff and/or staff at the study centre)
25. Suspicion of Gilbert's syndrome
26. Vulnerable persons (eg, persons kept in detention)

Primary outcomes:
measure: Change From Baseline in Trough FEV1 at Week 12
timeFrame: At week 12
Secondary outcomes:
measure: Change From Baseline in Trough FEV1 at Weeks 2, 4, 8 and Average Over the Treatment Period
timeFrame: At week 2, 4 and 8
measure: Change From Baseline in Fractional Exhaled Nitic Oxide (FENO) at Weeks 2, 4, 8, 12 and Average Over the Treatment Period
timeFrame: At week 2, 4, 8, and 12
measure: Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 and Average Over the Treatment Period
timeFrame: At week 12
measure: Change From Baseline in Asthma Control Questionnaire -5 (ACQ-5) at Week 12 and Average Over the Treatment Period
timeFrame: At week 12
measure: Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Change From Baseline in Average Evening PEF Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Change From Baseline in Average Daily Use of Rescue Medication Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Change From Baseline in Percent Night-time Awakening Days Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Change From Baseline in Average Daily Asthma Symptom Score Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Change From Baseline in Percent Asthma Control Days Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Change From Baseline in Percent Rescue-free Days Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Change From Baseline in Percent Symptom-free Days Over the Treatment Period
timeFrame: Week 0 (7 days prior to randomisation) to Week 12
measure: Observed Maximum Concentration at Steady State (Css,Max) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Observed Minimum Concentration at the End of the Dosing Interval (Css,Min) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Time to Maximum Concentration at Steady State, Taken Directly From the Individual Concentration-time Curve (Tss, Max) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Time of Last Quantifiable Analyte Concentration (Tlast) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Area Under the Plasma Concentration-curve From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUClast) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Area Under the Plasma Concentration-curve Within a Dosing Interval (AUCτ) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Average Plasma Concentration During a Dosing Interval at Steady State (Css,Avg) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Dose Normalised Css,Max (Css,Max/D) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Dose Normalised AUCτ (AUCτ/D) of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Percentage Fluctuation of AZD7594 at Day 84
timeFrame: Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose)
measure: Change From Baseline in Area Under Plasma Cortisol Concentration-time Curve (AUEC0-24hrs Post Dose), of AZD7594 vs Placebo at Day 84
timeFrame: At Day -1 (-24 to -12 h prior to the dose on Day 0) and at Day 84 (0 to 12 hours post dose)
measure: Number of Participants With Adverse Events
timeFrame: From screening to follow-up period (7 to 10 days after visit 7)
Other outcomes:
Locations:
city: Sheffield
country: United States
facility: Research Site
state: Alabama
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: Fullerton
country: United States
facility: Research Site
state: California
city: Gold River
country: United States
facility: Research Site
state: California
city: New Haven
country: United States
facility: Research Site
state: Connecticut
city: Celebration
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Port Orange
country: United States
facility: Research Site
state: Florida
city: Winter Park
country: United States
facility: Research Site
state: Florida
city: North Dartmouth
country: United States
facility: Research Site
state: Massachusetts
city: Farmington Hills
country: United States
facility: Research Site
state: Michigan
city: Charlotte
country: United States
facility: Research Site
state: North Carolina
city: Gastonia
country: United States
facility: Research Site
state: North Carolina
city: Raleigh
country: United States
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state: North Carolina
city: Cincinnati
country: United States
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state: Ohio
city: Dublin
country: United States
facility: Research Site
state: Ohio
city: Medford
country: United States
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state: Oregon
city: Portland
country: United States
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state: Oregon
city: Spartanburg
country: United States
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state: South Carolina
city: Boerne
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Gabrovo
country: Bulgaria
facility: Research Site
city: Kozloduy
country: Bulgaria
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Ruse
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Stara Zagora
country: Bulgaria
facility: Research Site
city: Vidin
country: Bulgaria
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Dortmund
country: Germany
facility: Research Site
city: Großhansdorf
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: Marburg
country: Germany
facility: Research Site
city: Wiesbaden
country: Germany
facility: Research Site
city: Balassagyarmat
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Gödöllő
country: Hungary
facility: Research Site
city: Komló
country: Hungary
facility: Research Site
city: Miskolc
country: Hungary
facility: Research Site
city: Nyíregyháza
country: Hungary
facility: Research Site
city: Pécs
country: Hungary
facility: Research Site
city: Szazhalombatta
country: Hungary
facility: Research Site
city: Szigetszentmiklós
country: Hungary
facility: Research Site
city: Szombathely
country: Hungary
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Himeji
country: Japan
facility: Research Site
city: Kagoshima-shi
country: Japan
facility: Research Site
city: Kishiwada-shi
country: Japan
facility: Research Site
city: Naka-gun
country: Japan
facility: Research Site
city: Osaka-shi
country: Japan
facility: Research Site
city: Sakaide-shi
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
city: Yanagawa-shi
country: Japan
facility: Research Site
city: Yokohama
country: Japan
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Częstochowa
country: Poland
facility: Research Site
city: Kielce
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Ksawerów
country: Poland
facility: Research Site
city: Ostrowiec Świętokrzyski
country: Poland
facility: Research Site
city: Proszowice
country: Poland
facility: Research Site
city: Skarżysko-Kamienna
country: Poland
facility: Research Site
city: Skierniewice
country: Poland
facility: Research Site
city: Sopot
country: Poland
facility: Research Site
city: Tarnów
country: Poland
facility: Research Site
city: Bellville
country: South Africa
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Mowbray
country: South Africa
facility: Research Site
city: Port Elizabeth
country: South Africa
facility: Research Site
city: Cherkasy
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kharkiv Region
country: Ukraine
facility: Research Site
city: Kharkiv Region
country: Ukraine
facility: Research Site
city: Kharkiv Region
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Lutsk
country: Ukraine
facility: Research Site
city: Odesa
country: Ukraine
facility: Research Site
city: Poltava
country: Ukraine
facility: Research Site
city: Sumy
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
city: Zaporizhzhia
country: Ukraine
facility: Research Site
Study officials:
affiliation: Insaf - Institut für Atemwegsforschung GmbH, D65187, Germany.
name: Kai Michael Beeh, Dr med
role: PRINCIPAL_INVESTIGATOR
References: