Clinical trial NCT02479412: A Multiple Dosing (14 Days) Study to Assess Efficacy and Safety of Three Dose Levels of AZD7594, Given Once Daily by Inhalation, in Patients With Mild to Moderate Asthma
Official title: A RANDOMIZED, DOUBLE BLIND, MULTIPLE DOSING (14 DAYS), PLACEBO-CONTROLLED, INCOMPLETE BLOCK CROSSOVER, MULTI CENTER STUDY TO ASSESS EFFICACY AND SAFETY OF THREE DOSE LEVELS OF AZD7594, GIVEN ONCE DAILY BY INHALATION, IN PATIENTS WITH MILD TO MODERATE ASTHMA
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Efficacy
Safety
Keywords: Mild to moderate asthma
FEV1
efficacy
safety
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2015-06-24
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This study will be a randomised, double-blind, multiple dose (14 days), placebo-controlled, multi-center study to assess efficacy and safety of three dose levels of AZD7594, given once daily by inhalation, in patients with mild to moderate asthma.

Detailed description: This is a randomized, double-blind, multiple dosing (14 ± 1 days), placebo-controlled, incomplete block crossover, multi-center study to assess efficacy and safety of 3 dose levels of AZD7594, given once daily by inhalation, in patients with mild to moderate asthma.

This multi-center study will be conducted at multiple sites in Europe. It is planned that approximately 48 patients with mild to moderate asthma will be randomized into the study

Eligibility criteria: Inclusion Criteria:

* Body mass index of 18 to 35 kg/m2
* Men and women 18 to 75 years of age, inclusive
* Patients need to be non-smokers or ex-smokers (quit ≥ 6 months before the Visit 1) with total smoking history of \< 10 pack years
* Documented clinical diagnosis of asthma for ≥ 6 months before the Visit 1
* Patients on low-dose inhaled corticosteroids (ICS) (equivalent of budesonide ≤ 400 μg per day) or low-dose ICS/long-acting β-2 agonist (LABA), or not on any inhaled steroids, or patients on montelukast
* Patients should be controlled on low dose budesonide during the first 14 ±2 days of Run-in Part 1, i.e., they need to have ACQ-5 of ≤ 1.5 at Visit 2.
* Prebronchodilator FEV1 at Visit 3 should be between 40% and 90% of predicted (mean of 2 predose measurements taken 30 minutes apart).
* All patients need to have FeNO concentrations of ≥ 25 parts per billion at Visit 3
* Demonstrate the ability to use the study inhalation device properly
* Women must be of nonchildbearing potential defined as meeting 1 of the following criteria:

  * Permanently or surgically sterilized, including hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy
  * Postmenopausal; aged ≤ 50 years and have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range
  * Postmenopausal; aged \> 50 years and have been amenorrheic for 12 months or more, following cessation of all exogenous hormonal treatments
* Male patients should be willing to use a condom to prevent pregnancy and exposure of a female partner to AZD7594 and should refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the last dose of IMP.

Exclusion Criteria:

* Known or suspected hypersensitivity to the IMPs or excipients, including lactose
* Systemic steroid use in the 6 weeks before Visit 1
* Any active disease other than asthma
* Patients on medium to high-dose ICS (equivalent of budesonide \> 400 μg per day) or on inhaled anticholinergic combination within the 6 weeks prior to Visit 1
* Compliance with the eDiary of at least 80% of the days is expected in both Run-in and Treatment Periods. Patients with \< 80% eDiary compliance during Run-in Periods would not be randomized
* Treatment with biologicals such as monoclonal antibodies or chimeric biomolecules including omalizumab within 6 months or 5 half-lives before Visit 1, whichever is longer
* History or clinical suspicion of any clinically relevant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study, or any other safety concerns in the opinion of the Investigator
* ACQ-5 ≥ 3 at any time between Visits 1 and 3
* Any contraindication against the use of vagolytic or sympathomimetic drugs as judged by the Investigator.
* Patients with hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus (HIV)
* Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1
* Pregnant woman or a nursing mother
* Suspicion of Gilbert's syndrome
* Vulnerable persons (e.g., persons kept in detention)
* ACQ-5 of ≥ 3 or daily rescue use of ≥ 12 puffs for ≥ 3 consecutive days during the enrollment period
* Hypersensitivity to the active substance or to any of the excipients of the Run-in medication (i.e., budesonide)

Primary outcomes:
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) on Day 15
timeFrame: On Day 1 (pre-dose) and on Day 15 in each period
Secondary outcomes:
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) on Day 8
timeFrame: On Day 1 (pre-dose) and on Day 8 in each period
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) on Day 15
timeFrame: On Day 1 (pre-dose) and on Day 15 in each period
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) on Day 8
timeFrame: On Day 1 (pre-dose) and on Day 8 (pre-dose) in each period
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Trough Forced Vital Capacity (FVC) on Day 15
timeFrame: On Day 1 (pre-dose) and on Day 15 (pre-dose) in each period
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Trough Forced Vital Capacity (FVC) on Day 8
timeFrame: On Day 1 (pre-dose) and on Day 8 (pre-dose) in each period
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Morning Peak Expiratory Flow (mPEF) Before Administration Over the Treatment Period
timeFrame: Every morning at pre-dose from Day 1 to Day 15
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Evening Peak Expiratory Flow (ePEF) Before Administration Over the Treatment Period
timeFrame: Every evening from Day 1 to Day 14 in each period
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline in Average Daily Use of Rescue Salbutamol Over the Treatment Period
timeFrame: Every day from Day 1 to Day 15 (from evening of Day 1 to morning of Day 15)
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline to Day 15 in Asthma Control Questionnaire-5
timeFrame: At baseline and on Day 15 in each period
measure: Efficacy of AZD7594 by Assessment of the Change From Baseline to Day 8 in Asthma Control Questionnaire-5
timeFrame: At baseline and on Day 8 in each period
measure: Efficacy of AZD7594 by Assessment of Night-time Awakenings
timeFrame: At baseline and from Day 2 to Day 15 in each period
measure: Efficacy of AZD7594 by Assessment of Daily Symptom Score
timeFrame: At baseline and from Day 1 to Day 14 in each period
measure: Efficacy of AZD7594 by Assessment of Asthma Control Days
timeFrame: At baseline and from Day 1 to Day 14 post-dose in each period
measure: Number of Participants With Adverse Events
timeFrame: From Screening to Follow-up (these two examinations are up to 165 days apart)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 by Assessment of Cmax of AZD7594
timeFrame: On Day 1 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 by Assessment of AUC(0-4) of AZD7594
timeFrame: On Day 1 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cmax,ss of AZD7594
timeFrame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of AUC(0-24) of AZD7594
timeFrame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of AUC(0-last) of AZD7594
timeFrame: On Day 1 and Day 14 in each period (in participants with intensive pharmacokinetic assessments, on Day 1 at pre-dose and 15 and 30 minutes, and 1, 2 and 4 h post-dose, on Day 14 at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 by Assessment of Tmax of AZD7594
timeFrame: On Day 1 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Tmax,ss of AZD7594
timeFrame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cavg,ss of AZD7594
timeFrame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cmax/D of AZD7594
timeFrame: On Day 1 in each period
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of AUC(0-24)/D of AZD7594
timeFrame: On Day 14 in each period
measure: Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cmin of AZD7594
timeFrame: On Day 14 at pre-dose in each period
Other outcomes:
Locations:
city: Sofia
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: Frankfurt
country: Germany
facility: Research Site
city: Großhansdorf
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: Wiesbaden
country: Germany
facility: Research Site
Study officials:
affiliation: PAREXEL International GmbH, Berlin, Germany
name: Rainard Fuhr, Dr. med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Pneumologisches Studienzentrum, Berlin, Germany
name: Ulrike Westerhausen, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: IKF Pneumologie GmbH, Frankfurt, Germany
name: Oliver Kornmann, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Insaf GmbH, Wiesbaden, Germany
name: Jutta Beier, Dr. med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Research Hamburg GmbH, Hamburg, Germany
name: Christine Grigat, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: KLB Gesundheitsforschung Lübeck GmbH, Lübeck, Germany
name: Andrea Ludwig-Sengpiel, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University hospital of Bonn, Department of Internal Medicine II, Bonn, Germany
name: Dirk Skowasch, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Pneumologisches Forschungsinstitut an der LungenClinic Großhansdorf, Großhansdorf, Germany
name: Anne-Marie Kirsten, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: COMAC Medical Ltd., Sofia, Bulgaria
name: Tanya Kralimarkova, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Praxis für Lungen- und Bronchialheilkunde, Allergologie und Umweltmedizin
name: Anneliese Linnhoff, Dr. med.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hamburger Institut für Therapie Forschung GmbH
name: Margret Jandl, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brown MN, Fuhr R, Beier J, Su HL, Chen Y, Forsman H, Hamren UW, Jackson H, Aggarwal A. Efficacy and safety of AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, in patients with asthma: a phase 2a randomized, double blind, placebo-controlled crossover trial. Respir Res. 2019 Feb 18;20(1):37. doi: 10.1186/s12931-019-1000-7.