Efficacy and Safety of Inhaled AZD1402 Administered for Four Weeks in Adults With Asthma on Medium-to-High Dose Inhaled Corticosteroids

Study Overview
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Brief Summary
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This is a randomised, placebo-controlled, double-blinded, multi-centre, 2-part study to assess the efficacy and safety of inhaled AZD1402. Part 1 will be performed in a Lead-in Cohort for each dose level to evaluate the safety and pharmacokinetics (PK) in a population with asthma controlled on medium dose inhaled corticosteroids (ICS)-long acting beta agonists (LABA) before progressing to dosing in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA in Part 2. The study will recruit participants receiving treatment with medium dose ICS with LABA for Part 1 and participants receiving treatment with medium-to-high dose ICS with LABA for Part 2 (separate inhalers or combination product). Part 2 will be initiated following evaluation of safety and PK at the relevant dose level in Part 1a. The entire study period for each participant in both Parts 1 and 2, is approximately 3.5 months; a 2-week Screening Period, a 4 week Run-in Period, 4 weeks of Treatment Period, and 4 weeks of Follow-Up Period.

Detailed Description
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Part 1 of the study will be randomised, double blind, placebo-controlled, and conducted in parallel for the 2 lower dose levels (Part 1a) followed by an unblinded safety review and escalation to the highest dose (Part 1b) dependent on the outcome of the safety review. Part 1a will consist of 30 participants who will be randomised 1:1:1 to receive 1 of the 2 lower AZD1402 dry power inhaler (DPI) doses (Dose 1 or Dose 2) or placebo in parallel. Part 1b will consist of 15 participants who will be randomised 2:1 to receive the highest AZD1402 DPI dose (Dose 3) or placebo. Part 1a Lead-in Cohort AZD1402 Dose 1 AZD1402 Dose 2 Placebo Part 1b Lead-in Cohort AZD1402 Dose 3 Placebo Part 2 will be randomised, double blind, placebo controlled and will include approximately 165 participants randomised 2:1 (active to placebo) to evaluate 2 inhaled dose levels of AZD1402 versus placebo. Part 2 will be started after the unblinded safety review for Part 1a. Part 2 will include: AZD1402 Dose 1 AZD1402 Dose 2 Placebo

Official Title
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A Two-part Phase IIa Randomised, Double-blind, Placebo-controlled, Dose-ranging, Multi-centre Study to Assess Efficacy and Safety of Inhaled AZD1402 Administered as a Dry Powder for Four Weeks in Adults With Asthma on Medium-to-High Dose Inhaled Corticosteroids

Conditions
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Asthma

Intervention / Treatment
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* Drug: AZD1402
* Drug: Placebo
* Drug: Short acting beta agonist (SABA) (rescue medication)
* Drug: Run-in medications (ICS-LABA combination)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who have a documented clinical diagnosis of asthma for ≥ 12 months before Visit 1. Participants who are able to perform acceptable pulmonary function testing for FEV1. Participants who are able to demonstrate the ability to use the study inhalation device properly. Male participants must be surgically sterile or agree to use highly-effective contraceptives. All female participants must have a negative serum pregnancy test at Screening. Female participants of non-childbearing potential, Female participants of childbearing potential must have a negative urine pregnancy test before the administration of first dose of study intervention and must agree to use a highly-effective method of birth control. Participant is a non smoker or an ex-smoker with a total smoking history of less than 10 pack-years. Only for Part 1: Documented treatment with medium dose ICS with LABA for at least 6 months prior to Screening. ICS and LABA must be on a stable dose for at least 3 months prior to Screening, during Screening and Run-in Periods and may be contained in a combination product or separate inhaler. No asthma exacerbations in last 12 months requiring oral or intravenous (IV) steroids or hospitalisation/ emergency room visit due to asthma. Pre-bronchodilator FEV1 ≥ 70% predicted at Screening and start of Run-in. Asthma Control Questionnaire 6 score of ≤ 1.0 at Screening and start of Run-in. Only for Part 2: Documented evidence of asthma. Documented treatment with medium-to-high dose ICS-LABA for at least 6 months prior to Screening. ICS and LABA must be on a stable dose for at least 4 weeks prior to Screening, during Screening and Run-in Periods. If on asthma maintenance controller medications in addition to ICS-LABA, the dose of the additional controller medications must be stable for at least 4 weeks prior to Screening, during Screening and Run-in Periods. Pre bronchodilator FEV1 of 40% to 85% (inclusive) predicted at Screening and start of Run-in. Blood eosinophil count of ≥ 150 cells/μL and FeNO ≥ 25 ppb at Screening. Asthma Control Questionnaire 6 score ≥ 1.5 at Screening. Specific Randomisation Criteria at Visit 3 For Part 1: Pre-bronchodilator FEV1 ≥ 70% predicted. At least 70% compliance with usual asthma controller ICS-LABA during Run-in Period (from Visit 2 to Visit 3) based on daily electronic diary (e-Diary). Minimum 80% compliance with ePRO completion. Asthma Control Questionnaire 6 score of ≤ 1.0. C-reactive protein < 5 mg/L on Day -1. For Part 2: Pre-bronchodilator FEV1 of 40% to 85% (inclusive) predicted. Asthma Control Questionnaire 6 score of ≥ 1.5. At least 70% compliance with usual asthma controller ICS-LABA during Run-in Period from (Visit 2 to Visit 3) based on daily e-Diary. Minimum 70% compliance with ePRO completion. C-reactive protein < 10 mg/L at Visit 2. A FeNO of ≥ 25 ppb. Exclusion Criteria: Women who are pregnant or breastfeeding, or who are planning to become pregnant during the study. Known or suspected hypersensitivity including anaphylaxis/anaphylactoid reaction following any biologic therapy, or known history of drug hypersensitivity to any component of the study intervention formulation. Evidence of any active clinically important pulmonary disease other than asthma, within 5 years at screening. History of pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts. History or clinical suspicion of any clinically relevant or active disease or disorder. History of severe COVID-19 infection requiring hospitalisation within the last 12 months or clinical history compatible with long COVID (symptoms beyond 12 weeks of acute infection). Confirmed symptomatic COVID-19 infection during Screening, Run-in or prior to randomisation. Current malignancy or history of malignancy. Significant history of recurrent or ongoing 'dry eye'. Diagnosis of Sjögren's syndrome. High risk of infection suggesting abnormal immune function. History of, or known significant infection or positivity at Screening period, including hepatitis B or C, or human immunodeficiency virus (HIV). Evidence of active tuberculosis. Clinically significant lower respiratory tract infection not resolved within 4 weeks prior to Screening and during Run-in. Clinically significant upper respiratory tract infection at Screening and during Run-in. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained. Any clinically important ECG abnormalities. Any clinically significant cardiac disease. Uncontrolled hypertension. History of life-threatening asthma attack or asthma attack requiring ventilation. Part 2 only: History of 3 or more severe asthma exacerbations. Daily rescue use of SABA ≥ 8 puffs for ≥ 3 consecutive days at any time during Run-in Period, before randomisation. History of anaphylaxis. Any clinically significant abnormalities in haematology. Alanine aminotransferase or AST level ≥ 3 times the upper limit of normal (ULN), confirmed by repeated testing during Screening Period. History of, drug or alcohol abuse within the past 2 years prior to Screening. Planned in-patient surgery, major dental procedure or hospitalisation during the study. Prior/Concomitant Therapy: Systemic corticosteroid use, AZD1402, marketed or investigational biologicals such as monoclonal antibodies or chimeric biomolecules, investigational nonbiologic drug within 60 days prior to Screening and during Run-in, any immunosuppressive therapy, Live or attenuated vaccine within 4 weeks of Screening and during Run-in, Receipt of COVID-19 vaccine (vaccine or booster dose) within 30 days prior to randomisation, Immunoglobulin or blood products within 4 weeks of Screening and during Run-in, Any immunotherapy within 3 months of Screening and during Run-in. Part 1 only: Additional asthma maintenance controller medications in addition to ICS-LABA (eg, leukotriene receptor inhibitors, theophylline, LAMA, chromones) within 3 months of Screening period and during Run-in.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 and Part 2: AZD1402 Dose 1<br>Randomised participants will receive oral inhalation of AZD1402 Dose 1 via DPI. | Drug: AZD1402<br>* Randomised participants will receive oral inhalation of AZD1402, via DPI.<br>Drug: Short acting beta agonist (SABA) (rescue medication)<br>* In addition to study intervention, all participants will be provided with a SABA as rescue medication (eg, salbutamol/albuterol), to be used throughout the Run-in and Treatment Periods. All participants should refrain from taking a SABA as rescue medication 6 hours prior to pulmonary function tests. Dosage levels: 100 μg per nominal dose 90 μg per nominal dose pro re nata (as required) (PRN)<br>Drug: Run-in medications (ICS-LABA combination)<br>* During the Run-in Period, the participants are required to maintain on their ICS-LABA dose. Controller medications (eg, ICS LABA) should remain at a stable dose and be taken after study intervention as applicable. These drugs are used as standard of care.<br>|
| Experimental: Part 1 and Part 2: AZD1402 Dose 2<br>Randomised participants will receive oral inhalation of AZD1402 Dose 2 via DPI. | Drug: AZD1402<br>* Randomised participants will receive oral inhalation of AZD1402, via DPI.<br>Drug: Short acting beta agonist (SABA) (rescue medication)<br>* In addition to study intervention, all participants will be provided with a SABA as rescue medication (eg, salbutamol/albuterol), to be used throughout the Run-in and Treatment Periods. All participants should refrain from taking a SABA as rescue medication 6 hours prior to pulmonary function tests. Dosage levels: 100 μg per nominal dose 90 μg per nominal dose pro re nata (as required) (PRN)<br>Drug: Run-in medications (ICS-LABA combination)<br>* During the Run-in Period, the participants are required to maintain on their ICS-LABA dose. Controller medications (eg, ICS LABA) should remain at a stable dose and be taken after study intervention as applicable. These drugs are used as standard of care.<br>|
| Experimental: Part 1: AZD1402 Dose 3<br>Randomised participants will receive oral inhalation of AZD1402 Dose 3 via DPI. | Drug: AZD1402<br>* Randomised participants will receive oral inhalation of AZD1402, via DPI.<br>Drug: Short acting beta agonist (SABA) (rescue medication)<br>* In addition to study intervention, all participants will be provided with a SABA as rescue medication (eg, salbutamol/albuterol), to be used throughout the Run-in and Treatment Periods. All participants should refrain from taking a SABA as rescue medication 6 hours prior to pulmonary function tests. Dosage levels: 100 μg per nominal dose 90 μg per nominal dose pro re nata (as required) (PRN)<br>Drug: Run-in medications (ICS-LABA combination)<br>* During the Run-in Period, the participants are required to maintain on their ICS-LABA dose. Controller medications (eg, ICS LABA) should remain at a stable dose and be taken after study intervention as applicable. These drugs are used as standard of care.<br>|
| Placebo Comparator: Part 1 and Part 2: Placebo<br>Randomised participants will receive oral inhalation of matching placebo via DPI. | Drug: Placebo<br>* Randomised participants will receive oral inhalation of matching placebo via DPI.<br>Drug: Short acting beta agonist (SABA) (rescue medication)<br>* In addition to study intervention, all participants will be provided with a SABA as rescue medication (eg, salbutamol/albuterol), to be used throughout the Run-in and Treatment Periods. All participants should refrain from taking a SABA as rescue medication 6 hours prior to pulmonary function tests. Dosage levels: 100 μg per nominal dose 90 μg per nominal dose pro re nata (as required) (PRN)<br>Drug: Run-in medications (ICS-LABA combination)<br>* During the Run-in Period, the participants are required to maintain on their ICS-LABA dose. Controller medications (eg, ICS LABA) should remain at a stable dose and be taken after study intervention as applicable. These drugs are used as standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of participants with adverse events (AEs) | To evaluate the safety and tolerability of AZD1402 compared to placebo at different dose levels in adults with asthma controlled on medium dose ICS-LABA. Safety and tolerability variables included AEs/ adverse events of special interest (AESIs) / serious adverse events (SAEs), vital signs (blood pressure and pulse rate), changes in clinical chemistry, haematology, and coagulation parameters, Immuno-biomarkers, Electrocardiograms (ECGs), Forced expiratory volume in 1 second (FEV1) and fractional exhaled nitric oxide (FeNO). | From Day 1 until Follow-up (Day 56 ± 4) | 
| Part 2: Change from baseline in pre-bronchodilator FEV1 at Week 4 | To investigate the efficacy of inhaled AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. | Baseline and Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and Part 2: Maximum observed serum (peak) drug concentration (Cmax) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Time to reach peak or maximum observed concentration or response following drug administration (tmax) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Observed lowest drug concentration reached before the next dose is administered (pre-dose) (Ctrough) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Terminal rate constant, estimated by log-linear least squares regression of the terminal part of the concentration-time curve (λz) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Area under the plasma concentration-curve from zero to the last quantifiable concentration (AUClast) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Area under plasma concentration-time curve in the dosing interval (AUCτ) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Area under the plasma concentration time curve in the dosing interval τ divided by the dose administered (Dose normalised AUCτ) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Maximum observed plasma (peak) drug concentration divided by the dose administered (Dose normalised Cmax) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Time of last observed (quantifiable) concentration (tlast) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Accumulation ratio for AUCτ (Rac AUC) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Accumulation ratio for Cmax (Rac Cmax) | To investigate the PK profile of AZD1402 (Part 1: full profile in all participants; Part 2: sparse in all, full profile in a subset of participants in each treatment arm). | Day 1 until Day 56 ± 4 | 
| Part 1 and Part 2: Antidrug antibodies (ADA) titers testing for all ADA-positive samples as measure of immunogenicity | To investigate the immunogenicity of AZD1402. | Day 1 until Day 56 ± 4 | 
| Part 2: Change from baseline in pre bronchodilator FEV1 average over the 4-week Treatment Period | To further investigate the efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. | Baseline, 4 weeks | 
| Part 2: Change from baseline in Asthma control questionnaire-6 (ACQ-6) at Week 4 and average over the Treatment Period | To further investigate the efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. The ACQ was developed to measure asthma control. In the ACQ-6, participants will be asked to recall how their asthma has been during the previous week by responding to one bronchodilation use question and 5 symptom questions. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Higher scores indicated worse outcome. The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.75 and ≤ 1.5 indicate partly controlled asthma, and scores > 1.5 indicate not well-controlled asthma. Individual changes of at least 0.5 are considered clinically meaningful. | Baseline, Week 4 | 
| Part 2: Proportion of participants with a decrease in ACQ 6 score of ≥ 0.5 from baseline to Week 4 | To further investigate the efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. The ACQ was developed to measure asthma control. In the ACQ-6, participants will be asked to recall how their asthma has been during the previous week by responding to one bronchodilation use question and 5 symptom questions. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Higher scores indicated worse outcome. The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between 0.75 and ≤ 1.5 indicate partly controlled asthma, and scores > 1.5 indicate not well-controlled asthma. Individual changes of at least 0.5 are considered clinically meaningful. | Baseline, Week 4 | 
| Part 2: Change from baseline in average morning Peak expiratory flow (PEF) over the Treatment Period | To further investigate the efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. Peak expiratory flow will be measured by the participant at home using a peak flow meter. | Baseline, 4 weeks | 
| Part 2: Change from baseline in average evening PEF over the Treatment Period | To further investigate the efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. Peak expiratory flow will be measured by the participant at home using a peak flow meter. | Baseline, 4 weeks | 
| Part 2: Change from baseline in daily average asthma symptom score (AM/PM) over the Treatment Period | To further investigate the efficacy of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. Severity scores for asthma symptoms will be recorded twice daily in the morning and evening and documented in the e-Diary. Asthma symptom scores during night-time and day-time will be assessed by the participant each morning and evening according to the following scoring system: 0: You have no asthma symptoms. You are aware of your asthma symptoms but you can easily tolerate the symptoms. Your asthma is causing you enough discomfort to cause problems with normal activities (or with sleep). You are unable to do your normal activities (or to sleep) because of your asthma. Higher scores indicated worse outcome. | Baseline, 4 weeks | 
| Part 2: Change from baseline in fractional exhaled nitric oxide (FeNO) (in-clinic) at Week 4 and average over the Treatment Period | To investigate the effect of AZD1402 compared to placebo on airway inflammation in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. To investigate the effect of AZD1402 on airway inflammation, the measurement of FeNO will be performed in accordance with ATS/ERS guidelines. Standardised conditions with regard to exhalation flow rate and duration of exhalation will be followed such that plateau definition can be evaluated over a minimum of 3 seconds. The concentration of FeNO will be measured in units of part per billion (ppb). | Baseline, Week 4 | 
| Part 2: Number of participants with adverse events (AEs) | To evaluate the safety and tolerability of AZD1402 compared to placebo in adults with asthma who are uncontrolled on medium-to-high dose ICS-LABA. Safety and tolerability variables included AEs/AESIs/SAEs, vital signs (blood pressure and pulse rate), changes in clinical chemistry, haematology, and coagulation parameters, Immuno-biomarkers, ECGs, FEV1 and FeNO. | From Day 1 until the Follow-up (Day 56 ± 4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD1402, placebo, Anticalin® protein, dry powder inhaler, inhaled corticosteroids, efficacy, safety