Phase 2a Study to Assess the Efficacy and Safety of AZD4604 in Adult Patients With Moderate-to-Severe Asthma Uncontrolled on Medium-High Dose ICS-LABA

Study Overview
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Brief Summary
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This is a Phase 2a, multicentre, randomised, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy, safety and PK of AZD4604 administered BID using a dry-powder inhaler at one dose level over a 12-week Treatment period in adult participants with uncontrolled moderate-to-severe asthma.

Official Title
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A Phase 2a Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AZD4604 Twice Daily for Twelve Weeks in Adult Patients With Moderate-to-Severe Asthma Uncontrolled on Medium-High Dose ICS-LABA

Conditions
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Asthma

Intervention / Treatment
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* Drug: AZD4604
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 80 years of age inclusive, at the time of signing the informed consent. Treated with medium-high dose ICS in combination with LABA at a stable dose for at least 3 months prior to Visit 1. Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Visit 1. Morning pre-BD FEV1 between ≥ 40% and ≤ 90% predicted at Visit 1 and Visit 3. Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria. Documented evidence of asthma in the 10 years up to or including Visit 1. An ACQ-6 score ≥ 1.5 at Visit 1 and at Visit 3. 9. Body weight of ≥ 40 kg and body mass index of < 35 kg/m2. 10. Male and/or female: Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. At the end of the Run-in period (Visit 3), participants must fulfil the following additional criteria in order to be randomised into the study and enter the Treatment period: Pre-BD FEV1 between ≥ 40% and ≤ 90% predicted. A pre-BD/pre-IMP dose FEV1 at Visit 3 that has not increased or decreased by 20% or more from the pre-BD FEV1 recorded at Visit 1 and at Visit 2. An ACQ-6 score of ≥ 1.5. At least 80% compliance with usual asthma background medication during Run-in period (from Visit 2 to Visit 3) based on the daily asthma ePROs. Minimum 80% compliance with daily eCOAs (electronic Clinical Outcome Assessments) during the Run-in period and during the 14 days preceding Visit 3. For female participants, a negative urine pregnancy test prior to administration of IMP. Exclusion Criteria: A severe asthma exacerbation within 8 weeks prior to randomisation. History of herpes zoster reactivation. Participants with a significant COVID-19 illness within 6 months of enrolment. Clinically important pulmonary disease other than asthma. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and could: affect the safety of the participant throughout the study, influence the findings of the study or the interpretation, or impede the participant's ability to complete the entire duration of study. Any clinically significant cardiac or cerebrovascular disease. History of venous thromboembolism. Participants who, as judged by the investigator, have evidence of active TB, or latent TB without completion of an appropriate course of treatment or appropriate ongoing prophylactic treatment. Participants with a recent history of, or who have a positive test for, infective hepatitis or unexplained jaundice, or participants who have been treated for hepatitis B, hepatitis C, or HIV. Current or prior history of alcohol or drug abuse (including marijuana), as judged by the investigator. History of malignancy other than superficial basal cell carcinoma. Treatment with systemic corticosteroid within 4 weeks (oral) or 8 weeks (intramuscular) before Visit 1. Any immunosuppressive therapy within 12 weeks prior to Visit 1. Treatment with marketed biologics within 6 months of Visit 1 or 5 half-lives, whichever is longer. Inhaled corticosteroid plus fast-acting β2 agonist as a reliever is not allowed 15 days prior to Visit 1, during Screening/Run-in and throughout the Treatment period and preferably 1 week after the last dose of IMP. Live, attenuated, or mRNA vaccines within 4 weeks of Visit 1. Immunoglobulin or blood products within 4 weeks of Visit 1. Any immunotherapy within 6 months of Visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to Visit 1 and expected to continue through to the end of the Follow-up period. Participant treated with any investigational drug within 4 months or 5 half-lives, whichever is longer, prior to Visit 1. Participants with a known hypersensitivity to AZD4604 or any of the excipients of the product. Abnormal findings identified on physical examination, ECG, or laboratory testing. For female participants only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding. Current smokers or participants with smoking history ≥ 10 pack-years. Participants with a known long-term exposure to occupational asbestos, silica, radon, heavy metals, and polycyclic aromatic hydrocarbons. Positive family history of lung cancer. Positive urine cotinine test or exhaled carbon monoxide test at Visit 1 and at any timepoint throughout the study. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>AZD4604 | Drug: AZD4604<br>* AZD4604<br>|
| Placebo Comparator: Arm 2<br>Placebo | Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first CompEx Asthma event | CompEx Asthma is a composite surrogate endpoint for exacerbations that captures: - acute worsening events based on a combination of events based on ePRO data (asthma symptoms and rescue medication use), PEF data, and severe asthma exacerbation events. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-BD FEV1 | Change from baseline in pre-bronchodilator forced expiratory volume in 1 second. | 12 weeks | 
| CAAT | Change from baseline in the Chronic Airways Assessment Test (CAAT). The CAAT is an 8-item patient-reported outcome measure developed to measure health status in patients with asthma and COPD. | 12 weeks | 
| ACQ-6 | Change from baseline in the Asthma Control Questionnaire 6 (ACQ-6). The ACQ-6 has 6 questions (regarding asthma symptoms and rescue bronchodilator use). Answering the questions results in a score out of 6. A Score of 0 indicates complete control and 6 reflects severely uncontrolled disease. | 12 weeks | 
| Average morning and average evening PEF | Change from baseline in average morning and evening Peak Expiratory Flow (PEF) measurement. | 12 weeks | 
| Daily asthma symptom score (total, daytime, and night-time) | Change from baseline in Daily asthma symptom score. Asthma symptoms are assessed (0 to 3 scale) twice daily, once in the morning and once in the evening. | 12 weeks | 
| Time to first CompEx acute worsening event | Time to first CompEx Asthma acute worsening event. | 12 weeks | 
| CompEx event rate | The number of CompEx Asthma events recorded in the 12-week period. | 12 weeks | 
| CompEx acute worsening event rate | The number of CompEx Asthma acute worsening events recorded in the 12-week period. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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asthma, Janus kinase inhibitor