A trial to learn how AZD4604 acts in the body and how safe it is in adults with asthma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

26 Sep 2024 → 15 Oct 2025

Decision date (initial)

2024-09-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Safety

To evaluate the effect of AZD4604 as
compared to placebo on gene expression in
airway epithelial cells

Secondary objectives 2

1. To evaluate the effect of AZD4604 as compared to placebo on STAT phosphorylation in the airways
2. To explore the effect of AZD4604 on cellular pathology in the airways as compared to placebo

Conditions and MedDRA coding

Asthma

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Participant must be 18 to 75 years of age inclusive at the time of signing the informed consent.
2. Documented physician-diagnosed asthma ≥ 12 months prior to screening (Visit 1)
3. Participants treated with medium-to-high dose ICS in combination with LABA at a stable dose for at least 2 months prior to Visit 1.Treatment with additional asthma controller therapies at a stable dose ≥ 2 months prior to Visit 1 is allowed. Treatment with maintenance systemic corticosteroids (oral or injectable) is not allowed.
4. A documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Visit 1 or ACQ-6 ≥ 1.5 at Visit 1.A severe asthma exacerbation is defined as a worsening of asthma that leads to any of the following: - Use of systemic corticosteroids for at least 3 consecutive days to treat symptoms of asthma worsening (a single depo-injectable dose of corticosteroids will be considered equivalent to a 3-day bolus/burst of systemic corticosteroids). - An emergency room visit (defined as evaluation and treatment for < 24 hours in an emergency department) due to asthma that required systemic corticosteroids. - An inpatient hospitalisation (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma. Acceptable documentation of a severe asthma exacerbation in this protocol is: - Documented prescription of systemic corticosteroids for at least 3 days to treat asthma worsening (a single depo-injectable dose of corticosteroids will be considered equivalent to a 3-day bolus/burst of systemic corticosteroids). In participants with an established self-management plan, documented filling of a prescription will be considered adequate. - Clinic visit or consultation (primary or specialised healthcare provider [HCP]) notes providing evidence of ≥ 1 exacerbation in the previous 12 months prior to enrolment. Telephone/remote consultations are allowable if appropriate documentation can be demonstrated. - Emergency room/hospital records that the participant attended an emergency room visit (defined as evaluation and treatment for < 24 hours in an emergency department) due to asthma that required systemic corticosteroids (as per the above). - Discharge summaries from hospital, emergency room, or urgent care facility indicating that a participant was hospitalised (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma. If participants were included based on ACQ-6 ≥ 1.5 at Visit 1, ACQ-6 must be confirmed to be ≥ 1.5 at Visit 3a prior to performing the bronchoscopy.
5. Morning pre-BD FEV1 ≥ 60% predicted at Visit 1.
6. Able to perform acceptable lung function testing for FEV1 according to American Thoracic Society/ European Respiratory Society (ATS/ERS) 2019 acceptability criteria.
7. Able and willing to undertake bronchoscopy. There should be no absolute contra-indications to bronchoscopy as outlined in the bronchoscopy manual.
8. Documented evidence of asthma as demonstrated by any of the following in the 5 years up to or including Visit 1: - Post-BD reversibility of FEV1 ≥ 12% and ≥ 200 mL, or - Average daily variability of PEF > 10% over a 2-week period, or - Variability of FEV1 > 12% and 200 mL between any 2 clinical visits, or - Positive bronchial challenge test (a positive test is defined as a fall in FEV1 from pre-challenge of ≥ 20% with standard doses of methacholine or histamine, or ≥ 15% with standardised hyperventilation, hypertonic saline, or mannitol challenge), or - Positive exercise challenge test (a positive test is defined as a fall in FEV1 of > 10% and > 200 mL from pre-challenge), or - A FeNO test with a value of ≥ 40 ppb despite confirmed ICS maintenance therapy.If documentation is not available to support any of these diagnostic criteria, and if in the opinion of the investigator the clinical diagnosis of asthma is still considered likely, the investigation and confirmation of an average daily variability of PEF > 10% over a 2-week period can also be considered as confirmatory of the diagnosis of asthma if undertaken during the screening and/or run-in periods.
9. Able and willing to comply with the requirements of the protocol including ability to read, write, be fluent in the translated language of all participant-facing questionnaires used at the study site, and use electronic devices, eg, spirometer.
10. Body weight ≥ 40 kg and body mass index < 35 kg/m2. Sex and Contraceptive/Barrier Requirements
11. Male and/or female Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. There are no restrictions on male participants or their female partners. Females not of childbearing potential are defined as females who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. The following age-specific requirements apply: - Females < 50 years old would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle-stimulating hormone (FSH) levels in the postmenopausal range. - Females ≥ 50 years old would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. - All FOCBP who are sexually active with a non-sterilised male partner must agree to use one highly effective method of birth control, as defined below, for a minimum of 3 months prior to Visit 1 and throughout the entire duration of the study, and for 1 month after the last IMP administration. Cessation of contraception after this point should be discussed with a responsible physician. A highly effective method of contraception is defined as one that can achieve a failure rate of < 1% per year when used consistently and correctly. - The following are not acceptable methods of contraception: periodic abstinence (calendar, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea. Female condom and male condom should not be used together. - All females must have a negative serum pregnancy test result at Visit 1. - Highly effective birth control methods include: total sexual abstinence (only deemed an acceptable method provided it is the usual lifestyle of the participant [defined as refraining from heterosexual intercourse during the entire period of risk associated with study]), a vasectomised partner, Implanon®, intrauterine device/levonorgestrel intrauterine system, Depo-Provera™ injections, oral contraceptive, and Evra Patch™, Xulane™, or NuvaRing®. Oral contraceptives are only highly effective when associated with inhibition of ovulation.
12. Capable of giving signed informed consent prior to any study-specific procedures as described in Appendix A, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
13. Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomics initiative research that supports the Genomic Initiative (see Appendix D 2). Additional Inclusion Criteria at Visit 3a and Visit 3c At the end of the run-in period (Visit 3a), participants must fulfil the following additional criteria in order to be randomised into the study and enter the treatment period at Visit 3c:
14. At least 70% compliance with usual asthma background medication during run-in period (from Visit 2 to Visit 3a) based on the daily asthma ePROs.
15. Minimum 70% compliance with daily electronic clinical outcome assessments. Compliance is defined as completing the daily ePRO questions and PEF measurement (morning and evening) at least 70% of the time during the 10 days preceding Visit 3a.
16. For FOCBP and females on HRT, a negative urine pregnancy test prior to IMP administration at Visit 3c.

Exclusion criteria 33

1. A severe asthma exacerbation within 8 weeks prior to Visit 1.
2. Current or prior history of alcohol or drug abuse (including marijuana), as judged by the investigator. Positive drug screening result that cannot be justified by participant’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.
3. History of malignancy other than superficial basal cell carcinoma. Prior/Concomitant Therapy
4. Treatment with systemic corticosteroid (short-term or maintenance) use within 8 weeks (oral) or 12 weeks (intramuscular) before Visit 1.
5. Any immunosuppressive therapy (including hydroxychloroquine, methotrexate, cyclosporine, and tacrolimus) within 12 weeks prior to Visit 1.
6. Treatment with marketed biologics including benralizumab, mepolizumab, reslizumab, omalizumab, dupilumab, and tezepelumab within 6 months or 5 half-lives of Visit 1, whichever is longer.
7. Inhaled corticosteroid plus fast-acting β2 agonist as a rescue medication (eg, Symbicort, Fostair, or Airsupra Maintenance and Reliever Treatment) is not allowed 30 days prior to Visit 1, during screening, run-in and baseline periods, throughout the treatment period, and preferably until 1 week after the last administration of the IMP.
8. Live, attenuated, or mRNA vaccines within 4 weeks of Visit 1
9. Immunoglobulin therapy or blood products within 4 weeks of Visit 1.
10. 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.
11. Anticoagulants (including vitamin K antagonists and Factor Xa inhibitors). Antiplatelet agents are allowable if in the opinion of the investigator they can be safely withheld for 7 days prior to the procedure. Prior/Concurrent Clinical Study Experience
12. History of herpes zoster reactivation (shingles).
13. Concurrent enrolment in another interventional clinical study.
14. Participant treated with any investigational drug within 3 months (or 5 half-lives, whichever is longer) prior to Visit 1.
15. Participants with a known hypersensitivity to AZD4604 or any of the excipients of the product.
16. Abnormal findings identified on physical examination, ECG, or laboratory testing include, but not limited to: - Alanine aminotransferase/transaminase (ALT) or aspartate aminotransferase/transaminase AST ≥ 1.5 × upper limit of normal (ULN). - Total bilirubin (TBL) ≥ ULN (unless due to known Gilbert’s disease). - Evidence of chronic liver disease. - International Normalised Ratio (INR) > 1.5. - Platelet count < 150,000 per microliter. - Abnormal vital signs, after 5 minutes of supine or sitting rest (confirmed by 1 controlled measurement), defined as any of the following: - Systolic blood pressure (BP) < 80 mmHg or ≥ 150 mmHg. - Diastolic BP < 50 mmHg or ≥ 95 mmHg. - Pulse < 50 bpm or > 100 bpm. - Signs of pulmonary oedema or volume overload. - Any clinically significant rhythm, conduction, or morphology abnormalities in the ECG including but not limited to QT interval corrected using Fridericia’s formula (QTcF) > 450 ms. In addition, any other clinically relevant abnormal findings on physical examination or laboratory testing including haematology, coagulation, serum chemistry, urinalysis, or ECG between Visit 1 and randomisation, that in the opinion of the investigator or medical monitor might compromise the safety of the participant in the study or interfere with evaluation of the IMP.
17. For female participants only – currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
18. Current smokers or participants with smoking history ≥ 10 pack-years. - Note: Pack-years are calculated as average number of cigarettes per day × number of years/20. For example, 1 pack year = 20 cigarettes smoked per day for 1 year or 10 cigarettes per day for 2 years. - Smokers with smoking history of < 10 pack-years or users of vapes or e-cigarettes, must have stopped at least 6 months prior to Visit 1.
19. Participants with a known long-term exposure to occupational asbestos, silica, radon, heavy metals, and polycyclic aromatic hydrocarbons.
20. Positive, first-degree family history of primary lung cancer.
21. Positive urine cotinine test at Visit 1 and at any timepoint throughout the study.
22. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
23. Participants with a significant COVID-19 illness within 6 months of enrolment defined as: - Participants with a diagnosis of COVID-19 pneumonia based on radiological assessment. - Participants with a diagnosis of COVID-19 requiring hospitalisation and/or oxygen supplementation therapy.
24. 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.
25. Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1.
26. Major surgery within 8 weeks prior to Visit 1, or planned inpatient surgery, major
27. Clinically important pulmonary disease other than asthma, eg, active lung infection, chronic obstructive pulmonary disease (COPD), bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, history or planned lung lobectomy, alpha-1 anti-trypsin deficiency, primary ciliary dyskinesia, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, and hyper-eosinophilic syndrome.
28. 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.
29. Any clinically significant cardiac or cerebrovascular disease: - Unstable angina, acute coronary syndrome (acute myocardial infarction, unstable angina), coronary intervention with percutaneous coronary intervention/coronary artery bypass surgery or stroke within 6 months of Visit 1. - Heart failure, New York Heart Association, Classes II to IV. - Systemic hypertension, except if well-controlled using 2 or fewer medications and stable for at least 6 months. - Untreated high degree atrioventricular block (second – third degree atrioventricular block)/significant sinus node dysfunction/pause or therapy requiring tachyarrhythmia. Participants with atrial fibrillation or flutter and optimally controlled ventricular rate at resting < 100 bpm might be included as judged by the investigator. - History or family history of long QT-syndrome or sudden cardiac death with age < 40 years old. - History of QT prolongation associated with other medications that required discontinuation of that medication. - Hypertrophic cardiomyopathy or clinically significant valvular heart disease. - Pulmonary arterial hypertension, either idiopathic or due to connective tissue or thromboembolic disease.
30. History of venous thromboembolism.
31. Participants who, as judged by the investigator, have evidence of active TB, either treated or untreated, or latent TB without completion of an appropriate course of treatment or appropriate ongoing prophylactic treatment. Evaluation will be according to the local standard of care as determined by local guidelines and may consist of history and physical examinations, chest X-ray, or TB test (eg, interferon-gamma release assay [IGRA]).
32. 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 human immunodeficiency virus (HIV). Any of the following would exclude the participant from the study: - Participants positive for hepatitis C antibody. Participants who have a positive Hepatitis C virus (HCV) antibody must be at least 12 weeks post anti-HCV treatment, if treated, and have undetectable HCV RNA levels. See SoA for details (Section 1.3). - Participants positive for hepatitis B virus (HBV) surface antigen. Participants who test positive for anti-HBV core antibody or anti-hepatitis B surface antibody during screening may continue to be screened and randomised if hepatitis B polymerase chain reaction (PCR) is confirmed negative prior to Visit 3. Positivity to hepatitis B surface antigen is a reason for exclusion. - Participants with history of infection or positivity of HIV.
33. Any history of bronchial thermoplasty.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline to end of IMP administration in expression of T2, non-T2, and JAK1-related genes and gene signatures in bronchial brushings.

Secondary endpoints 2

1. Change from baseline to end of IMP administration in STAT phosphorylation in bronchial biopsies
2. Change in number of airway cells, including but not limited to inflammatory cells, airway smooth muscle cells, and goblet cells from baseline to end of IMP administration in bronchial biopsies (cells per mm² determined by microscopic evaluation)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

3 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications