Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma (FLASH)

AstraZeneca

Status and phase: Enrolling; Phase 2

Conditions: Asthma

Treatments: Drug: Atuliflapon; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT05251259

2021-003338-35 (EudraCT Number)

D7552C00001

2023-509243-27-00 (Other Identifier)

Details and patient eligibility

About

This is a randomised, placebo-controlled, double-blind study to assess the efficacy and safety of Atuliflapon administered once daily over a 12-week treatment period to adult participants with moderate to severe uncontrolled asthma.

Full description

The study will enroll participants with moderate to severe uncontrolled asthma who are on low-dose inhaled corticosteroid (ICS) - a long-acting beta-agonist (LABA) or medium-to-high-dose ICS with or without LABA background treatment.

The study will be initiated by Lead-in pharmacokinetics (PK) cohort in asthma participants. Participant will be randmised globally, includig particpants in Lead-in PK cohort and in Part 1 of the study.

In the Lead-in PK cohort, participants will be randomised to Atuliflapon or placebo (recruitment completed).

In Part 1 of the study, participants will be stratified based on high or low levels of biomarker at screening (Visit 1) and randomised 1:1 to Atuliflapon or placebo. An event-driven interim analysis will be performed once 30 participants with at least 1 CompEx (Composite endpoint for Exacerbations) event are observed in the group having high levels of biomarker.

Enrollment: 666 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

Lead-in PK Cohort:

• 18 to 55 years of age inclusive at the time of signing the informed consent at screening Visit 1.
• Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m^2 (inclusive) at screening Visit 1.
• Documented asthma diagnosis ≥12 months prior to screening Visit 1.
• Able to perform acceptable lung function testing for FEV1 according to American Thoracic Society / European Respiratory Society (ATS/ERS) 2019 acceptability criteria.
• Morning pre- bronchodilator (BD) forced expiratory volume (FEV)1 ≥ 40% predicted at screening Visit 1 and Visit 2.
• Treated with low dose inhaled corticosteroid plus long-acting β2-agonist (ICS-LABA) or medium-high dose ICS alone or in combination with LABA at a stable dose for at least 3 months prior to screening Visit 1. Also, treatment with additional asthma controller therapies (eg, LAMA) at a stable dose ≥ 3 months prior to screening Visit 1 is allowed.
• Participant's influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2.

General Inclusion Criteria for Part 1:

• Body weight ≥ 40 kg and body mass index (BMI) < 35 kg/m^2.
• Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to screening Visit 1.
• Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria.
• Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at screening Visit 1 and Visit 3.
• An Asthma Control Questionnaire (ACQ)-6 score ≥ 1.5 at screening Visit 1 and at Visit 3.

Exclusion Criteria

• A severe asthma exacerbation within 8 weeks of screening (visit 1) or within 12 weeks of randomisation (Visit 3).
• A positive test result of an approved antigen test (confirmed by a positive RT-PCR test) or a positive RT-PCR test for SARS-CoV-2, the virus responsible for COVID-19, at screening Visit 1 or at Visit 2 for the PK Lead-in cohort. For Part 1 the testing will be done at Visit 3. Results from the mandatory tests at Visit 2 (PK Lead-in cohort) and Visit 3 (Part 1) must not be older than 48 hours and must be available before randomisation.
• 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.
• Any clinically significant cardiac disease.
• History of severe renal disease or history of creatinine clearance < 30 mL/min × m2 calculated using Cockcroft-Gault equation.
• Severe hepatic impairment (Child-Pugh class C).
• Previous hepatotoxicity related to zileuton or leukotriene receptor antagonist (LTRAs) (eg montelukast).
• 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).
• Evidence of active or untreated latent tuberculosis (TB).
• Current or history of alcohol or drug abuse (including marijuana).
• Current diagnosis of cancer, not including in-situ or non-melanoma skin cancer or other previous malignancies where curative therapy was completed at least 5 years prior to screening Visit 1.
• Clinically important ongoing or previous psychiatric disease, especially suicidal behaviour, that in the opinion of the investigator might compromise the safety of the participant in the study.
• Treatment with any serum creatinine-altering drugs within 1 month prior to screening Visit 1 including but not limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins.
• Treatment with systemic corticosteroid use within 8 weeks (oral) or 12 weeks (intramuscular) before screening (Visit 1) or 12 weeks (oral) or 16 weeks (IM) before randomization (Visit 3).
• Treatment with marketed biologics including benralizumab, mepolizumab, reslizumab, omalizumab, and dupilumab within 6 months of screening Visit 1 or 5 half-lives whichever is longer.
• Treatment with 5-lipoxygenase inhibitors (eg zileuton or other 5-LO inhibiting supplements) within 6 weeks prior to Visit 0 and within 8 weeks prior to Visit 1).Treatment with LTRAs (eg, montelukast) within 2 weeks prior to Visit 0 and within 4 weeks prior to screening Visit 1.
• Inhaled corticosteroid + fast-acting β2 agonist as a reliever (eg Symbicort or Fostair Maintenance and Reliever Treatment) is not allowed 15 days prior to screening Visit 1, during screening (Visit 1)/run-in and the treatment period and preferably 1 week after the last dose of study intervention.
• Live or attenuated vaccines within 4 weeks of screening Visit 1.
• Immunoglobulin or blood products within 4 weeks of screening Visit 1.
• Treatment with Gemfibrozil within 4 weeks of screening Visit 1.
• Any immunotherapy within 6 months of screening Visit 1, except for stable maintenance dose allergen-specific immunotherapy started at least 4 weeks prior to screening Visit 1 and expected to continue through to the end of the follow-up period.
• Potent inducers/inhibitors of cytochrome P450 3A4 within 4 weeks of screening Visit 1.
• Treatment with simvastatin, lovastatin, and atorvastatin at doses > 40 mg per day within 1 month prior to screening Visit 1. Treatment with sensitive cytochrome 3A substrates with narrow therapeutic window should be avoided from randomization to study drug.
• For female participants on ethinyl oestradiol containing combined oral contraceptives.
• Concurrent enrolment in another clinical study.
• Previous participation in the current clinical study.
• Participant treated with any investigational drug within 4 months prior to screening Visit 1.
• Known history of allergy or reaction to any component of the study intervention formulation.
• For female participants only: Currently pregnant or breast-feeding.
• Smokers with smoking history of < 10 pack-years or users of vaping or e-cigarettes, must have stopped at least 6 months prior to screening Visit 1.
• Involvement in the planning and/or conduct of the study.
• Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before screening Visit 1.
• Major surgery within 8 weeks prior to screening Visit 1, or planned inpatient surgery, major dental procedure or hospitalisation during the screening (Visit 1), treatment or follow-up periods.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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666 participants in 3 patient groups, including a placebo group

Lead-in PK Cohort (Atuliflapon)

Experimental group

Description:

Randomised participants will receive Atuliflapon

Treatment:

Drug: Atuliflapon

Part 1: Atuliflapon

Experimental group

Description:

Randomised participants will receive Atuliflapon

Treatment:

Drug: Atuliflapon

Lead-in PK, Part 1 Placebo

Placebo Comparator group

Description:

Randomised participants will receive placebo

Treatment:

Drug: Placebo