Clinical trial NCT05251259: Study to Assess the Efficacy and Safety of Atuliflapon in Moderate-to-Severe Uncontrolled Asthma
Official title: A Phase 2a, Randomised, Double-Blind, Placebo-Controlled Study to Assess Efficacy and Safety of Atuliflapon Given Orally Once Daily for Twelve Weeks in Adults With Moderate to Severe Uncontrolled Asthma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Asthma
Keywords: Efficacy
Safety
Multiple Dose Levels
Adults
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2022-02-22
Enrollment: 666
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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 randomised globally, including participants in Lead-in PK cohort (2 arms) and in Part 1 of the study (2 arms).

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 by geographical region, and grouped based on high or low levels of biomarker at screening (Visit 1).

Eligibility 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 tuberculosis (TB), either treated or untreated or latent 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, the ethinyl oestradiol doses exceeding 20 mcg per day.
* 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.
* 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.

Primary outcomes:
measure: Time to first CompEx Asthma event
timeFrame: Baseline up to Week 12
Secondary outcomes:
measure: Time to first CompEx Asthma event (Composite endpoint for Exacerbations)
timeFrame: From Baseline up to Week 12
measure: Time to first CompEx Asthma event (Composite endpoint for Exacerbations)
timeFrame: From Baseline up to Week 12
measure: Change from baseline in Pre-bronchodilator in forced expiratory volume in 1 second (FEV1)
timeFrame: From Baseline up to Week 2, Week 4 and Week 12
measure: Change from baseline in St. George's Respiratory Questionnaire
timeFrame: From Baseline up to Week 4 and Week 12
measure: Change from baseline in Asthma Control Questionnaire 6
timeFrame: From Baseline up to Week 4, Week 8, Week 12
measure: Change from baseline in average morning and evening Peak Expiratory Flow Measurement
timeFrame: From Baseline up to Week 4, Week 8, Week 12
measure: Change from baseline in Daily asthma symptom score (total, daytime, and night-time)
timeFrame: From Baseline up to Week 4, Week 8, Week 12
measure: Time to first severe asthma exacerbation
timeFrame: From Baseline up to Week 12
measure: Event status (CompEx Asthma event yes/no)
timeFrame: From Baseline up to Week 12
measure: Lead-in PK: Area under the curve (AUC)
timeFrame: Day 1 and Day 15
measure: Lead-in PK: Maximum (or peak) serum concentration (Cmax)
timeFrame: Day 1 and Day 15
measure: Lead-in PK cohort: Pre-dose trough concentration (Ctrough)
timeFrame: Day 15
measure: Part 1 Cohort: Atuliflapon plasma concentrations in all participants, pre-dose samples
timeFrame: Baseline, Week 4 and Week 12
measure: Number of participants with adverse events (AEs)
timeFrame: Baseline up to Week 12
Other outcomes:
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city: Zapopan
country: Mexico
facility: Research Site
city: Breda
country: Netherlands
facility: Research Site
city: Eindhoven
country: Netherlands
facility: Research Site
city: Groningen
country: Netherlands
facility: Research Site
city: Zutphens
country: Netherlands
facility: Research Site
city: Białystok
country: Poland
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Gdynia
country: Poland
facility: Research Site
city: Grudziadz
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Katowice
country: Poland
facility: Research Site
city: Kielce
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Ksawerów
country: Poland
facility: Research Site
city: Ostrowiec Świętokrzyski
country: Poland
facility: Research Site
city: Ostróda
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Rzeszów
country: Poland
facility: Research Site
city: Tarnów
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Wrocław
country: Poland
facility: Research Site
city: Wrocław
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Baia Mare
country: Romania
facility: Research Site
city: Brasov
country: Romania
facility: Research Site
city: Brasov
country: Romania
facility: Research Site
city: Brasov
country: Romania
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Caracal
country: Romania
facility: Research Site
city: Cluj-Napoca
country: Romania
facility: Research Site
city: Cluj-Napoca
country: Romania
facility: Research Site
city: Constanta
country: Romania
facility: Research Site
city: Deva
country: Romania
facility: Research Site
city: Iasi
country: Romania
facility: Research Site
city: Oradea
country: Romania
facility: Research Site
city: Resca, Com. Dobrosloveni
country: Romania
facility: Research Site
city: Timisoara
country: Romania
facility: Research Site
city: Timisoara
country: Romania
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Nis
country: Serbia
facility: Research Site
city: Sremska Kamenica
country: Serbia
facility: Research Site
city: Uzice
country: Serbia
facility: Research Site
city: Valjevo
country: Serbia
facility: Research Site
city: Humenne
country: Slovakia
facility: Research Site
city: Kezmarok
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Levice
country: Slovakia
facility: Research Site
city: Presov
country: Slovakia
facility: Research Site
city: Surany
country: Slovakia
facility: Research Site
city: Topolcany
country: Slovakia
facility: Research Site
city: Golnik
country: Slovenia
facility: Research Site
city: Jesenice
country: Slovenia
facility: Research Site
city: Kamnik
country: Slovenia
facility: Research Site
city: Ljubljana
country: Slovenia
facility: Research Site
city: Cape Town
country: South Africa
facility: Research Site
city: Centurion
country: South Africa
facility: Research Site
city: Germiston
country: South Africa
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
city: Krugersdorp
country: South Africa
facility: Research Site
city: Lenasia
country: South Africa
facility: Research Site
city: Mount Edgecombe
country: South Africa
facility: Research Site
city: Thohoyandou
country: South Africa
facility: Research Site
city: Vereeniging
country: South Africa
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Benalmádena
country: Spain
facility: Research Site
city: Jerez de la Frontera
country: Spain
facility: Research Site
city: Laredo
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Marbella
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Mérida
country: Spain
facility: Research Site
city: Sagunto(Valencia)
country: Spain
facility: Research Site
city: Xàtiva
country: Spain
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Bursa
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: Izmir
country: Turkey
facility: Research Site
city: Samsun
country: Turkey
facility: Research Site
city: Samsun
country: Turkey
facility: Research Site
city: Chernivtsі
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
city: Vinnytsya
country: Ukraine
facility: Research Site
city: Belfast
country: United Kingdom
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Bradford
country: United Kingdom
facility: Research Site
city: Cardiff
country: United Kingdom
facility: Research Site
city: Chorley
country: United Kingdom
facility: Research Site
city: Corby
country: United Kingdom
facility: Research Site
city: Cottingham
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Harefield
country: United Kingdom
facility: Research Site
city: Hexham
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: Liverpool
country: United Kingdom
facility: Research Site
city: Liverpool
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Norwich
country: United Kingdom
facility: Research Site
city: Portsmouth
country: United Kingdom
facility: Research Site
city: Reading
country: United Kingdom
facility: Research Site
city: Wakefield
country: United Kingdom
facility: Research Site
city: Watford
country: United Kingdom
facility: Research Site
Study officials:
References: