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    Summary
    EudraCT Number:2021-003338-35
    Sponsor's Protocol Code Number:D7552C00001
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-04-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2021-003338-35
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Assess the Efficacy and Safety of Atuliflapon in Moderate to Severe Uncontrolled Asthma
    A.3.2Name or abbreviated title of the trial where available
    FLASH
    A.4.1Sponsor's protocol code numberD7552C00001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05251259
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca AB
    B.5.2Functional name of contact pointClinical Study Information Center
    B.5.3 Address:
    B.5.3.1Street Addressn/a
    B.5.3.2Town/ cityn/a
    B.5.3.3Post coden/a
    B.5.3.4CountryUnited States
    B.5.6E-mailInformation.Center@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAtuliflapon
    D.3.2Product code AZD5718
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAtuliflapon
    D.3.9.1CAS number 2041075-86-7
    D.3.9.2Current sponsor codeAZD5718
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderate-to-Severe Uncontrolled Asthma
    E.1.1.1Medical condition in easily understood language
    Asthma (an illness that causes breathing difficulty) that is not fully controlled, so that episodes of breathing difficulty are still occurring despite the use of other available treatments
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003553
    E.1.2Term Asthma
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the clinical efficacy of Atuliflapon as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma.
    E.2.2Secondary objectives of the trial
    - To evaluate the clinical efficacy of Atuliflapon as compared to placebo in adult participants with moderate-to-severe uncontrolled asthma

    For further secondary objectives please refer to the protocol.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A PD sub-study will be conducted in a sub-set of participants. As part of this sub-study, additional PD samples will be collected.
    E.3Principal inclusion criteria
    Lead-in PK Cohort – Recruitment Completed
    1.Provision of signed informed consent prior to any study-specific procedures.
    2.Participant is willing and able to follow study procedures and restrictions.
    3.18 to 55 years of age inclusive at the time of signing the ICF at Screening (Visit 1).
    4.Bodyweight 50 to 120 kg (inclusive) and BMI 18 to 32 kg/m2 (inclusive) at Screening (Visit 1).
    5.Documented asthma diagnosis ≥ 12 months prior to Screening (Visit 1).
    6.Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019 acceptability criteria.
    7.Documented evidence of asthma.
    8.Morning pre-BD FEV1 ≥ 40% predicted at Screening (Visit 1) and Visit 2.
    9.Treated with low dose 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). (The ICS can be contained within an ICS-LABA fixed dose combination product)
    -Treatment with additional asthma controller therapies (eg, LAMA) at a stable dose ≥ 3 months prior to Screening (Visit 1) is allowed. Treatment with LTRAs or 5-LO inhibitors is not allowed (see exclusion criteria).
    10.Able and willing to comply with the requirements of the CSP including ability to read, write, be fluent in the translated language of all participants facing questionnaires used at site, and use electronic devices (eg, spirometer).
    11.Participant’s influenza/pneumonia vaccination is up to date as per local guidelines prior to Visit 2.
    12.For female participants, a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test prior to administration of study intervention (Visit 2).
    13.Contraceptive use by female participants 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.
    Part 1
    14.Capable of giving signed informed consent.
    15.Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.
    16.Participant is willing and able to follow study procedures and restrictions.
    17.Participant must be 18 to 80 years of age inclusive, at the time of signing the ICF.
    18.Body weight ≥ 40 kg and BMI < 35 kg/m2.
    19.Documented physician-diagnosed asthma ≥ 12 months prior to Screening (Visit 1).
    20.Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019
    acceptability criteria.
    21.Documented evidence of asthma.
    22.Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at Screening (Visit 1) and Visit 3.
    23.Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Screening (Visit 1).
    24.Treated with low dose 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). (The ICS can be contained within an ICS-LABA fixed dose combination product).
    -Treatment with additional asthma controller therapies (eg, LAMA) at a stable dose ≥ 3 months prior to Screening (Visit 1) is allowed. Treatment with LTRAs or 5-LO inhibitors is not allowed.
    25.An ACQ-6 score ≥ 1.5 at Screening (Visit 1) and at Visit 3.
    26.Able and willing to comply with the requirements of the CSP including ability to
    read, write, be fluent in the translated language of all participants facing questionnaires.
    used at site, and use electronic devices, eg, eCOA device and spirometry.
    27.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.
    28. Minimum 80% compliance with daily eCOA assessments. Compliance is defined as completing the daily ePRO questions and PEF measurement at least 80% of the time during the run-in period and during the 14 days preceding Visit 3.
    29.For female participants, a negative serum pregnancy test at Screening (Visit 1) and negative urine pregnancy test at Visit 3.
    30.Contraceptive use by female participants 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.
    Please refer to the protocol for the full list of inclusion criteria.
    E.4Principal exclusion criteria
    1. A severe asthma exacerbation within 8 weeks of Screening (Visit 1) or within 12 weeks
    of randomisation (Visit 3).
    2. 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.
    3. Participants with a significant COVID-19 illness within 6 months of enrolment:
    − 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.
    4. Clinically important pulmonary disease other than asthma eg, active lung infection,
    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.
    5. 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.
    − Impede the participant's ability to complete the entire duration of study.
    6. Any clinically significant cardiac disease:
    − Acute coronary syndrome (acute myocardial infarction, unstable angina) or coronary intervention with percutaneous coronary intervention/coronary artery bypass surgery within 6 months.
    − Heart failure NYHA II-IV.
    − Untreated high degree atrioventricular-block (≥ 3:1 conduction rate/Grade III block)/
    significant sinus node dysfunction/pause or therapy requiring tachyarrhythmia.
    − History or family history of long QT-syndrome.
    − History of QT prolongation associated with other medications that required discontinuation of that medication.
    − Hypertrophic cardiomyopathy or clinically significant valvular heart disease.
    − Stroke within 3 months of Screening (Visit 1).
    7. History of severe renal disease (CKD stage 4 or 5) or history of creatinine clearance < 30 mL/min × m2 calculated using Cockcroft-Gault equation.
    8. Severe hepatic impairment (Child-Pugh class C).
    9. Previous hepatotoxicity related to zileuton or LTRAs (eg, montelukast)
    10. 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. For the hepatitis B testing (HBsAg, anti-HBs, and anti-HBc), any of the following
    would exclude the participant from the study:
    − Participants positive for HBsAg.
    − Participants positive for anti-HBc.
    11. Evidence of active or untreated latent TB:
    − Positive IGRA, or repeated indeterminate IGRAs, untreated LTBI (unable to be treated for, or declines treatment of LTBI).
    − Participants newly diagnosed with LTBI at Screening (Visit 1) could be considered for rescreening if they complete a full course of treatment for LTBI in accordance with recommended treatment guidelines prior to rescreening. In this situation, repeat IGRA test is not required after completion of treatment for LTBI.
    − Participants with an indeterminate IGRA should undergo a repeat test and if still indeterminate may be enrolled only after being treated for LTBI.
    12. Abnormal findings identified on physical examination, ECG, or laboratory testing include, but are not limited to:
    − ALT or AST ≥ 2 × ULN.
    − TBL ≥ 1.5 × ULN (unless due to Gilbert’s disease).
    − Evidence of chronic liver disease.
    − Abnormal vital signs, after 5 minutes of supine or sitting rest (confirmed by one controlled measurement), defined as any of the following:
    o SBP < 80 mmHg or ≥ 150 mmHg.
    o DBP < 50 mmHg or ≥ 95 mmHg.
    o Pulse < 45 or > 100 beats per minute.
    − Signs of pulmonary oedema or volume overload.
    − Any clinically significant rhythm, conduction, or morphology abnormalities in the ECG including but not limited to QTcF > 450 ms.

    Please refer to the protocol for the full list of exclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    Time to first CompEx Asthma event
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    Clinical efficacy endpoints: change from baseline in:
    1 pre-BD FEV1: Baseline, Week 4, and Week 12
    2 SGRQ: Baseline, Week 4, and Week 12

    Clinical efficacy endpoints: change from baseline in:
    1 ACQ-6: Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period
    2 average morning and average evening PEF: Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period
    3 daily asthma symptom score (total, daytime, and night-time): Baseline, Week 4, Week 8, Week 12, and average over the 12-week treatment period

    Clinical efficacy endpoints:
    1 time to first severe asthma exacerbation
    2 event status (CompEx Asthma event yes/no)

    To evaluate the PK of Atuliflapon:
    1 Atuliflapon plasma concentrations and PK parameters
    2 Atuliflapon plasma concentrations: pre-dose samples at Baseline, Week 4, and Week 12

    Safety Endpoints:
    Safety and tolerability evaluations using AEs, vital sign measures, clinical laboratory assessments, ECG and C-SSRS

    Exploratory Endpoints:

    -Change from baseline in:
    1 Post BD FEV1: Baseline, and Week 12
    2 Percent reversibility: Baseline and Week 12
    3 Forced expiratory flow 25-75%: Baseline, Week 4, and Week 12

    - Change from baseline in FeNO: Baseline, Week 4, and Week 12

    - Change from baseline in cough VAS: Baseline, Week 4, and Week 12 and over the treatment period

    - Change from baseline in:

    1 home spirometry assessment: Baseline, Week 4 and Week 12

    - Change from baseline in:
    1 time to first CompEx Asthma event
    2 Pre-BD FEV1: Baseline, Week 4 and Week 12
    3 ACQ-6 and SGRQ: Baseline, Week 4, and Week 12
    4 FeNO: Baseline to Week 4 and Week 12

    - Blood and urine biomarker concentrations including Type 1, Type 2, and Type 17 cytokines and
    other arachidonic acid metabolites at baseline, Week 4, and Week 12

    - Endpoints:
    1 Creatinine normalised uLTE4, plasma LTE4
    2 Creatinine normalised uLTE4, plasma LTE4, plasma LTB4 (ex-vivo stimulation) at Week 4
    3 Blood and urine biomarker concentrations including LTE4, LTB4, pre-dose samples: Baseline, Week 4, and Week 12

    For full information please refer to the protocol.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, Week 4, Week 8 and Week 12
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA124
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Chile
    Australia
    Japan
    Korea, Republic of
    Mexico
    Serbia
    South Africa
    United Kingdom
    United States
    Bulgaria
    Croatia
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Romania
    Slovakia
    Slovenia
    Spain
    Türkiye
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days5
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 532
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 134
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state271
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 264
    F.4.2.2In the whole clinical trial 666
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-04-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-26
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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