| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate-to-Severe Uncontrolled Asthma |
|
| E.1.1.1 | Medical 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.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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.2.2 | Secondary objectives of the trial |
- To evaluate the clinical efficacy of Atuliflapon at different dose levels in adult participants with moderate-to-severe uncontrolled asthma
- 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.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A PK/PD sub-study will be conducted in a sub-set of participants randomised in Part 1 and Part 2. As part of this sub-study, additional PK and PD blood samples will be collected. |
|
| E.3 | Principal 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 and Part 2
1.Capable of giving signed informed consent.
2.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.
3.Participant is willing and able to follow study procedures and restrictions.
4.Participant must be 18 to 80 years of age inclusive, at the time of signing the ICF.
5.Body weight ≥ 40 kg and BMI < 35 kg/m2.
6.Documented physician-diagnosed asthma ≥ 12 months prior to Screening (Visit 1).
7.Able to perform acceptable lung function testing for FEV1 according to ATS/ERS 2019
acceptability criteria.
8.Documented evidence of asthma.
9.Morning pre-BD FEV1 between ≥ 40% and ≤ 85% predicted at Screening (Visit 1) and Visit 3.
10.Documented history of ≥ 1 severe asthma exacerbation within 1 year prior to Screening (Visit 1).
11.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.
12.An ACQ-6 score ≥ 1.5 at Screening (Visit 1) and at Visit 3.
13.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.
14.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.
15. 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.
16.For female participants, a negative serum pregnancy test at Screening (Visit 1) and negative urine pregnancy test at Visit 3.
17.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.4 | Principal exclusion criteria |
1. A severe asthma exacerbation within 8 weeks of Screening (Visit 1).
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), coronary intervention with percutaneous coronary intervention/coronary artery bypass surgery or stroke 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.5.1 | Primary end point(s) |
| Time to first CompEx Asthma event |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary 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: post-dose samples taken at Week 4
3 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 122 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If 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 |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Slovakia |
| Slovenia |
| Spain |
| Türkiye |
|
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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