| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 |
In a population with moderate-to-severe asthma:
• To assess the effect of dupilumab on preventing or slowing the rate of lung function decline by week 52 (year 1) compared to placebo in the FeNO population |
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| E.2.2 | Secondary objectives of the trial |
In a population with moderate-to-severe asthma
To evaluate the long-term effect of dupilumab :
• on preventing or slowing the rate of lung function decline by week 52 (year 1) compared to placebo in total population
• on preventing or slowing the rate of lung function decline by week 104 (year 2) compared to placebo in FeNO population
• on improving lung function parameters, exacerbations, asthma control and biomarker levels at week 52 compared to placebo in FeNO and total populations
• on improving lung function parameters, exacerbations, asthma control and biomarker levels at week 104 compared to placebo in FeNO and total populations
• in improving quality of life at week 52 and 104 compared to placebo in FeNO and total populations
• on preventing or slowing the rate of lung function decline by week 156 (year 3) compared to placebo in FeNO and total populations
• To evaluate the safety of dupilumab |
|
| 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 |
The optional substudy will be discontinued. Samples collected as well as assessments performed as part of the functional respiratory imaging
(FRI) and forced oscillometry technique (FOT) will be analyzed. No additional timepoints will be collected. |
|
| E.3 | Principal inclusion criteria |
- Participant must be at least 18 (or the legal age of consent in the jurisdiction in which the study is taking place) years of age inclusive, at
the time of signing the informed consent.
- Patients with a physician diagnosis of asthma (according to GINA 2021) for ≥12 months
- Treatment with medium to high dose ICS in combination with a second controller (eg, LABA, LTRA) with a stable dose ≥1 month prior to Visit 1. Patients requiring a third controller for their asthma will be considered eligible for this study, and it should also be on stable dose ≥1 month
prior to Visit 1. Patients requiring an additional controller as a fourth controller (Montelukast) for another type 2 comorbid condition such as
allergic rhinitis will be considered eligible for this study, and should be on a stable dose for ≥1 month prior to Visit 1.
- Pre-bronchodilator forced expiratory volume (FEV1) ≤ 80% of predicted normal for adults at Visits 1 and 2, prior to randomization
- Asthma Control Questionnaire 5-question version (ACQ-5) score ≥1.5 at Visits 1 and 2, prior to randomization.
- Variable airflow obstruction as documented by one or more of the following (at least 1 needs to be met):
i) Positive reversibility test: ≥12% and 200 mL improvement in FEV1 after SABA administration prior to randomization, or documented in the
24 months prior to Visit 1. OR,
ii) Positive bronchial challenge test: fall in FEV1 of ≥20% with standard dosis of methacholine, or ≥15% with standardized hyperventilation,
hypertonic saline or mannitol challenge prior to randomization or documented in the 24 months prior to Visit 1 OR,
iii) Average daily diurnal Peak flow variability of >10% over a 2-week period, documented in the past 24 months prior to Screening Visit 1. OR,
iv) Airflow variability in clinic FEV1 >12% and 200 mL between visits outside of respiratory infections, documented in the past 24 months
prior to Screening Visit 1. OR
v) FEV1 increases by more than 12% and 200mL from baseline after 4 weeks of anti-inflammatory treatment.
- Reversibility test: Three attempts may be made during the Screening Period until the Baseline visit to meet the qualifying criteria for
reversibility. This is only required if reversibility or other evidence of expiratory airflow limitation eligibility criteria was not performed within
24 months prior to Visit 1.
- FeNO ≥35 ppb at Visit 2, prior to randomization.
- History of ≥1 severe exacerbation(s) in the previous year before V1 defined as a deterioration of asthma requiring:
-- Use of systemic corticosteroids for ≥3 days; or
-- Hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. |
|
| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
- History or clinical evidence of COPD including Asthma-COPD Overlap Syndrome (ACOS) or any other significant lung disease (eg, emphysema, lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome).
- Severe asthma exacerbation requiring treatment with SCS in the past month before visit 1 or during the screening period.
- Current acute bronchospasm or status asthmaticus.
- Diagnosed pulmonary (other than asthma) or systemic disease associated with elevated peripheral eosinophil counts.
- Severe concomitant illness(es) that, in the Investigator's judgment, would adversely affect the participant's participation in the study. Examples include, but are not limited to, participants with short life expectancy, uncontrolled diabetes, cardiovascular conditions, severe renal conditions (eg, participants on dialysis), or other severe endocrinological, gastrointestinal, metabolic, pulmonary, psychiatric, or lymphatic diseases. The specific justification for participants excluded under this criterion will be noted in the study documents (chart notes, case report forms [CRFs], etc).
- Patients with active tuberculosis (TB) or non-tuberculous mycobacterial infection, or a history of incompletely treated TB will be excluded from the study unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing will be performed on a country by country basis, according to local guidelines if required by regulatory authorities or ethics boards, or if TB is suspected by the investigator
- Known or suspected immunodeficiency, including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal frequency or prolonged duration suggesting an immune-compromised status, as judged by the Investigator.
- Active malignancy or history of malignancy within 5 years before Visit 1 (screening visit), except completely treated in situ carcinoma of the cervix and completely treated and resolved non metastatic squamous or basal cell carcinoma of the skin.
- Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antifungals or receiving only symptomatic treatment (e.g. influenza or COVID-19) within 2 weeks before the screening visit (Visit 1) or during the screening period.
- History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Visit 1 (screening visit).
- Diagnosed with, suspected of, or at high risk of endoparasitic infection, and/or use of antiparasitic drugs within 2 weeks before Visit 1 (screening visit) or during the screening and run-in period
- Current smoker (cigarette or e-cigarette) or cessation of smoking within 6 months prior to Visit 1.
- Previous smoker with a smoking history >10 pack-years.
- History of systemic hypersensitivity or anaphylaxis to dupilumab or any other biologic therapy, including any excipient.
- Any biologic therapy (including experimental treatments and dupilumab) or any other biologic therapy/immunosuppressant/immunomodulators within 4 weeks prior to V1 or 5 half-lives, whichever is longer.
- Treatment with a live (attenuated) vaccine within 4 weeks before Visit 1 (screening visit) or during the screening period. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Rate of change from week 8 to week 52 on post-BD FEV1 slope in FeNO population ; Rate of change from week 8 to week 52 on post-bronchodilator (BD) forced expiratory volume in one second (FEV1) slope in FeNO population. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1 - Rate of change from week 8 to week 52 on post-BD FEV1 slope in the Total population ; Rate of change from week 8 to week 52 on post-BD FEV1 slope in the Total population.
2 - Rate of change from week 8 to week 104 on post-BD FEV1 slope in the FeNO population ; Rate of change from week 8 to week 104 on post-BD FEV1 slope in the FeNO population.
3 - Change from baseline to week 52 in pre-BD FEV1 in FeNO and Total populations ; Change from baseline to week 52 in pre-BD FEV1 in FeNO and Total populations.
4 - Change from baseline to week 52 in post-BD FEV1 in FeNO and Total populations ; Change from baseline to week 52 in post-BD FEV1 in FeNO and Total populations.
5 - Annualized severe exacerbation rate during the 52-week period in FeNO and Total populations ; Exacerbation defined as a deterioration of asthma requiring use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids.
6 - Change from baseline to week 52 in fractional exhaled nitric oxide (FeNO) levels in FeNO and Total populations ; Change from baseline to week 52 in FeNO levels in FeNO and Total populations.
7 - Change from baseline to week 52 in Asthma Control Questionnaire 7 items (ACQ-7) in FeNO and Total populations ; ACQ-7 was designed to measure both the adequacy of asthma control and change in asthma control. A global score ranges between 0 (totally controlled) and 6 (severely uncontrolled). Higher score indicates lower asthma control.
8 - Change from baseline to week 52 in pre-BD FEV1 % predicted in FeNO and Total populations ; Change from baseline to week 52 in pre-BD FEV1 % predicted in FeNO and Total populations.
9 - Change from baseline to week 52 in Forced Vital Capacity (FVC) in FeNO and Total populations ; Change from baseline to week 52 in FVC in FeNO and Total populations.
10 - Rate of change from week 8 to week 104 on post-BD FEV1 slope in Total Population ; Rate of change from week 8 to week 104 on post-BD FEV1 slope in Total Population.
11 - Change from baseline to week 104 in pre-BD FEV1 in FeNO and Total populations ; Change from baseline to week 104 in pre-BD FEV1 in FeNO and Total populations.
12 - Change from baseline to week 104 in post-BD FEV1 in FeNO and Total populations ; Change from baseline to week 104 in post-BD FEV1 in FeNO and Total populations.
13 - Annualized severe exacerbation rate during the 104-week period in FeNO and Total populations ; Exacerbation defined as a deterioration of asthma requiring use of systemic corticosteroids for ≥3 days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids.
14 - Change from baseline to week 104 in FeNO levels in FeNO and Total populations ; Change from baseline to week 104 in FeNO levels in FeNO and Total populations.
15 - Change from baseline to week 104 in ACQ-7 in FeNO and Total populations ; ACQ-7 was designed to measure both the adequacy of asthma control and change in asthma control. A global score ranges between 0 (totally controlled) and 6 (severely uncontrolled). Higher score indicates lower asthma control.
16 - Change from baseline to week 104 in pre-BD FEV1 % predicted in FeNO and Total populations ; Change from baseline to week 104 in pre-BD FEV1 % predicted in FeNO and Total populations.
17 - Change from baseline to week 104 FVC in FeNO and Total populations ; Change from baseline to week 104 FVC in FeNO and Total populations.
18 - Change from baseline to week 52 in Asthma Quality Of Life Questionnaire with Standardized Activities (AQLQ(S)) in FeNO and Total populations ; The AQLQ (S) was designed as a self-administered patient reported outcome to measure the functional impairments that are most troublesome to patients as a result of their asthma. A global score is calculated ranging from 1 to 7. Higher scores indicate better quality of life.
19 - Change from baseline to week 104 in AQLQ(S) in FeNO and Total populations ; The AQLQ (S) was designed as a self-administered patient reported outcome to measure the functional impairments that are most troublesome to patients as a result of their asthma. A global score is calculated ranging from 1 to 7. Higher scores indicate better quality of life.
20 - Rate of change from week 8 to week 156 on post-BD FEV1 slope in FeNO and Total populations ; Rate of change from week 8 to week 156 on post-BD FEV1 slope in FeNO and Total populations.
21 - Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) ; Incidence of TEAEs and SAEs.
22 - Incidence of adverse events of special interest (AESIs) ; Incidence of AESIs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 3, 4, 5, 6, 7, 8, 9 - Week 8 to Week 52
2, 10 - Week 8 to Week 104
11, 12, 13, 14, 15, 16, 17, 19 - Baseline to Week 104
18 - Baseline to Week 52
20 - Week 8 to Week 156
21, 22 - Baseline to Week 168 |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| 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 |
| Oman |
| Peru |
| United Arab Emirates |
| Ukraine |
| Taiwan |
| Brazil |
| Canada |
| India |
| Korea, Republic of |
| Mexico |
| Saudi Arabia |
| South Africa |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| Greece |
| Hungary |
| Ireland |
| Romania |
| Slovakia |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 4 |
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