Evaluation of Dupilumab's Long-term Impact on Lung Function Decline in Adults with Uncontrolled Moderate to Severe Asthma: A Randomized, Double-blind, Placebo-controlled Study
- Trial ID
- 2024-513423-16-00
- Protocol
- LPS16676
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is 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 patients with moderate-to-severe asthma, specifically within the FeNO population. This is clinically relevant as it addresses the need for effective long-term management strategies in asthma, a condition characterized by chronic inflammation and airway obstruction, which can lead to progressive lung function decline.
Secondary objectives include:
- Evaluating the long-term effect of dupilumab on preventing or slowing lung function decline by week 52 (year 1) and week 104 (year 2) in the total population and FeNO population.
- Assessing the effect of dupilumab on improving lung function parameters, exacerbations, asthma control, and biomarker levels at weeks 52 and 104 in both FeNO and total populations.
- Evaluating the long-term effect of dupilumab on improving quality of life at weeks 52 and 104 compared to placebo in FeNO and total populations.
- Assessing the long-term effect of dupilumab on preventing or slowing lung function decline by week 156 (year 3) in FeNO and total populations.
- Evaluating the safety of dupilumab.
Participants
The clinical trial involves a total of **3394 participants** diagnosed with **asthma**, specifically targeting individuals with moderate-to-severe forms of the condition. The study population includes both male and female subjects, aged 18 years and older, who have been diagnosed with asthma for at least 12 months. Participants are required to be on a stable regimen of medium to high-dose inhaled corticosteroids in combination with other asthma controllers. The trial population was selected based on specific criteria, including a pre-bronchodilator forced expiratory volume (FEV1) of 80% or less of the predicted normal value and an Asthma Control Questionnaire score of 1.5 or higher. Additionally, participants must have a history of at least one severe exacerbation in the previous year. The study considers lifestyle factors such as the stability of asthma medication doses and the presence of comorbid conditions like allergic rhinitis. Both genders are included, and the trial acknowledges the inclusion of a vulnerable population. The selection process ensures that participants meet the necessary health and treatment stability requirements to assess the effect of dupilumab on lung function over a 52-week period.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the long-term effects of **dupilumab** on preventing lung function decline in patients with uncontrolled moderate to severe **asthma**. The trial will span a total duration of approximately 156 weeks, with the estimated recruitment start date being June 30, 2022, and the anticipated end date on January 22, 2030. Participants will be randomly assigned to receive either **dupilumab** or a placebo, both administered as a **solution for injection in pre-filled syringes** via subcutaneous injection.
The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be assessed based on criteria such as age, asthma diagnosis, and current treatment regimen. Participants must have a history of asthma for at least 12 months and be on a stable dose of medium to high-dose inhaled corticosteroids combined with a second controller. The screening will also involve assessments of lung function and asthma control, including pre-bronchodilator forced expiratory volume (FEV1) and the Asthma Control Questionnaire (ACQ-5) score.
Follow-up visits will occur at regular intervals to monitor the rate of change in lung function, specifically the post-bronchodilator FEV1 slope, and to assess secondary endpoints such as changes in asthma control and exacerbation rates. The primary endpoint is the rate of change from week 8 to week 52 on the post-BD FEV1 slope in the FeNO population. Secondary endpoints include changes in FEV1 and FeNO levels, as well as the incidence of treatment-emergent adverse events.
The expected length of participant involvement is up to 156 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants will be closely monitored for safety and efficacy throughout the study, with data collected to evaluate the long-term impact of **dupilumab** on lung function and asthma control.
Treatment
The clinical trial involves the administration of **Dupilumab**, a monoclonal antibody, as the experimental medication. Dupilumab is provided in the form of a **solution for injection in a pre-filled syringe**. The medication is administered via **subcutaneous injection**. The dosage is set at 300 mg per administration, with a maximum daily dose of 300 mg. The treatment period extends up to 156 weeks. Dupilumab is developed by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR231893. The active substance, dupilumab, is classified as a protein of other origin.
The study also includes a **placebo** group, which receives a solution for injection in a pre-filled syringe that is identical in appearance to the experimental medication but contains no active substance. The placebo is administered following the same route and schedule as the experimental treatment to maintain the double-blind nature of the trial. The placebo serves as a comparator to evaluate the efficacy of dupilumab in preventing or slowing the rate of lung function decline in patients with uncontrolled moderate to severe asthma.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the effect of **dupilumab** on preventing or slowing the rate of lung function decline in patients with uncontrolled moderate to severe asthma. The primary endpoint for efficacy assessment is the rate of change from week 8 to week 52 on the post-bronchodilator forced expiratory volume in one second (post-BD FEV1) slope in the FeNO population. Secondary endpoints include the rate of change from week 8 to week 52 on post-BD FEV1 slope in the total population, change from baseline to week 52 in pre-BD FEV1 in both FeNO and total populations, and the annualized severe exacerbation rate during the 52-week period in both populations.
Additional secondary endpoints involve changes from baseline to week 52 in fractional exhaled nitric oxide (FeNO) levels, Asthma Control Questionnaire 7 items (ACQ-7), pre-BD FEV1 % predicted, and Forced Vital Capacity (FVC) in both FeNO and total populations. The trial will also assess the rate of change from week 8 to week 104 on post-BD FEV1 slope, change from baseline to week 104 in pre-BD FEV1, post-BD FEV1, FeNO levels, ACQ-7, pre-BD FEV1 % predicted, and FVC in both populations. The incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will also be monitored.
Inclusion and Exclusion Criteria
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 Global Initiative for Asthma (GINA) 2021) for ≥12 months
- Treatment with medium to high dose inhaled corticosteroids (ICS) in combination with a second controller (eg, long-acting beta-2 adrenergic receptor agonists (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.
Exclusion Criteria
- History or clinical evidence of chronic obstructive pulmonary disease (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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 30 Jun 2022 | 43 |
 Bulgaria | Not Recruiting | 30 Jun 2022 | 90 |
 Greece | Not Recruiting | 30 Jun 2022 | 80 |
 Hungary | Not Recruiting | 30 Jun 2022 | 94 |
 Ireland | Not Recruiting | 30 Jun 2022 | 14 |
 Romania | Not Recruiting | 30 Jun 2022 | 85 |
 Slovakia | Not Recruiting | 30 Jun 2022 | 100 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
dupilumab placebo, solution for injection in pre-filled syringe | Placebo | N/A | — | — | — | N/A |
Dupilumab | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 300 | 156 | PRD10065701 |