Randomized, Double Blind, Placebo Controlled Study to Evaluate the Effect of Dupilumab on Airway Inflammation Through Assessments of Lung Function, Mucus Plugging and Other Lung Imaging Parameters in Patients With Asthma
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- Sanofi
- 入组人数
- 109
- 试验地点
- 65
- 主要终点
- Percentage of Participants Who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (Ppb) at Week 24
研究概览
简要总结
Primary Objective:
• To assess the effect of dupilumab on lung inflammation and related changes in airway volumes detectable by functional respiratory imaging
Secondary Objective:
- To evaluate the effect of dupilumab at Week 24 on bronchodynamics, hyperinflation, airway resistance, airway wall thickness, ventilation defects and mucus plugging derived from high-resolution computed tomography (HRCT) scans, patient-reported outcomes, FeNO and spirometry.
- To evaluate safety of dupilumab
详细描述
The study duration for each participant was a total of minimum 29 weeks and up to 41 weeks. This included 4 weeks +/-1 week screening period, 24 weeks of treatment period and a follow-up period up to 12 weeks or until the participants switched to commercialized dupilumab (or other biologic products), whatever came first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •18 to 70 years of age inclusive with the diagnosis of asthma based on Global Strategy for Asthma Management and Prevention (GINA) 2019 at the time of signing the informed consent
- •History of ≥1 exacerbation(s) in the previous year
- •Uncontrolled moderate to severe asthma (ACQ-5 ≥1.5) at visit (V)1 and V2, prior to randomization
- •Pre-bronchodilator FEV1 ≤80% of predicted normal at V1 and V2, prior to randomization
- •Exhibit bronchodilator reversibility (≥12% and 200 mL improvement in FEV1 post SABA administration) during screening, prior to randomization
- •Blood eosinophil ≥300 cells /µL and FeNO ≥25 ppb during screening, prior to randomization
- •Historical values of blood eosinophil count meeting the eligibility criterion measured within 6 months prior to SV1 in the absence of OCS treatment are allowed.
- •FeNO value to be checked for eligibility at V2 as well. -Existing treatment with medium to high dose ICS in combination with a second controller (e.g. LABA, LTRA) ± a third controller. The dose regimen should be stable ≥1 month prior V1 and during screening.
排除标准
- •Current smoker (cigarette or e-cigarette) or cessation of smoking within 1 year prior randomization
- •Previous smoker with a smoking history >10 pack-years
- •Known hypersensitivity to dupilumab or any of its excipients
- •A subject who experiences an asthma exacerbation (defined as a deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with systemic steroids) during screening
- •Current acute bronchospasm or status asthmaticus
- •Diagnosed pulmonary (other than asthma) or systemic disease associated with elevated peripheral eosinophil counts
- •History or clinical evidence of chronic obstructive pulmonary disease (COPD) including Asthma-COPD Overlap Syndrome (ACOS) or any other significant lung disease (eg, lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome, etc)
- •Active tuberculosis, latent untreated tuberculosis or a history of incompletely treated tuberculosis or non-tuberculous mycobacterial infection unless it is well documented by a specialist that the participants has been adequately treated and the treatment with a biologic agent can be initiated, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing would only be performed on a country by country basis according to the routine clinical practice and the local guidelines, if required by regulatory authorities or ethics committees
- •History of or current evidence of clinically significant disease in any non-respiratory system (e.g. cardiovascular, hepatic, nervous system, gastrointestinal, endocrinological, rheumatological, dermatological), which, in the judgment of the Investigator, could interfere with the study or require treatment that might interfere with the study
- •Current evidence of clinically significant oncological disease, which in the opinion of the investigator may interfere with the objectives of the study or put the subject at undue risk
- •Participants with any of the following results at V1:
- •Positive (or indeterminate) hepatitis B surface antigen (HBs Ag) or
- •Positive Hepatitis B IgM core antibody (IgM HBc Ab) or
- •Positive total hepatitis B core antibody (total HBc Ab) confirmed by positive HBV DNA or
- •Positive hepatitis C antibody (HCV Ab) confirmed by positive HCV RNA
- •History of human immunodeficiency virus (HIV) infection or positive HIV serology at V1
- •Any biologic therapy (including experimental treatments and dupilumab) or any other biologic therapy/immunosuppressant within 3 months prior to V1
- •Treatment with live (attenuated) vaccine within 4 weeks before V
- •For participants who have vaccination with live, attenuated vaccines planned during the course of the study (based on national vaccination schedule/local guidelines), it will be determined, after consultation with a physician, whether the administration of vaccine can be postponed until after the end of the study, or preponed to before the start of the study without compromising the health of the participant:
- •Participants for whom administration of live (attenuated) vaccine can be safely postponed would be eligible to enroll into the study.
- •Participants who have their vaccination preponed can enroll in the study only after a gap of 4 weeks following administration of the vaccine.
- •Treatment with oral corticosteroids (OCS) within 2 weeks prior to V1
- •Enrolled in other ongoing studies regardless of the investigational product
- •Treatment with an investigational drug within 1 month or within 5 half-lives (if known), whichever is longer, prior to V1
- •Suspected or high risk of parasitic infection (helminthic infection), unless clinical and (if necessary) laboratory assessments have ruled out active infection prior to randomization
- •Females who are lactating, breastfeeding, or who are pregnant
- •Individuals accommodated in an institution because of regulatory or legal order; prisoners or subjects who are legally institutionalized
- •Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 of the ICH GCP Ordinance E6)
- •Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals
- •Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study
- •Any country-related specific regulation that would prevent the subject from entering the study
- •The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
研究组 & 干预措施
Dupilumab
Participants received a loading dose of dupilumab 600 mg as 2 subcutaneous (SC) injections on Day 1, followed by a single dupilumab 300 mg SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.
干预措施: Dupilumab (Drug)
Placebo
Participants received placebo matched to dupilumab as 2 x 2 mL SC injections on Day 1, followed by a single SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of Participants Who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (Ppb) at Week 24
时间窗: Week 24
FeNO was analyzed using a NIOX instrument using a flow rate of 50 milliliters per second (mL/s). This assessment was conducted prior to spirometry and following a fast of greater than or equal to (≥1) hour. The test was performed after a wash out period of bronchodilators.
Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC)
时间窗: Baseline (Day 1) to Week 24
Specific airway volume \[(s)iVaw\] is the change of volume of the airways (in mL), taking into account the lung volume changes (in liter \[L\]) as well. It corresponds to the ratio between the airway volume (iVaw) and the lobar volume. This way the air volumes are normalized across participants and become specific. Untrimmed distal \[s\]iVaw at TLC was assessed based on 3-dimensional (D) rendering of high-resolution computed tomography (HRCT) scans. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of investigational medicinal product (IMP).
次要结局
- Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC(Baseline (Day 1) to Week 24)
- Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Functional Residual Capacity (FRC)(Baseline (Day 1) to Week 24)
- Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC(Baseline (Day 1) to Week 24)
- Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7)(Baseline (Day 1) to Week 24)
- Change From Baseline to Week 24 in Global Lung Mucus Score (University of California, San Francisco [UCSF] Mucus Scoring)(Baseline (Day 1) to Week 24)
- Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC(Baseline (Day 1) to Week 24)
- Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone(Baseline (Day 1) to Week 24)
- Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone(Baseline (Day 1) to Week 24)
- Change From Baseline to Week 24 in FeNO(Baseline (Day 1) to Week 24)
- Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)(Baseline (Day 1) to Week 24)
- Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs)(From first dose of study drug (Day 1) up to end of study (up to 36 weeks))