Clinical trial NCT04400318: The Effect of Dupilumab on Lung Inflammation and Related Changes in Airway Volumes Detectable by Functional Respiratory Imaging in Patients With Moderate-severe Asthma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Asthma
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2020-05-22
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* 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

NOTES:

* 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.

Exclusion Criteria:

* 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 V1. 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.

Primary outcomes:
measure: Percentage of Participants Who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (Ppb) at Week 24
timeFrame: Week 24
measure: Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC)
timeFrame: Baseline (Day 1) to Week 24
Secondary outcomes:
measure: Change From Baseline to Week 24 in Global Lung Mucus Score (University of California, San Francisco [UCSF] Mucus Scoring)
timeFrame: Baseline (Day 1) to Week 24
measure: Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC
timeFrame: Baseline (Day 1) to Week 24
measure: Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Functional Residual Capacity (FRC)
timeFrame: Baseline (Day 1) to Week 24
measure: Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC
timeFrame: Baseline (Day 1) to Week 24
measure: Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline to Week 24 in FeNO
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
timeFrame: Baseline (Day 1) to Week 24
measure: Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7)
timeFrame: Baseline (Day 1) to Week 24
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs)
timeFrame: From first dose of study drug (Day 1) up to end of study (up to 36 weeks)
Other outcomes:
Locations:
city: Westminster
country: United States
facility: Allianz Research Institute Site Number : 8400020
state: California
city: Kansas City
country: United States
facility: University of Kansas School of Medicine Site Number : 8400008
state: Kansas
city: Ann Arbor
country: United States
facility: University of Michigan Site Number : 8400002
state: Michigan
city: Chesterfield
country: United States
facility: The Lung Research Center Site Number : 8400010
state: Missouri
city: Charlotte
country: United States
facility: American Health Research Site Number : 8400005
state: North Carolina
city: Medford
country: United States
facility: Velocity Clinical Research, Medford Site Number : 8400014
state: Oregon
city: Charleston
country: United States
facility: Medical University of South Carolina - Pulmonary & Critical Care Clinical Research Program Site Number : 8400009
state: South Carolina
city: Greenville
country: United States
facility: VitaLink Research-Greenville Site Number : 8400013
state: South Carolina
city: Spartanburg
country: United States
facility: VitaLink Research - Spartanburg Site Number : 8400011
state: South Carolina
city: Spartanburg
country: United States
facility: ~Spartanburg Medical Research Site Number : 8400004
state: South Carolina
city: Dupnitsa
country: Bulgaria
facility: Investigational Site Number : 1000013
city: Montana
country: Bulgaria
facility: Investigational Site Number : 1000004
city: Plovdiv
country: Bulgaria
facility: Investigational Site Number : 1000018
city: Plovdiv
country: Bulgaria
facility: Investigational Site Number : 1000012
city: Ruse
country: Bulgaria
facility: Investigational Site Number : 1000008
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000015
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000005
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000003
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000006
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000011
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000010
city: Sofia
country: Bulgaria
facility: Investigational Site Number : 1000002
city: Stara Zagora
country: Bulgaria
facility: Investigational Site Number : 1000007
city: Aarhus N
country: Denmark
facility: Investigational Site Number : 2080006
city: Copenhagen Nv
country: Denmark
facility: Investigational Site Number : 2080003
city: Copenhagen
country: Denmark
facility: Investigational Site Number : 2080002
city: Hvidovre
country: Denmark
facility: Investigational Site Number : 2080001
city: Montpellier
country: France
facility: Investigational Site Number : 2500001
city: Cona
country: Italy
facility: Investigational Site Number : 3800003
state: Ferrara
city: Rozzano
country: Italy
facility: Investigational Site Number : 3800004
state: Milano
city: Pisa
country: Italy
facility: Investigational Site Number : 3800001
city: Coimbra
country: Portugal
facility: Investigational Site Number : 6200004
city: Guimarães
country: Portugal
facility: Investigational Site Number : 6200005
city: Lisboa
country: Portugal
facility: Investigational Site Number : 6200006
city: Porto
country: Portugal
facility: Investigational Site Number : 6200003
city: Porto
country: Portugal
facility: Investigational Site Number : 6200001
city: Bragadiru
country: Romania
facility: Investigational Site Number : 6420005
city: Brasov
country: Romania
facility: Investigational Site Number : 6420008
city: Cluj-Napoca
country: Romania
facility: Investigational Site Number : 6420006
city: Cluj-Napoca
country: Romania
facility: Investigational Site Number : 6420001
city: Oradea
country: Romania
facility: Investigational Site Number : 6420007
city: Timisoara
country: Romania
facility: Investigational Site Number : 6420003
city: Dammam
country: Saudi Arabia
facility: Investigational Site Number : 6820008
city: Jeddah
country: Saudi Arabia
facility: Investigational Site Number : 6820004
city: Riyadh
country: Saudi Arabia
facility: Investigational Site Number : 6820006
city: Riyadh
country: Saudi Arabia
facility: Investigational Site Number : 6820001
city: Riyadh
country: Saudi Arabia
facility: Investigational Site Number : 6820002
city: Riyadh
country: Saudi Arabia
facility: Investigational Site Number : 6820010
city: Barcelona
country: Spain
facility: Investigational Site Number : 7240001
state: Barcelona [Barcelona]
city: Santiago de Compostela
country: Spain
facility: Investigational Site Number : 7240002
state: Galicia [Galicia]
city: Madrid
country: Spain
facility: Investigational Site Number : 7240005
state: Madrid, Comunidad De
city: Madrid
country: Spain
facility: Investigational Site Number : 7240003
state: Madrid, Comunidad De
city: Lund
country: Sweden
facility: Investigational Site Number : 7520001
city: Kaohsiung
country: Taiwan
facility: Investigational Site Number : 1580004
city: Taichung
country: Taiwan
facility: Investigational Site Number : 1580002
city: Tainan
country: Taiwan
facility: Investigational Site Number : 1580003
city: Taipei
country: Taiwan
facility: Investigational Site Number : 1580001
city: Chernivtsi
country: Ukraine
facility: Investigational Site Number : 8040003
city: Ivano-Frankivsk
country: Ukraine
facility: Investigational Site Number : 8040001
city: Kharkiv
country: Ukraine
facility: Investigational Site Number : 8040002
city: Kyiv
country: Ukraine
facility: Investigational Site Number : 8040004
city: Odesa
country: Ukraine
facility: Investigational Site Number : 8040005
city: Ternopil
country: Ukraine
facility: Investigational Site Number : 8040007
city: Leicester
country: United Kingdom
facility: Investigational Site Number : 8260001
state: Leicestershire
city: Bradford
country: United Kingdom
facility: Investigational Site Number : 8260002
Study officials:
References: