Trial Outcomes & Findings for The Effect of Dupilumab on Lung Inflammation and Related Changes in Airway Volumes Detectable by Functional Respiratory Imaging in Patients With Moderate-severe Asthma (NCT NCT04400318)

A total of 317 participants were screened from 20 Jun 2020 to 06 Jan 2023 at 72 study sites in 14 countries of which 208 participants were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.

A total of 109 participants were randomized in a ratio of 2:1 to receive dupilumab 300 milligrams (mg) or matching placebo every 2 weeks (Q2W) for 24 weeks. Randomization was stratified by inhaled corticosteroids (ICS) dose level (medium/high no less than 40% in 'high ICS' stratum) and region (Eastern Europe/Rest of the World \[ROW\]).

Only those participants with data available at baseline are reported.

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.

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).

The mucus scoring system was derived, with very minor differences, from UCSF mucus score. The mucus score was calculated by counting the number of bronchopulmonary segments which contained 1 or more mucus plug, up to a maximum score of 18 corresponding to the 18 bronchopulmonary segments present in most people. In this system, a mucus plug is defined as a complete occlusion of the airway visible at TLC. Each bronchopulmonary segment is given a score of 1 (mucus plug\[s\] present) or 0 (mucus plug\[s\] absent). The segment scores of each lobe are summed to generate a total mucus score for both lungs, yielding a mucus score ranging from 0-18. Higher scores indicate worse outcome. Baseline was defined as the last available valid (non-missing) value up to and including the date of first dose of IMP.

iRaw is defined as the total pressure drop over an airway, divided by the flow rate through that airway. The specific airway resistance (s)iRaw is derived from iRaw by multiplying the airway resistance with the lobar volume. This way, the airway resistances are normalized across participants and become specific. Trimmed distal (\[s\]iRaw) at TLC was assessed using HRCT scan. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of IMP.

(s)iVaw is the change of volume of the airways (mL), taking into account the lung volume changes (in L) as well. It corresponds to the ratio between the airway volume (iVaw) and the lobar volume. Untrimmed distal \[s\]iVaw at FRC was assessed based on 3-D rendering of HRCT scans. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of IMP.

iRaw is defined as the total pressure drop over an airway, divided by the flow rate through that airway. The specific airway resistance (s)iRaw is derived from iRaw by multiplying the airway resistance with the lobar volume. This way, the airway resistances are normalized across participants and become specific. Trimmed distal \[s\]iRaw at FRC was assessed using HRCT scan. Baseline was defined as the last available valid (non-missing) value up to and including the day of the first dose of IMP.

The lung volume was determined from the HRCT scan at TLC, by identifying and grouping the voxels that represent the air in the lungs. The total lung volume along with the volume of each lobe individually was determined which allowed to pick up substantial regional physiological changes of the airways and the lobe volumes. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of IMP.

The IAD was assessed in the upper and lower lung using HRCT scan. By segmenting the lobes at FRC and TLC for each participant, the participant-specific airflow distribution can be established by assessing lobar and volume expansion. Baseline was defined as the last available valid (non-missing) value up to and including the date of the first dose of IMP.

Blood vessel density can be considered a surrogate for perfusion, hence image-based perfusion (IQ) is calculated by blood vessel density at TLC multiplied by image-based volume at TLC. Image-based ventilation (IV) is calculated by the imaged volume at TLC subtracted from the image-based volume at FRC. The ventilation/perfusion ratio IV/Q is then the ratio IV/IQ. The iV/Q was assessed in the upper and lower lung using HRCT scan at TLC. Baseline was defined as the last available valid (non-missing) value up to and including the day of the first dose of IMP.

FeNO was analyzed using a NIOX instrument using a flow rate of 50 mL/s. This assessment was conducted prior to spirometry and following a fast of ≥1 hour. The test was performed after a wash out period of bronchodilators. Baseline was defined as the last available valid (non-missing) value up to and including the day of the first dose of IMP.

FEV1 was the volume of air exhaled in the first second of a forced expiration. Lung function parameters: pre- and post-bronchodilator FEV1 were measured by spirometry before IMP administration. Spirometry was performed after a wash out period of bronchodilators. Post-BD FEV1 was measured within 30 minutes after short-acting beta-2 agonists (2 to up to 4 puffs of albuterol/salbutamol) administration. Baseline was defined as the last available valid (non-missing) value up to and including the date of the first dose of IMP.

The ACQ-7 comprises of 7 items:first 5 items assess most common asthma symptoms: 1. frequency in past week awoken by asthma during the night; 2. severity of asthma symptoms in the morning; 3. limitation of daily activities due to asthma; 4. shortness of breath due to asthma; and 5. wheeze; plus questions 6. short-acting bronchodilator use; and 7. FEV1 (pre-bronchodilator use, % and % predicted use).Participants are asked to recall how their asthma has been during the previous week and to respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum impairment).Clinic staff scores the FEV1% predicted on a 7-point scale.A global score is calculated: the questions are equally weighted, and the overall ACQ-7 score is the mean of the 7 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled).Higher score indicates lower asthma control. Baseline=last available valid (non-missing) value up to and including day of the first dose of IMP.

AE: any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs: AEs that developed or worsened or became serious during the TEAE period, defined as the time from the first administration of the IMP (on Day 1) to the last administration of the IMP + 98 days and up to the end of the study follow-up. Serious adverse events (SAE): AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. AESI: AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor is required.