Asthma
Conditions
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.
Interventions
DRUGDupilumab
solution for injection subcutaneous
DRUGPlacebo
Solution for injection subcutaneous
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (Ppb) at Week 24 | 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) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | (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. |
| Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC | Baseline (Day 1) to Week 24 | 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. |
| Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC | Baseline (Day 1) to Week 24 | 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. |
| Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone | Baseline (Day 1) to Week 24 | 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. |
| 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 | 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. |
| Change From Baseline to Week 24 in FeNO | Baseline (Day 1) to Week 24 | 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. |
| 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 | 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. |
| Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7) | Baseline (Day 1) to Week 24 | 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. |
| 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) | 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. |
| 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 | 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. |
| Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC | Baseline (Day 1) to Week 24 | 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. |
Countries
Bulgaria, Denmark, France, Italy, Portugal, Romania, Saudi Arabia, Spain, Sweden, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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 \[ROW\]).
Participants by arm
| Arm | Count |
|---|---|
| Dupilumab 300 mg Q2W Participants received a loading dose of dupilumab 600 mg as 2 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. | 72 |
| 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. | 37 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Not Related to Coronavirus Disease 2019 Pandemic | 0 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Dupilumab 300 mg Q2W | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 51.0 years STANDARD_DEVIATION 12.81 | 50.4 years STANDARD_DEVIATION 12.62 | 49.4 years STANDARD_DEVIATION 12.33 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 10 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 64 Participants | 98 Participants | 34 Participants |
| Sex: Female, Male Female | 46 Participants | 68 Participants | 22 Participants |
| Sex: Female, Male Male | 26 Participants | 41 Participants | 15 Participants |
| Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC) | 1.90526 mL STANDARD_DEVIATION 0.954024 | 1.90539 mL STANDARD_DEVIATION 1.022934 | 1.90562 mL STANDARD_DEVIATION 1.161739 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 72 | 0 / 37 |
| other Total, other adverse events | 18 / 72 | 15 / 37 |
| serious Total, serious adverse events | 3 / 72 | 1 / 37 |
Outcome results
Primary
Percentage of Participants Who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (Ppb) at 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.
Time frame: Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dupilumab 300 mg Q2W | Percentage of Participants Who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (Ppb) at Week 24 | 56.9 percentage of participants |
| Placebo | Percentage of Participants Who Achieved Fractional Exhaled Nitric Oxide (FeNO) Less Than (<) 25 Parts Per Billion (Ppb) at Week 24 | 10.8 percentage of participants |
Comparison: Odds Ratio, 95% confidence interval (CI) of the odds ratio and p-value between the dupilumab and placebo group based on the Cochran-Mantel-Haenszel (CMH) test adjusted by ICS dose level (medium/high) and region (Eastern Europe/ROW).p-value: <0.00195% CI: [3.13, 30.82]Cochran-Mantel-Haenszel
Primary
Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC)
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).
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC) | 19.73 percent change | Standard Error 8.102 |
| Placebo | Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Total Lung Capacity (TLC) | -2.04 percent change | Standard Error 11.538 |
Comparison: The mixed model for repeated measures (MMRM) included study intervention, baseline value, region, ICS dose level, visits, study intervention by visit interaction, and baseline by visit interaction terms all as fixed effects. Region, ICS, study intervention and visits were considered as categorical parameters.p-value: 0.13895% CI: [-7.73, 51.25]MMRM
Secondary
Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7)
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7) | -1.36 score on a scale | Standard Error 0.101 |
| Placebo | Change From Baseline to Week 24 in 7 Item Asthma Control Questionnaire (ACQ-7) | -0.62 score on a scale | Standard Error 0.143 |
Secondary
Change From Baseline to Week 24 in FeNO
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in FeNO | -35.49 parts per billion | Standard Error 2.44 |
| Placebo | Change From Baseline to Week 24 in FeNO | -12.56 parts per billion | Standard Error 3.444 |
Secondary
Change From Baseline to Week 24 in Global Lung Mucus Score (University of California, San Francisco [UCSF] Mucus Scoring)
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in Global Lung Mucus Score (University of California, San Francisco [UCSF] Mucus Scoring) | -3.48 score on a scale | Standard Error 0.463 |
| Placebo | Change From Baseline to Week 24 in Global Lung Mucus Score (University of California, San Francisco [UCSF] Mucus Scoring) | 1.44 score on a scale | Standard Error 0.656 |
Comparison: MMRM model included study intervention (dupilumab, placebo), baseline value of global lung UCSF mucus scoring, region (Eastern Europe/ROW), ICS dose level (medium/high), visit (up to Week 24), study intervention-by-visit interaction and baseline-by-visit interaction as covariates.p-value: <0.00195% CI: [-6.5, -3.34]MMRM
Secondary
Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone | Upper Lung | -0.61 percentage of IAD | Standard Error 0.803 |
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone | Lower Lung | 0.61 percentage of IAD | Standard Error 0.803 |
| Placebo | Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone | Upper Lung | -0.11 percentage of IAD | Standard Error 1.133 |
| Placebo | Change From Baseline to Week 24 in HRCT-Based Internal Airflow Distribution (IAD) for Each Lung Zone | Lower Lung | 0.11 percentage of IAD | Standard Error 1.133 |
Secondary
Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone | Upper Lung | 1.42 Ratio | Standard Error 0.538 |
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone | Lower Lung | 1.75 Ratio | Standard Error 0.579 |
| Placebo | Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone | Upper Lung | -0.45 Ratio | Standard Error 0.758 |
| Placebo | Change From Baseline to Week 24 in Image-Based Ventilation/Perfusion (iV/Q) at TLC for Each Lung Zone | Lower Lung | -0.91 Ratio | Standard Error 0.817 |
Secondary
Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | Pre-Bronchodilator FEV1 | 0.655 liter | Standard Error 0.0637 |
| Dupilumab 300 mg Q2W | Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | Post-Bronchodilator FEV1 | 0.468 liter | Standard Error 0.0661 |
| Placebo | Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | Pre-Bronchodilator FEV1 | 0.274 liter | Standard Error 0.0885 |
| Placebo | Change From Baseline to Week 24 in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | Post-Bronchodilator FEV1 | 0.151 liter | Standard Error 0.0928 |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs)
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.
Time frame: From first dose of study drug (Day 1) up to end of study (up to 36 weeks)
Population: The safety analysis set included all randomized participants who received at least 1 injection of IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs) | Any TEAE | 31 Participants |
| Dupilumab 300 mg Q2W | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs) | Any TESAE | 3 Participants |
| Dupilumab 300 mg Q2W | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs) | Any AESI | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs) | Any TEAE | 21 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs) | Any TESAE | 1 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), and Adverse Events of Special Interest (AESIs) | Any AESI | 0 Participants |
Secondary
Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC | -0.98 percent change | Standard Error 1.691 |
| Placebo | Percent Change From Baseline to Week 24 in Global Lung Lobar Volumes (iVlobes) at TLC | -3.74 percent change | Standard Error 2.401 |
Secondary
Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC | 98.73 percent change | Standard Error 70.143 |
| Placebo | Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at FRC | 207.87 percent change | Standard Error 98.445 |
Secondary
Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC
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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC | 36.85 percent change | Standard Error 22.562 |
| Placebo | Percent Change From Baseline to Week 24 in Trimmed Distal Specific Airway Resistance ([s]iRaw) at TLC | 90.30 percent change | Standard Error 32.541 |
Comparison: MMRM model included study intervention (dupilumab, placebo), baseline value of trimmed distal \[s\]iRaw at TLC, region (Eastern Europe/ROW), ICS dose level (medium/high), visit (up to Week 24), study intervention-by-visit interaction, and baseline-by-visit interaction as covariates.p-value: 0.1895% CI: [-132.09, 25.19]MMRM
Secondary
Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Functional Residual Capacity (FRC)
(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.
Time frame: Baseline (Day 1) to Week 24
Population: The ITT analysis set consisted of randomized participants (participants with a study intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether the study intervention kit was used or not). Only participants with data collected at Week 24 are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dupilumab 300 mg Q2W | Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Functional Residual Capacity (FRC) | 225.91 percent change | Standard Error 92.25 |
| Placebo | Percent Change From Baseline to Week 24 in Untrimmed Distal Specific Airway Volumes ([s]iVaw) at Functional Residual Capacity (FRC) | -17.07 percent change | Standard Error 129.384 |