Chronic Obstructive Pulmonary Disease
Conditions
Brief summary
Primary Objective: To investigate effects of SAR440340 (anti-interleukin-33 \[IL-33\] monoclonal antibody \[mAb\]) compared with placebo, on the annualized rate of moderate-to-severe acute exacerbations of COPD (AECOPD) over up to 52 weeks of treatment. * Moderate exacerbations were recorded by the Investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. * Severe exacerbations were recorded by the Investigator and defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death. Secondary Objectives: To investigate effects of SAR440340 compared with placebo, on improving respiratory function, as assessed by pre-bronchodilator forced exploratory volume in 1 second (FEV1). To evaluate effects of SAR440340 compared with placebo, on post-bronchodilator FEV1. To evaluate effects of SAR440340 compared with placebo, on duration from baseline to first moderate or severe AECOPD event. To evaluate effects of SAR440340 compared with placebo, on safety and tolerability.
Detailed description
Study participation for each participant were up to a total of 46 weeks to 76 weeks including up to 10 days to 4 weeks of screening, 24-to-52 week treatment period on investigational medical product (IMP), and 20 weeks of post IMP treatment period.
Interventions
DRUGSAR440340
Pharmaceutical form: Solution for injection; Route of administration: SC
DRUGPlacebo
Pharmaceutical form: Solution for injection; Route of administration: SC
DRUGAny Inhaled Corticosteroids as prescribed by treating physician as standard of care
Pharmaceutical form: Aerosol or Dry Powder inhaler Route of administration: Inhaled
DRUGAny Long Acting Beta Agonist as prescribed by treating physician as standard of care
Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: Inhaled
DRUGAny Long Acting Muscarinic Agonist as prescribed by treating physician as standard of care
Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: Inhaled
DRUGAny short-acting β agonist as prescribed by treating physician as standard of care
Pharmaceutical form: Aerosol or Dry Powder inhaler; Route of administration: inhaled
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
: * Participants with a diagnosis of chronic obstructive pulmonary disease (COPD) for at least 1 year (based on Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] definition). * Participants with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 second \[FEV1\]/forced vital capacity \[FVC\] less than \[\<\] 70 percent (%) and post-bronchodilator FEV1% predicted \<80%, but greater than equal to \[\>=\] 30%). * Participants with COPD assessment test (CAT) score \>=10 at Screening. * Participants with reported history of signs and symptoms of chronic bronchitis (chronic productive cough for 3 months in the year up to screening in a participant in whom other causes of chronic cough \[e.g., gastroesophageal reflux, chronic rhinosinusitis, bronchiectasis\] had been excluded). * Participants with a documented history (e.g., medical record verification) of \>=2 moderate exacerbations or \>=1 severe exacerbation within the year prior to screening. A moderate exacerbation was defined as an acute exacerbation of COPD (AECOPD) requiring systemic corticosteroids (oral, intravenous, or intramuscular) and/or treatment with antibiotics (however, use of antibiotics alone does not qualify as a moderate exacerbation unless documentation was available that use of antibiotics was necessary for treatment of worsening symptoms of COPD). A severe exacerbation was defined as an AECOPD that required a hospitalization. * Participants with standard of care background therapy, for 3 months and at a stable dose for at least 1 month, including either: * Double therapy: Long acting beta agonist (LABA) + Long acting muscarinic agonist (LAMA) or inhaled corticosteroid (ICS) + LABA or ICS + LAMA. or * Triple therapy: LABA + LAMA + ICS. * Current or former smokers with a smoking history of \>=10 packs/year.
Exclusion criteria
* Concomitant severe diseases or diseases for which the use of ICS (e.g., active pulmonary tuberculosis, etc.) or LABA were contraindicated (e.g., diagnosis of a history of significant cardiovascular diseases, insulin-dependent diabetes mellitus, hyperthyroidism, thyrotoxicosis, pheochromocytoma, hypokalemia). * Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within previous 1 month or more than 4 courses of intravenous glucocorticosteroids within the previous 6 months. * Participants with bronchial thermoplasty procedure (up to 3 years prior to Visit 1). * A current diagnosis of asthma according to the Global Initiative for Asthma (GINA) guidelines. * Significant pulmonary disease other than COPD (e.g., lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, eosinophilic granulomatosis with polyangiitis, significant sleep apnea on Bilevel Positive Airway Pressure, etc.) or another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts. * Diagnosis of α-1 anti-trypsin deficiency. * Advanced COPD with need for chronic (greater than \[\>\] 15 hours/day) oxygen support. * Participant with a moderate or severe acute exacerbation of COPD event within previous 4 weeks. * A participant who has experienced an upper or lower respiratory tract infection within previous 4 weeks. * Prior history of or planned pneumonectomy or lung volume reduction surgery. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Moderate to Severe Acute Exacerbation Events in Chronic Obstructive Pulmonary Disease (AECOPD) Participants | From Baseline up to Week 52 | Moderate exacerbations events were recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations events were defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Change in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) From Baseline to Week 16 Through Week 24 | From Baseline to Week 16 through Week 24 | FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. A mixed-effect model with repeated measures (MMRM) was first used to model the change from baseline at each post randomization timepoint up to Week 24, then the predicted values of Week 16 to Week 24 were averaged to provide an overall assessment of change from baseline in FEV1. |
| Change From Baseline in Post-bronchodilator Forced Expiratory Volume (FEV1) in 1 Second at Week 24 | Baseline, Week 24 | FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator (4 puffs of salbutamol/albuterol \[100 micrograms {mcg}\] or ipratropium bromide \[20 mcg\]). |
| Time to First Moderate or Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) | From Baseline up to 52 weeks | The time to first moderate or severe exacerbation was defined as onset date of first moderate or severe AECOPD minus randomization date + 1. The median time to first severe exacerbation was derived from Kaplan-Meier estimates. Moderate exacerbations events were recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations events were defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death. |
Countries
Argentina, Australia, Canada, Chile, Germany, Poland, Russia, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 83 centers in 10 countries, out of which 78 centers randomized at least 1 participant. A total of 653 participants were screened from 16-July-2018 to 01-April-2019, of which 310 participants were screen failures mainly due to selection criteria not met.
Pre-assignment details
A total of 343 participants were randomized and treated in this study. Participants were randomized in 1:1 ratio to receive treatment SAR440340 and matching placebo for SAR440340.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo matched to SAR440340 administered as 2 SC injections Q2W. Participants were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52). | 171 |
| SAR440340 Participants received SAR440340 300 mg administered as 2 SC injections Q2W. Participants were treated for a minimum of 24 weeks and up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of IMP i.e., at Week 52). | 172 |
| Total | 343 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse events (AEs) | 7 | 10 |
| Overall Study | Lack of Efficacy | 1 | 1 |
| Overall Study | Other-unspecified | 1 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 9 |
Baseline characteristics
| Characteristic | Placebo | Total | SAR440340 |
|---|---|---|---|
| Age at diagnosis of chronic obstructive pulmonary disease (COPD) | 55.5 years STANDARD_DEVIATION 8 | 55.4 years STANDARD_DEVIATION 7.9 | 55.4 years STANDARD_DEVIATION 7.8 |
| Age, Continuous | 64.0 years STANDARD_DEVIATION 6.5 | 63.9 years STANDARD_DEVIATION 6.7 | 63.7 years STANDARD_DEVIATION 6.8 |
| Baseline blood eosinophil count | 0.25 Giga cells per liter STANDARD_DEVIATION 0.19 | 0.26 Giga cells per liter STANDARD_DEVIATION 0.22 | 0.27 Giga cells per liter STANDARD_DEVIATION 0.24 |
| Baseline COPD assessment test (CAT) score | 21.66 score on a scale STANDARD_DEVIATION 5.23 | 21.78 score on a scale STANDARD_DEVIATION 5.54 | 21.89 score on a scale STANDARD_DEVIATION 5.84 |
| Mean number of moderate COPD exacerbations experienced within 1 year before screening visit | 1.8 exacerbations STANDARD_DEVIATION 1.2 | 1.8 exacerbations STANDARD_DEVIATION 1.2 | 1.8 exacerbations STANDARD_DEVIATION 1.1 |
| Mean number of severe COPD exacerbations experienced within 1 year before screening visit | 0.4 exacerbations STANDARD_DEVIATION 0.6 | 0.4 exacerbations STANDARD_DEVIATION 0.6 | 0.3 exacerbations STANDARD_DEVIATION 0.6 |
| Number of participants with smoking history Current | 82 Participants | 156 Participants | 74 Participants |
| Number of participants with smoking history Former | 89 Participants | 187 Participants | 98 Participants |
| Predicted baseline post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) | 49.02 percent predicted FEVI STANDARD_DEVIATION 12.18 | 49.32 percent predicted FEVI STANDARD_DEVIATION 12.25 | 49.62 percent predicted FEVI STANDARD_DEVIATION 12.34 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 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 | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 169 Participants | 339 Participants | 170 Participants |
| Sex: Female, Male Female | 76 Participants | 149 Participants | 73 Participants |
| Sex: Female, Male Male | 95 Participants | 194 Participants | 99 Participants |
| Standard of care background therapy ICS+LABA | 34 Participants | 67 Participants | 33 Participants |
| Standard of care background therapy ICS+LABA+LAMA | 111 Participants | 226 Participants | 115 Participants |
| Standard of care background therapy ICS+LAMA | 0 Participants | 1 Participants | 1 Participants |
| Standard of care background therapy LABA+LAMA | 26 Participants | 49 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 171 | 3 / 172 |
| other Total, other adverse events | 78 / 171 | 60 / 172 |
| serious Total, serious adverse events | 36 / 171 | 29 / 172 |
Outcome results
Primary
Annualized Rate of Moderate to Severe Acute Exacerbation Events in Chronic Obstructive Pulmonary Disease (AECOPD) Participants
Moderate exacerbations events were recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations events were defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.
Time frame: From Baseline up to Week 52
Population: Analysis was performed on modified intent-to-treat (mITT) population that included all randomized participants who had received at least 1 dose of IMP, analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Annualized Rate of Moderate to Severe Acute Exacerbation Events in Chronic Obstructive Pulmonary Disease (AECOPD) Participants | 1.610 exacerbation per participant-year |
| SAR440340 | Annualized Rate of Moderate to Severe Acute Exacerbation Events in Chronic Obstructive Pulmonary Disease (AECOPD) Participants | 1.301 exacerbation per participant-year |
Comparison: Analysis was performed using negative binomial regression model with total number of events occurring during observation duration as response variable, treatment, baseline eosinophil strata, region, number of severe COPD exacerbations experienced in previous year(0 vs. 1+) at baseline, smoking history(current vs. former smoker), post-BD FEV1 percent(%) predicted (less than\[\<\] 50% vs greater than equal\[\>=\]50%) at baseline as covariates, and log-transformed observation duration as offset variable.p-value: 0.129695% CI: [0.613, 1.065]Negative binomial regression model
Secondary
Average Change in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) From Baseline to Week 16 Through Week 24
FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Spirometry was performed after a wash out period of bronchodilators according to their action duration. A mixed-effect model with repeated measures (MMRM) was first used to model the change from baseline at each post randomization timepoint up to Week 24, then the predicted values of Week 16 to Week 24 were averaged to provide an overall assessment of change from baseline in FEV1.
Time frame: From Baseline to Week 16 through Week 24
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Average Change in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) From Baseline to Week 16 Through Week 24 | 0.0 liters | Standard Error 0.02 |
| SAR440340 | Average Change in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) From Baseline to Week 16 Through Week 24 | 0.06 liters | Standard Error 0.02 |
Secondary
Change From Baseline in Post-bronchodilator Forced Expiratory Volume (FEV1) in 1 Second at Week 24
FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 referred to the spirometry performed within 30 minutes after administration of bronchodilator (4 puffs of salbutamol/albuterol \[100 micrograms {mcg}\] or ipratropium bromide \[20 mcg\]).
Time frame: Baseline, Week 24
Population: Analysis was performed on mITT population. Here, 'Overall number of participants analyzed ' signifies number of participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Post-bronchodilator Forced Expiratory Volume (FEV1) in 1 Second at Week 24 | 0.01 liters | Standard Deviation 0.22 |
| SAR440340 | Change From Baseline in Post-bronchodilator Forced Expiratory Volume (FEV1) in 1 Second at Week 24 | 0.04 liters | Standard Deviation 0.24 |
Secondary
Time to First Moderate or Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD)
The time to first moderate or severe exacerbation was defined as onset date of first moderate or severe AECOPD minus randomization date + 1. The median time to first severe exacerbation was derived from Kaplan-Meier estimates. Moderate exacerbations events were recorded by the investigator and defined as AECOPD that require either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. Severe exacerbations events were defined as AECOPD requiring hospitalization, emergency medical care visit or resulting in death.
Time frame: From Baseline up to 52 weeks
Population: Analysis was performed on mITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Moderate or Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) | 199.0 days |
| SAR440340 | Time to First Moderate or Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) | 277.0 days |