Asthma
Conditions
Brief summary
Primary Objective: To evaluate the effects of SAR440340 with or without dupilumab, compared to placebo, on reducing the incidence of loss of asthma control (LOAC) events. Secondary Objectives: To evaluate the effects of SAR440340/REGN3500 and coadministration of SAR440340 and dupilumab, compared with placebo, on forced expiratory volume in 1 second (FEV1). To evaluate the effects of coadministration of SAR440340 and dupilumab, compared with SAR440340 and compared with dupilumab, on FEV1. To assess safety and tolerability of SAR440340 alone and in coadministration with dupilumab.
Detailed description
The total duration of the study (per participant) was approximately 36 weeks, including 4 weeks screening, 12 weeks treatment, and 20 weeks post-treatment.
Interventions
DRUGSAR440340
Pharmaceutical form: Solution for Injection, Route of administration: SC
DRUGDupilumab
Pharmaceutical form: Solution for Injection, Route of administration: SC
DRUGFluticasone or Fluticasone/salmeterol combination
Pharmaceutical form: Aerosol, dry powder, Route of administration: Inhaled
DRUGPlacebo for SAR440340
Pharmaceutical form: Solution for Injection, Route of administration: SC
Pharmaceutical form: Solution for Injection, Route of administration: SC
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
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
: * Adult participants with a physician diagnosis of asthma for at least 12 months based on the Global Initiative for Asthma (GINA) 2017 Guidelines. * Participants with existing treatment with medium to high dose ICS (greater than or equal to \[\>=\] 250 microgram (mcg) of fluticasone propionate twice a day (BID) or equipotent ICS daily dosage to a maximum of 2000 mcg/day of fluticasone propionate or clinically comparable) in combination with a LABA as second controller for at least 3 months with a stable dose \>=1 month prior to Visit 1. * Participants with pre-bronchodilator FEV1 greater than (\>) 40 percent (%) of predicted normal at Visit 1/Screening. Pre-bronchodilator FEV1 \>=50% but less than or equal to (\<=) 85% of predicted normal at Visit 2/Baseline. * Participants with reversibility of at least 12% and 200 milliliters (mL) in FEV1 after administration of 2 to 4 puffs (200-400 microgram \[µg\]) of albuterol/salbutamol or levalbuterol/levosalbutamol during screening or documented history of a reversibility test that meets this criteria within 12 months prior to Visit 1 or documented positive response to methacholine challenge (a decrease in FEV by 20% \[PC20\] of less than \[\<\] 8 milligram per milliliter \[mg/mL\]) within 12 months prior to Visit 1/Screening is considered acceptable to meet this inclusion criterion. * Participants had experienced, within 1 year prior to Visit 1, any of the following events at least once: * Treatment with a systemic steroid (oral or parenteral) for worsening asthma. * Hospitalization or emergency medical care visit for worsening asthma. * Signed written informed consent.
Exclusion criteria
* Participants \<18 years or \>70 years of age (i.e., have reached the age of 71 at the screening visit). * Participants with body mass index (BMI) \<16. * Chronic lung disease (for example, chronic obstructive pulmonary disease \[COPD\], or idiopathic pulmonary fibrosis \[IPF\]), which might impair lung function. * History of life threatening asthma (i.e., severe exacerbation that required intubation). * Co-morbid disease that might interfere with the evaluation of investigational medicinal product (IMP). * Participants with any of the following events within the 4 weeks prior to their Screening Visit 1: * Treatment with 1 or more systemic (oral and/or parenteral) steroid bursts for worsening asthma; * Hospitalization or emergency medical care visit for worsening asthma. * Asthma Control Questionnaire 5-question version (ACQ-5) score \<1.25 or \>3.0 at Visit 2/randomization. During the screening period, an ACQ-5 of up to \<=4 was acceptable. * Anti-immunoglobulin E (IgE) therapy (e.g., omalizumab \[Xolair®\]) within 130 days prior to Visit 1 or any other biologic therapy (including anti interleukin-5 \[anti-IL5\] monoclonal antibodies \[mAb\]) or systemic immunosuppressant (e.g., methotrexate) to treat inflammatory disease or autoimmune disease (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) and other diseases, within 2 months or 5 half-lives prior to Visit 1, whichever was longer. * Participants with a history of a systemic hypersensitivity reaction to a biologic drug. * Participants on or initiation of bronchial thermoplasty within 2 years prior to Visit 1 or plan to begin therapy during the screening period or the randomized treatment period. * Current smoker or cessation of smoking within the 6 months prior to Visit 1. * Previous smoker with a smoking history \>10 pack-years. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Loss of Asthma Control | From Baseline up to Week 12 | An LOAC event during the 12-week treatment period was a deterioration of asthma defined as any of the following: a) 30 percent (%) or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days; b) greater than or equal to (\>=) 6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; c) increase in inhaled corticosteroid (ICS) \>=4 times the last prescribed ICS dose (or \>=50% of the prescribed ICS dose at Baseline if background therapy withdrawal completed); d) required use of systemic (oral and/or parenteral) steroid treatment; e) required hospitalization or emergency room visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | Baseline, Week 12 | FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Pre-bronchodilator FEV1 refers to the spirometry performed after a wash period of bronchodilators (i.e., not earlier than 6 hours) after the last dose of albuterol/salbutamol or levalbuterol/levosalbutamol from a primed meter dose inhaler and withholding the last dose of long-acting β2 adrenergic agonist (LABA) for at least 12 hours, and prior to administration of study drug. |
| Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second | Baseline, Week 12 | FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 refers to the spirometry performed within 30 minutes after administration of bronchodilator. |
Countries
Argentina, Chile, Mexico, Poland, Russia, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
The study was conducted from 12-March-2018 to 7-August-2019. Participants were screened at 70 centers across 8 countries, out of which 68 centers randomized at least 1 participant.
Pre-assignment details
A total of 499 participants were screened, out of which 296 participants were enrolled and randomized to 1 of the 4 treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received 2 SC injections of SAR440340 placebo along with 1 SC injection of dupilumab placebo Q2W for 12 weeks. | 74 |
| SAR440340 300 mg Participants received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab placebo, SC Q2W for 12 weeks. | 73 |
| SAR440340 + Dupilumab Participants received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab 300 mg, SC Q2W for 12 weeks. | 74 |
| Dupilumab 300 mg Participants received 1 injection of dupilumab 300 mg along with 2 injections of SAR440340 placebo, SC Q2W for 12 weeks. | 75 |
| Total | 296 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse event (AE) | 3 | 0 | 2 | 0 |
| Overall Study | Loss of asthma control (LOAC) | 28 | 16 | 20 | 14 |
| Overall Study | Other- Unspecified | 1 | 1 | 2 | 1 |
| Overall Study | Poor compliance to protocol | 0 | 0 | 0 | 1 |
| Overall Study | Randomized and not treated | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by participant | 1 | 1 | 3 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | Dupilumab 300 mg | SAR440340 + Dupilumab | SAR440340 300 mg |
|---|---|---|---|---|---|
| Age, Continuous | 47.0 years STANDARD_DEVIATION 11.4 | 49.1 years STANDARD_DEVIATION 12.6 | 51.3 years STANDARD_DEVIATION 12.7 | 49.1 years STANDARD_DEVIATION 12 | 49.0 years STANDARD_DEVIATION 13.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 6 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 71 Participants | 281 Participants | 73 Participants | 69 Participants | 68 Participants |
| Sex: Female, Male Female | 47 Participants | 189 Participants | 41 Participants | 51 Participants | 50 Participants |
| Sex: Female, Male Male | 27 Participants | 107 Participants | 34 Participants | 23 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 74 | 0 / 73 | 0 / 74 | 1 / 74 |
| other Total, other adverse events | 31 / 74 | 29 / 73 | 26 / 74 | 28 / 74 |
| serious Total, serious adverse events | 3 / 74 | 3 / 73 | 2 / 74 | 3 / 74 |
Outcome results
Primary
Percentage of Participants With Loss of Asthma Control
An LOAC event during the 12-week treatment period was a deterioration of asthma defined as any of the following: a) 30 percent (%) or greater reduction from baseline in morning peak expiratory flow (PEF) on 2 consecutive days; b) greater than or equal to (\>=) 6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; c) increase in inhaled corticosteroid (ICS) \>=4 times the last prescribed ICS dose (or \>=50% of the prescribed ICS dose at Baseline if background therapy withdrawal completed); d) required use of systemic (oral and/or parenteral) steroid treatment; e) required hospitalization or emergency room visit.
Time frame: From Baseline up to Week 12
Population: The analysis was performed on modified intent-to-treat (mITT) population that included all randomized participants who have received at least 1 dose of investigational medicinal product (IMP) analyzed according to the treatment group allocated by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Loss of Asthma Control | 40.5 percentage of participants |
| SAR440340 300 mg | Percentage of Participants With Loss of Asthma Control | 21.9 percentage of participants |
| SAR440340 + Dupilumab | Percentage of Participants With Loss of Asthma Control | 27.0 percentage of participants |
| Dupilumab 300 mg | Percentage of Participants With Loss of Asthma Control | 18.9 percentage of participants |
Comparison: Odds ratio, 95% confidence interval (CI), and p-value derived from logistic regression with treatment, baseline eosinophil strata, region, background ICS dose level at randomization and number of exacerbation events (defined as required use of systemic \[oral and/or parenteral\] steroid treatment, or required hospitalization or emergency room visit) within 1 year prior to screening.p-value: =0.021495% CI: [0.203, 0.88]Regression, Logistic
Comparison: Odds ratio, 95% CI, and p-value derived from logistic regression with treatment, baseline eosinophil strata, region, background ICS dose level at randomization and number of exacerbation events (defined as required use of systemic \[oral and/or parenteral\] steroid treatment, or required hospitalization or emergency room visit) within 1 year prior to screening.p-value: =0.070995% CI: [0.256, 1.057]Regression, Logistic
Secondary
Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second
FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Post-bronchodilator FEV1 refers to the spirometry performed within 30 minutes after administration of bronchodilator.
Time frame: Baseline, Week 12
Population: Analysis was performed on mITT population. Here, Overall number of participants analyzed signifies participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second | -0.02 liters | Standard Deviation 0.27 |
| SAR440340 300 mg | Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second | -0.00 liters | Standard Deviation 0.33 |
| SAR440340 + Dupilumab | Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second | 0.06 liters | Standard Deviation 0.41 |
| Dupilumab 300 mg | Change From Baseline at Week 12 in Post-bronchodilator Forced Expiratory Volume in 1 Second | 0.09 liters | Standard Deviation 0.42 |
Secondary
Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1)
FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Pre-bronchodilator FEV1 refers to the spirometry performed after a wash period of bronchodilators (i.e., not earlier than 6 hours) after the last dose of albuterol/salbutamol or levalbuterol/levosalbutamol from a primed meter dose inhaler and withholding the last dose of long-acting β2 adrenergic agonist (LABA) for at least 12 hours, and prior to administration of study drug.
Time frame: Baseline, Week 12
Population: Analysis was performed on mITT population. Here, Overall number of participants analyzed signifies participants with available data for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | 0.06 liters | Standard Deviation 0.35 |
| SAR440340 300 mg | Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | 0.11 liters | Standard Deviation 0.34 |
| SAR440340 + Dupilumab | Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | 0.06 liters | Standard Deviation 0.37 |
| Dupilumab 300 mg | Change From Baseline at Week 12 in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | 0.14 liters | Standard Deviation 0.43 |