Evaluation of SAR440340 and as Combination Therapy With Dupilumab in Moderate-to-Severe Asthma Participants

Study Overview
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Brief Summary
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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
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The total duration of the study (per participant) was approximately 36 weeks, including 4 weeks screening, 12 weeks treatment, and 20 weeks post-treatment.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, 12-week Proof-of-Concept (PoC) Study to Assess the Efficacy, Safety, and Tolerability of SAR440340 and the Coadministration of SAR440340 and Dupilumab in Patients With Moderate-to-Severe Asthma Who Are Not Well Controlled on Inhaled Corticosteroid (ICS) Plus Long-acting β2 Adrenergic Agonist (LABA) Therapy

Conditions
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Asthma

Intervention / Treatment
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* Drug: SAR440340
* Drug: Dupilumab
* Drug: Fluticasone or Fluticasone/salmeterol combination
* Drug: Placebo for SAR440340
* Drug: Placebo for dupilumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR440340<br>Participants received 2 injections of SAR440340 300 milligram (mg) along with 1 injection of dupilumab placebo, subcutaneous (SC) once every 2 weeks (Q2W) for 12 weeks. | Drug: SAR440340<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>* Other names: REGN3500;Drug: Fluticasone or Fluticasone/salmeterol combination<br>* Pharmaceutical form: Aerosol, dry powder, Route of administration: Inhaled<br>Drug: Placebo for dupilumab<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>|
| Active Comparator: Dupilumab<br>Participants received 1 injection of dupilumab 300 mg along with 2 injections of SAR440340 placebo, SC Q2W for 12 weeks. | Drug: Dupilumab<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>* Other names: SAR231893 (REGN668);Drug: Fluticasone or Fluticasone/salmeterol combination<br>* Pharmaceutical form: Aerosol, dry powder, Route of administration: Inhaled<br>Drug: Placebo for SAR440340<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>|
| Experimental: SAR440340 + Dupilumab<br>Participants received 2 injections of SAR440340 300 mg along with 1 injection of dupilumab 300 mg, SC Q2W for 12 weeks. | Drug: SAR440340<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>* Other names: REGN3500;Drug: Dupilumab<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>* Other names: SAR231893 (REGN668);Drug: Fluticasone or Fluticasone/salmeterol combination<br>* Pharmaceutical form: Aerosol, dry powder, Route of administration: Inhaled<br>|
| Placebo Comparator: Placebo<br>Participants received 2 SC injections of SAR440340 placebo along with 1 SC injection of dupilumab placebo Q2W for 12 weeks. | Drug: Fluticasone or Fluticasone/salmeterol combination<br>* Pharmaceutical form: Aerosol, dry powder, Route of administration: Inhaled<br>Drug: Placebo for SAR440340<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>Drug: Placebo for dupilumab<br>* Pharmaceutical form: Solution for Injection, Route of administration: SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Baseline up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Week 12 | 
| 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. | Baseline, Week 12 |