Dose Ranging Study of Amlitelimab in Adult Participants With Moderate-to-severe Asthma

Study Overview
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Brief Summary
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This is a parallel, Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, four-arms study for treatment. The purpose of this study is to assess the efficacy, safety, and tolerability of add-on therapy with amlitelimab in adult participants with moderate-to-severe asthma. Study details include: The study duration (per participant) will be up to approximately 76 weeks for participants not going into LTS study and will be up to approximately 64 weeks for participants going into LTS study. The randomized treatment duration will be up to approximately 60 weeks. The scheduled number of visits will be 13.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose Ranging Study to Assess the Efficacy, Safety, and Tolerability of Subcutaneous Amlitelimab in Adult Participants With Moderate-to-severe Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Amlitelimab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant must be between the ages of 18 and 75 inclusive at the time of signing the informed consent. Moderate to severe asthma diagnosed by a physician for ≥ 12 months according to stages 4 and 5 of the Global Initiative for Asthma (GINA ). Participants on existing therapy with medium to high doses of ICS (≥500 μg fluticasone propionate daily or comparable ICS dose in combination with at least one additional controller (e.g., long-acting beta agonist [LABA], leukotriene receptor antagonist [LTRA], long-acting muscarinic antagonist [LAMA], methylxanthines) for at least 3 months. ≥ 1 severe asthma exacerbation in the past year, with at least one exacerbation during treatment with medium to high doses of ICS (≥ 500 μg fluticasone propionate daily or one dose of ICS comparable). Participants with pre-BD forced expiratory volume in 1 second (FEV1) > 40% and < 80% of predicted normal at the screening visit. 5-item ACQ-5 score >1.5 at randomization. Participants with at least 12% reversibility and 200 mL post-BD FEV after administration of albuterol/salbutamol or levalbuterol/levosalbutamol at screening or documented history of a reversibility test. Weight ≥40 kg and ≤150 kg at the randomization visit. Exclusion Criteria: Participants are excluded from the study if any of the following criteria apply: Chronic lung disease other than asthma. Current or former smoker including active vaping of any products and/or marijuana with cessation within 6 months of screening or history of >10 pack-years. Participants who experience a deterioration of asthma that results in emergency treatment or hospitalization, or treatment with systemic steroids at any time from 1 month prior to screening. Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection during the screening period including known history of COVID-19 infection within 4 weeks prior to Screening; mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to COVID-19 within 3 months prior to Screening; COVID-19 infection who have not yet sufficiently recovered to participate in the procedures of a clinical trial. Active infection or history of clinically significant infection Known history of, or suspected, significant current immunosuppression, including history of invasive opportunistic or helminthic infections despite infection resolution or otherwise recurrent infections of abnormal frequency or prolonged duration. Active or latent tuberculosis (TB) A history of malignancy of any type (excluding basal and squamous cell skin cancer and in situ cervical carcinoma that has been excised and cured >3 years prior to baseline). History of solid organ transplant. Hepatitis B, C or HIV. Pregnant or breastfeeding. History (within last 2 years prior to Baseline) of prescription drug or substance abuse, including alcohol, considered significant by the Investigator. Any prior use of anti-OX40 or anti-OX40L mAb, including amlitelimab. 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. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Amlitelimab dose level 1<br>Initial loading dose of amlitelimab on Day 1, followed by one injection of amlitelimab dose level 1 every 4 weeks (Q4W) until Week 20 (inclusive) and every 12 weeks (Q12W) starting from Week 24 and thereafter. | Drug: Amlitelimab<br>* Injection solution Subcutaneous injection<br>|
| Experimental: Amlitelimab dose level 2<br>Initial loading dose of amlitelimab on Day 1, followed by one injection of amlitelimab dose level 2 Q4W until Week 20 (inclusive) and Q12W starting from Week 24 and thereafter. | Drug: Amlitelimab<br>* Injection solution Subcutaneous injection<br>|
| Experimental: Amlitelimab dose level 3<br>Initial loading dose of amlitelimab on Day 1, followed by one injection of amlitelimab dose level 3 Q4W until Week 20 (inclusive) and Q12W starting from Week 24 and thereafter. | Drug: Amlitelimab<br>* Injection solution Subcutaneous injection<br>|
| Placebo Comparator: Placebo<br>Initial loading dose of amlitelimab matching placebo on Day 1, followed by one injection of amlitelimab matching placebo Q4W until Week 20 (inclusive) and Q12W starting from Week 24 and thereafter. | Drug: Placebo<br>* Injection solution Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of severe exacerbation events over 48 weeks | Severe exacerbation events are defined as: worsening of asthma requiring the use of systemic corticosteroids for ≥3 days or, in the case of a stable maintenance regimen of oral corticosteroids for the treatment of asthma, a doubling of the dose for 3 or more days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. | Baseline through Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pre-bronchodilator (BD) FEV1 at Week 48 | Change from baseline in pre-bronchodilator (BD) FEV1 at Week 48. | Baseline to Week 48 | 
| Change from baseline in Asthma Control Questionnaire 5 (ACQ-5) score at Week 48 | The ACQ-5 has five questions on the asthma symptoms. The score ranges from 0 (totally controlled) and 6 (severely uncontrolled). A high score indicates low asthma control. | Baseline to Week 48 | 
| Change from baseline in Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ (S)) Self-Administered Score at Week 48 | The AQLQ(S) is designed as a self-administered participant reported outcome to measure the functional impairments. The overall score is 1 to 7. Higher AQLQ scores indicate better health-related quality of life. | Baseline to Week 48 | 
| Change from baseline in post-BD FEV1 at Week 48 | Change from baseline in post-BD FEV1 at Week 48. | Baseline to Week 48 | 
| The absolute change in the percent predicted FEV1 from baseline to Week 48 (pre-BD and post-BD) | The absolute change in the percent predicted FEV1 from baseline to Week 48 (pre-BD and post-BD). | Baseline to Week 48 | 
| Change from baseline in ACQ-5 score at Weeks 2, 4, 8, 12, 24, 36, and 60 | The ACQ-5 has five questions on the asthma symptoms. The score ranges from 0 (totally controlled) and 6 (severely uncontrolled). A high score indicates low asthma control. | Baseline to Weeks 2, 4, 8, 12, 24, 36, and 60 | 
| Time to first severe exacerbation event | Severe exacerbation events are defined as: worsening of asthma requiring the use of systemic corticosteroids for ≥3 days or, in the case of a stable maintenance regimen of oral corticosteroids for the treatment of asthma, a doubling of the dose for 3 or more days; or hospitalization or emergency room visit because of asthma, requiring systemic corticosteroids. | Baseline through Week 48 | 
| Change from baseline in pre-BD and post-BD FEV1 | Change from baseline in pre-BD and post-BD FEV1. | Baseline to Weeks 2, 4, 8, 12,16, 24, 36 and 60 | 
| Change from baseline in peak expiratory flow (PEF) and forced expiratory flow (FEF) 25-75% | Change from baseline in peak expiratory flow (PEF) and forced expiratory flow (FEF) 25-75%. | Baseline to Weeks 4, 12, 24, 36, 48 and 60 | 
| Change from baseline in forced vital capacity (FVC) | Change from baseline in forced vital capacity (FVC). | Baseline to Weeks 4, 12, 24, 36, 48 and 60 | 
| Change from baseline in FeNO at Weeks 2, 4, 8, 12, 16, 24, 36, 48 and 60 | Change from baseline in FeNO at Weeks 2, 4, 8, 12, 16, 24, 36, 48 and 60. | Baseline to Weeks 2, 4, 8, 12, 16, 24, 36, 48 and 60 | 
| Annualized rate of loss of asthma control (LOAC) events during 48 weeks of treatment | LOAC events are defined by one or several of the following criteria: A 30% or greater reduction from baseline in morning PEF on 2 consecutive days. ≥6 additional reliever puffs of short-acting beta-agonists (SABA) OR ≥4 additional puffs of low-dose inhaled corticosteroid (ICS)/formoterol in a 24-hour period (compared to baseline) on 2 consecutive days Increase in ICS ≥4 times than the Visit 2 dose Severe exacerbation event | Baseline through Week 48 | 
| Time to first LOAC event | LOAC events are defined by one or several of the following criteria: A 30% or greater reduction from baseline in morning PEF on 2 consecutive days. ≥6 additional reliever puffs of short-acting beta-agonists (SABA) OR ≥4 additional puffs of low-dose ICS/formoterol in a 24-hour period (compared to baseline) on 2 consecutive days Increase in ICS ≥4 times than the Visit 2 dose Severe exacerbation event | Baseline through Week 48 | 
| Change from baseline in the Asthma Daytime Symptom Diary (ADSD) 7-item daily morning score and in the Asthma Nighttime Symptom Diary (ANSD) 7-item daily evening scores at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | ADSD and ANSD have been designed to measure asthma symptoms. Both have overall score from 0- 10 with higher score indicating worse symptom. | Baseline to Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | 
| Annualized rate of severe asthma exacerbations requiring hospitalization or emergency room or urgent care visit during 48 weeks of treatment | Annualized rate of severe asthma exacerbations requiring hospitalization or emergency room or urgent care visit during 48 weeks of treatment. | Baseline through Week 48 | 
| Change from baseline in the numbers of inhalations/day of SABA or low-dose ICS/formoterol for symptom relief at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | Change from baseline in the numbers of inhalations/day of SABA or low-dose ICS/formoterol for symptom relief at Weeks 2, 4, 8, 12, 24, 36, 48, and 60. | Baseline to Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | 
| Serum amlitelimab concentrations measured throughout the study | Serum amlitelimab concentrations measured throughout the study. | Baseline thought Week 60 | 
| Incidence of anti-amlitelimab antibody positive response | Incidence of anti-amlitelimab antibody positive response. | Baseline through Week 60 | 
| Percentage of participants with treatment-emergent adverse events (TEAEs), including local reactions, AEs of special interest (AESIs), serious adverse events (SAEs) | Percentage of participants with treatment-emergent adverse events (TEAEs), including local reactions, AEs of special interest (AESIs), serious adverse events (SAEs). | Baseline through Week 60 | 
| Incidence of potentially clinically significant laboratory test, vital signs, and ECG abnormalities in the treatment period | Incidence of potentially clinically significant laboratory test, vital signs, and ECG abnormalities in the treatment period. | Baseline through Week 60 | 
| Change from baseline in Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ (S)) Self-Administered Score at Weeks 2, 4, 8, 12, 24, 36, and 60 | The AQLQ(S) is designed as a self-administered participant reported outcome to measure the functional impairments. The overall score is 1 to 7. Higher AQLQ scores indicate better health-related quality of life. | Baseline to Weeks 2, 4, 8, 12, 24, 36, and 60 | 
| Change from baseline in St. George's Respiratory Questionnaire (SGRQ) at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | The SGRQ is designed to measure and quantify health status in adult patients with chronic airflow limitation. A global score ranges from 0 to 100 where 0 indicates best and 100 indicates worst health. | Baseline to Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | 
| Proportion of participants with a decrease from baseline of at least 4 points in SGRQ total score at Week 48 | The SGRQ is designed to measure and quantify health status in adult patients with chronic airflow limitation. A global score ranges from 0 to 100 where 0 indicates best and 100 indicates worst health. | Week 48 | 
| Change from baseline in ACQ-6 score and ACQ-7 at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | The ACQ-6 is a validated asthma assessment tool that consists of 6 self-assessment questions. The overall scale ranges from 0 = 'totally controlled' to 6 = 'severely unc7ntrolled. The ACQ-7 is a validated asthma assessment tool that consists of 6 self-assessment questions. The overall scale ranges from 0 = 'totally controlled' to 6 = 'severely uncontrolled. | Baseline to Weeks 2, 4, 8, 12, 24, 36, 48, and 60 |