Efficacy and Safety Evaluation of Subcutaneous Amlitelimab in Adults with Moderate-to-Severe Asthma: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2024-510641-33-00
Protocol: DRI17509
Sponsor: Sanofi-Aventis Recherche & Developpement

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Diseases & Conditions

Asthma

Objectives

The primary objective of this study is to evaluate the **efficacy** of different doses of amlitelimab compared to placebo in participants with moderate-to-severe, uncontrolled asthma. This is clinically relevant as it aims to determine the optimal dosing strategy for amlitelimab, potentially improving asthma management and patient outcomes.

Secondary objectives include:

Evaluating the effects of amlitelimab compared to placebo on lung function as measured by forced expiratory volume in 1 second (FEV1).
Assessing the impact of amlitelimab on the Asthma Control Questionnaire 5 (ACQ-5) and on asthma symptoms.
Determining the effects on time to first severe exacerbation event and on time to first "loss of asthma control" (LOAC) event.
Evaluating the effects on other spirometry assessments and on the fraction of exhaled nitric oxide (FeNO).
Assessing the reduction in the incidence of severe asthma exacerbations requiring hospitalization or emergency care.
Evaluating the effects on bronchodilator therapy and participant-reported outcomes (PROs).
Assessing the pharmacokinetics of amlitelimab and the presence of anti-drug antibodies in participants with asthma.
Evaluating the safety of amlitelimab in participants with asthma.

These secondary objectives aim to provide a comprehensive understanding of amlitelimab's impact on asthma control, safety, and patient quality of life.

Participants

The clinical trial involves a total of **304 participants** diagnosed with **asthma**, specifically targeting individuals with moderate-to-severe, uncontrolled asthma. The study population includes both male and female subjects, aged between 18 and 75 years. Participants were selected based on their existing diagnosis of moderate to severe asthma, as confirmed by a physician for at least 12 months, and their current treatment regimen, which includes medium to high doses of inhaled corticosteroids (ICS) in combination with at least one additional controller medication. The trial population is characterized by a history of at least one severe asthma exacerbation in the past year and specific lung function criteria, such as a pre-bronchodilator forced expiratory volume in one second (FEV1) between 40% and 80% of the predicted normal. Participants are required to have a weight between 40 kg and 150 kg. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel-group, dose-ranging study to evaluate the efficacy, safety, and tolerability of subcutaneous **amlitelimab** in adult participants with moderate-to-severe **asthma**. The trial will span approximately 48 weeks, with an estimated recruitment start date of July 14, 2022, and an estimated end date of April 3, 2025. Participants will be randomly assigned to receive either amlitelimab or a placebo, with the primary objective being to assess the annualized rate of severe exacerbation events over the trial period.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, asthma severity, and treatment history. Participants must be between 18 and 75 years old, have a physician-diagnosed moderate-to-severe asthma for at least 12 months, and be on existing therapy with medium to high doses of inhaled corticosteroids (ICS) along with additional controllers. The screening visit will also include assessments of lung function and asthma control. Following randomization, participants will attend follow-up visits at specified intervals, including Weeks 2, 4, 8, 12, 24, 36, and 48, to monitor changes in lung function, asthma control, and quality of life, as well as to collect serum amlitelimab concentrations and assess the incidence of anti-amlitelimab antibody responses.

The end-of-study visit will occur at Week 48, where final assessments will be conducted to evaluate the primary and secondary endpoints, including changes in pre-bronchodilator forced expiratory volume in 1 second (FEV1), Asthma Control Questionnaire scores, and the incidence of treatment-emergent adverse events. Participant involvement is expected to last for the entire 48-week duration unless early termination is warranted due to conditions such as significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial is conducted under the auspices of a Phase 4 clinical trial, ensuring rigorous adherence to safety and efficacy standards.

Treatment

The clinical trial involves the administration of **Amlitelimab**, an experimental medication, to evaluate its efficacy, safety, and tolerability in adult participants with moderate-to-severe asthma. **Amlitelimab** is a novel human anti-OK40L monoclonal antibody (mAb) provided in the form of a **solution for injection**. The pharmaceutical form is specifically designed for **subcutaneous injection**. The maximum daily dose of **Amlitelimab** is 500 mg, with a total maximum dose of 2750 mg over a treatment period of 60 days. The administration schedule and dosing are carefully monitored to ensure participant compliance and safety throughout the trial.

The study also includes a **placebo** group to serve as a comparator for assessing the efficacy of **Amlitelimab**. The **placebo** is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The **placebo** does not contain any active pharmaceutical ingredients and is used to evaluate the true effect of the experimental medication by comparison. The administration of the **placebo** follows the same route and frequency as the experimental treatment to ensure consistency across study groups.

Efficacy

The efficacy of amlitelimab in the treatment of moderate-to-severe asthma will be assessed through a randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study. The primary endpoint for evaluating efficacy is the annualized rate of severe exacerbation events over a 48-week period. Secondary endpoints include changes from baseline in pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) at Week 48, changes in the Asthma Control Questionnaire 5 (ACQ-5) score at various timepoints including Week 48, and changes in the Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ (S)) Self-Administered Score at Week 48. Additional secondary endpoints involve changes in post-BD FEV1, peak expiratory flow (PEF), forced expiratory flow (FEF) 25-75%, and forced vital capacity (FVC), as well as changes in fractional exhaled nitric oxide (FeNO) at specified weeks.

Measurements will be collected at multiple timepoints, including Weeks 2, 4, 8, 12, 24, 36, 48, and 60, using validated scales and laboratory tests. The study will also monitor the time to first severe exacerbation event, the annualized rate of loss of asthma control (LOAC) events, and the incidence of anti-amlitelimab antibody positive responses. Serum amlitelimab concentrations will be measured throughout the study to assess pharmacokinetics. The efficacy assessments will be conducted using standardized tools and instruments, ensuring the reliability and validity of the collected data. The analysis will focus on comparing the efficacy of different doses of amlitelimab to placebo in achieving the desired clinical outcomes in participants with moderate-to-severe, uncontrolled asthma.

Inclusion and Exclusion 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.

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Exclusion Criteria

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