Asthma
Conditions
Brief summary
This was a parallel, Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, four-arms study for treatment. The purpose of this study was 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) was 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 was up to approximately 60 weeks. * The scheduled number of visits was 13.
Interventions
DRUGAmlitelimab
Injection solution Subcutaneous injection
DRUGPlacebo
Injection solution Subcutaneous injection
Sponsors
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 75 Years
Healthy volunteers
No
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 were 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 experienced 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Severe Asthma Exacerbation Events Over 48 Weeks | Baseline (Day 1) to Week 48 | Severe asthma exacerbation event was 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 (OCS) 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. Annualized rate was the total number of severe asthma exacerbation events divided by the total observation duration and was estimated based on negative binomial regression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) at Week 48 | Baseline (Day 1) and Week 48 | The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. The pre-BD spirometry was performed after a wash out period of BDs according to their action duration. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Asthma Control Questionnaire-5 (ACQ-5) Score at Week 48 | Baseline (Day 1) and Week 48 | The ACQ was a questionnaire that measured the adequacy of asthma control and any changes in asthma control that occurred spontaneously or as a result of treatment. The ACQ-5 had five questions on the asthma symptoms and participants were asked to recall how their asthma had been during the previous week. Each item of the ACQ was measured on a 7-point response scale (0=no impairment, 6=maximum impairment). The ACQ score was the mean of the item responses and ranged from 0 (totally controlled) and 6 (severely uncontrolled). A high score indicated low asthma control. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities [AQLQ(S)] Self-administered Score at Week 48 | Baseline (Day 1) and Week 48 | The AQLQ(S) was a self-administered participant reported outcome (PRO) to measure the functional impairments that were most troublesome to adolescents and adults \>=12 years of age as a result of their asthma over the past two weeks. The instrument comprised of 32 items, each rated on a 7-point Likert scales from 1 (severely impaired) to 7 (not impaired). The AQLQ(S) had 4 domains: symptoms (12 items), activity limitation (11 items, 5 of which were individualized), emotional function (5 items), and environmental exposure (4 items). The global score was the mean of response to each of the 32 questions and ranged from 1 (severe impairment) to 7 (no impairment). Higher scores indicated better quality of life. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in One Second at Week 48 | Baseline (Day 1) and Week 48 | The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. The post-BD spirometry was performed within 30 minutes after administration of BD. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Pre-Bronchodilator and Post-Bronchodilator Percent Predicted Forced Expiratory Volume in One Second at Week 48 | Baseline (Day 1) and Week 48 | The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. The pre-BD spirometry was performed after a wash out period of BDs according to their action duration. The post-BD spirometry was performed within 30 minutes after administration of BD. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Asthma Control Questionnaire-5 Score at Weeks 2, 4, 8, 12, 24, 36, and 60 | Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, and 60 | The ACQ was a questionnaire that measured the adequacy of asthma control and any changes in asthma control that occurred spontaneously or as a result of treatment. The ACQ-5 had five questions on the asthma symptoms and participants were asked to recall how their asthma had been during the previous week. Each item of the ACQ was measured on a 7-point response scale (0=no impairment, 6=maximum impairment). The ACQ score was the mean of the item responses and ranged from 0 (totally controlled) and 6 (severely uncontrolled). A high score indicated low asthma control. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Time to First Severe Asthma Exacerbation Event Over 48 Weeks | Baseline (Day 1) to Week 48 | Time to first severe asthma exacerbation event was defined as the onset date of the first severe asthma exacerbation minus randomization date + 1. Severe asthma exacerbation event was defined as worsening of asthma requiring the use of systemic corticosteroids for \>=3 days or, in the case of a stable maintenance regimen of OCS 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. |
| Change From Baseline in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Volume in One Second at Each Spirometry Timepoint | Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 36, and 60 for pre-BD; baseline (Day 1) and Weeks 4, 12, 24, 36, and 60 for post-BD | The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. The pre-BD spirometry was performed after a wash out period of BDs according to their action duration. The post-BD spirometry was performed within 30 minutes after administration of BD. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Pre-Bronchodilator and Post-Bronchodilator Peak Expiratory Flow (PEF) at Each Spirometry Timepoint | Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 36, 48, and 60 for pre-BD; baseline (Day 1) and Weeks 4, 12, 24, 36, 48, and 60 for post-BD | The PEF was a participant's maximum speed of expiration as measured with a peak flow meter. The pre-BD spirometry was performed after a wash out period of BDs according to their action duration. The post-BD spirometry was performed within 30 minutes after administration of BD. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Pre-Bronchodilator and Post-Bronchodilator Forced Vital Capacity (FVC) at Each Spirometry Timepoint | Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 36, 48, and 60 for pre-BD; baseline (Day 1) and Weeks 4, 12, 24, 36, 48, and 60 for post-BD | The FVC was defined as the volume of air that can be forcibly blown out after full inspiration in the upright position as measured by spirometer. The pre-BD spirometry was performed after a wash out period of BDs according to their action duration. The post-BD spirometry was performed within 30 minutes after administration of BD. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Pre-Bronchodilator and Post-Bronchodilator Forced Expiratory Flow (FEF) 25-75% at Each Spirometry Timepoint | Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 36, 48, and 60 for pre-BD; baseline (Day 1) and Weeks 4, 12, 24, 36, 48, and 60 for post-BD | The FEF was the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. The FEF 25-75% was defined as the FEF at 25% to 75% of FVC, where FVC was defined as the volume of air that can be forcibly blown out after full inspiration in the upright position. The pre-BD spirometry was performed after a wash out period of BDs according to their action duration. The post-BD spirometry was performed within 30 minutes after administration of BD. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) at Weeks 2, 4, 8, 12, 16, 24, 36, 48, and 60 | Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 24, 36, 48, and 60 | FeNO was a measure of nitric oxide in exhaled breath produced by epithelial cells in the lung and considered as a biomarker of Type-2 inflammation in asthma. FeNO levels were collected on site with a dedicated medical device. The FeNO test was completed prior to impulse oscillometry and spirometry. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Annualized Rate of Loss of Asthma Control (LOAC) Events Over 48 Weeks | Baseline (Day 1) to Week 48 | LOAC events were 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 2-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; worsening of asthma requiring the use of systemic corticosteroids for \>=3 days or, in the case of a stable maintenance regimen of OCS 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 severe exacerbation event. Annualized rate was the total number of severe asthma exacerbation events divided by the total observation duration and was estimated based on negative binomial regression. |
| Time to First Loss of Asthma Control Event Over 48 Weeks | Baseline (Day 1) to Week 48 | Time to first LOAC event was defined as the onset date of the first LOAC minus randomization date + 1. LOAC events were 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 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; worsening of asthma requiring the use of systemic corticosteroids for \>=3 days or, in the case of a stable maintenance regimen of OCS 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 severe exacerbation event. |
| Change From Baseline in the Asthma Daytime Symptom Diary (ADSD) 6-Item Daily Morning Score and in the Asthma Nighttime Symptom Diary (ANSD) 6-Item Daily Evening Score at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | ADSD and ANSD were PRO measures designed to measure asthma symptoms in adult and adolescent (\>=12 years of age) participants diagnosed with mild-to-severe asthma. Both scales assessed asthma severity based on participant self-report of asthma core symptoms, i.e., difficulty of breathing; wheezing; shortness of breath; chest tightness; chest pain; and cough. Participants were asked to complete ADSD every night before they go to bed, thinking about their asthma symptoms today, from when they got up this morning until now; ANSD when getting up, thinking about their asthma symptoms last night from when they went to bed until now. Both scales consisted 6 items rated using an 11-point numerical rating scale that ranged from 0 (none) to 10 (as bad as you can imagine). Total score was an average of all 6 items for ADSD and ANSD each and therefore ranged from 0 to 10. Higher scores indicated worse outcomes. Baseline: last available value before first dose of double-blind study treatment. |
| Annualized Rate of Severe Asthma Exacerbations Requiring Hospitalization or Emergency Room or Urgent Care Visit Over 48 Weeks | Baseline (Day 1) to Week 48 | Severe asthma exacerbation event was defined as worsening of asthma requiring the use of systemic corticosteroids for \>=3 days or, in the case of a stable maintenance regimen of OCS 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. Severe asthma exacerbation events requiring hospitalization or emergency room or urgent care visit during the 48-week treatment period were recorded. Annualized rate was the total number of severe asthma exacerbation events divided by the total observation duration and was estimated based on negative binomial regression. |
| Change From Baseline in the Numbers of Inhalations Per Day of Short-Acting Beta 2-Agonists or Low-Dose Inhaled Corticosteroid/Formoterol for Symptom Relief at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | Participants were administered SABA or low-dose ICS/formoterol via oral inhalation as reliever medication as needed during the study and the number of inhalations/day were recorded. Baseline was defined as last available value before first dose of double-blind study treatment. |
| Serum Amlitelimab Concentrations | Weeks 4, 8, 12, 16, 24, 36, 48, and 60 | Blood samples were collected at the specified timepoints for measurement of serum concentrations of amlitelimab. |
| Number of Participants With Anti-Drug Antibodies (ADA) to Amlitelimab | From first dose of study treatment (Day 1) up to end of study visit (Week 72) | Serum samples were collected to evaluate antibodies to amlitelimab. Participants with treatment-emergent ADAs were participants with at least one treatment-induced/boosted ADA. Participants with treatment-induced ADAs were participants with ADAs that developed during the treatment-emergent (TE) period and without pre-existing ADA (including participants without pre-treatment samples). Participants with treatment-boosted ADAs were participants with pre-existing ADAs that were boosted during the TE period to a significant higher titer than the baseline. Number of participants with treatment-emergent ADAs are reported. |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Adverse Events of Special Interest (TEAESIs) and Treatment-Emergent Serious Adverse Events (TESAEs) | From first dose of study treatment (Day 1) up to last dose of study treatment + 168 days, approximately 88 weeks | Adverse event (AE): any untoward medical occurrence in participant or clinical study participant, temporally associated with use of study treatment, whether or not considered related to study treatment. TEAEs: AEs that developed, worsened or became serious during TE period. Serious AE: any untoward medical occurrence that at any dose, met one or more of criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was congenital anomaly/birth defect or was significant medical event that jeopardized the participant or required medical or surgical intervention to prevent one of above outcomes. AESI: AE (serious or non-serious) of scientific and medical concern specific to Sponsor's product or program, for which ongoing monitoring and immediate notification by Investigator to Sponsor was required. Percentages are rounded off to tenth decimal place. |
| Change From Baseline in Asthma Quality of Life Questionnaire With Standardized Activities Self-administered Score at Weeks 2, 4, 8, 12, 24, 36, and 60 | Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, and 60 | The AQLQ(S) was a self-administered PRO to measure the functional impairments that were most troublesome to adolescents and adults \>=12 years of age as a result of their asthma over the past two weeks. The instrument comprised of 32 items, each rated on a 7-point Likert scales from 1 to (severely impaired) to 7 (not impaired). The AQLQ(S) had 4 domains: symptoms (12 items), activity limitation (11 items, 5 of which were individualized), emotional function (5 items), and environmental exposure (4 items). The global score was the mean of response to each of the 32 questions and ranged from 1 (severe impairment) to 7 (no impairment). Higher scores indicated better quality of life. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
| Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | SGRQ was 50-item questionnaire to measure and quantify health status in adult participants with chronic airflow limitation and consisted of three domains: symptoms (8 items \[covered symptomatology, frequency and severity of cough, sputum production, wheeze, breathlessness, duration and frequency of attacks of breathlessness/wheeze\]), activity (16 items \[covered disturbances to participants' daily physical activities\]), impacts (26 items \[covered effects that chest troubles had on participants' daily life and psycho-social functions\]). Global score was calculated by summing all positive responses in questionnaire and expressing result as percentage of total weight for questionnaire. Global and domain scores ranged from 0 to 100 with 100=worst possible health status and 0=best possible health status. Higher score=worse health status/heath related quality of life. Baseline: last available value before first dose of double-blind study treatment. |
| Percentage of Participants With a Decrease From Baseline of at Least 4 Points in St. George's Respiratory Questionnaire Total Score at Week 48 | Baseline (Day 1) to Week 48 | SGRQ was 50-item questionnaire to measure and quantify health status in adult participants with chronic airflow limitation and consisted of three domains: symptoms (8 items\[covered symptomatology, frequency and severity of cough, sputum production, wheeze, breathlessness, duration and frequency of attacks of breathlessness/wheeze\]), activity (16 items\[covered disturbances to participants' daily physical activities\]), impacts (26 items\[covered effects that chest troubles had on participants' daily life and psycho-social functions\]). Global score was calculated by summing all positive responses in questionnaire and expressing result as percentage of total weight for questionnaire. Global and domain scores ranged from 0 to 100; 100=worst possible health status and 0=best possible health status. Higher score=worse health status/heath related quality of life. Baseline:last available value before first dose of double-blind study treatment. Percentages are rounded off to tenth decimal place. |
| Change From Baseline in Asthma Control Questionnaire-6 (ACQ-6) and Asthma Control Questionnaire-7 Scores at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | Baseline (Day 1) and Weeks 2, 4, 8, 12, 24, 36, 48, and 60 | The ACQ was a questionnaire that measured the adequacy of asthma control and any changes in asthma control that occurred spontaneously or as a result of treatment. The ACQ-5 had five questions on the asthma symptoms and participants were asked to recall how their asthma had been during the previous week. The ACQ-6 included an additional item that scored the average number of daily puffs needed from a SABA BD during the past week and the ACQ-7 included this SABA item, plus a final clinic-assessed item scoring FEV1% predicted. Each item of the ACQ was measured on a 7-point response scale (0=no impairment, 6=maximum impairment). The ACQ-6 and ACQ-7 scores were the mean of the item responses in the respective scales and ranged from 0 (totally controlled) and 6 (severely uncontrolled). A high score indicated low asthma control. Baseline was defined as the last available value before the first dose of double-blind study treatment. |
Countries
Argentina, Brazil, Canada, Chile, Hungary, Italy, Japan, Mexico, Poland, South Africa, South Korea, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Participant flow
Recruitment details
The study was conducted at 112 centers in 14 countries. A total of 910 participants were screened from 30 June 2022 to 31 October 2023, of which 473 were screen failures. Screen failures were mainly due to not meeting the eligibility criteria.
Pre-assignment details
A total of 437 participants were randomized in a ratio of 2:1:2:2 to one of the following groups: placebo, amlitelimab 62.5 milligrams (mg) with 125 mg loading dose, amlitelimab 125 mg with 250 mg loading dose, or amlitelimab 250 mg with 500 mg loading dose. Randomization was stratified by region, screening blood eosinophil count (\<300 cells per \[/\] microliter \[mcL\] and \>=300 cells/mcL), and number of severe asthma exacerbations in the previous 12 months (=1 or \>1 exacerbations).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 55.4 years STANDARD_DEVIATION 12.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants |
| Race (NIH/OMB) Asian | 32 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 358 Participants |
| Sex: Female, Male Female | 97 Participants |
| Sex: Female, Male Male | 51 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 / 127 | 1 / 61 | 2 / 125 | 0 / 124 |
| other Total, other adverse events | 76 / 127 | 32 / 61 | 63 / 125 | 75 / 124 |
| serious Total, serious adverse events | 11 / 127 | 6 / 61 | 10 / 125 | 12 / 124 |
Outcome results
None listed