Bronchiectasis
Conditions
Brief summary
ACT18018 is a multinational, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study with 3 treatment groups. The purpose of this study was to evaluate efficacy, safety and tolerability with 2 dosing regimens of itepekimab compared with placebo in male and/or female participants with NCFB aged 18 years of age up to 85 years of age (inclusive). Study details include: * The study duration (screening, 24-52-week treatment, 20-week safety follow-up) was up to 47-77 weeks * The treatment duration was up to 24-52 weeks * The follow-up duration was 20 weeks * Site/phone visits were at a monthly interval
Interventions
* Pharmaceutical form: solution for injection in pre-filled syringe * Route of administration: subcutaneous
DRUGPlacebo
* Pharmaceutical form: solution for injection in pre-filled syringe * Route of administration: subcutaneous
Sponsors
Sanofi
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Participant must be 18 to 85 years of age inclusive * Clinical history consistent with NCFB (cough, chronic sputum production and/or recurrent respiratory infections) * Participants with a FEV1 % predicted ≥30% * Participants with at least 2 moderate or 1 severe Pulmonary exacerbations (PEs) in the past 12 months
Exclusion criteria
Participants were excluded from the study if any of the following criteria apply: * Had bronchiectasis due to CF, hypogammaglobulinemia, common variable immunodeficiency, known active nontuberculous mycobacteria (NTM) lung infection, or pulmonary fibrosis * Known or suspected immunodeficiency disorder * Pulmonary exacerbation which had not resolved clinically during screening period * Had significant haemoptysis * Had any clinically significant abnormal laboratory values at Screening or diseases or disorders * History of lung transplantation * History of malignancy within 5 years before Screening, or during the screening period * Was being treated with antimicrobial therapy for tuberculosis (TB) * Was on active treatment for allergic bronchopulmonary aspergillosis (ABPA) * Participants with active autoimmune disease or participants using immunosuppressive therapy for autoimmune disease * Known allergy to itepekimab or to excipients * Live-attenuated vaccine(s) within 4 weeks prior to Screening or planned to receive such vaccines during the study * Unstable ischemic heart disease * Cardiomyopathy or other relevant cardiovascular disorder * Clinically significant new abnormal electrocardiogram (ECG) within 6 months prior to, or at Screening * History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at Screening The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Adjudicated Moderate or Severe Pulmonary Exacerbations (PEs) Over the Treatment Period | Baseline (Day 1) up to Week 24 to 52 | PEs were recorded by Investigator. Moderate PEs were defined as acute worsening of respiratory symptoms (\>=3 symptoms for \>=48 hours) requiring antibiotic treatment. Severe PEs were moderate PEs resulting in intravenous antibiotic treatment, hospitalization, observation \>24 hours in emergency department/urgent care, or death. Events separated by \<14 days were considered as single events. All PE events were adjudicated by an independent committee. For both moderate and severe events to be counted as 2 separate events, they were separated by at least 14 days between any course of antibiotics and/or systemic corticosteroids or 14 days between discharge and new admission in case of hospitalization (severe events only). Annualized rate: number of events divided by total observation duration and was estimated based on negative binomial regression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Moderate or Severe Pulmonary Exacerbation Over the Treatment Period | Baseline (Day 1) up to Week 24 to 52 | Time to first moderate or severe PE was defined as the onset date of the first moderate or severe PE during the observation period (as per endpoint #1) minus (-) randomization date plus (+) 1. PEs were defined as an acute worsening of respiratory symptoms leading to a prescription in antibiotics (new, addition or change in) and/or systemic corticosteroids and were recorded by Investigator. For both moderate and severe events to be counted as 2 separate events, they must be separated by at least 14 days between any course of antibiotics or 14 days between discharge and new admission in case of hospitalization (severe events only). |
| Percentage of Participants Who Were Pulmonary Exacerbation Free Over the Treatment Period | Baseline (Day 1) up to Week 24 to 52 | PEs were defined as an acute worsening of respiratory symptoms leading to a prescription in antibiotics (new, addition or change in) and/or systemic corticosteroids and were recorded by Investigator. Percentage of participants who were moderate or severe PE free over the treatment period are reported. Moderate and severe PE as defined in endpoint #1. Percentages are rounded off to tenth decimal place. |
| Annualized Rate of Adjudicated Severe Pulmonary Exacerbations Over the Treatment Period | Baseline (Day 1) up to Week 24 to 52 | PEs were recorded by Investigator. Severe PEs were moderate PEs resulting in intravenous antibiotic treatment, hospitalization, observation \>24 hours in emergency department/urgent care, or death. All PE events were adjudicated by an independent committee. Annualized rate: number of events divided by total observation duration and was estimated based on negative binomial regression. |
| Percentage of Participants Who Were Severe Pulmonary Exacerbation Free Over the Treatment Period | Baseline (Day 1) up to Week 24 to 52 | PEs were defined as an acute worsening of respiratory symptoms) leading to a prescription in antibiotics (new, addition or change in) and/or systemic corticosteroids and were recorded by Investigator. Severe PE was defined as moderate PE described in endpoint #1 but resulting in intravenous antibiotic treatment, hospitalization, observation for \>24 hours in emergency department/urgent care facility or death. Percentage of participants who were severe PE free over the treatment period are reported. Percentages are rounded off to tenth decimal place. |
| Time to First Severe Pulmonary Exacerbation Over the Treatment Period | Baseline (Day 1) up to Week 24 to 52 | Time to first severe PE was defined as the onset date of the first severe PE during the observation period - randomization date + 1. PEs were defined as an acute worsening of respiratory symptoms leading to a prescription in antibiotics (new, addition or change in) and/or systemic corticosteroids and were recorded by Investigator. Severe PE was defined as moderate PE but resulting in intravenous antibiotic treatment, hospitalization, observation for \>24 hours in emergency department/urgent care facility or death. |
| Change From Baseline in Pre-bronchodilator (BD) Forced Expiratory Volume in One Second (FEV1) at Weeks 8 and 24 | Baseline (Day 1) and Weeks 8 and 24 | The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Pre-BD spirometry was performed after a washout period of BD according to their action duration following the European Respiratory Society/American Thoracic Society 2019 guidance. Baseline was defined as the last available value before the first dose of double-blind study drug. Model-based average change from baseline to Weeks 8 and 24 is presented. |
| Change From Baseline in Post-bronchodilator Forced Expiratory Volume in One Second at Weeks 8 and 24 | Baseline (Day 1) and Weeks 8 and 24 | The FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. Post-BD spirometry was performed after 4 actuations of short-acting beta-agonist (albuterol, salbutamol) with post-BD reversibility performed at least 15 minutes following the last actuation. Baseline was defined as the last available value before the first dose of double-blind study drug. Model-based average change from baseline to Weeks 8 and 24 is presented. |
| Median Days of New and/or Added (in Participants With Maintenance Antibiotic Use) Acute Antibiotics Used to Treat Pulmonary Exacerbation | Baseline (Day 1) up to Week 24 to 52 | PEs were defined as an acute worsening of respiratory symptoms leading to a prescription in antibiotics (new, addition or change in) and/or systemic corticosteroids and were recorded by Investigator. Systemic antibiotics used less than 60 days to treat a NCFB exacerbation were considered. Median number of days of new and/or added acute antibiotics used to treat PE in participants with maintenance antibiotic use is reported. |
| Change From Baseline in Quality-of-Life Questionnaire Bronchiectasis (QOL-B) Respiratory Symptoms Domain Score in Adult Participants at Week 24 | Baseline (Day 1) and Week 24 | QOL-B is self-administered patient reported outcome (PRO) that assesses symptoms, functioning and health-related QOL for participants with NCFB; contains 37 items in 8 domains (respiratory symptoms, physical functioning, role functioning, emotional functioning, social functioning, vitality, health perceptions and treatment burden). Respiratory Symptoms domain assesses respiratory symptom-related QOL;includes 9 questions (from 29 to 37 of QOL-B Questionnaire). Each of 37 items is scored from 1 to 4, and each of the 8 domains scale scores is standardized on a 0-100 point scale, with higher scores representing fewer symptoms or better functioning/ better QOL.Positive change from baseline=improvement in symptoms. Baseline:last available value before first dose of double-blind study drug. Model-based average change from baseline to Week 24 is presented. |
| Change From Baseline in Saint Georges Respiratory Questionnaire (SGRQ) Total Score at Week 24 | Baseline (Day 1) and Week 24 | SGRQ is a 50-item PRO instrument to measure health status of participants with airflow obstruction diseases. Questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to severity of respiratory symptoms in preceding 4 weeks; part 2 consists of 42 items related to daily activity and psychosocial impacts of individual's respiratory condition. Scores by dimension are calculated for 3 domains: symptoms, activity and impacts (psychosocial). Total score is calculated by summing all positive responses in questionnaire and expressing result as percentage of total weight for questionnaire; ranges 0 (best possible health status) to 100 (worst possible health status); lower score indicates better QOL. Baseline was defined as the last available value before first dose of double-blind study drug. Model-based average change from baseline to Week 24 is presented. |
| Percentage of Participants With a Decrease From Baseline of at Least 4 Points in Saint Georges Respiratory Questionnaire Total Score at Week 24 | Baseline (Day 1) and Week 24 | SGRQ is a 50-item PRO instrument to measure health status of participants with airflow obstruction diseases. Questionnaire is divided into 2 parts: part 1 consists of 8 items pertaining to severity of respiratory symptoms in preceding 4 weeks; part 2 consists of 42 items related to daily activity and psychosocial impacts of individual's respiratory condition. Scores by dimension are calculated for 3 domains: symptoms, activity and impacts (psychosocial). Total score is calculated by summing all positive responses in questionnaire and expressing result as percentage of total weight for questionnaire; ranges 0 (best possible health status) to 100 (worst possible health status); lower scores indicate better QOL. Baseline was defined as the last available value before first dose of double-blind study drug. Percentages are rounded off to tenth decimal place. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-Emergent AEs of Special Interest (TEAESIs), Treatment-emergent Serious Adverse Events (TESAEs) and TEAEs Leading to Permanent Study Drug Discontinuation | From first dose of study drug (Day 1) to a maximum of 72 weeks | AE was any untoward medical occurrence in a clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. AESI was any 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. SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were AEs that developed, worsened or became serious during the TE period. |
| Serum Concentrations of Itepekimab | Baseline (Day 1) and Weeks 4, 8, 24, 52, end of treatment (EOT) (Weeks 24-52) and end of study (EOS) (up to Week 72) | Blood samples were collected at specified timepoints to obtain serum concentrations of itepekimab. |
| Number of Participants With Treatment-emergent Anti-drug Antibodies (ADA) Response Against Itepekimab | From first dose of study drug (Day 1) to a maximum of 72 weeks | Blood samples were collected to evaluate antibodies to itepekimab. Treatment-emergent response was defined as a positive response in the ADA assay post first dose when baseline results were negative or missing. Number of participants with treatment-emergent ADAs against itepekimab is presented. |
Countries
Argentina, Brazil, Canada, Chile, China, Czechia, Denmark, France, Germany, Greece, Israel, Italy, Japan, Netherlands, Poland, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 117 sites in 20 countries. 386 participants were screened from 20-Feb-2024 to 07-Mar-2025 of which 72 were screen failures due to not meeting eligibility criteria. A total of 314 participants with non-cystic fibrosis bronchiectasis (NCFB) were randomized in this study in a 1:1:1 ratio to either receive placebo matched to itepekimab or itepekimab (once every 2 weeks \[Q2W\] or once every 4 weeks \[Q4W\]).
Pre-assignment details
This study had a variable treatment period of 24-52 weeks followed by a 20-week safety follow-up period. Note: Reason for not completed=Reason for study drug discontinuation.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 61.06 years STANDARD_DEVIATION 14.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 20 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 245 Participants |
| Sex: Female, Male Female | 73 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 102 | 1 / 103 | 1 / 107 |
| other Total, other adverse events | 57 / 102 | 48 / 103 | 60 / 107 |
| serious Total, serious adverse events | 24 / 102 | 20 / 103 | 16 / 107 |
Outcome results
None listed