Asthma
Conditions
Brief summary
This Phase III, randomized, double-blind, placebo-controlled, multicenter study will assess the efficacy and safety of lebrikizumab in adult patients with mild to moderate asthma treated with short-acting beta-agonist (SABA) therapy alone. Patients will be randomized in a 1:1:1 ratio to receive either blinded lebrikizumab or placebo treatment by subcutaneous (SC) injection (every 4 weeks for a total of 3 doses) or open-label treatment with Singulair (Montelukast; 10 mg daily). Time on study treatment will last 12 weeks.
Interventions
DRUGLebrikizumab
Lebrikizumab 125 mg subcutaneous (SC) injection given on Days 1, 29, and 57
DRUGMontelukast
10 mg tablet given orally once daily for 12 weeks, according to the approved label.
OTHERPlacebo
Lebrikizumab-matched placebo SC injection given on Days 1, 29, and 57
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Participants and investigators will remain blinded to the lebrikizumab and placebo arms only. Montelukast will be administered in tablet form and given in an open-label fashion.
Intervention model description
Participants will be randomized in a 1:1:1 ratio to receive lebrikizumab 125 mg, placebo, or Montelukast 10 mg.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 18-75 years old at study start * Asthma diagnosis for \>/= 12 months prior to study start * Bronchodilator response at screening * Pre-bronchodilator FEV1 of 60% - 85% predicted at both screening visits 2 and 3 * No other clinically significant lung disease as confirmed by chest X-ray or computed tomography (CT) scan * Stable and symptomatic asthma during the screening period * Use of effective contraception, as defined by the protocol, until 24 weeks after the last dose
Exclusion criteria
* Maintenance of corticosteroid therapy, defined as daily or alternate-day oral corticosteroid maintenance therapy within 3 months prior to study start * Treatment with systemic or inhaled corticosteroids within 4 weeks prior to study start or during the screening period for any reason, including an acute exacerbation event * Treatment with a leukotriene receptor antagonist (LTRA), long-acting beta-agonist (LABA) long-acting muscarinic antagonist (LAMA), zileuton, roflumilast, or theophylline within 2 weeks prior to study start * Documented prior treatment failure with Montelukast * Treatment with intra-articular corticosteroids within 4 weeks prior to study start or during the screening period or anticipated need for intra articular corticosteroids during the course of the study * Any infection requiring hospital, IV or IM antibiotic treatment or any respiratory infection within 4 weeks of study start. Any infection requiring oral antibiotic treatment within 2 weeks of study start, or any parasitic infection within 6 months of study start * Clinically significant abnormality found during screening or clinically significant medical disease that is uncontrolled despite treatment that is likely, in the opinion of the investigator, to impact the patient's ability to participate in the study, or impact the study assessments * History of interstitial lung disease, chronic obstructive pulmonary disease (COPD), or other clinically significant lung disease other than asthma * History of alcohol or drug abuse that would impair or risk the patient's full participation in the study, in the opinion of the investigator * Current or history of smoking (\> 10 pack-years), or unwillingness to abstain from smoking for the duration of the study * Past and/or current use of any anti-IL-13 or anti- IL4/IL-13 therapy, including lebrikizumab * Use of a licensed or investigational monoclonal antibody other than anti IL-13 or anti-IL-4/IL-13, including, but not limited to, omalizumab, anti-IL-5, or anti IL-17, within 6 months or 5 drug half-lives prior to Visit 1 (whichever is longer) or during screening * Use of a systemic immunomodulatory or immunosuppressive therapy within 3 months or 5 drug half-lives prior to study start or during screening * Use of other investigational therapy within 4 weeks or 5 drug half-lives prior to study start (whichever is longer) or during screening * Initiation of or change in allergen immunotherapy within 3 months prior to study start or during screening * Receipt of a live attenuated vaccine within 4 weeks prior to study start of during screening * Pregnancy or breast feeding * Body mass index \> 38 kg/m2 * Body weight \< 40 kg * History of bronchial thermoplasty
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | Baseline through Week 12 | FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. The active comparator treatment arm of open-label montelukast was included in the study design so that the sensitivity of the study could be evaluated with respect to the primary outcome measure, FEV1. Two mixed-effect models of repeated measures (MMRM) were used to estimate the absolute change from baseline values: one for the lebrikizumab vs. placebo primary comparison and the second for the montelukast vs. placebo sensitivity comparison. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lebrikizumab vs. Placebo: Change From Baseline in Asthma Reliever Medication Use at Week 12 | Baseline through Week 12 | Participants could only receive SABA therapy for asthma treatment as asthma reliever medication (\<10 puffs daily). SABA use was recorded in the eDiary. A mixed-effect model of repeated measures (MMRM) was used to estimate the absolute change from baseline values for the comparison between the double-blind lebrikizumab and placebo study arms. |
| Lebrikizumab vs. Placebo: Change From Baseline in the Standardized Asthma Quality of Life Questionnaire (AQLQ[S]) Overall Score at Week 12 | Baseline through Week 12 | The AQLQ\[S\] was used to assess the participant's asthma-specific health-related quality of life. The 32-item questionnaire contains four domains: activity limitations, symptoms, emotional function, and environmental stimuli. The AQLQ\[S\] has a recall specification of 2 weeks. Participants were asked to think about how they had been during the previous 2 weeks and to respond to each of the 32 questions on a 7-point scale (7 = not impaired at all; 1 = severely impaired). An increase in the AQLQ score indicates a better quality of life. The overall AQLQ score is the mean of all 32 responses and the individual domain scores are the means of the items in those domains. A mixed-effect model of repeated measures (MMRM) was used to estimate the change from baseline values. |
| Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) Levels at Week 12 | Baseline, Week 12 | — |
| Montelukast vs. Placebo: Change Fom Baseline in Morning Pre-bronchodilator Peak Expiratory Flow (PEF) at Week 12 | Baseline through Week 12 | PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. The active comparator treatment arm of open-label montelukast was included in the study design so that the sensitivity of the study could be evaluated with respect to this secondary outcome measure of PEF. A mixed-effect model of repeated measures (MMRM) was used to estimate the absolute change from baseline values for the sensitivity comparison between montelukast (open-label, active comparator) and placebo study arms. |
| Lebrikizumab vs. Placebo: Change From Baseline in Morning Pre-bronchodilator PEF at Week 12 | Baseline through Week 12 | Peak expiratory flow (PEF) is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. A mixed-effect model of repeated measures (MMRM) was used to estimate the absolute change from baseline values for the comparison between the double-blind lebrikizumab and placebo study arms. |
| Lebrikizumab vs. Placebo: Number of Participants With Treatment Failure | Baseline up to Week 12 | Treatment failure was defined as a worsening of asthma symptoms (per investigator's assessment of participant report) in association with either relative decline in pre-bronchodilator FEV1 \>=20%; or \>=20% decline in morning pre-bronchodilator PEF on 2 consecutive days compared with baseline; or use of \>=10 puffs of albuterol metered dose inhaler (MDI); or \>=2 additional administrations (or any new use) of nebulized short-acting β-agonist (SABA) therapy within any calendar day; or need for any inhaled, oral, or parenteral corticosteroid or for a controller medication. The hazard ratio from the Cox Proportional Hazards model compared the risk of treatment failure for the lebrikizumab-treated and placebo participants. |
| Lebrikizumab vs. Placebo: Time to Treatment Failure | Basleine up to Week 12 | Treatment failure was defined as a worsening of asthma symptoms (per investigator's assessment of participant report) in association with either relative decline in pre-bronchodilator FEV1 \>=20%; or \>=20% decline in morning pre-bronchodilator PEF on 2 consecutive days compared with baseline; or use of \>=10 puffs of albuterol metered dose inhaler (MDI); or \>=2 additional administrations (or any new use) of nebulized short-acting β-agonist (SABA) therapy within any calendar day; or need for any inhaled, oral, or parenteral corticosteroid or for a controller medication. Time to treatment failure was estimated using Kaplan-Meier method. |
| Change From Baseline in Blood Eosinophil Count at Week 12 | Baseline, Week 12 | — |
| Change From Baseline in Serum Periostin at Week 12 | Baseline, Week 12 | — |
| Change From Baseline in Total Immunoglobulin E (IgE) Levels at Week 12 | Baseline, Week 12 | — |
| Change From Baseline in C-C Motif Chemokine Ligand 13 (CCL-13) Levels at Week 12 | Baseline, Week 12 | — |
| Change From Baseline in CCL-17 Levels at Week 12 | Baseline, Week 12 | — |
| Maximum Serum Lebrikizumab Concentration (Cmax) After the First Dose | Predose on Day 0 and post-Day 1 dose on Day 7 | According to the protocol and statistical analysis plan, a single PK sample was collected per participant after the first dose at the expected time of the maximum serum lebrikizumab concentration. |
| Time to Reach Maximum Lebrikizumab Concentration After the First Dose (Tmax) | Post-Day 1 dose on Day 7 | According to the protocol and statistical analysis plan, the Tmax, Week1 (first dose) value was estimated on the basis of a single pharmacokinetic (PK) timepoint per participant after the first dose, which was taken at the expected time of the maximum serum lebrikizumab concentration. |
| Elimination Half-Life (t1/2) of Lebrikizumab | Predose on Days 0, 28, and 56, and on Days 7, 84, 112, and 140 | According to the protocol and statistical analysis plan, the t1/2 was estimated based on the seven total PK samples collected per participant. |
| Predose Serum Lebrikizumab Concentration (Cmin) at Week 4 | Predose on Day 28 (Week 4) | — |
| Serum Lebrikizumab Concentration at Week 12 | On Day 84 (Week 12) | — |
Countries
Brazil, Bulgaria, Canada, Czechia, New Zealand, Poland, Romania, Russia, South Africa, United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Participant flow
Pre-assignment details
Out of 313 enrolled participants, 3 were randomized but not treated during a 12-week treatment period where participants received blinded lebrikizumab/placebo or an open-label active comparator (montelukast sodium). The montelukast arm (active comparator) was included in the study design so that the sensitivity of the study could be evaluated with respect to the primary outcome measure of FEV1, and the secondary outcome measure of PEF.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 43.9 years STANDARD_DEVIATION 13.7 |
| Age, Customized 18 to <30 years | 58 Participants |
| Age, Customized 30 to <50 years | 139 Participants |
| Age, Customized 50 to <65 years | 93 Participants |
| Age, Customized ≥65 years | 20 Participants |
| Biomarker Classification According to Periostin and Eosinophil Levels Periostin <50 ng/ml and Eosinophils <300 cells/ul | 30 Participants |
| Biomarker Classification According to Periostin and Eosinophil Levels Periostin <50 ng/ml and Eosinophils ≥300 cells/ul | 11 Participants |
| Biomarker Classification According to Periostin and Eosinophil Levels Periostin ≥50 ng/ml and Eosinophils <300 cells/ul | 112 Participants |
| Biomarker Classification According to Periostin and Eosinophil Levels Periostin ≥50 ng/ml and Eosinophils ≥300 cells/ul | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Pre-bronchodilator FEV1 | 2.38 Liters (L) STANDARD_DEVIATION 0.57 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 11 Participants |
| Race (NIH/OMB) Black or African American | 43 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 253 Participants |
| Sex: Female, Male Female | 66 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 104 | 0 / 103 | 0 / 103 |
| other Total, other adverse events | 25 / 104 | 24 / 103 | 33 / 103 |
| serious Total, serious adverse events | 2 / 104 | 1 / 103 | 0 / 103 |
Outcome results
None listed