Asthma
Conditions
Keywords
safety, SB-240563, efficacy, placebo, eosinophils, mepolizumab, Severe refractory asthma
Brief summary
This study will evaluate two dose regimens of mepolizumab \[75mg intravenous (i.v.) or 100mg subcutaneous (SC) every 4 weeks\] compared with placebo over a 32 week treatment period in subjects with severe refractory asthma with elevated blood eosinophils. Efficacy will be measured by a reduction in the frequency of asthma exacerbations. Additional efficacy assessments will include measurements of lung function, symptom scores, and quality of life. Safety will be assessed by clinical laboratory samples, ECGs, immunogenicity and adverse events. This study is intended to replicate the Phase IIb/III study MEA112997. Subjects in MEA115588, who meet all eligibility criteria at screening visit, will enter the run-in period. Those subjects that are not able/eligible to be randomised at the end of the 6 week run-in period will be deemed run-in failures. Subjects will remain on their current maintenance therapy throughout the run-in, double-blind treatment administration and follow-up periods. Subjects who meet the randomisation eligibility criteria will be randomised in a 1:1:1 ratio to receive one of the following treatments every 4 weeks for a total of 8 doses: Mepolizumab 75 miligram (mg) i.v. and placebo SC, or Mepolizumab 100 mg SC and placebo i.v. or Placebo i.v. and placebo SC. Subjects that receive all 8 doses of double-blind treatment, and meet the eligibility criteria for the Open-Label Extension (OLE) Study, will be offered the opportunity to participate in the OLE trial.
Interventions
DRUGMepolizumab IV
Mepolizumab 75 mg IV will be administered every 4 weeks with the last dose at Week 28
DRUGMepolizumab SC
Mepolizumab 100 mg SC will be administered every 4 weeks with the last dose at Week 28
DRUGIV Placebo
Normal saline (placebo) will be administered IV every 4 weeks with the last dose at Week 28
DRUGSC Placebo
Normal saline (placebo) will be administered SC every 4 weeks with the last dose at Week 28
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able to give written informed consent prior to participation in the study * At least 12 years of age at visit 1 and a minimum weight of 45 kilogram (kg) * A well-documented requirement for regular treatment with high dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or without maintenance oral corticosteroids (OCS) * Current treatment with an additional controller medication, besides ICS, for at least 3 months or a documented failure in the past 12 months of an additional controller medication for at least 3 successive months * Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma * At Visit 1, a pre-bronchodilator FEV1 \<80% (for subjects \>= 18 years of age), a pre-bronchodilator FEV1 \<90% or FEV1:FVC ratio \<0.8 (for subjects 12-17 years of age). * Previously confirmed history of two or more exacerbations requiring treatment with systemic CS * Male or Eligible Female (females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control) * French subjects will be included only if either affiliated to or a beneficiary of a social security category.
Exclusion criteria
* Current smokers or former smokers with a smoking history of \>=10 pack years * Presence of a known pre-existing, clinically important lung condition other than asthma * A current malignancy or previous history of malignancy in less than 12 months * Known, pre-existing, unstable liver disease cirrhosis and known biliary abnormalities * Known, pre-existing severe or clinically significant cardiovascular disease * known, pre-existing other concurrent clinically significant medical conditions that are uncontrolled with standard treatment * Subjects with any eosinophilic diseases * QTc(F) ≥450msec or QTc(F) ≥480 msec * A history of alcohol/substance abuse * Subject with known immunodeficiency * Subjects who have received omalizumab within 130 days of Visit 1 or any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1 * Subjects who have received treatment with an investigational drug within the past 30 days or five terminal phase half-lives of the drug whichever is longer * Subjects with allergy/intolerance to a monoclonal antibody or biologic. * Subjects who are pregnant or breastfeeding * Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations * Previously participated in any study with mepolizumab and received investigational product (including placebo)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Clinically Significant Exacerbations of Asthma Per Year | From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose | Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year | From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose | Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable. |
| Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year | From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose | Clinically significant exacerbations of asthma is defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable. |
| Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32 | Baseline, Week 32 | FEV1 is defined as the volume of air expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using mixed model repeated measures with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by baseline and visit by treatment group. |
| Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32 | Baseline, Week 32 | The St. George's Respiratory Questionnaire is an established instrument, comprising 50 questions, evaluating symptoms, activity, and impacts; to measure Quality of Life in participants with diseases of airway obstruction and to elicit the participant's opinion of his/her health. The lowest possible value is zero and the highest possible value is 100. The higher values correspond to greater impairment in quality of life. The questionnaire was administered at Baseline (Visit 2) and at the Exit Visit (approximately 4 weeks after the last dose of study treatment). The change from baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using analysis of covariance with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), baseline % predicted FEV1, and treatment. |
Countries
Argentina, Australia, Belgium, Canada, Chile, France, Germany, Italy, Japan, Mexico, Russia, South Korea, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Par. who met the eligibility criteria at screening, entered the Run-in period for a minimum of 1 week and a maximum of 6 weeks. Par. who received all 8 doses and met the eligibility criteria were offered the opportunity to participate in an open label extension (OLE) study. Par. not entering the OLE study completed the Follow-up Visit.
Pre-assignment details
A total of 802 participants (par.) were screened; 82 were Screen failures; 140 were Run-in failures; 580 were randomized, of which 576 received at least 1 dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study. | 191 |
| Mepolizumab 75 mg IV Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study. | 191 |
| Mepolizumab 100 mg SC Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study. | 194 |
| Total | 576 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 1 | 2 |
| Overall Study | Lost to Follow-up | 0 | 2 | 2 |
| Overall Study | Physician Decision | 2 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 9 | 4 |
Baseline characteristics
| Characteristic | Placebo | Mepolizumab 75 mg IV | Mepolizumab 100 mg SC | Total |
|---|---|---|---|---|
| Age, Continuous | 49.2 Years STANDARD_DEVIATION 14.26 | 50.0 Years STANDARD_DEVIATION 14.03 | 51.2 Years STANDARD_DEVIATION 14.55 | 50.1 Years STANDARD_DEVIATION 14.28 |
| Race/Ethnicity, Customized African American/African Heritage | 3 Participants | 6 Participants | 7 Participants | 16 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 15 Participants | 15 Participants | 15 Participants | 45 Participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 18 Participants | 17 Participants | 17 Participants | 52 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 4 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Mixed Race | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White - Arabic/North African Heritage | 4 Participants | 3 Participants | 4 Participants | 11 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 144 Participants | 148 Participants | 148 Participants | 440 Participants |
| Sex: Female, Male Female | 107 Participants | 106 Participants | 116 Participants | 329 Participants |
| Sex: Female, Male Male | 84 Participants | 85 Participants | 78 Participants | 247 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 143 / 191 | 142 / 191 | 132 / 194 |
| serious Total, serious adverse events | 27 / 191 | 14 / 191 | 16 / 194 |
Outcome results
Primary
Number of Clinically Significant Exacerbations of Asthma Per Year
Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.
Time frame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
Population: Modified Intent-to-Treat (ITT) Population: all participants who were randomized and who received at least one dose of trial medication. 'Modified' implies that, in cases where there is is a discrepancy between randomized and actual treatment the analysis used the actual treatment received by the participant rather than the randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Clinically Significant Exacerbations of Asthma Per Year | 1.74 Number of exacerbations per year |
| Mepolizumab 75 mg IV | Number of Clinically Significant Exacerbations of Asthma Per Year | 0.93 Number of exacerbations per year |
| Mepolizumab 100 mg SC | Number of Clinically Significant Exacerbations of Asthma Per Year | 0.83 Number of exacerbations per year |
p-value: <0.00195% CI: [0.4, 0.72]Negative binomial model
p-value: <0.00195% CI: [0.35, 0.64]Negative binomial model
Secondary
Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32
FEV1 is defined as the volume of air expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using mixed model repeated measures with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by baseline and visit by treatment group.
Time frame: Baseline, Week 32
Population: ITT Population. Only participants with a Baseline FEV1 available and at least one post-Baseline FEV1 measurement were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32 | 86 Milliliters (mL) | Standard Error 31.4 |
| Mepolizumab 75 mg IV | Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32 | 186 Milliliters (mL) | Standard Error 31.5 |
| Mepolizumab 100 mg SC | Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32 | 183 Milliliters (mL) | Standard Error 31.1 |
Secondary
Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32
The St. George's Respiratory Questionnaire is an established instrument, comprising 50 questions, evaluating symptoms, activity, and impacts; to measure Quality of Life in participants with diseases of airway obstruction and to elicit the participant's opinion of his/her health. The lowest possible value is zero and the highest possible value is 100. The higher values correspond to greater impairment in quality of life. The questionnaire was administered at Baseline (Visit 2) and at the Exit Visit (approximately 4 weeks after the last dose of study treatment). The change from baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using analysis of covariance with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), baseline % predicted FEV1, and treatment.
Time frame: Baseline, Week 32
Population: ITT Population. Note that only participants with a Baseline and Week 32 assessment were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32 | -9.0 Scores on a scale | Standard Error 1.16 |
| Mepolizumab 75 mg IV | Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32 | -15.4 Scores on a scale | Standard Error 1.16 |
| Mepolizumab 100 mg SC | Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32 | -16.0 Scores on a scale | Standard Error 1.13 |
Secondary
Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year
Clinically significant exacerbations of asthma is defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.
Time frame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year | 0.10 Number of exacerbations per year |
| Mepolizumab 75 mg IV | Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year | 0.06 Number of exacerbations per year |
| Mepolizumab 100 mg SC | Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year | 0.03 Number of exacerbations per year |
Secondary
Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year
Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.
Time frame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year | 0.20 Number of exacerbations per year |
| Mepolizumab 75 mg IV | Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year | 0.14 Number of exacerbations per year |
| Mepolizumab 100 mg SC | Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year | 0.08 Number of exacerbations per year |