Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
eosinophils, SB240563, exacerbations, Chronic Obstructive Pulmonary Disease, mepolizumab
Brief summary
This is a multi-center, randomized, placebo-controlled, double-blind, parallel group trial evaluating mepolizumab 100 mg against placebo given every 4 weeks through subcutaneous (SC) injection. In severe COPD patients, sputum eosinophils levels are elevated similar as those seen in severe asthmatics. It is hypothesized that the reduction of eosinophils with mepolizumab in COPD patients would translate into a reduction of COPD exacerbations. The study will determine the reduction in exacerbations in subjects who are above and below the baseline blood eosinophil count of at least 150 cells/microlitres. The study will evaluate the efficacy and safety of mepolizumab on the frequency of moderate and severe exacerbations in COPD subjects at high risk of exacerbations, despite the use of optimized standard of care background therapy. Overall in this study, a total of 800 subjects will be randomised in 1:1 ratio to receive placebo or mepolizumab (100 milligram (mg)) administered SC. The total duration of this study will be approximately 62 weeks, consisting of a 1 to 2 week screening period, 52-week treatment period and 8-week follow-up period.
Interventions
DRUGMepolizumab
Humanised IgG antibody (IgG1, kappa) with human heavy and light chain frameworks, provided as a lyophilised cake in sterile vial. Vial to be reconstituted with Sterile Water for Injection, just prior to use.
DRUGPlacebo
Sterile 0.9% sodium chloride solution
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* COPD diagnosis: Subjects with a clinically documented history of COPD for at least 1 year in accordance with the definition by the American Thoracic Society/European Respiratory Society. * Severity of COPD: Subjects must present with the following: a measured pre and post-salbutamol Forced expiratory volume in one second/ Forced vital capacity (FEV1/FVC) ratio of \<0.70 at Visit 1 to confirm the diagnosis of COPD; a measured post-salbutamol FEV1\>20 percent and \<=80 percent of predicted normal values calculated using National Health and Nutrition Examination Survey (NHANES) III reference equations at Visit 1. * History of exacerbations: A well documented history (like medical record verification) in the 12 months prior to Visit 1 of: at least two moderate COPD exacerbations. Moderate is defined as the use of systemic corticosteroids (IM, intravenous, or oral) and/or treatment with antibiotics, or at least one severe COPD exacerbation. Severe is defined as having required hospitalization. Note: At least one exacerbation must have occurred while the subject was taking Inhaled corticosteroid (ICS) plus long acting beta2-agonist (LABA) plus long acting muscarinic antagonist (LAMA). Note: Prior use of antibiotics alone does not qualify as a moderate exacerbation unless the use was specifically for the treatment of worsening symptoms of COPD. * Concomitant COPD therapy: A well documented requirement for optimized standard of care (SoC) background therapy that includes ICS plus 2 additional COPD medications (i.e., triple therapy) for the 12 months prior to Visit 1 and meets the following criteria: Immediately prior to Visit 1, minimum of 3 months of use of an inhaled corticosteroid (at a dose \>=500 micrograms (mcg)/day fluticasone propionate dose equivalent plus); or LABA and LAMA. For subjects who are not continually maintained on ICS plus LABA plus LAMA for the entire 12 months prior to Visit 1 use of following is allowed (but not in the 3 months immediately prior to Visit 1): inhaled corticosteroid at a dose \>=500 mcg/day fluticasone propionate dose equivalent plus ; a LABA or a LAMA and use of at least one other class of COPD medication suggested by the 2013 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for patients who are prone to exacerbation (i.e., phosphodiesterase-4-inhibitors, methylxanthines, or a combination of short acting beta-2-agonist and short acting muscarinic antagonist). Note: Subjects must be willing to stay on their SoC COPD medication for the duration of the study. * Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials. * Gender: Male or Eligible Female; To be eligible for entry into the study females of child bearing potential must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after last study drug administration. * Age: At least 40 years of age at Visit 1. * Smoking status: Subject with confirmed COPD are eligible to participate independent of their smoking status and smoking history, i.e. current smokers, never smokers or ex-smokers can be enrolled into the study; Current smokers are defined as those with a history of cigarette smoking of \>=10 pack-years \[number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years)\]; Former smokers are defined as those who meet the definition of a current smoker but have stopped smoking for at least 6 months prior to Visit 1; Never smokers are those that do not meet the definition of a current or former smoker. * French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
Exclusion criteria
* Subjects having Asthma: Current and Former Smokers: Subjects with a current diagnosis of asthma (those with a prior history are eligible if they meet inclusion criteria for a current diagnosis of COPD); Never-Smokers: Subjects with any history of asthma; Other respiratory disorders: The investigator must judge that COPD is the primary diagnosis accounting for the clinical manifestations of the lung disease. Subjects with alpha-1-antitrypsin deficiency as the underlying cause of COPD are excluded. Also, excluded are subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases. Subjects are also excluded if maintenance use of bi-level positive airway pressure is required for the treatment of respiratory disorder. * COPD stability: Subjects with pneumonia, exacerbation, lower respiratory infection within the 4 weeks prior to Visit 1. * Lung resection: Subjects with lung volume reduction surgery within the 12 months prior to Visit 1. * Pulmonary rehabilitation program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded. * Oxygen: Subjects receiving treatment with oxygen more than 4.0 Litres/minute (L/min). While breathing supplemental oxygen, subjects should demonstrate an oxyhemoglobin saturation greater than or equal to 89 percent. * 12-lead Electrocardiography (ECG) finding: An abnormal and significant ECG finding from the 12-lead ECG conducted at Visit 1 if considered to be clinically significant by the Investigator. 12-lead ECGs will be over-read by a centralized independent cardiologist to assist in consistent evaluation of subject eligibility. Results from the 12-lead ECG over-read must be received prior to assessing eligibility at Visit 2. * Unstable or life threatening cardiac disease: Subjects with any of the following would be excluded: Myocardial infarction or unstable angina in the last 6 months ; Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months; New York Heart Association (NYHA) Class IV Heart failure. * Other diseases/abnormalities: Subjects with (historical or) current evidence of clinically significant, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or haematological abnormalities that are uncontrolled. Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. * Eosinophilic disease: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosinophilic syndromes including Eosinophilic Granulomatosis with Polyangiitis (EGPA, also known as Churg-Strauss Syndrome), or Eosinophilic Esophagitis. * Parasitic infection: Subjects with a pre-existing helminthes infestation within 6 months prior to Visit 1 are also excluded. * Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to Visit 1 (Subjects that had localized carcinoma of the skin or cervix which was resected for cure will not be excluded). Note for South Korea: Korean subjects with a diagnosis of malignancy within 5 years of Visit 1 are excluded. * Immunodeficiency: A known immunodeficiency e.g. human immunodeficiency virus (HIV), other than that explained by the use of corticosteroids taken for COPD. * Liver disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Chronic stable hepatitis B and C are acceptable if subject otherwise meets entry criteria (e.g. presence of hepatitis B surface antigen or positive hepatitis C test result within 3 months of screening). * Monoclonal antibodies: Subjects who have received any monoclonal antibody within 5 half-lives of Visit 1. * Investigational medications: Subjects who have received an investigational drug within 30 days of Visit 1, or within 5 drug half-lives of the investigational drug, whichever is longer (this also includes investigational formulations of a marketed product). * Hypersensitivity: Subjects with a known allergy or intolerance to another monoclonal antibody or biologic including history of anaphylaxis to another biologic * Inability to read: In the opinion of the investigator, any subject who is unable to read and/or would not be able to complete study related materials. * Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study procedures. Any infirmity, disability, or geographic location that would limit compliance for scheduled visits. * Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study. * Drug or alcohol abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1. * Previous participation: Subjects who have previously participated in any study of mepolizumab. * Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study. Randomization Criteria In order to be randomized to study drug the subject must meet the following randomization criteria at Visit 2: * Blood eosinophils: While there is no threshold for enrolment, information on eosinophil level should be obtained prior to randomization. * Electronic Diary Compliance: Compliance with completion of the eDiary defined as completion of all questions on 5 or more days out of the 7 days immediately preceding Visit 2. * 12-lead ECG: No evidence of an abnormal and significant ECG finding from the 12- lead ECG conducted at Visit 1 as indicated on the over-read provided by the centralized independent cardiologist. Subjects with a QT interval corrected with Fridericia's formulas (QTcF)\>=450 msec are not eligible. For subjects with a QRS interval \>=120 msec, those with QTcF\>=480 msec are not eligible. Specific ECG findings that preclude subject eligibility are listed in the protocol. * Abnormal chest X-ray (or Computerized Tomography \[CT scan\]): No chest X-ray (or CT scan) that reveals evidence of clinically significant abnormalities other than those believed to be due to the presence of COPD. If a chest X-ray or CT scan is not available within 6 months prior to Visit 1, then a chest X-ray must be taken at Visit 1 and the results reviewed prior to randomization. For sites in Germany: If a chest X-ray (or CT scan) within 6 months prior to Screening (Visit 1) is not available, the subject will not be eligible for the study. * Laboratory abnormality: No evidence of clinically significant abnormality in the haematological, biochemical, or urinalysis screen at Visit 1, as judged by the investigator. * Hepatitis B: Subjects who are HBsAg positive or HBcAb positive must not have a HBV DNA level \>= 2000 IU/ml. * Liver function test: Subjects must meet the following based on results from sample taken at Visit 1: Alanine aminotransferase (ALT) \<2x ULN (upper limit of normal); Alkaline Phosphatase (Alk Phos) \<=2x ULN; Bilirubin \<=1.5x ULN (isolated bilirubin\>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Moderate or Severe Exacerbations in Participants in the High Stratum | From randomization to Week 52 | Moderate exacerbations are defined as clinically significant exacerbations that require treatment with oral/systemic corticosteroids and/or antibiotics. Severe exacerbations are defined as clinically significant exacerbations that require in-patient hospitalization ( \>= 24 hours) or result in death. Moderate and severe exacerbations occurring from the start of investigational product (IP) up to the Week 52 visit, including exacerbations reported after early discontinuation from investigational product by subjects who remained in the study, were included in the analysis. The analysis was performed on the mITT high stratum (mITT-H) Population which comprised of participants in the mITT Population (all randomized participants who received at least one dose of study treatment) with blood eosinophil counts \>=150 cells/µL at Screening or \>=300 cells/ µL in the 12 months prior. |
| Rate of Moderate or Severe Exacerbations in the mITT Population | From randomization to Week 52 | Moderate and severe exacerbations occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on the mITT Population which comprised of all randomized participants who received at least one dose of trial medication. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Total St. George's Respiratory Questionnaire (SGRQ) Score in Participants in the High Stratum | Baseline and Week 52 | The SGRQ for COPD is a 40-item questionnaire derived from the original SGRQ, designed to measure health impairment by addressing the frequency of respiratory symptoms and current state of the participant. SGRQ Total Scores ranges from 0 to 100 with higher scores indicating worse health-related quality of life and reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Mean change from Baseline in SGRQ score at Week 52 has been presented. |
| Change From Baseline in Mean COPD Assessment Test (CAT) Score in Participants in the High Stratum | Baseline and Week 52 | The CAT is an 8-item questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Each question is assessed on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with the CAT score ranging from 0-40. Higher scores indicate greater disease impact with reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Mean change from Baseline in CAT score at Week 52 has been presented. |
| Time to First Moderate/Severe Exacerbation in the mITT Population | From randomization to Week 52 | Kaplan Meier estimates of the probability of a moderate/severe exacerbation are expressed as the percentage of participants with an exacerbation over time (by Week 8, 16, 24, 32, 40, 48, 52). The analysis was performed on the mITT population and included exacerbations reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP). |
| Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | From randomization to Week 52 | Kaplan Meier estimates of the probability of a moderate or severe exacerbation are expressed as the percentage of participants with an exacerbation over time (by Week 8, 16, 24, 32, 40, 48, 52). Analysis was performed on the mITT-H Population and included exacerbations reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study. |
| Change From Baseline in Mean Total SGRQ Score in the mITT Population | Baseline and Week 52 | The SGRQ for COPD is a 40-item questionnaire derived from the original SGRQ, designed to measure health impairment by addressing the frequency of respiratory symptoms and current state of the participant. SGRQ Total Scores ranges from 0 to 100 with higher scores indicating worse health-related quality of life and reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Mean change from Baseline in SGRQ score at Week 52 has been presented. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP). |
| Change From Baseline in Mean CAT Score in the mITT Population | Baseline and Week 52 | The CAT is an 8-item questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Each question is assessed on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with the CAT score ranging from 0-40. Higher scores indicate greater disease impact with reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Participants with a Baseline and at least one post-Baseline assessment were included in the analysis. Mean change from Baseline in CAT score at Week 52 has been presented. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP). |
| Rate of COPD Exacerbations Requiring ED Visit and/or Hosp in the mITT Population | From randomization to Week 52 | COPD exacerbations requiring ED visit and/or hosp occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on mITT Population. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP). |
| Rate of COPD Exacerbations Requiring an Emergency Department (ED) Visit and/or Hospitalization (Hosp.) in Participants in the High Stratum | From randomization to Week 52 | COPD exacerbations requiring an ED visit and/or hosp. occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on mITT-H Population. |
Countries
Australia, Belgium, Canada, Czechia, Estonia, France, Greece, Italy, Mexico, Norway, Peru, Poland, Russia, Spain, Sweden, United States
Participant flow
Recruitment details
Participants with chronic obstructive pulmonary disease (COPD) with frequent exacerbations and on high dose inhaled corticosteroid (ICS)-based triple inhaled maintenance therapy were included in this study. Participants were randomized to receive mepolizumab 100 milligrams (mg) or placebo by subcutaneous (SC) injection every 4 weeks for 52 weeks.
Pre-assignment details
A total of 836 participants were randomized and received at least one dose of study treatment and were included in the modified intent to treat (mITT) population. One participant randomized to the placebo group was withdrawn without receiving study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo - High Stratum Participants with blood eosinophil counts \>=150 cells/µL at Screening or \>=300 cells/µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study. | 229 |
| Mepolizumab 100 mg - High Stratum Participants with blood eosinophil counts \>=150 cells/µL at Screening or \>=300 cells/ µL in the 12 months prior were assigned to the high stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study. | 233 |
| Placebo - Low Stratum Participants with blood eosinophil counts \<150 cells/µL at Screening and no evidence of blood eosinophil counts \>=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received placebo by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study. | 190 |
| Mepolizumab 100 mg - Low Stratum Participants with blood eosinophil counts \<150 cells/µL at Screening and no evidence of blood eosinophil counts \>=300 cells/µL in the 12 months prior were assigned to the low stratum group. These participants were randomized to and received mepolizumab 100 mg by SC injection every 4 weeks for up to 52 weeks in addition to their SoC therapy. Salbutamol MDI was issued for use as rescue medication throughout the study. | 184 |
| Total | 836 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 7 | 11 | 11 |
| Overall Study | Lack of Efficacy | 0 | 1 | 3 | 2 |
| Overall Study | Lost to Follow-up | 0 | 0 | 2 | 1 |
| Overall Study | Physician Decision | 2 | 2 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 15 | 10 | 10 | 11 |
Baseline characteristics
| Characteristic | Placebo - High Stratum | Mepolizumab 100 mg - High Stratum | Placebo - Low Stratum | Mepolizumab 100 mg - Low Stratum | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65.3 Years STANDARD_DEVIATION 8.53 | 65.2 Years STANDARD_DEVIATION 8.36 | 65.2 Years STANDARD_DEVIATION 8.62 | 66.1 Years STANDARD_DEVIATION 9.14 | 65.4 Years STANDARD_DEVIATION 8.64 |
| Race/Ethnicity, Customized Race customized American Indian/ Alaska native Heritage | 14 Participants | 19 Participants | 22 Participants | 14 Participants | 69 Participants |
| Race/Ethnicity, Customized Race customized Asian- East Asian Heritage | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race customized Asian- Japanese Heritage | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Race customized Black/ African American Heritage | 4 Participants | 2 Participants | 3 Participants | 2 Participants | 11 Participants |
| Race/Ethnicity, Customized Race customized Multiple - American Indian/Alaska Native and White | 16 Participants | 11 Participants | 19 Participants | 23 Participants | 69 Participants |
| Race/Ethnicity, Customized Race customized White- Arabic/ North African Heritage | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race customized White- White/ Caucasian/ European Heritage | 190 Participants | 198 Participants | 145 Participants | 143 Participants | 676 Participants |
| Sex: Female, Male Female | 79 Participants | 84 Participants | 77 Participants | 76 Participants | 316 Participants |
| Sex: Female, Male Male | 150 Participants | 149 Participants | 113 Participants | 108 Participants | 520 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 | 8 / 229 | 6 / 233 | 9 / 190 | 10 / 184 |
| other Total, other adverse events | 146 / 229 | 136 / 233 | 116 / 190 | 108 / 184 |
| serious Total, serious adverse events | 80 / 229 | 65 / 233 | 51 / 190 | 50 / 184 |
Outcome results
Primary
Rate of Moderate or Severe Exacerbations in Participants in the High Stratum
Moderate exacerbations are defined as clinically significant exacerbations that require treatment with oral/systemic corticosteroids and/or antibiotics. Severe exacerbations are defined as clinically significant exacerbations that require in-patient hospitalization ( \>= 24 hours) or result in death. Moderate and severe exacerbations occurring from the start of investigational product (IP) up to the Week 52 visit, including exacerbations reported after early discontinuation from investigational product by subjects who remained in the study, were included in the analysis. The analysis was performed on the mITT high stratum (mITT-H) Population which comprised of participants in the mITT Population (all randomized participants who received at least one dose of study treatment) with blood eosinophil counts \>=150 cells/µL at Screening or \>=300 cells/ µL in the 12 months prior.
Time frame: From randomization to Week 52
Population: mITT-H Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo - High Stratum | Rate of Moderate or Severe Exacerbations in Participants in the High Stratum | 1.71 Moderate/severe exacerbations per year |
| Mepolizumab 100 mg - High Stratum | Rate of Moderate or Severe Exacerbations in Participants in the High Stratum | 1.40 Moderate/severe exacerbations per year |
p-value: =0.03695% CI: [0.68, 0.98]Negative binomial model
p-value: =0.02995% CI: [0.68, 0.98]Negative binomial mode
Primary
Rate of Moderate or Severe Exacerbations in the mITT Population
Moderate and severe exacerbations occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on the mITT Population which comprised of all randomized participants who received at least one dose of trial medication. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP).
Time frame: From randomization to Week 52
Population: mITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo - High Stratum | Rate of Moderate or Severe Exacerbations in the mITT Population | 1.52 Moderate/severe exacerbations per year |
| Mepolizumab 100 mg - High Stratum | Rate of Moderate or Severe Exacerbations in the mITT Population | 1.49 Moderate/severe exacerbations per year |
p-value: >0.99995% CI: [0.85, 1.12]Negative Binomial Model
p-value: =0.73195% CI: [0.85, 1.12]Negative binomial mode
Secondary
Change From Baseline in Mean CAT Score in the mITT Population
The CAT is an 8-item questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Each question is assessed on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with the CAT score ranging from 0-40. Higher scores indicate greater disease impact with reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Participants with a Baseline and at least one post-Baseline assessment were included in the analysis. Mean change from Baseline in CAT score at Week 52 has been presented. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP).
Time frame: Baseline and Week 52
Population: mITT Population. Participants analyzed represents those with a Baseline and at least one post-Baseline assessment, and with no missing covariates.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo - High Stratum | Change From Baseline in Mean CAT Score in the mITT Population | -0.4 Score on CAT scale | Standard Error 0.35 |
| Mepolizumab 100 mg - High Stratum | Change From Baseline in Mean CAT Score in the mITT Population | -1.0 Score on CAT scale | Standard Error 0.34 |
p-value: >0.99995% CI: [-1.5, 0.4]Mixed Model Repeated Measures Analysis
p-value: =0.25295% CI: [-1.5, 0.4]Mixed Model Repeated Measures Analysis
Secondary
Change From Baseline in Mean COPD Assessment Test (CAT) Score in Participants in the High Stratum
The CAT is an 8-item questionnaire developed for use in routine clinical practice to measure the health status of participants with COPD. Each question is assessed on a 6-point scale ranging from 0 (no impairment) to 5 (maximum impairment) with the CAT score ranging from 0-40. Higher scores indicate greater disease impact with reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Mean change from Baseline in CAT score at Week 52 has been presented.
Time frame: Baseline and Week 52
Population: mITT-H Population. Participants analyzed represents those with a Baseline and at least one post-Baseline assessment, and with no missing covariates.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo - High Stratum | Change From Baseline in Mean COPD Assessment Test (CAT) Score in Participants in the High Stratum | 0.0 Score on CAT scale | Standard Error 0.47 |
| Mepolizumab 100 mg - High Stratum | Change From Baseline in Mean COPD Assessment Test (CAT) Score in Participants in the High Stratum | -0.8 Score on CAT scale | Standard Error 0.45 |
p-value: >0.99995% CI: [-2, 0.5]Mixed Model Repeated Measures Analysis
p-value: =0.24495% CI: [-2, 0.5]Mixed Model Repeated Measures Analysis
Secondary
Change From Baseline in Mean Total SGRQ Score in the mITT Population
The SGRQ for COPD is a 40-item questionnaire derived from the original SGRQ, designed to measure health impairment by addressing the frequency of respiratory symptoms and current state of the participant. SGRQ Total Scores ranges from 0 to 100 with higher scores indicating worse health-related quality of life and reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Mean change from Baseline in SGRQ score at Week 52 has been presented. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP).
Time frame: Baseline and Week 52
Population: mITT Population. Participants analyzed represents those with a Baseline and at least one post-Baseline assessment, and with no missing covariates.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo - High Stratum | Change From Baseline in Mean Total SGRQ Score in the mITT Population | -4.0 Score on SGRQ scale | Standard Error 0.81 |
| Mepolizumab 100 mg - High Stratum | Change From Baseline in Mean Total SGRQ Score in the mITT Population | -3.2 Score on SGRQ scale | Standard Error 0.8 |
p-value: >0.99995% CI: [-1.5, 2.9]Mixed Model Repeated Measures Analysis
p-value: =0.53295% CI: [-1.5, 2.9]Mixed Model Repeated Measures Analysis
Secondary
Change From Baseline in Mean Total St. George's Respiratory Questionnaire (SGRQ) Score in Participants in the High Stratum
The SGRQ for COPD is a 40-item questionnaire derived from the original SGRQ, designed to measure health impairment by addressing the frequency of respiratory symptoms and current state of the participant. SGRQ Total Scores ranges from 0 to 100 with higher scores indicating worse health-related quality of life and reductions indicating improvement. The Baseline value will be the last measurement collected prior to the first dose of investigational product. Change from Baseline is calculated as the post-dose visit value minus the Baseline value. Mean change from Baseline in SGRQ score at Week 52 has been presented.
Time frame: Baseline and Week 52
Population: mITT-H Population. Participants analyzed represents those with a Baseline and at least one post-Baseline assessment, and with no missing covariates.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo - High Stratum | Change From Baseline in Mean Total St. George's Respiratory Questionnaire (SGRQ) Score in Participants in the High Stratum | -3.0 Score on SGRQ scale | Standard Error 1.11 |
| Mepolizumab 100 mg - High Stratum | Change From Baseline in Mean Total St. George's Respiratory Questionnaire (SGRQ) Score in Participants in the High Stratum | -2.8 Score on SGRQ scale | Standard Error 1.06 |
p-value: >0.99995% CI: [-2.8, 3.2]Mixed Model Repeated Measure Analysis
p-value: =0.90195% CI: [-2.8, 3.2]Mixed Model Repeated Measure Analysis
Secondary
Rate of COPD Exacerbations Requiring an Emergency Department (ED) Visit and/or Hospitalization (Hosp.) in Participants in the High Stratum
COPD exacerbations requiring an ED visit and/or hosp. occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on mITT-H Population.
Time frame: From randomization to Week 52
Population: mITT-H Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo - High Stratum | Rate of COPD Exacerbations Requiring an Emergency Department (ED) Visit and/or Hospitalization (Hosp.) in Participants in the High Stratum | 0.26 Exacerbations requiring ED/hosp per year |
| Mepolizumab 100 mg - High Stratum | Rate of COPD Exacerbations Requiring an Emergency Department (ED) Visit and/or Hospitalization (Hosp.) in Participants in the High Stratum | 0.30 Exacerbations requiring ED/hosp per year |
p-value: =0.59895% CI: [0.77, 1.75]Negative binomial model
p-value: =0.47995% CI: [0.77, 1.75]Negative binomial model
Secondary
Rate of COPD Exacerbations Requiring ED Visit and/or Hosp in the mITT Population
COPD exacerbations requiring ED visit and/or hosp occurring from the start of IP up to the Week 52 visit, including exacerbations reported after early discontinuation from IP by participants who remained in the study, were included in the analysis. The analysis was performed on mITT Population. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP).
Time frame: From randomization to Week 52
Population: mITT Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo - High Stratum | Rate of COPD Exacerbations Requiring ED Visit and/or Hosp in the mITT Population | 0.26 Exacerbations requiring ED/hosp per year |
| Mepolizumab 100 mg - High Stratum | Rate of COPD Exacerbations Requiring ED Visit and/or Hosp in the mITT Population | 0.29 Exacerbations requiring ED/hosp per year |
p-value: >0.99995% CI: [0.81, 1.49]Negative binomial model
p-value: =0.55695% CI: [0.81, 1.49]Negative binomial model
Secondary
Time to First Moderate/Severe Exacerbation in Participants in the High Stratum
Kaplan Meier estimates of the probability of a moderate or severe exacerbation are expressed as the percentage of participants with an exacerbation over time (by Week 8, 16, 24, 32, 40, 48, 52). Analysis was performed on the mITT-H Population and included exacerbations reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study.
Time frame: From randomization to Week 52
Population: mITT-H Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 24 | 53.4 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 40 | 68.5 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 16 | 45.5 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 48 | 71.8 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 32 | 60.9 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 52 | 75.2 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 8 | 28.1 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 52 | 64.6 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 8 | 20.2 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 16 | 34.9 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 24 | 45.8 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 32 | 55.3 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 40 | 59.3 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in Participants in the High Stratum | Week 48 | 62.0 Percentage of participants |
p-value: =0.03695% CI: [0.6, 0.94]Cox Proportional Hazards Model
p-value: =0.01295% CI: [0.6, 0.94]Cox Proportional Hazards Model
Secondary
Time to First Moderate/Severe Exacerbation in the mITT Population
Kaplan Meier estimates of the probability of a moderate/severe exacerbation are expressed as the percentage of participants with an exacerbation over time (by Week 8, 16, 24, 32, 40, 48, 52). The analysis was performed on the mITT population and included exacerbations reported on-treatment and those reported after early discontinuation from IP by participants who remained in the study. The strata were combined as pre-specified in the protocol and reporting and analysis plan (RAP).
Time frame: From randomization to Week 52
Population: mITT Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 24 | 49.2 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 40 | 63.8 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 16 | 39.8 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 48 | 67.3 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 32 | 57.3 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 52 | 71.2 Percentage of participants |
| Placebo - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 8 | 25.1 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 52 | 65.5 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 8 | 23.6 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 16 | 37.4 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 24 | 46.3 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 32 | 54.1 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 40 | 59.7 Percentage of participants |
| Mepolizumab 100 mg - High Stratum | Time to First Moderate/Severe Exacerbation in the mITT Population | Week 48 | 62.5 Percentage of participants |
p-value: >0.99995% CI: [0.75, 1.05]Cox Proportional Hazards Model
p-value: =0.1695% CI: [0.75, 1.05]Cox Proportional Hazards Model