| Study characteristics |
| Methods |
Multicentre, phase 3, randomised, placebo‐controlled, double‐blind, parallel‐group study
Study locations: Argentina, Australia, Canada, Chile, Denmark, Germany, Japan, Republic of Korea, the Netherlands, Romania, Slovakia, Taiwan, Ukraine, the United Kingdom, the United States
Study duration: 52 weeks |
| Participants |
674 participants aged at least 40 years with COPD. All participants had a blood eosinophil count of at least 150 per cubic millimetre at screening or at least 300 per cubic millimetre during the previous year.
Mepolizumab 300 mg: 225 participants, mean age 64.8 years (SD 8.96); females 67 (29.8%)
Mepolizumab 100 mg: 223 participants, mean age 64.8 (SD 9.06); females 91 (40.8%)
Placebo: 226 participants, mean age 65.8 years (SD 8.64); females 70 (31.0%)
Inclusion criteria:
COPD diagnosis: participants with a clinically documented history of COPD for at least 1 year in accordance with ATS/ERS definition. Severity of COPD: participants must present with the following: a measured pre‐ and post‐salbutamol FEV₁/FVC ratio of < 0.70 at Visit 1 to confirm the diagnosis of COPD; a measured post‐salbutamol FEV₁ > 20% and ≤ 80% of predicted normal values calculated using NHANES III reference equations at Visit 1. History of exacerbations: a well‐documented history (e.g. medical record verification) in the 12 months prior to Visit 1 of at least 2 moderate COPD exacerbations. 'Moderate' is defined as the use of systemic corticosteroids (IM, IV, or oral) and/or treatment with antibiotics; or at least 1 severe COPD exacerbation. 'Severe' is defined as having required hospitalisation. Note: at least 1 exacerbation must have occurred while the participant was taking ICS plus LABA or LAMA. 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 optimised standard of care 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 μg/day fluticasone propionate dose equivalent plus LABA and LAMA. For participants 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): ICS at a dose ≥ 500 μg/day fluticasone propionate dose equivalent plus a LABA or LAMA and use of at least 1 other class of COPD medication (i.e. phosphodiesterase‐4‐inhibitors, methylxanthines, or a combination of short acting beta₂‐agonist and short‐acting muscarinic antagonist). 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. Participants 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 childbearing 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: participants 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 who do not meet the definition of a current or former smoker. French participants: In France, participants are eligible for inclusion only if either affiliated to or a beneficiary of a social security category.
Exclusion criteria:
Participants with asthma: current and former smokers: participants 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: participants 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. Participants with alpha₁‐antitrypsin deficiency as the underlying cause of COPD are excluded. Participants with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases are also excluded. Participants are excluded if maintenance use of bi‐level positive airway pressure is required for the treatment of respiratory disorder. COPD stability: participants with pneumonia, exacerbation, lower respiratory infection within the 4 weeks prior to Visit 1. Lung resection: participants with lung volume reduction surgery within the 12 months prior to Visit 1. Pulmonary rehabilitation programme: participation in the acute phase of a pulmonary rehabilitation programme within 4 weeks prior to Visit 1. Participants who are in the maintenance phase of a pulmonary rehabilitation programme are not excluded. Oxygen: participants receiving treatment with oxygen more than 4.0 L/min. Whilst breathing supplemental oxygen, participants should demonstrate an oxyhaemoglobin saturation ≥ 89%. 12‐lead 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 centralised independent cardiologist to assist in consistent evaluation of participant 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: participants with any of the following are excluded: myocardial infarction or unstable angina in the last 6 months; unstable or life‐threatening cardiac arrhythmia requiring intervention in the last 3 months; NYHA Class IV heart failure. Other diseases/abnormalities: participants 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 participant at risk through participation, or that would affect the efficacy or safety analysis if the disease/condition exacerbated during the study. Eosinophilic disease: participants 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 oesophagitis. Parasitic infection: participants 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 (participants who had localised carcinoma of the skin or cervix which was resected for cure are not excluded). Participants in South Korea with a diagnosis of malignancy within 5 years of Visit 1 are excluded. Immunodeficiency: a known immunodeficiency (e.g. HIV) other than that explained by the use of corticosteroids taken for COPD. Liver disease: unstable liver disease (defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal 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 participant 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: participants who have received any monoclonal antibody within 5 half‐lives of Visit 1. Investigational medications: participants 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: participants 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 participant who is unable to read and/or would not be able to complete study‐related materials. Non‐compliance: participants 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: participants with a history of psychiatric disease, intellectual deficiency, poor motivation, or other conditions that would 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: participants who have previously participated in any study of mepolizumab. Affiliation with Investigator Site: is an investigator, sub‐investigator, study co‐ordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.
|
| Interventions |
3 arm trial: mepolizumab 100 mg versus mepolizumab 300 mg versus placebo.
Each participant received 100 mg or 300 mg mepolizumab SC injection or placebo every 4 weeks (13 administrations during 52‐week treatment period) along with their baseline standard of care COPD medication.
Placebo: sterile 0.9% sodium chloride solution
Salbutamol MDI was issued for use as rescue medication throughout the study. |
| Outcomes |
Primary outcome measures:
Secondary outcome measures:
Time to First Moderate/Severe Exacerbation. Time Frame: from randomisation to Week 52 Rate of COPD Exacerbations Requiring ED Visits and/or Hospitalisations. Time Frame: from randomisation to Week 52 Change From Baseline in Mean Total SGRQ Score. Time Frame: baseline and Week 52 Change From Baseline in Mean CAT Score. Time Frame: baseline and Week 52
|
| Notes |
Principal Investigator: GSK Clinical Trials
Sponsor: GlaxoSmithKline |
| Risk of bias |
| Bias |
Authors' judgement |
Support for judgement |
| Random sequence generation (selection bias) |
Low risk |
Randomisation was performed using a centralised, computer‐generated, permuted‐block design with fixed block size of 6; separate schedules were generated for each country. |
| Allocation concealment (selection bias) |
Unclear risk |
It is highly likely that the allocation concealment was adequate, but no details provided in the trial report. |
| Blinding of participants and personnel (performance bias)
All outcomes |
Low risk |
Participant, investigator, and outcomes assessor were masked (confirmed in clinicaltrials.gov/ct2/show/results/NCT02105961). |
| Blinding of outcome assessment (detection bias)
All outcomes |
Low risk |
Participant, investigator, and outcomes assessor were masked (confirmed in clinicaltrials.gov/ct2/show/results/NCT02105961). |
| Incomplete outcome data (attrition bias)
All outcomes |
Low risk |
Missing data sensitivity analyses conducted indicating robustness of primary efficacy results. |
| Selective reporting (reporting bias) |
Low risk |
No apparent indication of selective outcome reporting. |
| Other bias |
Low risk |
No apparent indication of other sources of bias. |
