| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Obstructive Pulmonary Disease (COPD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic Inflammation in the airways and the Lung |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10010952 |
| E.1.2 | Term | COPD |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of mepolizumab 100 mg subcutaneous (SC) compared to placebo, given every 4 weeks in liquid formulation by safety syringe (SS) to COPD participants at high risk of exacerbations despite the use of optimized COPD maintenance therapy |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate mepolizumab 100 mg subcutaneous (SC) compared to placebo given every 4 weeks in liquid formulation by safety syringe (SS) on additional efficacy assessments, health related quality of life (HRQoL), health care utilization, and symptoms |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetic Sub-study: China and US only
Objective: assess potential ethnic differences in the PK of mepolizumab 100 mg, in liquid formulation, between non-Asian participants in the US and Chinese participants in China
|
|
| E.3 | Principal inclusion criteria |
Further details for Inclusion can be found in the SRM
1.Participant must be at least 40 years of age at Screening Visit 1
2. A peripheral blood eosinophil count of ≥300 cells/μL from the hematology sample collected at Screening Visit 0 AND A documented historical blood eosinophil count of ≥150/μL in the 12 months prior to
Screening Visit 0 that meets the following: It must have been measured between 12
months and 1 month prior to Visit 0, and it must not have been measured within 14
days of a COPD exacerbation
Participants with no documented historical blood eosinophil count of ≥150 cells/μL
must meet this threshold based on the Screening Visit 1 assessment in order to return
for Randomization Visit 2
3.Participants 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
4.Participants must present with the following:
• A measured pre- and post-salbutamol FEV1/FVC ratio of <0.70 at Screening 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 Screening Visit 1
5.Participants must have a well-documented history (e.g., medical record verification) in the 12 months prior to Screening Visit 1 of
• Two or more moderate COPD exacerbations that were treated with systemic corticosteroids (intramuscular (IM), intravenous, or oral) with or without antibiotics. OR
• At least one severe COPD exacerbation requiring hospitalization
Note: At least one exacerbation must have occurred while participant was taking inhaled triple therapy.
Note: COPD exacerbations related to COVID-19 infection must not be counted as COPD exacerbations for inclusion in the study
6. Participants must have a well-documented requirement for optimized standard of care background therapy that includes ICS plus 2 additional COPD medications (i.e., ICS-based triple therapy) for the 12 months prior to Screening Visit 1 and meets the following criteria:
• Immediately prior to Screening Visit 1, minimum of 3 months of use of an a) inhaled corticosteroid at a dose ≥500 mcg/day fluticasone propionate dose equivalent plus b) LABA and c) LAMA unless documentation of safety or intolerance issues related to LABA or 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 the following is allowed (but not in the 3 months immediately prior to Visit 1):
a.inhaled corticosteroid at a dose ≥500 mcg/day fluticasone propionate dose equivalent plus
b.inhaled LABA or inhaled LAMA and c.Phosphodiesterase-4-inhibitors, methylxanthines, or scheduled daily use of short acting beta2-agonist (SABA) and/or short acting muscarinic antagonist (SAMA).
Note: Where intolerance or safety risk is documented for either LAMA or LABA, ICS-based inhaled dual maintenance therapy, either ICS plus LABA or ICS plus LAMA, is allowed in the 12 months prior to Visit 1 and during the clinical trial but must be discussed with the Medical Monitor.
7. Current or former cigarette smokers with a history of cigarette smoking of ≥10 pack-years at Screening (Visit 1) [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 have stopped smoking for at least 6 months prior to Screening Visit 1.
8. Contraceptive use for women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
Female Participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
o Is not a woman of childbearing potential (WOCBP)
o Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Appendix 5, during the intervention period and for at least 16 weeks after the last dose of study intervention. The principal investigator (PI) should evaluate the effectiveness of the contraceptive method in relation to the first dose of study intervention
• A WOCBP must have a negative highly sensitive pregnancy urine test within 24 hours before the first dose of study intervention
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
• The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk of inclusion of a woman with an early undetected pregnancy
9. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
|
|
| E.4 | Principal exclusion criteria |
1. Participants with a past history or concurrent diagnosis of asthma are excluded regardless of whether they have active or inactive disease.
2. The Investigator must judge that COPD is the primary diagnosis accounting for the clinical manifestations of the lung disease. Participants with α1-antitrypsin deficiency as the underlying cause of COPD are excluded. Also, excluded are participants with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases.
3. Participants with pneumonia, COPD exacerbation, or lower respiratory tract infection within the 4 weeks prior to Screening Visit 1.
4. Participants with lung volume reduction surgery within the 12 months prior to Screening Visit 1.
5. Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Screening Visit 1. Those in the maintenance phase are not excluded.
6. Participants receiving treatment with oxygen more than 2 L/min at rest over 24 hrs. These participants should demonstrate an oxyhemoglobin saturation greater than or equal to 89% while breathing supplemental oxygen.
7. Participants with a QT interval, from the ECG conducted at Screening Visit 1, corrected with Fridericia’s formula (QTcF) >450 msec (or QTcF >480 msec in participants with bundle branch block).
Participants are excluded if an abnormal ECG finding from the 12-lead ECG conducted at Screening Visit 1 is considered to be clinically significant and would impact the participant’s participation during the study, based on the evaluation of the Investigator.
Note: Where a single ECG demonstrates a prolonged QTcF interval, obtain two more ECGs readings at a minimum of 2 minutes apart over a brief recording period (e.g., 5-10 minutes), The average of the triplicate QTcF measurements should be used to determine eligibility
8. Participants with any of the following would be excluded:
• Myocardial infarction or unstable angina in the 6 months prior to Screening Visit 1
• Unstable or life threatening cardiac arrhythmia requiring intervention in the 3 months prior to Screening Visit 1
• New York Heart Association (NYHA) Class IV Heart failure
9. Participants with (historical or) current evidence of clinically significant, neurological, psychiatric, renal, hepatic, immunological, endocrine (including uncontrolled diabetes or thyroid disease) or hematological abnormalities that are uncontrolled.
10. Participants with other conditions that could lead to elevated eosinophils such as Hyper eosinophilic syndromes including Eosinophilic Granulomatosis with Polyangiitis (EGPA, also known as Churg-Strauss Syndrome), or Eosinophilic Esophagitis.
11. Participants with a known, pre-existing parasitic infestation within 6 months prior to Screening Visit 1.
12. A current malignancy or previous history of cancer in remission for less than 12 months prior to Screening Visit 1 (Participants that had localized carcinoma of the skin or cervix which was resected for cure will not be excluded).
13. A known immunodeficiency (e.g. HIV), other than that explained by the use of corticosteroids taken for COPD.
14. Cirrhosis or current unstable liver disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, or persistent jaundice. Stable noncirrhotic chronic liver disease (including Gilbert’s syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C) is acceptable if the participant otherwise meets entry criteria.
15. Participants who have received interventional product in previous mepolizumab.
16. Participants who have received any monoclonal antibody within 5 half-lives of Screening Visit 1
17. 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.
18. Participants who have received short term use of oral corticosteroids within 30 days of Visit 1
19. Participants with a known allergy or sensitivity to any of the study interventions, or components thereof, or drug or other allergy
20. Participants at risk of non-compliance, or unable to comply with the study procedures.
24. COVID-19: a- Participants that have a current active COVID-19 infection, either laboratory confirmed or according to the investigator's medical judgement.
Note: Participants who have confirmed or suspected COVID-19 infection may be re-screened 4 weeks or more after the resolution of the COVID-19 infection and only after written approval from the study Medical Monitor.
b- Participants known to be in contact with active COVID-19 positive individuals within the past 14 days.
Note: Participants may be re-screened 14 days or more following the contact, during which the participant should remain symptom free, and only after written approval from the study Medical Monitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Annualized rate of moderate/severe exacerbations |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| A period scaled down to a 12-month period (Annualized Rate) |
|
| E.5.2 | Secondary end point(s) |
•Time to first moderate/severe exacerbation.
•Proportion of COPD assessment test (CAT) responders (≥2 unit reduction in CAT score from baseline) at Week 52
• Proportion of St. George's Respiratory Questionnaire (SGRQ) total score responders (measured using the St. George's Respiratory Questionnaire for COPD [SGRQ-C], and defined as ≥4 point reduction in SGRQ total score from Baseline) at Week 52
• Proportion of Evaluating Respiratory Symptoms in COPD (E-RS: COPD) responders (≥2 unit reduction in total score from Baseline) at Week 52
• Annualized rate of exacerbations requiring Emergency Department (ED) visit and/or hospitalization |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Genetic, Biomarkers, Immunogenicity assessments |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 104 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Hong Kong |
| India |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| United States |
| Austria |
| France |
| Poland |
| Sweden |
| Netherlands |
| Spain |
| Germany |
| Greece |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Ireland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last scheduled visit, shown in the Schedule of Activities (SoA) for 52 weeks, for the last participant in the trial globally |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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