E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | PT |
E.1.2 | Classification code | 10009033 |
E.1.2 | Term | Chronic obstructive pulmonary disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
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 effect of benralizumab on COPD exacerbations in patients with moderate to very severe COPD |
|
E.2.2 | Secondary objectives of the trial |
- To evaluate the effect of benralizumab on severe COPD exacerbations (leading to hospitalization or death) - To evaluate the effect of benralizumab on COPD exacerbations involving emergency room visits and hospitalizations - To evaluate the effect of benralizumab on other parameters associated with COPD exacerbations - To evaluate the effect of benralizumab on health status/health-related quality of life - To evaluate the effect of benralizumab on respiratory symptoms - To evaluate the effect of benralizumab on pulmonary function - To evaluate the effect of benralizumab on all cause and respiratory-related mortality - To evaluate the effect of benralizumab on health care resource utilization due to COPD - To evaluate the pharmacokinetics and immunogenicity of benralizumab in this patient population |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1 Provision of informed consent
2 Age 40 to 85 years
3 Male and/or female.
4 Current or former smoker with a tobacco history of ≥10 pack-years.
5 History of moderate to very severe COPD with a post-bronchodilator FEV1/FVC<0.70 and FEV1 ≤65% of predicted normal value.
6 Documented history of 2 or more COPD exacerbations that required treatment with systemic corticosteroids and/or hospitalization within 52 weeks prior to enrollment. (a) Exacerbations treated with antibiotics alone are excluded unless accompanied by treatment with systemic corticosteroids and/or hospitalization. (b) Hospitalization is defined as an inpatient admission ≥24 hours (c) Previous exacerbations should be confirmed to have occurred while on stable triple therapy for COPD. (d) At least one qualifying COPD exacerbation should occur while on stable uninterrupted triple therapy prior to enrolment.
7 Documented use of triple (ICS/LABA/LAMA) background therapy for COPD for ≥3 months immediately prior to enrollment. (a) Treatment with at least double inhaled therapy containing ICS for the remaining of 52 weeks prior to enrolment. Use of LABA/LAMA is allowed if ICS cannot be tolerated. (b) ICS in a dose approved for COPD or equivalent to ≥250 mcg of fluticasone propionate daily (c) Total cumulative duration of not being on double or triple background therapy must not exceed 2 months. (d) Stable therapy/doses for the last 3 months prior to randomization.
8 Blood eosinophil count ≥300/μL at screening and documented historical eosinophil count of ≥150/μL within 52 weeks of enrollment (or repeated testing during run-in).
9 CAT total score ≥15 at Visit 1.
10 Negative pregnancy test for females of childbearing potential (WOCBP) at Visit 1.
11 Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control from enrollment throughout the study and within 12 weeks after last dose of IP.
Women not of childbearing potential are defined as women who are either permanently sterilized or postmenopausal (confirmed by FSH test for women <50 years). |
|
E.4 | Principal exclusion criteria |
1 Clinically important pulmonary disease other than COPD 2 Current diagnosis of asthma, prior history of asthma or asthma-COPD overlap according to GINA/GOLD. Childhood history of asthma is allowed and defined as asthma diagnosed and resolved before theage of 18. 3 Radiological findings of a respiratory disease other than COPD contributing to respiratory symptoms. Solitary pulmonary nodules without appropriate follow up or findings of acute infection. 4 Another pulmonary or systemic disease associated with elevated peripheral eosinophil counts. 5 Any unstable disorder that could affect patient safety, study findings or the patient’s ability to complete the study. 6 Any clinically significant abnormal findings in physical examination, vital signs, ECG, laboratory tests could affect patient safety, study findings or the patient’s ability to complete the study. 7 Cor pulmonale and/or right ventricular failure. 8 Long-term treatment with oxygen >4.0 L/min and/or oxyhemoglobin saturation <89% while breathing supplemental oxygen. 9 Use of any non-invasive positive pressure ventilation device (NIPPV). Note: use of CPAP for Sleep Apnea Syndrome is allowed. 10 Known immunodeficiency disorder, including positive HIV-1/2 testing. 11 Active liver disease. Chronic stable hepatitis B and C (including positive HBsAg or hepatitis C antibody testing), or other stable chronic liver disease are acceptable. 12 ALT or AST ≥3 times the upper limit of normal, confirmed by repeated testing during the run-in period. 13 Helminth parasitic infection within 24 weeks prior to enrollment, not treated or failed to respond to standard of care therapy. 14 Alcohol or drug abuse within the past year, which may compromise the study data. 15 Malignancy, current or within the past 5 years, except for adequately treated non invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma-in-situ treated with apparent success more than 1 year prior to Visit 1. Suspected malignancy or undefined neoplasms. 16 Evidence of active tuberculosis, as judged by investigator. Patients with a recent (within 2 years) first-time or newly positive PPD or Quantiferon test need to complete an appropriate course of treatment before enrollment. Evaluation will be according to the local standard of care. 17 Participation, or planned participation, in intensive COPD rehabilitation program (maintenance phase of a rehabilitation is allowed). 18 History of surgical or endoscopic lung volume reduction within the 6 months prior to enrollment. History of partial or total lung resection (single lobe or segmentectomy is acceptable). 19 Scheduled major surgical procedure during the study. Minor elective procedures are allowed. 20 History of anaphylaxis to any biologic therapy or vaccine. 21 Receipt of blood products or immunoglobulins within 30 days prior to randomization. 22 Receipt of marketed or investigational biologic product within 4 months or 5 half-lives prior to randomization, whichever is longer. Exception: Patients on stable therapy for 3 months before randomization who intend to stay on treatment throughout the study with marketed biologic products that are not likely to interfere with the safety assessment and/or efficacy of benralizumab, for example, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, ocular, cardiovascular, or metabolic diseases, can participate in the study. 23 Receipt of live attenuated vaccines 30 days prior to randomization. 24 Chronic use of immunosuppressive medication or expected need for chronic use during the study. 25 Chronic use of antibiotics if duration of treatment is <9 months prior to randomization. Chronic macrolide or other antibiotic therapy is allowed provided the patient has been on stable dose/regimen for ≥9 months prior to randomization and has had ≥2 COPD exacerbations while on stable therapy. 26 Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to enrollment. 27 Receipt of benralizumab within 12 months prior to enrollment. 28 Known history of allergy or reaction to any component of the IP formulation. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Annualized rate of moderate or severe COPD exacerbations, where a COPD exacerbation is defined by symptomatic worsening of COPD requiring:
• Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or
• Use of antibiotics; and/or
• An inpatient hospitalization or death due to COPD |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Annualized rate of severe COPD exacerbations, where a severe COPD exacerbation is defined by symptomatic worsening of COPD requiring an inpatient hospitalization or results in death due to COPD
2. Annualized rate of COPD exacerbations that are associated with an emergency room/emergency department visit or a hospitalization due to COPD
3. Time to first COPD exacerbation
4. • SGRQ total and domain scores • CAT total score
5. E-RS:COPD total and domain scores
6. Change from baseline in pre-dose/pre-bronchodilator FEV1 at the study site
7. Mortality rate
8. Annual rate of hospitalizations due to COPD; Length of hospital stay; ICU days; annual rate of hospitalizations and emergency department visits combined due to COPD; annual rate of unscheduled outpatient visits including unscheduled visits to study sites due to COPD; and annual rate of unscheduled healthcare encounters due to COPD
9. • Serum benralizumab concentration • Anti-benralizumab antibodies |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Over 56 weeks or through End of Treatment |
|
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 | No |
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | 353 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 91 |
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 |
Chile |
China |
Colombia |
Japan |
Korea, Republic of |
Mexico |
New Zealand |
Philippines |
United States |
Austria |
Poland |
Sweden |
Netherlands |
Spain |
Czechia |
Germany |
Greece |
Italy |
Belgium |
Denmark |
Hungary |
Turkey |
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 study is defined as the last expected visit/contact of the last patient undergoing the study. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 1 |