E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with severe asthma |
|
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 | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003553 |
E.1.2 | Term | Asthma |
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 efficacy of mepolizumab 100 mg subcutaneous (SC) every 4 weeks versus placebo on health-related quality of life (HR-QoL) in adult and adolescent subjects with severe eosinophilic asthma. |
|
E.2.2 | Secondary objectives of the trial |
● To assess the effects of mepolizumab compared to placebo on lung function.
● To assess the effects of mepolizumab compared to placebo on HR-QoL.
● To assess the effects of mepolizumab compared to placebo on asthma control. |
|
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 |
● Body Plethysmography Sub-Study - A body plethysmography sub-study will be conducted concurrently to the main study in a sub-set of subjects (see Section 4.3.1 of study protocol) to assess the effect of mepolizumab on lung volumes.
● Physical Activity Sub-Study - To explore the effects of mepolizumab compared to placebo on physical activity.
|
|
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in the study only if all of the following criteria
apply:
1. Age: At least 12 years of age at the time of signing the informed consent/assent.
[For those countries where local regulations permit enrolment of adults only, subject recruitment will be restricted to those who are ≥ 18 years of age]
2. Inhaled Corticosteroid: 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).
For subjects ≥ 18 years old:
- ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (exactuator) or equivalent daily.
- For ICS/LABA combination preparations, the highest approved
maintenance dose in the local country will meet this ICS criterion.
For subjects ≥ 12 to ≤ 17 years old:
- ICS dose must be ≥440 μg/day FP (ex-actuator) or equivalent daily.
- For ICS/LABA combination preparations, the mid-strength approved
maintenance dose in the local country will meet this ICS criterion.
3. Controller Medication: 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. [e.g., long-acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline.]
4. Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as per Randomisation Criteria 1 and 2 (see Section 5.3 of study protocol).
5. FEV1: Persistent airflow obstruction as indicated by :
- For subjects ≥ 18 years of age at visit 1, a pre-bronchodilator FEV1 <80% predicted (NHANES III) recorded at Visit 1
- For subjects 12-17 years of age at Visit 1:
- A pre-bronchodilator FEV1 <90% predicted (NHANES III) recorded
at Visit 1 OR
- FEV1:FVC ratio < 0.8 recorded at Visit 1
6. Exacerbation history: Previously confirmed history of two or more
exacerbations requiring treatment with systemic CS (intramuscular (IM), intravenous, or oral), in the 12 months prior to visit 1, despite the use of high-dose ICS. For subjects receiving maintenance CS, the CS treatment for the exacerbations must have been a two-fold dose increase or greater.
7. 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 (Refer to Appendix 5 of study Protocol) for the duration of the trial and for 4 months after the last study drug administration.
8. Informed Consent/Assent: Able to give written informed consent/assent prior to participation in the core study, which will include the ability to comply with the requirements and restrictions listed in the consent/assent form and in this protocol.
Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.
Written informed consent must be obtained from ALL patients/legally authorized representative(s); for patients 12-17 years old, written informed assent must be obtained in addition to the legally authorized representative(s)’ consent.
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.
Inclusion Criteria for the Physical Activity Sub-Study and Physical Activity Sub-Study:
A subject will be eligible for inclusion in the sub-study only if the following criteria apply:
1. Age: ≥ 18 years of age
2. Informed Consent: Provided written informed consent to participate in the main study and able to give written informed consent prior to participation in the substudy, which will include the ability to comply with the requirements and restrictions listed in the consent form and this protocol. |
|
E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in the study if any of the following criteria apply:
1. Smoking history: Current smokers or former smokers with a smoking history of
≥ 10 pack years (number of pack years = (number of cigarettes per day / 20) x number of years smoked). A former smoker is defined as a subject who quit smoking at least 6 months prior to Visit 1.
2. Concurrent Respiratory Disease: Presence of a known pre-existing, clinically important lung condition other than asthma. This includes current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.
3. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening (Subjects that had localized carcinoma of the skin which was resected for cure will not be excluded).
4. Liver Disease: Known, pre-existing, 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).
5. Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to:
a. known ejection fraction of <30% OR
b. severe heart failure meeting New York Heart Association Class IV (see Appendix 8 of study Protocol) classification OR
c. hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III (see Appendix 8 of study Protocol) OR
d. angina diagnosed less than 3 months prior to Visit 1 or at Visit 1
6. Other Concurrent Medical Conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.
7. Eosinophilic Diseases: Subjects with other conditions that could lead to elevated eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis; EGPA), or Eosinophilic Esophagitis. Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.
8. ECG Assessment:
QTc(F) ≥450msec or QTc(F) ≥480 msec for subjects with Bundle Branch Block at Visit 1.
9. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.
10. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus – HIV), other than that explained by the use of corticosteroids taken as therapy for asthma.
11. Xolair: Subjects who have received omalizumab (Xolair) within 130 days of Visit 1.
12. Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1.
13. Investigational Medications: 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, prior to Visit 1 (this also includes investigational formulations of marketed products).
14. Hypersensitivity: Subjects with allergy/intolerance to a monoclonal antibody or biologic.
15. Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation.
A urine pregnancy test is required of all women of child bearing potential. This test will be performed at the time points specified in the Time and Events Schedule (Table 7 of study Protocol)
16. Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.
Exclusion Criteria for the Physical Activity Sub-Study :
1. Cardiopulmonary Rehabilitation: Participation in a cardiopulmonary rehabilitation program.
2. Impaired biomechanical movement: Orthopaedic, neurological or other complaints that significantly impair normal biomechanical movement patterns and limit the ability to walk/cycle, as judged by the Investigator. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
● Mean change from baseline in St. George’s Respiratory Questionnaire
(SGRQ) score at Week 24 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
● Mean change from baseline in clinic prebronchodilator FEV1 at Week 24
● Percentage of subjects achieving a 4 point or greater reduction from baseline in SGRQ score at Week 24
● Mean change from baseline in Asthma Control Questionnaire (ACQ-5) score at Week 24 |
|
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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 |
Canada |
Russian Federation |
Ukraine |
United States |
|
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
|
|
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 | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |