| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with severe, refractory, uncontrolled asthma with elevated blood eosinphils |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with severe refractory uncontrolled asthma who have at least 2 or more exacerbations in the past 12 months |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
| MedDRA Classification |
| 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 75 mg intravenous (i.v.) or 100 mg subcutaneous (SC) every 4 weeks versus placebo on the frequency of clinically significant exacerbations in adult and adolescent subjects with severe, uncontrolled, refractory asthma |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of mepolizumab compared with placebo, in subjects with severe refractory asthma.
To evaluate the effects of mepolizumab compared with placebo on a range of clinical markers of asthma control, including, pulmonary function (FEV1), and St. George’s Respiratory Questionnaire. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study and entry into the run-in period must meet all of the following criteria:
1. 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.
2. Age: At least 12 years of age at visit 1 and a minimum weight of 45kg [For those countries where local regulations permit enrolment of adults only, subject recruitment will be restricted to those who are ≥ 18 years of age]
3. 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). [Maintenance OCS is defined
as a prescribed regimen of a minimum average daily dose of prednisone 5mg (or
equivalent)].
• For 18 years of age and older:
• ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (exactuator)
or equivalent daily. [NOTE for subjects in Japan requirement is ≥800 mcg/day FP or equivalent]
• For ICS/LABA combination preparations, the highest approved
maintenance dose in the local country will meet this ICS criterion.
• For ages 12-17
• ICS dose must be ≥440 μg/day fluticasone propionate (FP) (exactuator)
or equivalent daily. [NOTE for subjects in Japan requirement is ≥400 mcg/day FP or equivalent]
• For ICS/LABA combination preparations, the mid-strength approved
maintenance dose in the local country will meet this ICS criterion
4. 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.]
5. Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as per Randomisation Criteria 1 and 2.
6. 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
7. 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 increase or greater in the dose.
8. 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 (Appendix 4) for the duration of the trial and for 4 months after the last study drug administration.
A serum pregnancy test is required of all females. This test will be performed at
the initial Screening visit (Visit 1) and at the exit visit. In addition, a urine
pregnancy test will be performed for all females prior to randomisation, during
each scheduled study visit prior to the infusion of investigational product, and
during the Follow-up Visit.
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.
Randomisation Criteria:
1. Eosinophilic Phenotype: Airway inflammation characterized as eosinophilic in
nature as indicated by one of the following:
a. An elevated peripheral blood eosinophil count of ≥300/μL that is related to
asthma demonstrated in the past 12 months prior to Visit 1
OR
b. An elevated peripheral blood eosinophil count of ≥ 150/μL at Visit 1 that is
related to asthma.
2. Asthma: Evidence of asthma as documented by either:
a. Airway reversibility (FEV1≥12% and 200ml) demonstrated at Visit 1 or Visit
2 using the Maximum Post Bronchodilator Procedure OR
b. Airway reversibility (FEV1≥12% and 200ml) documented in the 12 months
prior to visit 2 (randomisation visit) OR
c. Airway hyperresponsiveness (PC20 of <8mg/mL or PD20 of <7.8 μmol
methacholine/histamine) documented in the 12 months prior to visit 2
(randomisation visit)OR
d. Airflow variability in clinic FEV1 ≥20% between two clinic visits
documented in the 12 months prior to visit 2 (randomisation visit) ( FEV1
recorded during an exacerbation will not be valid) OR
e. Airflow variability as indicated by >20% diurnal variability in peak flow
observed on 3 or more days during the run-in |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
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). [Note for South Korea: Korean subjects with a diagnosis of malignancy within 5 years are 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 known, pre-existing severe or clinically
significant cardiovascular disease uncontrolled with standard treatment.
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 Hypereosiniophilic Syndromes, including Churg-Strauss Syndrome, or Eosinophilic Esophaghitis. 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 screen.
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 Biologics: Subjects who have received any biological (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 termina- 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 serum pregnancy test is required of all females. This test will be performed at the initial screening visit (Visit 1) and at the Exit visit. In addition, a urine pregnancy test will be performed for all females prior to randomisation, during each scheduled study visit prior to the infusion of investigational product, and during the Follow-up Visit.
16. Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.
17. Previous participation: Previously participated in any study with mepolizumab and received investigational product (including placebo).
Re-screening of subjects will be allowed only upon approval by the medical monitor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Frequency of clinically significant exacerbations of asthma as defined by:
Worsening of asthma which requires use of systemic corticosteroids1and/or hospitalization and/or Emergency Department (ED) visits.
1 For all subjects, i.v. or oral steroid (e.g., prednisone) for at least 3 days or a single IM CS dose is required. For subjects on maintenance systemic corticosteroids, at least double the existing maintenance dose for at least 3 days is required.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From week 0 (randomization) through 4 weeks post last dose (week 32 for completers) |
|
| E.5.2 | Secondary end point(s) |
• Frequency of exacerbations requiring hospitalisation (including intubation and
admittance to an ICU) or ED visits
• Frequency of exacerbations requiring hospitalisation
• Mean change from baseline in clinic pre-bronchodilator FEV1 compared to placebo
• Mean change in St. George’s Respiratory Questionnaire
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bullets 1 ,2, and 3From week 0 (randomization) through 4 weeks post last dose (week 32 for completers) Bullet 4- visit 2 and at the exit visit
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | 3 |
| 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 | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Belgium |
| Canada |
| Chile |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
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