| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| severe uncontrolled refractory asthma. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
|
| 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 dose response, based on efficacy and safety of three doses of mepolizumab (75 mg, 250 mg and 750 mg) over a 52-week treatment period in adult and adolescent subjects with severe uncontrolled refractory asthma. |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the pharmacodynamic effect of mepolizumab on the number of eosinophils in blood, serum IL-5 and number of eosinophils in induced sputum. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Male or female subjects aged >=12, ≥65 years old with a minimum weight of 45Kg. [For countries where local regulations or the regulatory status of study medication permit enrolment of adults only, subjects recruited will be >=18 years].
2. Subjects with the clinical features of severe refractory asthma similar to those indicated in the ATS Workshop on Refractory Asthma [Proceeding of ATS workshop, 2000] for >=12 months prior to Visit 1 and mandated through meeting Inclusion Criteria 3, 4 and 5.
3. Subjects with a well-documented requirement for regular treatment with high
dose ICS [i.e. ≥ 880 μg/day fluticasone propionate (FP) or equivalent daily], with or
without maintenance oral corticosteroids (OCS), in the 12 months prior to Visit 1. View protocol page 20.
4. Subjects with a well-documented requirement for regular treatment with high dose ICS [i.e. ≥880 mcg/day fluticasone propionate (FP) or equivalent daily], with or without maintenance oral corticosteroids (OCS), in the 12 months prior to Visit 1.
5. Subjects with persistent airflow obstruction as indicated by a pre-bronchodilator FEV1 <80% predicted (NHANES III) recorded at Visit 1 or Visit 2 or peak flow diurnal variability of >20% on 3 or more days during the run-in period.
6. Subjects with airway inflammation which is likely to be eosinophilic in nature as indicated by one of the following characteristics demonstrated at Visit 1 or documented in the previous 12 months:
• An elevated peripheral blood eosinophil level of >=300/µL that is related to asthma or • Sputum eosinophils >=3% or • Exhaled nitric oxide >=50 ppb or • Prompt deterioration of asthma control (based on documented clinical history or objective measures) following a =<25% reduction in regular maintenance dose of inhaled or oral corticosteroid dose in the previous 12 months
7. Subjects with a previously confirmed history of two or more asthma exacerbations requiring treatment with oral or systemic corticosteroids in the 12 months prior to Visit 1, despite the use of high-dose ICS and additional controller medication. For subjects receiving maintenance OCS with high-dose ICS plus controller, the OCS treatment for exacerbations must be a two-fold or greater increase in the dose of OCS.
8. Evidence of asthma as documented by either:
• Airway reversibility (FEV1>=12% and 200 ml) demonstrated1 at Visit 1 or Visit 2 or documented in the previous 12 months OR
• Airway hyperresponsiveness (PC20 of <8mg/mL or PD20 of <7.8 µ mol methacholine/histamine) documented in the 12 months prior to Visit 1 OR
• Airflow variability in clinic FEV1 >=20% between two consecutive clinic visits documented in the 12 months prior to Visit 1 ( FEV1 recorded during an exacerbation will not be valid) OR
• Airflow variability as indicated by >20% diurnal variability in peak flow observed on 3 or more days during the run-in.
1For reversibility testing at Visit 1 or Visit 2, the Maximum Post-bronchodilator procedure should be employed in accordance with the methodology used by Asthma Clinical Research Network (see Study Procedures Manual)
9. ECG assessment (either QTcB or QTcF, machine or manual overread, males or females);
QTc < 450msec or QTc < 480 msec for patients with Bundle Branch Block.
10. Liver Function Tests;
ALT<2 x ULN (upper limit of normal)
AST<2 x ULN
Alk Phos ≤ 1.5 x ULN
Bilirubin ≤ 1.5 x ULN (isolated bilirubin>1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
11. A female is eligible to enter and participate in the study if she is of non-child bearing potential defined as pre-menopausal with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases of amenorrhea in perimenopausal women, a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MIU/ml is confirmatory of menopause (these levels are suggested guidelines and may need to be adjusted for specific laboratories/assays) [NOTE: Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use an acceptable method of contraception as outlined in Appendix 3 or discontinue HRT to allow confirmation of post-menopausal status]. Subjects of child bearing potential or whose child bearing potential is uncertain are required to have a negative pregnancy test at screening, and agree to use an acceptable contraceptive method consistently and correctly from one month prior to the first dose of investigational product until 4 months after the last dose of investigational product.
12. Subjects must be 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.
13. Read, comprehend, and write at a level sufficient to complete study related materials.
|
|
| E.4 | Principal exclusion criteria |
1. Current smokers or subjects with a smoking history of >=10 pack years (number of pack years = (number of cigarettes per day / 20) x number of years smoked).
2. Presence of a 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. Subjects with a diagnosis of malignancy or in the process of investigation for a malignancy. Subjects with a past medical history of malignancy can be allowed in the trial provided anyone with a diagnosis of a recurrent malignant tumour or having received treatment for a malignancy within 12 months are excluded.
4. 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. Subjects with a diagnosis of Churg-Strauss syndrome.
6. Subjects who have taken methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine or any experimental anti-inflammatory therapies within 3 months of screening.
7. Subjects who have received omalizumab [Xolair®] or any other any other biological for the treatment of inflammatory disease within 130 days of Visit 1.
8. Regular use of oral or systemic corticosteroids for diseases other than asthma within the past 12 months or any intra-articular, short-acting intramuscular corticosteroid with 1 month or intramuscular, long-acting depot corticosteroids within 3 months.
9. Subject with allergy/intolerance to the excipients in the mepolizumab formulation.
10. Subjects who have received treatment with an investigational drug within the past 30 days or five half-lives whichever is longer, prior to the first doses of study medication (this also includes investigational formulations of marketed products).
11. Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation.
12. Subjects who have clinically significant cardiovascular, endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment
13. Subjects with a history (or suspected history) of alcohol misuse or substance abuse to 2 years prior to Visit 1.
14. Subjects with a parasitic infestation within 6 months prior to Week -2 (Visit 1).
15. Subjects with a known immunodeficiency (e.g. human immunodeficiency virus – HIV), other than that explained by the use of corticosteroids taken as therapy for asthma.
16. Subjects who are unable to follow study instructions such as dosing directions, study electronic diary (eDiary) completion, or use of a standard metered dose inhaler.
17. Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.
18. Subjects who have previously participated in a study of mepolizumab and received study medication within 90 days prior to screening.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Frequency of clinically significant exacerbations of asthma as defined by:
Worsening of asthma requiring use of oral/systemic corticosteroids and/or hospitalisation and/or Emergency Department (ED) visits. For subjects on maintenance oral corticosteroids, an exacerbation requiring oral corticosteroids will be defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days.
Protocol defined exacerbations will be based on objective assessments of asthma.
|
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.6.13.1 | Other scope of the trial description |
| RNA Transcriptome and RNA Expression Analysis |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.3 |
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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 trial is defined as Follow-up visit 8 weeks following the last administration of study medication. This follow-up period of observation will allow for an evaluation of any potential delayed and/or cumulative post-treatment effects of mepolizumab. |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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