E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Adult asthmatic subjects with elevated blood eosinophil levels. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
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 |
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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 demonstrate that the PK/PD relationship between the exposure of SC administered mepolizumab and a marker of response, plasma eosinophil, is comparable to that observed following IV administration |
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E.2.2 | Secondary objectives of the trial |
• To assess the relative bioavailability of mepolizumab administered subcutaneously, as compared to mepolizumab administered intravenously, in asthmatic adult subjects with elevated blood eosinophil levels.
• To assess the immunogenicity of repeat doses of mepolizumab.
• To assess the safety and tolerability of repeat doses of mepolizumab when administered subcutaneously and intravenously to asthmatic adult subjects with elevated blood eosinophil levels
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males or eligible females between 18 and 65 years of age inclusive, at the time of
signing the informed consent; Non-childbearing potential is defined as pre menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147pmol/L) is confirmatory]. To be eligible for entry into the study, females of childbearing potential and females whose menopausal status is in question must commit to consistent and correct use of an acceptable method of birth control as defined in Section 7.1.1 of the protocol from one month prior to the first dose of investigational product until 4 months after the last dose of investigational product.
2. History of asthma for at least one year.
3. Subjects must be on a stable dose of an inhaled corticosteroid or combination (ICS+LABA) therapy for at least 12 weeks prior to screening.
4. FEV1≥45% and <90 % of predicted normal value during screening (obtained between 6:00 AM and 1:00 PM).
5. Evidence of airway reversibility (FEV1≥12%) within 30 minutes of inhalation of albuterol OR airway hyperresponsiveness (PC20 of <8mg/mL or PD20 of <7.8 μ mol methacholine/histamine) documented in the 12 months prior to randomization.
6. Subjects with documented evidence of elevated blood eosinophilia levels (>0.2 cells 10^9/L) within 12 months of screening and evidence of elevated blood eosinophilia levels (>0.2 cells 10^9/L) at screening.
7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. |
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E.4 | Principal exclusion criteria |
1. QTcF ≥450 msec; or QTcF ≥ 480 msec in subjects with Bundle Branch Block.
2. AST, ALT, alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin
<1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin ≥35%).
3. Subjects with elevated blood eosinophil levels which is not related to asthma
4. Current smokers (any subject who has smoked within the six months prior to
screening or has a positive urine cotinine at screening) or subjects with a smoking
history of >10 pack years calculated as follows:view protocol for further information.
5. Presence of a clinically important lung condition other than asthma including current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis,
Churg-Strauss syndrome, or diagnoses of emphysema or chronic bronchitis (chronic
obstructive pulmonary disease other than asthma) or a history of lung cancer.
6. An asthma exacerbation or respiratory tract infection within six weeks prior to
screening (an exacerbation is defined as worsening asthma requiring the use of
systemic corticosteroids and/or emergency department visit, hospitalisation).
7. Subjects with a parasitic infestation within six months of screening.
8. A current malignancy or previous history of cancer in remission for less than five
years prior screening (except for localized carcinoma of the skin that has been
resected for cure).
9. 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.
10. 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).
11. Subjects with a known immunodeficiency (e.g. human immunodeficiency virus –
HIV).
12. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within three months of screening.
13. Subjects who have received omalizumab [Xolair] within 130 days of administration of the first dose of study medication.
14. Subjects with recent history (within two years prior to screening) of alcohol misuse or substance abuse prior screening.
15. A positive pre-study drug/alcohol test at screening. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Change from baseline in blood eosinophil levels as assessed by the exposure-response relationship
• Area under the blood eosinophil time curve (AUC), maximum change from baseline in blood eosinophils (Emax), time to maximum change in blood eosinohil levels (Tmaxeos), time to 50% eosinophil repletion (Trep)
• Area under the plasma-concentration time curve (AUC), maximum plasma concentration (Cmax), time to Cmax (Tmax) and terminal half-life (t½) of mepolizumab |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Day1, Day 3, Day 7, Day 28, Day 56, Day 70, Day 84, Day 112 and Day 140. |
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E.5.2 | Secondary end point(s) |
• AUC and Cmax of mepolizumab (Day1, Day 3, Day 7, Day 28, Day 56, Day 70, Day 84, Day 112 and Day 140)
• Levels of anti-mepolizumab antibodies (Day 1, Day 112 and Day 140)
• Spontaneous and elicited adverse
events (AEs), (Day1, Day 3, Day 7, Day 28, Day 56, Day 70, Day 84, Day 112 and Day 140) vital signs,(Day-14, Day 1, Day 28, Day 56, Day 84, day 112 and Day 140) electrocardiograms (ECGs) (Day -14, Day 3)and clinical laboratory values (Day -14, Day1, Day 3, Day 7, Day 28, Day 56, Day 70, Day 84, Day 112 and Day 140)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Day1, Day 3, Day 7, Day 28, Day 56, Day 70, Day 84, Day 112 and Day 140. |
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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 | No |
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 | 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) | 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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | Yes |
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 |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 12 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 12 |