| Purpose: |
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A multi-center, randomized, open-label, parallel-group, repeat dose study in asthma patients
with elevated eosinophils. Eligible subjects will receive 3 doses (28 days apart) of
mepolizumab given intravenous (IV) or subcutaneously (SC). Blood samples for safety,
pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity analysis, as well as
safety/tolerability assessments will be collected throughout the study
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| Study Summary: |
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Mepolizumab (SB-240563) is a humanized monoclonal antibody that blocks human interleukin 5
(IL-5) from binding to its receptor. Mepolizumab is currently under development for severe
refractory asthma and a Phase IIB dose-ranging study using the IV route of administration is
currently on-going. This study will be a multi-center, randomized, open-label,
parallel-group, repeat dose study conducted in approximately 65 subjects with established
asthma and elevated blood eosinophil levels. Dosing will occur on three occasions, every
four weeks [Day 1, Day 28 (+/- 3 days) and Day 56 (+/- 3 days)]. Blood samples for safety,
pharmacodynamics (PD), pharmacokinetics (PK) and immunogenicity analysis, as well safety and
tolerability assessments will be collected/assessed throughout the study. Each subject will
participate in the study for up to approximately 22 weeks, including screening, dosing and
follow-up.
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| Criteria: |
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Inclusion Criteria:
- 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
(<147 pmol/L) is confirmatory]. To be eligible for entry into the study, females of
child-bearing 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 from one month prior to the first dose of investigational
product until 4 months after the last dose of investigational product.
- History of asthma for at least one year.
- Subjects must be on a stable dose of an inhaled corticosteroid or combination
(ICS+LABA) therapy for at least 12 weeks prior to screening.
- FEV1≥45% and <90 % of predicted normal value during screening (obtained between 6:00
AM and 1:00 PM).
- 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.
- Subjects with documented evidence of elevated blood eosinophilia levels (>0.3 cells
109/L) within 12 months of screening and evidence of elevated blood eosinophilia
levels (>0.3 cells 109/L) at screening.
- Capable of giving written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form.
Exclusion Criteria:
- QTcF ≥450 msec; or QTcF ≥ 480 msec in subjects with Bundle Branch Block.
- AST, ALT, alkaline phosphatase and bilirubin ≥ 1.5xULN (isolated bilirubin <1.5xULN
is acceptable if bilirubin is fractionated and direct bilirubin ≥35%).
- Subjects with elevated blood eosinophil levels which is not related to asthma
- 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:
Number of cigarettes per day X number of years smoked 20
- 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.
- 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).
- Subjects with a parasitic infestation within six months of screening.
- 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).
- 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.
- 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).
- Subjects with a known immunodeficiency (e.g. human immunodeficiency virus - HIV).
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within three months of screening.
- Subjects who have received omalizumab [Xolair] within 130 days of administration of
the first dose of study medication.
- Subjects with recent history (within two years prior to screening) of alcohol misuse
or substance abuse prior screening.
- A positive pre-study drug/alcohol test at screening.
- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, five half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).
- Subjects who have previously participated in a study of mepolizumab and received
study medication within 90 days prior to screening.
- Use of prescription or non-prescription drugs, including vitamins, herbal and dietary
supplements within seven days (or 14 days if the drug is a potential enzyme inducer)
or five half-lives (whichever is longer) prior to the first dose of study medication,
unless in the opinion of the Investigator and GSK Medical Monitor the medication will
not interfere with the study procedures or compromise subject safety.
- Exposure to live vaccine within the four weeks prior to screening and no intention to
receive live vaccine during the study.
- History of sensitivity to the study medications (or components thereof) or a history
of drug or other allergy that, in the opinion of the investigator or GSK Medical
Monitor, contraindicates their participation.
- Pregnant or lactating females; pregnancy as determined by positive pregnancy test at
screening or prior to dosing.
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