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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01000506
Registration number
NCT01000506
Ethics application status
Date submitted
22/10/2009
Date registered
23/10/2009
Date last updated
24/01/2018
Titles & IDs
Public title
Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma
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Scientific title
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group, Dose Ranging Study to Determine the Effect of Mepolizumab on Exacerbation Rates in Subjects With Severe Uncontrolled Refractory Asthma
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Secondary ID [1]
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112997
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Universal Trial Number (UTN)
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Trial acronym
DREAM
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Asthma
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Condition category
Condition code
Respiratory
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Asthma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Mepolizumab 750
Other interventions - Mepolizumab 250
Other interventions - Mepolizumab 75
Treatment: Drugs - Placebo saline
Active Comparator: Mepolizumab 750mg - Mepolizumab 750mcg i.v. every 4 weeks
Active Comparator: Mepolizumab 250mg - Mepolizumab 250mcg i.v. every 4 weeks
Active Comparator: Mepolizumab 75mg - Mepolizumab 75mcg i.v. every 4 weeks
Placebo Comparator: Placebo - Placebo saline every 4 weeks i.v.
Other interventions: Mepolizumab 750
Mepolizumab 750mg every four weeks by i.v.
Other interventions: Mepolizumab 250
Mepolizumab 250mg every four weeks by i.v.
Other interventions: Mepolizumab 75
Mepolizumab 75mg every four weeks by i.v.
Treatment: Drugs: Placebo saline
Placebo saline every four weeks by i.v.
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Intervention code [1]
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Other interventions
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Intervention code [2]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Clinically Significant Exacerbations of Asthma Per Year
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Assessment method [1]
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Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of oral/systemic corticosteroids (for participants on maintenance oral corticosteroids [OCS], an exacerbation requiring OCS is defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days) and/or hospitalization and/or emergency department (ED) visit. The frequency of clinically significant exacerbations of asthma over the 52-week treatment period is expressed as exacerbation rate per year. Analysis of the number of exacerbations was performed using a negative binomial regression model with covariates of treatment group, Baseline (BL) maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and BL percent (%) predicted forced expiratory volume in 1 second (FEV1), and with logarithm of time on treatment as an offset variable
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Timepoint [1]
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From randomization (Week 0) to Week 52 or early withdrawal (EW)
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Secondary outcome [1]
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Time to First Clinically Significant Exacerbation Requiring Oral or Systemic Corticosteroid, Hospitalization and/ or ED Visit
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Assessment method [1]
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Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of oral/systemic corticosteroids (for participants on maintenance OCS, an exacerbation requiring OCS is defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days) and/or hospitalization and/or ED visit. Kaplan-Meier estimates of the probability of an exacerbation is expressed as percentage of participants with an exacerbation over time (by Week 16, Week 32 and Week 52).
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Timepoint [1]
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From randomization (Week 0) to Week 52 or EW
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Secondary outcome [2]
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Number of Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visit Per Year
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Assessment method [2]
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The frequency of exacerbations of asthma requiring hospitalization (including intubation and admittance to an intensive care unit [ICU]) or ED visit over the 52-week treatment period is expressed as exacerbation rate per year. Analysis of the number of exacerbations was performed using a negative binomial regression model with covariates of treatment group, Baseline (BL) maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and BL percent (%) predicted forced expiratory volume in 1 second (FEV1), and with logarithm of time on treatment as an offset variable.
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Timepoint [2]
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From randomization (Week 0) to Week 52 or EW
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Secondary outcome [3]
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Time to First Exacerbation Requiring Hospitalization or ED Visit
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Assessment method [3]
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Exacerbations of asthma requiring hospitalization or ED visit were assessed. Kaplan-Meier estimates of the probability of an exacerbation is expressed as percentage of participants with an exacerbation over time (by Week 16, Week 32 and Week 52).
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Timepoint [3]
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From randomization (Week 0) to Week 52 or EW
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Secondary outcome [4]
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Number of All Recorded Exacerbations Per Year
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Assessment method [4]
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Clinically significant exacerbations (ex) of asthma are defined as worsening of asthma which required use of oral/systemic corticosteroids (for par. on maintenance OCS, an ex requiring OCS is defined as the use of oral/systemic corticosteroids at least double the existing maintenance dose for at least 3 days) and/or hospitalization and/or ED visit. In the case, an event described as an ex was not associated with a deterioration in >=1 of the objectives of eDiary parameters, the investigator (inv) provided an explanation to support the decision for defining the event as an ex. All recorded ex were defined as those recorded by inv, regardless of the outcome of the ex review process. Analysis was performed using Negative Binomial regression model with covariates of treatment group, BL maintenance OCS therapy (OCS vs. no OCS), region, ex in the year prior to the study (as an ordinal variable) and BL % predicted FEV1, and with logarithm of time on treatment as an offset variable.
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Timepoint [4]
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From randomization (Week 0) to Week 52 or EW
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Secondary outcome [5]
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Time to First All Recorded Exacerbation
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Assessment method [5]
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All recorded exacerbations are defined as those recorded by investigators, regardless of the outcome of the exacerbation review process. In the case, an event described as an exacerbation was not associated with a deterioration in at least one of the objectives of eDiary parameters, the investigator provided an explanation to support the decision for defining the event as an exacerbation. Kaplan-Meier estimates of the probability of an exacerbation is expressed as percentage of participants with an exacerbation over time (by week 16, week 32 and week 52).
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Timepoint [5]
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From randomization (Week 0) to Week 52 or EW
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Secondary outcome [6]
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Mean Change From Baseline in Clinic Pre-bronchodilator FEV1 Over the 52-week Treatment Period
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Assessment method [6]
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FEV1 is defined as the volume of air forcefully expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry at each clinic visit. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the Baseline value. Analysis was performed using mixed model repeated measures with covariates of Baseline, region, Baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group.
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Timepoint [6]
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From Baseline up to Week 52 or EW
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Secondary outcome [7]
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Mean Change From Baseline in Clinic Post-bronchodilator FEV1 Over the 52-week Treatment Period
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Assessment method [7]
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FEV1 is defined as the volume of air forcefully expelled from the lungs in 1 second. Post-bronchodilator FEV1 measurements were taken by spirometry at Baseline, Week 16, Week 32 and Week 52. Post bronchodilator values were recorded following reversibility testing, using the maximum post bronchodilator method. Participants unable to achieve >=12% reversibility and 200 mL change at Visit 1, reversibility test was repeated at Visit 2. These procedures to achieve the maximum post-bronchodilator are generated by the Asthma Clinical Research Network. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the Baseline value. Analysis was performed using mixed model repeated measures with covariates of Baseline, region, Baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by Baseline and visit by treatment
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Timepoint [7]
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From Baseline up to Week 52 or EW
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Secondary outcome [8]
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Mean Change From Baseline in Asthma Control Questionnaire (ACQ) Score Over the 52-week Treatment Period
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Assessment method [8]
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The ACQ-6 is a six-item questionnaire. The six questions enquire about the frequency and/or severity of symptoms (nocturnal awakening on waking in the morning, activity limitation, shortness of breath, wheeze) and use of short-acting bronchodilator over the previous week. The response options for all these questions consist of a 0 (no impairment/limitation) to 6 (total impairment/ limitation) scale. The overall ACQ score is calculated as the mean of the 6 questions and therefore ranges between 0 (totally controlled) and 6 (severely uncontrolled). Change from BL is defined as the difference between the value of the endpoint at the time point of interest and BL value. Analysis was performed using mixed model repeated measures with covariates of BL, region, BL maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), BL % predicted FEV1, treatment and visit, plus interaction terms for visit by BL and visit by treatment group.
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Timepoint [8]
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From Baseline up to Week 52 or EW
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Eligibility
Key inclusion criteria
- Male or female
- Aged 12 to 65 years inclusive
- Minimum weight 45kg
- Clinical features of severe refractory asthma
- Well documented requirement for high dose inhaled corticosteroids (ICS) [i.e. >=
880mcg/day fluticasone propionate or equivalent daily] for at least 12 months
- Using additional controller medication in addition to high dose ICS for at least 12
months
- Persistent airflow obstruction indicated by a pre-bronchodilator FEV1<80% predicted at
visit 1 or 2 or peak flow diurnal variability of >20% on 3 or more days during the
run-in
- Airway inflammation which is likely to be eosinophilic in nature demonstrated by
either raised peripheral blood eosinophils (>=300/microL), sputum eosinophils (>=3%),
exhaled nitric oxide (>=50ppb) or prompt deterioration of asthma control following a
<=25% reduction in regular maintenance dose of inhaled or oral corticosteroids (OCS)
- History of 2 or more exacerbations requiring systemic corticosteroids in the previous
12 months
- Evidence of asthma documented by airway reversibility, airway hyperresponsiveness or
airflow variability
- ECG assessment demonstrating QTc<450msec or QTc<480msec for patients with bundle
branch block
- Liver function tests demonstrating ALT<2xUpper Limit of Normal (ULN), AST<2xULN, Alk
Phos <=1.5xULN, bilirubin <=1.5xULN
- Female of non-child-bearing potential or child-bearing potential with a negative
pregnancy test at screening and prepared to agree to an acceptable method of
contraception
- Able to give written informed consent
- Able to read, comprehend and write at a sufficient level to complete study materials
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Minimum age
12
Years
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Maximum age
65
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Current smokers or smoking history of >=10 pack years
- Clinically important lung condition other than asthma
- Diagnosis of malignancy or in the process of investigation
- Unstable liver disease
- Churg-Strauss syndrome
- Using methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine or any
experimental anti-inflammatory therapy within 3 months of screening
- Omalizumab (Xolair) or any other biological for the treatment of inflammatory disease
within 6 months of Visit 1
- Regular use of oral or systemic corticosteroids for diseases other than asthma within
12 months or any intra-articular, short-acting intramuscular corticosteroid within 1
month or intramuscular, long-acting depot corticosteroid within 3 months
- Allergy/intolerance to the excipients in the mepolizumab formulation
- Any investigational drug within 30 days or 5 terminal half-lives, whichever is longer
- Pregnant or breastfeeding or planning to become pregnant
- Clinically significant disease which is uncontrolled with standard treatment
- History of alcohol misuse or substance abuse
- Parasitic infestation within previous 6 months
- Known immunodeficiency
- Unable to follow instructions, use the electronic diary or peak flow meter
- Known evidence of lack of adherence to controller medications and/or follow
physician's recommendations
- Previous participation in a study of mepolizumab and received study medication within
90 days
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/11/2009
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
23/03/2012
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Sample size
Target
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Accrual to date
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Final
621
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Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC,WA
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Recruitment hospital [1]
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GSK Investigational Site - New Lambton
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GSK Investigational Site - Adelaide
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GSK Investigational Site - Clayton
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GSK Investigational Site - Melbourne
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GSK Investigational Site - Nedlands
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2305 - New Lambton
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Recruitment postcode(s) [2]
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5000 - Adelaide
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Recruitment postcode(s) [3]
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3168 - Clayton
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Recruitment postcode(s) [4]
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3004 - Melbourne
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Recruitment postcode(s) [5]
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6009 - Nedlands
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Recruitment outside Australia
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Kyiv
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Ukraine
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Mykolayiv
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United Kingdom
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Leicestershire
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London
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Manchester
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Southampton
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
GlaxoSmithKline
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Address
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Ethics approval
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Summary
Brief summary
The purpose of this study is to show whether mepolizumab given every 4 weeks intravenously
(i.v.) can reduce the frequency of asthma exacerbations in subjects with severe asthma
despite receiving high doses of standard asthma medications. The study will look at different
doses of mepolizumab in comparison to a placebo.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01000506
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Trial related presentations / publications
Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012 Aug 18;380(9842):651-9. doi: 10.1016/S0140-6736(12)60988-X.
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Public notes
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Contacts
Principal investigator
Name
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GSK Clinical Trials
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Address
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GlaxoSmithKline
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01000506
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