Primary: To compare the effects of mepolizumab adjunctive therapy with placebo on reducing the use of maintenance oral corticosteroids (OCS).Secondary: Safety, tolerability, other efficacy parameters, quality of life.
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
% reduction of OCS dose at week 24 compared to the baseline.
Secondary outcome
Proportion of subjects who achieve a reduction of 50% or greater in their daily
OCS dose, proportion of subjects who achieve a reduction of OCS dose to less
than or equal to 5.0mg, proportion of subjects who achieve a total reduction of
OCS dose, median percentage reduction from baseline in daily OCS dose at week
24, proportion of eligible subject who achieve complete reduction of OCS,
clinically significant exacerbations, idem requiring hospitalization, idem
requiring ED visits, change in St. George*s Respiratory Questionnaire, FEV1.
Background summary
Mepolizumab is currently under clinical development for severe asthma.
Mepolizumab is a humanized antiinterleukin 5 (anti-IL5) antibody (IgG Kappa)
that binds to and inactivates IL-5. IL-5 is the principle eosinophilic
regulatory cytokine. It is critical for the development and release of
eosinophils from the bone marrow, enhances adhesion to endothelial cells, and
promotes the persistence and activation of eosinophils. Eosinophils are thought
to play a major role in maintaining airway inflammation. Mepolizumab binds with
high affinity to human interleukin-5 and blocks its binding to and the
activation of the IL-5 receptor (CD125). It is hypothesized that blocking IL-5
with mepolizumab will have a positive effect in reducing eosinophilic
inflammation in patients with severe refractory asthma who are dependent on
maintenance steroid to treat their asthma. This concept has been previously
investigated in a small study (N= 20) of asthmatics with persistent sputum
eosinophils. The results of this study demonstrated that mepolizumab was well
tolerated and effective in reducing the dose of prednisone while preventing
exacerbations, decreasing blood and sputum eosinophil numbers, and improving
lung function and quality of life.
Recently a study of IV mepolizumab of over 600 subjects with severe refractory
uncontrolled asthma has been completed. All 3 doses investigated (75mg, 250 mg
and 750mg) resulted in a clinically significant reduction in the frequency of
severe exacerbations when compared to placebo and produced a marked and
sustained suppression of blood eosinophils. The safety profile was similar
across all treatment arms and was similar to placebo.
A PK/PD model has been developed for mepolizumab with data obtained from prior
studies. Two of these 5 studies administered mepolizumab via the subcutaneous
(SC) route. The model well describes the relationship between plasma
mepolizumab concentration and eosinophil counts (irrespective of the route of
administration. Based on prior PK studies, the bioavailability of mepolizumab
administered SC is approximately 75% and therefore a dose of 100mg SC is
anticipated to provide similar exposure to the 75mg IV effective dose. A SC
route of administration has been chosen for the current study as it is
generally preferred by patients and is easy to administer.
The purpose of this study is to investigate the efficacy of adjunctive
mepolizumab therapy, in comparison to standard of care, to reduce the use of
oral corticosteroids while maintaining asthma control in subjects with severe
refractory asthma.
In NL no minors will be included.
Study objective
Primary: To compare the effects of mepolizumab adjunctive therapy with placebo
on reducing the use of maintenance oral corticosteroids (OCS).
Secondary: Safety, tolerability, other efficacy parameters, quality of life.
Study design
Studieopzet:
Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Phase III study.
Randomisation (1:1) to
* Mepolizumab 100 mg s.c. every 4 weeks
* Placebo every 4 weeks.
Continuation of standard treatment for asthma.
Salbutamol rescue medication.
Run-in period for determination of lowest effective oral prednis(ol)on dose
(3-8 weeks).
Treatment phase 24 weeks. Week 4-20: dose reduction of oral steroids.
Possibility to participate in open-label extension study.
Follow-up phase 8 weeks (for those not participating in extension study).
Approx. 120 patients.
Independent DSMB.
Intervention
Treatment with mepolizumab or placebo.
Study burden and risks
Risk: adverse events of study treatment.
Burden: 10 visits in approx. 6 months. Duration 1-3h.
6 s.c. injections (1 ml)
Blood draws 9x (total approx. 125 ml)
Physical examination 2x
Pulmonary function test 9x
ECG 6x
Daily peakflow measurements
Diary steoid use, rescue medication, symptoms, sleep quality, peak flow,
concomitant illnesses, new medications
Questionnaires (symptoms, sleep, depression, daily activities) 1x 6, 3x 5, 1x
2, 2x 1
Optinal pharmacogenetic testing (1x 6 ml blood)
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Listed location countries
Age
Inclusion criteria
* At least 12 years of age at Visit 1 and a minimum weight of 45kg (in NL at least 18 years).
* Severe asthma and a well-documented requirement for regular treatment with maintenance systemic corticosteroids in the 6 months prior to Visit 1 and using a stable oral corticosteroid dose for 4 weeks prior to Visit 1. See protocol page 23 for details.
* A documented requirement for regular treatment with high dose inhaled corticosteroid in the 6 months prior to Visit 1. See protocol page 23 for details.
* Current treatment with an additional controller medication for at least 3 months OR documentation of having used and failed an additional controller medication for at least 3 successive months during the prior 12 months.
* Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma. See protocol page 23 for details.
Exclusion criteria
* Current smokers or former smokers with a smoking history of *10 pack years.
* Clinically important lung condition other than asthma.
* Other conditions that could lead to elevated eosinophils.
* Omalizumab [Xolair] within 130 days of Visit 1.
* Any biological (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1.
* Previous participation in any study of mepolizumab and received Investigational Product.
* Pregnancy or breastfeeding
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | clinicaltrials.gov; registratienummer n.n.b. |
| EudraCT | EUCTR2012-001497-29-NL |
| CCMO | NL41502.018.12 |