Mepolizumab Steroid-Sparing Study in Subjects With Severe Refractory Asthma
Mepolizumab Steroid-Sparing Study in Subjects With Severe Refractory Asthma
This is a randomised, double-blind, placebo-controlled, parallel-group, multicenter study of
 mepolizumab in comparison with placebo in reducing Oral Corticosteroid (OCS) use in subjects
 with severe refractory asthma. The study consists of four phases, OCS Optimisation Phase
 (Week -8 to Week 0), and the double-blind treatment period divided into an Induction Phase
 (Week 0 to Week 4), OCS Reduction Phase (Week 5 upto Week 20) followed by Maintenance Phase
 (Week 20 to Week 24). During the Optimisation Phase the investigator will adjust the OCS
 (prednisone/prednisolone) dose according to the Optimisation titration schedule based on a
 review of Asthma Control Questionnaire (ACQ)-5 score and exacerbation. In the Induction Phase
 subjects will be randomized 1:1 (approximately 60 per arm) to receive either mepolizumab (100
 mg) administered subcutaneously (SC) or placebo every 4 weeks in addition to their existing
 maintenance asthma therapy with the lowest dose of OCS from Optimisation Phase. The Induction
 Phase will allow sufficient time for those subjects randomised to the mepolizumab arm to
 achieve a decrease in the eosinophilic inflammation prior to the reduction in OCS. During the
 Reduction Phase, subjects will continue receiving 100 mg mepolizumab/placebo every 4 weeks
 and the OCS dose reduction will be done every 4 weeks using the reduction titration schedule
 based on a review of eDiary parameters recorded by the subject, the subjects' exacerbation
 history, and a review of the signs and symptoms of adrenal insufficiency. In the Maintenance
 Phase subjects will be maintained without any further OCS dose adjustment. Subjects who
 complete the 24 week double-blind period and meet the eligibility criteria, will be offered
 the opportunity to participate in an open label extension (OLE) study otherwise they will
 return for a Follow-up Visit 12 weeks after their last dose of double blind study treatment.
 At each clinic visit, adverse events, safety labs, spirometery parameters and exacerbations
 will be assessed. The pharmacokinetic samples will be collected in the beginning of the
 treatment, prior to last dose, at the end of study (exit visit) and the follow up.
Inclusion Criteria:

 -  Informed Consent and Study Compliance: 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.

 -  Systemic Corticosteroids: 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. Subjects must be taking 5.0 to 35
 mg/day of prednisone or equivalent at Visit 1 and must agree to switch to study
 required prednisone/prednisolone as their oral corticosteroid and use it per protocol
 for the duration of the study.

 -  Inhaled Corticosteroids: Requirement for regular treatment with high dose inhaled
 corticosteroid in the 6 months prior to Visit 1. For 18 years of age and older:
 inhaled corticosteroid (ICS) dose must be >=880 microgram (µg)/day fluticasone
 propionate (FP) (ex-actuator) or equivalent daily. For ICS/ long acting beta2 agonist
 (LABA) combination preparations, the highest approved maintenance dose in the local
 country will meet this ICS criterion. For ages 12 to 17: ICS dose must be >=440 μg/day
 FP (ex-actuator) or equivalent daily.

 -  Controller Medication: 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 [e.g., LABA,
 leukotriene receptor antagonist (LTRA), or theophylline].

 -  Eosinophilic Asthma: Prior documentation of eosinophilic asthma or high likelihood of
 eosinophilic asthma.

 -  FEV1: Persistent airflow obstruction as indicated by a pre-bronchodilator FEV1 <80%
 predicted.

 -  Asthma: Evidence of asthma indicated by airway reversibility, hyperresponsiveness or
 airway variability.

 Exclusion Criteria:

 -  Smoking history: Current smokers or former smokers with a smoking history of >=10 pack
 years.

 -  Concurrent Respiratory Disease: Presence of a clinically important lung condition
 other than asthma.

 -  Malignancy: A current malignancy or previous history of cancer in remission for less
 than 12 months prior screening

 -  Liver Disease: Unstable liver disease

 -  Cardiovascular: Subjects who have severe or clinically significant cardiovascular
 disease uncontrolled with standard treatment.

 -  Other Concurrent Medical Conditions: Subjects who have known, pre-existing, clinically
 significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal,
 hepatic, haematological or any other system abnormalities that are uncontrolled with
 standard treatment.

 -  Eosinophilic Diseases: Subjects with other conditions that could lead to elevated
 eosinophils such as Hypereosiniophilic Syndromes, including Churg-Strauss Syndrome, or
 Eosinophilic Esophaghitis. Subjects with a known, pre-existing parasitic infestation
 within 6 months prior to Visit 1 are also to be excluded.

 -  ECG: ECG assessment QTcF >=450 milliseconds (msec) or QTcF >= 480 msec for subjects
 with Bundle Branch Block.

 -  Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus - HIV),
 other than that explained by the use of corticosteroids taken as therapy for asthma.

 -  Omalizumab Use: Subjects who have received omalizumab [Xolair] within 130 days of
 Visit 1.

 -  Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other
 than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1.

 -  Investigational Medications: Subjects who have received treatment with an
 investigational drug within the past 30 days or five terminal phase half-lives of the
 drug whichever is longer, prior to Visit 1 (this also includes investigational
 formulations of marketed products).

 -  Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal
 antibody or biologic.

 -  Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be enrolled
 if they plan to become pregnant during the time of study participation.

 -  Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or
 substance abuse within 2 years prior to Visit 1.

 -  Adherence: Subjects who have known evidence of lack of adherence to controller
 medications and/or ability to follow physician's recommendations.

 -  Previous participation: Subjects who have previously any study of mepolizumab and
 received Investigational Product.