Mepolizumab Steroid-Sparing Study in Subjects With Severe Refractory Asthma
Condition: Asthma
MeSH terms: Asthma
Intervention: Mepolizumab; Placebo; OCS (prednisone/prednisolone)
Intervention description: Mepolizumab is a fully humanised Immunoglobulin G antibody (IgG1, kappa) with human heavy and light chain frameworks.; Will be available as an equivalent volume of 0.9% sodium chloride.; Oral Corticosteroid (prednisone/prednisolone)
Intervention MeSH terms: Prednisone; Prednisolone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 135.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Safety; Steroid Reduction; Efficacy; SB-240563; Eosinophils; Quality of Life; Mepolizumab; Severe Refractory Asthma

Summary:

      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.
    

Eligibility criteria:

        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.