Cessation Versus Continuation of Long-term Mepolizumab in Severe Eosinophilic Asthma Patients
Condition: Asthma
MeSH terms: Asthma; Pulmonary Eosinophilia
Intervention: Mepolizumab 100mg; Placebo
Intervention description: Mepolizumab is a fully humanised Immunoglobulin (IgG) antibody (IgG1, kappa) with human heavy and light chain frameworks. Mepolizumab will be provided as a lyophilised cake in sterile vials for individual use.; The placebo will be 0.9% sodium chloride solution and will be provided by the study site.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 306.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: Severe eosinophilic asthma; mepolizumab; asthma exacerbation

Summary:

      Primary objective of the study is to evaluate whether patients with severe eosinophilic
      asthma who have received long-term treatment with mepolizumab (at least 3 years) need to
      maintain treatment with mepolizumab to continue to receive benefit. Subjects who participated
      in the open-label studies MEA115666 or 201312 with at least 6 months of treatment with
      mepolizumab prior to Visit 1 and who have no more than 2 consecutive missed doses of
      mepolizumab treatment will be eligible to participate in this study. This study will be
      conducted in 4 parts in approximately 300 subjects. Part A will be Variable Open-Label Run-in
      (for subjects with less than 3 years of mepolizumab treatment). Once the required 3 year
      exposure is reached, subjects will enter Part B- Fixed Open-Label Run-In (4 weeks to 8
      weeks). During Part A and B subjects will be administered Open-label mepolizumab (100
      milligram [mg] Subcutaneous [SC]) every 4 weeks. Part C will be the randomized double-blinded
      part. Upon completion of Part B, eligible subjects will be randomized to mepolizumab (100 mg
      SC) every 4 weeks or placebo administered SC every 4 weeks for 52 weeks.

      Subjects discontinuing investigational product (IP) due to a clinically significant asthma
      exacerbation will then enter optional Part D of the study. During Part D, subjects receive
      open-label mepolizumab in addition to their standard of care therapy for the remainder of the
      study, through Part D up to 52-weeks post-randomization. An Exit Visit will be conducted 52
      weeks after randomization in order to assess subject's efficacy parameters, immunogenicity
      status, and to conduct additional safety assessments. Eligible subjects will participate in
      the study ranging from 56 to192 weeks, depending on the duration of Part A (0 to 132 weeks)
      and Part B (4 to 8 weeks).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Informed Consent: Prior to commencing any study related activities, subjects must be
             able and willing to provide written informed consent, and an assent for subjects under
             18 years of age, at Visit 0 (or Visit 1 if these Visits are conducted on the same
             day).

          -  MEA115666 or 201312 Study Participation: Participation (through the Follow Up/Exit
             Visit or Early Withdrawal) in either study with documented evidence of at least 6
             months of continuous mepolizumab treatment prior to Visit 1. Continuous treatment with
             mepolizumab is defined as no more than 2 consecutive missed doses (no treatment gaps
             of more than 12 weeks [84 days] between any two doses).

          -  Current Anti-Asthma Therapy: Asthma is currently being treated with a controller
             medication and the subject has been on a controller medication for the past 12 weeks.
             Subjects will be expected to continue controller therapy for the duration of the
             study.

          -  Male or Eligible Female Subjects: A female is eligible to enter and participate in the
             study if she is of: Non-child bearing potential (i.e., physiologically incapable of
             becoming pregnant, including any female who is post-menopausal or surgically sterile).
             Surgically sterile females are defined as those with a documented hysterectomy and/or
             bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being
             amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g., age
             appropriate, > 45 years, in the absence of hormone replacement therapy.

        OR Child bearing potential, has a negative pregnancy test at screening, and agrees to
        acceptable contraceptive methods approved in their local country, when used consistently
        and correctly (i.e., in accordance with the approved product label and the instructions of
        the physician) for the duration of the study and for 4 months after the last study drug
        administration.

        A urine pregnancy test is required of all females of child-bearing potential at each
        scheduled study visit prior to the injection of study treatment, and at the Exit Visit,
        Early Withdrawal (EW) or Discontinuation of IP Visit.

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category.

        Exclusion Criteria:

          -  MEA115666 or 201312 IP Discontinuation: Subjects withdrawn from IP or withdrawn from
             study participation from either MEA115666 or 201312 for safety reasons.

          -  Health Status: Clinically significant deterioration in health status at the completion
             of participation or EW from either the MEA115666 or 201312 trials which in the opinion
             of the investigator would make the subject unsuitable for participation in this study.

          -  Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled
             if they plan to become pregnant during the time of study participation.

          -  Cardiovascular: Subjects who have severe or clinically significant cardiovascular
             disease uncontrolled with standard treatment. Including but not limited to:

        known ejection fraction of <30% OR severe heart failure meeting New York Heart Association
        Class IV classification OR hospitalised in the 12 months prior to Visit 1 for severe heart
        failure meeting New York Heart Association Class III OR angina diagnosed less than 3 months
        prior to Visit 1 or at Visit 1.

          -  12-Lead Electrocardiogram (ECG): ECG which has a clinically significant abnormality
             observed at the Screening Visit as determined by the investigator. Subjects with the
             following abnormalities are excluded from study participation: QT interval corrected
             for heart rate by Fridericia's formula (QTcF) > 450 milliseconds (msec), or QTcF >480
             msec for subjects with Bundle Branch Block.

          -  Malignancy: A current malignancy or previous history of cancer in remission for less
             than 12 months prior to screening (Subjects that had localized carcinoma of the skin
             which was resected for cure will not be excluded).

        Note for South Korea: Korean subjects with a diagnosis of malignancy within 5 years are
        excluded.

          -  Other Monoclonal Antibodies: Subjects who have received any monoclonal antibody (other
             than XOLAIR®) to treat inflammatory disease within 5 half-lives of Visit 1.

        XOLAIR is a registered trademark of Genentech USA, Inc. and Novartis Pharmaceuticals
        Corporation.

          -  Adherence: Subjects who have known evidence of lack of adherence within studies
             MEA115666 or 201312 (less than 80%) to controller medications, scheduled study visits
             and/or ability to follow physician's recommendations.

          -  Smoking status: Current smokers

          -  Inability to read: In the opinion of the Investigator, any subject who is unable to
             read and/or would not be able to complete a questionnaire.