Cessation Versus Continuation of Long-term Mepolizumab in Severe Eosinophilic Asthma Patients

• ClinicalTrials.gov Identifier: NCT02555371
• Recruitment Status: Completed
• First Posted: September 21, 2015
• Results First Posted: February 5, 2020
• Last Update Posted: February 5, 2020
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: September 17, 2015
• First Posted Date: September 21, 2015
• Results First Submitted Date: January 23, 2020
• Results First Posted Date: February 5, 2020
• Last Update Posted Date: February 5, 2020
• Actual Study Start Date: January 7, 2016
• Actual Primary Completion Date: July 24, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 23, 2020)

Percentage of Participants With First Clinically Significant Exacerbation in Part C [ Time Frame: Weeks 12, 24, 36 and 52 ]

Clinically significant exacerbation was defined as worsening of asthma which requires use of systemic corticosteroids (e.g., prednisone) for at least 3 days or a single intramuscular (IM) corticosteroid dose and/or hospitalization and/or emergency department (ED) visits. For participants on maintenance systemic corticosteroids, at least double the existing maintenance dose for at least 3 days is required. Percentage of participants with clinically significant exacerbation over time during the on-treatment period of Part C and 95% confidence interval were estimated using Kaplan-Meier estimates. Intent-to-Treat Population includes all randomized participants who received at least one dose of double-blind study medication within Part C.

Original Primary Outcome Measures (submitted: September 17, 2015)

Time to first clinically significant exacerbation [ Time Frame: Up to 52 weeks ]

Clinically significant exacerbations will be defined as worsening of asthma which requires use of systemic corticosteroids and/or hospitalisation and/or emergency department (ED) visits

Current Secondary Outcome Measures (submitted: January 23, 2020)

• Ratio to Baseline in Blood Eosinophil Count in Part C [ Time Frame: Baseline and Weeks 12, 24, 36 and 52 ]
  Blood samples were collected at specific time points to measure blood eosinophils level. Baseline was defined as the latest available assessment prior to first dose of double-blind treatment within Part C. Ratio to Baseline is defined as visit value divided by Baseline value and was analyzed using Mixed Model Repeated Measures with covariates of Baseline, region, exacerbations in the year prior to randomization (as an ordinal variable), Baseline maintenance oral corticosteroids (OCS) therapy (OCS versus no OCS), treatment and visit, plus interaction terms for visit by Baseline and visit by treatment group. The log transformation was applied to blood eosinophil counts prior to analysis. If a blood eosinophil count of zero was reported, a small value was added prior to log transforming the data. The dispersion measure used was log standard error.
• Percentage of Participants With 0.5 Point or More Increase in Asthma Control Questionnaire (ACQ)-5 Score From Baseline in Part C [ Time Frame: Baseline and Weeks 12, 24, 36 and 52 ]
  The ACQ-5 is a five-item, self-completed questionnaire. Five questions (concerning nocturnal awakening, waking in the morning, activity limitation, shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms over the previous week. The response ranges from zero (no impairment/limitation) to six (total impairment/ limitation) scale. Increase in score of >= 0.5 units from Baseline indicates decrease in asthma control. Baseline is the latest available assessment prior to first dose of double-blind treatment within Part C. Percentage of participants with a 0.5 point or more increase in ACQ-5 score from Baseline over time during the on-treatment period of Part C and its 95% confidence interval were estimated using Kaplan-Meier estimates.
• Percentage of Participants With Time to First Exacerbation Requiring Hospitalization or ED Visit in Part C [ Time Frame: Weeks 12, 24, 36 and 52 ]
  Exacerbations of asthma requiring hospitalization or ED visit were assessed. The analysis was performed from Cox Proportional Hazards Model with covariates of treatment group, region, exacerbations in the year prior to randomization (as an ordinal variable) and Baseline maintenance OCS therapy (OCS versus no OCS). Percentage of participants with an exacerbation over time and its 95% confidence intervals were estimated using Kaplan-Meier estimates

Original Secondary Outcome Measures (submitted: September 17, 2015)

• Ratio to baseline in blood eosinophil count [ Time Frame: Baseline (Week 0) and up to Week 52 ]
  Blood eosinophil counts will be recorded as part of the standard haematological assessments at Baseline (Week 0), weeks 12, 24, 36 and 52 in Part C
• Time to a decrease in asthma control, defined as an increase from baseline in Asthma Control Questionnaire-5 (ACQ-5) score of >= 0.5 units [ Time Frame: Baseline (Week 0) and up to Week 52 ]
  The ACQ-5 is a five-item questionnaire, which has been developed as a measure of subject' asthma control that can be quickly and easily completed by the subject. The five questions enquire about the frequency and/or severity of symptoms over the previous week (nocturnal awakening on waking in the morning, activity limitation, and shortness of breath, wheeze). The response options for all these questions consist of a zero (no impairment/limitation) to six (total impairment/ limitation) scale. ACQ score will be collected at Baseline (Week 0) and at Weeks 12, 24, 36, 48 and 56.
• Time to first exacerbation requiring hospitalization or ED visit [ Time Frame: Up to 52 weeks ]
  Clinically significant exacerbations will be defined as worsening of asthma which requires use of systemic corticosteroids and/or hospitalisation and/or ED visits

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cessation Versus Continuation of Long-term Mepolizumab in Severe Eosinophilic Asthma Patients
• Official Title: A Multi-center, Randomized, Double-blind, Placebo Controlled, Parallel Group Study to Compare Cessation Versus Continuation of Long-term Mepolizumab Treatment in Patients With Severe Eosinophilic Asthma (201810)

Brief 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).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Asthma

Intervention

• Biological: Mepolizumab 100mg
  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.
• Drug: Placebo
  The placebo will be 0.9% sodium chloride solution and will be provided by the study site.

Study Arms

• Experimental: Arm Mepolizumab 100 mg
  There will be 4 parts during the study. Part A will be Variable Open-Label Run-in (maximum up to 132 weeks). Part B- Fixed Open-Label Run-In (4 Weeks to 8 weeks). Part C will be randomized double-blind treatment period (Up to 52 weeks) and in case of clinically significant asthma exacerbation, optional open label switch Part D (Up to 52 weeks post randomization). Subjects will receive mepolizumab (100 mg SC) every 4 weeks throughout study
  Intervention: Biological: Mepolizumab 100mg
• Placebo Comparator: Arm Placebo
  There will be 4 parts during the study. Part A will be Variable Open-Label Run-in (maximum up to 132 weeks). Part B- Fixed Open-Label Run-In (4 Weeks to 8 weeks). Part C will be randomized double-blind treatment period (Up to 52 weeks) and in case of clinically significant asthma exacerbation, optional open label switch Part D (Up to 52 weeks post randomization). During Part A, B and D, subjects will receive open label mepolizumab (100 mg SC) every 4 weeks and during Part C, subjects will receive placebo SC every 4 weeks.
  Interventions:

  • Biological: Mepolizumab 100mg
  • Drug: Placebo

• Publications *: Moore WC, Kornmann O, Humbert M, Poirier C, Bel EH, Kaneko N, Smith SG, Martin N, Gilson MJ, Price RG, Bradford ES, Liu MC. Stopping versus continuing long-term mepolizumab treatment in severe eosinophilic asthma (COMET study). Eur Respir J. 2022 Jan 6;59(1). pii: 2100396. doi: 10.1183/13993003.00396-2021. Print 2022 Jan.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2020): 306
• Original Estimated Enrollment (submitted: September 17, 2015): 300
• Actual Study Completion Date: July 24, 2019
• Actual Primary Completion Date: July 24, 2019 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Canada, France, Germany, Japan, Korea, Republic of, Netherlands, Poland, Romania, Russian Federation, Spain, Ukraine, United States

Administrative Information

• NCT Number: NCT02555371
• Other Study ID Numbers: 201810; 2015-002361-32 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• URL: http://clinicalstudydatarequest.com

• Current Responsible Party: GlaxoSmithKline
• Original Responsible Party: Same as current
• Current Study Sponsor: GlaxoSmithKline
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: January 2020