A Phase 3a, Repeat Dose, Open-label, Long-term Safety Study of Mepolizumab in Asthmatic Subjects

• ClinicalTrials.gov Identifier: NCT02135692
• Recruitment Status: Completed
• First Posted: May 12, 2014
• Results First Posted: May 2, 2018
• Last Update Posted: December 3, 2019
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: May 8, 2014
• First Posted Date: May 12, 2014
• Results First Submitted Date: March 29, 2018
• Results First Posted Date: May 2, 2018
• Last Update Posted Date: December 3, 2019
• Actual Study Start Date: May 29, 2014
• Actual Primary Completion Date: October 5, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 15, 2018)

• Annualized Rate of On-treatment Exacerbations Per Year [ Time Frame: Baseline (Week 0) to Week 172 ]
  Exacerbations are defined as the worsening of asthma which requires use of systemic corticosteroids intravenous (IV) or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visit. On-Treatment data between first dose date and earliest of Withdrawal date/last dose + 28 days was considered for analysis. Analysis of the number of exacerbations was performed using a negative binomial generalized linear model.
• Number of Participants With Any On-treatment Adverse Event (AE) or On-treatment Serious AE (SAE) [ Time Frame: Baseline (Week 0) to Week 172 ]
  An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention or event associated with liver injury and impaired liver function were categorized as SAE. On-treatment AEs and on-treatment SAEs are the events occurring on/after the first dose of open-label mepolizumab date and before/on last dose+28 days.

Original Primary Outcome Measures (submitted: May 8, 2014)

• Annualized rate of exacerbations [ Time Frame: Up to Weeks 128 ]
  Exacerbations will be defined as worsening of asthma which requires use of systemic corticosteroids (CS) and/or hospitalisation and/or emergency department (ED) visits.
• Frequency of all adverse events (AEs) [ Time Frame: Up to Weeks 128 ]
  Descriptive analysis of the safety profile of mepolizumab.

Current Secondary Outcome Measures (submitted: May 15, 2018)

• Mean Change From Baseline in Asthma Control Questionnaire (ACQ)-5 On-treatment Score [ Time Frame: Baseline (Week 0) to Week 168 ]
  The ACQ-5 is a five-item questionnaire developed as a measure of participants asthma control. The five questions enquire about the frequency and/or severity of symptoms (nocturnal awakening on waking in the morning, activity limitation, shortness of breath, wheeze). The response options for all these questions consist of a 0 (no impairment/limitation) to 6 (total impairment/ limitation) scale. The overall ACQ score is calculated as the mean of the 5 questions and therefore ranges between 0 (totally controlled) and 6 (severely uncontrolled). Baseline was considered as the latest assessment prior to first dose of mepolizumab in this study. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and Baseline value.
• Mean Change From Baseline in On-treatment Clinic Pre-bronchodilator FEV1 [ Time Frame: Baseline (Week 0) to Week 168 ]
  FEV1 is defined as the volume of air forcefully expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry at Baseline and Weeks 24, 48, 72, 96, 120, 144 and 168. Spirometry was performed within 1 hour of the Baseline assessment. Baseline was considered as the latest assessment prior to first dose of mepolizumab in this study. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). Data between first dose date and earliest of Withdrawal date/last dose + 28 days considered on-treatment.
• Number of Participants Withdrawn From the Study Due to Lack of Efficacy and Adverse Events [ Time Frame: Baseline (Week 0) to Week 172 ]
  AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. Number of participants withdrawn due to lack of efficacy and adverse events from the study have been presented.
• Number of Participants Hospitalized Due to Adverse Events Including Asthma Exacerbations [ Time Frame: Baseline (Week 0) to Week 172 ]
  AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or all events of possible drug induced liver injury with hyperbilirubinemia. Number of participants requiring hospitalization due to an on-treatment serious adverse event including asthma exacerbations are presented. On-treatment SAEs are the events occurring on/after the first dose of mepolizumab date and before/on last dose of mepolizumab + 28 days.
• Number of Participants With AEs Including Both Systemic (Allergic and Non-allergic) and Local Site Reactions [ Time Frame: Baseline (Week 0) to Week 172 ]
  AEs were collected from the Baseline visit until the follow-up visit (Week 172). Participants were monitored to evaluate the AEs of systemic and local site reaction. AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. On treatment AEs were defined as events occurring from the first dose until 28 days after the last dose of mepolizumab. Number of participants with AEs including both systemic (i.e. allergic/immunoglobulin (Ig)E-mediated and non-allergic) and local site reactions have been presented.
• Mean Change From Baseline in QT Interval Corrected by Bazett's Method (QTcB) and QT Interval Corrected by Fridericia's Method (QTcF) Values for 12-lead Electrocardiogram (ECG) [ Time Frame: Baseline (Week 0) to Week 172 ]
  Twelve-lead ECG measurements were recorded after the participant has rested in the supine position for 5 minutes. The ECG was obtained before lung function testing followed by other study procedures. Baseline was considered as the latest assessment prior to first dose of mepolizumab in this study. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and Baseline value. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles)..
• Number of Participants With Maximum Change From Baseline in QTcB and QTcF Interval for ECG Assessed at Any Time Post Baseline [ Time Frame: Baseline (Week 0) to Week 172 ]
  Twelve-lead ECG measurements were recorded after the participant has rested in the supine position for 5 minutes. The ECG was obtained before lung function testing followed by other study procedures. Baseline was considered as the latest assessment prior to first dose of mepolizumab in this study. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and Baseline value. Participants with maximum change from Baseline were summarised at any time post Baseline for the following categories <-60, >=-60 to <-30, >=-30 to <0, >=0 to <30, >=30 to <60 and >=60. QTc intervals shown at any time post Baseline are the maximum seen in each participant over the course of the trial.
• Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure [ Time Frame: Baseline (Week 0) to Week 168 ]
  Vital sign measurements including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were done pre-injection with the participants sitting, having rested in this position for at least 5 minutes before each reading. They were taken before measurement of any clinic lung function tests or ECGs at the specified time point. Baseline was considered as the latest assessment prior to first dose of mepolizumab in this study. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and Baseline value.
• Change From Baseline in Pulse Rate [ Time Frame: Baseline (Week 0) to Week 168 ]
  Vital sign measurements including pulse rate was done pre-injection with the participants sitting, having rested in this position for at least 5 minutes before each reading. They were taken before measurement of any clinic lung function tests or ECGs at the specified time point. Baseline was considered as the latest assessment prior to first dose of mepolizumab in this study. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and Baseline value.
• Number of Participants With Positive Anti-mepolizumab Binding Antibodies (ADA) and Neutralizing Antibodies (NAb) [ Time Frame: Baseline (Week 0) to Week 172 ]
  Blood samples were collected for the determination of ADA just prior to administration of mepolizumab. Samples that tested positive for anti-mepolizumab antibodies were further tested for the presence of NAb. The highest value post-Baseline visit are based on each participant's highest post-Baseline titer. NAb assay result was only presented for participants with positive ADA assay. Highest value post-Baseline would be positive for a participant who had both negative and positive post-Baseline results. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
• Number of Participants With Potential Clinical Importance Values for Change From Baseline Relative to the Reference Range for Clinical Chemistry Parameters at Any Time Post-Baseline [ Time Frame: Baseline (Week 0) to Week 172 ]
  Blood samples were collected to assess clinical chemistry laboratory parameters. Number of participants with Potential Clinical Importance values for change from Baseline relative to the reference range at any time post-Baseline are presented. Any time post Baseline = all visits (including scheduled and unscheduled) post-Baseline. Participants are counted in the category that their value changes to (low, normal or high), unless there was no change in their category. If lab value category was unchanged, participants were recorded in the "To Normal or No Change" category. Alanine Aminotransferase=ALT. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).
• Number of Participants With Potential Clinical Importance Values for Change From Baseline Relative to the Reference Range for Hematology Parameters at Any Time Post-Baseline [ Time Frame: Baseline (Week 0) to Week 172 ]
  Blood samples were collected to assess hematology laboratory parameters. Number of participants with Potential Clinical Importance values for change from Baseline relative to the reference range at any time post-Baseline are presented. Any time post Baseline = all visits (including scheduled and unscheduled) post-Baseline. Participants are counted in the category that their value changes to (low, normal or high), unless there was no change in their category. If lab value category was unchanged, participants were recorded in the "To Normal or No Change" category.

Original Secondary Outcome Measures (submitted: May 8, 2014)

• Frequency of positive anti-mepolizumab binding antibodies/neutralizing antibodies [ Time Frame: Up to Weeks 128 ]
  Blood samples will be collected for the determination of anti-mepolizumab antibodies, just prior to administration of mepolizumab. Samples testing positive for anti-mepolizumab antibodies will be further tested for neutralising antibody.
• Asthma Control Questionnaire-5 score [ Time Frame: Up to Weeks 128 ]
  The Asthma Control Questionnaire-5 (ACQ-5) is a five-item questionnaire used to measures a subject's asthma control.
• Forced expiratory volume in 1 second (FEV1) [ Time Frame: Up to Weeks 128 ]
  FEV1 is a measure of lung function.
• Number of withdrawals due to lack of efficacy [ Time Frame: Up to Weeks 128 ]
  The number of subject withdrawals due to lack of efficacy will be summarized.
• Number of withdrawals due to AEs [ Time Frame: Up to Weeks 128 ]
  The number of subject withdrawals due to adverse events will be summarized.
• Number of hospitalizations due to AEs including asthma exacerbations [ Time Frame: Up to Weeks 128 ]
  The number of subject hospitalizations due to adverse events or exacerbations will be summarized.
• Frequency of both systemic (i.e., allergic and non-allergic) and local site reactions [ Time Frame: Up to Weeks 128 ]
  A summary of AEs of special interest.
• 12 lead ECG parameters [ Time Frame: Up to Weeks 128 ]
  A summary of the mean changes in specific safety ECG parameters from baseline.
• Safety as assessed by vital signs [ Time Frame: Up to Weeks 128 ]
  Vital signs including sitting pulse rate and blood pressure measurements.
• Safety as assessed by clinical laboratory parameters [ Time Frame: Up to Weeks 128 ]
  Clinical laboratory tests as measured by parameters for hematology and clinical chemistry.

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

Descriptive Information

• Brief Title: A Phase 3a, Repeat Dose, Open-label, Long-term Safety Study of Mepolizumab in Asthmatic Subjects
• Official Title: A Multi-Centre, Open-Label, Study of Mepolizumab in a Subset of Subjects With a History of Life Threatening/Seriously Debilitating Asthma Who Participated in the MEA115661 Trial
• Brief Summary: This is a multi-center, open-label, long-term study of subcutaneously (SC) administered mepolizumab 100mg in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. This study will enroll a subset of subjects from Study MEA115661 who have demonstrated clear benefit from therapy and who without continuation of mepolizumab therapy are individuals at greatest risk of serious deterioration of their health status. In order to target individuals at greatest risk for serious deterioration of their health status, only subjects from the MEA115661 study with a history of life-threatening or seriously debilitating asthma, will be allowed to participate. Subjects meeting all of the eligibility criteria for the study will be offered the opportunity to consent for this study of up to 128 weeks in length (including the Follow-Up Visit). This study will give opportunity to extend the collection of clinical data for long-term use and further assess the sustainability of efficacy in a population likely to experience significant loss of asthma control and the need for higher doses of systemic steroids if returned to SOC only.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Asthma

Intervention

• Biological: Mepolizumab
  Mepolizumab is a fully humanised IgG antibody (IgG1, kappa) with human heavy and light chain frameworks. Mepolizumab will be supplied as a lyophilised cake in sterile vials for individual use.
• Drug: SOC
  Standard of Care (SOC) will differ by participant, however it will generally include oral corticosteroids and an inhaled controller medicine (an inhaled corticosteroid plus a long acting beta agonist) and/or short acting beta agonists

Study Arms

Experimental: Mepolizumab 100 mg

All subjects will receive mepolizumab 100mg administered SC into the upper arm or thigh approximately every 4 weeks.

Interventions:

• Biological: Mepolizumab
• Drug: SOC

• Publications *: Khurana S, Brusselle GG, Bel EH, FitzGerald JM, Masoli M, Korn S, Kato M, Albers FC, Bradford ES, Gilson MJ, Price RG, Humbert M. Long-term Safety and Clinical Benefit of Mepolizumab in Patients With the Most Severe Eosinophilic Asthma: The COSMEX Study. Clin Ther. 2019 Oct;41(10):2041-2056.e5. doi: 10.1016/j.clinthera.2019.07.007. Epub 2019 Aug 22.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 19, 2018): 339
• Original Estimated Enrollment (submitted: May 8, 2014): 375
• Actual Study Completion Date: October 5, 2017
• Actual Primary Completion Date: October 5, 2017 (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.
• Male or Eligible Female Subjects: To be eligible for the study, females of child-bearing potential must commit to consistent and correct use of an acceptable method of birth control and for 4 months after the last study drug administration. A urine pregnancy test is required of all females of childbearing potential at the initial Baseline Visit (Visit 1).
• French Subjects Only: 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.
• MEA115661 Participation: Subjects must have completed Visit 14 of MEA115661.
• Current Anti-Asthma Therapy: The subject's asthma has been treated with an ICS controller medication for the last 8 months with fluticasone propionate (FP) >=500 mcg/day (or equivalent).
• Disease Severity: Subjects must be assessed as having life-threatening /serious debilitating asthma in order to enroll, as defined by the following: Subjects enrolled in MEA115588 must meet one of the following criteria: a) Subject has a history of at least one intubation during their lifetime; b) >=3 asthma exacerbations in the 12 months prior to screening for MEA115588; c) >=1 or more hospitalization for asthma exacerbation in the 12 months prior to screening for MEA115588. Subjects enrolled in MEA115575 must meet one of the following criteria: d) Subject has a history of at least one intubation during their lifetime; e) Their optimized dose at randomization in MEA115575 was >=10mg of prednisone; f) >=1 or more hospitalization for asthma exacerbation in the 12 months prior to screening for MEA115575.
• Clinical Benefit: Subjects must have experienced documented clinical benefit to enroll. Subjects must meet the following criteria demonstrating clinical benefit: Subjects enrolled in MEA115588 who received mepolizumab must meet all of the following criteria: a) Subject must have had a reduction in their exacerbation frequency by >=50% during MEA115588. The baseline for comparison is the total number of exacerbations reported in the 12 months prior to screening for MEA115588. b) The investigator response on the "Clinician-Rated Response to Therapy" questionnaire at Visit 10 was either: mildly improved, moderately improved or significantly improved. Subjects enrolled in MEA115588 who received placebo must meet all of the following criteria: c) Subject must have had a reduction in their exacerbation frequency by >=50% during the first 8 months of MEA115661. The baseline for comparison is the total number of exacerbations reported in the 12 months prior to screening for MEA115588; d) The investigator confirms that the subject demonstrated improvement during MEA115661. Subjects enrolled in MEA115575 who received mepolizumab must meet all of the following criteria: e) Subject must have reduced their oral corticosteroid dose by >=50% during MEA115575. The baseline for comparison is the subject's optimized oral corticosteroid (OCS) dose at randomization in MEA115575; f) The investigator response on the "Clinician-Rated Response to Therapy" questionnaire at Visit 9 was either: mildly improved, moderately improved or significantly improved. Subjects enrolled in MEA115575 who received placebo must meet all of the following criteria: g) Subject must have reduced their oral corticosteroid dose at randomization by >=50% in the first 6 months of MEA115661. The baseline for comparison is the subject's optimized OCS dose at randomization in MEA115575; h) The investigator confirms that the subject demonstrated improvement during MEA115661.

Exclusion Criteria

• Health Status: Clinically significant change in health status during MEA115661 which in the opinion of the investigator would make the subject unsuitable for participation in this long-term study.
• Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnanDeart during the time of study participation.
• Exacerbation History: Subjects who received placebo in MEA115588 and had NO exacerbations during the study.
• Oral Corticosteroid Use: Subjects who received placebo in MEA115575 and were able to discontinue oral corticosteroid therapy by the end of the study.
• Smoking Status: Current smokers
• Previous Significant Protocol Deviation: Subjects who were excluded from the per protocol analysis due to significant protocol deviations in either study MEA115575 or MEA115588.
• Electrocardiogram (ECG) Assessment: A clinically significant ECG abnormality at the exit visit of MEA115661, as determined by the investigator.

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, Belgium, Canada, Chile, Czechia, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Poland, Russian Federation, Spain, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02135692
• Other Study ID Numbers: 201312; 2014-000314-54 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

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 is available via the Clinical Study Data Request site (click on the link provided below)
• 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: https://clinicalstudydatarequest.com/Posting.aspx?ID=20059

• Responsible Party: GlaxoSmithKline
• Study Sponsor: GlaxoSmithKline
• Collaborators: Not Provided

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: November 2019