Clinical trial NCT01691521: Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Subjects With Severe Uncontrolled Refractory Asthma
Official title: MEA115588 A Randomised, Double-blind, Double-dummy, Placebo-controlled, Parallel-group, Multi-centre Study of the Efficacy and Safety of Mepolizumab Adjunctive Therapy in Subjects With Severe Uncontrolled Refractory Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: safety
SB-240563
efficacy
placebo
eosinophils
mepolizumab
Severe refractory asthma
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-09-24
Enrollment: 580
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate two dose regimens of mepolizumab \[75mg intravenous (i.v.) or 100mg subcutaneous (SC) every 4 weeks\] compared with placebo over a 32 week treatment period in subjects with severe refractory asthma with elevated blood eosinophils. Efficacy will be measured by a reduction in the frequency of asthma exacerbations. Additional efficacy assessments will include measurements of lung function, symptom scores, and quality of life. Safety will be assessed by clinical laboratory samples, ECGs, immunogenicity and adverse events.

This study is intended to replicate the Phase IIb/III study MEA112997. Subjects in MEA115588, who meet all eligibility criteria at screening visit, will enter the run-in period. Those subjects that are not able/eligible to be randomised at the end of the 6 week run-in period will be deemed run-in failures. Subjects will remain on their current maintenance therapy throughout the run-in, double-blind treatment administration and follow-up periods. Subjects who meet the randomisation eligibility criteria will be randomised in a 1:1:1 ratio to receive one of the following treatments every 4 weeks for a total of 8 doses: Mepolizumab 75 miligram (mg) i.v. and placebo SC, or Mepolizumab 100 mg SC and placebo i.v. or Placebo i.v. and placebo SC.

Subjects that receive all 8 doses of double-blind treatment, and meet the eligibility criteria for the Open-Label Extension (OLE) Study, will be offered the opportunity to participate in the OLE trial.


Eligibility criteria: Inclusion Criteria:

* Able to give written informed consent prior to participation in the study
* At least 12 years of age at visit 1 and a minimum weight of 45 kilogram (kg)
* A well-documented requirement for regular treatment with high dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or without maintenance oral corticosteroids (OCS)
* Current treatment with an additional controller medication, besides ICS, for at least 3 months or a documented failure in the past 12 months of an additional controller medication for at least 3 successive months
* Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma
* At Visit 1, a pre-bronchodilator FEV1 \<80% (for subjects \>= 18 years of age), a pre-bronchodilator FEV1 \<90% or FEV1:FVC ratio \<0.8 (for subjects 12-17 years of age).
* Previously confirmed history of two or more exacerbations requiring treatment with systemic CS
* Male or Eligible Female (females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control)
* French subjects will be included only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

* Current smokers or former smokers with a smoking history of \>=10 pack years
* Presence of a known pre-existing, clinically important lung condition other than asthma
* A current malignancy or previous history of malignancy in less than 12 months
* Known, pre-existing, unstable liver disease cirrhosis and known biliary abnormalities
* Known, pre-existing severe or clinically significant cardiovascular disease
* known, pre-existing other concurrent clinically significant medical conditions that are uncontrolled with standard treatment
* Subjects with any eosinophilic diseases
* QTc(F) ≥450msec or QTc(F) ≥480 msec
* A history of alcohol/substance abuse
* Subject with known immunodeficiency
* Subjects who have received omalizumab within 130 days of Visit 1 or any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1
* 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
* Subjects with allergy/intolerance to a monoclonal antibody or biologic.
* Subjects who are pregnant or breastfeeding
* Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations
* Previously participated in any study with mepolizumab and received investigational product (including placebo)

Primary outcomes:
measure: Number of Clinically Significant Exacerbations of Asthma Per Year
timeFrame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
Secondary outcomes:
measure: Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year
timeFrame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
measure: Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year
timeFrame: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
measure: Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32
timeFrame: Baseline, Week 32
measure: Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32
timeFrame: Baseline, Week 32
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: GSK Investigational Site
state: Alabama
city: Newport Beach
country: United States
facility: GSK Investigational Site
state: California
city: Riverside
country: United States
facility: GSK Investigational Site
state: California
city: Rolling Hills Estates
country: United States
facility: GSK Investigational Site
state: California
city: Denver
country: United States
facility: GSK Investigational Site
state: Colorado
city: New Haven
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Albany
country: United States
facility: GSK Investigational Site
state: Georgia
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Rochester
country: United States
facility: GSK Investigational Site
state: Minnesota
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Rochester
country: United States
facility: GSK Investigational Site
state: New York
city: Durham
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Winston-Salem
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cincinnati
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Hershey
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Salt Lake City
country: United States
facility: GSK Investigational Site
state: Utah
city: Mar del Plata
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Mar del Plata
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: San Rafael
country: Argentina
facility: GSK Investigational Site
state: Mendoza
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Mendoza
country: Argentina
facility: GSK Investigational Site
city: New Lambton
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Bedford Park
country: Australia
facility: GSK Investigational Site
state: South Australia
city: Clayton
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Nedlands
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Parkville
country: Australia
facility: GSK Investigational Site
city: Bruxelles
country: Belgium
facility: GSK Investigational Site
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Liège
country: Belgium
facility: GSK Investigational Site
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Winnipeg
country: Canada
facility: GSK Investigational Site
state: Manitoba
city: Burlington
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Windsor
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec City
country: Canada
facility: GSK Investigational Site
state: Quebec
city: St-Charles-Borromée
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Trois Rivieres
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Rancagua
country: Chile
facility: GSK Investigational Site
state: Reg Del Libert Bern Ohiggins
city: Santiago
country: Chile
facility: GSK Investigational Site
city: Talcahuano
country: Chile
facility: GSK Investigational Site
city: Le Kremlin-Bicêtre Cedex
country: France
facility: GSK Investigational Site
city: Lille cedex
country: France
facility: GSK Investigational Site
city: Lyon cedex 04
country: France
facility: GSK Investigational Site
city: Marseille cedex 20
country: France
facility: GSK Investigational Site
city: Montpellier cedex 5
country: France
facility: GSK Investigational Site
city: Perpignan
country: France
facility: GSK Investigational Site
city: Saint Pierre cedex
country: France
facility: GSK Investigational Site
city: Aschaffenburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Potsdam
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Ruedersdorf
country: Germany
facility: GSK Investigational Site
state: Brandenburg
city: Frankfurt am Main
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Frankfurt
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Gelnhausen
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Neu isenburg
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Magdeburg
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Napoli
country: Italy
facility: GSK Investigational Site
state: Campania
city: Parma
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Pietra Ligure (SV)
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Foggia
country: Italy
facility: GSK Investigational Site
state: Puglia
city: Pisa
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Perugia
country: Italy
facility: GSK Investigational Site
state: Umbria
city: Cittadella PD
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Fukuoka
country: Japan
facility: GSK Investigational Site
city: Gunma
country: Japan
facility: GSK Investigational Site
city: Hiroshima
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Hyogo
country: Japan
facility: GSK Investigational Site
city: Hyogo
country: Japan
facility: GSK Investigational Site
city: Ibaraki
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Kumamoto
country: Japan
facility: GSK Investigational Site
city: Mie
country: Japan
facility: GSK Investigational Site
city: Okinawa
country: Japan
facility: GSK Investigational Site
city: Okinawa
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Anyang-Si
country: Korea, Republic of
facility: GSK Investigational Site
city: Bucheon-si,
country: Korea, Republic of
facility: GSK Investigational Site
city: Cheongju, Chungcheongbuk-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Daegu
country: Korea, Republic of
facility: GSK Investigational Site
city: Donggu Gwangju
country: Korea, Republic of
facility: GSK Investigational Site
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Jeonju-si, Jeollabuk-Do
country: Korea, Republic of
facility: GSK Investigational Site
city: Kangwon-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Suwon, Kyonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Zapopan
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Zapopan
country: Mexico
facility: GSK Investigational Site
state: Jalisco
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: México DF
country: Mexico
facility: GSK Investigational Site
city: Chelyabinsk
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Pozuelo De Alarcón/Madrid
country: Spain
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kiev
country: Ukraine
facility: GSK Investigational Site
city: Mykolayiv
country: Ukraine
facility: GSK Investigational Site
city: Vinnytsia
country: Ukraine
facility: GSK Investigational Site
city: Bradford
country: United Kingdom
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Plymouth
country: United Kingdom
facility: GSK Investigational Site
city: Southampton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Lemiere C, Taille C, Lee JK, Smith SG, Mallett S, Albers FC, Bradford ES, Yancey SW, Liu MC. Impact of baseline clinical asthma characteristics on the response to mepolizumab: a post hoc meta-analysis of two Phase III trials. Respir Res. 2021 Jun 22;22(1):184. doi: 10.1186/s12931-021-01767-z.
citation: Gibson PG, Prazma CM, Chupp GL, Bradford ES, Forshag M, Mallett SA, Yancey SW, Smith SG, Bel EH. Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions. Respir Res. 2021 Jun 7;22(1):171. doi: 10.1186/s12931-021-01746-4.
citation: Best N, Price RG, Pouliquen IJ, Keene ON. Assessing efficacy in important subgroups in confirmatory trials: An example using Bayesian dynamic borrowing. Pharm Stat. 2021 May;20(3):551-562. doi: 10.1002/pst.2093. Epub 2021 Jan 21.
citation: Wardlaw A, Howarth PH, Israel E, Taille C, Quirce S, Mallett S, Bates S, Albers FC, Kwon N. Fungal sensitization and its relationship to mepolizumab response in patients with severe eosinophilic asthma. Clin Exp Allergy. 2020 Jul;50(7):869-872. doi: 10.1111/cea.13680. Epub 2020 Jun 25. No abstract available.
citation: Kim MK, Park HS, Park CS, Min SJ, Albers FC, Yancey SW, Mayer B, Kwon N. Efficacy and safety of mepolizumab in Korean patients with severe eosinophilic asthma from the DREAM and MENSA studies. Korean J Intern Med. 2021 Mar;36(2):362-370. doi: 10.3904/kjim.2019.198. Epub 2020 May 26.
citation: 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.
citation: Khurana S, Lyness JM, Mallett S, Nelsen LM, Prazma CM, Albers FC, Forshag M, Llanos JP, Yancey SW, Ortega HG. Association of depressive symptoms with health status and markers of uncontrolled severe asthma. Allergy Asthma Proc. 2019 Jul 1;40(4):230-239. doi: 10.2500/aap.2019.40.4229.
citation: Nelsen LM, Cockle SM, Gunsoy NB, Jones P, Albers FC, Bradford ES, Mullerova H. Impact of exacerbations on St George's Respiratory Questionnaire score in patients with severe asthma: post hoc analyses of two clinical trials and an observational study. J Asthma. 2020 Sep;57(9):1006-1016. doi: 10.1080/02770903.2019.1630640. Epub 2019 Jun 28.
citation: Yancey SW, Bradford ES, Keene ON. Disease burden and efficacy of mepolizumab in patients with severe asthma and blood eosinophil counts of >/=150-300 cells/muL. Respir Med. 2019 May;151:139-141. doi: 10.1016/j.rmed.2019.04.008. Epub 2019 Apr 8.
citation: Ortega HG, Meyer E, Brusselle G, Asano K, Prazma CM, Albers FC, Mallett SA, Yancey SW, Gleich GJ. Update on immunogenicity in severe asthma: Experience with mepolizumab. J Allergy Clin Immunol Pract. 2019 Sep-Oct;7(7):2469-2475.e1. doi: 10.1016/j.jaip.2019.03.042. Epub 2019 Apr 5. No abstract available.
citation: Ortega H, Menzies-Gow A, Llanos JP, Forshag M, Albers F, Gunsoy N, Bradford ES, Yancey SW, Kraft M. Rapid and Consistent Improvements in Morning PEF in Patients with Severe Eosinophilic Asthma Treated with Mepolizumab. Adv Ther. 2018 Jul;35(7):1059-1068. doi: 10.1007/s12325-018-0727-8. Epub 2018 Jun 15.
citation: Ortega H, Yancey SW, Keene ON, Gunsoy NB, Albers FC, Howarth PH. Asthma Exacerbations Associated with Lung Function Decline in Patients with Severe Eosinophilic Asthma. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):980-986.e1. doi: 10.1016/j.jaip.2017.12.019. Epub 2018 Feb 15.
citation: Gunsoy NB, Cockle SM, Yancey SW, Keene ON, Bradford ES, Albers FC, Pavord ID. Evaluation of Potential Continuation Rules for Mepolizumab Treatment of Severe Eosinophilic Asthma. J Allergy Clin Immunol Pract. 2018 May-Jun;6(3):874-882.e4. doi: 10.1016/j.jaip.2017.11.026. Epub 2017 Dec 16.
citation: Albers FC, Price RG, Smith SG, Yancey SW. Mepolizumab efficacy in patients with severe eosinophilic asthma receiving different controller therapies. J Allergy Clin Immunol. 2017 Nov;140(5):1464-1466.e4. doi: 10.1016/j.jaci.2017.06.010. Epub 2017 Jul 4. No abstract available.
citation: Magnan A, Bourdin A, Prazma CM, Albers FC, Price RG, Yancey SW, Ortega H. Treatment response with mepolizumab in severe eosinophilic asthma patients with previous omalizumab treatment. Allergy. 2016 Sep;71(9):1335-44. doi: 10.1111/all.12914. Epub 2016 May 24.
citation: Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014 Sep 25;371(13):1198-207. doi: 10.1056/NEJMoa1403290. Epub 2014 Sep 8.