Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Subjects With Severe Uncontrolled Refractory Asthma

Asthma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01691521
• Other study ID #: 115588
• Status: Completed
• Phase: Phase 3
• Start date: October 8, 2012
• Est. completion date: January 18, 2014

Study information

• Verified date: August 2018
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 580
• Est. completion date: January 18, 2014
• Est. primary completion date: January 1, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Mepolizumab IV
Mepolizumab 75 mg IV will be administered every 4 weeks with the last dose at Week 28
• Mepolizumab SC
Mepolizumab 100 mg SC will be administered every 4 weeks with the last dose at Week 28
• IV Placebo
Normal saline (placebo) will be administered IV every 4 weeks with the last dose at Week 28
• SC Placebo
Normal saline (placebo) will be administered SC every 4 weeks with the last dose at Week 28

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires
Argentina	GSK Investigational Site	Mar del Plata	Buenos Aires
Argentina	GSK Investigational Site	Mar del Plata	Buenos Aires
Argentina	GSK Investigational Site	Mendoza
Argentina	GSK Investigational Site	Rosario	Santa Fe
Argentina	GSK Investigational Site	San Rafael	Mendoza
Australia	GSK Investigational Site	Bedford Park	South Australia
Australia	GSK Investigational Site	Clayton	Victoria
Australia	GSK Investigational Site	Nedlands	Western Australia
Australia	GSK Investigational Site	New Lambton	New South Wales
Australia	GSK Investigational Site	Parkville
Belgium	GSK Investigational Site	Bruxelles
Belgium	GSK Investigational Site	Gent
Belgium	GSK Investigational Site	Leuven
Belgium	GSK Investigational Site	Liège
Canada	GSK Investigational Site	Burlington	Ontario
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Edmonton	Alberta
Canada	GSK Investigational Site	Hamilton	Ontario
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Quebec City	Quebec
Canada	GSK Investigational Site	St-Charles-Borromée	Quebec
Canada	GSK Investigational Site	Trois Rivieres	Quebec
Canada	GSK Investigational Site	Vancouver	British Columbia
Canada	GSK Investigational Site	Windsor	Ontario
Canada	GSK Investigational Site	Winnipeg	Manitoba
Chile	GSK Investigational Site	Rancagua	Reg Del Libert Bern Ohiggins
Chile	GSK Investigational Site	Santiago
Chile	GSK Investigational Site	Talcahuano
France	GSK Investigational Site	Le Kremlin-Bicêtre Cedex
France	GSK Investigational Site	Lille cedex
France	GSK Investigational Site	Lyon cedex 04
France	GSK Investigational Site	Marseille cedex 20
France	GSK Investigational Site	Montpellier cedex 5
France	GSK Investigational Site	Perpignan
France	GSK Investigational Site	Saint Pierre cedex
Germany	GSK Investigational Site	Aschaffenburg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Frankfurt	Hessen
Germany	GSK Investigational Site	Frankfurt am Main	Hessen
Germany	GSK Investigational Site	Gelnhausen	Hessen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Magdeburg	Sachsen-Anhalt
Germany	GSK Investigational Site	Mainz	Rheinland-Pfalz
Germany	GSK Investigational Site	Neu isenburg	Hessen
Germany	GSK Investigational Site	Potsdam	Brandenburg
Germany	GSK Investigational Site	Ruedersdorf	Brandenburg
Italy	GSK Investigational Site	Cittadella PD	Veneto
Italy	GSK Investigational Site	Foggia	Puglia
Italy	GSK Investigational Site	Genova	Liguria
Italy	GSK Investigational Site	Napoli	Campania
Italy	GSK Investigational Site	Parma	Emilia-Romagna
Italy	GSK Investigational Site	Perugia	Umbria
Italy	GSK Investigational Site	Pietra Ligure (SV)	Liguria
Italy	GSK Investigational Site	Pisa	Toscana
Japan	GSK Investigational Site	Chiba
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Gunma
Japan	GSK Investigational Site	Hiroshima
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Hyogo
Japan	GSK Investigational Site	Hyogo
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kumamoto
Japan	GSK Investigational Site	Mie
Japan	GSK Investigational Site	Okinawa
Japan	GSK Investigational Site	Okinawa
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Korea, Republic of	GSK Investigational Site	Anyang-Si
Korea, Republic of	GSK Investigational Site	Bucheon-si,
Korea, Republic of	GSK Investigational Site	Cheongju, Chungcheongbuk-do
Korea, Republic of	GSK Investigational Site	Daegu
Korea, Republic of	GSK Investigational Site	Donggu Gwangju
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Jeonju-si, Jeollabuk-Do
Korea, Republic of	GSK Investigational Site	Kangwon-do
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Suwon, Kyonggi-do
Mexico	GSK Investigational Site	México DF
Mexico	GSK Investigational Site	Monterrey	Nuevo León
Mexico	GSK Investigational Site	Zapopan	Jalisco
Mexico	GSK Investigational Site	Zapopan	Jalisco
Russian Federation	GSK Investigational Site	Chelyabinsk
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Saint-Petersburg
Russian Federation	GSK Investigational Site	St. Petersburg
Spain	GSK Investigational Site	Alicante
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Pozuelo De Alarcón/Madrid
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kiev
Ukraine	GSK Investigational Site	Mykolayiv
Ukraine	GSK Investigational Site	Vinnytsia
United Kingdom	GSK Investigational Site	Bradford
United Kingdom	GSK Investigational Site	Glasgow
United Kingdom	GSK Investigational Site	London
United Kingdom	GSK Investigational Site	Plymouth
United Kingdom	GSK Investigational Site	Southampton
United States	GSK Investigational Site	Albany	Georgia
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Chicago	Illinois
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Hershey	Pennsylvania
United States	GSK Investigational Site	Nashville	Tennessee
United States	GSK Investigational Site	New Haven	Connecticut
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Newport Beach	California
United States	GSK Investigational Site	Riverside	California
United States	GSK Investigational Site	Rochester	New York
United States	GSK Investigational Site	Rochester	Minnesota
United States	GSK Investigational Site	Rolling Hills Estates	California
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  Chile,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Mexico,  Russian Federation,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Clinically Significant Exacerbations of Asthma Per Year	Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.	From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
Secondary	Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year	Clinically significant exacerbations of asthma are defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization and/or emergency department (ED) visits. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.	From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
Secondary	Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year	Clinically significant exacerbations of asthma is defined as worsening of asthma which required use of systemic corticosteroids (IV or oral steroid like prednisone, for at least 3 days or a single intramuscular (IM) corticosteroid (CS) dose is required. For maintenance of systemic corticosteroids, at least double the existing maintenance dose for at least 3 days was required) and/or hospitalization. The frequency of clinically significant exacerbations of asthma over the 32-week treatment period is expressed as the number of exacerbations per year. Analysis of the number of exacerbations performed using a negative binomial model with covariates of treatment group, baseline maintenance OCS therapy (OCS vs. no OCS), region, exacerbations in the year prior to the study (as an ordinal variable) and baseline % predicted FEV1, and with logarithm of time on treatment as an offset variable.	From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose
Secondary	Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32	FEV1 is defined as the volume of air expelled from the lungs in 1 second. Pre-bronchodilator FEV1 measurements were taken by spirometry. The change from Baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using mixed model repeated measures with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), treatment and visit, plus interaction terms for visit by baseline and visit by treatment group.	Baseline, Week 32
Secondary	Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32	The St. George's Respiratory Questionnaire is an established instrument, comprising 50 questions, evaluating symptoms, activity, and impacts; to measure Quality of Life in participants with diseases of airway obstruction and to elicit the participant's opinion of his/her health. The lowest possible value is zero and the highest possible value is 100. The higher values correspond to greater impairment in quality of life. The questionnaire was administered at Baseline (Visit 2) and at the Exit Visit (approximately 4 weeks after the last dose of study treatment). The change from baseline is defined as the difference between the value of the endpoint at the time point of interest and the baseline value. Analysis performed using analysis of covariance with covariates of baseline, region, baseline maintenance OCS therapy (OCS vs. no OCS), exacerbations in the year prior to the study (as an ordinal variable), baseline % predicted FEV1, and treatment.	Baseline, Week 32

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