Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Participants With Severe Eosinophilic Asthma on Markers of Asthma Control

Asthma Clinical Trial

Official title:

A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multi-centre 24-week Study to Evaluate the Efficacy and Safety of Mepolizumab Adjunctive Therapy in Subjects With Severe Eosinophilic Asthma on Markers of Asthma Control

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02281318
• Other study ID #: 200862
• Status: Completed
• Phase: Phase 3
• Start date: December 11, 2014
• Est. completion date: June 10, 2016

Study information

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

Clinical Trial Summary

This is a multi-centre, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy and safety of mepolizumab adjunctive therapy in participants with severe eosinophilic asthma on markers of asthma control. The overall intent of the current study is to more fully explore the impact of mepolizumab on health-related quality of life (HR-QoL) and other measures of asthma control, including lung function.

Participants who meet the predefined criteria will be randomised to receive either mepolizumab or placebo in addition to standard of care asthma treatment. Approximately 780 participants with severe eosinophilic asthma will be screened to ensure the randomisation of 544 participants (272 participants per treatment group) into the study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 556
• Est. completion date: June 10, 2016
• Est. primary completion date: June 10, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion Criteria:

• Age: At least 12 years of age at the time of signing the informed consent/assent (For those countries where local regulations permit enrolment of adults only, participant recruitment will be restricted to those who are >=18 years of age)

• Inhaled Corticosteroid: 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). For participants >=18 years old: ICS dose must be >=880 micrograms (mcg)/day fluticasone propionate (FP) (exactuator) or equivalent daily. For ICS/long-acting beta-2-agonist (LABA) combination preparations, the highest approved maintenance dose in the local country will meet this ICS criterion. For participants >=12 to <=17 years old: ICS dose must be >=440 mcg/day FP (ex-actuator) or equivalent daily. For ICS/LABA combination preparations, the mid-strength approved maintenance dose in the local country will meet this ICS criterion

• Controller Medication: 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 (e.g. LABA, leukotriene receptor antagonist [LTRA], or theophylline)

• Eosinophilic asthma: Prior documentation of eosinophilic asthma or high likelihood of eosinophilic asthma as per Randomisation Criteria 1 and 2

• FEV1: Persistent airflow obstruction as indicated by : For participants >=18 years of age at visit 1, a pre-bronchodilator FEV1 <80% predicted (National Health and Nutrition Examination Survey [NHANES III]) recorded at Visit 1. For participants 12-17 years of age at Visit 1: A pre-bronchodilator FEV1 <90% predicted (NHANES III) recorded at Visit 1 OR FEV1:FVC ratio <0.8 recorded at Visit 1

• Exacerbation history: Previously confirmed history of two or more exacerbations requiring treatment with systemic Corticosteroid (CS) (intramuscular, intravenous, or oral), in the 12 months prior to visit 1, despite the use of high-dose inhaled corticosteroids (ICS). For participants receiving maintenance CS, the CS treatment for the exacerbations must have been a two-fold dose increase or greater.

• Gender: Male or Eligible Female. To be eligible for entry into the study, females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control listed in the protocol for the duration of the trial and for 4 months after the last study drug administration.

• Informed Consent/Assent: Able to give written informed consent/assent prior to participation in the core study, which will include the ability to comply with the requirements and restrictions listed in the consent/assent form and in this protocol. Participants must be able to read, comprehend, and write at a level sufficient to complete study related materials. Written informed consent must be obtained from ALL patients/legally authorized representative(s); for patients 12-17 years old, written informed assent must be obtained in addition to the legally authorized representative(s)' consent.

• French participants: In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

• Smoking history: Current smokers or former smokers with a smoking history of >=10 pack years (number of pack years = (number of cigarettes per day/20) x number of years smoked). A former smoker is defined as a participant who quit smoking at least 6 months prior to Visit 1.

• Concurrent Respiratory Disease: Presence of a known pre-existing, clinically important lung condition other than asthma. This includes current infection, bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than asthma) or a history of lung cancer.

• Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior to screening (Participants that had localized carcinoma of the skin which was resected for cure will not be excluded).

• Liver Disease: Known, pre-existing, unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

• Cardiovascular: Participants who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment. Including but not limited to: (a) known ejection fraction of <30% OR (b) severe heart failure meeting New York Heart Association Class IV classification OR (c) hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III OR (d) angina diagnosed less than 3 months prior to Visit 1 or at Visit 1.

• Other Concurrent Medical Conditions: Participants who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological or any other system abnormalities that are uncontrolled with standard treatment.

• Eosinophilic Diseases: Participants with other conditions that could lead to elevated eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome (Eosinophilic Granulomatosis with Polyangiitis [EGPA]), or Eosinophilic Esophagitis. Participants with a known, pre-existing parasitic infestation within 6 months prior to Visit 1 are also to be excluded.

• Electrocardiogram (ECG) Assessment: QT interval corrected for heart rate by Fridericia's formula (QTc(F)) >=450 milliseconds (msec) or QTc(F) >=480 msec for participants with Bundle Branch Block at Visit 1.

• Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Visit 1.

• Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency virus [HIV]), other than that explained by the use of corticosteroids taken as therapy for asthma.

• Xolair: Participants who have received omalizumab (Xolair) within 130 days of Visit 1.

• Other Monoclonal Antibodies: Participants who have received any monoclonal antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 1.

• Investigational Medications: Participants 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, prior to Visit 1 (this also includes investigational formulations of marketed products).

• Hypersensitivity: Participants with allergy/intolerance to a monoclonal antibody or biologic.

• Pregnancy: Participants who are pregnant or breastfeeding. Patients should not be enrolled if they plan to become pregnant during the time of study participation. A urine pregnancy test is required of all women of child bearing potential. This test will be performed at the time points specified in the Time and Events Schedule in protocol.

• Adherence: Participants who have known evidence of lack of adherence to controller medications and/or ability to follow physician's recommendations.

• Previous participation: Previously participated in any study with mepolizumab and received investigational product (including placebo)

Related Conditions & MeSH terms

• Asthma
• Pulmonary Eosinophilia

Intervention

Biological:
• Mepolizumab
Humanised Immunoglobulin G (IgG) antibody (IgG1, kappa) with human heavy and light chain frameworks, provided as a lyophilised cake in sterile vial. Vial to be reconstituted with sterile water for injection, just prior to use

Drug:
• Placebo
Sterile 0.9% sodium chloride solution
• SOC
Standard of Care (SOC) will differ by participants, however it will include high dose ICS with at least one other controller, e.g. LABA, with or without maintenance OCS

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires
Argentina	GSK Investigational Site	Concepcion del Uruguay	Entre Ríos
Argentina	GSK Investigational Site	La 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
Belgium	GSK Investigational Site	Brussels
Belgium	GSK Investigational Site	Erpent
Belgium	GSK Investigational Site	Gent
Belgium	GSK Investigational Site	Leuven
Belgium	GSK Investigational Site	Liège
Bulgaria	GSK Investigational Site	Pleven
Bulgaria	GSK Investigational Site	Sofia
Canada	GSK Investigational Site	Burlington	Ontario
Canada	GSK Investigational Site	Calgary	Alberta
Canada	GSK Investigational Site	Montreal	Quebec
Canada	GSK Investigational Site	Sainte-Foy	Quebec
Canada	GSK Investigational Site	St-Charles-Borromée	Ontario
Canada	GSK Investigational Site	Toronto	Ontario
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
Czechia	GSK Investigational Site	Brno
Czechia	GSK Investigational Site	Hlucin
Czechia	GSK Investigational Site	Hradec Kralove
Czechia	GSK Investigational Site	Kralupy nad Vltavou
Czechia	GSK Investigational Site	Olomouc
Czechia	GSK Investigational Site	Plzen
Czechia	GSK Investigational Site	Praha 4
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tallinn
Estonia	GSK Investigational Site	Tartu
France	GSK Investigational Site	Brest Cedex
France	GSK Investigational Site	Dijon 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	Nantes cedex 1
France	GSK Investigational Site	Paris Cedex 18
France	GSK Investigational Site	Pessac cedex
France	GSK Investigational Site	Reims Cedex
Germany	GSK Investigational Site	Bamberg	Bayern
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Koblenz	Rheinland-Pfalz
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Leipzig	Sachsen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Schleswig	Schleswig-Holstein
Germany	GSK Investigational Site	Witten	Nordrhein-Westfalen
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Haidari / Athens
Greece	GSK Investigational Site	Rethymnon, Crete
Greece	GSK Investigational Site	Thessaloniki
Greece	GSK Investigational Site	Thessaloniki
Greece	GSK Investigational Site	Thessaloniki
Italy	GSK Investigational Site	Bari	Puglia
Italy	GSK Investigational Site	Chieti	Abruzzo
Italy	GSK Investigational Site	Firenze	Toscana
Italy	GSK Investigational Site	Foggia	Puglia
Italy	GSK Investigational Site	Parma	Emilia-Romagna
Italy	GSK Investigational Site	Pisa	Toscana
Italy	GSK Investigational Site	Reggio Emilia	Emilia-Romagna
Netherlands	GSK Investigational Site	Amsterdam
Netherlands	GSK Investigational Site	Breda
Netherlands	GSK Investigational Site	Leeuwarden
Netherlands	GSK Investigational Site	Leiden
Netherlands	GSK Investigational Site	Rotterdam
Norway	GSK Investigational Site	Bergen
Norway	GSK Investigational Site	Oslo
Norway	GSK Investigational Site	Stavanger
Norway	GSK Investigational Site	Trondheim
Peru	GSK Investigational Site	Lima
Peru	GSK Investigational Site	Lima
Peru	GSK Investigational Site	Lima 27	Lima
Peru	GSK Investigational Site	San Martin de Porres	Lima
Peru	GSK Investigational Site	San Miguel	Lima
Russian Federation	GSK Investigational Site	Ekaterinburg
Russian Federation	GSK Investigational Site	Irkutsk
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	Saint Petesburg
Russian Federation	GSK Investigational Site	Sestroretsk
Russian Federation	GSK Investigational Site	St. Petersburg
Russian Federation	GSK Investigational Site	Stavropol
Russian Federation	GSK Investigational Site	Voronezh
Slovakia	GSK Investigational Site	Bojnice
Slovakia	GSK Investigational Site	Sala
Slovakia	GSK Investigational Site	Spisska Nova Ves
Slovakia	GSK Investigational Site	Vrable
Spain	GSK Investigational Site	Alcorcón (Madrid)
Spain	GSK Investigational Site	Alicante
Spain	GSK Investigational Site	Barcelona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Pozuelo De Alarcón/Madrid
Spain	GSK Investigational Site	Santander
Spain	GSK Investigational Site	Santiago de Compostela
Spain	GSK Investigational Site	Valencia
Ukraine	GSK Investigational Site	Dnepropetrovsk
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Odesa
Ukraine	GSK Investigational Site	Vinnytsia
Ukraine	GSK Investigational Site	Vinnytsia
Ukraine	GSK Investigational Site	Zaporizhia
United Kingdom	GSK Investigational Site	Bradford
United Kingdom	GSK Investigational Site	Oxford
United Kingdom	GSK Investigational Site	Plymouth
United Kingdom	GSK Investigational Site	Swansea
United States	GSK Investigational Site	Aventura	Florida
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Birmingham	Alabama
United States	GSK Investigational Site	Cincinnati	Ohio
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Durham	North Carolina
United States	GSK Investigational Site	Fresno	California
United States	GSK Investigational Site	Gastonia	North Carolina
United States	GSK Investigational Site	Long Beach	California
United States	GSK Investigational Site	New Haven	Connecticut
United States	GSK Investigational Site	Newport Beach	California
United States	GSK Investigational Site	Orangeburg	South Carolina
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Rapid City	South Dakota
United States	GSK Investigational Site	Richmond	Virginia
United States	GSK Investigational Site	Riverside	California
United States	GSK Investigational Site	Rochester	Minnesota
United States	GSK Investigational Site	Rochester	New York
United States	GSK Investigational Site	Rolling Hills Estates	California
United States	GSK Investigational Site	Salt Lake City	Utah
United States	GSK Investigational Site	Upland	Pennsylvania
United States	GSK Investigational Site	Upland	California
United States	GSK Investigational Site	Williamsburg	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Bulgaria,  Canada,  Czechia,  Estonia,  France,  Germany,  Greece,  Italy,  Netherlands,  Norway,  Peru,  Russian Federation,  Slovakia,  Spain,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change From Baseline (BL) in St. George's Respiratory Questionnaire (SGRQ) Score at Week 24	SGRQ consisted of 50 questions (scored from 0 to 100 where 0 indicates best and 100 indicates worst health) designed to measure Quality of Life in par. with diseases of airway obstruction, measuring symptoms, impact, and activity. Questions were completed by the par. with a recall over the past 4 weeks. SGRQ Total Score was calculated by summing the pre-assigned weights of answers, dividing by the sum of the maximum weights for items in SGRQ and multiplying by 100 to get a %. Change from BL in SGRQ was calculated as value at Week 24 minus value at BL for each par. and was analyzed using mixed model repeated measures allowing for covariates of BL value, region, BL maintenance oral corticosteroid (OCS) therapy, exacerbations in the year prior to the study (as an ordinal variable), BL % predicted FEV1 and visit, plus interaction terms for visit by BL and visit by treatment group. Modified Intent-to-Treat (mITT) Population consisted of all randomized par. who received >= 1 dose of drug.	Baseline and Week 24
Secondary	Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Week 24	FEV1 is the volume of air that can be forced out in one second after taking a deep breath. The change from Baseline in pre-bronchodilator FEV1 was calculated as the value at Week 24 minus the value at Baseline for each subject and was analyzed using a mixed model repeated measures adjusting for Baseline absolute pre-bronchodilator FEV1, region, Baseline maintenance OCS therapy, exacerbations in the year prior to the study and visit, plus interaction terms for visit by Baseline and visit by treatment group.	Baseline and Week 24
Secondary	Percentage of Participants Achieving a 4 Point or Greater Reduction From Baseline in SGRQ Score at Week 24	The percentage of participants achieving a 4 point or greater reduction from Baseline in SGRQ (scored from 0-100 with lower scores indicating better outcome) at Week 24 was compared between treatment groups using a logistic regression model with covariates of Baseline value, region, Baseline maintenance OCS therapy, exacerbations in the year prior to the study (as an ordinal variable) and Baseline % predicted FEV1.	Baseline (Visit 2-latest pre-dose assessment) and Week 24
Secondary	Mean Change From Baseline in Asthma Control Questionnaire (ACQ-5) Score at Week 24	The ACQ-5 is a five-item questionnaire, designed to be self-completed by the participants. ACQ-5 score is the mean score of 5 questions, each assessed on a 0-6 point scale to give a mean ranging between 0-6 with lower scores indicating better outcome. The five questions inquired about the frequency and/or severity of symptoms over the previous week. The response options for all these questions consisted of a zero (no impairment/limitation) to six (total impairment/limitation) scale. The mean change from Baseline was calculated as the value at Week 24 minus the Baseline value for each participant and analyzed using a mixed model repeated measures allowing for covariates of Baseline value, region, Baseline maintenance OCS therapy, exacerbations in the year prior to the study (as an ordinal variable), Baseline % predicted FEV1 and visit, plus interaction terms for visit by Baseline and visit by treatment group.	Baseline and Week 24

External Links

•   Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.