Clinical trial NCT02281318: Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Participants With Severe Eosinophilic Asthma on Markers of Asthma Control
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: Asthma control
Lung function
Health-related quality of life
Mepolizumab
Severe Eosinophilic asthma
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-11-02
Enrollment: 556
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 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.


Eligibility criteria: 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)

Primary outcomes:
measure: Mean Change From Baseline (BL) in St. George's Respiratory Questionnaire (SGRQ) Score at Week 24
timeFrame: Baseline and Week 24
Secondary outcomes:
measure: Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Week 24
timeFrame: Baseline and Week 24
measure: Percentage of Participants Achieving a 4 Point or Greater Reduction From Baseline in SGRQ Score at Week 24
timeFrame: Baseline (Visit 2-latest pre-dose assessment) and Week 24
measure: Mean Change From Baseline in Asthma Control Questionnaire (ACQ-5) Score at Week 24
timeFrame: Baseline and Week 24
Other outcomes:
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city: Concepcion del Uruguay
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city: Rosario
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state: Santa Fe
city: Buenos Aires
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facility: GSK Investigational Site
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city: Kralupy nad Vltavou
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city: Plzen
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city: Praha 4
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city: Tallinn
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city: Tallinn
country: Estonia
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city: Tartu
country: Estonia
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city: Brest Cedex
country: France
facility: GSK Investigational Site
city: Dijon Cedex
country: France
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city: Lille cedex
country: France
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city: Lyon cedex 04
country: France
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city: Marseille cedex 20
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city: Montpellier cedex 5
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city: Nantes cedex 1
country: France
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city: Paris Cedex 18
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city: Pessac cedex
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city: Reims Cedex
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city: Bamberg
country: Germany
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state: Bayern
city: Muenchen
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state: Nordrhein-Westfalen
city: Koblenz
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state: Sachsen
city: Leipzig
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state: Sachsen
city: Schleswig
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state: Schleswig-Holstein
city: Berlin
country: Germany
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city: Berlin
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city: Berlin
country: Germany
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city: Hamburg
country: Germany
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city: Hamburg
country: Germany
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city: Athens
country: Greece
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city: Athens
country: Greece
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city: Haidari / Athens
country: Greece
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city: Rethymnon, Crete
country: Greece
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country: Greece
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country: Greece
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country: Italy
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country: Netherlands
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country: Norway
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state: Lima
city: Lima
country: Peru
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country: Peru
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country: Russian Federation
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country: Russian Federation
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country: Russian Federation
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city: Novosibirsk
country: Russian Federation
facility: GSK Investigational Site
city: Saint Petesburg
country: Russian Federation
facility: GSK Investigational Site
city: Sestroretsk
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Stavropol
country: Russian Federation
facility: GSK Investigational Site
city: Voronezh
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facility: GSK Investigational Site
city: Spisska Nova Ves
country: Slovakia
facility: GSK Investigational Site
city: Vrable
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city: Alcorcón (Madrid)
country: Spain
facility: GSK Investigational Site
city: Alicante
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Pozuelo De Alarcón/Madrid
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Dnepropetrovsk
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Odesa
country: Ukraine
facility: GSK Investigational Site
city: Vinnytsia
country: Ukraine
facility: GSK Investigational Site
city: Vinnytsia
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhia
country: Ukraine
facility: GSK Investigational Site
city: Bradford
country: United Kingdom
facility: GSK Investigational Site
city: Oxford
country: United Kingdom
facility: GSK Investigational Site
city: Plymouth
country: United Kingdom
facility: GSK Investigational Site
city: Swansea
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: Yancey SW, Ortega HG, Keene ON, Bradford ES. Efficacy of add-on mepolizumab in adolescents with severe eosinophilic asthma. Allergy Asthma Clin Immunol. 2019 Sep 3;15:53. doi: 10.1186/s13223-019-0366-x. eCollection 2019.
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 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: Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM, Trevor JL, Magnan A, Ten Brinke A. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial. Lancet Respir Med. 2017 May;5(5):390-400. doi: 10.1016/S2213-2600(17)30125-X. Epub 2017 Apr 5.