Trial Outcomes & Findings for Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Subjects With Severe Uncontrolled Refractory Asthma (NCT NCT01691521)

Last Updated: 2018-08-06

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

580 participants

Primary outcome timeframe

From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose

Results posted on

2018-08-06

Participant Flow

Par. who met the eligibility criteria at screening, entered the Run-in period for a minimum of 1 week and a maximum of 6 weeks. Par. who received all 8 doses and met the eligibility criteria were offered the opportunity to participate in an open label extension (OLE) study. Par. not entering the OLE study completed the Follow-up Visit.

A total of 802 participants (par.) were screened; 82 were Screen failures; 140 were Run-in failures; 580 were randomized, of which 576 received at least 1 dose of study drug.

Participant milestones

Participant milestones
Measure	Placebo Participants received placebo intravenously (IV) plus placebo subcutaneously (SC) every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV Participants received mepolizumab 75 milligrams (mg) IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
Overall Study STARTED	191	191	194
Overall Study COMPLETED	179	175	185
Overall Study NOT COMPLETED	12	16	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants received placebo intravenously (IV) plus placebo subcutaneously (SC) every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV Participants received mepolizumab 75 milligrams (mg) IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
Overall Study Adverse Event	4	0	1
Overall Study Lack of Efficacy	1	1	2
Overall Study Protocol Violation	0	3	0
Overall Study Lost to Follow-up	0	2	2
Overall Study Physician Decision	2	1	0
Overall Study Withdrawal by Subject	5	9	4

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=191 Participants Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV n=191 Participants Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC n=194 Participants Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Total n=576 Participants Total of all reporting groups
Age, Continuous	49.2 Years STANDARD_DEVIATION 14.26 • n=5 Participants	50.0 Years STANDARD_DEVIATION 14.03 • n=7 Participants	51.2 Years STANDARD_DEVIATION 14.55 • n=5 Participants	50.1 Years STANDARD_DEVIATION 14.28 • n=4 Participants
Sex: Female, Male Female	107 Participants n=5 Participants	106 Participants n=7 Participants	116 Participants n=5 Participants	329 Participants n=4 Participants
Sex: Female, Male Male	84 Participants n=5 Participants	85 Participants n=7 Participants	78 Participants n=5 Participants	247 Participants n=4 Participants
Race/Ethnicity, Customized African American/African Heritage	3 Participants n=5 Participants	6 Participants n=7 Participants	7 Participants n=5 Participants	16 Participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	15 Participants n=5 Participants	15 Participants n=7 Participants	15 Participants n=5 Participants	45 Participants n=4 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	18 Participants n=5 Participants	17 Participants n=7 Participants	17 Participants n=5 Participants	52 Participants n=4 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	4 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	6 Participants n=4 Participants
Race/Ethnicity, Customized White - Arabic/North African Heritage	4 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	11 Participants n=4 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	144 Participants n=5 Participants	148 Participants n=7 Participants	148 Participants n=5 Participants	440 Participants n=4 Participants
Race/Ethnicity, Customized Mixed Race	2 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants

PRIMARY outcome

Timeframe: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose

Population: Modified Intent-to-Treat (ITT) Population: all participants who were randomized and who received at least one dose of trial medication. 'Modified' implies that, in cases where there is is a discrepancy between randomized and actual treatment the analysis used the actual treatment received by the participant rather than the randomized treatment.

Outcome measures

Outcome measures
Measure	Placebo n=191 Participants Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV n=191 Participants Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC n=194 Participants Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
Number of Clinically Significant Exacerbations of Asthma Per Year	1.74 Number of exacerbations per year	0.93 Number of exacerbations per year	0.83 Number of exacerbations per year

SECONDARY outcome

Timeframe: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose

Population: ITT Population

Outcome measures

Outcome measures
Measure	Placebo n=191 Participants Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV n=191 Participants Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC n=194 Participants Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an Intensive Care Unit [ICU]) or ED Visits Per Year	0.20 Number of exacerbations per year	0.14 Number of exacerbations per year	0.08 Number of exacerbations per year

SECONDARY outcome

Timeframe: From randomization (Week 0) to Week 32 or if Early Withdrawal (EW) 4 weeks post last dose

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	Placebo n=191 Participants Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV n=191 Participants Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC n=194 Participants Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
Number of Clinically Significant Exacerbations Requiring Hospitalization (Including Intubation and Admittance to an ICU) Per Year	0.10 Number of exacerbations per year	0.06 Number of exacerbations per year	0.03 Number of exacerbations per year

SECONDARY outcome

Timeframe: Baseline, Week 32

Population: ITT Population. Only participants with a Baseline FEV1 available and at least one post-Baseline FEV1 measurement were analyzed.

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.

Outcome measures

Outcome measures
Measure	Placebo n=189 Participants Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV n=188 Participants Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC n=192 Participants Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
Mean Change From Baseline in Clinic Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 32	86 Milliliters (mL) Standard Error 31.4	186 Milliliters (mL) Standard Error 31.5	183 Milliliters (mL) Standard Error 31.1

SECONDARY outcome

Timeframe: Baseline, Week 32

Population: ITT Population. Note that only participants with a Baseline and Week 32 assessment were included in the analysis.

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.

Outcome measures

Outcome measures
Measure	Placebo n=177 Participants Participants received placebo IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 75 mg IV n=174 Participants Participants received mepolizumab 75 mg IV plus placebo SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.	Mepolizumab 100 mg SC n=184 Participants Participants received placebo IV plus mepolizumab 100 mg SC every 4 weeks (for a total of 8 doses), with the last dose at Week 28. The SC dose and the IV dose were administered into separate arms. A topical anaesthetic was permitted at the injection site to minimize discomfort, as needed. Rescue personnel and rescue medications (salbutamol/albuterol) /equipment were available throughout the study.
Mean Change From Baseline in the St. George's Respiratory Questionnaire Total Score at Week 32	-9.0 Scores on a scale Standard Error 1.16	-15.4 Scores on a scale Standard Error 1.16	-16.0 Scores on a scale Standard Error 1.13

Adverse Events

Placebo

Serious events: 27 serious events

Other events: 143 other events

Deaths: 0 deaths

Mepolizumab 75 mg IV

Serious events: 14 serious events

Other events: 142 other events

Deaths: 0 deaths

Mepolizumab 100 mg SC

Serious events: 16 serious events

Other events: 132 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER