Study Investigators/Centers: GSK sponsored studies MEA112997, MEA115588, and MEA and a proof of concept investigator sponsored study CRT110184

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1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. GSK Medicine: Mepolizumab Study Number: Title: Meta-Analysis Plan for GSK sponsored studies MEA112997, MEA115588, and MEA and a proof of concept investigator sponsored study CRT of Mepolizumab (SB240563) in Severe Asthma Additional analysis to assess exacerbation rates and eosinophilic thresholds. Rationale: Meta-analyses of data from clinical studies of mepolizumab to investigate the effect of mepolizumab compared to placebo on the rate of relatively rare events of exacerbations requiring hospitalisation/emergency department (ED) visits and exacerbations requiring hospitalisation alone, and to investigate the relationship between efficacy endpoints and blood eosinophils in subjects with severe eosinophilic asthma. Study Period: 16 April 2015 to 03 July 2015 Objectives: The meta-analyses were conducted to generate estimates of the effect of mepolizumab on exacerbations requiring hospitalisation/ed visits and exacerbations requiring hospitalisation alone. Exacerbations requiring hospitalization/ed visits are serious for subjects, but are difficult to study in a single randomised controlled clinical trial as they occur relatively infrequently. The meta-analysis also investigated the relationship between efficacy endpoints and baseline blood eosinophils providing further information on the relationship between specific baseline blood eosinophils thresholds and the effects of treatment with mepolizumab. Indication: Severe Asthma Study Investigators/Centers: GSK sponsored studies MEA112997, MEA115588, and MEA and a proof of concept investigator sponsored study CRT Research Methods: These meta-analyses were conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Studies were identified using a search strategy on PubMed of ("clinical trial"[publication Type] AND (mepolizumab[title]) AND (asthma[title]) and a search on the GSK clinical trial register of mepolizumab and asthma. Clinicaltrials.gov was also searched to find any completed, unpublished studies that met the inclusion criteria. These searches were carried out in May Selection criteria for the meta-analyses of exacerbations requiring hospitalisations and exacerbations requiring hospitalisation/ed visits were: Placebo controlled studies of mepolizumab in severe eosinophilic asthma and duration of at least 24 weeks that involved at least six doses of the study drug. Four studies met the selection criteria (MEA112997, MEA115588, MEA and CRT110184). Selection criteria for the meta-analyses investigating the relationship between efficacy endpoints and blood eosinophils were: Placebo-controlled studies of mepolizumab in severe eosinophilic asthma; duration 32 weeks; maintenance oral corticosteroid (OCS) use kept constant; and analysis of blood samples using a central laboratory. Two studies met the selection criteria (MEA and MEA115588). All analyses were post-hoc, all doses of mepolizumab were combined for comparison with placebo. Data Source: Meta-analysis of exacerbations requiring hospitalisation/emergency department (ED) visits and exacerbations requiring hospitalisation alone was based on published results and GSK clinical study reports, some 1

2 information for study CRT was obtained from the relevant investigating centre. The meta-analysis investigating the relationship between efficacy endpoints and baseline blood eosinophils used individual subject data from GSK clinical trial databases. Study Design: Meta-analysis of data from clinical studies of mepolizumab in severe asthma to investigate 1) the effect of mepolizumab on the rates of exacerbations requiring hospitalisation/ed visits and exacerbations requiring hospitalisation alone, and 2) the relationship between efficacy endpoints and blood eosinophils. The individual studies selected for inclusion into each meta-analysis were as follows: MEA112997: A Phase IIb/III placebo controlled study which evaluated mepolizumab given for 52 weeks across a range of IV doses (75mg, 2mg and 7mg); MEA115588: A Phase III placebo controlled study which evaluated a 75mg IV dose and a 100mg SC dose of mepolizumab given for 32 weeks; MEA115575: A placebo controlled study which evaluated a 100mg SC dose over 24 weeks; CRT : A placebo controlled study which evaluated a 7mg IV dose over one year. Study Population: The majority of the key inclusion criteria for the individual studies selected for inclusion into the meta-analyses were similar: subjects of 12 years in all studies except CRT ( 18 years); Subjects required to have 2 exacerbations requiring corticosteroid treatment in previous year in all but MEA (where use of maintenance oral corticosteroids (OCS) was required). All subjects were required to have historical (past 12 months) or baseline evidence of eosinophilic asthma. Studies MEA and MEA required historical blood eosinophil count 300 cells/µl ora baseline blood eosinophil count 1 cells/µl.definition of eosinophilic asthma in MEA11297 was not confined to peripheral blood eosinophil levels; CRT used sputum eosinophils to define eosinophilic asthma. Study Exposures, Outcomes: The following doses of mepolizumab were included in the comparison of all doses mepolizumab vs placebo: MEA112997: 75mg, 2mg and 7mg IV; MEA115588: 75mg IV and a 100mg; MEA115575: 100mg SC; CRT110184: 7mg IV. The efficacy endpoints considered for the meta-analyses were clinically significant exacerbations, exacerbations requiring hospitalisation/ed visits and exacerbations requiring hospitalisation. Data Analysis Methods: Meta-analysis of relative rates of exacerbations was performed using the inverse variance fixed effects method to combine estimated rate ratios and standard errors from each individual study. Meta-analysis of relative risks for the proportion of subjects with at least one exacerbation was performed using Mantel-Haenszel methods. All outcomes were reported with 95% confidence intervals (CI). Statistical heterogeneity was tested with the I 2 statistic, with I 2 % indicating no significant heterogeneity. The subgroup analysis of exacerbations by baseline blood eosinophil threshold was performed using a separate negative binomial regression model for each blood eosinophil threshold, with covariates of treatment group (placebo versus mepolizumab), region, baseline maintenance OCS (OCS versus no OCS), baseline % predicted prebronchodilator FEV1 (continuous 0 100%), number of exacerbations in the year prior to the study (as an ordinal variable (2, 3, 4+) and study. All analyses were post-hoc and were based on the Intent-To-Treat (ITT) population, including all randomized subjects who received at least one dose of study medication.. Limitations: MEA was a steroid sparing study, exacerbation events may have been induced by a reduction in steroid dose in this study rather than being spontaneous as in the other studies. The maximum duration of treatment in all studies was 1 year, a relatively short period within which to capture data on rare events such as exacerbation requiring hospitalisation. 2

3 Endpoints: The primary endpoints for the meta-analyses of exacerbations requiring hospitalisations and hospitalisation/ed visits were the rate of exacerbations requiring hospitalisation/ed and rate of exacerbations requiring hospitalisation alone. The primary comparison of interest was all doses of mepolizumab compared to placebo from studies MEA112997, MEA115588, MEA and CRT The primary endpoint for the meta-analyses investigating the relationship between efficacy endpoints and blood eosinophils was the rate of clinically significant exacerbations. Clinically significant exacerbations were defined as worsening of asthma that required the use of systemic corticosteroids and/or hospitalization and/or ED visit. Asthma exacerbations reported from the start of treatment until completion of study or up to withdrawal (but 4 weeks after the last dose of study medication) were included in the analysis. Asthma exacerbations separated by <7 days were considered a continuation of the same exacerbation. Hospitalization included intensive care unit admission and intubation. 3

4 Study Results: Table 1 Subject characteristics from studies MEA112997, MEA115588, MEA and CRT (ITT Population) Characteristic Age, years (range) Asthma duration, years On maintenance OCS, n (%) Prebronchodilator FEV1, % predicted Prebronchodilator FEV1:FVC ratio, % Postbronchodilator FEV1, % predicted Postbronchodilator FEV1:FVC ratio, % Baseline blood eosinophil count, x10 9 /L Exacerbations in year prior to study start Exacerbations requiring admission in year prior to study start, n (%) 75 IV (n=153) (23 69) MEA (N=616) MEA (N=576) Mepo Placebo Mepo Placebo 2 IV (n=152) 49 (15 74) 7 IV (n=156) 49 (19 69) (n=155) 46 (20 68) 75 IV (n=191) (13 82) 100 SC (n=194) 51 (12 81) (n=191) 49 (12 76) 19 (14) 20 (14) 19 (15) 18 (14) 20 (14) 21 (13) 20 (15) 46 (30) (33) 47 (30) 45 (29) 48 (25) 52 (27) 44 (23) 60 (16) 59 (17) 61 (16) 59 (15) 61 (18) 59 (18) 62 (18) 64 (11) 63 (13) 63 (13) 63 (12) 64 (13) 63 (13) 64 (13) 71 (18) 71 (17) 70 (18) 71 (18) 71 (19) 70 (18) 72 (17) 68 (12) 66 (13) 68 (20) 67 (12) 67 (13) 66 (13) 67 (12) 0.25 (0.95) 3.7 (3.1) 0.23 (1.20) 3.4 (2.4) 0.25 (0.93) 3.5 (2.8) 0.28 (1.01) 3.7 (3.8) 0.28 (0.99) 3.5 (2.2) 0.29 (1.05) 3.8 (2.7) 0.32 (0.94) 3.6 (2.8) 35 (23) 36 (24) 39 (25) 40 (26) 41 (21) 33 (17) 35(18) Unless specified, values are means; *N=28; geometric mean (Loge SD); geometric mean (Log10 SD); rate per subject; based on any admissions to the intensive care unit before the study. FEV1, forced expiratory volume in one second; FVC, forced vital capacity; IV, intravenous; Mepo; mepolizumab; OCS, oral corticosteroids; SC, subcutaneous; SD, standard deviation. 4

5 Study Results (continued): Table 1 continued Subject characteristics from studies MEA112997, MEA115588, MEA and CRT (ITT Population) Characteristic Age, years (range) MEA (N=135) CRT (N=61) Mepo Placebo Mepo Placebo 100 SC (n=69) (16 74) (n=66) (28 70) 7 IV (n=29) 48 (21 63) (n=32) (24 72) Asthma duration, years 17 (12) 20 (14) 20 (16) 22 (15) On maintenance OCS, n (%) 69 (100) 66 (100) 16 (57*) 17 (53) Prebronchodilator FEV1, % predicted 60 (17) 58 (19) 75 (22) 72 (20) Prebronchodilator FEV1:FVC ratio, % 63 (12) 61 (12) 69 (11) 66 (12) Postbronchodilator FEV1, % predicted 72 (20) 68 (21) 78 (21) 78 (24) Postbronchodilator FEV1:FVC ratio, % 67 (13) 64 (13) 72 (10) 68 (14) Baseline blood eosinophil count, x10 9 /L Exacerbations in year prior to study start Exacerbations requiring admission in year prior to study start, n (%) 0.25 (1.25) 0.23 (1.00) 0.32 (0.38) 0.35 (0.30) 3.3 (3.4) 2.9 (2.8) (20) 9 (14) 8 (28) 10 (31) Unless specified, values are means; *N=28; geometric mean (Loge SD); geometric mean (Log10 SD); rate per subject; based on any admissions to the intensive care unit before the study. FEV1, forced expiratory volume in one second; FVC, forced vital capacity; IV, intravenous; Mepo; mepolizumab; OCS, oral corticosteroids; SC, subcutaneous; SD, standard deviation. 5

6 Study Results (continued): Table 2 Results of meta-analysis of exacerbations requiring hospitalization or hospitalization/ed visit (ITT Population) Study Subjects (n) Relative Rate (95% CI) I 2 (95% CI) Placebo Mepolizumab (All Doses) Exacerbations requiring hospitalisation+ MEA (0.29, 1.00) MEA (0.19, 1.02) CRT (0.03, 2.61) Combined (0.30, 0.80) 0% (0%, 53%) Exacerbations requiring hospitalisation/ed visit++ MEA (0.29, 0.85) MEA (0.28, 0.96) MEA (0.09, 1.40) Combined (0.33, 0.73) 0% (0%, 22%) + Study MEA not included in analysis - no hospitalisations in mepolizumab 100mg SC arm ++ Study CRT not included in analysis - no data available regarding emergency department visits Table 3 Percentage reduction in exacerbation rate stratified by baseline blood eosinophil counts (ITT Population) % reduction in exacerbations mepolizumab all doses vs placebo (rate ratio [95% CI]) Baseline blood eosinophils (cells/µl) MEA N=616 MEA115588* N=569 Combined N=1185* Baseline blood eosinophil count, cells/µl 1 54 (0 46 [0 35, 0 60]) (n=467) (0 42 [0 31, 0 56]) (n=302) (0.32 [0.23, 0.46]) (n=213) 0 73 (0.27 [0.19, 0.39]) (n=164) 53 (0 47 [0 35, 0 63]) (n=453) 61 (0 39 [0 28, 0 55]) (n=308) 68 (0.32 [0.22, 0.46]) (n=248) 73 (0.27 [0.18, 0.41]) (n=190) *7 subjects had missing baseline eosinophils in MENSA; CI, confidence interval; ITT, intent to treat 52 (0 48 [0 39, 0 58]) (n=920) 59 (0 41 [0 33, 0 51]) (n=610) 66 (0.34 [0.27, 0.44]) (n=461) 70 (0.30 [0.23, 0.40]) (n=354) 6

7 Conclusion: Treatment with mepolizumab (all doses) resulted in an approximate % reduction in the frequency of exacerbations requiring hospitalisation and/or ED visits compared with placebo in subjects with severe eosinophilic asthma, addressing a high unmet need in this patient population. Mepolizumab also approximately halved clinically significant exacerbations in subjects with the pre-specified baseline blood eosinophil threshold of 1 cells/μl and a positive association in the exacerbation rate-reduction was shown with increasing blood eosinophil count at baseline. The analyses of endpoints by baseline blood eosinophil levels confirmed that the threshold of 1 cells/µl at baseline is adequate to identify the severe asthma phenotype most likely to benefit from mepolizumab treatment. References: 1 Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012; 380: Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, Humbert M, Katz LE, Keene ON, Yancey SW, Chanez P. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med 2014; 371: Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, Ortega HG, Pavord ID. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371: Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360: