Bhabita Mayer

Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura : a randomised, double-blind, placebo-controlled trial

BACKGROUND Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg. METHODS In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per muL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per microL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per microL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739. FINDINGS 73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts >/=50 000 per microL; odds ratio [OR] 9.61 [95% CI 3.31-27.86]; p<0.0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0.49 [95% CI 0.26-0.89]; p=0.021). The frequency of grade 3-4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups. INTERPRETATION Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP.

Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies

BACKGROUND Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma. To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies, stratifying patients by different baseline blood eosinophil thresholds. METHODS We did a post-hoc analysis of data, which was completed on Sept 25, 2015, from two randomised, double-blind, placebo-controlled studies of at least 32 weeks duration (NCT01000506 [DREAM] and NCT01691521 [MENSA]) done between 2009 and 2014. In these studies, mepolizumab ( DREAM 75 mg, 250 mg, or 750 mg intravenously; MENSA: 75 mg intravenously or 100 mg subcutaneously) versus placebo was given at 4-week intervals in addition to standard care (high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids) to patients aged 12 years or older with a clinical diagnosis of asthma, a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment, and evidence of eosinophilic airway inflammation. The primary endpoint in both studies was the annual rate of clinically significant exacerbations (defined as worsening of asthma that required the use of systemic corticosteroids, or admission to hospital, or an emergency-room visit, or a combination of these occurrences). In our analysis, the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts (≥150 cells per μL, ≥300 cells per μL, ≥400 cells per μL, and ≥500 cells per μL) and baseline blood eosinophil ranges (<150 cells per μL, ≥150 cells per μL to <300 cells per μL, ≥300 cells per μL to <500 cells per μL, and ≥500 cells per μL). We based our analysis on the intention-to-treat populations of the two original studies, and all mepolizumab doses were combined for analysis. FINDINGS Of 1192 patients, 846 received mepolizumab and 346 received placebo. The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab (47% reduction; rate ratio [RR] 0·53, 95% CI 0·44-0·62; p<0·0001). The exacerbation rate reduction with mepolizumab versus placebo increased progressively from 52%; 0·48, 0·39-0·58) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70%; 0·30, 0·23-0·40]) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL, predicted efficacy of mepolizumab was reduced. INTERPRETATION Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations. We noted clinically relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline. The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab. FUNDING GlaxoSmithKline.

Mepolizumab for Eosinophilic Chronic Obstructive Pulmonary Disease

BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype may benefit from treatment with mepolizumab, a monoclonal antibody directed against interleukin‐5. METHODS We performed two phase 3, randomized, placebo‐controlled, double‐blind, parallel‐group trials comparing mepolizumab (100 mg in METREX, 100 or 300 mg in METREO) with placebo, given as a subcutaneous injection every 4 weeks for 52 weeks in patients with COPD who had a history of moderate or severe exacerbations while taking inhaled glucocorticoid‐based triple maintenance therapy. In METREX, unselected patients in the modified intention‐to‐treat population with an eosinophilic phenotype were stratified according to blood eosinophil count (≥150 per cubic millimeter at screening or ≥300 per cubic millimeter during the previous year). In METREO, all patients had a blood eosinophil count of at least 150 per cubic millimeter at screening or at least 300 per cubic millimeter during the previous year. The primary end point was the annual rate of moderate or severe exacerbations. Safety was also assessed. RESULTS In METREX, the mean annual rate of moderate or severe exacerbations in the modified intention‐to‐treat population with an eosinophilic phenotype (462 patients) was 1.40 per year in the mepolizumab group versus 1.71 per year in the placebo group (rate ratio, 0.82; 95% confidence interval [CI], 0.68 to 0.98; adjusted P=0.04); no significant between‐group differences were found in the overall modified intention‐to‐treat population (836 patients) (rate ratio, 0.98; 95% CI, 0.85 to 1.12; adjusted P>0.99). In METREO, the mean annual rate of moderate or severe exacerbations was 1.19 per year in the 100‐mg mepolizumab group, 1.27 per year in the 300‐mg mepolizumab group, and 1.49 per year in the placebo group. The rate ratios for exacerbations in the 100‐mg and 300‐mg mepolizumab groups versus the placebo group were 0.80 (95% CI, 0.65 to 0.98; adjusted P=0.07) and 0.86 (95% CI, 0.70 to 1.05; adjusted P=0.14), respectively. A greater effect of mepolizumab, as compared with placebo, on the annual rate of moderate or severe exacerbations was found among patients with higher blood eosinophil counts at screening. The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS Mepolizumab at a dose of 100 mg was associated with a lower annual rate of moderate or severe exacerbations than placebo among patients with COPD and an eosinophilic phenotype. This finding suggests that eosinophilic airway inflammation contributes to COPD exacerbations. (Funded by GlaxoSmithKline; METREX and METREO ClinicalTrials.gov numbers, NCT02105948 and NCT02105961.)

Repeated short-term use of eltrombopag in patients with chronic immune thrombocytopenia (ITP)

Eltrombopag is a thrombopoietin‐receptor agonist that stimulates platelet production and increases platelet counts in patients with chronic immune thrombocytopenia (ITP). This open‐label, single‐arm study evaluated consistency of response and safety following repeated intermittent dosing of eltrombopag 50 mg daily over 3 cycles (1 cycle = up to 6 weeks on therapy followed by up to 4 weeks off therapy). The primary endpoint was proportion of patients with a response (platelet count ≥50 × 109/l and ≥2× baseline) in Cycle 1 who subsequently responded in Cycle 2 or 3. Fifty‐two of 65 evaluable patients (80%) responded in Cycle 1; these responding patients comprised the primary analysis population. Of these, 45/52 (87%) responded in Cycle 2 or 3 [95% confidence interval (CI), 74–94%] and 34/48 (71%; 95% CI, 56–83%) responded in both Cycles 2 and 3. Time to response was consistent, with >50% of responders responding by Day 8 in each cycle. Bleeding rates relative to baseline decreased by approximately 50% during each treatment cycle. The frequency or severity of adverse events, most commonly headache, did not increase over successive cycles. If a chronic ITP patient not requiring consistent therapy responds to short‐term eltrombopag, then subsequent courses of eltrombopag, as needed, are likely to be safe and effective.

Meta-analysis of asthma-related hospitalization in mepolizumab studies of severe eosinophilic asthma.

Background: Studies show that mepolizumab can reduce the frequency of clinically significant exacerbations in patients with severe eosinophilic asthma, compared with placebo. However, important events such as hospitalizations and emergency room visits are rare and difficult to characterize in single studies. Objective: We sought to compare hospitalization or hospitalization and/or emergency room visit rates in patients with severe eosinophilic asthma treated with mepolizumab or placebo in addition to standard of care for at least 24 weeks. Methods: This study was conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta‐Analyses statement. PubMed and the GSK Clinical Study Register were searched for suitable studies. The primary end points were the rate of exacerbations requiring hospitalization and the rate of exacerbations requiring hospitalization/emergency room visit. The proportion of patients with 1 or more event was also assessed. All mepolizumab doses were combined and individual patient‐level data were analyzed. Results: Four studies (n = 1388) were eligible for inclusion. Mepolizumab significantly reduced the rate of exacerbations requiring hospitalization (relative rate, 0.49; 95% CI, 0.30‐0.80; P = .004) and hospitalization/emergency room visit (relative rate, 0.49; 95% CI, 0.33‐0.73; P < .001) versus placebo. Significant reductions of 45% and 38% were also observed for the proportion of patients experiencing 1 or more hospitalization and hospitalization and/or emergency room visit, respectively. Conclusions: Mepolizumab approximately halved exacerbations requiring hospitalization and/or emergency room visits compared with placebo in patients with severe eosinophilic asthma. This treatment addresses a key outcome in a patient population with a high unmet need (GSK Study 204664).

Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study

Preventing chemotherapy‐induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine‐based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 109/L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days −5 to −1 and days 2–6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 109/L, respectively. Mean platelet nadirs across cycles 2–6 were 115 × 109/L and 143 × 109/L for eltrombopag‐treated patients versus 53 × 109/L and 103 × 109/L for placebo‐treated patients in Groups A and B, respectively. No dose‐limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose‐escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3–6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.

Validation of a guideline-based composite outcome assessment tool for asthma control

BackgroundA global definition of asthma control does not currently exist. The purpose of this study was to validate two new guideline-based composite measures of asthma control, defined as totally controlled (TC) asthma and well controlled (WC) asthma.MethodsWe used data from 3416 patients randomised and treated in the multi-centre Gaining Optimal Asthma controL (GOAL) study. The criteria comprising the asthma control measures were based on Global Initiative for Asthma/National Institutes of Health guidelines. This validation study examined the measurement properties of the asthma control measures using data from run-in, baseline, 12 and 52 weeks. Forced expiratory volume in 1 second (FEV1) and the Asthma Quality of Life Questionnaire (AQLQ) were used as the reference criteria in the validation analysis.ResultsBoth measures had good discriminative ability showing significant differences in FEV1 and AQLQ scores between control classification both cross-sectionally and longitudinally (p < 0.001). Overall both of the composite measures accounted for more of the variance in FEV1 after 52 weeks than the individual components of each asthma control measure. Both of the reference criteria were independently related to each asthma control measure (p < 0.0001). The measures also had good predictive validity showing significant differences in FEV1 and AQLQ scores at 52 weeks by control classification at 12 weeks (p < 0.0001).ConclusionThe guideline-based composite asthma control measures of WC asthma and TC asthma have good psychometric properties and are both valid functional indices of disease control in asthma.

Reproducibility of a Single Blood Eosinophil Measurement as a Biomarker in Severe Eosinophilic Asthma

Recently there has been interest in characterizing eosinophilic inflammation in asthma. Clinical trials of biological agents for the treatment of asthma have explored the use of a single blood eosinophil measurement as an inclusion criterion and potential biomarker to identify patients with severe eosinophilic asthma (1, 2). When using biomarkers, clinical decisions are generally based on whether an individual result is greater than or less than a chosen cut point for the biomarker. Low/normal values are interpreted as indicating the absence of clinically important underlying disease activity (e.g., inflammation). Abnormally high values indicate its presence. However, it is important to know the performance characteristics that apply for a particular cut point and to adjust expectations of the test accordingly. As a result of diurnal and compartment variation (blood vs. tissue), the short half-life of eosinophils, and the sensitivity to external factors (e.g., allergen exposure, corticosteroid use), fluctuations in the blood eosinophil count may occur. Accordingly, we set out to determine the reproducibility of a single blood eosinophil count as a biomarker, using data previously derived from one, and now from a second of two, recently published multicenter clinical trials of mepolizumab treatment for severe eosinophilic asthma. For our post hoc analyses of both clinical trials, we modeled (on the log scale) postscreening blood eosinophil measurements, using a repeated measures model with fixed covariates of visit, screening blood eosinophil measurement, and an interaction term for visit by screening measurement. The geometric mean of the modeled postscreening measurements was plotted against the screening value for each subject to examine how well the screening measurement matched the post-screening average. We then examined the use of a single blood eosinophil measure compared with using the average of repeated 4-weekly consecutive eosinophil measurements. We previously reported (3) that in patients who received placebo (N = 115) in the Dose Ranging Efficacy and Safety with Mepolizumab in Severe Asthma (DREAM) study (4) (ClinicalTrials.gov NCT01000506) with eosinophils 150 cells/ml or greater at screening, 85% of patients remained above this level, on average, for post-screening measurements obtained over the subsequent 56 weeks (Figure 1A). Using blood samples from patients with an average of 150 cells/ml or greater from two, three, or four measurements, 85%, 90%, and 92% had a post-screening average eosinophil count above 150 cells/ml, respectively (Figure 2, blue bars). In the present study, we analyzed data derived from the Efficacy and Safety Study of Mepolizumab Adjunctive Therapy in Subjects with Severe Uncontrolled Refractory Asthma (MENSA) study (1) (ClinicalTrials.gov NCT01691521). Here, we report on 188 patients at screening who received placebo and had a blood eosinophil count of 150 cells/ml or greater (167 [89%] of 188 patients). Of the 167 patients, 143 (86%) had an average of 150 cells/ml or greater in the following 8 months (Figure 1B). Using the average of two, three, or four measurements (each taken 4 wk apart), of the patients with an average of 150 cells/ml or greater, 138 (88%), 140 (88%), and 139 (89%), respectively, have averages

Efficacy of eltrombopag in management of bleeding symptoms associated with chronic immune thrombocytopenia.

Bleeding is of particular clinical importance in the management of chronic immune thrombocytopenia (ITP), which involves impaired platelet production and accelerated destruction. We report the first comprehensive analysis of the impact of eltrombopag on bleeding in five clinical studies of adult chronic ITP: two 6-week phase 2 (TRA100773A) and phase 3 (TRA100773B) studies; a 6-month phase 3 study (RAISE); a phase 2 repeat-dose study (REPEAT); and a phase 3 extension study (EXTEND). Bleeding was assessed using the World Health Organization Bleeding Scale and categorized as no bleeding (grade 0), any bleeding (grades 1–4), and clinically significant bleeding (grades 2–4). Bleeding was also assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Across all studies, bleeding at baseline ranged from 50 to 73% for eltrombopag-treated patients; by week 2, bleeding had decreased, ranging from 26 to 39%. This trend was maintained throughout treatment. Similar results were observed for clinically significant bleeding. No such trend was seen in placebo-treated patients for any bleeding or clinically significant bleeding. For TRA100773B and RAISE, the odds of any bleeding across the entire treatment period were 51 and 76% lower for eltrombopag-treated versus placebo-treated patients (P = 0.021, P < 0.001). The odds of clinically significant bleeding in RAISE were 65% lower (P < 0.001). In conclusion, analysis of prospective data from five clinical studies demonstrates that eltrombopag significantly reduces bleeding in adult patients with chronic ITP.