固定剂量皮下注射reslizumab对重度非控制性哮喘患者哮喘急性发作和口服激素依赖性哮喘患者皮质类固醇剂量的影响：来自
2020/03/11
固定剂量皮下注射reslizumab对重度非控制性哮喘患者哮喘急性发作和口服激素依赖性哮喘患者皮质类固醇剂量的影响：来自两个3期随机双盲安慰剂对照试验的结果
摘要
背景：静脉注射Reslizumab 3 mg/kg可用于治疗难治性嗜酸性粒细胞性哮喘。我们评估了两个试验中皮下注射Reslizumab 110 mg治疗未控制难治性哮喘和血嗜酸性粒细胞增多患者的安全性和有效性。目的是确定皮下注射Reslizumab 110mg是否能降低这些患者的急性发作率（研究1）或降低激素依赖性哮喘患者的维持性口服皮质类固醇剂量（研究2）。
方法：两项研究均为随机、双盲、安慰剂对照的3期研究。研究1的进入标准是：不受控制的难治性哮喘、前一年两次或两次以上的哮喘急性发作、血液嗜酸性粒细胞计数为300个细胞/μL或更多（包括不超过30%的嗜酸性粒细胞计数<400个细胞/μL的患者），以及至少使用中等剂量的吸入皮质类固醇和一个或多个额外的哮喘控制性药物。研究2的患者患有严重哮喘，血嗜酸性粒细胞计数为300个/μL或更高，每日维持口服皮质类固醇（强的松5-40 mg或等效物），以及高剂量吸入皮质类固醇和另一控制性药物。在研究1和研究2中，患者被随机分配（1:1）给皮下注射reslizumab（110 mg）或安慰剂，每4周一次，持续52周。患者和研究人员在治疗任务中双盲。主要疗效结果是研究1中52周的急性发作频率和研究2中从基线到20-24周每日口服皮质类固醇剂量的百分比减少程度。主要疗效分析是通过意向性治疗分析，安全性分析包括所有接受至少一剂研究治疗的患者。这些研究在ClinicalTrials.gov、NCT 02452190（研究1）和NCT 02501629（研究2）中注册。
结果：在2015年8月12日至2018年1月31日期间，研究1中468名患者被随机分配到安慰剂组（n=232）或皮下注射Reslizumab组（n=236），研究2中177名患者被随机分配到安慰剂组（n=89）或皮下注射Reslizumab组（n=88）。在研究1中，我们发现reslizumab和安慰剂在意向治疗人群中的急性发作率没有显著差异（比值比 0.79，95%CI 0.56-1.12；p=0.19）。与安慰剂组相比，皮下注射reslizumab可降低血液嗜酸性粒细胞计数为400个/μL或更高（0.64，95%CI 0.43-0.95）的患者的急性发作频率。血清reslizumab浓度越高，年加重风险越低（p=0.0035），首次加重的时间越长。在研究2中，我们发现安慰剂组和固定剂量皮下注射reslizumab组在每日口服皮质类固醇剂量分类减少百分比上没有差异（reslizumab组与安慰剂组口服皮质类固醇使用更低剂量的比值比为1.23，95%可信区间为0.70-2.16；p=0.47）。在两项研究中，reslizumab的不良事件和严重不良事件的发生率与安慰剂相似。
说明：固定剂量（110毫克）皮下注射reslizumab对减少哮喘未控制患者的急性发作频率和血嗜酸性粒细胞的增加（≥300个细胞/μL）或减少口服皮质类固醇依赖的重症嗜酸性粒细胞哮喘患者的每日维持口服皮质类固醇剂量无效。为了达到最大的疗效，需要比皮下注射reslizumab 110毫克更高的暴露量。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(Lancet Respir Med. 2020 Feb 14. pii: S2213-2600(19)30372-8. doi: 10.1016/S2213-2600(19)30372-8.)
(Lancet Respir Med. 2020 Feb 14. pii: S2213-2600(19)30372-8. doi: 10.1016/S2213-2600(19)30372-8.)
Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma: results from two phase 3, randomised, double-blind, placebo-controlled trials.
Bernstein JA, Virchow JC, Murphy K, Maspero JF, Jacobs J, Adir Y, Humbert M, Castro M, Marsteller DA, McElhattan J, Hickey L, Garin M, Vanlandingham R, Brusselle G.
Abstract
BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2).
METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2).
FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies.
INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy.
