重组人血小板生成素治疗特发性血小板减少性紫癜的多中心随机对照临床试验

The Multicenter Randomized-control Trial of Recombinant Humanized Thrombopietin Treatment in Patients with Idiopathic Thrombocytopenia Purpura

目的评价重组人血小板生成素(rhTPO)治疗糖皮质激素无效的特发性血小板减少性紫癜(ITP)患者的有效性和安全性。方法采用多中心、随机开放、空白对照方法,将糖皮质激素治疗无效的患者随机分为试验组(rhTPO+达那唑)和对照组(达那唑)。两组患者在整个试验阶段均口服达那唑0.2g/次,3次/d。试验组皮下注射rhTPO1.0μg/kg,1次/d,疗程14d,停用rhTPO后观察14d。对照组口服达那唑14d后,如血小板仍≤20×109/L接受rhTPO治疗,用法如前,停用rhTPO后观察14d。试验的主要终点是比较两组间第一阶段(前14d内)血小板计数增加的最高值和血小板计数的曲线下面积;次要终点是比较两组间第一阶段的显效率和有效率,对照组第二阶段应用rhTPO前后的血小板计数、显效率和有效率。结果入选患者140例,试验组和对照组分别为73例和67例,最终进入FAS集者分别为73例和63例,进入PPS集者分别为60例和50例。主要终点FAS结果显示:试验组rhTPO治疗后血小板计数最高值平均增加101.2×109/L,显著高于对照组的33.3×109/L(P=0.0060);试验组血小板计数的曲线下面积749.6,显著高于对照组的316.2(P=0.0000)。次要终点FAS结果显示:试验组第一阶段的显效率和有效率(显效+良效)分别为38.4%和60.3%,明显高于对照组的7.9%(P=0.0003)和36.5%(P=0.0104);对照组第一阶段第14天血小板计数≤20×109/L的患者,接受rhTPO治疗后显效率和有效率分别达到31.1%和66.7%。试验组停用rhTPO后血小板计数逐渐下降,但停药14d时仍维持在50×109/L左右。rhTPO对白细胞计数、血红蛋白、胆红素、凝血试验、抗GPⅡb/Ⅲa和GPⅠb自身抗体无明显影响。不良事件的发生率,试验组和对照组分别为34.3%和26.2%,其中以肝胆指标异常最常见,分别为15.1%和16.9%。rhTPO相关的不良事件发生率13.6%,主要有轻度嗜睡、头晕、短暂性视野缺损、过敏样反应和乏力等。结论 rhTPO是一种治疗慢性ITP的疗效确切、较为安全的药物。

Objective To evaluate the efficacy and safety of recombinant humanized thrombopietin （rhTPO） treatment in patients with idiopathic thrombocytopenia purpura （ITP） who failed to glucocorticosteroids. Methods A multicenter randomized-control study was designed. Patients with ITP who failed to glucocorticosteroids were enrolled and randomized to experimental group （rhTPO＋danazol） and control group （danazol）. All patients took danazol orally of 0.2 three times per day during the whole trial. Patients in the experimental group were administered subcutaneously with rhTPO 1.0 μg/kg once daily for 14 days and then stopped to observe. Patients in contol group were administered rhTPO as above if their platelet counts were still lower than 20×109/L after 14 days treatment with danazol. Primary endpoints were comparing the mean maximal platelet counts increase and the area under curve （AUC） of the platelet counts during the first phase between two groups. Secondary endpoints were comparing the major response rate （MRR） and total response rate （TRR,including MRR＋Good RR） during the first phase,and the platelet counts,MRR,and TRR before and after rhTPO treatment in patients of control group. Results 140 patients were enrolled and randomly assigned 73 patients in experimental group and 67 patients in control group. At the end of study,73 and 63 patients fulfilled FAS,60 and 50 patients fulfilled PPS,respectively in experimental group and control group. Results from FAS and PPS were fully identical. During the first phase,the mean platelet counts increase were 101.2×109/L in experimental group,which was significantly higher than that in control group （33.3×109/L,P=0.0060）. The AUC 749.6 of experimental group was significantly higher than 316.2 of control group （P=0.0000）. The MRR and TRR were 38.4% and 60.3% respectively,which were significantly higher than that of control group （MRR 7.9%,P=0.0003; TRR 36.5%,P=0.0104）. 45 patients whose platelet counts lower than 20×109/L in control group were treated with rhTPO and achieved the MRR 31.1% and TRR 66.7%,which were extremely in accordance with the results of the first phase in experimental group. At day 14 after stopping treatment of rhTPO,the mean platelet counts in experimental group were still around 50×109/L. No influences of rhTPO on white blood count,hemoglobin,bilirubin,clotting tests,anti-GPⅡb/Ⅲa and anti-GPⅠb antibodies were found. The frequencies of adverse events were 34.3% in experimental group and 26.2% in control group,of which abnormal hepatobiliary indices was seen mostly （15.1% in experimental group and 16.9% in control group）. Frequency of rhTPO-related adverse events was 13.6%,including mild doss,dizziness,transit defect of vision field,allergic reaction and fatigue. Conclusion rhTPO was well tolerated,and markedly increased platelet counts in patients with chronic ITP. Stimulation of platelet production by rhTPO may provide a new therapeutic option for patients with ITP.