BACKGROUND The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. METHODS PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). FINDINGS Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3-201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4-169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). INTERPRETATION In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. FUNDING AOP Orphan Pharmaceuticals AG.

中文翻译：

---

Ropeginterferon alfa-2b与标准疗法治疗真性红细胞增多症（PROUD-PV和CONTINUATION-PV）：一项随机，非劣效的3期临床试验及其扩展研究。

背景PROUD-PV和CONTINUATION-PV试验旨在比较新型单聚乙二醇化干扰素绳索干扰素α-2b与羟基脲（治疗真性红细胞增多症患者的标准疗法）在3年的治疗时间。方法PROUD-PV及其扩展研究CONTINUATION-PV是在欧洲的48个诊所进行的第3期随机，对照，开放标签试验。如果根据WHO的2008年标准诊断为18岁或18岁以上的早期真性红细胞增多症（无细胞减少治疗史或以前的羟基脲治疗不到3年），则患者符合条件。患者被按1：1比例随机分配给ropginterferon alfa-2b（每两周皮下注射一次，剂量为100μg）或羟基脲（口服剂量为500 mg /天）。一年后，患者可以选择参加试验的扩展部分CONTINUATION-PV。PROUD-PV的主要终点是在12个月时，在正常脾脏大小（女性纵向直径≤12cm，男性纵向直径≤13cm）的完全血液学反应方面，ropeginterferon alfa-2b不比羟基脲低。在CONTINUATION-PV中，共同的主要终点是完全的血液学反应，脾脏大小正常化，疾病负担得到改善（即脾肿大，微血管障碍，瘙痒和头痛）。我们展示了PROUD-PV的最终结果以及在CONTINUATION-PV研究的36个月中的中期分析（根据统计分析计划）。对安全性和有效性的分析是按照协议进行的。该试验已在EudraCT，2012-005259-18（PROUD-PV）和2014-001357-17（CONTINUATION-PV，正在进行中）上注册。结果自2013年9月17日至3月13日招募患者 2015年注册306人。随机分配了257位患者，每组127位接受了治疗（三位患者在羟基脲组中撤回了同意），并且171位转入了CONTINUATION-PV试验。在标准治疗组中，ropeginterferon alfa-2b的中位随访时间为182·1周（IQR 166·3-201·7），在标准治疗组中为164·5周（144·4-169·3）。在PROUD-PV中，ropeginterferon alfa-2b组的122名患者中有26名（21％）和标准治疗组的123名患者中有34名（28％）达到了具有正常脾脏大小的完全血液学反应的复合主要终点。在CONTINUATION-PV中，ropeginterferon alfa-2b组中的95名患者中有50名（53％）达到了完全的血液学反应，而羟基脲组的74名患者中有28名（38％）达到了疾病负担，p = 0·044。 36个月 ropginterferon alfa-2b组与标准治疗组相比，没有脾脏标准的完全血液学反应为：123例患者中53（43％）比125例患者中57（46％），在12个月时p = 0·63（PROUD-PV ）和95例患者中的67例（占71％），而74例患者中的38例（占51％），在36个月时p = 0·012（CONTINUATION-PV）。ropginterferon alfa-2b组中最常报告的3级和4级与治疗相关的不良事件是γ-谷氨酰转移酶升高（127例患者中的7 [6％]）和丙氨酸转氨酶（127例患者中4 [3％]）的患者增加。 ，标准治疗组中的白血球减少症（127名患者中的6 [5％]）和血小板减少症（127名患者中的5 [4％]）。与治疗有关的严重不良事件发生在ropeginterferon alfa-2b组的127名患者中的三名（2％）和羟基脲组的127名患者中的五名（4％）。在标准治疗组中报告了1例与治疗有关的死亡（急性白血病）。解释在主要表现为无脾肿大的早期真性红细胞增多症患者中，ropeginterferon alfa-2b可有效诱导血液学反应。在12个月时未显示出对血液反应和正常脾脏大小不逊于羟基脲。然而，与羟基脲相比，在36个月时，对ropeginterferon alfa-2b的反应随着时间的推移持续增加，并且反应改善。考虑到较高的和持久的血液和分子反应及其良好的耐受性，ropeginterferon alfa-2b提供了一种有价值且安全的长期治疗方案，其特点不同于羟基脲。资助AOP Orphan Pharmaceuticals AG。