德国低剂量泼尼松龙与B族维生素治疗新冠感染后综合征：PreVitaCOV随机临床试验。
完整摘要 · 中文译文
背景：新冠后综合征（Post-COVID-19 syndrome）疾病负担沉重，目前尚缺乏充分的治疗手段，持续症状包括疲劳、呼吸困难和认知功能障碍。泛美卫生组织建议对可能有益的干预措施进行严格评估。我们研究了泼尼松龙及维生素B1、B6和B12在新冠后综合征患者中的疗效和安全性。 方法：本项随机、双盲、安慰剂对照的3期试验（2×2析因设计）在德国三个大学中心站点的新冠后综合征成人患者中开展。纳入标准为：有记录的SARS-CoV-2感染≥12周后仍存在持续症状的成年患者，且无急性COVID-19、无重大合并症、非妊娠或哺乳期、既往未因COVID-19接受过重症监护治疗、近期未使用试验药物、未使用可能发生相互作用的合并用药。自2023年1月13日至2024年7月25日，参与者被随机分配接受为期28天的每日一次口服治疗：泼尼松龙（第1-5天20 mg，第6-28天5 mg）、B族维生素（硝酸硫胺素[B1] 100 mg、盐酸吡哆醇[B6] 50 mg和氰钴胺素[B12] 500 μg）、泼尼松龙联合B族维生素、或安慰剂。主要结局为基线至第28天总体症状严重程度的变化，在意向性治疗人群（至少接受一剂研究药物的参与者）中于随机化后首次随访时采用定制的患者报告结局测量信息系统（PROMIS）总T评分进行评估。变化≥3分被视为具有临床意义 有效。疗效通过预先设定的析因分析评估泼尼松龙和B族维生素的主要效应。安全性通过分析所有随机化患者（安全性人群）中不良事件的频率和严重程度进行评估。该已完成的试验在ClinicalTrials.gov注册（NCT05638633）。 结果：在2498名接受资格评估的患者中，323名被随机化，310名患者具有可评估的结局数据。平均年龄为44岁（标准差（SD）13），200名参与者为女性。PROMIS T评分的平均变化为：泼尼松龙组-4.3（SD 5.1），B族维生素组-3.2（SD 5.0），泼尼松龙加B族维生素组-4.5（SD 4.5），安慰剂组-2.9（SD 4.6）。接受泼尼松龙治疗与未接受泼尼松龙治疗的参与者之间的校正平均差异为-1.4分（95%置信区间（CI），-2.5至-0.4；p = 0.008），主要由疲劳子评分的变化驱动（-6.4分，p < 0.001）。与未使用B族维生素相比，B族维生素未显示统计学显著或临床有意义的差异（校正平均差异（MD），-0.1分；95% CI，-1.2至+1.0；p = 0.85）。不良事件在各组间分布均衡，无与研究药物相关的严重不良事件。 解释：该试验显示，低剂量泼尼松龙可统计学显著地短期降低COVID后患者PROMIS评分五个维度的症状严重程度。然而，该效应未达到预先设定的临床相关性阈值。需要进一步研究以确认 泼尼松龙，并确定最佳剂量和治疗持续时间，同时权衡获益与长期不良反应。 资助：德国联邦研究、技术和空间部，Vogel Stiftung Dr. Eckernkamp，Hevert-Arzneimittel GmbH & Co. KG。
完整摘要 · 英文原文
BACKGROUND: Post-COVID-19 syndrome is burdensome and not yet adequately treatable, with persistent symptoms including fatigue, dyspnoea, and cognitive impairment. The Pan American Health Organisation recommends rigorous evaluation of potentially beneficial interventions. We investigated the efficacy and safety of prednisolone and vitamins B1, B6, and B12 in patients with post-COVID-19. METHODS: This randomised, double-blind, placebo-controlled phase 3 trial (2 × 2 factorial design) was conducted in adults with post-COVID-19 at three university sites in Germany. Adult patients with persistent symptoms after a documented SARS-CoV-2 infection ≥12 weeks ago and without acute COVID-19, major comorbidities, pregnancy or breastfeeding, prior intensive care treatment for COVID-19, recent use of trial drugs, or potentially interacting concomitant medications were included. From January 13, 2023 until July 25, 2024 participants were randomly assigned to 28 days of once-daily oral treatment with prednisolone (20 mg on days 1-5, 5 mg on days 6-28), B vitamins (thiamine nitrate [B1], 100 mg, pyridoxine hydrochloride [B6] 50 mg, and cyanocobalamin [B12] 500 μg), prednisolone and B vitamins, or placebo. The primary outcome was change in overall symptom severity from baseline to day 28, assessed in the intention-to-treat population (participants who received at least one dose of study drug) at the first follow-up visit after randomisation with a customised Patient-Reported Outcomes Measurement Information System (PROMIS) total T-score. A change of ≥3 points was considered clinically meaningful. Efficacy was assessed using a pre-specified factorial analysis of the main effects of prednisolone and B vitamins. Safety was assessed by analysing frequency and severity of adverse events in all randomised patients (safety population). This completed trial is registered with ClinicalTrials.gov (NCT05638633). FINDINGS: Of 2498 patients assessed for eligibility, 323 were randomised and 310 patients had evaluable data for the outcomes. The mean age was 44 (standard deviation (SD) 13) years, 200 participants were women. The mean change in PROMIS T-score was -4·3 (SD 5·1) with prednisolone, -3·2 (SD 5·0) with B vitamins, -4·5 (SD 4·5) with prednisolone plus B vitamins, and -2·9 (SD 4·6) with placebo. The adjusted mean difference between participants treated with prednisolone and those not treated was -1·4 points (95% confidence interval (CI), -2·5 to -0·4; p = 0·008), driven primarily by the change in the fatigue subscore (-6·4 points, p < 0·001). B vitamins showed no statistically significant or clinically meaningful difference compared with no B vitamins (adjusted mean difference (MD), -0·1 points; 95% CI, -1·2 to +1·0; p = 0·85). Adverse events were equally distributed between groups, with no study-drug-related serious adverse events. INTERPRETATION: This trial showed a statistically significant short-term reduction in symptom severity in the five dimensions of the PROMIS score in patients with post-COVID with low-dose prednisolone. However, the effect did not reach the prespecified threshold for clinical relevance. Further research is needed to confirm the efficacy of prednisolone and to determine the optimal dose and treatment duration while balancing benefits against longer-term adverse effects. FUNDING: German Federal Ministry of Research, Technology and Space, Vogel Stiftung Dr. Eckernkamp, Hevert-Arzneimittel GmbH & Co. KG.