Anti-influenza Hyperimmune Intravenous Immunoglobulin for Adults With Influenza A or B Infection (FLU-IVIG): A Double-Blind, Randomised, Placebo-Controlled Trial

Richard T Davey Jr, Eduardo Fernández-Cruz, Norman Markowitz, et al

Lancet Respir Med 2019; 7: 951-963

Background 背景

Since the 1918 influenza pandemic, non-randomised studies and small clinical trials have suggested that convalescent plasma or anti-influenza hyperimmune intravenous immunoglobulin (hIVIG) might have clinical benefit for patients with influenza infection, but definitive data do not exist. We aimed to evaluate the safety and efficacy of hIVIG in a randomised controlled trial.

自从1918年流感大流行以来，非随机研究及小样本临床试验提示，恢复期血浆或抗流感高免疫hIVIG可使流感感染患者临床获益，但尚缺乏明确的数据。我们旨在通过随机临床试验评价hIVIG的安全性及疗效。

Methods 方法

This randomised, double-blind, placebo-controlled trial was planned for 45 hospitals in Argentina, Australia, Denmark, Greece, Mexico, Spain, Thailand, UK, and the USA over five influenza seasons from 2013–14 to 2017–18. Adults (≥18 years of age) were admitted for hospital treatment with laboratory-confirmed influenza A or B infection and were randomly assigned (1:1) to receive standard care plus either a single 500-mL infusion of high-titre hIVIG (0·25 g/kg bodyweight, 24·75 g maximum; hIVIG group) or saline placebo (placebo group). Eligible patients had a National Early Warning score of 2 points or greater at the time of screening and their symptoms began no more than 7 days before randomisation. Pregnant and breastfeeding women were excluded, as well as any patients for whom the treatment would present a health risk. Separate randomisation schedules were generated for each participating clinical site using permuted block randomisation. Treatment assignments were obtained using a web-based application by the site pharmacist who then masked the solution for infusion. Patients and investigators were masked to study treatment. The primary endpoint was a six-category ordinal outcome of clinical status at day 7, ranging in severity from death to resumption of normal activities after discharge. The choice of day 7 was based on haemagglutination inhibition titres from a pilot study. It was analysed with a proportional odds model, using all six categories to estimate a common odds ratio (OR). An OR greater than 1 indicated that, for a given category, patients in the hIVIG group were more likely to be in a better category than those in the placebo group. Prespecified primary analyses for safety and efficacy were based on patients who received an infusion and for whom eligibility could be confirmed. This trial is registered with ClinicalTrials.gov, NCT02287467.

这项随机双盲安慰剂对照临床试验在阿根廷、澳大利亚、丹麦、希腊、墨西哥、西班牙、泰国、英国和美国的45所医院进行，历经2013-14至2017-18年间5个流感季节。实验室确诊甲型或乙型流感感染且住院接受治疗的成年患者 (≥18 岁) 按照1:1的比例接受随机分组，除标准治疗外，分别接受500-mL高滴度 hIVIG (0·25 g/kg 体重，最大剂量 24·75 g；hIVIG组) 或生理盐水 (安慰剂组)。入选患者在筛选时国家早期预警评分2分或更高，随机分组前临床症状出现不超过7天。排除标准包括妊娠、哺乳或具有治疗相关风险。对每个参研中心进行单独随机化，且采用置换区组随机。参研中心药师通过网络获取随机分组信息后，负责对输注液体的隐藏。研究分组对患者及研究者隐藏。主要预后终点为第7天的临床状态，根据6级顺序预后评分评估，严重程度从死亡到出院后能够进行正常活动。根据先导试验结果确定选择第7天进行评估。采用比例优势模型进行分析，采用所有6级分类估计比数比(OR)。OR > 1提示，对于某个分级而言，hIVIG组患者预后较安慰剂更好。对接受输注且满足入选标准的患者进行预先确定的安全性及疗效分析。试验在ClinicalTrials.gov注册，注册号 NCT02287467。

Findings 结果

313 patients were enrolled in 34 sites between Dec 11, 2014, and May 28, 2018. We also used data from 16 patients enrolled at seven of the 34 sites during the pilot study between Jan 15, 2014, and April 10, 2014. 168 patients were randomly assigned to the hIVIG group and 161 to the placebo group. 21 patients were excluded (12 from the hIVIG group and 9 from the placebo group) because they did not receive an infusion or their eligibility could not be confirmed. Thus, 308 were included in the primary analysis. hIVIG treatment produced a robust rise in haemagglutination inhibition titres against influenza A and smaller rises in influenza B titres. Based on the proportional odds model, the OR on day 7 was 1·25 (95% CI 0·79–1·97; p=0·33). In subgroup analyses for the primary outcome, the OR in patients with influenza A was 0·94 (0·55–1·59) and was 3·19 (1·21–8·42) for those with influenza B (interaction p=0·023). Through 28 days of follow-up, 47 (30%) of 156 patients in the hIVIG group and in 45 (30%) of 152 patients in the placebo group had the composite safety outcome of death, a serious adverse event, or a grade 3 or 4 adverse event (hazard ratio [HR] 1·06, 95% CI 0·70–1·60; p=0·79). Six (4%) patients in the hIVIG group and five (3%) in the placebo group died, but these deaths were not necessarily related to treatment.

2014年12月11日至2018年5月28日期间，313名患者入选。我们还纳入了2014年1月15日至2014年4月10日间先导试验中34个中心中的7个入选的16名患者。168名患者随机分至hIVIG组，161名患者分至安慰剂组。21名患者(hIVIG组12名，安慰剂组9名)因为没有接受输注或不满足入选标准被排除。因此，308名患者纳入主要分析。hIVIG治疗组甲型流感凝血素抑制滴度显著升高，乙型流感滴度轻度升高。根据比例优势模型，第7天OR为1·25 (95% CI 0·79–1·97; p=0·33)。针对主要预后终点的亚组分析中，甲型流感OR为0·94 (0·55–1·59)，乙型流感为3·19 (1·21–8·42) (交互作用 p=0·023)。经过28天随访，hIVIG组156名患者中 47名 (30%) 以及安慰剂组152名患者中45名 (30%) 发生安全性复合终点事件，即死亡、严重不良事件或3或4级不良事件 (风险比 [HR] 1·06, 95% CI 0·70–1·60; p=0·79)。hIVIG组6名 (4%) 患者及安慰剂组5名 (3%) 患者死亡，但是这些患者死亡并非与治疗相关。

Interpretation 结论

When administered alongside standard care (most commonly oseltamivir), hIVIG was not superior to placebo for adults hospitalised with influenza infection. By contrast with our prespecified subgroup hypothesis that hIVIG would result in more favourable responses in patients with influenza A than B, we found the opposite effect. The clinical benefit of hIVIG for patients with influenza B is supported by antibody affinity analyses, but confirmation is warranted.

对于因流感感染住院的成年患者，除标准治疗(最常用的是奥司他韦)外，hIVIG并不优于安慰剂。与我们预先确定的亚组假设即hIVIG对于甲型流感较乙型流感更有效不同，我们发现了相反的治疗效果。抗体分析支持乙型流感患者使用hIVIG的临床疗效，但需要进一步证实。

Funding 资助

NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.