Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial

INSIGHT FLU-IVIG Study Group

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41 Scopus citations

Abstract

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.

Original languageEnglish (US)
Pages (from-to)951-963
Number of pages13
JournalThe Lancet Respiratory Medicine
Volume7
Issue number11
DOIs
StatePublished - Nov 2019

Bibliographical note

Funding Information:
The research protocol, statistical analysis plan, and informed consent documents are available immediately upon publication of this Article. The protocol and informed consent can be found on the INSIGHT website, www.insight-trials.org . Primary and secondary study outcomes from this trial will be entered into ClinicalTrials.gov within 1 year following publication of the primary study results. Requests for access to more detailed study data and deidentified patient data can be submitted to the INSIGHT Scientific Steering Committee using the Research Proposal Form on the INSIGHT website at any time for review and approval on the basis of scientific merit of submitted proposals. Accepted proposals will be issued a letter of endorsement by the Committee. Acknowledgments The INSIGHT FLU-IVIG trial was primarily funded by the NIAID Intramural Research Program and the NIAID Division of Clinical Research, NIH, and the legal sponsor for the trial was the University of Minnesota. This project has been funded in whole or in part with US federal funds from the National Cancer Institute, National Institutes of Health, under contracts HHSN261200800001E and HHSN2612015000031. IND15771 is held by Regulatory Compliance and Human Subjects Protection Branch, NIAID. Support for the London and Copenhagen International Coordinating Centres was also provided by the UK Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation. The content of this Article does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organisations imply endorsement by the US Government. There were no agreements concerning confidentiality of the data between the sponsor and the authors or the institutions named in the credit line. The authors wish to thank the patients who participated in this study.

Funding Information:
The INSIGHT FLU-IVIG trial was primarily funded by the NIAID Intramural Research Program and the NIAID Division of Clinical Research, NIH, and the legal sponsor for the trial was the University of Minnesota. This project has been funded in whole or in part with US federal funds from the National Cancer Institute, National Institutes of Health, under contracts HHSN261200800001E and HHSN2612015000031. IND15771 is held by Regulatory Compliance and Human Subjects Protection Branch, NIAID. Support for the London and Copenhagen International Coordinating Centres was also provided by the UK Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation. The content of this Article does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products, or organisations imply endorsement by the US Government. There were no agreements concerning confidentiality of the data between the sponsor and the authors or the institutions named in the credit line. The authors wish to thank the patients who participated in this study.

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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