Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial
Identifieur interne : 000096 ( Pmc/Checkpoint ); précédent : 000095; suivant : 000097Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial
Auteurs : Richard T. Davey [États-Unis] ; Eduardo Fernández-Cruz [Espagne] ; Norman Markowitz [États-Unis] ; Sarah Pett [Royaume-Uni] ; Abdel G. Babiker [Royaume-Uni] ; Deborah Wentworth [États-Unis] ; Surender Khurana [États-Unis] ; Nicole Engen [États-Unis] ; Fred Gordin [États-Unis] ; Mamta K. Jain [États-Unis] ; Virginia Kan [États-Unis] ; Mark N. Polizzotto [Australie] ; Paul Riska [États-Unis] ; Kiat Ruxrungtham [Thaïlande] ; Zelalem Temesgen [États-Unis] ; Jens Lundgren [Danemark] ; John H. Beigel [États-Unis] ; H Clifford Lane [États-Unis] ; James D. Neaton [États-Unis]Source :
- The Lancet. Respiratory Medicine [ 2213-2600 ] ; 2019.
Abstract
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.
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
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.
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.
NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.
Url:
DOI: 10.1016/S2213-2600(19)30253-X
PubMed: 31582358
PubMed Central: 6868512
Affiliations:
- Australie, Danemark, Espagne, Royaume-Uni, Thaïlande, États-Unis
- Angleterre, Communauté de Madrid, District de Columbia, Grand Londres, Hovedstaden, Maryland, Michigan, Minnesota, Texas, État de New York
- Copenhague, Londres, Madrid
- University College de Londres
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial</title>
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<author><name sortKey="Fernandez Cruz, Eduardo" sort="Fernandez Cruz, Eduardo" uniqKey="Fernandez Cruz E" first="Eduardo" last="Fernández-Cruz">Eduardo Fernández-Cruz</name>
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<author><name sortKey="Kan, Virginia" sort="Kan, Virginia" uniqKey="Kan V" first="Virginia" last="Kan">Virginia Kan</name>
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<author><name sortKey="Polizzotto, Mark N" sort="Polizzotto, Mark N" uniqKey="Polizzotto M" first="Mark N" last="Polizzotto">Mark N. Polizzotto</name>
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<author><name sortKey="Riska, Paul" sort="Riska, Paul" uniqKey="Riska P" first="Paul" last="Riska">Paul Riska</name>
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<author><name sortKey="Ruxrungtham, Kiat" sort="Ruxrungtham, Kiat" uniqKey="Ruxrungtham K" first="Kiat" last="Ruxrungtham">Kiat Ruxrungtham</name>
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<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok</wicri:regionArea>
<wicri:noRegion>Bangkok</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff12">The HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Centre, Bangkok, Thailand</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>The HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Centre, Bangkok</wicri:regionArea>
<wicri:noRegion>Bangkok</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Temesgen, Zelalem" sort="Temesgen, Zelalem" uniqKey="Temesgen Z" first="Zelalem" last="Temesgen">Zelalem Temesgen</name>
<affiliation wicri:level="2"><nlm:aff id="aff13">Mayo Clinic Hospital, Saint Marys Campus, Rochester, MN, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Mayo Clinic Hospital, Saint Marys Campus, Rochester, MN</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lundgren, Jens" sort="Lundgren, Jens" uniqKey="Lundgren J" first="Jens" last="Lundgren">Jens Lundgren</name>
<affiliation wicri:level="3"><nlm:aff id="aff14">CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark</nlm:aff>
<country xml:lang="fr">Danemark</country>
<wicri:regionArea>CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen</wicri:regionArea>
<placeName><settlement type="city">Copenhague</settlement>
<region type="région" nuts="2">Hovedstaden</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Beigel, John H" sort="Beigel, John H" uniqKey="Beigel J" first="John H" last="Beigel">John H. Beigel</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>National Institute of Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lane, H Clifford" sort="Lane, H Clifford" uniqKey="Lane H" first="H Clifford" last="Lane">H Clifford Lane</name>
<affiliation wicri:level="2"><nlm:aff id="aff1">National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>National Institute of Allergy and Infectious Diseases, Bethesda, MD</wicri:regionArea>
<placeName><region type="state">Maryland</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Neaton, James D" sort="Neaton, James D" uniqKey="Neaton J" first="James D" last="Neaton">James D. Neaton</name>
<affiliation wicri:level="2"><nlm:aff id="aff5">Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN</wicri:regionArea>
<placeName><region type="state">Minnesota</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">The Lancet. Respiratory Medicine</title>
<idno type="ISSN">2213-2600</idno>
<idno type="eISSN">2213-2619</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><title>Summary</title>
<sec><title>Background</title>
<p>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.</p>
</sec>
<sec><title>Methods</title>
<p>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 <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" id="interrefs10">ClinicalTrials.gov</ext-link>
, <ext-link ext-link-type="ClinicalTrials.gov" xlink:href="NCT02287467" id="interrefs20">NCT02287467</ext-link>
.</p>
</sec>
<sec><title>Findings</title>
<p>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.</p>
</sec>
<sec><title>Interpretation</title>
<p>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.</p>
</sec>
<sec><title>Funding</title>
<p>NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Lancet Respir Med</journal-id>
<journal-id journal-id-type="iso-abbrev">Lancet Respir Med</journal-id>
<journal-title-group><journal-title>The Lancet. Respiratory Medicine</journal-title>
</journal-title-group>
<issn pub-type="ppub">2213-2600</issn>
<issn pub-type="epub">2213-2619</issn>
<publisher><publisher-name>Elsevier</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31582358</article-id>
<article-id pub-id-type="pmc">6868512</article-id>
<article-id pub-id-type="publisher-id">S2213-2600(19)30253-X</article-id>
<article-id pub-id-type="doi">10.1016/S2213-2600(19)30253-X</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="au10"><name><surname>Davey</surname>
<given-names>Richard T</given-names>
<suffix>Jr</suffix>
</name>
<degrees>MD</degrees>
<email>rdavey@niaid.nih.gov</email>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="cor1" ref-type="corresp">*</xref>
<xref rid="fn1" ref-type="fn">*</xref>
</contrib>
<contrib contrib-type="author" id="au20"><name><surname>Fernández-Cruz</surname>
<given-names>Eduardo</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff2" ref-type="aff">b</xref>
<xref rid="fn1" ref-type="fn">*</xref>
</contrib>
<contrib contrib-type="author" id="au30"><name><surname>Markowitz</surname>
<given-names>Norman</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff3" ref-type="aff">c</xref>
<xref rid="fn1" ref-type="fn">*</xref>
</contrib>
<contrib contrib-type="author" id="au40"><name><surname>Pett</surname>
<given-names>Sarah</given-names>
</name>
<degrees>MBBS</degrees>
<xref rid="aff4" ref-type="aff">d</xref>
<xref rid="fn1" ref-type="fn">*</xref>
</contrib>
<contrib contrib-type="author" id="au50"><name><surname>Babiker</surname>
<given-names>Abdel G</given-names>
</name>
<degrees>Prof</degrees>
<degrees>PhD</degrees>
<xref rid="aff4" ref-type="aff">d</xref>
</contrib>
<contrib contrib-type="author" id="au60"><name><surname>Wentworth</surname>
<given-names>Deborah</given-names>
</name>
<degrees>MPh</degrees>
<xref rid="aff5" ref-type="aff">e</xref>
</contrib>
<contrib contrib-type="author" id="au70"><name><surname>Khurana</surname>
<given-names>Surender</given-names>
</name>
<degrees>PhD</degrees>
<xref rid="aff6" ref-type="aff">f</xref>
</contrib>
<contrib contrib-type="author" id="au80"><name><surname>Engen</surname>
<given-names>Nicole</given-names>
</name>
<degrees>MSc</degrees>
<xref rid="aff5" ref-type="aff">e</xref>
</contrib>
<contrib contrib-type="author" id="au90"><name><surname>Gordin</surname>
<given-names>Fred</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff7" ref-type="aff">g</xref>
<xref rid="fn3" ref-type="fn">‡</xref>
</contrib>
<contrib contrib-type="author" id="au100"><name><surname>Jain</surname>
<given-names>Mamta K</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff8" ref-type="aff">h</xref>
</contrib>
<contrib contrib-type="author" id="au110"><name><surname>Kan</surname>
<given-names>Virginia</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff7" ref-type="aff">g</xref>
</contrib>
<contrib contrib-type="author" id="au120"><name><surname>Polizzotto</surname>
<given-names>Mark N</given-names>
</name>
<degrees>MBBS</degrees>
<xref rid="aff9" ref-type="aff">i</xref>
</contrib>
<contrib contrib-type="author" id="au130"><name><surname>Riska</surname>
<given-names>Paul</given-names>
</name>
<degrees>MD</degrees>
<xref rid="aff10" ref-type="aff">j</xref>
</contrib>
<contrib contrib-type="author" id="au140"><name><surname>Ruxrungtham</surname>
<given-names>Kiat</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff11" ref-type="aff">k</xref>
<xref rid="aff12" ref-type="aff">l</xref>
</contrib>
<contrib contrib-type="author" id="au150"><name><surname>Temesgen</surname>
<given-names>Zelalem</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff13" ref-type="aff">m</xref>
</contrib>
<contrib contrib-type="author" id="au160"><name><surname>Lundgren</surname>
<given-names>Jens</given-names>
</name>
<degrees>Prof</degrees>
<degrees>MD</degrees>
<xref rid="aff14" ref-type="aff">n</xref>
</contrib>
<contrib contrib-type="author" id="au170"><name><surname>Beigel</surname>
<given-names>John H</given-names>
</name>
<degrees>MD</degrees>
<xref rid="aff1" ref-type="aff">a</xref>
</contrib>
<contrib contrib-type="author" id="au180"><name><surname>Lane</surname>
<given-names>H Clifford</given-names>
</name>
<degrees>MD</degrees>
<xref rid="aff1" ref-type="aff">a</xref>
</contrib>
<contrib contrib-type="author" id="au190"><name><surname>Neaton</surname>
<given-names>James D</given-names>
</name>
<degrees>Prof</degrees>
<degrees>PhD</degrees>
<xref rid="aff5" ref-type="aff">e</xref>
</contrib>
<on-behalf-of>on behalf of the </on-behalf-of>
<contrib contrib-type="author"><collab>INSIGHT FLU-IVIG Study Group<xref rid="fn2" ref-type="fn">†</xref>
<contrib-group><contrib contrib-type="author" id="au200"><name><surname>Davey</surname>
<given-names>Richard T</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au210"><name><surname>Fernández-Cruz</surname>
<given-names>Eduardo</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au220"><name><surname>Markowitz</surname>
<given-names>Norman</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au230"><name><surname>Pett</surname>
<given-names>Sarah</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au240"><name><surname>Babiker</surname>
<given-names>Abdel G</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au250"><name><surname>Wentworth</surname>
<given-names>Deborah</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au260"><name><surname>Khurana</surname>
<given-names>Surender</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au270"><name><surname>Engen</surname>
<given-names>Nicole</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au280"><name><surname>Gordin</surname>
<given-names>Fred</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au290"><name><surname>Jain</surname>
<given-names>Mamta K</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au300"><name><surname>Kan</surname>
<given-names>Virginia</given-names>
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<contrib contrib-type="author" id="au310"><name><surname>Polizzotto</surname>
<given-names>Mark N</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au320"><name><surname>Riska</surname>
<given-names>Paul</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au330"><name><surname>Ruxrungtham</surname>
<given-names>Kiat</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au340"><name><surname>Temesgen</surname>
<given-names>Zelalem</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au350"><name><surname>Lundgren</surname>
<given-names>Jens</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au360"><name><surname>Beigel</surname>
<given-names>John H</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au370"><name><surname>Lane</surname>
<given-names>H Clifford</given-names>
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<contrib contrib-type="author" id="au380"><name><surname>Neaton</surname>
<given-names>James D</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au390"><name><surname>Butts</surname>
<given-names>Jessica</given-names>
</name>
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<contrib contrib-type="author" id="au400"><name><surname>Denning</surname>
<given-names>Eileen</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au410"><name><surname>DuChene</surname>
<given-names>Alain</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au420"><name><surname>Krum</surname>
<given-names>Eric</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au430"><name><surname>Harrison</surname>
<given-names>Merrie</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au440"><name><surname>Meger</surname>
<given-names>Sue</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au450"><name><surname>Peterson</surname>
<given-names>Ross</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au460"><name><surname>Quan</surname>
<given-names>Kien</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au470"><name><surname>Shaughnessy</surname>
<given-names>Megan</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au480"><name><surname>Thompson</surname>
<given-names>Greg</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au490"><name><surname>Vock</surname>
<given-names>David</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au500"><name><surname>Metcalf</surname>
<given-names>Julia</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au510"><name><surname>Dewar</surname>
<given-names>Robin</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au520"><name><surname>Rehman</surname>
<given-names>Tauseef</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au530"><name><surname>Natarajan</surname>
<given-names>Ven</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au540"><name><surname>McConnell</surname>
<given-names>Rose</given-names>
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<contrib contrib-type="author" id="au550"><name><surname>Flowers</surname>
<given-names>Emily</given-names>
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</contrib>
<contrib contrib-type="author" id="au560"><name><surname>Smith</surname>
<given-names>Kenny</given-names>
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<contrib contrib-type="author" id="au570"><name><surname>Hoover</surname>
<given-names>Marie</given-names>
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<given-names>Elizabeth M</given-names>
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<contrib contrib-type="author" id="au590"><name><surname>Munroe</surname>
<given-names>David</given-names>
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<contrib contrib-type="author" id="au600"><name><surname>Aagaard</surname>
<given-names>Bitten</given-names>
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<contrib contrib-type="author" id="au610"><name><surname>Pearson</surname>
<given-names>Mary</given-names>
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<contrib contrib-type="author" id="au620"><name><surname>Cursley</surname>
<given-names>Adam</given-names>
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<contrib contrib-type="author" id="au630"><name><surname>Webb</surname>
<given-names>Helen</given-names>
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<contrib contrib-type="author" id="au640"><name><surname>Hudson</surname>
<given-names>Fleur</given-names>
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<contrib contrib-type="author" id="au650"><name><surname>Russell</surname>
<given-names>Charlotte</given-names>
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<contrib contrib-type="author" id="au660"><name><surname>Sy</surname>
<given-names>Aminata</given-names>
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<contrib contrib-type="author" id="au670"><name><surname>Purvis</surname>
<given-names>Cara</given-names>
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<contrib contrib-type="author" id="au680"><name><surname>Jackson</surname>
<given-names>Brooke</given-names>
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<contrib contrib-type="author" id="au690"><name><surname>Collaco-Moraes</surname>
<given-names>Yolanda</given-names>
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<contrib contrib-type="author" id="au700"><name><surname>Carey</surname>
<given-names>Dianne</given-names>
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<contrib contrib-type="author" id="au710"><name><surname>Robson</surname>
<given-names>Rosemary</given-names>
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<contrib contrib-type="author" id="au720"><name><surname>Sánchez</surname>
<given-names>Adriana</given-names>
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<contrib contrib-type="author" id="au730"><name><surname>Finley</surname>
<given-names>Elizabeth</given-names>
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<contrib contrib-type="author" id="au740"><name><surname>Conwell</surname>
<given-names>Donna</given-names>
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<given-names>Marcelo H</given-names>
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<given-names>Luciana</given-names>
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<contrib contrib-type="author" id="au770"><name><surname>Abela</surname>
<given-names>Cecilia</given-names>
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<contrib contrib-type="author" id="au780"><name><surname>Lopez</surname>
<given-names>Paco</given-names>
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<contrib contrib-type="author" id="au790"><name><surname>Alonso</surname>
<given-names>Helena</given-names>
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<contrib contrib-type="author" id="au800"><name><surname>Touloumi</surname>
<given-names>Giota</given-names>
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<contrib contrib-type="author" id="au810"><name><surname>Gioukari</surname>
<given-names>Vicky</given-names>
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<contrib contrib-type="author" id="au820"><name><surname>Anagnostou</surname>
<given-names>Olga</given-names>
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<given-names>Anchalee</given-names>
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<contrib contrib-type="author" id="au840"><name><surname>Pussadee</surname>
<given-names>Kanitta</given-names>
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<contrib contrib-type="author" id="au850"><name><surname>Ubolyam</surname>
<given-names>Sasiwimol</given-names>
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<contrib contrib-type="author" id="au860"><name><surname>Omotosho</surname>
<given-names>Bola</given-names>
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<contrib contrib-type="author" id="au870"><name><surname>Solórzano</surname>
<given-names>Clemencia</given-names>
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</contrib>
<contrib contrib-type="author" id="au880"><name><surname>Petersen</surname>
<given-names>Tianna</given-names>
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</contrib>
<contrib contrib-type="author" id="au890"><name><surname>Vysyaraju</surname>
<given-names>Kranthi</given-names>
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<contrib contrib-type="author" id="au900"><name><surname>Rizza</surname>
<given-names>Stacey A</given-names>
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<given-names>Jennifer A</given-names>
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<given-names>Raquel</given-names>
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<contrib contrib-type="author" id="au930"><name><surname>Baxter</surname>
<given-names>John</given-names>
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<contrib contrib-type="author" id="au940"><name><surname>Coburn</surname>
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<given-names>Leslie</given-names>
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<contrib contrib-type="author" id="au980"><name><surname>Pastor</surname>
<given-names>Erica</given-names>
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</contrib>
<contrib contrib-type="author" id="au990"><name><surname>Makohon</surname>
<given-names>Linda</given-names>
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<contrib contrib-type="author" id="au1000"><name><surname>MacArthur</surname>
<given-names>Rodger A</given-names>
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<contrib contrib-type="author" id="au1010"><name><surname>Hillman</surname>
<given-names>L Monique</given-names>
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<contrib contrib-type="author" id="au1020"><name><surname>Farrough</surname>
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<contrib contrib-type="author" id="au1040"><name><surname>Clark</surname>
<given-names>Linda A</given-names>
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<contrib contrib-type="author" id="au1050"><name><surname>Colon</surname>
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<given-names>Ken M</given-names>
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<given-names>June Y</given-names>
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<contrib contrib-type="author" id="au1120"><name><surname>Morris</surname>
<given-names>Alison</given-names>
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<given-names>Robert T</given-names>
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<given-names>Daniel</given-names>
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<contrib contrib-type="author" id="au1250"><name><surname>Muttera</surname>
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<given-names>Ariel E</given-names>
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<given-names>Weerawat</given-names>
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</contrib>
<contrib contrib-type="author" id="au1300"><name><surname>Thaonyen</surname>
<given-names>Supeda</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au1310"><name><surname>Chiewcharn</surname>
<given-names>Thaniya</given-names>
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</contrib>
<contrib contrib-type="author" id="au1320"><name><surname>Suwanpimolkul</surname>
<given-names>Gompol</given-names>
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</contrib>
<contrib contrib-type="author" id="au1330"><name><surname>Gatechumpol</surname>
<given-names>Sivaporn</given-names>
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</contrib>
<contrib contrib-type="author" id="au1340"><name><surname>Bunpasang</surname>
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<given-names>Brian J</given-names>
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<given-names>Monique</given-names>
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<contrib contrib-type="author" id="au1370"><name><surname>Morgan</surname>
<given-names>Marcus</given-names>
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<contrib contrib-type="author" id="au1380"><name><surname>Minton</surname>
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<given-names>Maria N</given-names>
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<given-names>Joe</given-names>
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<given-names>Martin J</given-names>
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<given-names>Jonathan</given-names>
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<contrib contrib-type="author" id="au1440"><name><surname>Carbone</surname>
<given-names>Javier</given-names>
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<given-names>Jose R</given-names>
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<contrib contrib-type="author" id="au1460"><name><surname>Montejano</surname>
<given-names>Rocio</given-names>
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<contrib contrib-type="author" id="au1470"><name><surname>Lobo Beristain</surname>
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<given-names>Iñaki Z</given-names>
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<contrib contrib-type="author" id="au1490"><name><surname>Barberan</surname>
<given-names>Jose</given-names>
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<contrib contrib-type="author" id="au1500"><name><surname>Hernandez</surname>
<given-names>Paola</given-names>
</name>
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<contrib contrib-type="author" id="au1510"><name><surname>Dwyer</surname>
<given-names>Dominic E</given-names>
</name>
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<contrib contrib-type="author" id="au1520"><name><surname>Kok</surname>
<given-names>Jen</given-names>
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<contrib contrib-type="author" id="au1530"><name><surname>Borges</surname>
<given-names>Alvaro</given-names>
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<contrib contrib-type="author" id="au1540"><name><surname>Brandt</surname>
<given-names>Christian T</given-names>
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<given-names>Lene S</given-names>
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<contrib contrib-type="author" id="au1560"><name><surname>Sypsas</surname>
<given-names>Nikolaos</given-names>
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</contrib>
<contrib contrib-type="author" id="au1570"><name><surname>Constantinou</surname>
<given-names>Costas</given-names>
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<contrib contrib-type="author" id="au1580"><name><surname>Markogiannakis</surname>
<given-names>Antonios</given-names>
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<contrib contrib-type="author" id="au1590"><name><surname>Zakynthinos</surname>
<given-names>Spyros</given-names>
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<contrib contrib-type="author" id="au1600"><name><surname>Katsaounou</surname>
<given-names>Paraskevi</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au1610"><name><surname>Kalomenidis</surname>
<given-names>Ioannis</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au1620"><name><surname>Mykietiuk</surname>
<given-names>Analia</given-names>
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<contrib contrib-type="author" id="au1630"><name><surname>Alzogaray</surname>
<given-names>Maria F</given-names>
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</contrib>
<contrib contrib-type="author" id="au1640"><name><surname>Obed</surname>
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<given-names>Laura M</given-names>
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<given-names>Juan</given-names>
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<contrib contrib-type="author" id="au1670"><name><surname>Burgoa</surname>
<given-names>Patricia</given-names>
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</contrib>
<contrib contrib-type="author" id="au1680"><name><surname>Nannini</surname>
<given-names>Esteban</given-names>
</name>
</contrib>
<contrib contrib-type="author" id="au1690"><name><surname>Lahitte</surname>
<given-names>Matias</given-names>
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<contrib contrib-type="author" id="au1700"><name><surname>Perez-Patrigeon</surname>
<given-names>Santiago</given-names>
</name>
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<contrib contrib-type="author" id="au1710"><name><surname>Martínez-Orozco</surname>
<given-names>José Arturo</given-names>
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<contrib contrib-type="author" id="au1720"><name><surname>Ramírez-Hinojosa</surname>
<given-names>Juan Pablo</given-names>
</name>
</contrib>
</contrib-group>
</collab>
</contrib>
</contrib-group>
<aff id="aff1"><label>a</label>
National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA</aff>
<aff id="aff2"><label>b</label>
Hospital General Universitario Gregorio Marañón, Servicio de Immunología Clínica, Madrid, Spain</aff>
<aff id="aff3"><label>c</label>
Henry Ford Hospital, Division of Infectious Diseases, Detroit, MI, USA</aff>
<aff id="aff4"><label>d</label>
Medical Research Council Clinical Trials Unit, University College London, London, UK</aff>
<aff id="aff5"><label>e</label>
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA</aff>
<aff id="aff6"><label>f</label>
Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA</aff>
<aff id="aff7"><label>g</label>
Veteran Affairs Medical Center, Washington, DC, USA</aff>
<aff id="aff8"><label>h</label>
UT Southwestern Medical Center, Dallas, TX, USA</aff>
<aff id="aff9"><label>i</label>
The Kirby Institute, University of New South Wales Australia, Sydney, NSW, Australia</aff>
<aff id="aff10"><label>j</label>
Montefiore Medical Center, Bronx, NY, USA</aff>
<aff id="aff11"><label>k</label>
Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand</aff>
<aff id="aff12"><label>l</label>
The HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Centre, Bangkok, Thailand</aff>
<aff id="aff13"><label>m</label>
Mayo Clinic Hospital, Saint Marys Campus, Rochester, MN, USA</aff>
<aff id="aff14"><label>n</label>
CHIP Centre of Excellence for Health, Immunity, and Infections, Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark</aff>
<author-notes><corresp id="cor1"><label>*</label>
Correspondence to: Dr Richard T Davey Jr, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892–1504, USA <email>rdavey@niaid.nih.gov</email>
</corresp>
<fn id="fn1"><label>*</label>
<p id="cenpara30">Co-chaired the INSIGHT FLU-IVIG protocol</p>
</fn>
<fn id="fn2"><label>†</label>
<p id="cenpara40">The members of the INSIGHT FLU-IVIG Study Group are listed in the <xref rid="sec1" ref-type="sec">appendix</xref>
</p>
</fn>
<fn id="fn3"><label>‡</label>
<p id="cenpara50">Prof Gordin died in March, 2018</p>
</fn>
</author-notes>
<pub-date pub-type="pmc-release"><day>1</day>
<month>11</month>
<year>2019</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub"><month>11</month>
<year>2019</year>
</pub-date>
<volume>7</volume>
<issue>11</issue>
<fpage>951</fpage>
<lpage>963</lpage>
<permissions><copyright-statement>© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="CC BY-NC-ND" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).</license-p>
</license>
</permissions>
<related-article related-article-type="article-reference" id="d31e12" ext-link-type="doi" xlink:href="10.1016/S2213-2600(19)30199-7"></related-article>
<related-article related-article-type="article-reference" id="d31e17" ext-link-type="doi" xlink:href="10.1016/S2213-2600(19)30265-6"></related-article>
<abstract id="ceab10"><title>Summary</title>
<sec><title>Background</title>
<p>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.</p>
</sec>
<sec><title>Methods</title>
<p>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 <ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" id="interrefs10">ClinicalTrials.gov</ext-link>
, <ext-link ext-link-type="ClinicalTrials.gov" xlink:href="NCT02287467" id="interrefs20">NCT02287467</ext-link>
.</p>
</sec>
<sec><title>Findings</title>
<p>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.</p>
</sec>
<sec><title>Interpretation</title>
<p>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.</p>
</sec>
<sec><title>Funding</title>
<p>NIAID and NIH. Partial support was provided by the Medical Research Council (MRC_UU_12023/23) and the Danish National Research Foundation.</p>
</sec>
</abstract>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>Danemark</li>
<li>Espagne</li>
<li>Royaume-Uni</li>
<li>Thaïlande</li>
<li>États-Unis</li>
</country>
<region><li>Angleterre</li>
<li>Communauté de Madrid</li>
<li>District de Columbia</li>
<li>Grand Londres</li>
<li>Hovedstaden</li>
<li>Maryland</li>
<li>Michigan</li>
<li>Minnesota</li>
<li>Texas</li>
<li>État de New York</li>
</region>
<settlement><li>Copenhague</li>
<li>Londres</li>
<li>Madrid</li>
</settlement>
<orgName><li>University College de Londres</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Maryland"><name sortKey="Davey, Richard T" sort="Davey, Richard T" uniqKey="Davey R" first="Richard T" last="Davey">Richard T. Davey</name>
</region>
<name sortKey="Beigel, John H" sort="Beigel, John H" uniqKey="Beigel J" first="John H" last="Beigel">John H. Beigel</name>
<name sortKey="Engen, Nicole" sort="Engen, Nicole" uniqKey="Engen N" first="Nicole" last="Engen">Nicole Engen</name>
<name sortKey="Gordin, Fred" sort="Gordin, Fred" uniqKey="Gordin F" first="Fred" last="Gordin">Fred Gordin</name>
<name sortKey="Jain, Mamta K" sort="Jain, Mamta K" uniqKey="Jain M" first="Mamta K" last="Jain">Mamta K. Jain</name>
<name sortKey="Kan, Virginia" sort="Kan, Virginia" uniqKey="Kan V" first="Virginia" last="Kan">Virginia Kan</name>
<name sortKey="Khurana, Surender" sort="Khurana, Surender" uniqKey="Khurana S" first="Surender" last="Khurana">Surender Khurana</name>
<name sortKey="Lane, H Clifford" sort="Lane, H Clifford" uniqKey="Lane H" first="H Clifford" last="Lane">H Clifford Lane</name>
<name sortKey="Markowitz, Norman" sort="Markowitz, Norman" uniqKey="Markowitz N" first="Norman" last="Markowitz">Norman Markowitz</name>
<name sortKey="Neaton, James D" sort="Neaton, James D" uniqKey="Neaton J" first="James D" last="Neaton">James D. Neaton</name>
<name sortKey="Riska, Paul" sort="Riska, Paul" uniqKey="Riska P" first="Paul" last="Riska">Paul Riska</name>
<name sortKey="Temesgen, Zelalem" sort="Temesgen, Zelalem" uniqKey="Temesgen Z" first="Zelalem" last="Temesgen">Zelalem Temesgen</name>
<name sortKey="Wentworth, Deborah" sort="Wentworth, Deborah" uniqKey="Wentworth D" first="Deborah" last="Wentworth">Deborah Wentworth</name>
</country>
<country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Fernandez Cruz, Eduardo" sort="Fernandez Cruz, Eduardo" uniqKey="Fernandez Cruz E" first="Eduardo" last="Fernández-Cruz">Eduardo Fernández-Cruz</name>
</region>
</country>
<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Pett, Sarah" sort="Pett, Sarah" uniqKey="Pett S" first="Sarah" last="Pett">Sarah Pett</name>
</region>
<name sortKey="Babiker, Abdel G" sort="Babiker, Abdel G" uniqKey="Babiker A" first="Abdel G" last="Babiker">Abdel G. Babiker</name>
</country>
<country name="Australie"><noRegion><name sortKey="Polizzotto, Mark N" sort="Polizzotto, Mark N" uniqKey="Polizzotto M" first="Mark N" last="Polizzotto">Mark N. Polizzotto</name>
</noRegion>
</country>
<country name="Thaïlande"><noRegion><name sortKey="Ruxrungtham, Kiat" sort="Ruxrungtham, Kiat" uniqKey="Ruxrungtham K" first="Kiat" last="Ruxrungtham">Kiat Ruxrungtham</name>
</noRegion>
<name sortKey="Ruxrungtham, Kiat" sort="Ruxrungtham, Kiat" uniqKey="Ruxrungtham K" first="Kiat" last="Ruxrungtham">Kiat Ruxrungtham</name>
</country>
<country name="Danemark"><region name="Hovedstaden"><name sortKey="Lundgren, Jens" sort="Lundgren, Jens" uniqKey="Lundgren J" first="Jens" last="Lundgren">Jens Lundgren</name>
</region>
</country>
</tree>
</affiliations>
</record>
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