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Concept for a study design in patients with severe community-acquired pneumonia: A randomised controlled trial with a novel IGM-enriched immunoglobulin preparation – The CIGMA study

Open AccessPublished:April 02, 2015DOI:https://doi.org/10.1016/j.rmed.2015.03.008

      Summary

      Introduction

      Severe community-acquired pneumonia is defined as community-acquired pneumonia that requires intensive medical care. Mortality in these patients is still high depending on time and admission. Since bad outcomes may occur despite antibiotic therapy to treat severe community-acquired pneumonia, the focus has shifted to targeting the host response. The CIGMA Study examines the safety and efficacy of the novel IgM-enriched immunoglobulin preparation BT086 when added to standard of care treatment.

      Methods/design

      The aim of this multicentre, randomised, placebo-controlled, double-blind, parallel-group, adaptive group-sequential phase II study is to determine the efficacy and safety of BT086, an IgM-enriched immunoglobulin preparation, as an adjunctive treatment in mechanically-ventilated patients with severe community-acquired pneumonia. The increase of ventilator-free days is the primary endpoint in this study. For this trial, ventilator-free days are defined as the number of days between successful extubation from endotracheal ventilation and day 28 after enrolment of the patient into the study. Two interim analyses were considered for this study.

      Discussion

      Several novel agents for treatment of sepsis have been evaluated in the last two decades; however, none has significantly reduced mortality rates. Failure was attributed to the heterogeneity of septic patients or sepsis. Severe community-acquired pneumonia was chosen as the indication for this study to increase homogeneity within this patient population.

      Trial registration

      EUDRACT 2010-022380-35.

      Keywords

      Abbreviations:

      ATC (anatomical therapeutical chemical), APC (activated protein C), ATS (American Thoracic Society), CAP (community-acquired pneumonia), CI (confidence interval), CRO (Clinical Research Organisation), DSMB (Data Safety Monitoring Board), ICU (intensive care unit), IDSA (Infectious Disease Society of America), IVIG (intravenous immunoglobulin), PEEP (positive end-expiratory pressure), PI (probabilistic index), RR (relative risk), rTFPI (recombinant tissue factor pathway inhibitor), SBT (spontaneous breathing trial), sCAP (severe community-acquired pneumonia), SOFA (Sequential Organ Failure Assessment (score)), SD (standard deviation), TLR4 (toll-like receptor 4), VFD (ventilator-free day), WBC (white blood cell)

      Introduction

      The CIGMA (Concentrated IgM for Application) Study is a multicentre, multi-national, randomised, placebo-controlled, parallel-group, adaptive group-sequential phase II study to determine the efficacy and safety of the IgM-enriched immunoglobulin preparation BT086 as an adjunctive treatment in severe community-acquired pneumonia (sCAP).
      Community-acquired pneumonia (CAP) occurring in individuals who have not recently been in hospital is a significant cause of morbidity and mortality in adults. CAP mortality rates are high and have not changed significantly over the past several decades despite the availability of improved broad-spectrum antibiotics [
      • Bartlett J.G.
      • Dowell S.F.
      • Mandell L.A.
      • File Jr., T.M.
      • Musher D.M.
      • Fine M.J.
      Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America.
      ,
      • Sibila O.
      • Restrepo M.I.
      • Anzueto A.
      What is the best antimicrobial treatment for severe community-acquired pneumonia (including the role of steroids and statins and other immunomodulatory agents)?.
      ]. CAP incidence varies by geographic region, gender (more common in men than in women), and age (more common in people aged ≥65 years). Mortality has been reported to vary from <1% to 48% and is associated with advanced age, co-morbid conditions, and CAP severity [
      • Welte T.
      • Torres A.
      • Nathwani D.
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ]. In the United States, CAP is the number one cause of death from infectious diseases and the eighth leading cause of death, with an estimated 1.3 million hospitalisations each year and an estimated cost of $40 billion [
      • Niederman M.S.
      Community-acquired pneumonia: the US perspective.
      ].
      sCAP is usually defined clinically as CAP that requires intensive medical care. Up to 10% of hospitalized adult CAP patients require intensive medical care and are transferred to intensive care units (ICUs) [
      • Ewig S.
      • Torres A.
      Community acquired pneumonia as an emergency: time for an aggressive intervention to lower mortality.
      ] with great impact on health care costs [
      • Welte T.
      • Torres A.
      • Nathwani D.
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ,
      • Oosterheert J.J.
      • Bonten M.J.
      • Hak E.
      • Schneider M.M.
      • Hoepelman A.I.
      Severe community-acquired pneumonia: what's in a name?.
      ] and outcome. Mortality of sCAP patients admitted to ICUs usually ranges from 35 to 58% depending on time and admission to hospital [
      • Woodhead M.
      • Welch C.A.
      • David A.H.
      • Geoff B.
      • Jon G.A.
      Community-acquired pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database.
      ]. However, two recent trials on sCAP found a mortality rate of only 17.9% [ 8] and 23.1% [
      • Sirvent J.M.
      • Carmen de la Torre M.
      • Lorencio C.
      • Taché A.
      • Ferri C.
      • Garcia-Gil J.
      • et al.
      Predictive factors of mortality in severe community-acquired pneumonia: a model with data on the first 24h of ICU admission.
      ].
      A review published by Cillóniz et al. [
      • Cillóniz C.
      • Ewig S.
      • Polverino E.
      • Marcos M.A.
      • Esquinas C.
      • Gabarrús A.
      • et al.
      Microbial aetiology of community-acquired pneumonia and its relation to severity.
      ] reported that the aetiology for CAP was unknown in more than 50% of cases despite the use of ever improving microbiological techniques. The most common identified cause of CAP and sCAP remains the bacterium Streptococcus pneumoniae [
      • Welte T.
      • Torres A.
      • Nathwani D.
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ,
      • Cillóniz C.
      • Ewig S.
      • Polverino E.
      • Marcos M.A.
      • Esquinas C.
      • Gabarrús A.
      • et al.
      Microbial aetiology of community-acquired pneumonia and its relation to severity.
      ].
      Widespread increased resistance of common respiratory pathogens to antibiotics is becoming a major challenge in treating this life-threatening condition [
      • Welte T.
      • Torres A.
      • Nathwani D.
      Clinical and economic burden of community-acquired pneumonia among adults in Europe.
      ,
      • Lynch 3rd, J.P.
      • Zhanel G.G.
      Escalation of antimicrobial resistance among Streptococcus pneumoniae: implications for therapy.
      ].
      Since bad outcomes may occur despite antibiotic therapy in sCAP, attention has turned to targeting the host response in an attempt to improve sCAP outcomes. This approach is supported by the observation that systemic cytokine response to pathogens leads to the progression of sCAP, and the spectrum of circulating cytokines in hospitalised sCAP patients is indicative of elevated inflammation in most cases, irrespective of sepsis [
      • Kellum J.A.
      • Kong L.
      • Fink M.P.
      • Weissfeld L.A.
      • Yealy D.M.
      • Pinsky M.R.
      • et al.
      Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study.
      ]. Recombinant tissue factor pathway inhibitors (rTFPI), activated protein C (APC), corticosteroids, and intravenous immunoglobulins have been investigated for their potential as adjunctive and host-targeted treatments for sCAP [
      • Sibila O.
      • Restrepo M.I.
      • Anzueto A.
      What is the best antimicrobial treatment for severe community-acquired pneumonia (including the role of steroids and statins and other immunomodulatory agents)?.
      ].
      The rTFPI tifacogin has been shown to restore regulation of tissue factor pathways, reducing mortality, inflammation, and lung injury in a number of animal models. After promising initial results in small patient populations, a controlled trial (2138 patients) was conducted with tifacogin in adults with sCAP [
      • Wunderink R.G.
      • Laterre P.F.
      • Francois B.
      • Perrotin D.
      • Artigas A.
      • Vidal L.O.
      • et al.
      CAPTIVATE Trial Group
      Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.
      ]. In this large trial tifacogin treatment had no mortality benefit in patients with sCAP, despite evidence of biological activity as an anticoagulant protein.
      APC has antithrombotic, anti-inflammatory, and pro-fibrinolytic properties that might be beneficial in the treatment of sCAP. The PROWESS trial, conducted in 1690 patients with severe sepsis, reported that treatment with APC (drotrecogin alfa activated [Xigris®]) significantly reduced mortality in patients with severe sepsis but may be associated with an increased risk of bleeding [
      • Bernard G.R.
      • Vincent J.L.
      • Laterre P.F.
      • LaRosa S.P.
      • Dhainaut J.F.
      • Lopez-Rodriguez A.
      • et al.
      Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis.
      ]. In contrast, the PROWESS SHOCK trial conducted in 1697 patients with septic shock showed that APC did not reduce mortality significantly after 28 or 90 days [
      • Ranieri V.M.
      • Thompson B.T.
      • Barie P.S.
      • Dhainaut J.F.
      • Douglas I.S.
      • Finfer S.
      • et al.
      Drotrecogin alfa (activated) in adults with septic shock.
      ]. In 2011 drotrecogin alfa activated was withdrawn from the market.
      The anti-inflammatory properties of corticosteroids may reduce the intense pro-inflammatory cytokine response and thus modify the occurrence and severity of organ failures. However, results to date have been inconclusive [
      • Confalonieri M.
      • Kodric M.
      • Santagiuliana M.
      • Longo C.
      • Biolo M.
      • Cifaldi R.
      • et al.
      To use or not to use corticosteroids for pneumonia? A clinician's perspective.
      ]. Meijvis et al. [
      • Meijvis S.C.
      • Hardeman H.
      • Remmelts H.H.
      • Heijligenberg R.
      • Rijkers G.T.
      • van Velzen-Blad H.
      • et al.
      Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.
      ] recently reported that non-immunocompromised CAP patients had significantly shorter length of hospital stays (without excess complications) when treated with dexamethasone in a randomised, double-blind, placebo-controlled clinical trial. Based on the results from four studies evaluating the use of corticosteroids for sCAP, Salluh et al. [
      • Salluh J.I.F.
      • Póvoa P.
      • Soares M.
      • Castro-Faria-Neto H.C.
      • Bozza F.A.
      • Bozza P.T.
      The role of corticosteroids in severe community acquired pneumonia: a systematic review.
      ] did not recommend the use of corticosteroids as adjunctive therapy for this indication. In patients with septic shock, the large CORTICUS trial (499 patients) found that hydrocortisone did not improve survival or reversal of shock [
      • Sprung C.L.
      • Annane D.
      • Keh D.
      • Moreno R.
      • Singer M.
      • Freivogel K.
      • et al.
      CORTICUS Study Group
      Hydrocortisone therapy for patients with septic shock.
      ].
      TLR4 (toll-like receptor 4) is a receptor stimulated primarily by endotoxin leading to the production of pro-inflammatory cytokines. Blocking this receptor may possibly reduce the pro-inflammatory response. However, in a phase III study in 1961 patients with severe sepsis the TLR4 antagonist Eritoran did not show reduced 28-day mortality compared to placebo [
      • Opal S.M.
      • Laterre P.F.
      • Francois B.
      • LaRosa S.P.
      • Angus D.C.
      • Mira J.P.
      • et al.
      Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.
      ].
      In addition various types of intravenous immunoglobulin preparations have been investigated as possible adjunctive treatment for sepsis. Pentaglobin® with 12% IgM, 12% IgA and 76% IgG is currently the sole approved immunoglobulin preparation enriched with IgM having a variety of anti-bacterial and anti-inflammatory properties. It can neutralise bacterial endo- and exotoxins [
      • Esen F.
      • Tugrul S.
      IgM-enriched immunoglobulins in sepsis.
      ,
      • Trautmann M.
      • Held T.K.
      • Susa M.
      • Karajan M.A.
      • Wulf A.
      • Cross A.S.
      • et al.
      Bacterial lipopolysaccharide (LPS)-specific antibodies in commercial human immunoglobulin preparations: superior antibody content of an IgM-enriched product.
      ], increase opsonisation and bacterial phagocytosis [
      • Garbett N.D.
      • Munro C.S.
      • Cole P.J.
      Opsonic activity of a new intravenous immunoglobulin preparation: Pentaglobin compared with Sandoglobulin.
      ], and can enhance bacterial lysis due to specific complement activation [
      • Stephan W.
      Investigations to demonstrate the antibacterial and antitoxic efficacy of an IgM-enriched intravenous immunoglobulin preparation.
      ]. It can also exhibit anti-inflammatory and immunomodulatory effects via scavenging of excessively activated complement factors [
      • Rieben R.
      • Roos A.
      • Muizert Y.
      • Tinguely C.
      • Gerritsen A.F.
      • Daha M.R.
      Immunoglobulin M-enriched human intravenous immunoglobulin prevents complement activation in vitro and in vivo in a rat model of acute inflammation.
      ], and modulation of the immune response via Fcγ receptor interactions in case of severe bacterial infections [
      • Ehrenstein M.R.
      • Notley C.A.
      The importance of natural IgM: scavenger, protector and regulator.
      ].
      The majority of clinical trials with Pentaglobin® have been performed thus far in patients with severe bacterial infections and not explicitly in sCAP patients.
      Two relevant systematic reviews of clinical trials concluded that immunoglobulins and in particular the immunoglobulin preparation enriched with IgM, are of benefit in adult and older paediatric sepsis patients [
      • Kreymann K.G.
      • de Heer G.
      • Nierhaus A.
      • Kluge S.
      Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock.
      ,
      • Alejandria M.M.
      • Lansang M.A.
      • Dans L.F.
      • Mantaring 3rd, J.B.
      Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock.
      ].
      Kreymann et al. [
      • Kreymann K.G.
      • de Heer G.
      • Nierhaus A.
      • Kluge S.
      Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock.
      ] conducted a comprehensive systematic review of all published trials examining the effect of various polyclonal immunoglobulin preparations on mortality in patients with sepsis or septic shock. 15 trials in adults or children and 12 in on-term or preterm neonates (27 trials in 2202 patients in total) were examined, in which the estimate of the pooled risk revealed a significant relative reduction of overall mortality of 21% and 44%, respectively. In the IgM-enriched immunoglobulin preparation subgroups, a notably higher, but not statistically significant reduction in overall mortality was observed with a 34% mortality reduction in adults or children and 50% in neonates. Alejandria et al. [
      • Alejandria M.M.
      • Lansang M.A.
      • Dans L.F.
      • Mantaring 3rd, J.B.
      Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock.
      ] conducted a comprehensive systematic review of all published trials examining the effects of all intravenous immunoglobulins (IVIG) on mortality and duration of hospitalisation in patients with sepsis or septic shock. Subgroup analysis of 10 polyclonal IVIG trials in adults (n = 1430) and 7 trials on IgM-enriched polyclonal IVIGs (n = 528) showed significant reductions in mortality compared to placebo or no intervention (relative risk [RR] 0.81; 95% confidence interval [CI]) 0.70 to 0.93 and RR 0.66; 95% CI 0.51 to 0.85, respectively). A sensitivity analysis of only those trials with a low risk of bias showed no reduction in mortality in adults irrespective of treatment with polyclonal IVIG or the IgM-enriched immunoglobulin preparation. The CIGMA Study will provide further data to elucidate the controversial results of these two meta-analyses.
      A large study with 653 patients with severe sepsis (SBITS trial) showed that the administration of polyclonal IVIG preparations (not enriched with IgM) could not reduce the mortality rate [
      • Werdan K.
      • Pilz G.
      • Bujdoso O.
      • Fraunberger P.
      • Neeser G.
      • Schmieder R.E.
      • et al.
      Score-based immunoglobulin G therapy of patients with sepsis: the SBITS study.
      ]. For that reason in the German Sepsis Guideline [
      • Reinhart K.
      • Brunkhorst F.M.
      • Bone H.-G.
      • Bardutzky J.
      • Dempfle C.-E.
      • Forst H.
      • et al.
      Prevention, diagnosis, therapy and follow-up care of sepsis: 1st revision of S-2k guidelines of the German Sepsis Society (Deutsche Sepsis-Gesellschaft e.V. (DSG)) and the German Interdisciplinary Association of Intensive Care and Emergency Medicine (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)).
      ] IgM-enriched immunoglobulins could be considered for patients with severe sepsis and septic shock, whereas IVIGs not enriched with IgM are not recommended.
      Berlot et al. [
      • Berlot G.
      • Vassallo M.C.
      • Busetto N.
      • Bianchi M.
      • Zornada F.
      • Rosato I.
      • et al.
      Relationship between the timing of administration of IgM and IgA enriched immunoglobulins in patients with severe sepsis and septic shock and the outcome: a retrospective analysis.
      ] have reported that the efficacy of Pentaglobin® in patients with severe sepsis and septic shock is time dependent, similar to broad spectrum antibiotics. They found that every 24 h of delay in administration of IgM resulted in a linear increase in mortality by 2.8%. This finding may be an important factor to explain the inconsistent findings reported from systematic reviews.
      The question if reduced IgM levels are a risk factor for severe infections was recently addressed in different populations including patients with CAP, influenza (H1N1) pdm09 and sepsis [
      • de la Torre M.C.
      • Bolíbar I.
      • Vendrell M.
      • de Gracia J.
      • Vendrell E.
      • Rodrigo M.J.
      • et al.
      Serum immunoglobulins in the infected and convalescent phases in community-acquired pneumonia.
      ,
      • Justel M.
      • Socias L.
      • Almansa R.
      • Ramírez P.
      • Gallegos M.C.
      • Fernandez V.
      • et al.
      IgM levels in plasma predict outcome in severe pandemic influenza.
      ,
      • Päsler M.
      • Dietz S.
      • Werdan K.
      Hypogammaglobulinemia in sepsis.
      ,
      • Giamarellos-Bourboulis E.J.
      • Apostolidou E.
      • Lada M.
      • Perdios I.
      • Gatselis N.K.
      • Tsangaris I.
      • et al.
      Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome.
      ]. Results in patients with severe sepsis progressing to septic shock and in patients with viral infections showed that non-survivors had lower levels of IgM compared to survivors [
      • Giamarellos-Bourboulis E.J.
      • Apostolidou E.
      • Lada M.
      • Perdios I.
      • Gatselis N.K.
      • Tsangaris I.
      • et al.
      Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome.
      ,
      • Justel M.
      • Socias L.
      • Almansa R.
      • Ramírez P.
      • Gallegos M.C.
      • Fernandez V.
      • et al.
      IgM levels in plasma predict outcome in severe pandemic influenza.
      ]. De la Torre et al. [
      • de la Torre M.C.
      • Bolíbar I.
      • Vendrell M.
      • de Gracia J.
      • Vendrell E.
      • Rodrigo M.J.
      • et al.
      Serum immunoglobulins in the infected and convalescent phases in community-acquired pneumonia.
      ] described for the first time that CAP patients had lower immunoglobulin levels compared with healthy volunteers. Immunoglobulin levels were especially low at the time of diagnosis, and in patients infected with S. pneumoniae. Immunoglobulin levels are also to be measured in a subgroup of the patients in the CIGMA Study.
      The novel product BT086 was developed to generate a preparation with double the content of IgM compared to Pentaglobin®. BT086 contains approximately 23% IgM, 23% IgA, and 54% IgG compared to Pentaglobin® (12% IgM, 12% IgA, and 76% IgG). In addition, a new manufacturing process for BT086 was established to obtain more native immunoglobulins with highly active binding sites.
      First-in-man clinical data are available from a phase I dose escalation study performed to investigate the safety, tolerability, and pharmacokinetics of BT086 after single and repeated doses given as intravenous infusions to healthy subjects [
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg-Demand A.
      • Remy A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a dose escalating single dose phase I study.
      ,
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg Demand A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a multiple dose phase I study.
      ]. Administration of BT086 was well tolerated. Intravenous single infusion of BT086 (mean baseline value 105.5 mg/dL) led to the expected increase of IgM of up to 102 mg/dL [
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg-Demand A.
      • Remy A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a dose escalating single dose phase I study.
      ]. With repeated infusions, 5 administrations of one dosage of BT086 on 5 consecutive days, (mean IgM baseline concentrations 123.8 mg/dL), IgM Cmax reached 172.4 mg/dL and a t1/2 was estimated at about 7.6 days [
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg Demand A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a multiple dose phase I study.
      ].
      BT086 has a broad range of activity against clinically relevant gram negative and gram positive bacteria. In the phase I study specific antibody activities against the following indicator pathogens were measured: E. coli, C. albicans, and the sCAP pathogen S. pneumoniae . Specific antibody activities were increased in the serum of healthy subjects after treatment with BT086 compared to the control group (unpublished results).
      To further evaluate BT086, the CIGMA Study in sCAP patients has been initiated and is introduced here. The sponsor of the study is Biotest (Dreieich, Germany) and has appointed Accovion Clinical Research Organisation (CRO) to manage the CIGMA study in all countries.

      Methods and patient population

      160 patients are planned to be included in the CIGMA Study (the original sample size of 82 patients was increased to 160 patients after an interim analysis on the first 40 patients). Eligible patients are to be diagnosed with sCAP based on clinical and radiological findings, be in need of endotracheal ventilation, and have received antibiotic therapy.
      For a correct allocation of hospitalised patients, the Infectious Disease Society of America (IDSA) and the American Thoracic Society (ATS) have issued guidelines on the management of CAP that include severity criteria to identify those patients that should receive ICU care [
      • Mandell L.A.
      • Wunderink R.G.
      • Anzueto A.
      • Bartlett J.G.
      • Campbell G.D.
      • Dean N.C.
      • et al.
      Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
      ]. The major criteria of the IDSA/ATS guidelines refer to patients with acute respiratory failure requiring invasive endotracheal ventilation or with septic shock.
      Inclusion and exclusion criteria in the CIGMA Study have been developed on the basis of the CAP/sCAP criteria of the IDSA/ATS guidelines [
      • Mandell L.A.
      • Wunderink R.G.
      • Anzueto A.
      • Bartlett J.G.
      • Campbell G.D.
      • Dean N.C.
      • et al.
      Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
      ], the Food and Drug Administration's Guidance for Industry [
      • U.S. Department of Health and Human Services, Food and Drug Administration
      Guidance for industry. community-acquired bacterial pneumonia: developing drugs for treatment.
      ], and the German S3 Guidelines [
      • Höffken G.
      • Lorenz L.
      • Kern W.
      • Welte T.
      • Bauer T.
      • Dalhoff K.
      • et al.
      Epidemiology, diagnosis, antimicrobial therapy and management of community-acquired pneumonia and lower respiratory tract infections in adults. Guidelines of the Paul-Ehrlich-Society for Chemotherapy, the German Respiratory Society, the German Society for Infectiology and the Competence Network CAPNETZ Germany.
      ].
      The key inclusion criteria are:
      • Patient must have at least one of the following signs and symptoms of pneumonia: new or increased cough; production of purulent sputum or change in sputum characteristics; dyspnoea or tachypnoea (respiratory rate >20 breaths/minute); pleuritic chest pain; auscultatory findings on pulmonary examination of rales and/or crackles and/or evidence of pulmonary consolidation (e.g. dullness on percussion, bronchial breath sounds, or egophony).
      • Radiological (or other imaging technique) evidence of (an) infiltrate(s) consistent with bacterial pneumonia.
      • Major sCAP criterion: need for endotracheal ventilation.
      • Pneumonia has been acquired outside hospital. In hospital-admitted patients, pneumonia has been diagnosed a maximum of 72 h after admission. Patients from nursing homes or similar institutions are eligible. Male or female patients aged 18 years or older.
      • Patient receiving adequate antibiotic treatment for pneumonia.
      • Prior to endotracheal ventilation and therapy, the patient must have at least one of the following two signs of inflammation: fever/hypothermia or white blood cell (WBC) count >10,000/mm3 or WBC <4500/mm3.
      • Treatment of patient with BT086 must start within 12 h but not earlier than 1 h after start of endotracheal ventilation.
      The key exclusion criteria are:
      • Patients with suspected hospital-acquired pneumonia.
      • Severe lung diseases interfering with sCAP therapy.
      • Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing uncorrectable medical condition).
      • Patients with neutrophil count <1000/mm3 or platelet count <50,000/mm3.

      Primary endpoint

      The primary endpoint of the study is the increase of ventilator-free days (VFDs). VFDs are defined as the number of days between successful extubation from endotracheal ventilation and day 28 after enrolment of the patient into the study. VFDs are defined as “0” if the patient dies before day 28 or in case endotracheal ventilation is stopped at day 28 or later. VFDs are assessed in mechanically ventilated sCAP patients receiving appropriate standard of care treatment in addition to either BT086 or placebo.

      Secondary endpoints

      Secondary endpoints include VFDs in surviving patients, 28-day all-cause mortality, 28-day pneumonia-cause mortality, time to discharge from ICU, time to discharge from hospital, Sequential Organ Failure Assessment (SOFA) Score, Glasgow Coma Score and vasopressor-free days.

      Other objectives

      Safety parameters are to be collected in all patients to ensure accurate monitoring of safety and tolerability. Pharmacodynamic and pharmacokinetic parameters are to be measured in a subgroup of patients.

      Dose selection

      Dose selection was based on results from Rodriguez et al. [
      • Rodríguez A.
      • Rello J.
      • Neira J.
      • Maskin B.
      • Ceraso D.
      • Vasta L.
      • et al.
      Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery.
      ] and the phase I first-in-man study [
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg-Demand A.
      • Remy A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a dose escalating single dose phase I study.
      ,
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg Demand A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a multiple dose phase I study.
      ]. In this study, a BT086 dose of 42 mg IgM/kg body weight demonstrated reproducible dose-dependent elevated plasma levels of IgM after repeated application. Therefore, this dose was selected for the CIGMA Study, and is to be administered for 5 consecutive days.

      Design

      The CIGMA Study is a multicentre, randomised, placebo-controlled, double-blind, parallel-group, adaptive group-sequential phase II study. The purpose of the study is to determine the efficacy and safety of BT086 as an adjunctive treatment in mechanically ventilated patients with sCAP.
      In this trial, BT086 is to be given in addition to the best standard of treatment and is to be compared against a control arm consisting of the best standard of treatment and placebo (1% albumin). Thus far, no approved treatment has demonstrated efficacy in addition to the best standard of treatment in sCAP patients that could be used as an active comparator in this study. Eligible patients are to be randomised 1:1 to treatment with BT086 or placebo. Infusion with BT086 is to begin between ≥1 h and ≤12 h after starting endotracheal ventilation. During the treatment phase, patients are to be treated with 42 mg IgM/kg body weight or equal volume of 1% albumin for 5 consecutive days (Fig. 1). Patients are to remain in the CIGMA Study up to day 28 or hospital discharge, whichever occurs first.
      Figure thumbnail gr1
      Figure 1All 160 patients were to be randomised in a 1:1 ratio to BT086 or to placebo (1% albumin). Pretreatment phase: patients were to be screened and randomised into the study between 1 and 12 h after starting ventilation. Treatment phase: after randomisation patients were to be treated for 5 days with 42 mg IgM/kg bw/day or placebo. Follow-up phase: patients were to remain in the trial until day 28 or discharge from hospital, whichever occurred first.
      Since ventilation and weaning procedures might differ among sites and countries, a study-specific guidance on endotracheal ventilation and weaning was developed for this trial.
      This guidance is mainly based on the concept of lung protective ventilation [
      • Esan A.
      • Hess D.
      • Sessler C.
      • George L.
      • Oribabor C.
      • Khusid F.
      • et al.
      Ventilator strategies in severe hypoxaemic respiratory failure.
      ]. The main goals of mechanical ventilation are to achieve adequate oxygenation; PaO2 target level >65 mm Hg; appropriate alveolar ventilation, PaCO2 target level intended to achieve arterial pH between 7.25 and 7.45 with minimal risk of barotrauma, volutrauma, or atelectrauma; end-inspiratory plateau pressure ideally below 30 cm H2O; and use of minimal level of positive end-expiratory pressure (PEEP). Minimal haemodynamic deterioration can be achieved by avoiding excessive ventilation and PEEP, and by using the minimal necessary level of analgesia-sedation. Patients are to be evaluated daily for clinical stability, normal consciousness, and improvement of respiratory failure to decide whether to withdraw mechanical ventilation and to start a spontaneous breathing trial [
      • MacIntyre N.R.
      The ventilator discontinuation process: an expanding evidence base.
      ] (SBT). The duration of the SBT is to be between 30 and 120 min; the presence and persistence of criteria for SBT failure is to be assessed during the trial.
      The decision to extubate or to reconnect a patient to the ventilator is to be based on the absence of signs of SBT failure [
      • Thille A.W.
      • Richard J.C.
      • Brochard L.
      The decision to extubate in the intensive care unit.
      ] after 30–120 min, adequate mental status, and cough with ability to expectorate. If these conditions are not fulfilled, patients are to be reconnected to the ventilator. Subsequent attempts are to be performed daily provided that patients still fulfil criteria for the withdrawal of mechanical ventilation. After extubation, patients are to receive Venturi oxygen therapy.

      Data Safety Monitoring Board

      For this phase II study, the sponsor Biotest established a Data Safety Monitoring Board (DSMB) for the following reasons:
      • The study is to be conducted in patients with sCAP, a life-threatening disease with high rates of mortality.
      • The study is to include blinded study treatment groups.
      • The study is to be conducted in patients unable to provide informed consent by themselves.

      Statistical methods

      All statistical methods, the primary and secondary endpoints, all variables, as well as the statistical methods to be used for both interim analyses and the final analysis are described a priori in the study protocol and were detailed in the statistical analysis plan.

      Analysis of VFDs

      Treatment effects on VFDs may be attributed to changes in mortality or to changes in the duration of ventilation in survivors; as a result, differences between two treatments cannot be meaningfully expressed in terms of mean or median differences. Therefore, statistical tests powered to detect a shift in means or medians do not appropriately assess a treatment effect in a composite endpoint like VFDs.
      The statistical approach in this study is based on the concept of stochastic dominance of distribution functions. The probabilistic index [
      • Acion L.
      • Peterson J.J.
      • Temple S.
      • Arndt S.
      Probabilistic index: an intuitive non-parametric approach to measuring the size of treatment effects.
      ] (PI) is used to quantify the probability that any patient in a given treatment group has a better outcome than any patient in the other group. As patients benefit from a treatment that increases their chances to survive or to have a shorter duration of ventilation, the cumulated frequency distribution of VFDs (from 0 to 28) in the superior treatment is located below the frequency distribution of the inferior treatment (Fig. 2). If two treatments are identical, a patient has an equal chance to benefit from one or from the other, expressed by a PI of 0.5. Values above 0.5 indicate that a treatment is superior, values below 0.5 indicate inferiority. The PI can be derived from Mann–Whitney's U-statistic, divided by the number of all possible pairs of observations from each group. The corresponding statistical test is the Wilcoxon-Mann-Whitney-test. Asymptotically, the PI is normally distributed allowing easy computation of CIs.
      Figure thumbnail gr2
      Figure 2Treatment A, upper curve, shows a cumulative distribution of ventilator-free days (VFDs) in a patient population with a mean value of 6 VFDs (standard deviation = 6.8). The probability of zero VFDs due to fatal events or 28 VFDs or more is 40%. Treatment B curve shows the cumulated distribution of VFDs in a population with a higher chance of surviving or more VFDs: the probability of zero VFDs is 25% with a mean value of 8.9 VFDs (standard deviation = 7.5). The probabilistic index is 0.62 indicating that any patient on treatment B has a 62% chance of more VFDs (or survival) compared with any patient on treatment A.

      Group sequential-adaptive design

      To adapt the study to accumulating data, a group-sequential adaptive design was chosen which allows design modifications such as sample size re-estimation or planning of further analyses based on interim results. This design combines features of a classic group-sequential design with the theory of adaptive designs based on combination tests. Group-sequential designs allow to perform pre-planned interim analyses on the accumulating data and to stop the study at interim if the study objective has been met or if it is unlikely that the study will reach its objectives. Because each interim look increases the risk of a false positive decision, the critical values of the tests (stopping boundaries) are adjusted accordingly. More flexibility can be gained if the study stages are evaluated separately and an adaptive combination test used to combine the stage-wise results. In this study, a combination test based on the inverse normal method is used to combine the stage-wise test-statistics [
      • Lehmacher W.
      • Wassmer G.
      Adaptive sample size calculations in group sequential trials.
      ]. This combination test allows to use the boundaries of a classic group-sequential design: to preserve the overall level of significance (2.5%, one-sided), an alpha-spending approach with O'Brien-Fleming boundaries to adjust critical values and significance levels of the interim and final analyses (alpha 1 = 0.23%, alpha 2 = 2.41%) was used. One-sided statistical tests were chosen to avoid contradictory results in the interim and the final analyses leading to an overall significant but not clinically meaningful result. It is also planned that the study can be stopped for futility if the conditional power (probability of success in case of a true treatment effect) is below 10%.

      Sample size estimation

      The sample size of the study was planned based on an expected mean difference between BT086 and placebo of 2 VFDs and a standard deviation (SD) of 3 VFDs. Using Noether's formula for the sample size of the Wilcoxon-Mann-Whitney-test, the sample size calculation for the group-sequential design resulted in a sample size of 82 patients who are to be randomised in a 1:1 allocation ratio [
      • Noether G.E.
      Sample size determination for some common nonparametric statistics.
      ] to achieve a power of at least 80%. 40 patients were recruited in the first stage of the study.

      Sample size re-estimation based on conditional power

      After the first interim analysis, the sample size for the second stage was re-estimated based on a conditional power of 80% to confirm a true treatment effect of BT086 on VFDs. The conditional power was determined by the PI and the corresponding p-value in the first stage, and the significance level and sample size of the second stage. Calculations were done using an R program.

      Evaluation of secondary endpoints and other variables

      Demographic and medical background data, secondary endpoints and safety variables are to be analysed by means of descriptive and exploratory methods. Continuous variables are to be summarised by the number of patients, mean, SD, median, quartiles, and range. Categorical variables are to be summarised using number and percentages by category. Medical terms and adverse events are to be coded using the Medical Dictionary for Regulatory Activities (Version 15.0) and summarised according to system organ class and preferred term. Concomitant medications are to be coded using the World Health Organization – Drug Dictionary and summarised according to the anatomical therapeutical chemical (ATC) terminology.

      General statistical concepts

      All statistical analyses are to be performed in a modified intent-to-treat population which includes all randomised patients with at least one post-baseline observation of the primary variable.
      The SAS® system is to be used for statistical analyses. nQuery Advisor® 7.0 [
      • Elashoff J.
      nQuery Advisor® Version 7.0 User's Guide.
      ] and ADDPLAN™ 5.0 [
      • Wassmer and Eisebitt
      ADDPLAN Adaptive Designs – Plans and Analyses® User's Guide, Release 5.0.
      ] were used for the sample size calculations for the group-sequential adaptive design. An R program developed by one of the authors was used to perform the conditional power calculations.

      Interim analyses

      To terminate the study early in case of superiority of BT086 or in case of futility, or to evaluate the assumptions of the sample size estimation and to adjust the sample size, an adaptive group-sequential design was used.
      The first interim analysis was planned to be performed after 20 patients per group (in total 40 patients) have completed treatment. The sample size of the second stage of the trial was determined based on a weighted average of the expectations before the start of the study and the actual results of the first stage.
      A second interim analysis was performed after 100 patients completed treatment. The second interim analysis allowed termination of the study, where appropriate, and to claim statistically significant superiority of BT086 over placebo, if the observed p-value for the primary variable (VFDs) in this analysis was below the conditional type I error rate determined by means of the recursive combination test method.
      Based on the results from the second interim analysis, a statistician was to recommend whether the study should be stopped in the case of a significant result, or whether it should continue up to the planned sample size.

      Study status as of June 2014

      At the beginning of the trial, study sites were opened in Germany and Spain. The first patient was enrolled on 04 October 2011.
      The first interim analysis was completed on 07 March 2013, and was performed after the first 40 patients completed the CIGMA Study. The cut-off date for this analysis was defined as the date when data for the primary endpoint, VFDs, became available.
      As a result of the first interim analysis, the trial was not terminated early due to superiority or futility of BT086.
      Results from the first interim analysis showed that the variability of the VFDs quantified by the SD in the interim study population was an overall SD of 9.61 VFDs. A sample size of 120 patients (60 on BT086 and 60 on placebo) was estimated for the second stage of the study based on conditional power after results from the first stage. As a result, the total number of patients to demonstrate statistical significance was recalculated to 160 patients. With this sample size, statistical significance to demonstrate the efficacy of BT086 was expected to be achieved.
      After the first interim analysis, new sites were added in Germany, the UK, and Belgium.
      A second interim analysis was planned to be performed after results from the first 60 randomised patients in the second stage (100 patients in total) became available. The second interim analysis took place on the 31 March 2014. As a result of the second interim analysis, the trial was not terminated early.
      Publication of the interim and final results is planned after completion of the study.
      Unblinded data sets have been reviewed by the DSMB for the first six consecutive patients, and for the 12, 24, and 36 patients thereafter who completed the study. No safety issues have been raised by the DSMB members at any time.
      As of 03 June 2014, 124 patients have been randomised in the study.

      Discussion

      Patients affected by sepsis have a high mortality rate in spite of the wide availability of antibiotics. Furthermore, widespread resistance of pathogens to antibiotics has increased the medical need to look for alternate treatments shifting the focus to host response.
      During the last two decades, the efficacy and safety of several novel agents to treat sepsis have been evaluated in many clinical trials; however, none of the agents tested has significantly reduced the high mortality rates [
      • Vincent J.L.
      • Van Nuffelen M.
      Septic shock: new pharmacotherapy options or better trial design?.
      ]. Failure was attributed to the heterogeneity of septic patients or sepsis [
      • Vincent J.L.
      • Van Nuffelen M.
      Septic shock: new pharmacotherapy options or better trial design?.
      ]. A very large population of patients develops sepsis from sCAP [
      • Laterre P.F.
      • Garber G.
      • Levy H.
      • Wunderink R.
      • Kinasewitz G.T.
      • Sollet J.P.
      • et al.
      Severe community-acquired pneumonia as a cause of severe sepsis: data from the PROWESS study.
      ]. This indication was chosen for the CIGMA Study with the aim to increase homogeneity within this patient population. To achieve this goal, the CIGMA Study is restricted to mechanically-ventilated sCAP patients. Patients with sCAP have very high mortality rates, are in the ICU and on endotracheal ventilation.
      A literature search of different randomised controlled clinical trials in ICUs reported that relatively few trials (10/72) using mortality as a primary outcome show a beneficial impact of the intervention on the survival of critically ill patients [
      • Ospina-Tascón G.A.
      • Büchele G.L.
      • Vincent J.L.
      Multicenter, randomized, controlled trials evaluating mortality in intensive care: doomed to fail?.
      ]. While mortality may be the most robust outcome for patients with sCAP, other outcomes including VFDs and quality-adjusted life-years may also be suitable, and could reduce the sample size requirements [
      • Arnold D.M.
      • Cook D.J.
      The intensive care unit.
      ].
      VFDs are clinical endpoints that combine mortality and duration of ventilation in survivors [
      • Schoenfeld D.A.
      • Bernard G.R.
      ARDS Network. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome.
      ]. In addition, VFDs provide information about the length of ventilation, an important aspect in this patient population because the longer patients are ventilated, the greater the risk of complications and additional infections. VFDs increase the patient's quality of life and decrease treatment costs.
      In the CIGMA Study, VFDs are the primary endpoint and 28 day mortality is one of the secondary endpoints.
      Ventilation and weaning procedures might differ among sites and countries. Therefore for the CIGMA Study, a mechanical ventilation protocol, including weaning procedures, was developed and implemented in all study centres to standardise the ventilation procedure.
      Limited information about the efficacy and safety of BT086 was available during the study design phase. An adaptive study design was chosen for the CIGMA Study because it allows to re-estimate the sample size based on the observed variance and treatment effect or to stop the study early in case of overwhelming efficacy or futility after an interim analysis.
      Clinical studies generally include patients at different stages in the pathological process. The degree and nature of the inflammatory response vary among patients, and over time, within the same patient [
      • Vincent J.L.
      • Van Nuffelen M.
      Septic shock: new pharmacotherapy options or better trial design?.
      ]. Vincent et al. [
      • Vincent J.L.
      • Van Nuffelen M.
      Septic shock: new pharmacotherapy options or better trial design?.
      ] concluded that the timing of immunomodulatory therapy is likely to be crucial for a successful study design, an aspect that has not been explored enough in past sepsis trials. Berlot et al. [
      • Berlot G.
      • Vassallo M.C.
      • Busetto N.
      • Bianchi M.
      • Zornada F.
      • Rosato I.
      • et al.
      Relationship between the timing of administration of IgM and IgA enriched immunoglobulins in patients with severe sepsis and septic shock and the outcome: a retrospective analysis.
      ] reported that the efficacy of the IgM-enriched immunoglobulin Pentaglobin® in patients with severe sepsis and septic shock is time dependent; every 24 h of delay in administration resulted in a linear increase in mortality by 2.8%. In light of Berlot's findings, it can be assumed that the administration of BT086 early in the clinical course of a severe infection such as sCAP may provide an additional treatment effect for these patients. Given these findings, in the CIGMA Study, patients were to start treatment within 12 h after starting endotracheal ventilation.
      Another important parameter influencing efficacy in sepsis trials is adequate dosing of the medication [
      • Vincent J.L.
      • Van Nuffelen M.
      Septic shock: new pharmacotherapy options or better trial design?.
      ]. The dose for the CIGMA Study was chosen based on results from the phase I first-in-man study with BT086 where a dose of 42 mg IgM/kg body weight demonstrated reproducible and dose dependant results [
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg-Demand A.
      • Remy A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a dose escalating single dose phase I study.
      ,
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg Demand A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a multiple dose phase I study.
      ]. The equivalent dosage of IgM was used in the randomised controlled trial with Pentaglobin® performed by Rodriguez et al. [
      • Rodríguez A.
      • Rello J.
      • Neira J.
      • Maskin B.
      • Ceraso D.
      • Vasta L.
      • et al.
      Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery.
      ]. Results from this trial showed clinical benefit in terms of reduced mortality compared with the control group. In the first-in-man study with BT086 [
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg Demand A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a multiple dose phase I study.
      ] and in the study with Pentaglobin® led by Rodriguez [
      • Rodríguez A.
      • Rello J.
      • Neira J.
      • Maskin B.
      • Ceraso D.
      • Vasta L.
      • et al.
      Effects of high-dose of intravenous immunoglobulin and antibiotics on survival for severe sepsis undergoing surgery.
      ], patients were treated for 5 days. Similarly, BT086 is to be infused for 5 consecutive days in the CIGMA Study.
      Pentaglobin® has shown efficacy as adjuvant therapy to treat severe bacterial infections when used in addition to antibiotic therapy [
      • Kreymann K.G.
      • de Heer G.
      • Nierhaus A.
      • Kluge S.
      Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock.
      ]. In addition, measurements of IgM levels in patients with sepsis and viral infections showed that non-survivors had lower levels of IgM compared to survivors [
      • Giamarellos-Bourboulis E.J.
      • Apostolidou E.
      • Lada M.
      • Perdios I.
      • Gatselis N.K.
      • Tsangaris I.
      • et al.
      Kinetics of circulating immunoglobulin M in sepsis: relationship with final outcome.
      ,
      • Justel M.
      • Socias L.
      • Almansa R.
      • Ramírez P.
      • Gallegos M.C.
      • Fernandez V.
      • et al.
      IgM levels in plasma predict outcome in severe pandemic influenza.
      ]. These results highlight the importance of IgM in the host defense mechanism. IgM is the most important class of immunoglobulins in the defense of bacterial infections and it occurs first in the immune response. Because of its pentameric structure, IgM may be superior to IgG in toxin neutralisation and bacterial agglutination. IgM is more effective than IgG at killing bacteria because it activates up to 400 times more complement than IgG [
      • Stephan W.
      Investigations to demonstrate the antibacterial and antitoxic efficacy of an IgM-enriched intravenous immunoglobulin preparation.
      ], and it has been reported to be up to 1000 times more active in the opsonisation of bacteria [
      • Stephan W.
      Investigations to demonstrate the antibacterial and antitoxic efficacy of an IgM-enriched intravenous immunoglobulin preparation.
      ].
      In view of the fact that IgM plays an important role in the host response, the concentration of IgM in BT086 has been increased to approximately 23% compared to that of 12% in Pentaglobin®. In addition, a new manufacturing process for BT086 was established to obtain more native immunoglobulins with highly active binding sites. Data from the first-in-man study with BT086 showed that the administration of BT086 resulted in the expected increases in serum IgM, and was safe and well tolerated [
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg-Demand A.
      • Remy A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a dose escalating single dose phase I study.
      ,
      • Schmiedl S.
      • Szymanski J.
      • Wartenberg Demand A.
      • Thuerman P.
      Evaluation of pharmacokinetics and safety of the IgM enriched immunoglobulin concentrate BT086 in healthy volunteers – results of a multiple dose phase I study.
      ]. BT086 has a broad range of activity against clinically relevant gram negative and gram positive bacteria. Specific antibody activities against the indicator pathogens E. coli, C. albicans, and the sCAP pathogen Streptococcus pneumoniae were measured in the serum of healthy subjects after treatment with BT086 (unpublished results).
      In view of the high mortality rates combined with increased widespread resistance of pathogens to antibiotics, the high unmet medical need in patients with sepsis and sCAP warrant the exploration of alternate therapies to treat sCAP, e.g. host-targeted treatments.

      Authorship

      All the authors contributed to the design of the concept for this study, provided scientific input during the drafting process, read and approved the final version of the manuscript.

      Conflict of interest

      PD, TW, HE, MF, SO, KW, AT are members of the Biotest BT086 Advisory Board.
      TW, HE, MF, KW, AT are investigators of the CIGMA study.
      KW has received honoraria for giving lectures to Biotest audiences. He has also received research funding from Biotest, and is a member of the committee for the German sepsis guidelines.
      SO is a member of the Scientific Advisory Board for Arsanis, BioAegis, Sciclone. He has received grants from Cardeas and Asahi-Kasei and is a member of the Data Monitoring Committee for Achaogen, Tetraphase, and Spectral Diagnostics.
      DS and AW are employees of Biotest, the sponsor of the CIGMA study.
      KL is an employee of the CRO Accovion, GmbH and is responsible for the statistical analysis of the CIGMA Study for Biotest.

      Acknowledgements

      We thank Marcela Juárez-Hernández and Damien Lynch, employees of the CRO Accovion GmbH, for providing medical writing services, and Drs. Ulrike Wippermann and Iris Bobenhausen, employees of Biotest, for performing critical reviews of the manuscript.

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