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Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure


Substantial attention and resources have been directed to improving outcomes of patients with critical illnesses, in particular sepsis, but all recent clinical trials testing various interventions or strategies have failed to detect a robust benefit on mortality. Acute heart failure is also a critical illness, and although the underlying etiologies differ, acute heart failure and sepsis are critical care illnesses that have a high mortality in which clinical trials have been difficult to conduct and have not yielded effective treatments. Both conditions represent a syndrome that is often difficult to define with a wide variation in patient characteristics, presentation, and standard management across institutions. Referring to past experiences and lessons learned in acute heart failure may be informative and help frame research in the area of sepsis. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on dyspnea assessments and all-cause mortality as the primary measures of efficacy, and recent trials have been designed to assess novel clinical composite endpoints assessing organ dysfunction and mortality while still assessing all-cause mortality as a separate measure of safety. Applying the lessons learned in acute heart failure trials to severe sepsis and septic shock trials might be useful to advance the field. Novel endpoints beyond all-cause mortality should be considered for future sepsis trials.


Sepsis, defined as "life-threatening organ dysfunction due to a dysregulated host response to infection" [1], is a major cause of mortality and morbidity worldwide [26]. Literature estimates of sepsis incidence vary widely [7]. One US study reported an absolute incidence ranging from 300 to 1031 cases per 100,000 population [7, 8]. The annual incidence of sepsis globally has been roughly estimated at 15 to 19 million [7, 9]. A systematic review of 33 studies originating in North America, Europe, Asia, and Australia found a population incidence for hospital-treated sepsis of 256 cases per 100,000 person-years [10]. The authors extrapolated these findings to estimate a global incidence for sepsis of 30.7 million cases, contributing to an estimated 6 million deaths each year [10].

Sepsis mortality has declined over the last decade from ~40 to ~20 % [11]. Improved processes of care (e.g., earlier diagnosis; timely resuscitation with appropriate therapies; low tidal volume during mechanical ventilation) may explain this observation [1215]. However, neuromuscular, psychological, metabolic, cardiovascular, and renal complications persist and lead to impaired long-term outcomes among sepsis survivors [16, 17]. In addition, many sepsis patients are elderly and have other life-limiting comorbidities. Survival may be less important to these patients than measures reflecting independence and quality of life [18]. The long-term outcome and morbidity burden of sepsis survivors is an emerging, important research and clinical care concern.

Effective therapies are needed to better manage sepsis patients [19]. Therapeutic goals include not only improving survival but also reducing morbidity, preventing organ failure, and shortening convalescence [2, 20]. Substantial attention has been directed at reducing mortality in sepsis, but all recent multinational trials have failed to improve survival [2126].

Other critical care conditions (e.g., acute heart failure) have faced similar challenges with efforts to prolong survival in clinical trials. Acute heart failure and sepsis are both critical care illnesses with high mortality. Both conditions represent syndromes with wide variation in patient characteristics, presentation, and standard management. Further, the underlying pathophysiology in both conditions is related to many processes, but pharmacologic interventions generally target single pathways and have not translated into survival benefits. All-cause mortality is usually the primary endpoint chosen for phase 3 pivotal trials in sepsis and acute heart failure, but no treatments to date have effectively reduced the high mortality associated with either of these conditions (Fig. 1). In a survey of acute heart failure experts, most felt it was unlikely that improvements in short-term mortality could be shown as a single primary endpoint in acute heart failure trials [27]. Thus, recent and ongoing acute heart failure trials have been designed with composite clinical primary endpoints, reserving all-cause mortality assessments for safety [28]. This approach recently adopted in some acute heart failure trials may help frame research in sepsis, since both of these critical care illnesses have faced similar challenges in clinical research.

Fig. 1
figure 1

In-hospital mortality rates for septicemia, respiratory failure, and acute heart failure. Acute coronary syndrome included as an example of a critical care cardiovascular condition where reductions in in-hospital mortality have been realized. Rates are per 100 discharges for acute coronary syndrome, septicemia, and respiratory failure and were extracted from National Hospital Discharge Survey [6668]. Rates for acute heart failure were based on published registry data [69] and represent percent of patients in the registries who died in the hospital. Data shown are from ADHERE [70] and OPTIMIZE [71] (2000), EHFS II (2004) [72], ALARM (2007) [73], AHEAD (2010) [74], and ATTEND (2011) [75]. The acute heart failure data should be interpreted considering the differences in registry populations and severity of illness

The European Drug Development Hub brought together experts in critical care/sepsis and acute heart failure with the objective of sharing the collective clinical research experience in these critical care illnesses. The ultimate goal was to discuss better approaches to conducting clinical trials in critical care illnesses with high mortality (i.e., sepsis and acute heart failure) to promote advances in the care of these patients (Paris, France, January 2015). This paper summarizes the key developments from the meeting, focusing on clinical trial designs and endpoints that should be considered for use in future sepsis trials.


Clinical trials in sepsis

Why have outcomes failed to improve in clinical trials?

An overview of the results from a selection of recent large, rigorously designed and conducted sepsis clinical trials reveals a consistent theme (Table 1). All trials were designed with short-term all-cause mortality as the primary endpoint, but none of the interventions has improved short-term survival for a variety of possible reasons (Table 2).

Table 1 Overview of key recent critical care sepsis trials
Table 2 Reasons for lack of survival improvements in sepsis clinical trials

Mortality rates due to sepsis are declining but remain high [5]. Statistical power is dependent on several parameters, including the population’s baseline risk, the modifiable mortality, and on the treatment effect size and its variability within the study sample. In some recent sepsis trials, all-cause mortality ranged from 19 to 45 % depending on the study population and follow-up duration (Table 1). Achieving lower than expected event rates in trials (e.g., due to declining overall mortality, unintended enrollment of a lower-risk population, intentional exclusion of patients with an imminent risk of death) reduces the likelihood of identifying true treatment effects. As the overall mortality rate declines in the general sepsis population, the potential absolute effect of any given treatment is attenuated, if by nothing else, a lower fraction of modifiable mortality [19, 29]. At the same time, if baseline risk is higher than estimated, more patients will be needed as the expected treatment effect decreases (Fig. 2).

Fig. 2
figure 2

Estimated sample sizes by baseline mortality and absolute mortality reduction. This figure examines the total sample size needed to identify an absolute mortality reduction of 3 to 15 % assuming three control group mortality rates (30, 20, and 10 %). The assumptions in this figure is that power is 80 % for a two-sided test and that 1:1 randomization will be employed (for example, a total N of 3000 on the y-axis implies a n = 1500 in each treatment arm). Source: author calculations (MOH)

Over- or under-estimating treatment effects should be avoided when designing clinical trials [30]. Researchers have struggled and often over-estimated control group mortality when planning sample size and power estimates. For example, usual care group mortality rates were over-estimated by 5.1 % in Protocolized Care for Early Septic Shock (PROCESS) [26], 9.7 % in Sepsis and Mean Arterial Pressure (SEPSISPAM) [21], 19.4 % in Australasian Resuscitation in Sepsis Evaluation (ARISE) [24], and 10.8 % in Protocolized Management in Sepsis (ProMISE) [31], similar to previous over-estimates in septic shock trials (Vasopressin and Septic Shock Trial (VASST) over-estimate was 11 %) [32].

Sepsis is a complex syndrome characterized by the interplay of many pathways and systems. Sepsis therapies must either (1) control several pathways with several interventions or (2) hit “upstream” nodes that control a number of pathways. The treatment approach for sepsis has ranged from inhibiting the uncontrolled, inflammatory host response to enhancing the host immune response [33]. These seemingly conflicting approaches illustrate the complexity of the process and the significant (and ongoing) evolution in the understanding of sepsis pathophysiology. Analogously, the failure of positive inotropes to improve outcomes in clinical heart failure trials [34] was initially unexpected, but it was better understood as the knowledge of heart failure pathophysiology evolved.

Whether sepsis treatments targeting a single aspect of this complex syndrome could be reasonably expected to reduce all-cause mortality is uncertain. All-cause mortality is a robust endpoint because it reflects the net benefit of an intervention [28]. A benefit on all-cause mortality shows that the effect of the intervention is strong enough to overcome the influence of events on which the treatment has no or minimal effect [28]. While this approach works well when most deaths are directly related to the disease being studied, it may be less informative when heterogeneity in cause of death is common and mortality is often attributable to factors indirectly related to the disease such as occurs in sepsis [35].

In sepsis trials, significant patient heterogeneity exists in time to presentation and diagnosis, organisms(s), type and source of infection, organ involvement, degree of organ impairment, severity of illness, location of enrollment (e.g., emergency department vs. ICU), pre-existing conditions, and differences in standard of care across institutions or geographical regions (Additional file 1: Table S1) [36]. Recent consensus definitions for sepsis and septic shock should help to reduce this variation in future clinical trials (Additional file 1: Table S1) [1, 37]. The selection of sites participating in a clinical trial can substantially influence endpoints (e.g., variation in comorbidities or application of background therapies can impact event rates across high and low enrolling centers) and make interpretation of trial results difficult, a challenge that has been experienced in acute heart failure trials [38]. Genetic variants also appear to influence severity [39]. Treatment responses might vary, perhaps considerably, within such a group of patients according to clinical and genetic heterogeneity. Recent observational cohort studies highlighted the wide variation in mortality rates according to infection source [40]. At present, most trials do not consider heterogeneous treatment effects when estimating sample sizes. As a result, subgroup analyses, though often employed, are likely to miss important signals from treatments and interventions [19].

Approaches to design clinical trials in sepsis

Characterization of pathophysiology: matching the treatment to the disease

Animal models used in sepsis do not accurately reflect the presentation of sepsis in humans [41, 42], in large part because there is no single presentation of sepsis in human disease. Validated and more clinically relevant animal models are needed to understand the disease process and enable therapy selection targeting specific pathophysiologic mechanisms. These models should replicate the duration of clinical intensive care treatment [42], integrate standard intensive care measures and advanced supportive care [42, 43], investigate higher order species to minimize the physiological and immunological differences between small animal species and humans [4446], and investigate older animals with chronic comorbidities to better reflect real-world patient populations [42]. An alternate approach that might be more informative is to use the heterogeneity of animal models to understand predictors of treatment response, and then seek to replicate the predictors in a human trial. This approach has been explored in a systematic review of anti-tumor necrosis factor (anti-TNF) animal studies [47]. Biomarkers may play a role if they aid in diagnosis, prognosis (e.g., troponin in acute coronary syndrome [48] or N-terminal brain natriuretic peptide (NT-proBNP) in heart failure [49]), or identify patient subsets likely to respond to specific interventions (i.e., predictive biomarkers). Multi-biomarker approaches may be promising [50].

Although many advances in cardiovascular medicine were realized using the concept of large, simple trials, moving towards precision medicine has been proposed [51] (e.g., targeting patients with elevated systolic blood pressure for vasodilator trials in acute heart failure [52]). A similar approach has been suggested for sepsis trials, with emphasis on defining pathophysiology through better pre-clinical models, targeting drug development to specific pathophysiologic abnormalities, and selecting patients with clinical features likely to respond to a specific therapeutic approach or who are at sufficient risk for poor outcomes based on validated risk scores [42].

Appropriate endpoints for sepsis clinical trials: insights from acute heart failure clinical trials

All-cause mortality

Reducing the morbidity burden in surviving patients is an important therapeutic goal that is not reflected in an all-cause mortality endpoint [53]. All-cause mortality is an appropriate endpoint when the population has a significant mortality risk and minimal competing risks and the intervention has the potential to alter the mortality risk. Short-term survival should predict longer-term survival with an acceptable quality of life. Sepsis satisfies the first criterion, but it performs poorly on the others. First, patients with sepsis die from many causes, but it is often impossible to determine which is primary (e.g., renal, hepatic, pulmonary, cardiac) [33]. Death occurs via many pathways, some of which are unrelated to the therapy being studied and will not be impacted by the treatment (e.g., a decision to withdraw support in many ICU cases [2]). The “noise” of non-response can obscure a beneficial effect on disease-specific death (i.e., the death that the intervention is able to impact). Thus, cause-specific mortality is a more informative endpoint to determine the benefit of a drug or intervention, whereas all-cause mortality is more meaningful when information on the net benefit of an intervention (i.e., benefit in the context of adverse events or non-response) is being sought [54]. In sepsis, cause-specific mortality is difficult to define but perhaps could be achieved in a clinical trial by increasing the “signal” (e.g., enrolling patients with the abnormality targeted by the intervention and exclude patients at low risk of death) and decreasing the “noise” (e.g., excluding patients with competing mortality risks from conditions unrelated to the sepsis episode). Cause-specific mortality might be useful in sepsis trials to identify agents with a significant treatment effect on specific components of the illness.

Similar to sepsis, patients with acute heart failure have high short-term mortality, a factor which usually makes mortality trials easier to conduct. However, in the case of acute heart failure, most therapies primarily target symptoms rather than the underlying pathophysiology that leads to death. Additionally, acute heart failure drugs are administered for a short-duration; both of these factors reduce the likelihood that all-cause mortality will be influenced over the intermediate or long-term (e.g., 180 days). Although the European Medicines Agency guideline still specifies all-cause mortality as the preferred primary endpoint in acute heart failure trials, it states that symptomatic improvement might be acceptable as a primary endpoint for short-term trials provided mortality is not adversely affected [55]. Regulatory agencies have recently agreed to a primary hierarchical clinical composite endpoint in an acute heart failure trial that combines a global assessment of symptoms, persistent or worsening heart failure requiring an intervention, and all-cause mortality assessed at 6, 24, and 48 h. Patients are categorized as improved (moderate or marked improvement in clinical status at all planned assessments without hospitalization for heart failure or death), unchanged (modest improvement or worsening in clinical status), or worsened (moderate or marked worsening of clinical status at any planned assessment, hospitalization for heart failure requiring intravenous or mechanical interventions, or death). The distribution of patients in each category is compared between treatment groups to assess the treatment effect [56, 57]. This endpoint has the advantage of reflecting considerations that are important to patients (both symptoms and outcomes), and it allows for a short-term assessment of morbidity and mortality during the period when the pharmacologic effect is present. Importantly, long-term all-cause mortality should still be assessed for safety, and the study should be powered to demonstrate that long-term mortality is not increased by a pre-specified safety margin [52].

Regulatory agencies might consider a similar clinical composite endpoint adapted for sepsis trials, where endpoints describing end-organ function, need for mechanical support, or need for other interventions are combined with short-term mortality (ideally sepsis-related mortality if consensus can be reached on a standard definition) as a primary endpoint, with longer-term all-cause mortality assessed for safety. This approach also has the advantage of reflecting relevant factors other than survival that are important to patients. Rigorous definitions for such endpoints are keys to ensure consistency and to reduce bias in the results and to ensure that the endpoint can be translated into a metric that is important to patients.

Non-fatal endpoints

Total or ICU length of stay has been considered as an endpoint for sepsis trials. It is relevant because ICU stays are costly, but it is dependent on external factors that are unrelated to drug therapy (e.g., physician judgment, no accepted standards for discharge readiness, availability of step-down beds, payer influence, local standards of care). These same limitations have been recognized in acute heart failure trials [58]. Thus, the length of stay is unsuitable as a primary endpoint for pivotal trials, but it can be useful as a secondary endpoint or to inform health technology and economic (cost/benefit) assessments. Other problems with using non-fatal endpoints include ascertainment bias, competing risks, and informative dropout when comparing treatment and control groups (i.e., patients who die cannot be hospitalized and patients who die early have decreased length of stay) [19].

Organ dysfunction is a relevant endpoint for sepsis trials. Multiple organs are impaired in sepsis [42], but all-cause mortality is insensitive to determine which organ or organ(s) are the primary driver of death. Conceptually, integrating a measure of organ dysfunction into a mortality endpoint (e.g., days alive and free of organ dysfunction) would provide a more comprehensive assessment of morbidity and mortality. Organ dysfunction is theoretically a more sensitive measure of the effect of an intervention on progression of the sepsis syndrome, but this concept has not yet been validated in trials. Since short-term organ dysfunction is associated with long-term outcome [17, 59], it is plausible that improvements in organ function might translate into improved survival, but this relationship has not yet been shown and the hypothesis still requires confirmation. The primary value of measuring organ dysfunction at the current time is to gain an understanding of how an intervention impacts physiology and organ function. Correlations between change in short-term organ dysfunction and long-term sepsis-associated morbidity could also be derived from large robust registries that include long-term follow-up and outcomes. If used as an endpoint, organ dysfunction should be pre-defined in the protocol and statistical analysis plan. Ideally, consensus about how to define organ dysfunction should be sought so that definitions are used consistently across clinical trials.

Days alive and free from mechanical ventilation, renal replacement therapy, or vasopressors (i.e., organ failure free days) has also been proposed. These endpoints are clinically meaningful, and widespread use of the Surviving Sepsis Campaign guidelines has led to more consistent timing and application of life support interventions. Nonetheless, the decision to institute supportive therapies is often subjective and can be influenced by external factors (e.g., reimbursement incentives, interactions of various medical specialists (e.g., intensivists and nephrologists)), which introduces increased variability (i.e., random noise) in the study and possibly bias if the study is not blinded. Other complex issues also warrant consideration, including whether patients value more event-free days equally regardless of when they occur (e.g., moving from 0 to 1 day is the same/better/worse than moving from 29 to 30 days), handling inclusion of multiple organs (i.e., are all organs of equal value or should failure in some organs be weighted more heavily than others), and methodology to account for pre-existing organ dysfunction. Interventions can be effective in preventing organ dysfunction (in patients who do not have organ dysfunction) and/or preventing progression of organ dysfunction (in patients who already have some degree of organ dysfunction). An adequate organ dysfunction scoring system must capture both of these possibilities.

In general, there are no accepted surrogates for safety [60], although death is not the only safety measure. Safety is difficult to assess in sepsis trials because of the high incidence of organ dysfunction in sepsis. Differences in organ dysfunction scores between treatment groups could also be seen as a safety outcome (e.g., prevention of organ dysfunction due to side effects of excessive vasopressor doses and duration). Other events (e.g., anaphylaxis) might be relevant for specific drugs. Even if a beneficial effect was shown on organ dysfunction or other non-fatal endpoint, adequate assurance of safety would still have to be demonstrated, either in a pivotal clinical trial, in the entirety of the drug’s database, or based on experience with similar drugs or interventions [60]. Consultation with regulatory agencies is needed to determine the size of the safety database and the confidence level required to rule out an adverse effect on mortality; these decisions are often dependent on the severity of illness in the population studied and the specific benefit of the drug (e.g., a drug that improves a clinically important outcome vs. a drug that improves control of a biomarker).

Role of alternative study designs

Adaptive designs

Adaptive designs or seamless phase II/III designs have the potential to improve the efficiency of clinical trials. Adaptive designs can be particularly useful in fields in which data are limited to inform trial planning assumptions in the areas of expected event rates, anticipated effect sizes, heterogeneity of treatment effect, variance, safety, or drop-outs [61, 62]. In sepsis, many uncertainties exist at the time of trial design, and adaptive design is a promising approach for both exploratory and confirmatory stages of drug development, especially in the context of moving towards exploration of novel endpoints for sepsis trials. These designs are well accepted for feasibility and early phase studies, but as experience with their use has increased, they are becoming more accepted for pivotal trials as well [63]. Potential challenges include maintaining confidentiality and blinding of interim ongoing results and avoiding the introduction of bias resulting from the adaptations [63]. Strict control of type I error risk and understanding the potential biases are important issues; rapid progress is being made around these issues [64, 65].

Realistic trial simulation is the key tool to address these challenges and advance the field. Trial simulation of traditional and adaptive trial designs furthers understanding of strengths and weaknesses of proposed trial designs and will illustrate vulnerabilities from minor deviations to study design assumptions (e.g., event rates, missing data).

Ideally, trial design should be a multi-step, collaborative, and interactive multidisciplinary process between scientific, clinical, and statistical domain experts to increase the quality and chance of success. This concept applies to all types of trials, but it is particularly important for adaptive design. Early interaction with regulators is highly recommended when using adaptive designs in the later stages of a drug development program [61, 62].


Sepsis is a major burden with high mortality, and the lack of progress in identifying effective treatments is discouraging for researchers and industry. The clinical research challenges that have been encountered in sepsis trials closely resemble those experienced by investigators in acute heart failure trials. After decades of research, it has become clear in the acute heart failure community that the substantial patient heterogeneity contributes to the difficulties in identifying effective therapies for the condition. The recent consensus definitions for sepsis and septic shock are important advances in this regard [1, 37].  Additionally, assessing all-cause mortality alone is insufficient to fully characterize the burden of disease because it omits important aspects of symptoms and functional status. Academic heart failure investigators and industry have worked closely with regulators for many years to transition acute heart failure trials away from relying on short-term symptoms and all-cause mortality as the primary efficacy measures, and ongoing trials are assessing novel clinical composite endpoints reflecting organ dysfunction and mortality while still evaluating all-cause mortality as a separate safety measure. Applying the lessons learned in acute heart failure trials to sepsis trials might be useful to advance the field (Table 3). Selecting high-risk patients with clinical phenotypes considered likely to respond to the intervention under study may help to reduce patient heterogeneity within clinical trials and enable signals of benefit to be more readily detected. Additionally, novel endpoints beyond all-cause mortality should be considered for future sepsis trials.

Table 3 Priorities for future sepsis clinical trials



Acute Decompensated Heart Failure National Registry


Acute Heart Failure Database


Acute Heart Failure Global Registry of Standard Treatment


Albumin Italian Outcome Sepsis Study


anti-tumor necrosis factor


acute respiratory distress syndrome


Australasian Resuscitation in Sepsis Evaluation


Acute Decompensated Heart Failure Syndrome


chest radiography


emergency department


early goal-directed therapy


Second EuroHeart Failure Survey




intensive care unit


mean arterial pressure


N-terminal pro brain natriuretic peptide


Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure

PaCO2 :

partial pressure of arterial carbon dioxide


Protocolized Care for Early Septic Shock


Protocolized Management in Sepsis


Sepsis and Mean Arterial Pressure


systemic inflammatory response syndrome


Transfusion Requirements in Septic Shock


Vasopressin and Septic Shock Trial


  1. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:762–74.

    Article  PubMed  Google Scholar 

  2. Kahn JM, Le T, Angus DC, Cox CE, Hough CL, White DB, et al. The epidemiology of chronic critical illness in the United States*. Crit Care Med. 2015;43:282–7.

    Article  PubMed  Google Scholar 

  3. Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014;5:4–11.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ogura H, Gando S, Saitoh D, Takeyama N, Kushimoto S, Fujishima S, et al. Epidemiology of severe sepsis in Japanese intensive care units: a prospective multicenter study. J Infect Chemother. 2014;20:157–62.

    Article  PubMed  Google Scholar 

  5. Quenot JP, Binquet C, Kara F, Martinet O, Ganster F, Navellou JC, et al. The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study. Crit Care. 2013;17:R65.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Taniguchi LU, Bierrenbach A, Toscano CM, Schettino G, Azevedo L. Sepsis-related deaths in Brazil: an analysis of the national mortality registry from 2002 to 2010. Crit Care. 2014;18:608.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614.

    Article  PubMed  Google Scholar 

  8. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med. 2013;41:1167–74.

    Article  PubMed  Google Scholar 

  9. Adhikari NK, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the global burden of critical illness in adults. Lancet. 2010;376:1339–46.

    Article  PubMed  Google Scholar 

  10. Fleischmann C, Scherag A, Adhikari N. Global burden of sepsis: a systematic review [abstract]. Crit Care. 2015;19:P21.

    Article  PubMed Central  Google Scholar 

  11. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014;311:1308–16.

    Article  CAS  PubMed  Google Scholar 

  12. Eisner MD, Thompson T, Hudson LD, Luce JM, Hayden D, Schoenfeld D, et al. Efficacy of low tidal volume ventilation in patients with different clinical risk factors for acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;164:231–6.

    Article  CAS  PubMed  Google Scholar 

  13. Funk DJ, Kumar A. Antimicrobial therapy for life-threatening infections: speed is life. Crit Care Clin. 2011;27:53–76.

    Article  PubMed  Google Scholar 

  14. Gao F, Melody T, Daniels DF, Giles S, Fox S. The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study. Crit Care. 2005;9:R764–70.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Jones AE, Focht A, Horton JM, Kline JA. Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest. 2007;132:425–32.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Linder A, Guh D, Boyd JH, Walley KR, Anis AH, Russell JA. Long-term (10-year) mortality of younger previously healthy patients with severe sepsis/septic shock is worse than that of patients with nonseptic critical illness and of the general population. Crit Care Med. 2014;42:2211–8.

    Article  PubMed  Google Scholar 

  17. Linder A, Fjell C, Levin A, Walley KR, Russell JA, Boyd JH. Small acute increases in serum creatinine are associated with decreased long-term survival in the critically ill. Am J Respir Crit Care Med. 2014;189:1075–81.

    Article  CAS  PubMed  Google Scholar 

  18. Fried TR, Bradley EH, Towle VR, Allore H. Understanding the treatment preferences of seriously ill patients. N Engl J Med. 2002;346:1061–6.

    Article  PubMed  Google Scholar 

  19. Harhay MO, Wagner J, Ratcliffe SJ, Bronheim RS, Gopal A, Green S, et al. Outcomes and statistical power in adult critical care randomized trials. Am J Respir Crit Care Med. 2014;189:1469–78.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580–637.

    Article  PubMed  Google Scholar 

  21. Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370:1583–93.

    Article  CAS  PubMed  Google Scholar 

  22. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412–21.

    Article  CAS  PubMed  Google Scholar 

  23. Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014;371:1381–91.

    Article  PubMed  Google Scholar 

  24. Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371:1496–506.

    Article  CAS  PubMed  Google Scholar 

  25. Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014;370:2191–200.

    Article  PubMed  Google Scholar 

  26. Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370:1683–93.

    Article  CAS  PubMed  Google Scholar 

  27. Gheorghiade M, Adams KF, Cleland JG, Cotter G, Felker GM, Filippatos GS, et al. Phase III clinical trial end points in acute heart failure syndromes: a virtual roundtable with the Acute Heart Failure Syndromes International Working Group. Am Heart J. 2009;157:957–70.

    Article  PubMed  Google Scholar 

  28. Zannad F, Garcia AA, Anker SD, Armstrong PW, Calvo G, Cleland JG, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail. 2013;15:1082–94.

    Article  PubMed  Google Scholar 

  29. Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med. 1984;3:409–22.

    Article  CAS  PubMed  Google Scholar 

  30. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis*. Crit Care Med. 2014;42:625–31.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mouncey PR, Osborn TM, Power GS, Harrison DA, Sadique MZ, Grieve RD, et al. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372:1301–11.

    Article  CAS  PubMed  Google Scholar 

  32. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–87.

    Article  CAS  PubMed  Google Scholar 

  33. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med. 2003;348:138–50.

    Article  CAS  PubMed  Google Scholar 

  34. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med. 1998;339:1810–6.

    Article  CAS  PubMed  Google Scholar 

  35. Gayat E, Lemasle L, Payen D. Drotrecogin alfa (activated) in severe sepsis. Lancet Infect Dis. 2013;13:109–10.

    Article  PubMed  Google Scholar 

  36. Gattinoni L, Ranieri VM, Pesenti A. Sepsis: needs for defining severity. Intensive Care Med. 2015;41:551–2.

    Article  PubMed  Google Scholar 

  37. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS et al. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315:775–87.

    Article  PubMed  Google Scholar 

  38. Gheorghiade M, Vaduganathan M, Greene SJ, Mentz RJ, Adams Jr KF, Anker SD, et al. Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions. Heart Fail Rev. 2014;19:135–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Toubiana J, Courtine E, Pene F, Viallon V, Asfar P, Daubin C, et al. IRAK1 functional genetic variant affects severity of septic shock. Crit Care Med. 2010;38:2287–94.

    Article  CAS  PubMed  Google Scholar 

  40. Leligdowicz A, Dodek PM, Norena M, Wong H, Kumar A, Kumar A. Association between source of infection and hospital mortality in patients who have septic shock. Am J Respir Crit Care Med. 2014;189:1204–13.

    Article  PubMed  Google Scholar 

  41. Opal SM, Dellinger RP, Vincent JL, Masur H, Angus DC. The next generation of sepsis clinical trial designs: what is next after the demise of recombinant human activated protein C?*. Crit Care Med. 2014;42:1714–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–51.

    Article  CAS  PubMed  Google Scholar 

  43. Fink MP, Heard SO. Laboratory models of sepsis and septic shock. J Surg Res. 1990;49:186–96.

    Article  CAS  PubMed  Google Scholar 

  44. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110:3507–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Osuchowski MF, Remick DG, Lederer JA, Lang CH, Aasen AO, Aibiki M, et al. Abandon the mouse research ship? Not just yet! Shock. 2014;41:463–75.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Radermacher P, Haouzi P. A mouse is not a rat is not a man: species-specific metabolic responses to sepsis—a nail in the coffin of murine models for critical care research? Intensive Care Med Exp. 2013;1:7.

    Article  Google Scholar 

  47. Lorente JA, Marshall JC. Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock. 2005;24 Suppl 1:107–19.

    Article  CAS  PubMed  Google Scholar 

  48. Amsterdam EA, Wenger NK, Brindis RG, Casey Jr DE, Ganiats TG, Holmes Jr DR, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:e139–228.

    Article  PubMed  Google Scholar 

  49. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347:161–7.

    Article  CAS  PubMed  Google Scholar 

  50. Wong HR, Walley KR, Pettila V, Meyer NJ, Russell JA, Karlsson S, et al. Comparing the prognostic performance of ASSIST to interleukin-6 and procalcitonin in patients with severe sepsis or septic shock. Biomarkers. 2015;20:132–5.

    Article  CAS  PubMed  Google Scholar 

  51. Jackson N, Atar D, Borentain M, Breithardt G, van Eickels M, Endres M, et al. Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Roundtable of the European Society of Cardiology. Eur Heart J. 2015. doi: 10.1093/eurheartj/ehv213.

  52. Mebazaa A, Longrois D, Metra M, Mueller C, Richards AM, Roessig L, et al. Agents with vasodilator properties in acute heart failure: how to design successful trials. Eur J Heart Fail. 2015;17:652–64.

    Article  PubMed  Google Scholar 

  53. Iwashyna TJ, Angus DC. Declining case fatality rates for severe sepsis: good data bring good news with ambiguous implications. JAMA. 2014;311:1295–7.

    Article  CAS  PubMed  Google Scholar 

  54. Zannad F, Stough WG, Pitt B, Cleland JG, Adams KF, Geller NL, et al. Heart failure as an endpoint in heart failure and non-heart failure cardiovascular clinical trials: the need for a consensus definition. Eur Heart J. 2008;29:413–21.

    Article  PubMed  Google Scholar 

  55. European Medicines Agency (9-20-2012) Guideline on clinical investigation of medicinal products for the treatment of acute heart failure (CHMP/EWP/2986/03 Rev. 1). Accessed 5/1/2015.

  56. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail. 2001;7:176–82.

    Article  CAS  PubMed  Google Scholar 

  57. (10-1-2014) Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure (TRUE-AHF). Accessed 11/19/2014.

  58. Allen LA, Hernandez AF, O’Connor CM, Felker GM. End points for clinical trials in acute heart failure syndromes. J Am Coll Cardiol. 2009;53:2248–58.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Nfor TK, Walsh TS, Prescott RJ. The impact of organ failures and their relationship with outcome in intensive care: analysis of a prospective multicentre database of adult admissions. Anaesthesia. 2006;61:731–8.

    Article  CAS  PubMed  Google Scholar 

  60. Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA. 1999;282:790–5.

    Article  CAS  PubMed  Google Scholar 

  61. European Medicines Agency (10-18-2007) Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design.

  62. Food and Drug Administration (2-1-2010) guidance for industry: adaptive design clinical trials for drugs and biologics.

  63. Bretz F, Koenig F, Brannath W, Glimm E, Posch M. Adaptive designs for confirmatory clinical trials. Stat Med. 2009;28:1181–217.

    Article  PubMed  Google Scholar 

  64. Mehta C, Gao P, Bhatt DL, Harrington RA, Skerjanec S, Ware JH. Optimizing trial design: sequential, adaptive, and enrichment strategies. Circulation. 2009;119:597–605.

    Article  PubMed  Google Scholar 

  65. Muller HH, Schafer H. Adaptive group sequential designs for clinical trials: combining the advantages of adaptive and of classical group sequential approaches. Biometrics. 2001;57:886–91.

    Article  CAS  PubMed  Google Scholar 

  66. CDC/NCHS National Hospital Discharge Survey (12-31-2007) Number, rate, and standard error of deaths for discharges from short-stay hospitals, by age and selected first-listed diagnosis: United States, 2007.

  67. Kozak LJ, Hall MJ, Owings MF. National hospital discharge survey: 2000 annual summary with detailed diagnosis and procedure data. Vital Health Stat 13. 2002;153:1–194.

    PubMed  Google Scholar 

  68. Kozak LJ, DeFrances CJ, Hall MJ. National hospital discharge survey: 2004 annual summary with detailed diagnosis and procedure data. National Center for Health Statistics. Vital Health Stat. 2006;13:34.

    Google Scholar 

  69. Ambrosy AP, Fonarow GC, Butler J, Chioncel O, Greene SJ, Vaduganathan M, et al. The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. J Am Coll Cardiol. 2014;63:1123–33.

    Article  PubMed  Google Scholar 

  70. Adams Jr KF, Fonarow GC, Emerman CL, LeJemtel TH, Costanzo MR, Abraham WT, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149:209–16.

    Article  PubMed  Google Scholar 

  71. Fonarow GC, Abraham WT, Albert NM, Gattis Stough W, Gheorghiade M, Greenberg BH, et al. Influence of a performance-improvement initiative on quality of care for patients hospitalized with heart failure: results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). Arch Intern Med. 2007;167:1493–502.

    Article  PubMed  Google Scholar 

  72. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola VP, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27:2725–36.

    Article  PubMed  Google Scholar 

  73. Follath F, Yilmaz MB, Delgado JF, Parissis JT, Porcher R, Gayat E, et al. Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). Intensive Care Med. 2011;37:619–26.

    Article  CAS  PubMed  Google Scholar 

  74. Spinar J, Parenica J, Vitovec J, Widimsky P, Linhart A, Fedorco M, et al. Baseline characteristics and hospital mortality in the Acute Heart Failure Database (AHEAD) Main registry. Crit Care. 2011;15:R291.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Sato N, Kajimoto K, Keida T, Mizuno M, Minami Y, Yumino D, et al. Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND Registry). Circ J. 2013;77:944–51.

    Article  CAS  PubMed  Google Scholar 

  76. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644–55.

    Article  CAS  PubMed  Google Scholar 

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The authors thank EDDH - Fondation Transplantation for the logistical and administrative support.

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Correspondence to Alexandre Mebazaa.

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Competing interests

Alexandre Mebazaa received a speaker’s honoraria from The Medicines Company, Novartis, Orion, Roche, and Servier and fees for Advisory Boards and Steering Committees from Cardiorentis, The Medicines Company, Adrenomed, MyCartis, ZS Pharma, and Critical Diagnostics.

James A. Russell patents owned by the University of British Columbia (UBC) that are related to PCSK9 inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. Dr. Russell is an inventor on these patents. Dr. Russell is a founder, Director, and shareholder in Cyon Therapeutics Inc. (developing a sepsis therapy). Dr. Russell has share options in Leading Biosciences Inc. Dr. Russell reports receiving consulting fees from Cubist Pharmaceuticals (formerly Trius Pharmaceuticals) (developing antibiotics), Ferring Pharmaceuticals (manufactures vasopressin and is developing selepressin), Grifols (sells albumin), MedImmune (regarding sepsis), Leading Biosciences (developing a sepsis therapeutic), La Jolla Pharmaceuticals (developing a sepsis therapeutic), CytoVale Inc. (developing a sepsis diagnostic), and Sirius Genomics Inc. (now closed; had done pharmacogenomics research in sepsis). Dr. Russell reports having received grant support from Sirius Genomics and Ferring Pharmaceuticals that was provided to and administered by UBC.

Andreas Bergmann is an employee of Adrenomed AG.

Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number F31HL127947 awarded to Michael O. Harhay. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Oliver Hartmann is an employee of Adrenomed AG.

Frauke Hein is a cofounder and employee of Adrenomed AG.

Anne Louise Kjolbye is an employee of Ferring Pharmaceuticals.

Dr. Lewis serves as the senior medical scientist at Berry Consultants, LLC, a statistical consulting group that specializes in the design and support of adaptive clinical trials, including adaptive clinical trials focused on the evaluation of treatments for severe sepsis and septic shock.

John C. Marshall received personal fees (DSMB member) from Asahi Kasei.

Gernot Marx received research grants from EU project THALEA, BBraun Melsungen AG, personal fees (honoraria for lecturing and consulting) from BBraun Melsungen AG, Adrenomed, Philips and a patent pending for modulation of TLR4-signaling pathway.

Peter Radermacher received research grants from Adrenomed AG, Boehringer Ingelheim Pharma GmbH & Co., German Ministry of Defense, and Poxel SA and personal fees from Boehringer Ingelheim Pharma GmbH & Co.

Mathias Schroedter is an employee of Adrenomed AG.

Wendy Gattis Stough is a consultant to European Drug Development Hub, Relypsa, CHU Nancy, European Society of Cardiology, Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, Overcome, Stealth BioTherapeutics, Covis Pharmaceuticals, University of Gottingen, and University of North Carolina.

Joachim Struck is an employee of Adrenomed AG.

Derek C. Angus received personal fees from Bayer HealthCare, Ferring Pharmaceuticals, GlaxoSmithKline, Ibis Biosciences, and Medimmune (consulting, advisory boards).

All other authors declare that they have no competing interests.

Authors’ contributions

AM conceived, planned, and organized the meeting where discussions on this manuscript topic took place. AM and WGS drafted the manuscript. All authors presented and participated in the discussions during the meeting held in Paris France, January 2015. All authors critically revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.

Additional file

Additional file 1: Table S1.

This table describes the definitions of sepsis and septic shock that have been used in pivotal sepsis trials. (DOCX 21 KB)

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Mebazaa, A., Laterre, P.F., Russell, J.A. et al. Designing phase 3 sepsis trials: application of learned experiences from critical care trials in acute heart failure. j intensive care 4, 24 (2016).

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