DIABOLO: Anakinra in Sepsis with Organ Failure (2021)

“In this randomized clinical trial of 137 patients with sepsis and organ failure, anakinra, compared with placebo, did not significantly improve organ function scores at day 7.”

  • Adapted from the DIABOLO Investigators

1. Publication Details

  • Trial Title: Efficacy and Safety of Anakinra in Critically Ill Patients With Sepsis and Organ Failure (DIABOLO): A Randomized Clinical Trial
  • Citation: Kyriazopoulou E, Poulakou G, Milionis H, et al. Efficacy and Safety of Anakinra in Critically Ill Patients With Sepsis and Organ Failure (DIABOLO): A Randomized Clinical Trial. JAMA Netw Open. 2021;4(9):e2125873. DOI: 10.1001/jamanetworkopen.2021.25873
  • Published: September 23, 2021, in JAMA Network Open
  • Author: Evangelia Kyriazopoulou, M.D., Ph.D.
  • Funding: Hellenic Institute for the Study of Sepsis.

2. Keywords

  • Sepsis, Organ Dysfunction, Anakinra, Interleukin-1, Immunomodulation, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with sepsis and multiple organ dysfunction (Population), does treatment with the interleukin-1 receptor antagonist anakinra (Intervention) compared to placebo (Comparison) improve organ dysfunction scores at day 7 (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Sepsis is characterized by a dysregulated host immune response leading to life-threatening organ dysfunction. Interleukin-1 (IL-1) is a key pro-inflammatory cytokine implicated in this process. Anakinra, an IL-1 receptor antagonist, was a promising immunomodulatory therapy.
  • Knowledge Gap: Previous trials of anti-cytokine therapies in unselected sepsis populations had failed. It was unknown if targeting a specific inflammatory pathway with anakinra in a more defined population of septic patients with organ failure would be beneficial.
  • Proposed Hypothesis: The authors hypothesized that treatment with anakinra would be superior to placebo in reducing organ dysfunction in patients with sepsis.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 18 intensive care units (ICUs) in Greece.
  • Trial Period: Enrollment ran from October 2017 to December 2019.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with sepsis (Sepsis-3 criteria) and at least one organ failure in addition to the organ of primary infection.
    • Exclusion Criteria: Included severe neutropenia, HIV infection, and recent use of other immunomodulatory drugs.
  • Intervention: Patients received intravenous anakinra (100 mg) once daily for 7 days.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All patients received standard care for sepsis and organ support according to international guidelines.
  • Power and Sample Size: The authors calculated that a sample size of 136 patients would provide 80% power to detect a 1.5-point difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: The mean daily Sequential Organ Failure Assessment (SOFA) score from day 1 to day 7.
    • Secondary Outcomes: Included 28-day mortality and the incidence of adverse events.

6. Key Results

  • Enrollment and Baseline: 137 patients were randomized (69 to anakinra and 68 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The mean daily SOFA score was 7.6 in the anakinra group and 7.9 in the placebo group (p=0.66).
  • Secondary Outcomes: There was no significant difference in 28-day mortality (33% in the anakinra group vs. 37% in the placebo group; p=0.59).
  • Adverse Events: The incidence of adverse events, including secondary infections, was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a linear mixed-effects model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean daily SOFA scores between the two groups.
  • Key Statistic(s) Reported: The key statistics were the mean SOFA scores and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.66 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of 18 diverse ICUs increases the applicability of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome (change in SOFA score).
  • Patient-Centered Outcomes: The study included the crucial patient-centered outcome of mortality, even though it was a secondary endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study population was a broad group of sepsis patients. The intervention might be more effective in a more specific, hyper-inflammatory phenotype of sepsis.
  • Other: The primary outcome was a surrogate marker (organ function score) rather than a direct patient-centered outcome like mortality. The study was not powered to detect a difference in mortality.

10. Conclusion of the Authors

  • The authors concluded that in a population of critically ill patients with sepsis and organ failure, treatment with anakinra did not improve organ dysfunction scores or survival.

11. To Summarize

  • Impact on Current Practice: This trial provided important negative evidence, suggesting that broad, untargeted anti-inflammatory therapy with an IL-1 antagonist is not effective in a general population of sepsis patients.
  • Specific Recommendations:
    • Patient Selection: For adult patients with sepsis and multiple organ dysfunction.
    • Actionable Intervention: The results do not support the routine use of anakinra in this population.
  • What This Trial Does NOT Mean: This trial does NOT mean that immunomodulation has no role in sepsis. It only suggests that this specific drug, given to this broad population, was not effective.
  • Implementation Caveats: The findings of this trial should discourage the routine use of anakinra for sepsis outside of a clinical trial.

12. Context and Related Studies

  • Building on Previous Evidence: The DIABOLO trial (2021) was part of a long history of trials investigating anti-cytokine therapies in sepsis, most of which have been negative.
  • Influence on Subsequent Research: The neutral findings of this trial, along with others, have reinforced the idea that future immunomodulatory therapies in sepsis need to be targeted to specific patient phenotypes (e.g., those with a proven hyper-inflammatory state) rather than being used in all patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether there is a specific subgroup of sepsis patients with a predominantly IL-1-driven hyper-inflammatory response who might still benefit from anakinra.
  • Future Directions: Future research in this area is focused on using biomarkers to identify specific inflammatory endotypes of sepsis, which could then be targeted with more precise immunomodulatory drugs.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was relevant, testing a promising immunomodulatory agent for a deadly condition.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological point for discussion is the choice of a surrogate primary outcome (SOFA score) instead of a patient-centered outcome like mortality, which limited the trial’s ability to draw definitive conclusions about survival.
  • Results: The study reported a clear neutral finding for its primary outcome and for the secondary outcome of mortality.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The trial provides strong evidence that the untargeted use of anakinra in a broad population of sepsis patients is not effective.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
Scroll to Top