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Empirical meropenem versus piperacillin/tazobactam for adult patients with sepsis (EMPRESS) trial : Protocol

Granholm, Anders ; Munch, Marie Warrer ; Meier, Nick ; Sjövall, Fredrik LU orcid ; Helleberg, Marie ; Hertz, Frederik Boëtius ; Kaas-Hansen, Benjamin Skov ; Thorsen-Meyer, Hans Christian ; Andersen, Lars Wiuff and Rasmussen, Bodil Steen , et al. (2024) In Acta Anaesthesiologica Scandinavica
Abstract

Background: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. Methods: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant... (More)

Background: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. Methods: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90- and 180-day all-cause mortality and 180-day health-related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow-up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference <2.5%-points) and response-adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios. Conclusions: EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice.

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organization
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type
Contribution to journal
publication status
epub
subject
keywords
adaptive clinical trial, carbapenems, empirical antibiotics, meropenem, piperacillin/tazobactam, randomised clinical trial, sepsis, septic shock
in
Acta Anaesthesiologica Scandinavica
publisher
Wiley-Blackwell
external identifiers
  • pmid:38769040
  • scopus:85193628392
ISSN
0001-5172
DOI
10.1111/aas.14441
language
English
LU publication?
yes
id
6c1f380b-16e8-45c8-b548-141c8b1f1c73
date added to LUP
2024-06-14 12:24:34
date last changed
2024-06-28 13:43:32
@article{6c1f380b-16e8-45c8-b548-141c8b1f1c73,
  abstract     = {{<p>Background: Piperacillin/tazobactam may be associated with less favourable outcomes than carbapenems in patients with severe bacterial infections, but the certainty of evidence is low. Methods: The Empirical Meropenem versus Piperacillin/Tazobactam for Adult Patients with Sepsis (EMPRESS) trial is an investigator-initiated, international, parallel-group, randomised, open-label, adaptive clinical trial with an integrated feasibility phase. We will randomise adult, critically ill patients with sepsis to empirical treatment with meropenem or piperacillin/tazobactam for up to 30 days. The primary outcome is 30-day all-cause mortality. The secondary outcomes are serious adverse reactions within 30 days; isolation precautions due to resistant bacteria within 30 days; days alive without life support and days alive and out of hospital within 30 and 90 days; 90- and 180-day all-cause mortality and 180-day health-related quality of life. EMPRESS will use Bayesian statistical models with weak to somewhat sceptical neutral priors. Adaptive analyses will be conducted after follow-up of the primary outcome for the first 400 participants concludes and after every 300 subsequent participants, with adaptive stopping for superiority/inferiority and practical equivalence (absolute risk difference &lt;2.5%-points) and response-adaptive randomisation. The expected sample sizes in scenarios with no, small or large differences are 5189, 5859 and 2570 participants, with maximum 14,000 participants and ≥99% probability of conclusiveness across all scenarios. Conclusions: EMPRESS will compare the effects of empirical meropenem against piperacillin/tazobactam in adult, critically ill patients with sepsis. Due to the pragmatic, adaptive design with high probability of conclusiveness, the trial results are expected to directly inform clinical practice.</p>}},
  author       = {{Granholm, Anders and Munch, Marie Warrer and Meier, Nick and Sjövall, Fredrik and Helleberg, Marie and Hertz, Frederik Boëtius and Kaas-Hansen, Benjamin Skov and Thorsen-Meyer, Hans Christian and Andersen, Lars Wiuff and Rasmussen, Bodil Steen and Andersen, Jakob Steen and Albertsen, Trine Lynge and Kjær, Maj Brit Nørregaard and Jensen, Aksel Karl Georg and Lange, Theis and Perner, Anders and Møller, Morten Hylander}},
  issn         = {{0001-5172}},
  keywords     = {{adaptive clinical trial; carbapenems; empirical antibiotics; meropenem; piperacillin/tazobactam; randomised clinical trial; sepsis; septic shock}},
  language     = {{eng}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Acta Anaesthesiologica Scandinavica}},
  title        = {{Empirical meropenem versus piperacillin/tazobactam for adult patients with sepsis (EMPRESS) trial : Protocol}},
  url          = {{http://dx.doi.org/10.1111/aas.14441}},
  doi          = {{10.1111/aas.14441}},
  year         = {{2024}},
}