Ignite Creation Date:
2024-05-06 @ 7:55 PM
Last Modification Date:
2024-10-26 @ 3:16 PM
Study NCT ID:
NCT06184659
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-04-16
First Post:
2023-12-14
Brief Title:
Empirical Meropenem Versus PiperacillinTazobactam for Adult Patients With Sepsis
Sponsor:
Scandinavian Critical Care Trials Group
Organization:
Scandinavian Critical Care Trials Group
Study Overview
Official Title:
Empirical Meropenem Versus PiperacillinTazobactam for Adult Patients With Sepsis EMPRESS Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EMPRESS
Brief Summary:
The EMPRESS trial aims to test the two most commonly used antibiotics meropenem and piperacillintazobactam among intensive care patients with sepsis blood poisoning as the safety of these two drugs is unclear in this group of patients
Detailed Description:
Background Piperacillintazobactam and meropenem are commonly used as empirical agents for patients with sepsis or septic shock In a recent systematic review comparing empirical andor definitive treatment with piperacillintazobactam versus meropenem for patients with severe bacterial infections including sepsis and septic shock it was shown that piperacillintazobactam may be associated with less favourable outcomes based on low or very low certainty of evidence At present it is unclear if piperacillintazobactam and meropenem are equally effective and safe for adults with sepsis
Objectives To assess the effects of empirical meropenem vs piperacillintazobactam on mortality and other patient-important outcomes in critically ill adults with sepsis
Design Investigator-initiated international parallel-group randomised open-label adaptive clinical trial with an integrated feasibility phase The EMPRESS trial will employ adaptive stopping rules to increase the chance that the trial will be conclusive and response-adaptive randomisation to increase each participants chance of being randomised to the superior intervention arm
Inclusion and exclusion criteria We will screen all adult patients who are critically ill with sepsis and who have indication for empirical treatment with meropenem or piperacillintazobactam We will exclude patients with preceding intravenous treatment with meropenem or piperacillintazobactam for 24 hours or more known pregnancy known hypersensitivity or allergy to beta-lactam antibiotics suspected or documented central nervous system infection known infection or colonialisation with microorganism with acquired resistance to meropenem or piperacillintazobactam current use of valproate co-enrolment in other interventional trial where protocols collide previous randomisation in EMPRESS informed consent following inclusion expected to be unobtainable and patients who are under coercive measures
Experimental intervention IV meropenem 1 g three times daily for up to 30 days
Control intervention IV piperacillintazobactam 405 g four times daily for up to 30 days
Outcomes The primary outcome is all-cause mortality at 30 days after randomisation The secondary outcomes are the occurrence at least one serious adverse reaction ie anaphylactic reaction to IV piperacillintazobactam or meropenem invasive fungal infection pseudomembranous colitis or toxic epidermal necrolysis within 30 days of randomisation the occurrence of new isolation precautions due to resistant bacteria within 30 days of randomisation days alive without life support ie invasive mechanical ventilation circulatory support or renal replacement therapy from randomisation to day 30 and 90 days alive and out of hospital from randomisation to day 30 and 90 all-cause mortality at day 90 and 180 and health-related quality of life at day 180 using EQ-5D-5L index values and EQ VAS The feasibility outcomes are time to completion of feasibility phase ie 200 participants randomised recruitment proportion proportion of participants without consent to the use of data protocol adherence and retention proportion
Statistics and stopping rules The trial will be analysed using Bayesian statistical methods with the primary analyses conducted in the intention-to-treat population Outcomes will be analysed using logistic and linear regression models adjusted for relevant baseline characteristics and neutral and weakly informative to somewhat sceptical priors Results will be presented as adjusted sample average treatment effects using both absolute risk and mean differences and relative risk ratios and ratios of means differences with 95 credible intervals and probabilities of benefitharm Adaptive analyses will start after follow-up and data collection concludes for 400 participants and every subsequent 300 participants up to a maximum of 14000 participants Adaptations will be based on data for the primary outcome EMPRESS will use constant symmetrical stopping rules for inferioritysuperiority calibrated to keep the type 1 error rate at 5 Further the trial will be stopped for practical equivalence if there is 90 probability that the absolute risk difference between arms is less than 25-points Restricted response-adaptive randomisation will be used to ensure minimum allocation probabilities of 40 to both groups
Missing data will be imputed and relevant secondary analyses sensitivity analyses and analyses of heterogeneity in treatment effects according to pre-defined baseline characteristics will be undertaken once the trial has been stopped
Trial design performance metrics Performance characteristics were evaluated assuming a 25 event probability for the primary outcome in the piperacillintazobactam arm and scenarios with no small and large differences corresponding to event probabilities of 25 225 and 20 in the meropenem arm respectively The expected mean sample sizes under these scenarios are 5189 5859 and 2570 respectively The probabilities of conclusiveness ie superiority or equivalence are 99 in all scenarios and the probabilities of superiority power are 72 and 99 in the small and large difference scenarios respectively
Estimated timeline
Primo 2024 authority approvals and first participant randomised
Primo 2025 feasibility phase analysis concluded
Medio 2028 expected inclusion of the last participant if trial continues to the expected sample size in the small-difference scenario ie the largest expected sample size under the three different scenarios assessed section 199
Medio 2032 expected inclusion of the last participant if the trial continues to the maximum sample size n14000 section 199
Approximately 3 months after inclusion of the last participant primary report on 30-day outcomes submitted
Approximately 6 months after inclusion of the last participant report on 90-day outcomes submitted
Approximately 9 months after inclusion of the last participant report on 180-day outcomes submitted
Objectives To assess the effects of empirical meropenem vs piperacillintazobactam on mortality and other patient-important outcomes in critically ill adults with sepsis
Design Investigator-initiated international parallel-group randomised open-label adaptive clinical trial with an integrated feasibility phase The EMPRESS trial will employ adaptive stopping rules to increase the chance that the trial will be conclusive and response-adaptive randomisation to increase each participants chance of being randomised to the superior intervention arm
Inclusion and exclusion criteria We will screen all adult patients who are critically ill with sepsis and who have indication for empirical treatment with meropenem or piperacillintazobactam We will exclude patients with preceding intravenous treatment with meropenem or piperacillintazobactam for 24 hours or more known pregnancy known hypersensitivity or allergy to beta-lactam antibiotics suspected or documented central nervous system infection known infection or colonialisation with microorganism with acquired resistance to meropenem or piperacillintazobactam current use of valproate co-enrolment in other interventional trial where protocols collide previous randomisation in EMPRESS informed consent following inclusion expected to be unobtainable and patients who are under coercive measures
Experimental intervention IV meropenem 1 g three times daily for up to 30 days
Control intervention IV piperacillintazobactam 405 g four times daily for up to 30 days
Outcomes The primary outcome is all-cause mortality at 30 days after randomisation The secondary outcomes are the occurrence at least one serious adverse reaction ie anaphylactic reaction to IV piperacillintazobactam or meropenem invasive fungal infection pseudomembranous colitis or toxic epidermal necrolysis within 30 days of randomisation the occurrence of new isolation precautions due to resistant bacteria within 30 days of randomisation days alive without life support ie invasive mechanical ventilation circulatory support or renal replacement therapy from randomisation to day 30 and 90 days alive and out of hospital from randomisation to day 30 and 90 all-cause mortality at day 90 and 180 and health-related quality of life at day 180 using EQ-5D-5L index values and EQ VAS The feasibility outcomes are time to completion of feasibility phase ie 200 participants randomised recruitment proportion proportion of participants without consent to the use of data protocol adherence and retention proportion
Statistics and stopping rules The trial will be analysed using Bayesian statistical methods with the primary analyses conducted in the intention-to-treat population Outcomes will be analysed using logistic and linear regression models adjusted for relevant baseline characteristics and neutral and weakly informative to somewhat sceptical priors Results will be presented as adjusted sample average treatment effects using both absolute risk and mean differences and relative risk ratios and ratios of means differences with 95 credible intervals and probabilities of benefitharm Adaptive analyses will start after follow-up and data collection concludes for 400 participants and every subsequent 300 participants up to a maximum of 14000 participants Adaptations will be based on data for the primary outcome EMPRESS will use constant symmetrical stopping rules for inferioritysuperiority calibrated to keep the type 1 error rate at 5 Further the trial will be stopped for practical equivalence if there is 90 probability that the absolute risk difference between arms is less than 25-points Restricted response-adaptive randomisation will be used to ensure minimum allocation probabilities of 40 to both groups
Missing data will be imputed and relevant secondary analyses sensitivity analyses and analyses of heterogeneity in treatment effects according to pre-defined baseline characteristics will be undertaken once the trial has been stopped
Trial design performance metrics Performance characteristics were evaluated assuming a 25 event probability for the primary outcome in the piperacillintazobactam arm and scenarios with no small and large differences corresponding to event probabilities of 25 225 and 20 in the meropenem arm respectively The expected mean sample sizes under these scenarios are 5189 5859 and 2570 respectively The probabilities of conclusiveness ie superiority or equivalence are 99 in all scenarios and the probabilities of superiority power are 72 and 99 in the small and large difference scenarios respectively
Estimated timeline
Primo 2024 authority approvals and first participant randomised
Primo 2025 feasibility phase analysis concluded
Medio 2028 expected inclusion of the last participant if trial continues to the expected sample size in the small-difference scenario ie the largest expected sample size under the three different scenarios assessed section 199
Medio 2032 expected inclusion of the last participant if the trial continues to the maximum sample size n14000 section 199
Approximately 3 months after inclusion of the last participant primary report on 30-day outcomes submitted
Approximately 6 months after inclusion of the last participant report on 90-day outcomes submitted
Approximately 9 months after inclusion of the last participant report on 180-day outcomes submitted
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 2023-509703-33-00 | OTHER | EUCT CTIS | None |