SepsisPhase 3PITAGORENCT05565222
Piperacillin-tazobactam and Temocillin as Carbapenem-alternatives for the Treatment of Severe Infections Due to Extended-spectrum Beta-lactamase-Producing Gram-negative Enterobacteriaceae in the Intensive Care Unit
A Phase 3 study testing Piperacillin/tazobactam or temocillin and Meropenem in people with Sepsis and Septic Shock, run by Assistance Publique - Hôpitaux de Paris at 2 sites in France.
Trial summary
Infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are a major public health concern, in particular in the intensive care unit (ICU), due to the increase in their incidence. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Sepsis, Septic Shock
- What is being tested?
- Piperacillin/tazobactam or temocillin and Meropenem
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 600 participants
- Where
- 2 sitesFrance
- Study dates
- 11 Mar 2023to Jun 2026
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients ≥ 18-year-old
- Hospitalized in the ICU
- Severe infection, eg sepsis or septic shock (according to the Sepsis-3 definition) Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by an increase of Sequential Organ Failure Assessment (SOFA) score of 2 points or more. This increase in 2 points will be calculated the day infection is diagnosed (day of positive culture serving as reference for the infection) as compared to the day before infection onset.
- Septic shock is defined as sepsis and persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mmHg and having a serum lactate level >2 mmol/l despite adequate volume resuscitation.
- This criterion (sepsis or septic shock) has to be fulfilled within a time frame of +/- 24 hours from the day of infection diagnosis (i.e. the day of positive bacteriological sample).
- Pathogen responsible for infection is an ESBL-producing Enterobacteriaceae susceptible to meropenem and either to piperacillin/tazobactam (minimum inhibitory concentration <8 mg/L) or to temocillin (minimum inhibitory concentration ≤8 mg/L)
- Signed Informed consent from patient/a legal representative/a family member/a close relative. According to the specifications of emergency inclusion, randomization without the close relative or surrogate consent could be performed if the patient is unable to give his/her consent and when the legal representative/family member or close relative are absent except patients included in another study for which emergency inclusion has already been used (see exclusion criteria n° 8). For these patients, emergency inclusion cannot be used). Close relative/surrogate/family consent will be asked as soon as possible. The patient will be asked to give his/her consent for the continuation of the trial when his/her condition will allow
- Affiliation to social security (AME excluded)
Who cannot join
- Pregnancy or breastfeeding
- Known allergy to beta-lactam
- Patient with severe neutropenia, as defined by absolute neutrophil count <0.5x109/L
- Infection requiring prolonged antimicrobial treatment (endocarditis; mediastinitis; osteomyelitis/septic arthritis; undrainable/undrained abscess; unremovable/unremoved prosthetic-associated infection)
- Moribund, defined by a SAPS II score at inclusion >75
- Decision of withholding/withdrawing care
Show all 9Show fewer
- Patient with concomitant infection requiring antibiotics with activity against Gram-negative bacilli, including patient with polymicrobial infection with pathogen resistant to study drugs
- Participation in another interventional study evaluating drugs or being in the exclusion period at the end of a previous study evaluating drugs .
- Hypersensitivity to any components of the formulations
Trial locations and contacts
2 sites in 1 country.
France2 sites, 2 recruiting
- Recruiting
LUYT Charles -Edouard
Paris, 75013
LUYT Charles -Edouard, MD, 0142163824, charles-edouard.luyt@aphp.fr
- Recruiting
MAYAUX Julien
Paris, 75013
MAYAUX Julien, MD, 0142167756, julien.mayaux@aphp.fr
About this study
Infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are a major public health concern, in particular in the intensive care unit (ICU), due to the increase in their incidence. Carbapenems are the treatment of choice of these infections, but their increased use may select for carbapenem resistance in Gram-negative bacilli, which currently represents the greatest threat in terms of antibiotic resistance. Several retrospective studies have shown that the use of non-carbapenem antibiotics (mainly the association of piperacillin/tazobactam, but also cefepime and temocillin) may be safe alternatives to carbapenems to treat these pathogens when the strain is susceptible to the corresponding antibiotic. However, one recent randomized controlled study, the Merino trial, failed to demonstrate the non-inferiority of piperacillin/tazobactam, as compared to meropenem, in patients with Gram-negative bacilli bacteremia resistant to third generation cephalosporins (mainly ESBL producers). However, the patients included in that study were not ICU patients, dosing and modalities of piperacillin/tazobactam administration were not optimal (30-min infusion whereas 4-hours infusion may be associated with better outcome), and cause of death of patients in the piperacillin/tazobactam arm were not due to antimicrobial treatment failure (mostly death due to care withdrawal in cancer patients). Recently, a retrospective bicenter study performed in ICU patients showed that outcome of patients with severe infection (i.e. sepsis and septic shock according to the Sepsis-3 definition) due to ESBL-producing Enterobacteriaceae susceptible to non-carbapenem agents treated with a non-carbapenem agent was similar to that of patients treated with carbapenems.
Given the scarcity of data in ICU patients, the disputable results of the Merino trial, we will therefore conduct a multicenter, randomized, open-label trial of non-carbapenem beta-lactam (piperacillin/tazobactam or temocillin) treatment vs. meropenem treatment for ESBL-producing Enterobaceriaceae severe infection in ICU patients. Our hypothesis is that a non-carbapenem beta-lactam treatment is non-inferior to carbapenem treatment in patients with ESBL-producing Enterobacteriaceae severe infection in the ICU.
- Conditions
- Sepsis, Septic Shock
- Being tested
- Piperacillin/tazobactam or temocillin, Meropenem
- Keywords
- carbapenem-alternatives, severe infections
- Medical subject headings
- Sepsis, Shock, Septic, Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Piperacillin/tazobactam or temocillinDrug
Piperacillin/tazobactam : 4.5 g by intravenous route every 6 hours (adjusted in case of renal failure).
Temocillin : 6g/24 hours infused continuously by intravenous route after 2 g loading dose (adjusted in case of renal failure)
MeropenemDrug
2 g every 8 hours by intravenous route (adjusted in case of renal failure)
| Study group | Role | What they receive |
|---|---|---|
| Piperacillin/tazobactam or temocillin | Experimental | Piperacillin/tazobactam, 4.5 g by intravenous route every 6 hours (adjusted in case of renal failure). Piperacillin/tazobactam will be infused over 4 hours. Duration of treatment will be adjusted according to the site of infection Temocillin, 6g/24 hours infused continuously by intravenous route after 2 g loading dose (adjusted in case of renal failure). Temocillin will be infused continuously. Duration of treatment will be adjusted according to the site of infection Receives: Drug: Piperacillin/tazobactam or temocillin |
| Meropenem | Active comparator | 2 g every 8 hours by intravenous route (adjusted in case of renal failure). Meropenem will be infused over 2 hours. Duration of treatment will be adjusted according to the site of infection Receives: Drug: Meropenem |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Measured: Day 30
Secondary outcomes (14)
Mortality
Measured: Day 90
Relapses rates of extended-spectrum beta-lactamase infection
Measured: Day 30
Clinical failure rate
relapse of ESBL infection or death
Measured: Day 30
Rate of antibiotic allergy
Measured: Day 30
Incidence of adverse drug reactions
Measured: Between randomization and Day 90
Duration of hospitalization stay
Measured: Between randomization and Day 90
Duration of ICU stay
Measured: Between randomization and Day 90
Number of days alive without antibiotics
Measured: Between randomization and Day 30
Days with organ failure asessed by sequential organ failure assessment
Measured: Between randomization and Day 30
Rate of faecal colonization with carbapenem-resistant Gram-negative bacilli
Measured: End of treatment, ICU discharge and day 90
Rate of Clostridium difficile infection
Measured: Day 90
Rate of secondary nosocomial infection
Measured: Day 90
Proportion of patients in whom duration of antimicrobial treatment of the index episode has been exceeded compared to the recommended duration
Measured: Through completion of study treatment, an average of 10 days and up to 21 days
Proportion of patients who change their treatment before the recommended duration without relapse
= cross-over
Measured: Through completion of study treatment, an average of 10 days and up to 21 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Oct 2022
- Study start11 Mar 2023
- Primary completionApr 2026 (estimated)
- Study completionJun 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 600 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05565222
- Sponsor's protocol ID
- APHP211034
- Acronym
- PITAGORE
- Status last verified
- Apr 2023
- First submitted
- 26 Sep 2022
- Last updated
- 18 Apr 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Apr 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Piperacillin-tazobactam and Temocillin as Carbapenem-alternatives for the Treatment of Severe Infections Due to Extended-spectrum Beta-lactamase-Producing Gram-negative Enterobacteriaceae in the Intensive Care Unit
- ClinicalTrials.gov ID
- NCT05565222
- Acronym / sponsor ID
- PITAGORE / APHP211034
- Conditions
- Sepsis, Septic Shock
- Keywords
- carbapenem-alternatives, severe infections
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 600 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 11 Mar 2023 (actual)
- Primary completion
- Apr 2026 (estimated)
- Study completion
- Jun 2026 (estimated)
- First posted
- 4 Oct 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Infections due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are a major public health concern, in particular in the intensive care unit (ICU), due to the increase in their incidence. Carbapenems are the treatment of choice of these infections, but their increased use may select for carbapenem resistance in Gram-negative bacilli, which currently represents the greatest threat in terms of antibiotic resistance. Several retrospective studies have shown that the use of non-carbapenem antibiotics (mainly the association of piperacillin/tazobactam, but also cefepime and temocillin) may be safe alternatives to carbapenems to treat these pathogens when the strain is susceptible to the corresponding antibiotic. However, one recent randomized controlled study, the Merino trial, failed to demonstrate the non-inferiority of piperacillin/tazobactam, as compared to meropenem, in patients with Gram-negative bacilli bacteremia resistant to third generation cephalosporins (mainly ESBL producers). However, the patients included in that study were not ICU patients, dosing and modalities of piperacillin/tazobactam administration were not optimal (30-min infusion whereas 4-hours infusion may be associated with better outcome), and cause of death of patients in the piperacillin/tazobactam arm were not due to antimicrobial treatment failure (mostly death due to care withdrawal in cancer patients). Recently, a retrospective bicenter study performed in ICU patients showed that outcome of patients with severe infection (i.e. sepsis and septic shock according to the Sepsis-3 definition) due to ESBL-producing Enterobacteriaceae susceptible to non-carbapenem agents treated with a non-carbapenem agent was similar to that of patients treated with carbapenems.
Given the scarcity of data in ICU patients, the disputable results of the Merino trial, we will therefore conduct a multicenter, randomized, open-label trial of non-carbapenem beta-lactam (piperacillin/tazobactam or temocillin) treatment vs. meropenem treatment for ESBL-producing Enterobaceriaceae severe infection in ICU patients. Our hypothesis is that a non-carbapenem beta-lactam treatment is non-inferior to carbapenem treatment in patients with ESBL-producing Enterobacteriaceae severe infection in the ICU.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Piperacillin/tazobactam or temocillin | Experimental | Drug: Piperacillin/tazobactam or temocillinPiperacillin/tazobactam, 4.5 g by intravenous route every 6 hours (adjusted in case of renal failure). Piperacillin/tazobactam will be infused over 4 hours. Duration of treatment will be adjusted according to the site of infection Temocillin, 6g/24 hours infused continuously by intravenous route after 2 g loading dose (adjusted in case of renal failure). Temocillin will be infused continuously. Duration of treatment will be adjusted according to the site of infection |
| Meropenem | Active comparator | Drug: Meropenem2 g every 8 hours by intravenous route (adjusted in case of renal failure). Meropenem will be infused over 2 hours. Duration of treatment will be adjusted according to the site of infection |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Patients ≥ 18-year-old
- Hospitalized in the ICU
- Severe infection, eg sepsis or septic shock (according to the Sepsis-3 definition) Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by an increase of Sequential Organ Failure Assessment (SOFA) score of 2 points or more. This increase in 2 points will be calculated the day infection is diagnosed (day of positive culture serving as reference for the infection) as compared to the day before infection onset.
- Septic shock is defined as sepsis and persisting hypotension requiring vasopressors to maintain mean arterial pressure ≥65 mmHg and having a serum lactate level >2 mmol/l despite adequate volume resuscitation.
- This criterion (sepsis or septic shock) has to be fulfilled within a time frame of +/- 24 hours from the day of infection diagnosis (i.e. the day of positive bacteriological sample).
Key exclusion criteria (9 listed)
- Pregnancy or breastfeeding
- Known allergy to beta-lactam
- Patient with severe neutropenia, as defined by absolute neutrophil count <0.5x109/L
- Infection requiring prolonged antimicrobial treatment (endocarditis; mediastinitis; osteomyelitis/septic arthritis; undrainable/undrained abscess; unremovable/unremoved prosthetic-associated infection)
- Moribund, defined by a SAPS II score at inclusion >75
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Piperacillin/tazobactam or temocillinPiperacillin/tazobactam : 4.5 g by intravenous route every 6 hours (adjusted in case of renal failure). Temocillin : 6g/24 hours infused continuously by intravenous route after 2 g loading dose (adjusted in case of renal failure) | Drug | Piperacillin/tazobactam or temocillin |
| Meropenem2 g every 8 hours by intravenous route (adjusted in case of renal failure) | Drug | Meropenem |
Primary outcome
Mortality
Time frame: Day 30
14 secondary outcomes
Mortality
Time frame: Day 90
Relapses rates of extended-spectrum beta-lactamase infection
Time frame: Day 30
Clinical failure rate
Time frame: Day 30
Rate of antibiotic allergy
Time frame: Day 30
Incidence of adverse drug reactions
Time frame: Between randomization and Day 90
Duration of hospitalization stay
Time frame: Between randomization and Day 90
Duration of ICU stay
Time frame: Between randomization and Day 90
Number of days alive without antibiotics
Time frame: Between randomization and Day 30
Days with organ failure asessed by sequential organ failure assessment
Time frame: Between randomization and Day 30
Rate of faecal colonization with carbapenem-resistant Gram-negative bacilli
Time frame: End of treatment, ICU discharge and day 90
Rate of Clostridium difficile infection
Time frame: Day 90
Rate of secondary nosocomial infection
Time frame: Day 90
Proportion of patients in whom duration of antimicrobial treatment of the index episode has been exceeded compared to the recommended duration
Time frame: Through completion of study treatment, an average of 10 days and up to 21 days
Proportion of patients who change their treatment before the recommended duration without relapse
Time frame: Through completion of study treatment, an average of 10 days and up to 21 days
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Apr 2023.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Piperacillin/tazobactam or temocillin and Meropenem in people with Sepsis and Septic Shock, run by Assistance Publique - Hôpitaux de Paris at 2 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Apr 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: Day 30). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Apr 2023.