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 (PITAGORE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

11 Mar 2023 → ongoing

Decision date (initial)

2024-09-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Organisation name Direction Générale de l’Offre des Soins du Ministère de la santé et de la prévent

External identifiers

EU CT number

2024-511866-36-00

EudraCT number

2022-002636-31

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The primary objective of the study is to demonstrate that among patients hospitalized in ICU with ESBL-producing Enterobacteriaceae severe infection, a treatment with a carbapenem-sparing agent (piperacillin/tazobactam or temocillin) is non-inferior to a carbapenem in terms of mortality.

Secondary objectives 6

1. To compare carbapemen-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms of relapse/recurrence of ESBL infection,
2. To compare carbapemen-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms secondary nosocomial infection
3. To compare carbapemen-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms of antibiotic allergy and adverse events.
4. To compare carbapemen-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms of antibiotic consumption
5. To compare carbapemen-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms of ICU and hospital length of stay.
6. To compare carbapemen-sparing agents (piperacillin/tazobactam or temocillin) to carbapenem in terms of organ failure kinetics

Conditions and MedDRA coding

patients hospitalized in ICU with ESBL-producing Enterobacteriaceae severe infection

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Patients ≥ 18-year-old
2. Hospitalized in the ICU
3. Severe infection, eg infection in patient hospitalized in ICU with or without sepsis or septic shock (according to the Sepsis-3 definition) If present sepsis or septic shock have to be fulfilled within a time frame of +/- 24 hours from the day of infection diagnosis (i.e. the day of positive bacteriological sample).
4. 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)
5. 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
6. Affiliation to social security (AME excluded)

Exclusion criteria 9

1. Pregnancy or breastfeeding
2. Known allergy to beta-lactam
3. Patient with severe neutropenia, as defined by absolute neutrophil count <0.5x109/L
4. Infection requiring prolonged antimicrobial treatment (endocarditis; mediastinitis; osteomyelitis/septic arthritis; undrainable/undrained abscess; unremovable/unremoved prosthetic-associated infection)
5. Moribund, defined by a SAPS II score at inclusion >75
6. Decision of withholding/withdrawing care
7. Patient with concomitant infection requiring antibiotics with activity against Gram-negative bacilli, including patient with polymicrobial infection with pathogen resistant to study drugs
8. Participation in another interventional study evaluating drugs or being in the exclusion period at the end of a previous study evaluating drugs.
9. Hypersensitivity to any components of the formulations

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Mortality at 30 days from the date of randomization

Secondary endpoints 16

1. 90-day mortality rate.
2. Relapse rates of ESBL infection at day 30.
3. Clinical failure rate at day 30 (relapse of ESBL infection or death between randomization and day 30).
4. Rate of antibiotic allergy at day 30.
5. Rate of adverse events at day 30,
6. ICU length of stay
7. Hospital length of stay
8. ICU-free days at day 30
9. Hospital-free days at day 30
10. Antibiotic-free days at day 30
11. Kinetics of organ failure from randomization to day 30 post-randomization, assessed by the sequential organ failure assessment (SOFA) score and its components
12. Rate of faecal colonization with carbapenem-resistant Gram-negative bacilli at end of treatment, ICU discharge and day 90
13. Rate of Clostridium difficile infection at day 90.
14. Rate of secondary nosocomial infection at day 90
15. Proportion of patients in whom duration of antimicrobial treatment of the index episode (the episode that led to inclusion in the study) has been exceeded compared to the recommended duration.
16. Proportion of patients who change their treatment before the recommended duration without relapse (= cross-over)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating Investigator

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating Investigator

Locations

1 EU/EEA country · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications