Beta-lactam Intermittent Versus Continuous Infusion and Combination Antibiotic Therapy in Sepsis

NCT ID: NCT05681442

Last Updated: 2025-11-24

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE4

Total Enrollment

600 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-11-13

Study Completion Date

2025-12-01

Brief Summary

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Patients hospitalized in ICU with sepsis (infection with life-threatening organ dysfunction according to sepsis 3.0 definitions) or septic shock presumably due to MDR-GNB (multidrug resistant Gram-negative bacteria). The study will be a prospective multicentre, randomized, open-label comparative continuous vs. intermittent pivotal βL (Beta Lactamine) antibiotic infusion strategies and combination vs. monotherapy trial conducted with a 2X2 factorial design.

Detailed Description

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The study will be a prospective multicentre, randomized, open-label comparative continuous vs. intermittent pivotal βL antibiotic infusion strategies and combination vs. monotherapy trial conducted with a 2X2 factorial design.

Patients will be randomized to one of four of the following treatment groups in a 1:1:1:1 ratio. Randomization will be stratified on the centre and the initial βL administered (meropenem versus other) to receive (i) βL antibiotic either as a continuous infusion: CID group or as intermittent infusion: IID group, and (ii) either at most 1 dose (short duration) : AMT group or 5 days (long duration) : ACT group of aminoglycoside

* Arm A: continuous infusion dosing of a pivotal βL-AB (Antibiotics) (CID group) AND AG (Aminoglycoside) infusion for 5 days (long duration) as appropriate combination therapy (ACT group)
* Arm B: intermittent infusion dosing of a pivotal βL-AB (IID = control group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT = group)
* Arm C: continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group)
* Arm D: intermittent infusion dosing of a pivotal βL-AB (IID = group) AND AG infusion at most 1 dose (AMT group)

The primary objective of the study is to compare the 30-day mortality of patients with hospital-acquired sepsis in the ICU according to the mode of administration of the pivotal βL antibiotic (CID group vs. IID group).

The primary endpoint is the mortality rate at day 30 between CID and IID groups while the Co-primary objective is to compare the MAKE 30 (Major Adverse Kidney Events within 30 days) between patients that will receive an appropriate monotherapy with βL (AMT group) or an appropriate combination therapy with βL and 5 days of AG (ACT group).

moreover, The co-primary criterion is the percentage of patients with a MAKE 30, i.e. when patients met one of the following criteria within day 30: in-hospital mortality, receipt of renal replacement therapy (RRT) or persistent renal dysfunction (discharge serum creatinine/baseline serum creatinine ≥200%) between AMT and ACT groups.

Conditions

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Sepsis

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

The study will be a prospective multicentre, randomized, open-label comparative continuous vs. intermittent pivotal βL antibiotic infusion strategies and combination vs. monotherapy trial conducted with a 2X2 factorial design
Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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continuous infusion dosing of a pivotal AND AG infusion for 5 days

continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT group)

Group Type EXPERIMENTAL

continuous pivotal βL-AB

Intervention Type DRUG

continuous pivotal βL-AB

AG infusion for 5 days

Intervention Type DRUG

AG infusion for 5 days (ACT Group)

intermittent infusion dosing of a pivotal βL-AB ND AG infusion for 5 days

intermittent infusion dosing of a pivotal βL-AB (IID = control group) AND AG infusion for 5 days (long duration) as appropriate combination therapy (ACT = group)

Group Type EXPERIMENTAL

intermittent pivotal βL-AB

Intervention Type DRUG

intermittent pivotal βL-AB (IID = control group)

AG infusion for 5 days

Intervention Type DRUG

AG infusion for 5 days (ACT Group)

continuous infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose

continuous infusion dosing of a pivotal βL-AB (CID group) AND AG infusion at most 1 dose (AMT group )

Group Type EXPERIMENTAL

continuous pivotal βL-AB

Intervention Type DRUG

continuous pivotal βL-AB

AG infusion most 1 dose

Intervention Type DRUG

AG infusion most 1 dose (AMT group )

intermittent infusion dosing of a pivotal βL-AB AND AG infusion at most 1 dose

intermittent infusion dosing of a pivotal βL-AB (IID = group) AND AG infusion at most 1 dose (AMT group)

Group Type EXPERIMENTAL

intermittent pivotal βL-AB

Intervention Type DRUG

intermittent pivotal βL-AB (IID = control group)

AG infusion most 1 dose

Intervention Type DRUG

AG infusion most 1 dose (AMT group )

Interventions

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continuous pivotal βL-AB

continuous pivotal βL-AB

Intervention Type DRUG

intermittent pivotal βL-AB

intermittent pivotal βL-AB (IID = control group)

Intervention Type DRUG

AG infusion most 1 dose

AG infusion most 1 dose (AMT group )

Intervention Type DRUG

AG infusion for 5 days

AG infusion for 5 days (ACT Group)

Intervention Type DRUG

Other Intervention Names

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CID group IID control group AMT group ACT Group

Eligibility Criteria

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Inclusion Criteria

* Adults (≥ 18 years)
* Hospital-acquired sepsis (according to sepsis 3.0 definitions) :

* Patient hospitalized for more than 48 hours OR Patient discharged less than 48 hours ago
* AND sepsis diagnosed within the last 24 hours
* One of the following risk factors for gram negative multidrug resistant pathogens:

* Prior intravenous antibiotic use within 7 days prior to sepsis onset with the exception of antibiotic effective only against Gram-positive bacteria, penicillin A and macrolides
* Prolonged hospital stay (≥ 15 days of hospitalization) within 3 months prior to sepsis onset Prolonged mechanical ventilation (≥ 5 days on mechanical ventilation) within 3 months prior to sepsis onset
* Patients with indwelling devices (dialysis access lines, intravascular lines, urinary catheter, endotracheal or tracheostomy tube, gastrostomy or jejunostomy feeding tube)
* Patients known to be infected, colonized or carriers of MDR gram negative bacteria within 3 months prior to sepsis onset
* Exposure to an antibiotic (amoxicillin-clavulanic acid, C2G, C3G, fluoroquinolones) within 3 months prior to sepsis onset
* A trip abroad to known geographical areas at risk (in particular the Indian subcontinent, South-East Asia, the Middle East and North Africa, the Mediterranean Basin) within 3 months prior to sepsis onset
* A functional or organic abnormality of the urinary tract in case of urinary tract infection.
* Appropriate bacteriological sampling performed before starting antimicrobial therapy
* Expected stay in ICU of more than 3 days

Exclusion Criteria

* A priori known resistance to all the proposed beta-lactams or to amikacin
* Need for extrarenal treatment at inclusion according to the criteria of Gaudry et al.
* Known hypersensitivity to ceftazidime, piperacillin-tazobactam, cefepime, meropenem, ceftazidime-avibactam, ceftazolane-avibactam or to any of the excipients included in the corresponding pharmaceutical drugs,
* Known hypersensitivity to any cephalosporin antibacterial agent,
* Know hypersentitivity to any penem antibacterial agent,
* Severe known hypersensitivity (eg, anaphylactic reaction, severe skin reaction) to any other beta-lactam antibiotic (eg, penicillins or monobactam ) or to any of its excipients.
* Known contraindication to the aminoglycoside family including

* Hypersensitivity to the active substance, to any aminoglycoside antibacterial agent or to any of the excipients included in the corresponding pharmaceutical drugs,
* Cirrhosis of grades B and C according to the Child-Pugh classification.
* Myasthenia gravis.
* Simultaneous administration of another aminoglycoside
* Association with ataluren
* Non-complicated urinary tract infection (corresponding to a positive ECBU not responsible for sepsis)
* Bone marrow transplant or chemotherapy-induced neutropenia
* Infections for which long-term antibiotic treatment \> 8 days is strongly recommended (i.e., infective endocarditis, osteoarticular infections, anterior mediastinitis after cardiac surgery, hepatic or cerebral abscesses, chronic prostatitis for instance
* Presence of antibiotic therapyfor the new sepsis before randomisation: (\> 2 doses of antibiotics or \> 16h for continuous infusion
* Limitation of life support (comfort care applied only) at the time of screening
* Enrolment to another interventional drug study
* Pregnancy or breastfeeding
* Subject deprived of freedom, subject under a legal protective measure
* Non affiliation to any health insurance system
* Refusal to participate to the study (patient or legal representative or family member or close relative if present)
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Aline DECHANET

Role: STUDY_CHAIR

Assistance Publique - Hôpitaux de Paris (AP-HP)

Locations

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Médecine intensive - réanimation - CHU Amiens-Picardie

Amiens, , France

Site Status WITHDRAWN

Réanimation polyvalente - CH d'Argenteuil - Hôpital Victor Dupuy

Argenteuil, , France

Site Status RECRUITING

Réanimation polyvalente - CH Avignon

Avignon, , France

Site Status RECRUITING

Médecine intensive - réanimation - CHU Bordeaux - Hôpital Pellegrin

Bordeaux, , France

Site Status RECRUITING

Médecine intensive - réanimation - Ambroise Paré

Boulogne-Billancourt, , France

Site Status RECRUITING

Médecine intensive - réanimation - CHU Gabriel Montpied

Clermont-Ferrand, , France

Site Status RECRUITING

Anesthésie - Réanimation - Beaujon

Clichy, , France

Site Status RECRUITING

Réanimation polyvalente/Surveillance continue - CH Sud Essonne-Etampes

Étampes, , France

Site Status RECRUITING

Médecine intensive - réanimation-Centre Hospitalier Départemental Vendée

La Roche-sur-Yon, , France

Site Status RECRUITING

Médecine intensive - réanimation - CHU Grenoble-Alpes Hôpital Michallon

La Tronche, , France

Site Status RECRUITING

Réanimation polyvalente - CH de Versailles - Hôpital André Mignot

Le Chesnay, , France

Site Status RECRUITING

Réanimation Médico Chirurgicale & USC - CH Le Mans

Le Mans, , France

Site Status RECRUITING

Médecine Intensive Réanimation - Hôpital Croix Rousse

Lyon, , France

Site Status RECRUITING

Médecine intensive - réanimation - HCL - Edouard Herriot

Lyon, , France

Site Status RECRUITING

Réanimation polyvalente - CHR Metz-Thionville - Hôpital de Mercy

Metz, , France

Site Status RECRUITING

Médecine intensive - réanimation - CHU Montpellier - Hôpital Lapeyronie

Montpellier, , France

Site Status RECRUITING

Réanimation Chirurgicale - Saint Eloi

Montpellier, , France

Site Status RECRUITING

Médecine Intensive Réanimation - Pasteur 2

Nice, , France

Site Status RECRUITING

Médecine intensive - réanimation - CHU Nice - Hôpital Archet

Nice, , France

Site Status RECRUITING

Médecine intensive - réanimation

Orléans, , France

Site Status RECRUITING

Anesthésie - Réanimation - CHU Orléans

Orléans, , France

Site Status RECRUITING

Médecine intensive et réanimation infectieuse - Bichat

Paris, , France

Site Status RECRUITING

Réanimation chirurgicale - Bichat

Paris, , France

Site Status RECRUITING

Institut Mutualiste du Montsouris

Paris, , France

Site Status RECRUITING

Médecine intensive - réanimation - CHU Poitiers - Site de la Milétrie

Poitiers, , France

Site Status RECRUITING

Médecine intensive et réanimation polyvalente 6 CHU de Reims - Hôpital Robert Debré

Reims, , France

Site Status WITHDRAWN

Médecine intensive - réanimation-CH St Denis - Hôpital Delafontaine

Saint-Denis, , France

Site Status RECRUITING

Médecine intensive - réanimation - CHU de Strasbourg - Nouvel Hôpital Civil

Strasbourg, , France

Site Status RECRUITING

Countries

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France

Central Contacts

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Jean-François TIMSIT, MD-PhD

Role: CONTACT

Lila BOUADMA, MD-PhD

Role: CONTACT

01.40.25.77.07

Facility Contacts

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Olivier PAJOT, MD-PhD

Role: primary

Sébastien MOSSCHIETTO, MD - PhD

Role: primary

Alexandre BOYER, MD - PhD

Role: primary

Antoine VIELLARD-BARON, MD-PhD

Role: primary

Claire DUPUIS, MD - Phd

Role: primary

Emmanuel WEISS, MD-PhD

Role: primary

Shidasp SIAMI, MD-PhD

Role: primary

Konstantinos BACHOUMAS, MD - PhD

Role: primary

Anais DARTEVEL, MD - PhD

Role: primary

Gilles TROCHE, MD - PhD

Role: primary

Cédric DARREAU, MD - PhD

Role: primary

Jean-christophe RICHARD

Role: primary

Laurent ARGAUD, MD-PhD

Role: primary

Guillaume LOUIS, MD - PhD

Role: primary

Kada KLOUCHE, MD - PhD

Role: primary

Samir JABER

Role: primary

ROBERT Alexandre

Role: primary

Clément SACCHERI, MD - PhD

Role: primary

François BARBIER

Role: primary

BARBIER François

Role: primary

Lila BOUADMA, MD-Phd

Role: primary

Philippe MONTRAVERS, MD- pHd

Role: primary

WICKY P Paul-Henri

Role: primary

François ARRIVE, MD - PhD

Role: primary

Daniel DA SILVA, MD - PhD

Role: primary

Ferhat MEZIANI, MD - PhD

Role: primary

Other Identifiers

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APHP180596

Identifier Type: -

Identifier Source: org_study_id

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