Clinical trial NCT05443854: Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01)
Official title: Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: A Randomized 2 by 2 Factorial Design Randomized Pragmatic Trial.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Sepsis
Septic Shock
Hematologic Malignancy
Tumor
Allogeneic Stem Cell Transplantation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2022-07-05
Enrollment: 340
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: Sepsis remains the leading cause of ICU admission in neutropenic patients. This condition remains associated with a high morbidity and mortality, with hospital mortality of 60% when vasopressors are required.

Full protective isolation (including geographic isolation, technical isolation, high-efficiency air filtration, and digestive decontamination) proved to be efficient in patients with profound and prolonged neutropenia with regard to infection rate. However, these studies are biased and were performed up to 40 years ago. More recent studies, performed in patients with less profound neutropenia, or performed without digestive decontamination or with partial protective isolation led however to negative results. More importantly, isolation has been demonstrated to limit access to patients' room and to be associated with suboptimal monitoring, with increased rate of severe and avoidable adverse events. This may explain the uneven use of protective isolation in hematology ward and expert's suggestion to appraise protective isolation benefits using large well conducted RCT.

In neutropenic patients with suspected sepsis, urgent broad antibiotic therapy is mandatory and failure to initiate adequate antibiotic therapy within 1 hour has been associated with a 10 fold increase in adjusted mortality. Current IDSA guidelines recommend using preferentially large anti-pseudomonas beta-lactam therapy. Routine antibiotic combination using aminoglycosides is controversial and not recommended. On one hand, meta-analyses suggested not-only a lack of benefit from this association but also increased rate of renal failure and a trend towards a higher mortality rate with aminoglycosides use. On the other hand, subgroup analysis and low-level evidences studies suggest however a benefit from aminoglycosides in critically-ill patients, patients with severe sepsis, or those with documented gram negative infection. Along this line, both the recent Cochran systematic review and the recent French guidelines focusing on neutropenia management in critically-ill patients advocated additional trials in this field focusing in the sickest patients.

The current study aims to assess benefits of protective isolation and systematic use of aminoglycosides combination antibiotic therapy in critically-ill patients with cancer-related neutropenia and sepsis or septic shock. To do so, the investigators intend to perform a 2x2 factorial design randomized pragmatic trial comparing on one hand benefits of protective isolation (versus no protective isolation) and in the other hand benefits of systematic aminoglycosides antibiotics combination (versus no systematic combination).


Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Sepsis or septic shock as defined by SEPSIS3 definition
* Underlying tumor, allogeneic stem cell transplantation or hematological malignancy
* Neutropenia (defined by either absolute neutrophil count \<500/mm3 or leucocytes \<1000/mm3) related to an underlying malignancy or its treatment
* Informed or deferred consent

Exclusion Criteria:

* Pregnancy and breastfeeding
* Moribund patients (death expected within 48 hours by attending physician)
* Previous participation to this study
* No affiliation to social security
* Patients under legal protection according to French Law
* Patient having received more than 1 injection of aminoglycosides in the 3 days preceding ICU admission
* Contraindication to aminoglycosides as mentioned in SpC section 4.3:

  * Hypersensitivity to amikacin, to other antibiotics from the aminoglycoside family, or to any excipient from the amikacin used.
  * Patients with documented allergy to aminoglycosides
  * Myasthenia gravis
  * Concomitant administration of intravenous Polymyxin- Delay between admission for a new sepsis and inclusion\>24 hours or (in patients previously admitted in the ICU for another reason) delay between new sepsis in study inclusion \>24h

Primary outcomes:
measure: Mortality
timeFrame: at day 90
Secondary outcomes:
measure: Mortality
timeFrame: at Day-28
measure: Hospital mortality
timeFrame: at hospital discharge within 3 months
measure: Incidence of acute kidney injury
timeFrame: within 3 months
measure: Severity of acute kidney injury
timeFrame: within 3 months
measure: Duration of acute kidney injury
timeFrame: within 3 months
measure: Major Adverse Kidney Events
timeFrame: at day-28
measure: Major Adverse Kidney Events
timeFrame: at day 90
measure: Incidence of clinically apparent loss of hearing
timeFrame: at ICU discharge
measure: Incidence of clinically apparent loss of hearing
timeFrame: at dat 90
measure: Rate of adherence of hand hygiene
timeFrame: at 24 hours
measure: Incidence density of selected serious adverse events
timeFrame: within 3 months
measure: Incidence density of new bacterial episodes
timeFrame: within 3 months
measure: Incidence density of new viral infection episodes
timeFrame: within 3 months
measure: Incidence density of new fungal episodes
timeFrame: within 3 months
measure: Number of days free from organ support therapy (mechanical ventilation, vasopressors or RRT)
timeFrame: at day 28
measure: Rate of clinical cure
timeFrame: within 3 months
measure: Frequency of initial antibiotic therapy inadequate as regard to microbiological documentation.
timeFrame: at inclusion
measure: Number of day free of antibiotic therapy
timeFrame: at day-28
measure: Duration of aminoglycoside therapy
timeFrame: within 3 months
measure: Rate of aminoglycoside overdosage according to residual concentration
timeFrame: within 3 months
measure: Rate of overuse when compared to experts recommendations
timeFrame: within 3 months
Other outcomes:
Locations:
Study officials:
References: