Impact of Aminoglycosides-based Antibiotics Combination and Protective Isolation on Outcomes in Critically-ill Neutropenic Patients With Sepsis: (Combination-Lock01)

Sepsis Clinical Trial

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.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05443854
• Other study ID #: APHP180690
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: September 2022
• Est. completion date: June 2024

Study information

• Verified date: June 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Michael Darmon
• Phone: 01 42 49 94 19
• Email: michael.darmon[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 340
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Allogeneic Stem Cell Transplantation
• Hematologic Malignancy
• Hematologic Neoplasms
• Sepsis
• Septic Shock
• Toxemia
• Tumor

Intervention

Drug:
• Aminoglycosides intervention
Antibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines [3, 28, 50]. Systematic aminoglycoside therapy using Amikacin at a dose of 25 to 30 mg/Kg per dose, at a rate of a maximum of 1 infusion per day will be delivered. Recommended duration will be of three days or until microbiological documentation.

Behavioral:
• Lack of protective isolation intervention
Protective isolation will be avoided until ICU discharge is deemed possible. Specific measures regarding nutrition (including avoidance of food consider at risk of fungal contamination) and water protection will be maintained. Extended universal hygiene measures will be maintained and use of mask will be advocated during viral epidemic periods. A high degree of compliance as regard to antifungal prophylaxis guidelines and local standard hygiene procedures will be advocated

Other:
• No systematic aminoglycosides intervention - standard arm
Antibiotic therapy and prophylaxis will be in line with more recent IDSA and ESCMID guidelines [3, 28, 50]. No systematic aminoglycoside therapy will be provided except in presence of predefined specific organ infection (such intra-vascular infection such endocarditis for example) or drug-resistant infection requiring aminoglycosides.
• Protective isolation intervention - standard arm
Protective isolation will be provided systematically as currently practiced in participating centers. Modality will be in line with recent SRLF guidelines, we will recommend for the patients to receive an isolation the maximal available isolation with the aim to provide: High-efficiency air filtration [filtration of 99.7% of particles greater than or equal to 0.3 µm; International Organization for Standardization (ISO) class 5 or better] Geographical isolation in an individual room Technical isolation, including a face mask and a cap. This approach of isolation will however be pragmatic on the basis of the "best available" level of isolation in line with recommendation, while not delaying ICU admission and patients' care

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	Overall death	at day 90
Secondary	Mortality	Overall death	at Day-28
Secondary	Hospital mortality	Mortality at hospital discharge	at hospital discharge within 3 months
Secondary	Incidence of acute kidney injury	Acute kidney injury (AKI) will be defined according to KDIGO criteria	within 3 months
Secondary	Severity of acute kidney injury	Acute kidney injury (AKI) will be defined according to KDIGO criteria	within 3 months
Secondary	Duration of acute kidney injury	Acute kidney injury (AKI) will be defined according to KDIGO criteria	within 3 months
Secondary	Major Adverse Kidney Events		at day-28
Secondary	Major Adverse Kidney Events		at day 90
Secondary	Incidence of clinically apparent loss of hearing		at ICU discharge
Secondary	Incidence of clinically apparent loss of hearing		at dat 90
Secondary	Rate of adherence of hand hygiene	hand hygiene will be assessed by external observer	at 24 hours
Secondary	Incidence density of selected serious adverse events		within 3 months
Secondary	Incidence density of new bacterial episodes		within 3 months
Secondary	Incidence density of new viral infection episodes		within 3 months
Secondary	Incidence density of new fungal episodes		within 3 months
Secondary	Number of days free from organ support therapy (mechanical ventilation, vasopressors or RRT)		at day 28
Secondary	Rate of clinical cure		within 3 months
Secondary	Frequency of initial antibiotic therapy inadequate as regard to microbiological documentation.		at inclusion
Secondary	Number of day free of antibiotic therapy		at day-28
Secondary	Duration of aminoglycoside therapy		within 3 months
Secondary	Rate of aminoglycoside overdosage according to residual concentration		within 3 months
Secondary	Rate of overuse when compared to experts recommendations		within 3 months