Evaluation of Amikacin Sulfate-Based Antibiotic Regimen and Protective Isolation in Critically Ill Neutropenic Adults with Sepsis: A 2x2 Factorial RCT

The primary objective of this study is to evaluate the impact on **day-90 mortality** of two distinct strategies in critically-ill neutropenic patients with sepsis, utilizing a 2x2 factorial design randomized controlled trial (RCT). The first strategy involves the routine association of **aminoglycoside** to initial antibiotic therapy compared to the standard of care. The second strategy examines the lack of routine use of protective isolation compared to the standard of care. This objective is clinically relevant as it aims to determine the effectiveness of these interventions in reducing mortality rates in a vulnerable patient population.

Secondary objectives include assessing various clinical outcomes and safety parameters:

• Day-28 and hospital outcome
• Incidence, severity, and duration of **acute kidney injury (AKI)**
• Incidence of clinically apparent loss of hearing
• Rate of adherence to hand hygiene
• Rate of selected adverse events
• Rate of nosocomial bacterial, viral, and fungal infection episodes
• Organ support during ICU stay and organ support duration
• Failure of initial antibiotic therapy
• Antibiotic duration
• Rate of aminoglycosides overdosage and overuse

The clinical trial involves **adult patients** admitted to intensive care units, focusing on those with sepsis or septic shock as defined by the SEPSIS3 criteria. The study population includes both male and female participants aged 18 years and older. Participants are selected based on their admission to one of the participating ICUs and must have an underlying tumor, allogeneic stem cell transplantation, or hematological malignancy. Additionally, they must exhibit neutropenia, characterized by an absolute neutrophil count of less than 500/mm³ or leucocytes less than 1000/mm³, related to an underlying malignancy or its treatment. The trial includes a vulnerable population, and informed or deferred consent is required. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the impact of two distinct strategies on day-90 mortality in critically ill neutropenic patients with sepsis. This study employs a **randomized**, 2x2 factorial design, which is a pragmatic approach to assess the effects of the interventions. The trial is not categorized as low intervention and is conducted in the therapeutic use phase III. The estimated duration of the trial spans from November 16, 2022, to August 16, 2025, with the primary endpoint being day-90 mortality. Secondary endpoints include day-28 and hospital mortality, incidence and severity of acute kidney injury (AKI) according to KDIGO definition, and other clinically relevant outcomes.

Participants will be adult patients admitted to intensive care units (ICUs) with sepsis or septic shock, as defined by the SEPSIS3 criteria, and must have underlying conditions such as tumors, allogeneic stem cell transplantation, or hematological malignancies. Neutropenia, defined by an absolute neutrophil count of less than 500/mm³ or leukocytes less than 1000/mm³, related to an underlying malignancy or its treatment, is also a criterion for inclusion. Informed or deferred consent is required for participation. The trial does not specify any principal exclusion criteria.

The sequence of study visits begins with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria. Follow-up visits will be scheduled to monitor the participants' health status, adherence to the intervention protocols, and to collect data on the primary and secondary endpoints. The end-of-study visit will occur at the conclusion of the participant's involvement in the trial, which is expected to last up to 90 days, depending on the individual's health status and response to the interventions. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that compromise the participant's safety.

The investigational product, **amikacin sulfate**, will be administered intravenously, with a maximum daily dose of 30 mg/kg and a total maximum dose of 90 mg/kg over a treatment period of up to 3 days. The trial aims to compare the routine association of aminoglycosides with initial antibiotic therapy against the standard of care, as well as the impact of not using protective isolation compared to standard practices. The study will also assess the incidence of adverse events, including unexpected cardiac arrest and new bacterial, viral, or fungal episodes, as well as the rate of adherence to hand hygiene protocols.

The clinical trial involves the administration of **amikacin sulfate**, an aminoglycoside antibiotic, as the experimental medication. The pharmaceutical form of amikacin sulfate is designated as PHF00231MIG. The medication is administered intravenously, with a maximum daily dose of 30 mg/kg and a maximum total dose of 90 mg/kg over a treatment period of up to 3 days. The administration schedule is designed to ensure optimal therapeutic levels while minimizing potential toxicity. Participant compliance with the dosing regimen is monitored through regular assessments and documentation of intravenous administration.

In addition to the experimental treatment, the study includes a standard-of-care therapy as a comparator. This involves the routine use of aminoglycosides in combination with initial antibiotic therapy, which is compared against the standard treatment protocol without the routine use of aminoglycosides. The trial employs a 2x2 factorial design to evaluate the impact of these strategies on day-90 mortality in critically-ill neutropenic patients with sepsis. The study also examines the effects of protective isolation practices as part of the standard-of-care comparison. Compliance with non-experimental treatments is monitored through adherence to established clinical guidelines and documentation of treatment administration.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **day-90 mortality** as the primary endpoint. This endpoint will provide a direct measure of the impact of the interventions on patient survival over a 90-day period. Secondary endpoints will include a comprehensive set of parameters to further evaluate the efficacy of the interventions. These include day-28 and hospital mortality, incidence and severity of acute kidney injury (AKI) according to the KDIGO definition, and major adverse kidney events at day-28 and day-90, which encompass a composite of death, new renal replacement therapy, or persistent renal dysfunction.

Additional secondary endpoints will assess the incidence of clinically apparent loss of hearing at the end of the ICU stay and day-90, the rate of adherence to adequate hand hygiene as assessed by an external observer, and the incidence density of selected serious adverse events, including unexpected cardiac arrest. The trial will also measure the incidence density of new bacterial, viral, or fungal episodes, the number of days free from organ support therapy (mechanical ventilation, vasopressors, or renal replacement therapy) at day-28, and the rate of clinical cure. Furthermore, the frequency of initial antibiotic therapy inadequacy concerning microbiological documentation, the number of days free of antibiotic therapy at day-28, and the duration of aminoglycoside therapy will be evaluated. The rate of aminoglycoside overdosage according to residual concentration and overuse compared to expert recommendations will also be assessed.