Evaluation of the Pharmacokinetics of Subcutaneous Administration of Piperacillin/Tazobactam: An Open-Label, Multicentric, Non-Inferiority Randomized Clinical Trial (STUPITA01)

The primary objective of this trial is to evaluate the non-inferiority of the pharmacokinetic profile of piperacillin/tazobactam when administered subcutaneously compared to the standard intravenous route. This assessment is clinically relevant as it may provide an alternative administration route for this beta-lactam/beta-lactamase inhibitor combination, potentially offering advantages in settings where intravenous access is challenging or for patients requiring prolonged antibiotic therapy for bacterial infections.

The secondary objectives include:

- To assess the non-inferiority of subcutaneous versus intravenous administration of piperacillin/tazobactam in achieving target concentrations based on pharmacokinetic/pharmacodynamic clinical breakpoints;
- To compare the efficacy of subcutaneous versus intravenous administration of piperacillin/tazobactam in treating bacterial infections;
- To assess the safety and tolerability in the administration of piperacillin/tazobactam;
- To assess the evolution of infection as clinical response up to end of treatment;
- To assess the treatment failure up to end of treatment;
- To evaluate patient satisfaction and experience with subcutaneous administration compared to intravenous administration;
- To explore the perception of nurses in subcutaneous versus intravenous administration of piperacillin/tazobactam.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population included both **male** and **female** participants aged 18 years and older, comprising adults and elderly individuals. Participants were required to have a clinical indication for treatment with **piperacillin/tazobactam** 18g per day in continuous infusion, including conditions such as severe **pneumonia**, **neutropenic fever** suspected to be caused by bacterial infection, or other severe **bacterial infections** deemed appropriate for this dosage regimen by the investigator. Female participants of childbearing potential were required to have negative pregnancy tests at screening and end-of-treatment visits. Participants were admitted to authorized hospital wards for enrollment. The trial focused on individuals with **infectious disease** requiring antibiotic therapy with piperacillin/tazobactam administered via different routes to evaluate pharmacokinetic profiles.

This is an open-label, multicentric, non-inferiority randomized clinical trial designed to evaluate the pharmacokinetics of subcutaneous administration of piperacillin/tazobactam compared to the standard intravenous route. The study is classified as a Phase 4 trial investigating an authorized medicinal product administered via a different route. The investigational medicinal product is piperacillin and tazobactam in powder form for solution for infusion, containing piperacillin and tazobactam as active substances of chemical origin. The maximum daily dose is 18 grams with a maximum total dose of 180 grams over a treatment period of up to 10 days.

The primary objective is to evaluate the non-inferiority of the pharmacokinetic profile of piperacillin/tazobactam when administered subcutaneously compared to the standard intravenous route. The primary endpoint is the area under the plasma concentration-time curve (AUC) of piperacillin/tazobactam, demonstrating that subcutaneous administration is non-inferior to intravenous administration. The pharmacokinetic profile will be evaluated through plasma antibiotic concentrations obtained by sample collection. Secondary endpoints include therapeutic drug monitoring of piperacillin to ensure target concentrations non-inferior to or equal to 40 mg/L between groups, clinical cure rate at the end of treatment defined as partial or complete resolution of clinical signs and symptoms of infection without the need for additional antibiotic therapy, microbiologic success rate at end of treatment, and incidence of adverse events up to one day after the end of treatment.

The study will enroll participants with clinical indication for treatment with piperacillin/tazobactam 18 grams per day in continuous infusion, including severe pneumonia, neutropenic fever suspected to be caused by bacterial infection, or other severe bacterial infections for which this dosage regimen is appropriate based on investigator judgment. Principal inclusion criteria require participants to be at least 18 years old, provide free written informed consent, and be admitted to one of the wards authorized for enrollment. Female participants of childbearing potential must have a negative serum pregnancy test at screening and negative urine β-HCG test at end of treatment. The trial is expected to commence recruitment in November 2025 with an estimated completion date in April 2027.

Participant involvement extends throughout the treatment period of up to 10 days, with follow-up for adverse event monitoring continuing until one day after the end of treatment. The study includes a screening visit for eligibility assessment, treatment visits during which pharmacokinetic sampling and therapeutic drug monitoring will be performed, and an end-of-treatment visit on day 9. Clinical and microbiological assessments will be conducted to evaluate treatment efficacy and safety throughout the study duration.

The experimental medication under investigation is **Piperacillina e Tazobactam Ibigen** 4 g/0.5 g powder for solution for infusion. The product contains two **active substances**: **piperacillin** and **tazobactam**, both of chemical origin. The **pharmaceutical form** is a solution for infusion, prepared from powder. The medication is administered via **intravenous**, **subcutaneous**, or **intramuscular** routes as specified in the trial protocol. The **maximum daily dose** is 18 grams, with a **maximum total dose** of 180 grams over the treatment period. The **maximum treatment period** is 10 days. The study specifically evaluates the pharmacokinetic profile of subcutaneous administration compared to the standard intravenous route. The product is classified under **ATC code** J01CR05, designated as piperacillin and enzyme inhibitor combination. This is not a **paediatric formulation** and does not have **orphan drug** designation. Participant compliance with the dosing schedule and administration route will be monitored throughout the trial duration to ensure adherence to the protocol requirements.

Efficacy will be assessed through evaluation of the pharmacokinetic profile of piperacillin/tazobactam administered via different routes. The primary endpoint is the area under the plasma concentration-time curve (AUC) of piperacillin/tazobactam, which will be used to demonstrate non-inferiority of subcutaneous administration compared to intravenous administration. The pharmacokinetic profile will be evaluated through plasma antibiotic concentrations obtained by sample collection.

Secondary efficacy endpoints include therapeutic drug monitoring of piperacillin to ensure target concentrations non-inferior to or equal to 40 mg/L between groups, aligning with established pharmacokinetic/pharmacodynamic clinical breakpoints. Clinical cure rate at the end of the treatment period will be assessed, defined as partial or complete resolution of clinical signs and symptoms of infection without the need for additional antibiotic therapy. Microbiologic success rate at end of treatment will also be evaluated. Additionally, the incidence of adverse events will be monitored up to 1 day after the end of treatment.