C3601008 - A PHASE 2A MULTICENTER, OBSERVER-BLINDED, RANDOMIZED 2 ARM STUDY TO INVESTIGATE PHARMACOKINETICS, SAFETY, TOLERABILITY AND EFFICACY OF INTRAVENOUS AZTREONAM-AVIBACTAM ± METRONIDAZOLE COMPARED TO BEST AVAILABLE THERAPY (BAT) IN PEDIATRIC PARTICIPANTS 9 MONTHS TO LESS THAN 18 YEARS OF AGE WITH SERIOUS GRAM-NEGATIVE BACTERIAL INFECTIONS INCLUDING COMPLICATED INTRA-ABDOMINAL INFECTION

The primary objective of this study is to evaluate the **pharmacokinetics** (PK) of Aztreonam-Avibactam (ATM-AVI) for the treatment of serious gram-negative bacterial infections in pediatric participants aged 9 months to less than 18 years. Additionally, the study aims to assess the safety and tolerability of ATM-AVI and Best Available Therapy (BAT) in this population. Understanding the PK profile is crucial for optimizing dosing regimens, ensuring therapeutic efficacy, and minimizing potential adverse effects in pediatric patients, who may have different metabolic rates compared to adults.

Secondary objectives include describing the efficacy of ATM-AVI and BAT for the treatment of serious gram-negative bacterial infections in the specified age group. This evaluation is important to determine the clinical effectiveness of these treatments in managing infections that are often resistant to standard therapies, thereby providing critical data to inform treatment guidelines and improve patient outcomes.

The clinical trial involves a total of **34 participants** aged from 9 months to less than 18 years, encompassing both male and female subjects. The study population includes individuals with suspected or confirmed **complicated gram-negative bacterial infections**, such as sepsis, urinary tract infection, hospital-acquired pneumonia, intra-abdominal infection, ventilator-associated pneumonia, and bloodstream infection. Participants are required to be hospitalized and in need of intravenous antibiotic treatment. The trial population was selected based on specific inclusion criteria, ensuring that all female participants of post-menarchal age have a negative serum or urine pregnancy test. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, given the age range and the serious nature of the medical conditions being studied.

The clinical trial is designed as a **randomized**, observer-blinded, two-arm study to evaluate the **pharmacokinetics**, safety, tolerability, and efficacy of intravenous Aztreonam-Avibactam with or without Metronidazole compared to the best available therapy in pediatric participants aged 9 months to less than 18 years with serious gram-negative bacterial infections. The trial will span an estimated duration from April 2024 to December 2025. Participants will be involved for a maximum treatment period of 14 days, with the possibility of early termination if adverse events occur or if the participant withdraws consent.

The study visits are structured to include an initial **screening** visit to confirm eligibility, followed by treatment visits where participants receive the investigational product or comparator. The primary endpoints include pharmacokinetic parameters such as clearance, maximum concentration, and area under the curve, as well as safety assessments through adverse events and laboratory tests. Secondary endpoints focus on clinical and microbiological outcomes at the end of intravenous treatment, end of treatment, and test of cure visits. The end-of-study visit will assess the overall health status and any long-term effects of the treatment.

Inclusion criteria require participants to be hospitalized and in need of intravenous antibiotic treatment for conditions such as complicated intra-abdominal infection, complicated urinary tract infection, hospital-acquired pneumonia, ventilator-associated pneumonia, or bloodstream infection. The trial will exclude participants based on specific criteria not detailed in the source. The study aims to provide comprehensive data on the efficacy and safety of the investigational treatment in the pediatric population, contributing to the understanding of its role in managing serious bacterial infections.

The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. The experimental medication, **Aztreonam and Avibactam (1.5g/0.5g) Powder for Concentrate for Solution for Infusion**, is administered intravenously. The maximum daily dose is 6500 mg, with a total maximum dose of 84500 mg over a treatment period of 14 days. This medication is a chemical compound provided in a solution for infusion form.

Another experimental medication, **Metronidazole**, is administered as a solution for injection or infusion. The maximum daily dose is 1500 mg, with a total maximum dose of 21000 mg over a 14-day treatment period. This chemical compound is also administered intravenously.

The **comparator treatment** includes **Colistin**, administered via injection. The maximum daily dose is 9000000 IU, with a total maximum dose of 9000000 IU over a 14-day treatment period. This medication is a chemical compound provided in a pharmaceutical form coded as PHF00231MIG.

**Moxifloxacin** is another comparator treatment, administered via infusion. The maximum daily dose is 400 mg/kg, with a total maximum dose of 400 mg/kg over a 14-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00230MIG.

**Linezolid** is administered as a solution for infusion, with a maximum daily dose of 1200 mg/kg and a total maximum dose of 1200 mg/kg over a 28-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00101MIG.

**Clindamycin** is administered intravenously, with a maximum daily dose of 1200 mg and a total maximum dose of 1200 mg over a 10-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00242MIG.

**Imipenem and Enzyme Inhibitor** is administered via infusion, with a maximum daily dose of 1000 mg and a total maximum dose of 1000 mg over a 14-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00230MIG.

**Amikacin** is administered intravenously, with a maximum daily dose of 20 mg/kg and a total maximum dose of 20 mg/kg over a 10-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00231MIG.

**Teicoplanin** is administered intravenously, with a maximum daily dose of 12 mg/kg and a total maximum dose of 12 mg/kg over a 21-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00169MIG.

**Piperacillin and Enzyme Inhibitor** is administered intravenously, with a maximum daily dose of 12 g and a total maximum dose of 12 g over a 14-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00230MIG.

**Vancomycin** is administered as a solution for infusion, with a maximum daily dose of 40 mg/kg and a total maximum dose of 40 mg/kg over a 14-day treatment period. This chemical compound is provided in a pharmaceutical form coded as PHF00230MIG.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the pharmacokinetics, safety, and tolerability of the experimental medications compared to the best available therapy in pediatric participants with serious gram-negative bacterial infections.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include pharmacokinetic (PK) parameters such as clearance (CL), maximum concentration (Cmax), minimum concentration (Cmin), area under the curve (AUC), and half-life (t1/2). Additionally, plasma concentrations of aztreonam (ATM) and avibactam (AVI) will be measured on Day 1 and at steady state (Day 2 or later). Safety assessments will include monitoring for adverse events (AEs) and serious adverse events (SAEs), as well as adverse events leading to discontinuation and those resulting in death. Liver and renal function tests will be conducted at baseline, during treatment, and after the end of treatment.

Secondary endpoints will focus on clinical outcomes and microbiological response at the end of intravenous treatment (EOIV), end of treatment (EOT), and test of cure (TOC). These assessments will provide a comprehensive evaluation of the treatment's efficacy in managing serious gram-negative bacterial infections in pediatric participants aged 9 months to less than 18 years. The trial is designed to ensure rigorous monitoring and analysis of these parameters to determine the efficacy of the treatment regimen.