Evaluation of Automated Carbon Dioxide Injection for Contrast Medium Reduction in Peripheral Arterial Disease Patients to Prevent Major Adverse Kidney Events

The primary objective of this study is to evaluate if an iodinated contrast medium sparing strategy using automated **Carbon Dioxide (CO2) Injection** prevents Major Adverse Kidney Events up to 90 days (MAKE90) in patients at moderately elevated risk for contrast-associated acute kidney injury (CA-AKI) undergoing infrainguinal peripheral vascular interventions (PVI). This is clinically relevant as it aims to reduce the incidence of kidney-related complications following procedures that require contrast media, which is particularly important for patients with pre-existing risk factors for kidney injury.

Secondary objectives include evaluating if the iodinated contrast medium sparing strategy using automated CO2 Injection prevents post-procedural acute kidney injury (AKI). Additionally, the strategy will be compared to the standard of care strategy with iodinated contrast medium with respect to: other indicators for kidney injury, such as Major Adverse Kidney Events at discharge and single components of MAKE90; technical as well as procedural success; intra-procedural, in-hospital, and 90 days safety; and 1-year mortality. These secondary objectives aim to provide a comprehensive assessment of the safety and efficacy of the contrast medium sparing strategy in various clinical outcomes.

The clinical trial focuses on patients diagnosed with **Peripheral Arterial Disease (PAD)**, specifically those presenting with symptomatic conditions as per Rutherford clinical categories I-IIb for acute symptoms or categories 3-6 for chronic symptoms. The study population includes both male and female participants aged 18 years and older, without any specific mention of vulnerable populations. Participants are selected based on their planned peripheral vascular intervention of infrainguinal arteries due to femoropopliteal and/or infrapopliteal lesions, and an increased risk of contrast-associated acute kidney injury (CA-AKI) identified by a baseline risk score of ≥ 5 points and a pre-angiographic estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m². The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria ensure that both angiographic strategies are feasible at the investigator's discretion, and all participants have provided written informed consent. Lifestyle considerations such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to evaluate the efficacy of a contrast medium sparing strategy using automated Carbon Dioxide (CO2) Injection in preventing **Major Adverse Kidney Events** (MAKE) up to 90 days in patients with **Peripheral Arterial Disease** (PAD) undergoing infrainguinal peripheral vascular interventions. This is a randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is expected to commence on November 1, 2024, and conclude by May 31, 2029, with participant involvement lasting up to 90 days post-intervention.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as symptomatic PAD, planned peripheral vascular intervention, and increased risk of contrast-associated acute kidney injury (CA-AKI). The primary endpoint is the occurrence of MAKE within 90 days post-intervention, while secondary endpoints include post-procedural acute kidney injury and technical and procedural success. Follow-up visits will be scheduled to monitor the participants' kidney function and overall health status, with the final visit marking the end of the study period.

The expected length of participant involvement is approximately 90 days, with conditions for early termination including withdrawal of consent or any adverse events that compromise participant safety. The trial will utilize various iodinated contrast media, such as **iopamidol**, **iomeprol**, and **iopromide**, administered via intravenous injection or infusion. The maximum treatment period for these substances is limited to one day, with specific dosing parameters adhered to for safety and efficacy. The trial's methodology and design are structured to provide robust data on the potential benefits of CO2 injection in reducing kidney-related adverse events in this patient population.

The clinical trial involves the administration of several **contrast media** solutions, each with specific characteristics and dosing regimens. The first experimental medication is Solutrast 200, containing **iopamidol** as the active substance, with a concentration of 200 mg Iod/ml. It is provided as a solution for injection and is administered via intravenous (IV) injection or infusion. The maximum daily and total dose is 7.5 milliliters per kilogram, with a treatment period limited to one day.

Imeron 350, another experimental medication, contains **iomeprol** at a concentration of 350 mg Iod/ml. It is available as a solution for injection or infusion and is administered through IV injection or infusion. The maximum daily and total dose is 250 milliliters, with a treatment period of one day.

Imeron 300, also containing **iomeprol**, is provided at a concentration of 300 mg Iod/ml. It is administered similarly to Imeron 350, with a maximum daily and total dose of 250 milliliters and a one-day treatment period.

Ultravist®-370, containing **iopromide**, is available at a concentration of 370 mg Iod/ml. It is administered as a solution for injection or infusion, with a maximum daily and total dose of 4 milliliters per kilogram, and a treatment period of one day.

VISIPAQUETM 320, containing **iodixanol**, is provided at a concentration of 320 mg/ml. It is administered via IV injection or infusion, with a maximum daily and total dose of 6.25 milliliters per kilogram, and a treatment period of one day.

Imeron 400, another formulation containing **iomeprol**, is available at a concentration of 400 mg Iod/ml. It is administered through IV injection or infusion, with a maximum daily and total dose of 250 milliliters, and a treatment period of one day.

Solutrast 250, containing **iopamidol**, is provided at a concentration of 250 mg Iod/ml. It is administered via IV injection or infusion, with a maximum daily and total dose of 6 milliliters per kilogram, and a treatment period of one day.

Ultravist®-240, containing **iopromide**, is available at a concentration of 240 mg Iod/ml. It is administered as a solution for injection or infusion, with a maximum daily and total dose of 6.25 milliliters per kilogram, and a treatment period of one day.

Solutrast 300, another formulation containing **iopamidol**, is provided at a concentration of 300 mg Iod/ml. It is administered via IV injection or infusion, with a maximum daily and total dose of 5 milliliters per kilogram, and a treatment period of one day.

ACCUPAQUE™ 240, containing **iohexol**, is available at a concentration of 240 mg Iod/ml. It is administered through IV injection or infusion, with a maximum daily and total dose of 6.25 milliliters per kilogram, and a treatment period of one day.

Solutrast 370, containing **iopamidol**, is provided at a concentration of 370 mg Iod/ml. It is administered via IV injection or infusion, with a maximum daily and total dose of 4.1 milliliters per kilogram, and a treatment period of one day.

VISIPAQUETM 270, containing **iodixanol**, is available at a concentration of 270 mg/ml. It is administered through IV injection or infusion, with a maximum daily and total dose of 7.41 milliliters per kilogram, and a treatment period of one day.

ACCUPAQUE™ 350, containing **iohexol**, is provided at a concentration of 350 mg Iod/ml. It is administered via IV injection or infusion, with a maximum daily and total dose of 4.3 milliliters per kilogram, and a treatment period of one day.

Optiray 320, containing **ioversol**, is available at a concentration of 320 mg Iod/ml. It is administered as a solution for injection or infusion, with a maximum daily and total dose of 250 milliliters, and a treatment period of one day.

Ultravist®-300, containing **iopromide**, is provided at a concentration of 300 mg Iod/ml. It is administered via IV injection or infusion, with a maximum daily and total dose of 5 milliliters per kilogram, and a treatment period of one day.

ACCUPAQUE™ 300, containing **iohexol**, is available at a concentration of 300 mg Iod/ml. It is administered through IV injection or infusion, with a maximum daily and total dose of 5 milliliters per kilogram, and a treatment period of one day.

The efficacy of the clinical trial will be assessed by evaluating the prevention of **Major Adverse Kidney Events** up to 90 days (MAKE90) in patients undergoing infrainguinal peripheral vascular interventions. The primary endpoint is the occurrence of MAKE90, which will be measured up to 90 days post-intervention. Secondary endpoints include post-procedural acute kidney injury (AKI), Major Adverse Kidney Events up to day 7 (MAKE-7), single components of MAKE90, and Major Adverse Kidney Events at 90 days considering a drop in estimated glomerular filtration rate (eGFR) by at least 40% compared to baseline. Additionally, technical and procedural success will be evaluated.

The trial will utilize a contrast medium sparing strategy with automated Carbon Dioxide Injection to assess its efficacy in preventing these kidney events. The endpoints will be measured and collected at specified time points, including up to 7 days and 90 days post-intervention. The analysis will focus on the comparison of outcomes between the intervention and control groups, with particular attention to the reduction in the incidence of adverse kidney events.