Evaluation of Extended Fosaprepitant Prophylaxis for Delayed Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients: A Double-Blind, Placebo-Controlled, Crossover Phase III Trial

The primary objective of this study is to evaluate the effect of prolonged duration of **(fos)aprepitant** prophylaxis on the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in children. This is clinically relevant as delayed CINV can significantly impact the quality of life and treatment adherence in pediatric patients undergoing moderate or highly emetogenic chemotherapy. The study aims to compare the current 3-day regimen followed by placebo with a regimen of (fos)aprepitant prophylaxis during the complete course of chemotherapy, up to a maximum of 8 days, using a double-blind, randomized crossover design.

Secondary objectives include:

• Evaluating the effect of prolonged (fos)aprepitant prophylaxis on the prevention of acute and overall CINV in children.
• Comparing the efficacy endpoint of no vomiting, regardless of rescue medication use, in the acute, delayed, and overall phases.
• Assessing the safety and tolerability of (fos)aprepitant according to a prolonged dosing regimen.
• Evaluating the pharmacokinetics of (fos)aprepitant during a prolonged dosing regimen by constructing a population pharmacokinetics model.
• Assessing the improvement of CINV complaints in children using the validated Pediatric Nausea Assessment Tool (PeNAT) and the Baxter Retching Faces.
• Determining which of two patient-report nausea assessment tools (PeNAT or BARF) performs better in terms of validity criteria, responsiveness, or feasibility.
• Assessing the cost-effectiveness of a prolonged dosing regimen.

The clinical trial focuses on evaluating the effect of prolonged duration of (fos)aprepitant prophylaxis on the prevention of **delayed chemotherapy-induced nausea and vomiting (CINV)** in children undergoing moderate or highly emetogenic chemotherapy. The study population includes both male and female participants aged between 6 months and 18 years. Participants are required to have a life expectancy of at least 3 months and must not have a history of QT prolongation or underlying gastrointestinal diseases that could interfere with medication absorption. The trial includes a vulnerable population, as it involves children. Participants must not receive scheduled blocks of chemotherapy containing corticosteroids during the study period and should not have used antiemetic treatment within 48 hours before treatment. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are in a stable health condition, with specific requirements for serum creatinine, AST, ALT, and total bilirubin levels. Additionally, lifestyle considerations include the prohibition of certain medications, such as CYP3A4 substrates, inhibitors, and inducers, within specified timeframes before treatment. Female participants of childbearing potential must have a negative pregnancy test prior to enrollment and agree to use effective contraception during the study. The trial aims to provide insights into the efficacy of (fos)aprepitant prophylaxis in managing delayed CINV in a pediatric population.

The clinical trial is designed to evaluate the effect of prolonged **(fos)aprepitant** prophylaxis on the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in pediatric patients undergoing moderate or highly emetogenic chemotherapy. This study employs a **randomized**, **double-blind**, **placebo-controlled**, **crossover** design, where each participant serves as their own control across two similar chemotherapy cycles, which may not be consecutive. The trial aims to compare the current 3-day regimen followed by placebo with a regimen of (fos)aprepitant prophylaxis throughout the entire chemotherapy course, lasting up to a maximum of 8 days.

Participants will be involved in the study for a period that includes two chemotherapy cycles, each lasting up to 8 days. The trial is expected to conclude by December 23, 2024. The inclusion visit, or screening, will assess eligibility based on criteria such as age (6 months to 18 years), life expectancy, and absence of certain medications or conditions that could interfere with the study. Follow-up visits will occur during each chemotherapy cycle to monitor the primary endpoint, which is the proportion of patients achieving a complete response (no vomiting, no retching, and no use of rescue medication) during the delayed phase (24-72 hours post-chemotherapy).

The end-of-study visit will evaluate the overall response, including the acute phase (up to 24 hours post-chemotherapy) and the safety of prolonged (fos)aprepitant use. Participants may be withdrawn from the study if they experience significant adverse events, fail to adhere to the protocol, or if the investigator deems it necessary for their safety. The trial will also assess secondary endpoints such as the time to first vomiting episode, pharmacokinetic parameters, and the cost-effectiveness of the dosing regimen. The study is not categorized as low intervention and is classified as a Phase III clinical trial.

The clinical trial involves the administration of **Aprepitant Teva 80 mg**, which is provided in the form of hard capsules. The active substance in this medication is **aprepitant**, a chemical compound. The capsules are administered orally, with a maximum daily dose of 80 mg and a total maximum dose of 400 mg over a treatment period of up to 5 days. This medication is produced by TEVA B.V. and is identified by the EU marketing product number PRD7166695. The trial aims to evaluate the efficacy of this medication in preventing chemotherapy-induced nausea and vomiting (CINV) in children.

Another experimental treatment used in the trial is **IVEMEND 150 mg**, a powder for solution for infusion. The active substance in this formulation is **fosaprepitant**, also a chemical compound. This medication is administered intravenously, with a maximum daily dose of 80 mg and a total maximum dose of 400 mg over a treatment period of up to 5 days. IVEMEND is manufactured by MERCK SHARP & DOHME B.V. and is identified by the EU marketing product number PRD2822015. This treatment is also evaluated for its effectiveness in preventing delayed CINV in pediatric patients undergoing chemotherapy.

The trial includes the use of a **placebo** in the form of an **Aprepitant Placebo Tablet**. This placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered in a manner consistent with the active treatment to ensure comparability in the study design.

Additionally, **NaCl I.V.** is used as a non-experimental treatment in the trial. This is an intravenous saline solution, administered with a maximum daily dose of 80 ml and a total maximum dose of 400 ml over a treatment period of up to 5 days. The use of NaCl I.V. serves as a standard supportive care measure during the trial, ensuring that participants receive necessary hydration and electrolyte balance during chemotherapy.

Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of patients who achieve a complete response, defined as no vomiting, no retching, and no use of rescue medication, during the delayed phase, which is the period from 24 to 72 hours after the final dose of chemotherapy. Secondary endpoints include the proportion of patients achieving a complete response during the acute phase (from the start of chemotherapy until 24 hours after the final dose) and the overall phase (both acute and delayed phases). Additionally, the time from the initiation of emetogenic chemotherapy to the first vomiting episode and the first use of rescue medication will be measured.

Further secondary endpoints involve the safety of prolonged use of **(fos)aprepitant**, assessed through adverse events considered related by investigators, and pharmacokinetic parameters such as clearance and volume of distribution. The trial will also evaluate the improvement of chemotherapy-induced nausea and vomiting (CINV) complaints using the Pediatric Nausea Assessment Tool (PeNAT) and the Baxter Retching Faces (BARF) scale. The validity, responsiveness, and feasibility of these tools will be assessed, along with the cost-effectiveness of the prolonged **(fos)aprepitant** dosing regimen.