Efficacy of Naloxegol Oxalate in Preventing Opioid-Induced Gastrointestinal Motility Disorders in Patients with Brain Injury: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of the NIPA study is to evaluate the efficacy of **naloxegol** administration in preventing early constipation and reducing the incidence of early ventilator-associated pneumonitis in patients with brain injuries. This is clinically relevant as gastrointestinal motility disorders and ventilator-associated pneumonitis are common complications in such patients, potentially impacting recovery and overall prognosis.

Secondary objectives include assessing the effect of naloxegol on:

• Tolerance of enteral nutrition
• Time to first bowel movement in cases of late constipation (after day 6)
• Rectal laxative use
• Incidence of late-onset ventilator-associated pneumonia (after day 7)
• ICU and neurological prognosis at 6 months
• Occurrence of intracranial hypertension

The clinical trial involves a **study population** comprising both male and female participants aged 18 years and older. The participants are individuals admitted to the intensive care unit due to **head trauma** or **subarachnoid hemorrhage**, without other life-threatening injuries. The trial population is selected based on specific criteria, including the requirement for sedation with **morphinomimetics** for neuro-protective purposes and an estimated duration of invasive mechanical ventilation and sedation of at least 48 hours. Participants are also expected to undergo intracranial pressure monitoring and receive enteral feeding via oro/nasogastric tube. The trial includes individuals affiliated with or benefiting from a social security scheme. The sponsor has not provided information regarding the total number of participants. The trial considers a vulnerable population due to the critical health status of the participants, and lifestyle factors such as diet and physical activity are controlled within the clinical setting. Key inclusion criteria focus on the medical condition and treatment requirements, ensuring a targeted and relevant participant group for evaluating the efficacy of naloxegol administration on early constipation and ventilator-associated pneumonitis.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of **naloxegol oxalate** in preventing gastrointestinal motility disturbances in patients with brain injuries. The trial will involve the administration of Moventig 25 mg film-coated tablets or a placebo, with the primary objective being to assess the impact on early constipation and the incidence of early ventilator-associated pneumonitis. The study is expected to commence on May 15, 2024, and conclude by September 15, 2026, with a maximum treatment period of 20 days for each participant.

Participants will be required to meet specific inclusion criteria, such as being 18 years or older, admitted to an intensive care unit for head trauma or subarachnoid hemorrhage, and undergoing sedation with morphinomimetics for less than 24 hours. The study will exclude individuals with other life-threatening injuries. The trial will consist of several key visits, starting with a screening visit to confirm eligibility based on the inclusion criteria. Following randomization, participants will receive either the active drug or placebo orally, with follow-up visits scheduled to monitor efficacy and safety outcomes.

The primary endpoint is a composite criterion defined by the absence of bowel movements before day 6 of hospitalization or the incidence of ventilator-associated pneumonitis before day 7. Secondary endpoints include the proportion of patient-days achieving caloric objectives, the number of patients requiring additional medications for vomiting or constipation, and the length of stay in the intensive care unit. Participants will be involved in the study for the duration of their treatment period, with the possibility of early termination if they experience adverse events or fail to comply with the study protocol.

The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the overall outcomes and any long-term effects. The study aims to provide valuable insights into the management of gastrointestinal motility disorders in patients with brain injuries, contributing to improved therapeutic strategies in this population.

The clinical trial involves the administration of **Moventig 25 mg film-coated tablets**, which contain the active substance **naloxegol oxalate**. This experimental medication is provided in the form of film-coated tablets and is administered orally. The dosage is set at 25 mg per day, with a maximum total dose of 500 mg over the course of the treatment. The maximum treatment period is 20 days. The active substance, naloxegol oxalate, is of chemical origin. The pharmaceutical product is manufactured by Kyowa Kirin Holdings B.V. and is authorized for use in the European Union under the marketing authorization number EU/1/14/962/004. The administration of the drug is monitored to ensure compliance with the dosing schedule.

The study also includes a **placebo** group, which receives a placebo of Moventig 25 mg. The placebo is designed to match the experimental medication in appearance but does not contain any active substance. The placebo is used to provide a control for evaluating the efficacy of the experimental treatment. The administration of the placebo follows the same schedule as the experimental medication, ensuring that the study remains double-blind. Participants' adherence to the dosing regimen is monitored throughout the trial to maintain the integrity of the study results.

The efficacy of **naloxegol** administration in preventing opioid-induced gastrointestinal motility disturbance in brain-injured patients will be assessed through a randomized double-blind control clinical trial. The primary efficacy endpoint is a composite criterion defined by the occurrence of either absence of bowel movements before day 6 of hospitalization or the incidence of ventilator-associated pneumonitis (VAP) before day 7 of hospitalization. Secondary endpoints include the proportion of patient-days achieving the theoretical caloric objective of enteral nutrition (≥25 Kcal/kg/day), the number of patients requiring erythromycin and/or metoclopramide for vomiting during enteral feeding, and the number of patients who received at least one rectal laxative for constipation. Additional secondary endpoints are the time in days to the first bowel movement in cases of delayed constipation, the number of patients with late VAP after 7 days of invasive mechanical ventilation, the number of days without invasive mechanical ventilation, the length of stay in the intensive care unit, the Glasgow Outcome Scale Extended (GOSE) score at 6 months, and the number of patients with an episode of high intracranial pressure requiring further sedation or other interventions.