The NIPA Study Naloxegol Administration to Prevent Opioids Induced Gastrointestinal Motility Disturbance in Brain Injured PAtients (NIPA)

The NIPA Study: A Randomized Double-blind Control Clinical Trial Naloxegol Administration to Prevent Opioids Induced Gastrointestinal Motility Disturbance in Brain Injured PAtients

Impaired gastrointestinal transit (IGT) especially constipation, is common among patients under mechanical ventilation, occurring in up to 80 % of the patients during the first week, and has been associated with worse outcome in intensive care unit (ICU). Although IGT in critically ill patients is multifactorial and some components are due to complex disease, there is increasing evidence that exogenous opioids contribute to bowel dysmotility.

Sedatives and especially opioids are largely used in the brain injured population to control intracranial pression, reduce metabolic rate, manage or prevent seizures, and improve mechanical ventilator synchrony. Therefore, brain injured patients are particularly at risk to develop IGT. The occurrence of IGT is associated with adverse outcomes in intensive care unit. Both gastric reflux and impaired peristaltic contractions are associated with ventilator-acquired pneumonia.

The actual challenge is to prevent motility disorders before it occurs. A preventive strategy could in turn reduce the occurrence of complications related to impaired gastrointestinal transit such as ventilator-acquired pneumonia, bacteremia etc. It could also reduce the complications of feed intolerance and thus reduce morbidity and mortality in ICU.

Naloxegol is a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting µ-opioid receptor antagonist. Contrary to naloxone, naloxegol has a very low penetration into the central nervous system, therefore it could be a relevant option for ileus prevention without the risk of impaired sedation.

The aim of our study is to assess the efficacy of the administration of naloxegol on the onset of early constipation and early ventilator-acquired pneumonia in brain injured patients receiving opioids for analgosedation.

Study Overview

• Status: Recruiting
• Conditions: Brain Injuries
• Intervention / Treatment: Drug: Naloxegol; Drug: Placebo

Detailed Description

Multicenter, randomized, double-blind, placebo-controlled experimental study of Naloxegol.

• Study Type: Interventional
• Enrollment (Estimated): 370
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Olivier Huet, PU-PH; Phone Number: +33 2 98 34 72 88; Email: olivier.huet@chu-brest.fr
• Study Contact Backup: Name: Philippe Aries, PH; Phone Number: +33 2 98 34 72 88; Email: philippe.aries@chu-brest.fr

Study Locations

• France
  • Bordeaux, France, 33000
    • Recruiting
    • CHU Bordeaux
    • Contact: Hugues De Courson, PH
    • Principal Investigator: Hugues De Courson, PH
  • Brest, France, 29609
    • Recruiting
    • CHU Brest
    • Contact: Philippe Aries, PH
    • Principal Investigator: Philippe Aries, PH
  • Clermont-Ferrand, France, 63003
    • Not yet recruiting
    • Chu Clermont-Ferrand
    • Contact: Russell Chabanne, PH
    • Principal Investigator: Russell Chabanne
  • Lille, France, 59000
    • Not yet recruiting
    • CHU de Lille
    • Contact: Christophe HUZ; Phone Number: 0320445962; Email: christophe.huz@chu-lille.fr
  • Montpellier, France, 34295
    • Recruiting
    • CHU de Montpellier
    • Contact: Pierre-François PERRIGAULT; Email: pf-perrigault@chu-montpellier.fr
  • Nantes, France, 44093
    • Recruiting
    • CHU Nantes
    • Contact: Yannick Hourmant, PH
    • Principal Investigator: Yannick HOURMANT
  • Paris, France, 75013
    • Recruiting
    • Hôpital La Pitié Salpétrière (APHP)
    • Contact: Vincent Degos, PU-PH
    • Principal Investigator: Vincent Degos, PU-PH
  • Strasbourg, France, 67098
    • Active, not recruiting
    • CHU de Strasbourg
  • Tours, France, 37000
    • Active, not recruiting
    • CHU Tours - Hôpital Bretonneau
  • Tours, France, 37170
    • Recruiting
    • CHU Tours - Hôpital Trousseau
    • Contact: Romain MIGUEL-MONTANES; Phone Number: 02 47 47 20 45; Email: r.miguelmontanes@chu-tours.fr
  • France
    • Bordeaux, France, France, 33000
      • Not yet recruiting
      • CHU de Bordeaux - Réanimation chirurgicale
      • Contact: Matthieu BIAS; Phone Number: 05 57 82 10 19; Email: matthieu.biais@chu-bordeaux.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ to 18 years old
2. Admission to intensive care unit for traumatic brain injury or subarachnoid hemorrhage without other life-threatening injury
3. Patients under sedation with administration of opiate-agonists, μ receptor agonists (Sufentanil, Fentanyl, Remifentanil, Morphine) for less than 24 hours
4. Expected duration of invasive mechanical ventilation and sedation of 48 hours or more
5. Intracranial pressure monitoring
6. Enteral feeding by oro / nasogastric tube
7. Affiliated or beneficiary of the French social security system

Exclusion Criteria:

1. Patient who received opioids for more than 24 hours
2. Patient with refractory intracranial hypertension at the time of inclusion: intracranial hypertension requiring therapy other than analgo-sedation (thiopental, targeted temperature management, decompressive craniectomy)
3. Acute or chronic renal failure with creatinine clearance <60ml / min
4. Known or suspected acute gastrointestinal obstruction

5. Risk of digestive perforation:

   • history of peptic ulcer
   • Crohn's disease
   • Ogilvie syndrome
   • acute diverticulitis
   • infiltrating gastrointestinal tumor
   • recurrent or advanced ovarian cancer
   • peritoneal metastasis
   • recent abdominal trauma with risk of digestive perforation
6. Concomitant treatment with a strong or moderate inhibitory effect of CYP 3A4 (For example: clarithromycin, ketaconazole, itraconazole, telithromycin, ritonavir, indinavir, saquinavir) or with a strong inducing effect (carbamazepin, rifampicin, millepertuis)
7. Concomitant treatment with vascular endothelial growth factor (VEGF) inhibitor
8. Allergy to Naloxegol or one of its excipients
9. Recent history of myocardial infarction within the past 6 months, symptomatic congestive cardiovascular disease, QT ≥ 500 msec
10. Patient with a medical decision for rapid palliative care
11. Pregnancy and / or breastfeeding
12. Child Pugh C stage cirrhosis
13. Patient under legal protection or deprived of liberty
14. Patient with another life-threatening injury
15. History of clinically important alterations of the blood-brain barrier: primary brain tumors, metastasis or other inflammatory pathologies in the CNS, active multiple sclerosis, Alzheimer's disease at an advanced stage.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naloxegol; Administration of Naloxegol 25 mg per day by nasogastric tube (NG) or orogastric tube (OG). The administration should be started within the first 24 hours after the patient is admitted to intensive care unit and continued for the duration of the administration of the morphine derivative and until 48 hours after its discontinuation. Management of constipation and gastroparesis according to the recommendations.	Drug: Naloxegol; Administration of Naloxegol 25 mg per day by nasogastric tube (SNG) or orogastric tube (SOG). The administration should be started within the first 24 hours after the patient is admitted to intensive care and continued for the duration of the administration of the morphine derivative and until 48 hours after its discontinuation.
Placebo Comparator: Placebo; Administration of the placebo according to the same procedures as the experimental arm.	Drug: Placebo; Administration of the placebo according to the same procedures as the experimental arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of bowel movement	6 days
Incidence of ventilator-acquired pneumonia	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patient-days who received the daily calorie goal (25 Kcal / kg / day)		10 days
Number of patients who required one or more administration of erythromycin and / or metoclopramide for vomiting occurring during enteral feeding		10 days
Number of patients who received one or more rectal laxative for constipation		10 days
Time in days of occurrence of the first bowel movement (in case of late constipation)		10 days
Number of patients with ventilator-acquired pneumonia after D7 of invasive mechanical ventilationventilation (after D7 of invasive mechanical ventilation)		10 days
Number of days without invasive mechanical ventilation		10 days
Duration of hospitalization in intensive care unit		10 days
Glasgow Outcome Scale Extended Score	The Glasgow Outcome Scale (GOS) is a comprehensive assessment scale for functional outcome that classifies a patient's condition into one of five categories: Death, Vegetative State, Severe Handicap, Moderate Handicap or Good Recovery. The extended GOS scale (GOSE) allows a more detailed classification into eight categories, thanks to a subdivision into two levels (lower and higher) of the categories "severe handicap", "moderate handicap" and "good recovery"	6 month
Number of patients who experienced an episode of intracranial hypertension requiring targeted temperature management, barbiturates, or decompression craniectomy.		10 days

Collaborators and Investigators

• Sponsor: University Hospital, Brest
• Investigators: Principal Investigator: Olivier Huet, PU-PH, CHU Brest

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2022
• Primary Completion (Estimated): March 15, 2026
• Study Completion (Estimated): September 15, 2026

Study Registration Dates

• First Submitted: August 10, 2021
• First Submitted That Met QC Criteria: August 16, 2021
• First Posted (Actual): August 17, 2021

Study Record Updates

• Last Update Posted (Actual): November 21, 2025
• Last Update Submitted That Met QC Criteria: November 18, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Traumatic brain injury; Subarachnoid Hemorrhage; Impaired gastrointestinal transit
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Wounds and Injuries; Pathologic Processes; Hemorrhage; Craniocerebral Trauma; Trauma, Nervous System; Intracranial Hemorrhages; Pathological Conditions, Signs and Symptoms; Brain Injuries, Traumatic; Brain Injuries; Subarachnoid Hemorrhage; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; naloxegol
• Other Study ID Numbers: 29BRC18.0262 (NIPA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected data that underlie results in a publication
• IPD Sharing Time Frame: Data will be available beginning five years and ending fifteen years following the final study report completion
• IPD Sharing Access Criteria: Data access requests will be reviewed by the internal committee of Brest UH. Requestors will be required to sign and complete a data access agreement
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No