Clinical trial NCT05008926: The NIPA Study Naloxegol Administration to Prevent Opioids Induced Gastrointestinal Motility Disturbance in Brain Injured PAtients
Official title: The NIPA Study: a Randomized Double-blind Control Clinical Trial Naloxegol Administration to Prevent Opioids Induced Gastrointestinal Motility Disturbance in Brain Injured PAtients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Brain Injuries
Keywords: Impaired gastrointestinal transit
Subarachnoid Hemorrhage
Traumatic brain injury
Lead sponsor: University Hospital, Brest
Sponsor class: OTHER
First posted: 2021-08-17
Enrollment: 370
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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

Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of bowel movement
timeFrame: 6 days
measure: Incidence of ventilator-acquired pneumonia
timeFrame: 7 days
Secondary outcomes:
measure: Proportion of patient-days who received the daily calorie goal (25 Kcal / kg / day)
timeFrame: 10 days
measure: Number of patients who required one or more administration of erythromycin and / or metoclopramide for vomiting occurring during enteral feeding
timeFrame: 10 days
measure: Number of patients who received one or more rectal laxative for constipation
timeFrame: 10 days
measure: Time in days of occurrence of the first bowel movement (in case of late constipation)
timeFrame: 10 days
measure: Number of patients with ventilator-acquired pneumonia after D7 of invasive mechanical ventilationventilation (after D7 of invasive mechanical ventilation)
timeFrame: 10 days
measure: Number of days without invasive mechanical ventilation
timeFrame: 10 days
measure: Duration of hospitalization in intensive care unit
timeFrame: 10 days
measure: Glasgow Outcome Scale Extended Score
timeFrame: 6 month
measure: Number of patients who experienced an episode of intracranial hypertension requiring targeted temperature management, barbiturates, or decompression craniectomy.
timeFrame: 10 days
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Bordeaux
country: France
facility: CHU de Bordeaux - Réanimation chirurgicale
city: Brest
country: France
facility: CHU Brest
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Lille
country: France
facility: CHU de Lille
city: Montpellier
country: France
facility: CHU de Montpellier
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Hôpital La Pitié Salpétrière (APHP)
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Tours
country: France
facility: CHU Tours - Hôpital BRETONNEAU
city: Tours
country: France
facility: CHU Tours - Hôpital TROUSSEAU
Study officials:
affiliation: CHU Brest
name: Olivier Huet, PU-PH
role: PRINCIPAL_INVESTIGATOR
References: