Effect of Naloxegol on Postoperative Ileus in Patients Undergoing Cardiac Surgery (TRANSIT)

Time to Transit Recovery After Treatment With Naloxegol in Cardiac Surgery Intensive Care Trial

Postoperative ileus, defined as the transient postoperative functional inhibition of propulsive bowel activity, commonly occurs in patients after cardiac surgery and contributes to postoperative morbidity.

Naloxegol is a peripheral opioid receptor antagonist. Recent studies showed that naloxegol is effective in the treatment of chronic opioid-induced constipation but there is no data on its use in the management of postoperative ileus after cardiac surgery.

The main objective of this prospective, double-blind, randomized, placebo-controlled trial is to assess the effectiveness of the perioperative use of naloxegol in reducing the duration of the postoperative ileus in patients undergoing cardiac surgery.

Study Overview

• Status: Completed
• Conditions: Postoperative Ileus (Post Cardiac Surgery Constipation)
• Intervention / Treatment: Drug: Naloxegol; Drug: inert tablet

Detailed Description

Digestive complications following cardiac surgery, such as paralytic ileus and Ogilvie syndrome, are frequent and worsen the prognosis of patients. They pose a real problem of care in intensive care, inducing morbidity and mortality, extended hospital stay and a significant post-operative cost.

Few treatments are effective to reduce transit recovery time, except the neostigmine which has a serious side effects including cardiac ones.

During cardiac surgery, opioid treatments are frequently used to relieve the pain like sternotomy pain.

The pharmacologic effect of opioid induces the postoperative uleus. Opioid receptors are distributed in the central nervous system, where they are involved in the perception of pain, and in the peripheral nervous system, especially in the mesenteric nervous system, where they regulate intestinal peristalsis.

Morphine receptors antagonist are a target for prevention and treatment of post operative ileus syndrome such as alvimopan and naloxone.

A therapeutic trial demonstrates a decrease in the rate of pneumonia in intensive care patient mechanically ventilated who received naloxone.

Naloxegol is a peripheral antagonist of opioid receptor, from the alvimopan family. It has been designed to antagonize the peripheral, but not central, effects of opioids at therapeutic doses. Naloxegol is a substrate for cytochrome P450 (CYP 3A4). Following oral administration, naloxegol is absorbed rapidly, with peak concentrations achieved at less than 2 hours.

After once daily administration, plasma concentration equilibrium is reached within 2-3 days with minimal accumulation.

The main route of elimination for naloxegol is hepatic. Naloxegol has been shown to be effective in randomized trials of chronic opioid induced constipation, but there is no data on its use in the postoperative ileus.

Research hypothesis: the addition of naloxegol in pre and postoperative cardiac surgery could reduce the time to transit recovery and the rate of digestive and respiratory complications.

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Neuilly Sur Seine
    • Neuilly-sur-Seine, Neuilly Sur Seine, France, 92200
      • CMC Ambroise Paré

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• > 18 years old,
• Undergoing cardiac surgery with cardiopulmonary bypass,
• For women of child bearing potential without contraception, beta-HCG negative result
• Having signed a written informed consent form,
• Affiliation to the social security system.

Exclusion Criteria:

• Allergy or known hypersensitivity to Naloxegol or any of the excipients or any other opioid antagonist
• Pregnant or breastfeeding women
• Severe hepatic failure, history of cirrhosis
• Moderate or severe renal failure (GFR<60ml/min)
• Concomitant treatment with a strong cytochrome P450 3A4 inhibitor
• History of acute gastro-intestinal obstruction known or suspected
• History of digestive arteritis
• Clinically relevant alteration of the blood-brain-barrier
• Cancer with increased risk of gastro-duodenal perforation
• Disorder that could alter the integrity of the gastrointestinal lining
• Regular treatment with laxative drugs
• Concomitant treatment with methadone
• Patient unable to take a drug by oral route
• Patient under protection of the adults (guardianship, curators or safeguard of justice),
• Patient included or planning to be included in another research protocol relating to medications.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Naloxegol group; naloxégol tablet by oral route	Drug: Naloxegol; one naloxegol 12.5 mg tablet will be administrated 2 hours before surgery. One 25 mg naloxegol tablet per day will be administrated from 24h post-surgery until bowel movement; for maximum 5 days.
Placebo Comparator: Placebo group; inert tablet by oral route	Drug: inert tablet; one inert tablet will be administrated 2 hours before surgery. One inert tablet per day will be administrated from 24h post-surgery until bowel movement; for maximum 5 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the effect of perioperative naloxegol administration on the duration of postoperative ileus after cardiac surgery	Time (hour) to transit recovery after cardiac surgery	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of digestive complications	rate of digestive complications	30 days
Evaluate the effect of the administration of Naloxegol on respiratory complications	rate of respiratory complications	30 days
Evaluate the effect of the administration of Naloxegol on infectious complications	rate of infectious complications	30 days
Verify the effectiveness of analgesia	Pain Visual Analogue Scale (VAS) ranging from 0 to 10 (0=no pain, 10=worst possible pain)	day 1, day2, day3
Compare the length of hospital stay	Duration of hospital stay (days)	30 days
Compare the length of ICU stay	Duration of ICU stay (days)	30 days

Collaborators and Investigators

• Sponsor: CMC Ambroise Paré

Study record dates

Study Major Dates

• Study Start (Actual): October 14, 2020
• Primary Completion (Actual): January 28, 2022
• Study Completion (Actual): March 3, 2022

Study Registration Dates

• First Submitted: June 12, 2020
• First Submitted That Met QC Criteria: June 12, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): March 8, 2022
• Last Update Submitted That Met QC Criteria: March 7, 2022
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: cardiac surgery; Opioid induced constipation; transit recovery
• Additional Relevant MeSH Terms: Digestive System Diseases; Signs and Symptoms, Digestive; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Obstruction; Constipation; Ileus; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Naloxegol
• Other Study ID Numbers: 2019-09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No