The Effect of Naloxegol on Refractory Constipation in the Intensive Care Unit

Critical Illness Clinical Trial

— NaRC-ICU  

Official title:

The Effect of Naloxegol on Refractory Constipation in the Intensive Care Unit

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02705378
• Other study ID #: NaRC-ICU_temp
• Status: Withdrawn
• Phase: Phase 3
• Start date: May 2017
• Est. completion date: December 2019

Study information

• Verified date: April 2021
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Naloxegol has recently been approved by the US Food and Drug Administration to treat opioid induced constipation in non-cancer chronic pain patients. Its effectiveness in acute care patients, however, is not known. Therefore, the researchers' goal is to investigate whether naloxegol is superior to osmotic laxatives for refractory constipation in ICU patients already receiving prophylactic stool softeners and simulant laxatives through a double-blind, randomized control trial.

Description:

Constipation is often defined as the absence of a bowel movement for 3 consecutive days. The incidence of constipation in critically ill patients is estimated to be 50-80%. Constipation in the ICU is associated with various undesirable clinical outcomes, including: increased rate of infections, prolonged duration of mechanical ventilation, greater hospital length of stay, worsening of organ dysfunction, and even higher mortality.

Typical first-line agents for the management of ICU constipation include stool softeners (e.g. docusate) and bowel stimulants (e.g. senna glycol or bisacodyl), and these are often used prophylactically in critically ill patients. However, a significant proportion of patients require additional therapy to promote laxation , the most common being osmotic agents such as propylene glycol or lactulose. Often, multiple doses of osmotic agents over several days are required to achieve acceptable laxation rates during critical illness. As such, this has prompted the need for targeted therapy to improve constipation in the ICU.

Among major risk factors for constipation in the ICU are the lack of bowel stimulation via nutrition and exposure to high doses of continuous opioids . Indeed, clinical data suggests that early enteral nutrition promotes laxation in ICU patients. And recently, methylnaltrexone, a peripherally acting μ-opioid receptor antagonist, has shown promising results in its ability to reverse opioid-induced constipation. However, methylnaltrexone is delivered via subcutaneous injection and its absorption is likely to be variable in critically ill patients who often receive aggressive fluid resuscitation and have significant peripheral edema. The US Food and Drug Administration recently approved the use of naloxegol, a μ-opioid receptor antagonist available in tablet form, for the management of opioid-induced constipation in non-cancer chronic pain patients.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2019
• Est. primary completion date: April 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age =18 years

2. Admitted to an ICU at Massachusetts General Hospital (MGH)

3. Received =72 hours of continuous opioid infusion

4. Anticipated to require =48 hours of additional care in the ICU

5. Did not have a bowel movement in =72 hours

6. Allowed to receive (and tolerating) medications via nasogastric, orogastric, gastric, gastrojejunal, or oral route

7. Receiving at least trophic (10 mL/hr) of enteral nutrition

Exclusion Criteria:

1. Unable to provide informed consent or unavailable healthcare proxy

2. Not expected to survive >48 hours from time of enrollment

3. "Comfort measures only" status (i.e. palliative care)

4. Received medication other that docusate and senna glycoside for laxation

5. Had abdominal surgery that is expected to cause significant ileus

6. Mechanical bowel obstruction

7. Total bowel rest/exclusively receiving total parenteral nutrition

8. History of chronic constipation unrelated to opioid use

9. Compromised blood-brain-barrier

10. Current diagnosis of solid organ or hematologic cancer

11. On moderate/strong CYP3A4 inhibitors or strong CYP3A4 inducers

12. On other opioid antagonists

13. Pregnant or lactating females

Related Conditions & MeSH terms

• Constipation
• Critical Illness

Intervention

Drug:
• Polyethylene glycol
Intervention would be given by oro-gastric (OG) or naso-gastric (NG) tube
• naloxegol
Intervention would be given by OG or NG tube

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	AstraZeneca

Country where clinical trial is conducted

United States, 

References & Publications (13)

Azevedo RP, Freitas FG, Ferreira EM, Machado FR. Intestinal constipation in intensive care units. Rev Bras Ter Intensiva. 2009 Aug;21(3):324-31. English, Portuguese. — View Citation

Gacouin A, Camus C, Gros A, Isslame S, Marque S, Lavoué S, Chimot L, Donnio PY, Le Tulzo Y. Constipation in long-term ventilated patients: associated factors and impact on intensive care unit outcomes. Crit Care Med. 2010 Oct;38(10):1933-8. doi: 10.1097/CCM.0b013e3181eb9236. — View Citation

Herndon CM, Jackson KC 2nd, Hallin PA. Management of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy. 2002 Feb;22(2):240-50. Review. — View Citation

Hewitt K, Lin H, Faraklas I, Morris S, Cochran A, Saffle J. Use of methylnaltrexone to induce laxation in acutely injured patients with burns and necrotizing soft-tissue infections. J Burn Care Res. 2014 Mar-Apr;35(2):e106-11. doi: 10.1097/BCR.0b013e31829b399d. — View Citation

Masri Y, Abubaker J, Ahmed R. Prophylactic use of laxative for constipation in critically ill patients. Ann Thorac Med. 2010 Oct;5(4):228-31. doi: 10.4103/1817-1737.69113. — View Citation

Mostafa SM, Bhandari S, Ritchie G, Gratton N, Wenstone R. Constipation and its implications in the critically ill patient. Br J Anaesth. 2003 Dec;91(6):815-9. — View Citation

Nassar AP Jr, da Silva FM, de Cleva R. Constipation in intensive care unit: incidence and risk factors. J Crit Care. 2009 Dec;24(4):630.e9-12. doi: 10.1016/j.jcrc.2009.03.007. Epub 2009 Jul 9. — View Citation

Patanwala AE, Abarca J, Huckleberry Y, Erstad BL. Pharmacologic management of constipation in the critically ill patient. Pharmacotherapy. 2006 Jul;26(7):896-902. — View Citation

Reintam A, Parm P, Kitus R, Starkopf J, Kern H. Gastrointestinal failure score in critically ill patients: a prospective observational study. Crit Care. 2008;12(4):R90. doi: 10.1186/cc6958. Epub 2008 Jul 14. Erratum in: Crit Care. 2008;12(6):435. — View Citation

Reintam Blaser A, Poeze M, Malbrain ML, Björck M, Oudemans-van Straaten HM, Starkopf J; Gastro-Intestinal Failure Trial Group. Gastrointestinal symptoms during the first week of intensive care are associated with poor outcome: a prospective multicentre study. Intensive Care Med. 2013 May;39(5):899-909. doi: 10.1007/s00134-013-2831-1. Epub 2013 Jan 31. — View Citation

Sawh SB, Selvaraj IP, Danga A, Cotton AL, Moss J, Patel PB. Use of methylnaltrexone for the treatment of opioid-induced constipation in critical care patients. Mayo Clin Proc. 2012 Mar;87(3):255-9. doi: 10.1016/j.mayocp.2011.11.014. — View Citation

van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA, van Roon EN, Zandstra DF, van der Voort PH. Laxation of critically ill patients with lactulose or polyethylene glycol: a two-center randomized, double-blind, placebo-controlled trial. Crit Care Med. 2007 Dec;35(12):2726-31. — View Citation

van der Spoel JI, Schultz MJ, van der Voort PH, de Jonge E. Influence of severity of illness, medication and selective decontamination on defecation. Intensive Care Med. 2006 Jun;32(6):875-80. Epub 2006 Apr 28. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Laxation within 48 hours of starting second-line agent	Documented bowel movement (Yes/No) within 48 hours of randomization to receive second-line laxative agent	From 72 hours after ICU admission until 120 hours after ICU admission
Secondary	Time to first bowel movement after starting second-line agent	Number of hours from initiation of a second-line laxative agent until first documented bowel movement	From 72 hours after ICU admission until 120 hours after ICU admission
Secondary	Doses of second-line laxative agent before bowel movement	Number of doses of second-line laxative agent until first documented bowel movement	From 72 hours after ICU admission until 120 hours after ICU admission
Secondary	Protein/caloric deficit	Cumulative calorie and protein deficits will be calculated in kcals and grams, respectively, utilizing standard clinical formulas from the day of ICU admission until day 7 of ICU admission	From admission to the ICU until the end of day 7 after ICU admission
Secondary	Feeding interruptions	Number of interruptions to enteral nutrition for high gastric residual volume during study period	From admission to the ICU until the end of day 7 after ICU admission

External Links

•   Constipation in critically ill patients and its relationship to feeding and weaning from respiratory support