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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Constipation, Critical Illness

Intervention / Treatment
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* Drug: Polyethylene glycol
* Drug: naloxegol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Admitted to an ICU at Massachusetts General Hospital (MGH) Received ≥72 hours of continuous opioid infusion Anticipated to require ≥48 hours of additional care in the ICU Did not have a bowel movement in ≥72 hours Allowed to receive (and tolerating) medications via nasogastric, orogastric, gastric, gastrojejunal, or oral route Receiving at least trophic (10 mL/hr) of enteral nutrition Exclusion Criteria: Unable to provide informed consent or unavailable healthcare proxy Not expected to survive >48 hours from time of enrollment Comfort measures only status (i.e. palliative care) Received medication other that docusate and senna glycoside for laxation Had abdominal surgery that is expected to cause significant ileus Mechanical bowel obstruction Total bowel rest/exclusively receiving total parenteral nutrition History of chronic constipation unrelated to opioid use Compromised blood-brain-barrier Current diagnosis of solid organ or hematologic cancer On moderate/strong CYP3A4 inhibitors or strong CYP3A4 inducers On other opioid antagonists Pregnant or lactating females

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Polyethylene glycol<br>17g power qday; reconstituted in water for naso/orogastric tube administration | Drug: Polyethylene glycol<br>* Intervention would be given by oro-gastric (OG) or naso-gastric (NG) tube<br>* Other names: glycolax;|
| Experimental: naloxegol<br>25mg qday; crushed pill reconstituted in water for naso/orogastric tube administration | Drug: naloxegol<br>* Intervention would be given by OG or NG tube<br>* Other names: Movantik;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intensive care unit, ICU, Critical Illness, Constipation