The Effect of Naloxegol on Refractory Constipation in the Intensive Care Unit (NaRC-ICU)

Mass General Brigham

Status and phase: Withdrawn; Phase 3

Conditions: Critical Illness; Constipation

Treatments: Drug: Polyethylene glycol; Drug: naloxegol

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02705378

NaRC-ICU_temp

Details and patient eligibility

About

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.

Full 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.

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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0 participants in 2 patient groups

Polyethylene glycol

Active Comparator group

Description:

17g power qday; reconstituted in water for naso/orogastric tube administration

Treatment:

Drug: Polyethylene glycol

naloxegol

Experimental group

Description:

25mg qday; crushed pill reconstituted in water for naso/orogastric tube administration

Treatment:

Drug: naloxegol