Naloxegol to Prevent Lower Gastrointestinal Paralysis in Critically Ill Adults Administered Opioids

NCT ID: NCT02977286

Last Updated: 2023-02-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-01
• Study Completion Date: 2019-10-09

Brief Summary

This study evaluates the addition of naloxegol (Movantik) to a laxative protocol in critically ill adults requiring scheduled opioid (e.g. fentanyl) therapy. Half of the participants will receive naloxegol and a laxative protocol and half the participants will receive a placebo and a laxative protocol.

Detailed Description

Among the more than 5 million adults who are admitted to the ICU each year in the USA, most have pain and thus receive a pain (analgesic) medication called an opioid. Opioid use in critically ill adults continues to increase given the greater awareness of untreated pain in the ICU and that an opioid-first approach be used to optimize patient safety and comfort and improve tolerance with breathing machines (i.e. mechanical ventilation). Similar to constipation, paralysis of the lower gastrointestinal (GI) tract is defined as the inability to pass stool due to impaired gut movement, and is a common effect of opioid use in the critically ill. Lower GI tract paralysis may lead to nausea, vomiting, aspiration, compromise the ability to administer tube feeds (enteral nutrition), an increase abdominal pain, delirium and delay getting off mechanical ventilation. One recent randomized study found that aggressive use of laxatives to prevent lower GI tract paralysis in critically ill adults was associated with lower daily organ dysfunction [as measured by the Sequential Organ Failure Assessment (SOFA) score]. The lower GI tract paralysis that occurs in the critically ill often responds poorly to laxative medication therapy (e.g., senna, bisacodyl, lactulose). While stool softener medications like docusate are routinely administered to patients on opioids, laxative-based protocols are frequently not initiated in the ICU until signs of lower GI tract paralysis start to appear. There is therefore an important and unmet need for a safe and efficacious medication to prevent lower GI tract paralysis in critically ill adults who are initiated on opioid therapy. Naloxegol (Movantik) is a naloxone-like drug that blocks the effect of opioids on the opioid µ receptor in the gut but is not absorbed in the brain (and therefore does not block the pain effects of opioids). Naloxegol is currently approved by the Food and Drug Administration (FDA) for the treatment of opioid-induced constipation (OIC) in non-ICU patients receiving scheduled moderate to high dose opioids for the treatment of chronic non-cancer pain. Naloxegol has a mechanism of action, efficacy, convenience of administration, and safety profile that make it an ideal candidate for use as a preventative medication for lower GI tract paralysis in critically ill adults receiving scheduled opioid therapy. The investigators propose a pilot study in which they will test the hypothesis that naloxegol (versus placebo) will reduce the time to the first spontaneous bowel movement (SBM) that an ICU patient has, that it will prevent lower GI tract paralysis in critically ill adults initiated on scheduled IV opioid therapy, and its use will not result in side effects that are concerning to doctors or patients. The investigators will randomize 36 critically ill ICU patients (18 in each arm) to receive naloxegol [25mg or 12.5mg (in patients with a creatinine clearance ≤ 60ml/min)] or placebo. This pilot study will provide valuable information to help guide future, larger studies evaluating the role of naloxegol in critically ill adults.

Conditions

Constipation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Naloxegol Oral Tablet

Intervention: Naloxegol 25 mg (or 12.5 mg) tablet po (enteral) daily AND Docusate Sodium 100mg Oral Capsule twice daily AND Study laxative protocol daily [that may include Senna 217 mg Oral Tablet, Polyethylene Glycols (Miralax), Magnesium Citrate Oral Liquid Product (Citromag), Bisacodyl 10 mg Suppository (Dulcolax) and Methylnaltrexone (Relistor)] until one of the following:

1. Adverse event potentially attributable to the study drug.

2. Use of Relistor.

3. Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.

4. The participant has been administered 10 days of study medication.

5. The participant is discharged from the ICU.

6. The participant requires the initiation of a strong CYP3A4 inhibitor medication.

Other Name: Movantik

Group Type: EXPERIMENTAL

Naloxegol Oral Tablet

Intervention Type: DRUG

Naloxegol Oral Tablet 25 mg (or 12.5 mg) po (enteral) daily

Docusate Sodium 100 Mg oral capsule [Colace]

Intervention Type: DRUG

Docusate Sodium 100 mg po (enteral) twice daily

Senna 217 Mg Oral Tablet

Intervention Type: DRUG

Senna 127 mg oral tablet daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to two senna 127 mg tables if no no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=5 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=6 days after scheduled opioid initiation.

Polyethylene Glycols

Intervention Type: DRUG

Polyethylene Glycols 17 g daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to 34 g daily if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation.

Bisacodyl 10 mg Suppository

Intervention Type: DRUG

Insert one suppository if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation.

Magnesium Citrate Oral Liquid Product

Intervention Type: DRUG

Administer one 10 oz bottle if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation.

Methylnaltrexone

Intervention Type: DRUG

Administer 8 mg or 16 mg (depending on subject's weight) subcutaneously x 1 if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation, consult surgery/gastroenterology and discontinue study medication.

Placebo Oral Tablet

Intervention: Placebo tablet po (enteral) daily AND Docusate Sodium 100 mg Oral Capsule twice daily AND Study laxative protocol daily [that may include Senna 217 mg Oral Tablet, Polyethylene Glycols (Miralax), Magnesium Citrate Oral Liquid Product (Citromag), Bisacodyl 10 mg Suppository (Dulcolax) and Methylnaltrexone (Relistor)] until one of the following:

1. Adverse event potentially attributable to the study drug.

2. Use of Relistor.

3. Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.

4. The participant has been administered 10 days of study medication.

5. The participant is discharged from the ICU.

6. The participant requires the initiation of a strong CYP3A4 inhibitor medication.

Other Name: AstraZeneca provided Movantik placebo

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

Placebo Oral Tablet po (enteral) twice daily

Docusate Sodium 100 Mg oral capsule [Colace]

Intervention Type: DRUG

Docusate Sodium 100 mg po (enteral) twice daily

Senna 217 Mg Oral Tablet

Intervention Type: DRUG

Senna 127 mg oral tablet daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to two senna 127 mg tables if no no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=5 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=6 days after scheduled opioid initiation.

Polyethylene Glycols

Intervention Type: DRUG

Polyethylene Glycols 17 g daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to 34 g daily if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation.

Bisacodyl 10 mg Suppository

Intervention Type: DRUG

Insert one suppository if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation.

Magnesium Citrate Oral Liquid Product

Intervention Type: DRUG

Administer one 10 oz bottle if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation.

Methylnaltrexone

Intervention Type: DRUG

Administer 8 mg or 16 mg (depending on subject's weight) subcutaneously x 1 if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation, consult surgery/gastroenterology and discontinue study medication.

Interventions

Naloxegol Oral Tablet

Naloxegol Oral Tablet 25 mg (or 12.5 mg) po (enteral) daily

Intervention Type: DRUG

Placebo Oral Tablet

Placebo Oral Tablet po (enteral) twice daily

Intervention Type: DRUG

Docusate Sodium 100 Mg oral capsule [Colace]

Docusate Sodium 100 mg po (enteral) twice daily

Intervention Type: DRUG

Senna 217 Mg Oral Tablet

Senna 127 mg oral tablet daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to two senna 127 mg tables if no no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=5 days after scheduled opioid initiation. Repeat two senna 127 mg tablets if no spontaneous bowel movement \>/=6 days after scheduled opioid initiation.

Intervention Type: DRUG

Polyethylene Glycols

Polyethylene Glycols 17 g daily if no spontaneous bowel movement \>/=3 days after scheduled opioid initiation; increase to 34 g daily if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat 34 g daily if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation.

Intervention Type: DRUG

Bisacodyl 10 mg Suppository

Insert one suppository if no spontaneous bowel movement \>/=4 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation. Repeat if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation.

Intervention Type: DRUG

Magnesium Citrate Oral Liquid Product

Administer one 10 oz bottle if no spontaneous bowel movement \>/= 5 days after scheduled opioid initiation.

Intervention Type: DRUG

Methylnaltrexone

Administer 8 mg or 16 mg (depending on subject's weight) subcutaneously x 1 if no spontaneous bowel movement \>/= 6 days after scheduled opioid initiation, consult surgery/gastroenterology and discontinue study medication.

Intervention Type: DRUG

Other Intervention Names

Movantik; Official AstraZeneca placebo for Movantik; Colace; Senokot; Miralax; Dulcolax; Citromag; Relistor

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 years
• Admitted to an ICU
• Expected to require admission to an ICU for ≥ 48 hours
• Intravenous opioid administration in the prior 24 hours of ≥ 100 mcg fentanyl equivalents

Exclusion Criteria

• Scheduled use of an opioid ≥ 10 mg morphine equivalents per day in the week prior to ICU admission
• History of constipation (≤ 2 SBM per week and current use of stool softener or laxative therapy) prior to ICU admission
• Current scheduled use of a medication affecting gastric motility
• Current use of a medication known to be a strong CYP3A4 inhibitor
• History of a neurologic condition that may affect the permeability of the blood-brain barrier
• Acute GI condition (e.g., clinical evidence of acute fecal impaction/complete obstruction, acute surgical abdomen, acute GI bleeding)
• Condition affecting GI motility or function (e.g. inflammatory bowel disease requiring immunosuppressive therapy, symptomatic Clostridium difficile, active diverticular disease, surgery on the colon or abdomen within 60 days of ICU admission)
• Current use of total parenteral nutrition
• Administration of enteral nutrition through a jejunal tube
• Severe hepatic dysfunction
• Endstage renal disease defined as either i. calculated creatinine clearance ≤ 10ml/min or ii. Any current use of renal replacement therapy
• Inability to enroll in study and initiate study medication within 48 hours of the patient begin first initiated on scheduled IV opioid therapy after ICU admission
• Unreliable method for enteral, gastric and/or oral medication administration (e.g., no feeding tube, nasogastric tube is on suction)
• Current or previous use of an opioid antagonist agent (e.g., naloxegol, methylnaltrexone) in the past 30 days
• Pregnant or actively lactating females
• Current participation in another interventional clinical study
• Inability to obtain informed consent

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Tufts Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Erik Garpestad, MD

Role: PRINCIPAL_INVESTIGATOR

Tufts Medical Center

Locations

Tufts Medical Center

Boston, Massachusetts, United States

Countries

United States

References

Reintam Blaser A, Malbrain ML, Starkopf J, Fruhwald S, Jakob SM, De Waele J, Braun JP, Poeze M, Spies C. Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the ESICM Working Group on Abdominal Problems. Intensive Care Med. 2012 Mar;38(3):384-94. doi: 10.1007/s00134-011-2459-y. Epub 2012 Feb 7.

Reference Type: BACKGROUND

PMID: 22310869 (View on PubMed)

de Azevedo RP, Freitas FG, Ferreira EM, Pontes de Azevedo LC, Machado FR. Daily laxative therapy reduces organ dysfunction in mechanically ventilated patients: a phase II randomized controlled trial. Crit Care. 2015 Sep 16;19(1):329. doi: 10.1186/s13054-015-1047-x.

Reference Type: BACKGROUND

PMID: 26373705 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

11200

Identifier Type: -

Identifier Source: org_study_id