Clinical trial NCT02977286: Naloxegol to Prevent Lower Gastrointestinal Paralysis in Critically Ill Adults Administered Opioids
Official title: Impact of Naloxegol on Prevention of Lower GI Tract Paralysis in Critically Ill Adults Initiated on Scheduled Intravenous Opioid Therapy: A Randomized, Double-Blind, Placebo-Controlled, Phase II, Single-Center, Proof of Concept Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Constipation
Lead sponsor: Tufts Medical Center
Sponsor class: OTHER
First posted: 2016-11-30
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Time to First Spontaneous Bowel Movement (SBM) Administration
timeFrame: First occurrence after study randomization during period of ICU admission or a maximum of 10 ICU days
Secondary outcomes:
measure: Time to First Spontaneous Bowel Movement (SBM)
timeFrame: First occurrence after initiation of IV opioid therapy during period of ICU admission or a maximum of 10 ICU days
measure: ICU Days Without a SBM
timeFrame: During period of ICU admission or a maximum of 10 ICU days
measure: Occurrence of Lower GI Tract Paralysis (≥3 Days Without a SBM)
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Average Daily Opioid Requirement [in IV Fentanyl Equivalents (mcg Per Day)]
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Number of Patients With Loose and Unformed or Liquid SBM
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Number of Patients That Required Use of the Study Laxative Protocol
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Percentage of Daily Goal Reached for Enteral Nutrition Administration
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Daily Fluid Balance
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Daily Maximal Pain Scale Score
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Daily Maximal Sedation Assessment Scale (SAS) Score
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Daily Presence of Delirium Using the Intensive Care Delirium Screening Checklist (ICDSC)
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Occurrence of Lower GI Tract Paralysis Requiring GI/Surgical Consultation
timeFrame: From randomization to ICU discharge or a maximum of 10 ICU days
measure: Days Without Mechanical Ventilation Support for Duration of ICU Stay
timeFrame: From ICU admission to ICU discharge or a maximum of 10 ICU days
measure: Abdominal Pressure Measurement
timeFrame: From randomization to ICU discharge (or removal of foley catheter) or a maximum of 10 ICU days
measure: Time to First Episode of Diarrhea
timeFrame: Study drug initiation to first episode of diarrhea in hours.
measure: Daily Difference in the Pre-dose and Post-dose Clinical Opioid Withdrawal Scale (COWS) Score
timeFrame: One hour before the daily study drug administration and 2 hours after the daily study drug administration
Other outcomes:
Locations:
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
Study officials:
affiliation: Tufts Medical Center
name: Erik Garpestad, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.