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
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Time to First Spontaneous Bowel Movement (SBM) Administration
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: Movantik
干预措施: Naloxegol Oral Tablet (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: Movantik
干预措施: Docusate Sodium 100 Mg oral capsule [Colace] (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: Movantik
干预措施: Senna 217 Mg Oral Tablet (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: Movantik
干预措施: Polyethylene Glycols (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: Movantik
干预措施: Bisacodyl 10 mg Suppository (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: Movantik
干预措施: Magnesium Citrate Oral Liquid Product (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: Movantik
干预措施: Methylnaltrexone (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: AstraZeneca provided Movantik placebo
干预措施: Placebo Oral Tablet (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: AstraZeneca provided Movantik placebo
干预措施: Docusate Sodium 100 Mg oral capsule [Colace] (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: AstraZeneca provided Movantik placebo
干预措施: Senna 217 Mg Oral Tablet (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: AstraZeneca provided Movantik placebo
干预措施: Polyethylene Glycols (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: AstraZeneca provided Movantik placebo
干预措施: Bisacodyl 10 mg Suppository (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: AstraZeneca provided Movantik placebo
干预措施: Magnesium Citrate Oral Liquid Product (Drug)
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:
- Adverse event potentially attributable to the study drug.
- Use of Relistor.
- Scheduled opioid therapy is stopped for ≥ 24 hours and participant has ≥ 1 SBM since enrollment.
- The participant has been administered 10 days of study medication.
- The participant is discharged from the ICU.
- The participant requires the initiation of a strong CYP3A4 inhibitor medication.
Other Name: AstraZeneca provided Movantik placebo
干预措施: Methylnaltrexone (Drug)
结局指标
主要结局
Time to First Spontaneous Bowel Movement (SBM) Administration
时间窗: First occurrence after study randomization during period of ICU admission or a maximum of 10 ICU days
Time to first spontaneous bowel movement during ICU admission after randomization
次要结局
- Time to First Spontaneous Bowel Movement (SBM)(First occurrence after initiation of IV opioid therapy during period of ICU admission or a maximum of 10 ICU days)
- Percentage of Daily Goal Reached for Enteral Nutrition Administration(From randomization to ICU discharge or a maximum of 10 ICU days)
- Daily Maximal Pain Scale Score(From randomization to ICU discharge or a maximum of 10 ICU days)
- Abdominal Pressure Measurement(From randomization to ICU discharge (or removal of foley catheter) or a maximum of 10 ICU days)
- ICU Days Without a SBM(During period of ICU admission or a maximum of 10 ICU days)
- Number of Patients That Required Use of the Study Laxative Protocol(From randomization to ICU discharge or a maximum of 10 ICU days)
- Daily Fluid Balance(From randomization to ICU discharge or a maximum of 10 ICU days)
- Daily Maximal Sedation Assessment Scale (SAS) Score(From randomization to ICU discharge or a maximum of 10 ICU days)
- Occurrence of Lower GI Tract Paralysis Requiring GI/Surgical Consultation(From randomization to ICU discharge or a maximum of 10 ICU days)
- Days Without Mechanical Ventilation Support for Duration of ICU Stay(From ICU admission to ICU discharge or a maximum of 10 ICU days)
- Time to First Episode of Diarrhea(Study drug initiation to first episode of diarrhea in hours.)
- Occurrence of Lower GI Tract Paralysis (≥3 Days Without a SBM)(From randomization to ICU discharge or a maximum of 10 ICU days)
- Average Daily Opioid Requirement [in IV Fentanyl Equivalents (mcg Per Day)](From randomization to ICU discharge or a maximum of 10 ICU days)
- Daily Difference in the Pre-dose and Post-dose Clinical Opioid Withdrawal Scale (COWS) Score(One hour before the daily study drug administration and 2 hours after the daily study drug administration)
- Number of Patients With Loose and Unformed or Liquid SBM(From randomization to ICU discharge or a maximum of 10 ICU days)
- Daily Presence of Delirium Using the Intensive Care Delirium Screening Checklist (ICDSC)(From randomization to ICU discharge or a maximum of 10 ICU days)