Naloxegol for Opioid-Related Gastroparesis

Study Overview
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Brief Summary
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The objective of this study is to evaluate the effects of naloxegol (a peripheral mu-opioid receptor antagonist [PAMORA]) in opioid-related gastroparesis on 1) symptoms of gastroparesis; 2) gastric emptying; and 3) pain control. The endpoints will be gastroparesis symptoms (PAGI-SYM), gastric emptying (GEBT), and pain control (McGill Pain Inventory). The hypothesis to be tested is that naloxegol improves symptoms of gastroparesis in patients who are taking opioids as well as improves their gastric emptying while maintaining control of patient's pain. This study will entail an initial double-blind, randomized, placebo-controlled, 4-week treatment period of naloxegol vs placebo in patients with opioid-related gastroparesis followed by a 4-week open label period to demonstrate the improvement in symptoms and gastric emptying with naloxegol.

Detailed Description
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Medicines can delay gastric emptying and produce similar symptoms to gastroparesis. In particular, narcotic analgesics, can produce a gastroparesis picture, by delaying gastric emptying. The slowing effect of opioids on gastric, small bowel, and colonic motility has been well characterized. Unfortunately, many of these patients cannot stop their pain medications due to their underlying condition, such as back pain, fibromyalgia. On top of this, the narcotics can reduce the effectiveness of prokinetics agents used to treat gastroparesis, such as metoclopramide and domperidone. At this time, there is no good treatment for gastroparesis, especially for opioid-related gastroparesis. Data suggests a relationship between opioid use and decreased gastric motility. Literature suggests that peripherally acting opioid agonist may provide relief in the instance of GI dysfunction (Holzer 2007). Movantik (Naloxegol) is an opioid agonist specifically designed to work outside of the central nervous system. Movantik (Naloxegol) can alleviate the adverse effects associated in chronic pain patients on opioid treatment - reduction of the undesired peripheral effects of opioids without disrupting analgesic effects. The use of Movantik (Naloxegol) has the potential to improve gastric dysmotility while preserving pain relief of the opioid analgesic. The objective of this study is to evaluate the effects of naloxegol in opioid-related gastroparesis. This will be a randomized, double-blind study comparing Movantik 25 mg to placebo. The dose of Movantik is the dose that is currently FDA approved for opioid-induced constipation. The four-week study period is the duration of the phase 2b studies for Movantik for opioid-induced constipation in which the response rates were 60% and 35% with active treatment and placebo (Chey 2015). The investigators have included a unique aspect of this study to better balance the benefits for patients participating in this randomized double-blind study in which half the patients receive a placebo agent. All patients in the treatment group and the placebo group will be invited to participate in the 4-week open-label extension for this study. This also serves to study the duration of the potential favorable effects of Movantik (Naloxegol) in this patient population as well as offering an extended time period to assess safety and tolerability.

Official Title
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Naloxegol for Opioid-Related Gastroparesis: A Double-Blind Study With an Open Label Extension

Conditions
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Gastroparesis, Opioid Use

Intervention / Treatment
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* Drug: Naloxegol 25 MG Oral Tablet [Movantik]
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-84, Males or Females Daily use of narcotic analgesics for treatment of pain. Patients need to be on a stable daily dose of opiates for the last 4 weeks prior to enrollment Patients with symptoms of gastroparesis with GCSI score (from the PAGI-SYM) of >2.0. These symptoms of gastroparesis must be present after starting opioid treatment. Delayed gastric emptying based on previous scintigraphy (Percent gastric retention >60% at 2 hours and/or >10% retention at 4 hours Signing informed consent prior to any study specific procedures Exclusion Criteria: Prior gastric resective surgery such as bariatric surgery, antrectomy. Presence of severe renal impairment (CrCl<60 ml/min) Presence of severe hepatic impairment - Child-Pugh Classification Class C, generally AST>200 or ALT>200 or Total bilirubin >3.0. Other conditions besides gastroparesis that could potentially slow gastric emptying, such as untreated hypothyroidism. Concomitants use of strong CYP 3A4 inhibitors (such as ketoconazole, diltiazem, erythromycin, clarithromycin), use of CYP3A4 inducer. Use of NSAIDs and/or Plavix/Clopidogrel Any prior use of Movantik (the study drug) or other opioid receptor antagonist (e.g., Relistor (methylnaltrexone), naltrexone, or naloxone) before the screening visit. Patients with known cancer or cancer history within last 5 years prior to the screening visit. Patients with GI obstruction and/or perforation or conditions with potential for GI perforation. Patients with disruption to the blood-brain barrier; Current use of a medication affecting gastric motility such as metoclopramide, domperidone, and erythromycin; Pregnant women, females planning to become pregnant, and nursing mothers. Women of childbearing potential who are unwilling to use contraceptives throughout the course of treatment Subjects with severe co-morbidities (Cardiovascular, respiratory, renal, hepatic, hematologic, endocrine, neurologic) based on PI's clinical judgment. Active substance abuse. History of major comorbid psychiatric conditions including mania and schizophrenia or severe current depression At-risk populations, including prisoners and mentally challenged. Any condition or the patient is in a situation which may put him/her at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study (e.g., difficulty hearing, cognitive impairment) Patients in which Movantik is clinically inadvisable Subject unable to consent or is unwilling to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 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
Interventional Model Description: The investigators have included a unique aspect of this study to better balance the benefits for patients participating in this randomized double-blind study in which half the patients receive a placebo agent. All patients in the treatment group and the placebo group will be invited to participate in the 4-week open-label extension for this study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Group<br>Naloxegol 25 mg, oral tablet, daily for 4 weeks | Drug: Naloxegol 25 MG Oral Tablet [Movantik]<br>* Patients will be given the study drug (Movantik 25 mg).They will take this daily in the morning 1 hour before breakfast for four weeks.<br>* Other names: Study;|
| Placebo Comparator: Placebo Control<br>Placebo Oral Tablet, 25 mg, oral tablet, daily for 4 weeks | Drug: Placebo Oral Tablet<br>* Patients will be given Placebo (Placebo 25 mg).They will take this daily in the morning 1 hour before breakfast for four weeks.<br>* Other names: Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastric Emptying (GE t-1/2) | Improvement in gastric emptying (GE t-1/2) compared to Placebo | 4 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Symptom Improvement using the GCSI-DD (Gastroparesis Cardinal Symptom Index-Daily Diary) | Improvements of gastroparesis symptoms using the GCSI-DD (Gastroparesis Cardinal Symptom Index-Daily Diary) | 4 weeks | 
| Symptom Improvement using PAGI-SYM | Improvements of gastroparesis symptoms using PAGI-SYM | 4 weeks | 
| Pain Management using the McGill Pain Inventory | Changes in pain control using the McGill Pain Inventory | 4 weeks | 
| Overall improvement in Gastric Emptying (GE t-1/2) | Improvement in gastric emptying (GE t-1/2) compared to Placebo | 8 week | 
| Quality of Life based on SF-36 | QOL score changes based on SF-36 | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastroparesis, Opioid-Induced, Delayed Gastric Emptying