Naloxegol for Opioid-Related Gastroparesis

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.

Inclusion Criteria:

1. Age 18-84, Males or Females

2. 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

3. 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.

4. Delayed gastric emptying based on previous scintigraphy (Percent gastric retention
>60% at 2 hours and/or >10% retention at 4 hours

5. Signing informed consent prior to any study specific procedures

Exclusion Criteria:

1. Prior gastric resective surgery such as bariatric surgery, antrectomy.

2. Presence of severe renal impairment (CrCl<60 ml/min)

3. Presence of severe hepatic impairment - Child-Pugh Classification Class C, generally
AST>200 or ALT>200 or Total bilirubin >3.0.

4. Other conditions besides gastroparesis that could potentially slow gastric emptying,
such as untreated hypothyroidism.

5. Concomitants use of strong CYP 3A4 inhibitors (such as ketoconazole, diltiazem,
erythromycin, clarithromycin), use of CYP3A4 inducer.

6. Use of NSAIDs and/or Plavix/Clopidogrel

7. Any prior use of Movantik (the study drug) or other opioid receptor antagonist (e.g.,
Relistor (methylnaltrexone), naltrexone, or naloxone) before the screening visit.

8. Patients with known cancer or cancer history within last 5 years prior to the
screening visit.

9. Patients with GI obstruction and/or perforation or conditions with potential for GI
perforation.

10. Patients with disruption to the blood-brain barrier;

11. Current use of a medication affecting gastric motility such as metoclopramide,
domperidone, and erythromycin;

12. Pregnant women, females planning to become pregnant, and nursing mothers.

13. Women of childbearing potential who are unwilling to use contraceptives throughout the
course of treatment

14. Subjects with severe co-morbidities (Cardiovascular, respiratory, renal, hepatic,
hematologic, endocrine, neurologic) based on PI's clinical judgment.

15. Active substance abuse.

16. History of major comorbid psychiatric conditions including mania and schizophrenia or
severe current depression

17. 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)

18. Patients in which Movantik is clinically inadvisable

19. Subject unable to consent or is unwilling to provide informed consent