Naloxegol for Opioid-Related Gastroparesis

Opioid Use Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03036891
• Other study ID #: 24102
• Status: Withdrawn
• Phase: Phase 2
• Start date: December 29, 2016
• Est. completion date: September 30, 2019

Study information

• Verified date: August 2020
• Source: Temple University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 30, 2019
• Est. primary completion date: September 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 84 Years

Eligibility

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

Related Conditions & MeSH terms

• Gastroparesis
• Opioid Use

Intervention

Drug:
• Naloxegol 25 MG Oral Tablet [Movantik]
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.
• Placebo Oral Tablet
Patients will be given Placebo (Placebo 25 mg).They will take this daily in the morning 1 hour before breakfast for four weeks.

Locations

Country	Name	City	State
United States	Lewis Katz School of Medicine at Temple University	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Temple University	AstraZeneca

Country where clinical trial is conducted

United States, 

References & Publications (18)

Abell TL, Bernstein RK, Cutts T, Farrugia G, Forster J, Hasler WL, McCallum RW, Olden KW, Parkman HP, Parrish CR, Pasricha PJ, Prather CM, Soffer EE, Twillman R, Vinik AI. Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil. 2006 Apr;18(4):263-83. Review. — View Citation

Abell TL, Camilleri M, Donohoe K, Hasler WL, Lin HC, Maurer AH, McCallum RW, Nowak T, Nusynowitz ML, Parkman HP, Shreve P, Szarka LA, Snape WJ Jr, Ziessman HA; American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. J Nucl Med Technol. 2008 Mar;36(1):44-54. doi: 10.2967/jnmt.107.048116. Epub 2008 Feb 20. — View Citation

Anantharamu T, Sharma S, Gupta AK, Dahiya N, Singh Brashier DB, Sharma AK. Naloxegol: First oral peripherally acting mu opioid receptor antagonists for opioid-induced constipation. J Pharmacol Pharmacother. 2015 Jul-Sep;6(3):188-92. doi: 10.4103/0976-500X.162015. — View Citation

Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014 Jun 19;370(25):2387-96. doi: 10.1056/NEJMoa1310246. Epub 2014 Jun 4. — View Citation

Culpepper-Morgan JA, Inturrisi CE, Portenoy RK, Foley K, Houde RW, Marsh F, Kreek MJ. Treatment of opioid-induced constipation with oral naloxone: a pilot study. Clin Pharmacol Ther. 1992 Jul;52(1):90-5. — View Citation

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Maranki JL, Lytes V, Meilahn JE, Harbison S, Friedenberg FK, Fisher RS, Parkman HP. Predictive factors for clinical improvement with Enterra gastric electric stimulation treatment for refractory gastroparesis. Dig Dis Sci. 2008 Aug;53(8):2072-8. Epub 2007 Dec 14. — View Citation

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Parkman HP, Hasler WL, Fisher RS; American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004 Nov;127(5):1592-622. Review. — View Citation

Parkman HP, Yates K, Hasler WL, Nguyen L, Pasricha PJ, Snape WJ, Farrugia G, Koch KL, Calles J, Abell TL, McCallum RW, Lee L, Unalp-Arida A, Tonascia J, Hamilton F; National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol. 2011 Dec;9(12):1056-64; quiz e133-4. doi: 10.1016/j.cgh.2011.08.013. Epub 2011 Aug 24. — View Citation

Peachey JE, Lei H. Assessment of opioid dependence with naloxone. Br J Addict. 1988 Feb;83(2):193-201. — View Citation

Revicki DA, Camilleri M, Kuo B, Norton NJ, Murray L, Palsgrove A, Parkman HP. Development and content validity of a gastroparesis cardinal symptom index daily diary. Aliment Pharmacol Ther. 2009 Sep 15;30(6):670-80. doi: 10.1111/j.1365-2036.2009.04078.x. Epub 2009 Jun 25. — View Citation

Revicki DA, Rentz AM, Dubois D, Kahrilas P, Stanghellini V, Talley NJ, Tack J. Development and validation of a patient-assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom Index. Aliment Pharmacol Ther. 2003 Jul 1;18(1):141-50. — View Citation

Revicki DA, Rentz AM, Tack J, Stanghellini V, Talley NJ, Kahrilas P, De La Loge C, Trudeau E, Dubois D. Responsiveness and interpretation of a symptom severity index specific to upper gastrointestinal disorders. Clin Gastroenterol Hepatol. 2004 Sep;2(9):769-77. — View Citation

Szarka LA, Camilleri M, Vella A, Burton D, Baxter K, Simonson J, Zinsmeister AR. A stable isotope breath test with a standard meal for abnormal gastric emptying of solids in the clinic and in research. Clin Gastroenterol Hepatol. 2008 Jun;6(6):635-643.e1. doi: 10.1016/j.cgh.2008.01.009. Epub 2008 Apr 14. — View Citation

Tompkins DA, Bigelow GE, Harrison JA, Johnson RE, Fudala PJ, Strain EC. Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend. 2009 Nov 1;105(1-2):154-9. doi: 10.1016/j.drugalcdep.2009.07.001. Epub 2009 Aug 3. — View Citation

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* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Gastric Emptying (GE t-1/2)	Improvement in gastric emptying (GE t-1/2) compared to Placebo	4 week
Secondary	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
Secondary	Symptom Improvement using PAGI-SYM	Improvements of gastroparesis symptoms using PAGI-SYM	4 weeks
Secondary	Pain Management using the McGill Pain Inventory	Changes in pain control using the McGill Pain Inventory	4 weeks
Secondary	Overall improvement in Gastric Emptying (GE t-1/2)	Improvement in gastric emptying (GE t-1/2) compared to Placebo	8 week
Secondary	Quality of Life based on SF-36	QOL score changes based on SF-36	4 weeks