<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02998606</url>
  </required_header>
  <id_info>
    <org_study_id>23289</org_study_id>
    <nct_id>NCT02998606</nct_id>
  </id_info>
  <brief_title>Movantik for Opioid-Related Esophageal Disorders</brief_title>
  <official_title>Movantik for Opioid-Related Esophageal Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Temple University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Temple University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To date, few studies have assessed the effect of opioids on esophageal motility, mostly&#xD;
      assessed the effect of single-dose intravenous morphine on esophageal motility. Recently a&#xD;
      large retrospective study assessing the effect of opioids on esophageal motility found that&#xD;
      esophageal motor dysfunction are common in chronic opioid users whether studied on opioids&#xD;
      and off opioids. In addition, current opioid users also had significantly higher integrated&#xD;
      relaxation pressure and manometric patterns consistent with type III achalasia. (Ratuapli&#xD;
      2015) Peripherally acting mu opioid receptor antagonists (PAMORA) appear to be useful to&#xD;
      reduce the peripheral effects of mu opioid receptor agonists to delay gastrointestinal&#xD;
      transit without affecting the centrally mediated analgesic effects. MOVANTIK™ (Naloxegol) is&#xD;
      the first oral peripherally acting mu opioid receptor antagonists for opioid-induced&#xD;
      constipation. MOVANTIK™ (Naloxegol) has been recently approved for opioid-induced&#xD;
      constipation. Given orally, 25 mg daily it improves symptoms of constipation. At this dose,&#xD;
      MOVANTIK™ (Naloxegol) is effective and safe, with a limited side effect profile and is&#xD;
      associated with preservation of centrally mediated analgesia.&#xD;
&#xD;
      This study will explore the safety and tolerability of MOVANTIK™ (Naloxegol) in this patient&#xD;
      population.&#xD;
&#xD;
      The investigational hypothesis is that MOVANTIK™ (Naloxegol) could improve opioid- induced&#xD;
      esophageal motility disorders&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background MOVANTIK™ (Naloxegol) can alleviate the adverse effects associated with frequent&#xD;
      opiate use. The GI system is a common site for their unintended effects of opiate use, but&#xD;
      literature suggests that peripherally acting opioid agonist may provide relief in the&#xD;
      instance of GI dysfunction. (Holzer 2007) Toxicology and pharmacology summary&#xD;
&#xD;
      14 Phase I studies were completed with 439 health volunteers participating. MOVANTIK™&#xD;
      (Naloxegol) has been tested in a standard range of safety pharmacology studies including an&#xD;
      absorption, distribution, metabolism and excretion study, a QTc (corrected QT interval)&#xD;
      study, several PK (pharmacokinetic) studies, and a study to determine its central and&#xD;
      peripheral pharmacodynamics effects. MOVANTIK™ (Naloxegol) is metabolized primarily by&#xD;
      cytochrome P450 enzyme (CYP)-3A4 and CYP3A5 and is a substrate for a P-glycoprotein&#xD;
      transporter. Drug-drug interaction studies were performed for a strong and a moderate CYP3A4&#xD;
      inhibitor, a CYP3A5 inhibitor and P-glycoprotein transporter inhibitor.&#xD;
&#xD;
      Clinical Safety summary MOVANTIK™ (Naloxegol) was initially tested in 439 healthy volunteers&#xD;
      across 14 Phase I studies. Ascending-dosing studies were performed with first dose ranging&#xD;
      from 8-1000 mg, followed by twice daily dosing ranging from 25-250 mg, all administered&#xD;
      intravenously. Another ascending dose study was completed in older volunteers (age 65 and&#xD;
      older) in Japan to determine the effects of advanced age on PK values. Phase IIb and II&#xD;
      studies exposed 1497 patients to dosages ranging from 5 mg to 50 mg for periods of time&#xD;
      varying from 24 to 52 weeks. MOVANTIK™ (Naloxegol) has shown acceptable safety profile and&#xD;
      was well-tolerated at 5 mg and 25 mg. The 50 mg cohort had shown increased frequency of GI&#xD;
      adverse events (abdominal pain, nausea and diarrhea) when compared to the 25 mg and 5 mg&#xD;
      cohorts. The 25 mg dose was the maximum used across the 5 phase III studies. Two 12 week&#xD;
      placebo-controlled double-blind studies were completed to confirm safety and efficacy, as&#xD;
      well as a 12 week double-blind safety extension, a randomized 52-week open-label parallel&#xD;
      group, long-term safety study and a placebo-controlled, double-blind study in patients with&#xD;
      cancer-related pain. The efficacy studies demonstrated the therapeutic effect of MOVANTIK™&#xD;
      (Naloxegol) was independent of age, gender, race, body mass index, region, use of&#xD;
      anticholinergics, response to previous laxative use, type of opioid, or dose of opioid. Phase&#xD;
      III studies demonstrated that MOVANTIK™ (Naloxegol) is generally safe and well tolerated at&#xD;
      doses up to 25 mg once daily in patients with OIC (opioid-induced constipation) up to 52&#xD;
      weeks of treatment.&#xD;
&#xD;
      Acute and chronic use of opioids is associated with a variety of adverse effects on the&#xD;
      gastrointestinal tract. The effect of opioids on gastric, small bowel, and colonic motility&#xD;
      has been well characterized. The main esophageal abnormalities seen were impaired LES (lower&#xD;
      esophageal sphincter) relaxation. Recently a large retrospective study assessing the effect&#xD;
      of opioids on esophageal motility using, for the first time, HREM and the Chicago&#xD;
      classification of esophageal motility disorders v3.0 found that Esophageal motor dysfunction&#xD;
      are common in chronic opioid users whether studied on opioids and off opioids. (K raichely&#xD;
      2010) However, opioid use within 24 h of manometry was associated with increased EGJ (&#xD;
      Esophagogastric junction) outflow obstruction and other spastic esophageal motor&#xD;
      abnormalities. In addition, current opioid users also had significantly higher integrated&#xD;
      relaxation pressure and manometric patterns consistent with type III achalasia.&#xD;
&#xD;
      Benefit/risk and ethical assessment Preliminary data suggests a relationship between opioid&#xD;
      use and esophageal dysfunction. The decline in quality of life associated with esophageal&#xD;
      disorders may discourage patients from taking opioids, subjecting them to unwarranted pain.&#xD;
      MOVANTIK™ (Naloxegol) is an opioid antagonist specifically designed to work outside of the&#xD;
      central nervous system. This allows relief from undesired peripheral effects of opioids&#xD;
      without disrupting analgesic effects. The use of MOVANTIK™ (Naloxegol) has the potential to&#xD;
      mediate esophageal dysfunction while preserving vital pain relief.&#xD;
&#xD;
      Patients for whom MOVANTIK™ (Naloxegol) is contraindicated will be excluded as well as those&#xD;
      taking strong CYP3A4 inhibitors or strong CYP3A4 inducers and other opioid antagonists. In&#xD;
      the Phase III studies, adverse events of abdominal pain (21% v 7%), diarrhea (9% v 5%),&#xD;
      nausea (8% v 5%), flatulence (6% v 3%), vomiting (5% v 4%), headache (4% v 3%), and&#xD;
      hyperhidrosis (3% v &lt;1%) were observed at greater rates among the 25 mg cohort when compared&#xD;
      to placebo.. The current study is designed to explore the potential benefit or effect of&#xD;
      Naloxegol on upper GI motility and clinical symptoms inpatients receiving opioid&#xD;
&#xD;
      Study design This is a single center, randomized, placebo-controlled, double-blind study to&#xD;
      determine the effect of MOVANTIK™ (Naloxegol) on opioid-related esophageal motility&#xD;
      disorders.&#xD;
&#xD;
      This study consists of 2 week screening period, a 4 week treatment period and a 2 week&#xD;
      follow-up period. Eligible patients will be placed in either a study group or a control&#xD;
      group, with 15 patients in each study arm. Patients will receive a High Resonance Esophageal&#xD;
      Manometry (HREM) at Visits 2 and 3.&#xD;
&#xD;
      Visit one (Day -14) Patients will be seen and informed consent will be obtained. Inclusion&#xD;
      and exclusion criteria will be review to determine eligibility.&#xD;
&#xD;
      At visit 1 the following procedures will be performed:&#xD;
&#xD;
        -  Obtain demographic, endoscopic, clinical, and prior manometric data to determine&#xD;
           eligibility&#xD;
&#xD;
        -  Review medication history&#xD;
&#xD;
        -  Physical Examination&#xD;
&#xD;
        -  Obtain Weight and Height&#xD;
&#xD;
        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)&#xD;
&#xD;
        -  Collect blood sample for Serum Pregnancy Test1&#xD;
&#xD;
        -  Patients complete the following questionnaires&#xD;
&#xD;
           o Patient Assessment of GI Symptoms (PAGI-SYM)&#xD;
&#xD;
        -  Patients will be given a daily diary to complete throughout the next two weeks.&#xD;
&#xD;
      Visit two (Day 0 ± 3 days) Patients will return to clinic after fasting2, except for&#xD;
      medications with water in the morning, and will undergo a HREM. Review the daily diary,&#xD;
      manometric and the inclusion/exclusion criteria to determine eligibility. The following&#xD;
      procedures will occur before the patient receives study drug. After the procedure, patients&#xD;
      will be started on the study drug (Movantik 25 mg) or Placebo daily on a random double blind&#xD;
      basis.&#xD;
&#xD;
      At visit 2 the following procedures will be performed:&#xD;
&#xD;
        -  Review and record adverse event which have occurred from the signing of the ICF&#xD;
           (informed consent form) to Visit 2&#xD;
&#xD;
        -  Review concomitant medications and Daily diary&#xD;
&#xD;
        -  Obtain Weight and Height&#xD;
&#xD;
        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)&#xD;
&#xD;
        -  Patients complete the following questionnaires&#xD;
&#xD;
             -  Patient Assessment of GI Symptoms (PAGI-SYM)&#xD;
&#xD;
             -  Lower GI symptoms questionnaire&#xD;
&#xD;
             -  McGill Pain inventory&#xD;
&#xD;
             -  SF-36&#xD;
&#xD;
             -  Chest pain symptom questionnaire&#xD;
&#xD;
             -  GERD (gastroesophageal reflux disease) symptom check list&#xD;
&#xD;
        -  Patients will undergo a HREM&#xD;
&#xD;
        -  Obtain study number, randomize patients and dispense investigational product.&#xD;
&#xD;
      Visit Three (Day 2± 3 days) Patients will receive a phone call to assess their initial&#xD;
      response to treatment two days after they start the study drug and better assess the safety&#xD;
      of the drug.&#xD;
&#xD;
      During Visit 3the following procedures will be performed:&#xD;
&#xD;
        -  Review and record adverse event which have occurred from the signing of the ICF to Visit&#xD;
           3&#xD;
&#xD;
        -  Review concomitant medications&#xD;
&#xD;
      Visit four (Day 28 ± 3 days)&#xD;
&#xD;
        -  Review and record adverse event which have occurred from Visit 3 to Visit 4&#xD;
&#xD;
        -  Review concomitant medications and Daily diary&#xD;
&#xD;
        -  Obtain Weight and Height&#xD;
&#xD;
        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)&#xD;
&#xD;
        -  Patients complete the following questionnaires&#xD;
&#xD;
             -  Patient Assessment of GI Symptoms (PAGI-SYM)&#xD;
&#xD;
             -  Lower GI symptoms questionnaire&#xD;
&#xD;
             -  McGill Pain inventory&#xD;
&#xD;
             -  SF-36&#xD;
&#xD;
             -  Chest pain symptom questionnaire&#xD;
&#xD;
             -  GERD symptom check list&#xD;
&#xD;
        -  Patients will undergo a HREM2 (High Resonance Esophageal Manometry)&#xD;
&#xD;
        -  Perform investigational product accountability.&#xD;
&#xD;
      Visit five (Day 42 ± 7 days) Patients will be seen to ensure collection of the daily diaries&#xD;
      and for a final safety assessment&#xD;
&#xD;
        -  Review and record adverse event which have occurred from Visit 4 to Visit 5 and further&#xD;
           detail any adverse event that have occurred throughout the study&#xD;
&#xD;
        -  Review concomitant medications and return daily diary&#xD;
&#xD;
        -  Obtain Weight and Height&#xD;
&#xD;
        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)&#xD;
&#xD;
      Early Withdrawal/Early Termination&#xD;
&#xD;
      Patients who withdraw early will be encouraged to complete their Visit 3 requirements:&#xD;
&#xD;
        -  Review and record adverse event which have occurred from Visit 2 to withdrawal&#xD;
           (termination) date&#xD;
&#xD;
        -  Review concomitant medications and Daily diary&#xD;
&#xD;
        -  Obtain Weight and Height&#xD;
&#xD;
        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)&#xD;
&#xD;
        -  Patients complete the following questionnaires&#xD;
&#xD;
             -  Patient Assessment of GI Symptoms (PAGI-SYM)&#xD;
&#xD;
             -  Lower GI symptoms questionnaire&#xD;
&#xD;
             -  McGill Pain inventory&#xD;
&#xD;
             -  SF-36&#xD;
&#xD;
             -  Chest pain symptom questionnaire&#xD;
&#xD;
             -  GERD symptom check list&#xD;
&#xD;
        -  Perform investigational product accountability&#xD;
&#xD;
      Rationale for study design, doses and control groups This study seeks to determine the&#xD;
      effectiveness of MOVANTIK™ (Naloxegol) in treating patients with opioid-induced esophageal&#xD;
      disorders. MOVANTIK™ (Naloxegol) has already been shown to be effective in other opioid&#xD;
      induced gastric disorders. To the Investigator's knowledge there has been no double-blind&#xD;
      randomized control trial evaluating the effects of MOVANTIK™ (Naloxegol) on opioid&#xD;
      induced-esophageal disorders. The same dosage that has been proven effective in other patient&#xD;
      populations will be used. The use of a control group eliminates potential bias in the&#xD;
      patient-reported outcome endpoints. The enrollment goal is 50 patients for this study. A&#xD;
      recent study showed all 15 enrolled patients showed signs of opioid-induced motility&#xD;
      abnormalities on HREM. (Kraichely 2010) Relatively large effects can be expected in this&#xD;
      sample size. Using G* power 3 will ensure that that a sample size of 42 patients will give&#xD;
      provide a 95% chance of detecting a large effect size (defined as 0.80 population s.d.&#xD;
      between groups) between the two groups as significant at the 5% level (two tailed) using t&#xD;
      -test between means. Enrolling 50 patients ensures an adequate amount of patients complete&#xD;
      the course of treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Investigator left Institution&#xD;
  </why_stopped>
  <start_date>January 2017</start_date>
  <completion_date type="Actual">October 2018</completion_date>
  <primary_completion_date type="Actual">October 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Manometric improvement in IRP (Integrated Relaxation Pressure)</measure>
    <time_frame>28 days</time_frame>
    <description>The effect of MOVANTIK™ (Naloxegol) on motor function, categorized as a 25% (mmHg) improvement in IRP (Integrated Relaxation Pressure) on high resolution esophageal manometry from baseline to visit three, comparing study group to placebo control group.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Symptom Management</measure>
    <time_frame>28 days</time_frame>
    <description>Mean change from baseline to visit three in subject esophageal symptom scores according to the PAGI-SYM.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Management</measure>
    <time_frame>28 days</time_frame>
    <description>Mean change from baseline to visit three in subject esophageal symptom scores according to the McGill pain inventory.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>GERD Symptom Management</measure>
    <time_frame>28 days</time_frame>
    <description>Mean change from baseline to visit three in subject esophageal symptom scores according to the GERD symptom check list.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chest Pain Management</measure>
    <time_frame>28 days</time_frame>
    <description>Mean change from baseline to visit three in subject esophageal symptom scores according to the chest pain symptom questionnaire.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily Symptom Management</measure>
    <time_frame>28 days</time_frame>
    <description>Mean change from baseline to visit three in subject esophageal symptom scores according to the daily diary</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability</measure>
    <time_frame>42 days</time_frame>
    <description>The occurrence of adverse events and early withdrawal in study group when compared to placebo control group to determine safety and tolerability.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life</measure>
    <time_frame>28 days</time_frame>
    <description>Mean change in patient-reported quality of life according to the SF-36</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Opioid-Induced Disorders</condition>
  <condition>Esophagus Disorder</condition>
  <arm_group>
    <arm_group_label>Study Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>MOVANTIK™ (Naloxegol) 25 mg oral capsule, daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo Oral Capsule 25 mg, daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naloxegol</intervention_name>
    <description>MOVANTIK™ 25 mg, daily</description>
    <arm_group_label>Study Group</arm_group_label>
    <other_name>Movantik</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Capsule</intervention_name>
    <description>Placebo 25 mg, daily</description>
    <arm_group_label>Control Group</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
          2. Age 18-85, Males and Females&#xD;
&#xD;
          3. On a stable daily opioid dose for various indications for at least 4 weeks prior to&#xD;
             the HREM (High Resonance Esophageal Manometry&#xD;
&#xD;
          4. Symptoms of odynophagia, dysphagia, or chest pain based on symptoms recorded on the&#xD;
             PAGI-SYM&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Renal impairment (cct&lt;60) or severe Hepatic impairment as defined by the Child-Pugh&#xD;
             Classification (Appendix J)&#xD;
&#xD;
          2. Concomitant use of strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers,&#xD;
             NSAIDS, Plavix/Clopidogrel and other opioid antagonists&#xD;
&#xD;
          3. History of GI obstruction, bowel perforation, or with potential for either based on&#xD;
             investigator's clinical judgment&#xD;
&#xD;
          4. Subjects with known Barrett's esophagus or peptic stricture on endoscopy&#xD;
&#xD;
          5. Subjects with previous upper gastrointestinal surgery&#xD;
&#xD;
          6. Pregnant, plan to be pregnant, or are breastfeeding&#xD;
&#xD;
          7. Women of childbearing potential who are unwilling to use contraceptives throughout the&#xD;
             course of treatment&#xD;
&#xD;
          8. Subjects with serious co-morbidities (Cardiovascular, respiratory, renal, hepatic,&#xD;
             hematologic, endocrine, neurologic) which may prevent the patient to participate in&#xD;
             the study based on PI's clinical judgment or malignancy&#xD;
&#xD;
          9. Patients with an increased risk of gastrointestinal perforation due to conditions that&#xD;
             may be associated with localized or diffuse reduction of structural integrity in the&#xD;
             wall of the gastrointestinal tract (e.g. peptic ulcer disease, Ogilvie's syndrome,&#xD;
             diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal&#xD;
             metastases).&#xD;
&#xD;
         10. Subjects with upper airway symptoms (such as hoarseness, wheezing or laryngospasm)&#xD;
&#xD;
         11. Patients taking baclofen or sucralfate and those unwilling to discontinue prohibited&#xD;
             medications.&#xD;
&#xD;
         12. Known history of substance abuse&#xD;
&#xD;
         13. Subject unable to consent or is unwilling to provide informed consent&#xD;
&#xD;
         14. History of major comorbid psychiatric conditions including mania and schizophrenia or&#xD;
             severe current depression&#xD;
&#xD;
         15. At-risk populations, including prisoners and mentally challenged. Any condition or is&#xD;
             in a situation which may put him/her at significant risk, may confound the study&#xD;
             results, or may interfere significantly with the subject's participation in the study&#xD;
             (e.g., difficulty hearing, cognitive impairment)&#xD;
&#xD;
         16. Known allergy to MOVANTIK™ (Naloxegol)&#xD;
&#xD;
         17. Patients with a history of cancer within past 5 years prior to the screening visit&#xD;
&#xD;
         18. Patients with a medical condition which may disrupt the blood-brain barrier&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ron Schey, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Temple University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Temple University</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19140</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Holzer P. Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs. 2007 Feb;16(2):181-94. doi: 10.1517/13543784.16.2.181.</citation>
    <PMID>17243938</PMID>
  </reference>
  <reference>
    <citation>Ratuapli SK, Crowell MD, DiBaise JK, Vela MF, Ramirez FC, Burdick GE, Lacy BE, Murray JA. Opioid-Induced Esophageal Dysfunction (OIED) in Patients on Chronic Opioids. Am J Gastroenterol. 2015 Jul;110(7):979-84. doi: 10.1038/ajg.2015.154. Epub 2015 Jun 2.</citation>
    <PMID>26032150</PMID>
  </reference>
  <reference>
    <citation>Mittal RK, Frank EB, Lange RC, McCallum RW. Effects of morphine and naloxone on esophageal motility and gastric emptying in man. Dig Dis Sci. 1986 Sep;31(9):936-42. doi: 10.1007/BF01303214.</citation>
    <PMID>3731985</PMID>
  </reference>
  <reference>
    <citation>Penagini R, Bartesaghi B, Zannini P, Negri G, Bianchi PA. Lower oesophageal sphincter hypersensitivity to opioid receptor stimulation in patients with idiopathic achalasia. Gut. 1993 Jan;34(1):16-20. doi: 10.1136/gut.34.1.16.</citation>
    <PMID>8381758</PMID>
  </reference>
  <reference>
    <citation>Penagini R, Picone A, Bianchi PA. Effect of morphine and naloxone on motor response of the human esophagus to swallowing and distension. Am J Physiol. 1996 Oct;271(4 Pt 1):G675-80. doi: 10.1152/ajpgi.1996.271.4.G675.</citation>
    <PMID>8897888</PMID>
  </reference>
  <reference>
    <citation>Dowlatshahi K, Evander A, Walther B, Skinner DB. Influence of morphine on the distal oesophagus and the lower oesophageal sphincter--a manometric study. Gut. 1985 Aug;26(8):802-6. doi: 10.1136/gut.26.8.802.</citation>
    <PMID>4018646</PMID>
  </reference>
  <reference>
    <citation>Penagini R, Bianchi PA. Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation. Gastroenterology. 1997 Aug;113(2):409-14. doi: 10.1053/gast.1997.v113.pm9247457.</citation>
    <PMID>9247457</PMID>
  </reference>
  <reference>
    <citation>Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009 Nov;41(4):1149-60. doi: 10.3758/BRM.41.4.1149.</citation>
    <PMID>19897823</PMID>
  </reference>
  <reference>
    <citation>Kraichely RE, Arora AS, Murray JA. Opiate-induced oesophageal dysmotility. Aliment Pharmacol Ther. 2010 Mar;31(5):601-6. doi: 10.1111/j.1365-2036.2009.04212.x. Epub 2009 Dec 8.</citation>
    <PMID>20003176</PMID>
  </reference>
  <reference>
    <citation>Conklin JL. Evaluation of Esophageal Motor Function With High-resolution Manometry. J Neurogastroenterol Motil. 2013 Jul;19(3):281-94. doi: 10.5056/jnm.2013.19.3.281. Epub 2013 Jul 8.</citation>
    <PMID>23875094</PMID>
  </reference>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>December 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>December 20, 2018</last_update_submitted>
  <last_update_submitted_qc>December 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 24, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Esophageal Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naloxegol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02998606
org study id: 23289
nct id: NCT02998606
lead sponsor: 
collaborator: 
has dmc: No
To date, few studies have assessed the effect of opioids on esophageal motility, mostly
      assessed the effect of single-dose intravenous morphine on esophageal motility. Recently a
      large retrospective study assessing the effect of opioids on esophageal motility found that
      esophageal motor dysfunction are common in chronic opioid users whether studied on opioids
      and off opioids. In addition, current opioid users also had significantly higher integrated
      relaxation pressure and manometric patterns consistent with type III achalasia. (Ratuapli
      2015) Peripherally acting mu opioid receptor antagonists (PAMORA) appear to be useful to
      reduce the peripheral effects of mu opioid receptor agonists to delay gastrointestinal
      transit without affecting the centrally mediated analgesic effects. MOVANTIK™ (Naloxegol) is
      the first oral peripherally acting mu opioid receptor antagonists for opioid-induced
      constipation. MOVANTIK™ (Naloxegol) has been recently approved for opioid-induced
      constipation. Given orally, 25 mg daily it improves symptoms of constipation. At this dose,
      MOVANTIK™ (Naloxegol) is effective and safe, with a limited side effect profile and is
      associated with preservation of centrally mediated analgesia.

      This study will explore the safety and tolerability of MOVANTIK™ (Naloxegol) in this patient
      population.

      The investigational hypothesis is that MOVANTIK™ (Naloxegol) could improve opioid- induced
      esophageal motility disorders
Background MOVANTIK™ (Naloxegol) can alleviate the adverse effects associated with frequent
      opiate use. The GI system is a common site for their unintended effects of opiate use, but
      literature suggests that peripherally acting opioid agonist may provide relief in the
      instance of GI dysfunction. (Holzer 2007) Toxicology and pharmacology summary

      14 Phase I studies were completed with 439 health volunteers participating. MOVANTIK™
      (Naloxegol) has been tested in a standard range of safety pharmacology studies including an
      absorption, distribution, metabolism and excretion study, a QTc (corrected QT interval)
      study, several PK (pharmacokinetic) studies, and a study to determine its central and
      peripheral pharmacodynamics effects. MOVANTIK™ (Naloxegol) is metabolized primarily by
      cytochrome P450 enzyme (CYP)-3A4 and CYP3A5 and is a substrate for a P-glycoprotein
      transporter. Drug-drug interaction studies were performed for a strong and a moderate CYP3A4
      inhibitor, a CYP3A5 inhibitor and P-glycoprotein transporter inhibitor.

      Clinical Safety summary MOVANTIK™ (Naloxegol) was initially tested in 439 healthy volunteers
      across 14 Phase I studies. Ascending-dosing studies were performed with first dose ranging
      from 8-1000 mg, followed by twice daily dosing ranging from 25-250 mg, all administered
      intravenously. Another ascending dose study was completed in older volunteers (age 65 and
      older) in Japan to determine the effects of advanced age on PK values. Phase IIb and II
      studies exposed 1497 patients to dosages ranging from 5 mg to 50 mg for periods of time
      varying from 24 to 52 weeks. MOVANTIK™ (Naloxegol) has shown acceptable safety profile and
      was well-tolerated at 5 mg and 25 mg. The 50 mg cohort had shown increased frequency of GI
      adverse events (abdominal pain, nausea and diarrhea) when compared to the 25 mg and 5 mg
      cohorts. The 25 mg dose was the maximum used across the 5 phase III studies. Two 12 week
      placebo-controlled double-blind studies were completed to confirm safety and efficacy, as
      well as a 12 week double-blind safety extension, a randomized 52-week open-label parallel
      group, long-term safety study and a placebo-controlled, double-blind study in patients with
      cancer-related pain. The efficacy studies demonstrated the therapeutic effect of MOVANTIK™
      (Naloxegol) was independent of age, gender, race, body mass index, region, use of
      anticholinergics, response to previous laxative use, type of opioid, or dose of opioid. Phase
      III studies demonstrated that MOVANTIK™ (Naloxegol) is generally safe and well tolerated at
      doses up to 25 mg once daily in patients with OIC (opioid-induced constipation) up to 52
      weeks of treatment.

      Acute and chronic use of opioids is associated with a variety of adverse effects on the
      gastrointestinal tract. The effect of opioids on gastric, small bowel, and colonic motility
      has been well characterized. The main esophageal abnormalities seen were impaired LES (lower
      esophageal sphincter) relaxation. Recently a large retrospective study assessing the effect
      of opioids on esophageal motility using, for the first time, HREM and the Chicago
      classification of esophageal motility disorders v3.0 found that Esophageal motor dysfunction
      are common in chronic opioid users whether studied on opioids and off opioids. (K raichely
      2010) However, opioid use within 24 h of manometry was associated with increased EGJ (
      Esophagogastric junction) outflow obstruction and other spastic esophageal motor
      abnormalities. In addition, current opioid users also had significantly higher integrated
      relaxation pressure and manometric patterns consistent with type III achalasia.

      Benefit/risk and ethical assessment Preliminary data suggests a relationship between opioid
      use and esophageal dysfunction. The decline in quality of life associated with esophageal
      disorders may discourage patients from taking opioids, subjecting them to unwarranted pain.
      MOVANTIK™ (Naloxegol) is an opioid antagonist specifically designed to work outside of the
      central nervous system. This allows relief from undesired peripheral effects of opioids
      without disrupting analgesic effects. The use of MOVANTIK™ (Naloxegol) has the potential to
      mediate esophageal dysfunction while preserving vital pain relief.

      Patients for whom MOVANTIK™ (Naloxegol) is contraindicated will be excluded as well as those
      taking strong CYP3A4 inhibitors or strong CYP3A4 inducers and other opioid antagonists. In
      the Phase III studies, adverse events of abdominal pain (21% v 7%), diarrhea (9% v 5%),
      nausea (8% v 5%), flatulence (6% v 3%), vomiting (5% v 4%), headache (4% v 3%), and
      hyperhidrosis (3% v <1%) were observed at greater rates among the 25 mg cohort when compared
      to placebo.. The current study is designed to explore the potential benefit or effect of
      Naloxegol on upper GI motility and clinical symptoms inpatients receiving opioid

      Study design This is a single center, randomized, placebo-controlled, double-blind study to
      determine the effect of MOVANTIK™ (Naloxegol) on opioid-related esophageal motility
      disorders.

      This study consists of 2 week screening period, a 4 week treatment period and a 2 week
      follow-up period. Eligible patients will be placed in either a study group or a control
      group, with 15 patients in each study arm. Patients will receive a High Resonance Esophageal
      Manometry (HREM) at Visits 2 and 3.

      Visit one (Day -14) Patients will be seen and informed consent will be obtained. Inclusion
      and exclusion criteria will be review to determine eligibility.

      At visit 1 the following procedures will be performed:

        -  Obtain demographic, endoscopic, clinical, and prior manometric data to determine
           eligibility

        -  Review medication history

        -  Physical Examination

        -  Obtain Weight and Height

        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

        -  Collect blood sample for Serum Pregnancy Test1

        -  Patients complete the following questionnaires

           o Patient Assessment of GI Symptoms (PAGI-SYM)

        -  Patients will be given a daily diary to complete throughout the next two weeks.

      Visit two (Day 0 ± 3 days) Patients will return to clinic after fasting2, except for
      medications with water in the morning, and will undergo a HREM. Review the daily diary,
      manometric and the inclusion/exclusion criteria to determine eligibility. The following
      procedures will occur before the patient receives study drug. After the procedure, patients
      will be started on the study drug (Movantik 25 mg) or Placebo daily on a random double blind
      basis.

      At visit 2 the following procedures will be performed:

        -  Review and record adverse event which have occurred from the signing of the ICF
           (informed consent form) to Visit 2

        -  Review concomitant medications and Daily diary

        -  Obtain Weight and Height

        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

        -  Patients complete the following questionnaires

             -  Patient Assessment of GI Symptoms (PAGI-SYM)

             -  Lower GI symptoms questionnaire

             -  McGill Pain inventory

             -  SF-36

             -  Chest pain symptom questionnaire

             -  GERD (gastroesophageal reflux disease) symptom check list

        -  Patients will undergo a HREM

        -  Obtain study number, randomize patients and dispense investigational product.

      Visit Three (Day 2± 3 days) Patients will receive a phone call to assess their initial
      response to treatment two days after they start the study drug and better assess the safety
      of the drug.

      During Visit 3the following procedures will be performed:

        -  Review and record adverse event which have occurred from the signing of the ICF to Visit
           3

        -  Review concomitant medications

      Visit four (Day 28 ± 3 days)

        -  Review and record adverse event which have occurred from Visit 3 to Visit 4

        -  Review concomitant medications and Daily diary

        -  Obtain Weight and Height

        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

        -  Patients complete the following questionnaires

             -  Patient Assessment of GI Symptoms (PAGI-SYM)

             -  Lower GI symptoms questionnaire

             -  McGill Pain inventory

             -  SF-36

             -  Chest pain symptom questionnaire

             -  GERD symptom check list

        -  Patients will undergo a HREM2 (High Resonance Esophageal Manometry)

        -  Perform investigational product accountability.

      Visit five (Day 42 ± 7 days) Patients will be seen to ensure collection of the daily diaries
      and for a final safety assessment

        -  Review and record adverse event which have occurred from Visit 4 to Visit 5 and further
           detail any adverse event that have occurred throughout the study

        -  Review concomitant medications and return daily diary

        -  Obtain Weight and Height

        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

      Early Withdrawal/Early Termination

      Patients who withdraw early will be encouraged to complete their Visit 3 requirements:

        -  Review and record adverse event which have occurred from Visit 2 to withdrawal
           (termination) date

        -  Review concomitant medications and Daily diary

        -  Obtain Weight and Height

        -  Obtain Seated Vital Signs (Includes Oral temperature, Pulse, BP and respiratory rate)

        -  Patients complete the following questionnaires

             -  Patient Assessment of GI Symptoms (PAGI-SYM)

             -  Lower GI symptoms questionnaire

             -  McGill Pain inventory

             -  SF-36

             -  Chest pain symptom questionnaire

             -  GERD symptom check list

        -  Perform investigational product accountability

      Rationale for study design, doses and control groups This study seeks to determine the
      effectiveness of MOVANTIK™ (Naloxegol) in treating patients with opioid-induced esophageal
      disorders. MOVANTIK™ (Naloxegol) has already been shown to be effective in other opioid
      induced gastric disorders. To the Investigator's knowledge there has been no double-blind
      randomized control trial evaluating the effects of MOVANTIK™ (Naloxegol) on opioid
      induced-esophageal disorders. The same dosage that has been proven effective in other patient
      populations will be used. The use of a control group eliminates potential bias in the
      patient-reported outcome endpoints. The enrollment goal is 50 patients for this study. A
      recent study showed all 15 enrolled patients showed signs of opioid-induced motility
      abnormalities on HREM. (Kraichely 2010) Relatively large effects can be expected in this
      sample size. Using G* power 3 will ensure that that a sample size of 42 patients will give
      provide a 95% chance of detecting a large effect size (defined as 0.80 population s.d.
      between groups) between the two groups as significant at the 5% level (two tailed) using t
      -test between means. Enrolling 50 patients ensures an adequate amount of patients complete
      the course of treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Manometric improvement in IRP (Integrated Relaxation Pressure)
time frame: 28 days
description: The effect of MOVANTIK™ (Naloxegol) on motor function, categorized as a 25% (mmHg) improvement in IRP (Integrated Relaxation Pressure) on high resolution esophageal manometry from baseline to visit three, comparing study group to placebo control group.
measure: Overall Symptom Management
time frame: 28 days
description: Mean change from baseline to visit three in subject esophageal symptom scores according to the PAGI-SYM.
measure: Pain Management
time frame: 28 days
description: Mean change from baseline to visit three in subject esophageal symptom scores according to the McGill pain inventory.
measure: GERD Symptom Management
time frame: 28 days
description: Mean change from baseline to visit three in subject esophageal symptom scores according to the GERD symptom check list.
measure: Chest Pain Management
time frame: 28 days
description: Mean change from baseline to visit three in subject esophageal symptom scores according to the chest pain symptom questionnaire.
measure: Daily Symptom Management
time frame: 28 days
description: Mean change from baseline to visit three in subject esophageal symptom scores according to the daily diary
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability
time frame: 42 days
description: The occurrence of adverse events and early withdrawal in study group when compared to placebo control group to determine safety and tolerability.
measure: Quality of Life
time frame: 28 days
description: Mean change in patient-reported quality of life according to the SF-36
arm group label: Study Group
arm group type: Experimental
description: MOVANTIK™ (Naloxegol) 25 mg oral capsule, daily
arm group label: Control Group
arm group type: Placebo Comparator
description: Placebo Oral Capsule 25 mg, daily
intervention type: Drug
intervention name: Naloxegol
description: MOVANTIK™ 25 mg, daily
arm group label: Study Group
other name: Movantik
intervention type: Drug
intervention name: Placebo Oral Capsule
description: Placebo 25 mg, daily
arm group label: Control Group
other name: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Ron Schey, MD
role: Principal Investigator
affiliation: Temple University
facility: 
country: United States
citation: Holzer P. Treatment of opioid-induced gut dysfunction. Expert Opin Investig Drugs. 2007 Feb;16(2):181-94. doi: 10.1517/13543784.16.2.181.
PMID: 17243938
citation: Ratuapli SK, Crowell MD, DiBaise JK, Vela MF, Ramirez FC, Burdick GE, Lacy BE, Murray JA. Opioid-Induced Esophageal Dysfunction (OIED) in Patients on Chronic Opioids. Am J Gastroenterol. 2015 Jul;110(7):979-84. doi: 10.1038/ajg.2015.154. Epub 2015 Jun 2.
PMID: 26032150
citation: Mittal RK, Frank EB, Lange RC, McCallum RW. Effects of morphine and naloxone on esophageal motility and gastric emptying in man. Dig Dis Sci. 1986 Sep;31(9):936-42. doi: 10.1007/BF01303214.
PMID: 3731985
citation: Penagini R, Bartesaghi B, Zannini P, Negri G, Bianchi PA. Lower oesophageal sphincter hypersensitivity to opioid receptor stimulation in patients with idiopathic achalasia. Gut. 1993 Jan;34(1):16-20. doi: 10.1136/gut.34.1.16.
PMID: 8381758
citation: Penagini R, Picone A, Bianchi PA. Effect of morphine and naloxone on motor response of the human esophagus to swallowing and distension. Am J Physiol. 1996 Oct;271(4 Pt 1):G675-80. doi: 10.1152/ajpgi.1996.271.4.G675.
PMID: 8897888
citation: Dowlatshahi K, Evander A, Walther B, Skinner DB. Influence of morphine on the distal oesophagus and the lower oesophageal sphincter--a manometric study. Gut. 1985 Aug;26(8):802-6. doi: 10.1136/gut.26.8.802.
PMID: 4018646
citation: Penagini R, Bianchi PA. Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation. Gastroenterology. 1997 Aug;113(2):409-14. doi: 10.1053/gast.1997.v113.pm9247457.
PMID: 9247457
citation: Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009 Nov;41(4):1149-60. doi: 10.3758/BRM.41.4.1149.
PMID: 19897823
citation: Kraichely RE, Arora AS, Murray JA. Opiate-induced oesophageal dysmotility. Aliment Pharmacol Ther. 2010 Mar;31(5):601-6. doi: 10.1111/j.1365-2036.2009.04212.x. Epub 2009 Dec 8.
PMID: 20003176
citation: Conklin JL. Evaluation of Esophageal Motor Function With High-resolution Manometry. J Neurogastroenterol Motil. 2013 Jul;19(3):281-94. doi: 10.5056/jnm.2013.19.3.281. Epub 2013 Jul 8.
PMID: 23875094
responsible party type: Sponsor
mesh term: Esophageal Diseases
mesh term: Naloxegol
sharing ipd: No