<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/NCT02194764</url>
  </required_header>
  <id_info>
    <org_study_id>2012115600086371</org_study_id>
    <secondary_id>1R43DA028740-01A1</secondary_id>
    <nct_id>NCT02194764</nct_id>
  </id_info>
  <brief_title>An Adherence Tool to Manage Narcotic -Addicted HIV Patients</brief_title>
  <official_title>A Breath-based Naltrexone Adherence Tool to Manage Narcotic-addicted HIV Patients.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Xhale Assurance</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Xhale Assurance</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to develop a cost-effective breath-based medication adherence&#xD;
      monitoring system that can monitor whether recovering opiate addicts actually take a specific&#xD;
      treatment medication called naltrexone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will have two parts. In the first part we will create eight SMART capsule-based&#xD;
      naltrexone systems using 4 general types of pharma formulation strategies. Model naltrexone&#xD;
      (50mg) formulations containing the GRAS taggant, 2-butanol (40 or 80 mg) will be prepared and&#xD;
      preliminary stability studies executed. Type 1 is a hydrophobic system, Type 2 is a&#xD;
      hydrophilic system, Type 3 is a reverse micelle system and Type 4 is a water-in-oil&#xD;
      microemulsion system. All formulations will be prepared using USP-grade excipients,&#xD;
      2-butanol, naltrexone base and naltrexone HCl. Naltrexone HCl has significant water&#xD;
      solubility and will be used in the preparation of formulation types 2 and 4, whereas the more&#xD;
      lipid soluble free base of naltrexone will be used in formulation types 1 and 3.&#xD;
      Manufacturer's specifications supplied by Capsugel will be used to determine compatibility&#xD;
      between the capsule material and the proposed excipients, and will guide capsule selection&#xD;
      (gelatin or HPMC).Prepared formulations will be characterized by particle size analysis and&#xD;
      analyzed to determine the actual concentrations of naltrexone and 2-butanol. Particle sizing&#xD;
      will be accomplished by dynamic light scattering using a 90Plus particle size analyzer. With&#xD;
      formulation types 1 and 2, the technique will demonstrate the homogeneity of the mixture and&#xD;
      the absence of particulates. With types 3 and 4, particle size distributions will be measured&#xD;
      to confirm the presence of monodisperse reverse micelles or nanoscale droplets. The&#xD;
      concentration of naltrexone in each final formulation will be verified by Liquid&#xD;
      chromatography-mass spectrometry (LC-MS) and /or Ultra Performance Liquid Chromatography&#xD;
      (UPLC). The concentration of 2-butanol will be determined by gas chromatography-Mass&#xD;
      Spectrometry (GC-MS). Following the initial characterization, the formulations will be stored&#xD;
      in sealed vials and placed in ICH standard stability conditions and tested at weekly&#xD;
      intervals over 1, 3 and 6 months. The three outstanding formulation candidates will be&#xD;
      selected to use in part two of the study.&#xD;
&#xD;
      In the second part the three formulations will be selected from those meeting the criteria&#xD;
      for stability, solubility, particle size, color and concentration of 2-butanol in the first&#xD;
      part of the study. Each of these formulations will be prepared by a certified pharmacy. In&#xD;
      addition to the three selected naltrexone formulations, a fourth dosage form, a&#xD;
      capsule-in-capsule (CIC) design, will be prepared in the pharmacy by incorporating 40 or 80&#xD;
      mg (determined from the first part of the study) of 2-butanol which is encapsulated (size 3&#xD;
      capsule) plus 50 mg of naltrexone (HCI form) in a size 0 double blind hard gel capsule. This&#xD;
      capsule-in-capsule design will serve as a formulation-free positive control.&#xD;
&#xD;
      Note: All naltrexone formulations, which will be administered to human subjects, will contain&#xD;
      quantities of excipients/components already designated by the FDA as being safe (e.g.,&#xD;
      inactive ingredient list, permissible daily exposure [PDE], GRAS/direct food additive&#xD;
      designation).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2014</start_date>
  <completion_date type="Actual">July 2014</completion_date>
  <primary_completion_date type="Actual">July 2014</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Concentration of 2-butanol determined by gas chromatography mass spectroscopy (GC-MS)</measure>
    <time_frame>Weekly intervals over 1, 3 and 6 months.</time_frame>
    <description>The primary outcome is to identify three outstanding candidates based on physiochemical principles and the concentration of 2-butanol determined by GC-MS. Following the initial characterization, the formulations will be stored in sealed vials and placed in ICH standard stability conditions and tested at weekly intervals over 1, 3 and 6 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>breath concentration versus time</measure>
    <time_frame>-5, 0, 5, 10, 20, 40, 60, 90 min</time_frame>
    <description>The relationship between the breath concentration (measured via mGC-MOS and gas chromatography mass spectroscopy [GC-MS]) of 2-butanol (taggant) and 2-butanone (metabolite) versus time will be determined after the oral administration of 3 promising naltrexone formulations selected from part of 1 of the study and a positive control.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Breath Pharmacokinetics (Cmax) of the Naltrexone Formulations</measure>
    <time_frame>-5, 0, 5, 10, 20, 40, 60, 90</time_frame>
    <description>The secondary outcome will be to examine the breath pharmacokinetics of 2-butanol, 2-butanone, and cyclopropylcarboxaldehyde [CPCA, a natural metabolite of naltrexone] in human subjects following oral administration of the three selected naltrexone formulations or a positive control containing 2-butanol. Using an endpoint of differing CMAX in a repeated measures design, a difference in means of approximately 150 ppb (parts-per-million based on molar concentration [not mass]), a standard deviation of 75 ppb (based on pilot studies of oral capsules), 8 subjects per group are required (n=8/group) for a ANOVA repeated measures design with maximal tolerated Type I and II errors of 0.05 and 0.20.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Healthy Adults</condition>
  <arm_group>
    <arm_group_label>Expirimental Formulation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will be administered a single encapsulated dose of the test formulation (Model Naltrexone 50mg containing 2-butanol). Breath samples will be taken over 90 minutes (-5, 0, 5, 10, 20, 40, 60, 90). Subjects will then be randomly crossed over to the four interventions (Formulation 1, Formulation 2, Formulation 3, Formulation-free positive control) three formulations from the first part of the study and a control administration (a capsule-in-capsule design).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Naltrexone and 2-butanol</intervention_name>
    <description>50mg of Naltrexone and 40 or 80 mg of 2-butanol (depending on Stability Formulation in the first part of the study)</description>
    <arm_group_label>Expirimental Formulation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>2-butanol which is encapsulated (size 3 capsule) plus 50 mg of naltrexone (HCl form)</intervention_name>
    <description>a capsule-in-capsule (CIC) design, will be prepared in the pharmacy by incorporating 40 or 80 mg (determined from the first part of the study) of 2-butanol which is encapsulated (size 3 capsule) plus 50 mg of naltrexone (HCl form) in a size 0 double blind hard gel capsule.</description>
    <arm_group_label>Expirimental Formulation</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to understand and provide written informed consent&#xD;
&#xD;
          -  Subject is at least 18 Years of Age&#xD;
&#xD;
          -  Subject must be willing to comply with study procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  &lt;18 years&#xD;
&#xD;
          -  Subject has a history of opioid use disorder&#xD;
&#xD;
          -  current chronic opioid therapy or recent (past week) acute opioid therapy,&#xD;
&#xD;
          -  currently pregnant&#xD;
&#xD;
          -  contraindications to naltrexone use per FDA label.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Donn Dennis, M.D., F.A.H.A.</last_name>
    <role>Study Director</role>
    <affiliation>Xhale Smart, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>July 15, 2014</study_first_submitted>
  <study_first_submitted_qc>July 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 18, 2014</study_first_posted>
  <last_update_submitted>July 17, 2014</last_update_submitted>
  <last_update_submitted_qc>July 17, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 18, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naltrexone</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02194764
org study id: 2012115600086371
secondary id: 1R43DA028740-01A1
nct id: NCT02194764
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to develop a cost-effective breath-based medication adherence
      monitoring system that can monitor whether recovering opiate addicts actually take a specific
      treatment medication called naltrexone.
This study will have two parts. In the first part we will create eight SMART capsule-based
      naltrexone systems using 4 general types of pharma formulation strategies. Model naltrexone
      (50mg) formulations containing the GRAS taggant, 2-butanol (40 or 80 mg) will be prepared and
      preliminary stability studies executed. Type 1 is a hydrophobic system, Type 2 is a
      hydrophilic system, Type 3 is a reverse micelle system and Type 4 is a water-in-oil
      microemulsion system. All formulations will be prepared using USP-grade excipients,
      2-butanol, naltrexone base and naltrexone HCl. Naltrexone HCl has significant water
      solubility and will be used in the preparation of formulation types 2 and 4, whereas the more
      lipid soluble free base of naltrexone will be used in formulation types 1 and 3.
      Manufacturer's specifications supplied by Capsugel will be used to determine compatibility
      between the capsule material and the proposed excipients, and will guide capsule selection
      (gelatin or HPMC).Prepared formulations will be characterized by particle size analysis and
      analyzed to determine the actual concentrations of naltrexone and 2-butanol. Particle sizing
      will be accomplished by dynamic light scattering using a 90Plus particle size analyzer. With
      formulation types 1 and 2, the technique will demonstrate the homogeneity of the mixture and
      the absence of particulates. With types 3 and 4, particle size distributions will be measured
      to confirm the presence of monodisperse reverse micelles or nanoscale droplets. The
      concentration of naltrexone in each final formulation will be verified by Liquid
      chromatography-mass spectrometry (LC-MS) and /or Ultra Performance Liquid Chromatography
      (UPLC). The concentration of 2-butanol will be determined by gas chromatography-Mass
      Spectrometry (GC-MS). Following the initial characterization, the formulations will be stored
      in sealed vials and placed in ICH standard stability conditions and tested at weekly
      intervals over 1, 3 and 6 months. The three outstanding formulation candidates will be
      selected to use in part two of the study.

      In the second part the three formulations will be selected from those meeting the criteria
      for stability, solubility, particle size, color and concentration of 2-butanol in the first
      part of the study. Each of these formulations will be prepared by a certified pharmacy. In
      addition to the three selected naltrexone formulations, a fourth dosage form, a
      capsule-in-capsule (CIC) design, will be prepared in the pharmacy by incorporating 40 or 80
      mg (determined from the first part of the study) of 2-butanol which is encapsulated (size 3
      capsule) plus 50 mg of naltrexone (HCI form) in a size 0 double blind hard gel capsule. This
      capsule-in-capsule design will serve as a formulation-free positive control.

      Note: All naltrexone formulations, which will be administered to human subjects, will contain
      quantities of excipients/components already designated by the FDA as being safe (e.g.,
      inactive ingredient list, permissible daily exposure [PDE], GRAS/direct food additive
      designation).
allocation: N/A
intervention model: Single Group Assignment
masking: Triple (Participant, Care Provider, Investigator)
measure: Concentration of 2-butanol determined by gas chromatography mass spectroscopy (GC-MS)
time frame: Weekly intervals over 1, 3 and 6 months.
description: The primary outcome is to identify three outstanding candidates based on physiochemical principles and the concentration of 2-butanol determined by GC-MS. Following the initial characterization, the formulations will be stored in sealed vials and placed in ICH standard stability conditions and tested at weekly intervals over 1, 3 and 6 months.
measure: breath concentration versus time
time frame: -5, 0, 5, 10, 20, 40, 60, 90 min
description: The relationship between the breath concentration (measured via mGC-MOS and gas chromatography mass spectroscopy [GC-MS]) of 2-butanol (taggant) and 2-butanone (metabolite) versus time will be determined after the oral administration of 3 promising naltrexone formulations selected from part of 1 of the study and a positive control.
measure: Breath Pharmacokinetics (Cmax) of the Naltrexone Formulations
time frame: -5, 0, 5, 10, 20, 40, 60, 90
description: The secondary outcome will be to examine the breath pharmacokinetics of 2-butanol, 2-butanone, and cyclopropylcarboxaldehyde [CPCA, a natural metabolite of naltrexone] in human subjects following oral administration of the three selected naltrexone formulations or a positive control containing 2-butanol. Using an endpoint of differing CMAX in a repeated measures design, a difference in means of approximately 150 ppb (parts-per-million based on molar concentration [not mass]), a standard deviation of 75 ppb (based on pilot studies of oral capsules), 8 subjects per group are required (n=8/group) for a ANOVA repeated measures design with maximal tolerated Type I and II errors of 0.05 and 0.20.
arm group label: Expirimental Formulation
arm group type: Experimental
description: Participants will be administered a single encapsulated dose of the test formulation (Model Naltrexone 50mg containing 2-butanol). Breath samples will be taken over 90 minutes (-5, 0, 5, 10, 20, 40, 60, 90). Subjects will then be randomly crossed over to the four interventions (Formulation 1, Formulation 2, Formulation 3, Formulation-free positive control) three formulations from the first part of the study and a control administration (a capsule-in-capsule design).
intervention type: Drug
intervention name: Naltrexone and 2-butanol
description: 50mg of Naltrexone and 40 or 80 mg of 2-butanol (depending on Stability Formulation in the first part of the study)
arm group label: Expirimental Formulation
intervention type: Drug
intervention name: 2-butanol which is encapsulated (size 3 capsule) plus 50 mg of naltrexone (HCl form)
description: a capsule-in-capsule (CIC) design, will be prepared in the pharmacy by incorporating 40 or 80 mg (determined from the first part of the study) of 2-butanol which is encapsulated (size 3 capsule) plus 50 mg of naltrexone (HCl form) in a size 0 double blind hard gel capsule.
arm group label: Expirimental Formulation
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Donn Dennis, M.D., F.A.H.A.
role: Study Director
affiliation: Xhale Smart, Inc.
facility: 
country: United States
responsible party type: Sponsor
mesh term: Naltrexone