xml: <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/NCT05962151</url>
    </required_header>
    <id_info>
      <org_study_id>NAL04-201</org_study_id>
      <nct_id>NCT05962151</nct_id>
    </id_info>
    <brief_title>Refractory Chronic Cough Improvement Via NAL ER (RIVER)</brief_title>
    <acronym>RIVER</acronym>
    <official_title>A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Two-Period Crossover Efficacy and Safety Study of Nalbuphine ER Tablets for the Treatment of Refractory Chronic Cough</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Trevi Therapeutics</agency>
        <agency_class>Industry</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Trevi Therapeutics</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>Yes</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        A 2-period crossover study for the treatment of cough in patients with Refractory Chronic&#xD;
        Cough via Nalbuphine ER (NAL ER). Each period will last 21 days and are separated by 21 days.&#xD;
        Subjects will be randomized in Treatment Period 1 to either NAL ER or matching placebo and&#xD;
        evaluated for 21 days. After completion of the first phase, subjects who received NAL ER will&#xD;
        crossover to placebo and subjects who received placebo will crossover to NAL ER to complete&#xD;
        Treatment Period 2.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        A double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of&#xD;
        cough with NAL ER in subjects with Refractory Chronic Cough.&#xD;
  &#xD;
        Based on the screening cough monitor results, the study will enroll subjects in a 1:1 ratio&#xD;
        to subgroups of 10-19 coughs/hour and ≥20 coughs/hour.&#xD;
  &#xD;
        After meeting eligibility during the screening period, subjects will be randomly assigned to&#xD;
        one of the following sequences:&#xD;
  &#xD;
          -  NAL ER in Treatment Period 1, followed by Placebo (PBO) in Treatment Period 2 OR&#xD;
  &#xD;
          -  PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2.&#xD;
  &#xD;
        Each treatment period lasts 21 days and are separated by a 21-day washout period. Subjects on&#xD;
        NAL ER will have the dose titrated from 27 mg once a day (QD) to 108 mg twice a day (BID).&#xD;
  &#xD;
        Study visits in each treatment period will be at Day -1 for Baseline cough assessments, and&#xD;
        at Days 6, 13, and 20. Subjects will have blood drawn for pharmacokinetic (PK) analysis of&#xD;
        nalbuphine plasma concentration. Subjects will also complete questionnaires for efficacy&#xD;
        evaluations and undergo safety evaluations including an electrocardiogram (ECG).&#xD;
  &#xD;
        At the Screening and Baseline visits and on Days 6, 13, and 20 during each treatment period,&#xD;
        site staff will place an electronic cough monitor on the subject, which will be worn for a&#xD;
        24-hour recording period to assess cough frequency. At the end of each recording session&#xD;
        (Days 7, 14, and 21), the monitor will be removed at home by the subject, and the subjects&#xD;
        will complete Patient Reported Outcomes (PROs) questionnaires in the electronic diary.&#xD;
  &#xD;
        Subjects will be taken off study drug at the end of Treatment Period 2 and followed off&#xD;
        treatment for an additional 2 weeks.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">October 2024</completion_date>
    <primary_completion_date type="Anticipated">September 2024</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>Crossover Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Double (Participant, Investigator)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>24 hr cough frequency</measure>
      <time_frame>Day 21 versus Baseline</time_frame>
      <description>Relative change in frequency (coughs per hour) versus Placebo</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Number of participants with treatment related adverse events, as assessed by CTCAE v.5.0</measure>
      <time_frame>Baseline through follow-up</time_frame>
      <description>Adverse events, clinical labs, vital signs, physical exams, electrocardiograms</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Subjective Opiate Withdrawal Scale</measure>
      <time_frame>Daily for 14 days after last dose in Period 2</time_frame>
      <description>16 item questionnaire for 14 days following last dose of study drug</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>24 hour cough frequency</measure>
      <time_frame>Days 7 and 14 versus Baseline</time_frame>
      <description>Relative change in frequency (coughs per hour) versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>24 hour cough frequency</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>Proportion of responders with &gt;=30%, 50% and 75% reduction in frequency versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Awake cough frequency</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>Relative change in frequency (coughs per hour) versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Sleep cough frequency</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>Relative change in frequency (coughs per hour) versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cough Severity Visual Analogue Scale</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>1 item scale with minimum score of 0 (no cough) to 10 (worst cough) versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Leicester Cough Questionnaire</measure>
      <time_frame>Day 21 versus Baseline</time_frame>
      <description>19 item questionnaire with a grading of 1 (all the time ) to 7 (none of the time) versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Patient-Reported Cough Frequency (change)</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>Change versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Patient-Reported Cough Frequency (proportion)</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>Proportion of responders with improvement in at least one category versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Patient Global Impression of Cough Severity</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>1 item question with a grading from &quot;no cough, to mild, moderate or severe&quot; versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Patient Global Impression of Cough Change</measure>
      <time_frame>Days 7, 14, and 21 versus Baseline</time_frame>
      <description>1 item question with a 7 point grading from &quot;much better to much worse&quot; versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinicians Global Impression of Cough Severity</measure>
      <time_frame>Day 21 versus Baseline (both treatment periods)</time_frame>
      <description>1 item question with a grading from &quot;no cough, to mild, moderate or severe&quot; versus Placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clinicians Global Impression of Cough Change</measure>
      <time_frame>Day 21 versus Baseline (both treatment periods)</time_frame>
      <description>1 item question with a 7 point grading from &quot;very much improved to very much worse&quot; versus Placebo</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">60</enrollment>
    <condition>Refractory Chronic Cough</condition>
    <arm_group>
      <arm_group_label>NAL ER</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>NAL ER, tablets, 27 mg QD to BID, 54 mg BID, 108 mg BID</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Placebo, tablets, 0 mg QD to BID, 0 mg BID, 0 mg BID</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Nalbuphine ER</intervention_name>
      <description>Oral tablets</description>
      <arm_group_label>NAL ER</arm_group_label>
      <other_name>Active</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Oral tablets</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Key Inclusion Criteria:&#xD;
  &#xD;
            -  Diagnosis of refractory chronic cough (RCC) for at least one year&#xD;
  &#xD;
            -  Chest radiograph or CT of thorax within 24 months or during screening not&#xD;
               demonstrating any significant abnormalities contributing to RCC&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Diagnosis of sleep apnea&#xD;
  &#xD;
            -  Respiratory tract infection within 6 weeks of Baseline&#xD;
  &#xD;
            -  History of bronchiectasis, COPD, or IPF&#xD;
  &#xD;
            -  History of uncontrolled asthma&#xD;
  &#xD;
            -  Current smokers/vapers, quit smoking with &lt;=12 months, using nicotine supplements, or&#xD;
               history of &gt;=20 pack years&#xD;
  &#xD;
            -  History of major psychiatric disorder&#xD;
  &#xD;
            -  History of substance abuse&#xD;
  &#xD;
            -  Pregnant or lactating females&#xD;
  &#xD;
            -  Known intolerance to opioids&#xD;
  &#xD;
            -  Abnormal kidney or liver functions based on Screening lab results.&#xD;
  &#xD;
            -  Known hypersensitivity to nalbuphine or to NAL ER excipients&#xD;
  &#xD;
            -  Previous participation in a nalbuphine ER clinical study&#xD;
  &#xD;
            -  Use of opiates, benzodiazepines, or MAOIs within 14 days of Baseline&#xD;
  &#xD;
            -  Use of pregabalin, gabapentin, thalidomide for treatment of cough within 14 days of&#xD;
               Baseline&#xD;
  &#xD;
            -  Use of ACE inhibitors within 12 weeks of Baseline&#xD;
  &#xD;
            -  Use of a medication having a &quot;known risk&quot; of Torsade de Pointes (categorized as &quot;KR&quot;&#xD;
               on the Credible Meds® website.) 4 weeks prior to Baseline&#xD;
  &#xD;
            -  Use of unstable doses of medications associated with a potential risk of QT&#xD;
               prolongation but not clearly associated with Torsade de Pointes within 4 weeks of&#xD;
               screening.&#xD;
  &#xD;
            -  Use of unstable doses of cough suppressants within 14 days of Baseline&#xD;
  &#xD;
            -  Use of unstable doses of medications that affect serotonergic neurotransmission that&#xD;
               may cause serotonin syndrome with opioids within14 days of Baseline&#xD;
  &#xD;
            -  Use of unstable doses of P450 isozyme inhibitors/inducers within 14 days of Baseline&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>David Clark, MD</last_name>
      <role>Study Director</role>
      <affiliation>Trevi Therapeutics</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Sherry Minor</last_name>
      <phone>203-684-1308</phone>
      <email>Sherry.Minor@trevitherapeutics.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Connie Crum, RN</last_name>
      <phone>203-599-0265</phone>
      <email>Connie.Crum@trevitherapeutics.com</email>
    </overall_contact_backup>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 7, 2023</study_first_submitted>
    <study_first_submitted_qc>July 18, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 27, 2023</study_first_posted>
    <last_update_submitted>August 14, 2023</last_update_submitted>
    <last_update_submitted_qc>August 14, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 18, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>RCC</keyword>
    <keyword>Cough</keyword>
    <keyword>Nalbuphine</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Cough</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Nalbuphine</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05962151
  org study id: NAL04-201
  nct id: NCT05962151
  lead sponsor: 
  has dmc: No
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: Yes
  A 2-period crossover study for the treatment of cough in patients with Refractory Chronic
        Cough via Nalbuphine ER (NAL ER). Each period will last 21 days and are separated by 21 days.
        Subjects will be randomized in Treatment Period 1 to either NAL ER or matching placebo and
        evaluated for 21 days. After completion of the first phase, subjects who received NAL ER will
        crossover to placebo and subjects who received placebo will crossover to NAL ER to complete
        Treatment Period 2.
  A double-blind, randomized, placebo-controlled, 2-period crossover study for the treatment of
        cough with NAL ER in subjects with Refractory Chronic Cough.
  
        Based on the screening cough monitor results, the study will enroll subjects in a 1:1 ratio
        to subgroups of 10-19 coughs/hour and ≥20 coughs/hour.
  
        After meeting eligibility during the screening period, subjects will be randomly assigned to
        one of the following sequences:
  
          -  NAL ER in Treatment Period 1, followed by Placebo (PBO) in Treatment Period 2 OR
  
          -  PBO in Treatment Period 1, followed by NAL ER in Treatment Period 2.
  
        Each treatment period lasts 21 days and are separated by a 21-day washout period. Subjects on
        NAL ER will have the dose titrated from 27 mg once a day (QD) to 108 mg twice a day (BID).
  
        Study visits in each treatment period will be at Day -1 for Baseline cough assessments, and
        at Days 6, 13, and 20. Subjects will have blood drawn for pharmacokinetic (PK) analysis of
        nalbuphine plasma concentration. Subjects will also complete questionnaires for efficacy
        evaluations and undergo safety evaluations including an electrocardiogram (ECG).
  
        At the Screening and Baseline visits and on Days 6, 13, and 20 during each treatment period,
        site staff will place an electronic cough monitor on the subject, which will be worn for a
        24-hour recording period to assess cough frequency. At the end of each recording session
        (Days 7, 14, and 21), the monitor will be removed at home by the subject, and the subjects
        will complete Patient Reported Outcomes (PROs) questionnaires in the electronic diary.
  
        Subjects will be taken off study drug at the end of Treatment Period 2 and followed off
        treatment for an additional 2 weeks.
  allocation: Randomized
  intervention model: Crossover Assignment
  primary purpose: Treatment
  masking: Double (Participant, Investigator)
  measure: 24 hr cough frequency
  time frame: Day 21 versus Baseline
  description: Relative change in frequency (coughs per hour) versus Placebo
  measure: Number of participants with treatment related adverse events, as assessed by CTCAE v.5.0
  time frame: Baseline through follow-up
  description: Adverse events, clinical labs, vital signs, physical exams, electrocardiograms
  measure: Subjective Opiate Withdrawal Scale
  time frame: Daily for 14 days after last dose in Period 2
  description: 16 item questionnaire for 14 days following last dose of study drug
  measure: 24 hour cough frequency
  time frame: Days 7 and 14 versus Baseline
  description: Relative change in frequency (coughs per hour) versus Placebo
  measure: 24 hour cough frequency
  time frame: Days 7, 14, and 21 versus Baseline
  description: Proportion of responders with >=30%, 50% and 75% reduction in frequency versus Placebo
  measure: Awake cough frequency
  time frame: Days 7, 14, and 21 versus Baseline
  description: Relative change in frequency (coughs per hour) versus Placebo
  measure: Sleep cough frequency
  time frame: Days 7, 14, and 21 versus Baseline
  description: Relative change in frequency (coughs per hour) versus Placebo
  measure: Cough Severity Visual Analogue Scale
  time frame: Days 7, 14, and 21 versus Baseline
  description: 1 item scale with minimum score of 0 (no cough) to 10 (worst cough) versus Placebo
  measure: Leicester Cough Questionnaire
  time frame: Day 21 versus Baseline
  description: 19 item questionnaire with a grading of 1 (all the time ) to 7 (none of the time) versus Placebo
  measure: Patient-Reported Cough Frequency (change)
  time frame: Days 7, 14, and 21 versus Baseline
  description: Change versus Placebo
  measure: Patient-Reported Cough Frequency (proportion)
  time frame: Days 7, 14, and 21 versus Baseline
  description: Proportion of responders with improvement in at least one category versus Placebo
  measure: Patient Global Impression of Cough Severity
  time frame: Days 7, 14, and 21 versus Baseline
  description: 1 item question with a grading from "no cough, to mild, moderate or severe" versus Placebo
  measure: Patient Global Impression of Cough Change
  time frame: Days 7, 14, and 21 versus Baseline
  description: 1 item question with a 7 point grading from "much better to much worse" versus Placebo
  measure: Clinicians Global Impression of Cough Severity
  time frame: Day 21 versus Baseline (both treatment periods)
  description: 1 item question with a grading from "no cough, to mild, moderate or severe" versus Placebo
  measure: Clinicians Global Impression of Cough Change
  time frame: Day 21 versus Baseline (both treatment periods)
  description: 1 item question with a 7 point grading from "very much improved to very much worse" versus Placebo
  arm group label: NAL ER
  arm group type: Experimental
  description: NAL ER, tablets, 27 mg QD to BID, 54 mg BID, 108 mg BID
  arm group label: Placebo
  arm group type: Placebo Comparator
  description: Placebo, tablets, 0 mg QD to BID, 0 mg BID, 0 mg BID
  intervention type: Drug
  intervention name: Nalbuphine ER
  description: Oral tablets
  arm group label: NAL ER
  other name: Active
  intervention type: Drug
  intervention name: Placebo
  description: Oral tablets
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: David Clark, MD
  role: Study Director
  affiliation: Trevi Therapeutics
  last name: Sherry Minor
  phone: 203-684-1308
  email: Sherry.Minor@trevitherapeutics.com
  last name: Connie Crum, RN
  phone: 203-599-0265
  email: Connie.Crum@trevitherapeutics.com
  responsible party type: Sponsor
  mesh term: Cough
  mesh term: Nalbuphine
  sharing ipd: No