<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/NCT04475029</url>
  </required_header>
  <id_info>
    <org_study_id>004581</org_study_id>
    <secondary_id>2019-004581-18</secondary_id>
    <nct_id>NCT04475029</nct_id>
  </id_info>
  <brief_title>Methadone in Cystectomy Patients</brief_title>
  <acronym>METAMORF</acronym>
  <official_title>Clinical Effectiveness and Safety of Intraoperative Methadone in Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Aarhus</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The role of a single-dose intraoperative methadone on postoperative pain and opioid&#xD;
      consumption in patients undergoing Surgeon Accuracy Robot Assistant cystectomy. A prospective&#xD;
      double-blind, randomized controlled trial investigating the effect of a single-dose of&#xD;
      intraoperative methadone in patients undergoing robotassisted cystectomy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      During early recovery after surgery, intravenous opioids are typically administered to&#xD;
      control the pain, either as intermittent bolus administration by nursing staff or by a&#xD;
      patient-controlled analgesia device. Unfortunately, repeated doses or boluses of&#xD;
      shorter-acting opioids, such as morphine, oxycodone and fentanyl, result in fluctuating blood&#xD;
      concentrations, with the inherent risk of only relatively brief periods of adequate pain&#xD;
      relief. Moreover, the use of shorter-acting opioids increases the risk of opioid-associated&#xD;
      side effects, such as sedation, nausea and vomiting. An alternative approach to the&#xD;
      postoperative use of shorter-acting opioids is therefore called for.&#xD;
&#xD;
      In this respect, methadone is an opioid with unique pharmalogical properties that may be&#xD;
      advantageous when applied intraoperatively. A single-dose of this long acting opioid could&#xD;
      provide a stable analgesia and potentially reduce the need for shorter-acting opioids&#xD;
&#xD;
      Method:&#xD;
&#xD;
      110 patients will be included in an investigator-initiated, prospective, randomised,&#xD;
      double-blind, controlled trial with two arms: intervention arm (methadone 0.15 mg/kg ideal&#xD;
      body weight). Control arm (morphine 0.15 mg/kg ideal body weight). The study will be&#xD;
      GCP-monitored, and is approved by the Danish Health and Medicines Authority (2020041652) and&#xD;
      the Central Denmark Region Committees on Health Research Ethics (1-10-72-275-19).&#xD;
&#xD;
      Hypothesis We hypothesize that a single-dose of intravenous intraoperative methadone is&#xD;
      efficient and safe for the treatment of postoperative pain after cystectomy.&#xD;
&#xD;
      Objectives The primary objective is to determine whether a single-dose of intravenous&#xD;
      methadone reduces postoperative opioid consumption when compared to morphine. The secondary&#xD;
      objectives are to compare the effect and safety of intravenous methadone and morphine on&#xD;
      postoperative pain, side effects, patient satisfaction and length of stay.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 6, 2020</start_date>
  <completion_date type="Actual">August 17, 2023</completion_date>
  <primary_completion_date type="Actual">August 15, 2023</primary_completion_date>
  <phase>N/A</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>
    <intervention_model_description>Randomized controlled trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Randomization and medication will be handled by hospital pharmacy. Randomisation list will be concealed until all statistical analyses are made.&#xD;
plan for data analysis was decided upon at a meeting with a statistician on September 7th, 2023. The plan was made before A and B lists were obtained from the hospital pharmacy. This study will be undertaken as an equivalence trial with the application of intention to treat analysis. Missing data are assumed to be missing at random. Primary outcome will be analyzed paired or unpaired t-test for difference, depending on distribution. Analysis of secondary outcome NRS will be reported as median(interquartile range) and compared between groups at the various times using the Mann-Whitney U test. If normal distributed multilevel mixed effects linear regression will be carried out. Analysis of other secondary outcomes will be dichotomized and presented for 3 and 24 hours with X2 test.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Opioid consumption (morphine mg equivalents)</measure>
    <time_frame>3 hours</time_frame>
    <description>• Opioid consumption within the first 3 hours after extubation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Opioid consumption (morphine mg equivalents)</measure>
    <time_frame>24 hours</time_frame>
    <description>• Opioid consumption within the first 24 hours after extubation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pain intensity</measure>
    <time_frame>within 24 hours</time_frame>
    <description>NRS (0-10) at rest and when coughing. Questionnaires answered by nurse.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Opioid consumption (morphine mg equivalents)</measure>
    <time_frame>72 hours</time_frame>
    <description>• Opioid consumption within the first 72 hours after extubation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PONV</measure>
    <time_frame>Within 24 hours</time_frame>
    <description>• Nausea and/or vomiting (PONV) on a 4-point Likert scale (none/mild/moderate/severe). Questionnaires answered by nurse.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Level of sedation</measure>
    <time_frame>3 hours</time_frame>
    <description>Level of sedation (Ramsey Sedation Score) assessed by PACU nurse.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>6 hours</time_frame>
    <description>Any adverse events registered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient satisfaction from 0-10.</measure>
    <time_frame>24 hours</time_frame>
    <description>Patient satisfaction with pain management (NRS 0-10) Questionnaires answered by nurse.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Discharge</measure>
    <time_frame>6 days</time_frame>
    <description>• Time from arrival to discharge from PACU and hospital (hours and minutes)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Pain intensity</measure>
    <time_frame>32-72 hours</time_frame>
    <description>• Pain intensity (NRS, 0-10) at rest and coughing, questionnaires answered by nurse.</description>
  </other_outcome>
  <other_outcome>
    <measure>PONV</measure>
    <time_frame>32-72 hours</time_frame>
    <description>• Nausea and/or vomiting (PONV) on a 4-point Likert scale (none/mild/moderate/severe). Questionnaires answered by nurse.</description>
  </other_outcome>
  <other_outcome>
    <measure>Gastrointestinal function</measure>
    <time_frame>6-72 hours</time_frame>
    <description>Gastrointestinal function (flatus, stools) and laxatives ordained.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">114</enrollment>
  <condition>Pain, Postoperative</condition>
  <condition>Postoperative Complications</condition>
  <condition>Pathologic Processes</condition>
  <condition>Bladder Cancer</condition>
  <condition>Pain</condition>
  <condition>Signs and Symptoms</condition>
  <condition>Neurologic Manifestations</condition>
  <condition>Neurologic Symptoms</condition>
  <condition>Side Effect of Drug</condition>
  <arm_group>
    <arm_group_label>Methadone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A 10 ml syringe with 2 mg/ml of methadone will be prepared and and study drug will be administered as intravenous bolus dose (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Morphine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A 10 ml syringe with 2 mg/ml of morphine will be prepared and and study drug will be administered as intravenous bolus dose (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methadone</intervention_name>
    <description>One intravenous administration of methadone (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.</description>
    <arm_group_label>Methadone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Morphine</intervention_name>
    <description>One intravenous administration of morphine (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.</description>
    <arm_group_label>Morphine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - All patients (≥18 years) scheduled for elective robot assisted cystectomy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  American Society of Anesthesiologists (ASA) physical status IV or V&#xD;
&#xD;
          -  Prolonged QTc-interval assessed by electrocardiogram (&gt; 440 milliseconds)&#xD;
&#xD;
          -  Existing treatment with a high risk of QTc-interval prolongation&#xD;
&#xD;
          -  Allergy to study drugs&#xD;
&#xD;
          -  Preoperative daily use of opioids&#xD;
&#xD;
          -  Inability to provide informed consent&#xD;
&#xD;
          -  Severe respiratory insufficiency (oxygen treatment at home)&#xD;
&#xD;
          -  Heart failure (ejection fraction &lt; 30%)&#xD;
&#xD;
          -  Acute abdominal pain&#xD;
&#xD;
          -  Signs of severe liver dysfunction (cirrhosis, inflammation/hepatitis or liver&#xD;
             malignancy)&#xD;
&#xD;
          -  Severe kidney insufficiency (estimated Glomerular Filtration Rate &lt; 30 ml/min)&#xD;
&#xD;
          -  Treatment with rifampicin&#xD;
&#xD;
          -  Phaeochromocytoma&#xD;
&#xD;
          -  Treatment with MAO-inhibitor during the last 14 days&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Nursing mothers&#xD;
&#xD;
          -  Intraoperative conversion to open surgery (secondary inclusion criterion)&#xD;
&#xD;
          -  Epidural analgesia in relation to surgical procedure&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>110 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Aarhus University Hospital</name>
      <address>
        <city>Aarhus</city>
        <zip>8200</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>July 9, 2020</study_first_submitted>
  <study_first_submitted_qc>July 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>September 11, 2023</last_update_submitted>
  <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>morphine</keyword>
  <keyword>methadone</keyword>
  <keyword>analgesics</keyword>
  <keyword>opioids</keyword>
  <keyword>effect of drugs</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurologic Manifestations</mesh_term>
    <mesh_term>Pain, Postoperative</mesh_term>
    <mesh_term>Postoperative Complications</mesh_term>
    <mesh_term>Pathologic Processes</mesh_term>
    <mesh_term>Drug-Related Side Effects and Adverse Reactions</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Morphine</mesh_term>
    <mesh_term>Methadone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 7, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/29/NCT04475029/SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04475029
org study id: 004581
secondary id: 2019-004581-18
nct id: NCT04475029
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The role of a single-dose intraoperative methadone on postoperative pain and opioid
      consumption in patients undergoing Surgeon Accuracy Robot Assistant cystectomy. A prospective
      double-blind, randomized controlled trial investigating the effect of a single-dose of
      intraoperative methadone in patients undergoing robotassisted cystectomy.
During early recovery after surgery, intravenous opioids are typically administered to
      control the pain, either as intermittent bolus administration by nursing staff or by a
      patient-controlled analgesia device. Unfortunately, repeated doses or boluses of
      shorter-acting opioids, such as morphine, oxycodone and fentanyl, result in fluctuating blood
      concentrations, with the inherent risk of only relatively brief periods of adequate pain
      relief. Moreover, the use of shorter-acting opioids increases the risk of opioid-associated
      side effects, such as sedation, nausea and vomiting. An alternative approach to the
      postoperative use of shorter-acting opioids is therefore called for.

      In this respect, methadone is an opioid with unique pharmalogical properties that may be
      advantageous when applied intraoperatively. A single-dose of this long acting opioid could
      provide a stable analgesia and potentially reduce the need for shorter-acting opioids

      Method:

      110 patients will be included in an investigator-initiated, prospective, randomised,
      double-blind, controlled trial with two arms: intervention arm (methadone 0.15 mg/kg ideal
      body weight). Control arm (morphine 0.15 mg/kg ideal body weight). The study will be
      GCP-monitored, and is approved by the Danish Health and Medicines Authority (2020041652) and
      the Central Denmark Region Committees on Health Research Ethics (1-10-72-275-19).

      Hypothesis We hypothesize that a single-dose of intravenous intraoperative methadone is
      efficient and safe for the treatment of postoperative pain after cystectomy.

      Objectives The primary objective is to determine whether a single-dose of intravenous
      methadone reduces postoperative opioid consumption when compared to morphine. The secondary
      objectives are to compare the effect and safety of intravenous methadone and morphine on
      postoperative pain, side effects, patient satisfaction and length of stay.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized controlled trial.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Randomization and medication will be handled by hospital pharmacy. Randomisation list will be concealed until all statistical analyses are made.
plan for data analysis was decided upon at a meeting with a statistician on September 7th, 2023. The plan was made before A and B lists were obtained from the hospital pharmacy. This study will be undertaken as an equivalence trial with the application of intention to treat analysis. Missing data are assumed to be missing at random. Primary outcome will be analyzed paired or unpaired t-test for difference, depending on distribution. Analysis of secondary outcome NRS will be reported as median(interquartile range) and compared between groups at the various times using the Mann-Whitney U test. If normal distributed multilevel mixed effects linear regression will be carried out. Analysis of other secondary outcomes will be dichotomized and presented for 3 and 24 hours with X2 test.
measure: Opioid consumption (morphine mg equivalents)
time frame: 3 hours
description: • Opioid consumption within the first 3 hours after extubation
measure: Opioid consumption (morphine mg equivalents)
time frame: 24 hours
description: • Opioid consumption within the first 24 hours after extubation
measure: Pain intensity
time frame: within 24 hours
description: NRS (0-10) at rest and when coughing. Questionnaires answered by nurse.
measure: Opioid consumption (morphine mg equivalents)
time frame: 72 hours
description: • Opioid consumption within the first 72 hours after extubation
measure: PONV
time frame: Within 24 hours
description: • Nausea and/or vomiting (PONV) on a 4-point Likert scale (none/mild/moderate/severe). Questionnaires answered by nurse.
measure: Level of sedation
time frame: 3 hours
description: Level of sedation (Ramsey Sedation Score) assessed by PACU nurse.
measure: Adverse events
time frame: 6 hours
description: Any adverse events registered.
measure: Patient satisfaction from 0-10.
time frame: 24 hours
description: Patient satisfaction with pain management (NRS 0-10) Questionnaires answered by nurse.
measure: Discharge
time frame: 6 days
description: • Time from arrival to discharge from PACU and hospital (hours and minutes)
measure: Pain intensity
time frame: 32-72 hours
description: • Pain intensity (NRS, 0-10) at rest and coughing, questionnaires answered by nurse.
measure: PONV
time frame: 32-72 hours
description: • Nausea and/or vomiting (PONV) on a 4-point Likert scale (none/mild/moderate/severe). Questionnaires answered by nurse.
measure: Gastrointestinal function
time frame: 6-72 hours
description: Gastrointestinal function (flatus, stools) and laxatives ordained.
arm group label: Methadone
arm group type: Experimental
description: A 10 ml syringe with 2 mg/ml of methadone will be prepared and and study drug will be administered as intravenous bolus dose (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.
arm group label: Morphine
arm group type: Active Comparator
description: A 10 ml syringe with 2 mg/ml of morphine will be prepared and and study drug will be administered as intravenous bolus dose (0.15 mg/kg treatment weight (height (cm) - 100)). The study drug will be administered 1 hour prior to expected extubation.
intervention type: Drug
intervention name: Methadone
description: One intravenous administration of methadone (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.
arm group label: Methadone
intervention type: Drug
intervention name: Morphine
description: One intravenous administration of morphine (0.15 mg/kg treatment weight (height(cm)-100)) one hour prior to expected extubation.
arm group label: Morphine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 110 Years
healthy volunteers: No
facility: 
country: Denmark
responsible party type: Sponsor
mesh term: Neurologic Manifestations
mesh term: Pain, Postoperative
mesh term: Postoperative Complications
mesh term: Pathologic Processes
mesh term: Drug-Related Side Effects and Adverse Reactions
mesh term: Morphine
mesh term: Methadone
sharing ipd: No
provided document: 