<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/NCT01687751</url>
  </required_header>
  <id_info>
    <org_study_id>FHREB 2012-057</org_study_id>
    <nct_id>NCT01687751</nct_id>
  </id_info>
  <brief_title>Pilot Study Comparing Treatment With Dexmedetomidine to Midazolam for Symptom Control in Advanced Cancer Patients</brief_title>
  <official_title>Dexmedetomidine Compared to Midazolam for Symptom Control in Advanced Cancer Patients: A Pilot Randomized Controlled Trial (RCT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fraser Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fraser Health</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cancer patients with very difficult to control symptoms at the Abbotsford (AC) and Fraser&#xD;
      Valley (FVC) Cancer Centers are referred and admitted to the Tertiary Palliative Care Units&#xD;
      at the Abbotsford Regional Hospital and Cancer Center(ARHCC). For symptom management,&#xD;
      patients are sometimes given midazolam continuously through a needle placed underneath the&#xD;
      skin. While effective in symptom management, midazolam can be sedating, leaving patients&#xD;
      unable to interact with loved ones in their last days.&#xD;
&#xD;
      This study is a pilot project. Before proceeding to a full-scale study, a &quot;pilot study&quot; or&#xD;
      &quot;feasibility study&quot; is often carried out first to test the design of a study, the likelihood&#xD;
      of successful recruitment or the acceptability of the intervention to potential subjects. The&#xD;
      basic idea is to find out whether it will be practical to proceed to a larger study that will&#xD;
      include more subjects. This type of study involves only a small number of subjects and&#xD;
      therefore the results can only be used as a guide for further larger studies.&#xD;
&#xD;
      The investigators also will determine whether palliative care cancer patients taking a&#xD;
      medication called dexmedetomidine would have improved rousability (more easily and fully&#xD;
      awakened) and symptom control (pain, shortness of breath, nausea or confusion) compared with&#xD;
      those taking standard of care which is receiving the medication midazolam. The use of&#xD;
      dexmedetomidine in other clinical situations (in the Operating Room or Intensive Care Unit&#xD;
      where the patient can still respond to the doctor) has been shown to be effective in symptom&#xD;
      control and to provide a better degree of rousability to patients but has not been well&#xD;
      studied in the palliative care environment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION AND BACKGROUND&#xD;
&#xD;
      Advanced cancer patients nearing the end of life suffer from pain, anxiety and other symptoms&#xD;
      that can be very difficult to control. The current practice within Fraser Health Authority is&#xD;
      to admit these patients to one of three tertiary palliative care units (TPCUs) for pain and&#xD;
      symptom management. Once admitted, if pain and symptom relieving measures are insufficient,&#xD;
      patients are given a continuous subcutaneous infusion (CSCI) of the drug midazolam for&#xD;
      symptom management. While effective, sedation with midazolam often leaves patients unable to&#xD;
      eat or drink or interact with their environment.&#xD;
&#xD;
      Dexmedetomidine is a unique and promising agent for managing intractable symptoms in&#xD;
      palliative patients at the end of life . In addition to providing proportional sedation for&#xD;
      symptom control, compared to midazolam, dexmedetomidine has the additional attributes of&#xD;
      providing improved management of pain, dyspnea and delirium. Of special interest to patients&#xD;
      who would like to continue to be involved in decision making and to be able to communicate&#xD;
      with loved ones at the end of life is the quality of rousability possible when&#xD;
      dexmedetomidine is used for sedation instead of midazolam. These features have been well&#xD;
      studied in the ICU and anaesthesia literature but not in the palliative care environment.&#xD;
&#xD;
      PURPOSE AND JUSTIFICATION&#xD;
&#xD;
      Currently, standard care for patients with difficult or intractable symptoms for patients&#xD;
      admitted to the tertiary palliative care units in Fraser Health is the administration of&#xD;
      midazolam by CSCI as recommended in the evidence based Fraser Health Authority (FHA) Hospice&#xD;
      Palliative Care Program Symptom Guideline &quot;Refractory Symptoms and Palliative Sedation&#xD;
      Therapy Guideline&quot;. The same guideline states that among the criteria for implementation of&#xD;
      palliative sedation therapy is that &quot;in all but the most unusual circumstances, death is&#xD;
      anticipated within hours to days&quot;. However, many other patients with difficult or intractable&#xD;
      symptoms have a natural course of their illness that is longer than 'hours to days'. These&#xD;
      patients would benefit from a degree of sedation that is proportional to the severity of&#xD;
      their symptoms. Therefore, particularly in these circumstances, an option other than deep&#xD;
      palliative sedation with midazolam is necessary where the patient would very often like to be&#xD;
      aware of those around them and still not be confused or in pain.&#xD;
&#xD;
      Despite many studies among ICU and anaesthesia patients, only two reports with four patients&#xD;
      have evaluated use of dexmedetomidine in the palliative care environment. The first case was&#xD;
      a 45 year old man with cervical paraganglioma, palliative performance scale (PPS) 10% with&#xD;
      uncontrolled pain, insomnia, anxiety and severe psychological distress. Combined with&#xD;
      morphine, a continuous intravenous infusion (CIVI) of dexmedetomidine provided relief of pain&#xD;
      and anxiety within 30 minutes. The patient was sleeping without sign of pain, but prompt&#xD;
      communication with his sister was possible. The infusion continued 24 hrs with good physical&#xD;
      and psychological symptom control. The second case was 54 year old woman with breast cancer,&#xD;
      PPS 20%, delirium and hypercalcemia. Treatment also included CIVI morphine, haloperidol 10&#xD;
      mg/day. Dexmedetomidine CIVI for 48 hr infusion improved agitation and the patient was able&#xD;
      to transfer out of the bed, sit in a chair and communicate when necessary. When intravenous&#xD;
      access was lost, the patient was sedated with midazolam CSCI 5 mg/hr and died 72 hours hours&#xD;
      later. The third case was a 40 year old woman with advanced cervical cancer, PPS 10%, renal&#xD;
      failure, hypercalcemia, intractable agitated delirium and pain with movement. Treatment&#xD;
      included CSCI morphine, hydration and haloperidol 8 mg/day. Dexmedetomidine infusion&#xD;
      temporarily improved delirium for 5 hours, but not pain with movement. When restlessness&#xD;
      returned, dexmedetomidine was changed to midazolam 12 mg/hr for the 4 days until the patient&#xD;
      died. The fourth case was a 46 year old woman with intractable back and left abdominopelvic&#xD;
      pain radiating into her left leg. She was diagnosed with adenocarcinoma of unknown primary&#xD;
      with a progressively expanding left retroperitoneal mass involving the psoas muscle and&#xD;
      adjacent vertebral bodies. After the titration phase of dexmedetomidine, pain decreased to&#xD;
      6/10 as measured by a numerical pain scale which was considered tolerable by the patient.&#xD;
      There was no significant sedation. By the third day, the pain increased to 9/10. As it was&#xD;
      the patient's wish to go home, instead of up titrating the dexmedetomidine, a continuous&#xD;
      epidural was started with bupivicaine and clonidine.&#xD;
&#xD;
      Current ongoing studies of dexmedetomidine use in the palliative care environment is limited&#xD;
      to a Phase II study of dexmedetomidine in treating symptoms of distress in advanced cancer&#xD;
      patients. The objective of this nine patient cohort study at Duke University Medical Center&#xD;
      is to assess the effectiveness of 3 separate doses of dexmedetomidine (0.7, 1.5, 2.5 mg/kg/hr&#xD;
      by continuous intravenous infusion) as add-on treatment for intractable pain, agitation and&#xD;
      or delirium in terminally ill cancer patients in their last week of life until death.&#xD;
      Overall, there is limited evidence in the literature to guide practice of using&#xD;
      dexmedetomidine in the palliative care environment.&#xD;
&#xD;
      Given this gap in knowledge, the investigators propose to conduct a pilot randomized&#xD;
      controlled trial (RCT) of dexmedetomidine CSCI compared to midazolam CSCI in advanced cancer&#xD;
      patients in the palliative care setting.&#xD;
&#xD;
      The subcutaneous route is chosen for this pilot study as the preferred route of drug delivery&#xD;
      as this conforms to the current standard of care according the FHA Hospice Palliative Care&#xD;
      symptom guideline &quot;Refractory Symptoms and Palliative Sedation Therapy Guideline&quot;: &quot;Where&#xD;
      feasible, the use of midazolam by CSCI is preferred to permit responsive titration. In&#xD;
      general, subcutaneous administration is preferred to intravenous administration because of&#xD;
      the practical advantage of subcutaneous infusion and the greater risk of apnea when bolus&#xD;
      injections are administered intravenously&quot;. &quot;The subcutaneous route is the most commonly used&#xD;
      parenteral route in palliative care&quot;, &quot;Drugs given via the subcutaneous route tend to have a&#xD;
      high bioavailability (generally near 100 %)&quot; &quot;Subcutaneous infusion provides blood levels&#xD;
      comparable to those from intravenous administration&quot;, &quot;Perfusion of subcutaneous tissue is&#xD;
      similar to that of muscle, but rate of absorption is slower.&quot;&#xD;
&#xD;
      Dexmedetomidine has been successfully administered by CSCI in the pediatric population, but&#xD;
      so far has not been used by CSCI in palliative care patients. Neither midazolam or&#xD;
      dexmedetomidine are currently approved for use by the subcutaneous route, but Health Canada&#xD;
      approval will be obtained for the subcutaneous (SC) route for both dexmedetomidine and&#xD;
      midazolam before starting the study to provide for use of the preferred subcutaneous route&#xD;
      (over intravenous) in the palliative care environment. The goal of this trial is to assess&#xD;
      the feasibility and methodological issues before enrolling subjects in a larger, multi-centre&#xD;
      RCT to assess the effectiveness of dexmedetomidine in controlling pain, dyspnea, nausea&#xD;
      and/or delirium compared to midazolam. Altogether, findings from this research program (pilot&#xD;
      RCT and multi-centre RCT) will provide critical information for both clinicians and health&#xD;
      policy makers on the use of dexmedetomidine in patients with advanced cancer with difficult&#xD;
      to control or intractable symptoms.&#xD;
&#xD;
      RESEARCH QUESTION:&#xD;
&#xD;
      The overall goal of the investigators is to answer the following question: Does&#xD;
      dexmedetomidine enhance control of pain, dyspnea, nausea and/or delirium, but with improved&#xD;
      rousability, compared to midazolam in patients with advanced cancer? However, for the&#xD;
      purposes of this pilot study, the investigators will address the following question: What is&#xD;
      the feasibility of a multicentre RCT comparing dexmedetomidine with midazolam in enhancing&#xD;
      control of pain, dyspnea, nausea and/or delirium in advanced cancer patients?&#xD;
&#xD;
      RESEARCH OBJECTIVE(S):&#xD;
&#xD;
      The objectives of this pilot study are:&#xD;
&#xD;
        -  To identify facilitators and barriers to recruiting and consenting palliative care&#xD;
           advanced cancer patients&#xD;
&#xD;
        -  To assess site irritation when administering dexmedetomidine by continuous subcutaneous&#xD;
           infusion as an alternate route to continuous intravenous infusion in advanced cancer&#xD;
           patients&#xD;
&#xD;
        -  To assess feasibility of collecting study measures&#xD;
&#xD;
        -  To assess utility of a new study measurement of acceptable improvement of symptoms as&#xD;
           assessed by patient, family, and staff&#xD;
&#xD;
      Other objectives of interest are:&#xD;
&#xD;
        -  To compare arousability of palliative care advanced cancer patients when symptoms are&#xD;
           controlled with dexmedetomidine as compared to midazolam&#xD;
&#xD;
        -  To compare pain, dyspnea, nausea, delirium symptoms of palliative care advanced cancer&#xD;
           patients sedated with dexmedetomidine as compared to midazolam&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Study design determined to be not likely feasible&#xD;
  </why_stopped>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">November 2014</completion_date>
  <primary_completion_date type="Actual">November 2014</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>Supportive Care</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of subjects needed to recruit for a multicenter double blind randomized controlled phase III trial comparing dexmedetomidine to midazolam for symptom control in advanced cancer patients</measure>
    <time_frame>one year</time_frame>
    <description>Sample size determination for significant improvement in:&#xD;
Pain&#xD;
Dyspnea&#xD;
Nausea&#xD;
Delirium&#xD;
Rousability</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in pain (0 to 10 numerical scale)</measure>
    <time_frame>Up to 10 days</time_frame>
    <description>Pain will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in dyspnea (0 to 10 numerical scale)</measure>
    <time_frame>Up to 10 days</time_frame>
    <description>Dyspnea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in nausea (0 to 10 numerical scale)</measure>
    <time_frame>Up to 10 days</time_frame>
    <description>Nausea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in delirium (16 item clinician rated scale)</measure>
    <time_frame>Up to 10 days</time_frame>
    <description>Delirium will be assessed using the Delirium Rating Scale-Revised-98 (DRS-R-98)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rousability (10 point scale)</measure>
    <time_frame>Up to 10 days</time_frame>
    <description>Rousability will be measured using the Richmond Agitation and Sedation Scale (RASS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acceptable symptom control (yes/no)</measure>
    <time_frame>Up to 10 days</time_frame>
    <description>Acceptable symptom control of the difficult to control or intractable symptoms of pain, dyspnea, nausea or delirium will be assessed by a two part question addressed to each of subject, family member and assigned palliative care nurse. Subjective responses will be collected from each as binary variables (0/1) with two positive responses indicating acceptable symptom control overall.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Time to enroll 20 subjects</measure>
    <time_frame>One year</time_frame>
    <description>This information will be used to determine accrual rate. The accrual rate and the primary outcome measure of number needed to recruit will be used to determine the number of sites required for a multi-center double blind randomized controlled Phase III trial comparing dexmedetomidine to midazolam for symptom control in advanced cancer patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cost determination for developing a budget for a large multi-center trial</measure>
    <time_frame>One year</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Pain Intractable</condition>
  <condition>Delirium</condition>
  <condition>Dyspnea</condition>
  <condition>Nausea</condition>
  <arm_group>
    <arm_group_label>Dexmedetomidine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dexmedetomidine 0.2 to 1.1 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Midazolam</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Midazolam 10 to 100 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexmedetomidine</intervention_name>
    <description>Study drugs will be administered by continuous subcutaneous infusion using a weight based protocol at a rate between 1.0 to 5.5 mL/hr.&#xD;
The study drug will be started at a rate of 1.0 mL/hr.&#xD;
The infusion rate is incremented by 0.5 ml/hr every 30 minutes until acceptable symptom control, bradycardia (heart rate &lt; 40) or hypotension (systolic blood pressure &lt; 80) prevent further increase or maximum infusion rate of 5.5 ml/hr, whichever comes first. Achievement of acceptable symptom control will be defined, for purposes of this trial, as a consensus between reports from patient, family care giver and attending registered nurse</description>
    <arm_group_label>Dexmedetomidine</arm_group_label>
    <other_name>Precedex</other_name>
    <other_name>DIN 02339366</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>Study drugs will be administered by continuous subcutaneous infusion using a weight based protocol at a rate between 1.0 to 5.5 mL/hr.&#xD;
The study drug will be started at a rate of 1.0 mL/hr.&#xD;
The infusion rate is incremented by 0.5 ml/hr every 30 minutes until acceptable symptom control, bradycardia (heart rate &lt; 40) or hypotension (systolic blood pressure &lt; 80) prevent further increase or maximum infusion rate of 5.5 ml/hr, whichever comes first. Achievement of acceptable symptom control will be defined, for purposes of this trial, as a consensus between reports from patient, family care giver and attending registered nurse</description>
    <arm_group_label>Midazolam</arm_group_label>
    <other_name>DIN 02240286</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater or equal to 19 years of age&#xD;
&#xD;
          -  Advanced cancer patient admitted to the Abbotsford Tertiary Palliative Care Unit&#xD;
&#xD;
          -  Difficult to control or intractable symptom (REF 38, page 3)&#xD;
&#xD;
          -  Midazolam CSCI would normally be considered for symptom management&#xD;
&#xD;
          -  Informed consent is able to be provided in the English language&#xD;
&#xD;
          -  Goals of care include do not resuscitate (DNR)&#xD;
&#xD;
          -  For intractable symptoms, patient would prefer proportional sedation rather than no&#xD;
             sedation or total sedation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Second or third degree heart block (without pacemaker)&#xD;
&#xD;
          -  Uncompensated congestive heart failure&#xD;
&#xD;
          -  Heart rate less than 50 beats per minute&#xD;
&#xD;
          -  Mean arterial blood pressure (MAP) &lt; 60&#xD;
&#xD;
          -  Weight below 35 kg. or above 85 kg.&#xD;
&#xD;
          -  Prior use within the preceding 14 days of high dose benzodiazepines equivalent to the&#xD;
             use of 30 mg or more of midazolam or 6 mg or more of lorazepam per 24 hours.&#xD;
&#xD;
          -  Currently enrolled in any other research study involving drugs or devices&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Neil K Hilliard, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>1. BC Cancer Agency 2. Fraser Health Authority</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Stuart Brown, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fraser Health Authority</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Abbotsford Regional Hospital and Cancer Center</name>
      <address>
        <city>Abbotsford</city>
        <state>British Columbia</state>
        <zip>V2S 0C2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
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    <PMID>19042839</PMID>
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  <verification_date>January 2013</verification_date>
  <study_first_submitted>August 29, 2012</study_first_submitted>
  <study_first_submitted_qc>September 14, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 19, 2012</study_first_posted>
  <last_update_submitted>May 22, 2015</last_update_submitted>
  <last_update_submitted_qc>May 22, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 25, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>feasibility studies</keyword>
  <keyword>conscious sedation/</keyword>
  <keyword>dexmedetomidine/</keyword>
  <keyword>midazolam/</keyword>
  <keyword>infusions, subcutaneous/</keyword>
  <keyword>palliative care/</keyword>
  <keyword>terminal care/</keyword>
  <keyword>terminally ill/</keyword>
  <keyword>neoplasms/</keyword>
  <keyword>treatment outcome</keyword>
  <keyword>Precedex</keyword>
  <keyword>&quot;end of life&quot;</keyword>
  <keyword>Dying</keyword>
  <keyword>Advanced cancer</keyword>
  <keyword>mood/delirium/delirious</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dyspnea</mesh_term>
    <mesh_term>Delirium</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Dexmedetomidine</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/NCT01687751
org study id: FHREB 2012-057
nct id: NCT01687751
lead sponsor: 
has dmc: No
Cancer patients with very difficult to control symptoms at the Abbotsford (AC) and Fraser
      Valley (FVC) Cancer Centers are referred and admitted to the Tertiary Palliative Care Units
      at the Abbotsford Regional Hospital and Cancer Center(ARHCC). For symptom management,
      patients are sometimes given midazolam continuously through a needle placed underneath the
      skin. While effective in symptom management, midazolam can be sedating, leaving patients
      unable to interact with loved ones in their last days.

      This study is a pilot project. Before proceeding to a full-scale study, a "pilot study" or
      "feasibility study" is often carried out first to test the design of a study, the likelihood
      of successful recruitment or the acceptability of the intervention to potential subjects. The
      basic idea is to find out whether it will be practical to proceed to a larger study that will
      include more subjects. This type of study involves only a small number of subjects and
      therefore the results can only be used as a guide for further larger studies.

      The investigators also will determine whether palliative care cancer patients taking a
      medication called dexmedetomidine would have improved rousability (more easily and fully
      awakened) and symptom control (pain, shortness of breath, nausea or confusion) compared with
      those taking standard of care which is receiving the medication midazolam. The use of
      dexmedetomidine in other clinical situations (in the Operating Room or Intensive Care Unit
      where the patient can still respond to the doctor) has been shown to be effective in symptom
      control and to provide a better degree of rousability to patients but has not been well
      studied in the palliative care environment.
INTRODUCTION AND BACKGROUND

      Advanced cancer patients nearing the end of life suffer from pain, anxiety and other symptoms
      that can be very difficult to control. The current practice within Fraser Health Authority is
      to admit these patients to one of three tertiary palliative care units (TPCUs) for pain and
      symptom management. Once admitted, if pain and symptom relieving measures are insufficient,
      patients are given a continuous subcutaneous infusion (CSCI) of the drug midazolam for
      symptom management. While effective, sedation with midazolam often leaves patients unable to
      eat or drink or interact with their environment.

      Dexmedetomidine is a unique and promising agent for managing intractable symptoms in
      palliative patients at the end of life . In addition to providing proportional sedation for
      symptom control, compared to midazolam, dexmedetomidine has the additional attributes of
      providing improved management of pain, dyspnea and delirium. Of special interest to patients
      who would like to continue to be involved in decision making and to be able to communicate
      with loved ones at the end of life is the quality of rousability possible when
      dexmedetomidine is used for sedation instead of midazolam. These features have been well
      studied in the ICU and anaesthesia literature but not in the palliative care environment.

      PURPOSE AND JUSTIFICATION

      Currently, standard care for patients with difficult or intractable symptoms for patients
      admitted to the tertiary palliative care units in Fraser Health is the administration of
      midazolam by CSCI as recommended in the evidence based Fraser Health Authority (FHA) Hospice
      Palliative Care Program Symptom Guideline "Refractory Symptoms and Palliative Sedation
      Therapy Guideline". The same guideline states that among the criteria for implementation of
      palliative sedation therapy is that "in all but the most unusual circumstances, death is
      anticipated within hours to days". However, many other patients with difficult or intractable
      symptoms have a natural course of their illness that is longer than 'hours to days'. These
      patients would benefit from a degree of sedation that is proportional to the severity of
      their symptoms. Therefore, particularly in these circumstances, an option other than deep
      palliative sedation with midazolam is necessary where the patient would very often like to be
      aware of those around them and still not be confused or in pain.

      Despite many studies among ICU and anaesthesia patients, only two reports with four patients
      have evaluated use of dexmedetomidine in the palliative care environment. The first case was
      a 45 year old man with cervical paraganglioma, palliative performance scale (PPS) 10% with
      uncontrolled pain, insomnia, anxiety and severe psychological distress. Combined with
      morphine, a continuous intravenous infusion (CIVI) of dexmedetomidine provided relief of pain
      and anxiety within 30 minutes. The patient was sleeping without sign of pain, but prompt
      communication with his sister was possible. The infusion continued 24 hrs with good physical
      and psychological symptom control. The second case was 54 year old woman with breast cancer,
      PPS 20%, delirium and hypercalcemia. Treatment also included CIVI morphine, haloperidol 10
      mg/day. Dexmedetomidine CIVI for 48 hr infusion improved agitation and the patient was able
      to transfer out of the bed, sit in a chair and communicate when necessary. When intravenous
      access was lost, the patient was sedated with midazolam CSCI 5 mg/hr and died 72 hours hours
      later. The third case was a 40 year old woman with advanced cervical cancer, PPS 10%, renal
      failure, hypercalcemia, intractable agitated delirium and pain with movement. Treatment
      included CSCI morphine, hydration and haloperidol 8 mg/day. Dexmedetomidine infusion
      temporarily improved delirium for 5 hours, but not pain with movement. When restlessness
      returned, dexmedetomidine was changed to midazolam 12 mg/hr for the 4 days until the patient
      died. The fourth case was a 46 year old woman with intractable back and left abdominopelvic
      pain radiating into her left leg. She was diagnosed with adenocarcinoma of unknown primary
      with a progressively expanding left retroperitoneal mass involving the psoas muscle and
      adjacent vertebral bodies. After the titration phase of dexmedetomidine, pain decreased to
      6/10 as measured by a numerical pain scale which was considered tolerable by the patient.
      There was no significant sedation. By the third day, the pain increased to 9/10. As it was
      the patient's wish to go home, instead of up titrating the dexmedetomidine, a continuous
      epidural was started with bupivicaine and clonidine.

      Current ongoing studies of dexmedetomidine use in the palliative care environment is limited
      to a Phase II study of dexmedetomidine in treating symptoms of distress in advanced cancer
      patients. The objective of this nine patient cohort study at Duke University Medical Center
      is to assess the effectiveness of 3 separate doses of dexmedetomidine (0.7, 1.5, 2.5 mg/kg/hr
      by continuous intravenous infusion) as add-on treatment for intractable pain, agitation and
      or delirium in terminally ill cancer patients in their last week of life until death.
      Overall, there is limited evidence in the literature to guide practice of using
      dexmedetomidine in the palliative care environment.

      Given this gap in knowledge, the investigators propose to conduct a pilot randomized
      controlled trial (RCT) of dexmedetomidine CSCI compared to midazolam CSCI in advanced cancer
      patients in the palliative care setting.

      The subcutaneous route is chosen for this pilot study as the preferred route of drug delivery
      as this conforms to the current standard of care according the FHA Hospice Palliative Care
      symptom guideline "Refractory Symptoms and Palliative Sedation Therapy Guideline": "Where
      feasible, the use of midazolam by CSCI is preferred to permit responsive titration. In
      general, subcutaneous administration is preferred to intravenous administration because of
      the practical advantage of subcutaneous infusion and the greater risk of apnea when bolus
      injections are administered intravenously". "The subcutaneous route is the most commonly used
      parenteral route in palliative care", "Drugs given via the subcutaneous route tend to have a
      high bioavailability (generally near 100 %)" "Subcutaneous infusion provides blood levels
      comparable to those from intravenous administration", "Perfusion of subcutaneous tissue is
      similar to that of muscle, but rate of absorption is slower."

      Dexmedetomidine has been successfully administered by CSCI in the pediatric population, but
      so far has not been used by CSCI in palliative care patients. Neither midazolam or
      dexmedetomidine are currently approved for use by the subcutaneous route, but Health Canada
      approval will be obtained for the subcutaneous (SC) route for both dexmedetomidine and
      midazolam before starting the study to provide for use of the preferred subcutaneous route
      (over intravenous) in the palliative care environment. The goal of this trial is to assess
      the feasibility and methodological issues before enrolling subjects in a larger, multi-centre
      RCT to assess the effectiveness of dexmedetomidine in controlling pain, dyspnea, nausea
      and/or delirium compared to midazolam. Altogether, findings from this research program (pilot
      RCT and multi-centre RCT) will provide critical information for both clinicians and health
      policy makers on the use of dexmedetomidine in patients with advanced cancer with difficult
      to control or intractable symptoms.

      RESEARCH QUESTION:

      The overall goal of the investigators is to answer the following question: Does
      dexmedetomidine enhance control of pain, dyspnea, nausea and/or delirium, but with improved
      rousability, compared to midazolam in patients with advanced cancer? However, for the
      purposes of this pilot study, the investigators will address the following question: What is
      the feasibility of a multicentre RCT comparing dexmedetomidine with midazolam in enhancing
      control of pain, dyspnea, nausea and/or delirium in advanced cancer patients?

      RESEARCH OBJECTIVE(S):

      The objectives of this pilot study are:

        -  To identify facilitators and barriers to recruiting and consenting palliative care
           advanced cancer patients

        -  To assess site irritation when administering dexmedetomidine by continuous subcutaneous
           infusion as an alternate route to continuous intravenous infusion in advanced cancer
           patients

        -  To assess feasibility of collecting study measures

        -  To assess utility of a new study measurement of acceptable improvement of symptoms as
           assessed by patient, family, and staff

      Other objectives of interest are:

        -  To compare arousability of palliative care advanced cancer patients when symptoms are
           controlled with dexmedetomidine as compared to midazolam

        -  To compare pain, dyspnea, nausea, delirium symptoms of palliative care advanced cancer
           patients sedated with dexmedetomidine as compared to midazolam
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of subjects needed to recruit for a multicenter double blind randomized controlled phase III trial comparing dexmedetomidine to midazolam for symptom control in advanced cancer patients
time frame: one year
description: Sample size determination for significant improvement in:
Pain
Dyspnea
Nausea
Delirium
Rousability
measure: Change in pain (0 to 10 numerical scale)
time frame: Up to 10 days
description: Pain will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)
measure: Change in dyspnea (0 to 10 numerical scale)
time frame: Up to 10 days
description: Dyspnea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)
measure: Change in nausea (0 to 10 numerical scale)
time frame: Up to 10 days
description: Nausea will be evaluated using the Edmonton Symptom Assessment Scale (ESASr)
measure: Change in delirium (16 item clinician rated scale)
time frame: Up to 10 days
description: Delirium will be assessed using the Delirium Rating Scale-Revised-98 (DRS-R-98)
measure: Rousability (10 point scale)
time frame: Up to 10 days
description: Rousability will be measured using the Richmond Agitation and Sedation Scale (RASS)
measure: Acceptable symptom control (yes/no)
time frame: Up to 10 days
description: Acceptable symptom control of the difficult to control or intractable symptoms of pain, dyspnea, nausea or delirium will be assessed by a two part question addressed to each of subject, family member and assigned palliative care nurse. Subjective responses will be collected from each as binary variables (0/1) with two positive responses indicating acceptable symptom control overall.
measure: Time to enroll 20 subjects
time frame: One year
description: This information will be used to determine accrual rate. The accrual rate and the primary outcome measure of number needed to recruit will be used to determine the number of sites required for a multi-center double blind randomized controlled Phase III trial comparing dexmedetomidine to midazolam for symptom control in advanced cancer patients.
measure: Cost determination for developing a budget for a large multi-center trial
time frame: One year
arm group label: Dexmedetomidine
arm group type: Experimental
description: Dexmedetomidine 0.2 to 1.1 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days
arm group label: Midazolam
arm group type: Active Comparator
description: Midazolam 10 to 100 mcg/kg/hr by continuous subcutaneous infusion for up to 10 days
intervention type: Drug
intervention name: Dexmedetomidine
description: Study drugs will be administered by continuous subcutaneous infusion using a weight based protocol at a rate between 1.0 to 5.5 mL/hr.
The study drug will be started at a rate of 1.0 mL/hr.
The infusion rate is incremented by 0.5 ml/hr every 30 minutes until acceptable symptom control, bradycardia (heart rate < 40) or hypotension (systolic blood pressure < 80) prevent further increase or maximum infusion rate of 5.5 ml/hr, whichever comes first. Achievement of acceptable symptom control will be defined, for purposes of this trial, as a consensus between reports from patient, family care giver and attending registered nurse
arm group label: Dexmedetomidine
other name: Precedex
other name: DIN 02339366
intervention type: Drug
intervention name: Midazolam
description: Study drugs will be administered by continuous subcutaneous infusion using a weight based protocol at a rate between 1.0 to 5.5 mL/hr.
The study drug will be started at a rate of 1.0 mL/hr.
The infusion rate is incremented by 0.5 ml/hr every 30 minutes until acceptable symptom control, bradycardia (heart rate < 40) or hypotension (systolic blood pressure < 80) prevent further increase or maximum infusion rate of 5.5 ml/hr, whichever comes first. Achievement of acceptable symptom control will be defined, for purposes of this trial, as a consensus between reports from patient, family care giver and attending registered nurse
arm group label: Midazolam
other name: DIN 02240286
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: Neil K Hilliard, MD
role: Principal Investigator
affiliation: 1. BC Cancer Agency 2. Fraser Health Authority
last name: Stuart Brown, MD
role: Principal Investigator
affiliation: Fraser Health Authority
facility: 
country: Canada
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responsible party type: Sponsor
mesh term: Dyspnea
mesh term: Delirium
mesh term: Midazolam
mesh term: Dexmedetomidine