<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/NCT03785158</url>
  </required_header>
  <id_info>
    <org_study_id>5506</org_study_id>
    <nct_id>NCT03785158</nct_id>
  </id_info>
  <brief_title>MIND After Surgery</brief_title>
  <acronym>MIND</acronym>
  <official_title>Melatonin for Preventing Postoperative Delirium in Elderly Patients; a Multi-centre Randomized Placebo Controlled Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>McMaster University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>St. Joseph's Healthcare Hamilton</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>McMaster University</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>
      Delirium is the most common neurological adverse outcome in elderly surgical patients. It is&#xD;
      associated with an increased mortality and morbidity, including need for prolonged hospital&#xD;
      stay and institutional care. Despite this, there are no effective preventive strategies.&#xD;
      Melatonin is a hormone released from the pineal gland. It is used to improve sleep quality&#xD;
      and to treat jet lag. Small studies have suggested that it can decrease the chances of&#xD;
      delirium. Since the existing literature is small and uncertain, it is important to test its&#xD;
      benefit in a large sample to help guide clinicians. This proposed trial is aimed at testing&#xD;
      assessing the feasibility of a large, multi-center, randomized control trial to decrease the&#xD;
      incidence of postoperative delirium.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Delirium is defined as an acute and fluctuating disturbance in cognition characterized by&#xD;
      alterations in the level of attention and awareness, which develops over a relative short&#xD;
      period of time and represents a change from the subject's baseline. Its incidence increases&#xD;
      with age and occurs in nearly 50% of elderly inpatients. Postoperative delirium (POD)&#xD;
      increases the risk of patient morbidity and mortality and thereby increasing the cost for the&#xD;
      health care system. Increased risk of mortality persists even three years after&#xD;
      hospitalization, and is an independent risk factor for urinary incontinence, falls, and&#xD;
      decubitus ulcers.&#xD;
&#xD;
      A large prospective study of 1341 patients having non-cardiac surgery with a postoperative&#xD;
      stay of at least 48 hours, reported an overall incidence of 9% in &gt;50 years and 15% in &gt;70&#xD;
      years. Another recent study involving 566 patients of similar surgical cohort reported an&#xD;
      incidence of 24%.&#xD;
&#xD;
      With no current effective treatment, there is a greater focus on prevention of delirium.&#xD;
      Approximately 15% of all POD could be preventable. Preventive strategies can be&#xD;
      pharmacological and non-pharmacological. Non-pharmacological strategies are multifaceted and&#xD;
      involve different interventions. Among attempted pharmacological options, none have really&#xD;
      shown much promise and many suffer from associated adverse effects.&#xD;
&#xD;
      Melatonin is a pineal gland hormone that regulates the sleep-wake rhythm. Disruption of the&#xD;
      sleep-wake cycle is observed in delirium. Abnormal tryptophan metabolism is hypothesized as a&#xD;
      cause for delirium and melatonin supplementation is observed to decrease the breakdown of&#xD;
      tryptophan and serotonin through positive feedback. In patients who develop POD, low&#xD;
      tryptophan and serum melatonin levels were observed. Other advantages of melatonin, being a&#xD;
      natural supplement, include improved sleep, sparing of sedatives, minimal potential for&#xD;
      abuse, or hangover effects.&#xD;
&#xD;
      Systematic reviews done with the existing literature specific to melatonin by a literature&#xD;
      search of MEDLINE, EMBASE and Cochrane databases for combination of terms &quot;melatonin&quot; and&#xD;
      &quot;delirium&quot;, restricted to clinical trials and up to October 25, 2017 found one relevant&#xD;
      systematic review: this systematic review looked at the use of melatonin for delirium&#xD;
      prevention and found four randomized control trials (RCT), out of which three showed positive&#xD;
      results and one showed a negative result. Presently, despite its potential to reduce POD and&#xD;
      improve sleep, the role of melatonin in the elderly surgical population is uncertain. There&#xD;
      is a clear need for a large, well-designed study to establish definitive evidence.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">September 14, 2021</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">January 2024</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>This is a randomised, placebo-controlled, two arm parallel design pilot RCT</intervention_model_description>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Recruitment rate</measure>
    <time_frame>6 months</time_frame>
    <description>Recruitment rate: assessed as at least 4-5 patients/week, and completion of recruitment (60 patients/site) in each site over 3-4 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Medication compliance</measure>
    <time_frame>8 days</time_frame>
    <description>Proportion of patients who are able to take at least two doses of study medications, assessed as &gt;85% of study patients.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Follow up to 3 months</measure>
    <time_frame>3 months</time_frame>
    <description>Proportion of patients who complete 3 months follow up. For feasibility we expect &gt;90% patients to complete study follow up.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of patients recruited from screening</measure>
    <time_frame>6 months</time_frame>
    <description>To identify the proportion of screened patients meeting the study inclusion criteria</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Delirium</measure>
    <time_frame>8 days</time_frame>
    <description>This will be captured from observing the patient from the time of their discharge from pre-anesthetic care unit (PACU), until the time of discharge. Presence or absence will be captured using the Confusion Assessment Method (CAM)-short form. If patient is mechanically ventilated, the assessment will be performed using Confusion Assessment Method-Intensive Care Unit (CAM-ICU) tool.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of Delirium</measure>
    <time_frame>8 days</time_frame>
    <description>When an episode of post-operative delirium is observed, the severity will be assessed using Confusion Assessment Method (CAM) severity form. We will only record the severity for the first episode of post operative delirium observed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep quality</measure>
    <time_frame>8 days</time_frame>
    <description>Quality of sleep will be assessed daily using Richards-Campbell Sleep Questionnaire (RCSQ). It is a visual analogue scale 0-100mm; zero indicating the worst possible sleep to 100 indicating the best sleep.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of ICU care</measure>
    <time_frame>8 days</time_frame>
    <description>Need for ICU or critical care during hospitalization: This will be captured along with the reason and duration of such a stay from hospital records/patient charts</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prolonged hospital stay</measure>
    <time_frame>8 days</time_frame>
    <description>Prolonged hospital stay (beyond anticipated for each patient) will be captured from hospital records/patient charts along with the reason and duration of such a stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Institutional discharge</measure>
    <time_frame>3 months</time_frame>
    <description>This will be recorded from hospital records.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive Status</measure>
    <time_frame>3 months</time_frame>
    <description>This will be captured using Mini Mental Status Examination (MMSE)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>3 months</time_frame>
    <description>This outcome will be captured as in-hospital mortality and up to 3 months after discharge.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse effects</measure>
    <time_frame>7 days</time_frame>
    <description>Observe significant sedation using Pasero Opioid-induced Sedation Scale (validated, commonly used) S=Sleep, easy to arouse&#xD;
Awake and alert&#xD;
Slightly drowsy, easily aroused&#xD;
(S, 1, 2 all acceptable; no action necessary; may increase opioid dose if needed)&#xD;
Frequently drowsy, arousable, drifts off to sleep during conversation Unacceptable; monitor respiratory status and sedation level closely until sedation level is stable at &lt;3 and respiratory status is satisfactory; decrease opioid dose 25% to 50%, or notifiy prescriber or anesthesiologist for orders; consider a non-sedation, opioid-sparing nonopioid if not contraindicated&#xD;
Somnolent, minimal or no response to verbal and physical stimulation Unacceptable; stop opioid; consider administering naloxone; notifiy prescriber or anesthesiologist; monitor respiratory status and sedation level closely until sedation level is stable at &lt;3 and respiratory status is acceptable</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Post-operative Delirium</condition>
  <condition>Major Non-cardiac Surgery</condition>
  <arm_group>
    <arm_group_label>Melatonin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>3 mg of liquid melatonin by oral route for 8 days. The 1st dose will be given 1-2 hours prior to the surgery, followed by bed time doses (between 7-9 pm) given on postoperative day (POD) 1 until discharge or for the first 7 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Similar looking/tasting 3 mg (5 ml) placebo syrup administered preoperatively by oral route and for the next 7 days or until discharge. The 1st dose will be given 1-2 hours prior to the surgery, followed by bed time doses (between 7-9 pm) given on postoperative day (POD) 1 until discharge or for the first 7 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Liquid Melatonin</intervention_name>
    <description>Melatonin is a natural supplement.</description>
    <arm_group_label>Melatonin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Similar looking/tasting placebo syrup</description>
    <arm_group_label>Placebo Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt;65 years&#xD;
&#xD;
          -  having a major non-cardiac surgery (which involve major vascular, thoracic,&#xD;
             orthopedic, gynecological, otolaryngeal, general and gastrointestinal surgeries) with&#xD;
             an expected hospital stay of 2 days or more, and&#xD;
&#xD;
          -  ability to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  active delirium or dementia&#xD;
&#xD;
          -  ongoing melatonin treatment&#xD;
&#xD;
          -  unable to take oral medications&#xD;
&#xD;
          -  planned postoperative ventilation&#xD;
&#xD;
          -  previous study participation&#xD;
&#xD;
          -  allergy to melatonin&#xD;
&#xD;
          -  hepatic impairment defined as alanine aminotransferase greater than 500 IU/L&#xD;
&#xD;
          -  previous liver transplant or liver cirrhosis of Child-Pugh classes B and C&#xD;
&#xD;
          -  not willing to participate&#xD;
&#xD;
          -  language barrier&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Toni Tidy, BHSc</last_name>
    <phone>905-525-9140</phone>
    <phone_ext>21737</phone_ext>
    <email>tonitidy@mcmaster.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Harsha Shanthanna, MD</last_name>
    <phone>905-522-1155</phone>
    <phone_ext>33853</phone_ext>
    <email>shanthh@mcmaster.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>St. Joseph's Healthcare Hamilton</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8N 4A6</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Harsha Shanthanna, MD</last_name>
      <phone>905-522-1155</phone>
      <phone_ext>33853</phone_ext>
      <email>shanthh@mcmaster.ca</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hamilton Health Sciences-Juravinski Hospital Location</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8V 1C3</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>James E Paul, MD</last_name>
      <phone>905-525-9140</phone>
      <phone_ext>21736</phone_ext>
      <email>paulj@mcmaster.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>December 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 2018</study_first_posted>
  <last_update_submitted>January 12, 2023</last_update_submitted>
  <last_update_submitted_qc>January 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Delirium</keyword>
  <keyword>Elderly patients having non-cardiac surgery</keyword>
  <keyword>Melatonin</keyword>
  <keyword>sleep quality</keyword>
  <keyword>sleep deprivation</keyword>
  <keyword>sleep-wake cycle</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Delirium</mesh_term>
    <mesh_term>Emergence Delirium</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melatonin</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/NCT03785158
org study id: 5506
nct id: NCT03785158
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Delirium is the most common neurological adverse outcome in elderly surgical patients. It is
      associated with an increased mortality and morbidity, including need for prolonged hospital
      stay and institutional care. Despite this, there are no effective preventive strategies.
      Melatonin is a hormone released from the pineal gland. It is used to improve sleep quality
      and to treat jet lag. Small studies have suggested that it can decrease the chances of
      delirium. Since the existing literature is small and uncertain, it is important to test its
      benefit in a large sample to help guide clinicians. This proposed trial is aimed at testing
      assessing the feasibility of a large, multi-center, randomized control trial to decrease the
      incidence of postoperative delirium.
Delirium is defined as an acute and fluctuating disturbance in cognition characterized by
      alterations in the level of attention and awareness, which develops over a relative short
      period of time and represents a change from the subject's baseline. Its incidence increases
      with age and occurs in nearly 50% of elderly inpatients. Postoperative delirium (POD)
      increases the risk of patient morbidity and mortality and thereby increasing the cost for the
      health care system. Increased risk of mortality persists even three years after
      hospitalization, and is an independent risk factor for urinary incontinence, falls, and
      decubitus ulcers.

      A large prospective study of 1341 patients having non-cardiac surgery with a postoperative
      stay of at least 48 hours, reported an overall incidence of 9% in >50 years and 15% in >70
      years. Another recent study involving 566 patients of similar surgical cohort reported an
      incidence of 24%.

      With no current effective treatment, there is a greater focus on prevention of delirium.
      Approximately 15% of all POD could be preventable. Preventive strategies can be
      pharmacological and non-pharmacological. Non-pharmacological strategies are multifaceted and
      involve different interventions. Among attempted pharmacological options, none have really
      shown much promise and many suffer from associated adverse effects.

      Melatonin is a pineal gland hormone that regulates the sleep-wake rhythm. Disruption of the
      sleep-wake cycle is observed in delirium. Abnormal tryptophan metabolism is hypothesized as a
      cause for delirium and melatonin supplementation is observed to decrease the breakdown of
      tryptophan and serotonin through positive feedback. In patients who develop POD, low
      tryptophan and serum melatonin levels were observed. Other advantages of melatonin, being a
      natural supplement, include improved sleep, sparing of sedatives, minimal potential for
      abuse, or hangover effects.

      Systematic reviews done with the existing literature specific to melatonin by a literature
      search of MEDLINE, EMBASE and Cochrane databases for combination of terms "melatonin" and
      "delirium", restricted to clinical trials and up to October 25, 2017 found one relevant
      systematic review: this systematic review looked at the use of melatonin for delirium
      prevention and found four randomized control trials (RCT), out of which three showed positive
      results and one showed a negative result. Presently, despite its potential to reduce POD and
      improve sleep, the role of melatonin in the elderly surgical population is uncertain. There
      is a clear need for a large, well-designed study to establish definitive evidence.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a randomised, placebo-controlled, two arm parallel design pilot RCT
primary purpose: Supportive Care
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor
measure: Recruitment rate
time frame: 6 months
description: Recruitment rate: assessed as at least 4-5 patients/week, and completion of recruitment (60 patients/site) in each site over 3-4 months.
measure: Medication compliance
time frame: 8 days
description: Proportion of patients who are able to take at least two doses of study medications, assessed as >85% of study patients.
measure: Follow up to 3 months
time frame: 3 months
description: Proportion of patients who complete 3 months follow up. For feasibility we expect >90% patients to complete study follow up.
measure: Proportion of patients recruited from screening
time frame: 6 months
description: To identify the proportion of screened patients meeting the study inclusion criteria
measure: Incidence of Delirium
time frame: 8 days
description: This will be captured from observing the patient from the time of their discharge from pre-anesthetic care unit (PACU), until the time of discharge. Presence or absence will be captured using the Confusion Assessment Method (CAM)-short form. If patient is mechanically ventilated, the assessment will be performed using Confusion Assessment Method-Intensive Care Unit (CAM-ICU) tool.
measure: Severity of Delirium
time frame: 8 days
description: When an episode of post-operative delirium is observed, the severity will be assessed using Confusion Assessment Method (CAM) severity form. We will only record the severity for the first episode of post operative delirium observed.
measure: Sleep quality
time frame: 8 days
description: Quality of sleep will be assessed daily using Richards-Campbell Sleep Questionnaire (RCSQ). It is a visual analogue scale 0-100mm; zero indicating the worst possible sleep to 100 indicating the best sleep.
measure: Incidence of ICU care
time frame: 8 days
description: Need for ICU or critical care during hospitalization: This will be captured along with the reason and duration of such a stay from hospital records/patient charts
measure: Prolonged hospital stay
time frame: 8 days
description: Prolonged hospital stay (beyond anticipated for each patient) will be captured from hospital records/patient charts along with the reason and duration of such a stay
measure: Institutional discharge
time frame: 3 months
description: This will be recorded from hospital records.
measure: Cognitive Status
time frame: 3 months
description: This will be captured using Mini Mental Status Examination (MMSE)
measure: Mortality
time frame: 3 months
description: This outcome will be captured as in-hospital mortality and up to 3 months after discharge.
measure: Adverse effects
time frame: 7 days
description: Observe significant sedation using Pasero Opioid-induced Sedation Scale (validated, commonly used) S=Sleep, easy to arouse
Awake and alert
Slightly drowsy, easily aroused
(S, 1, 2 all acceptable; no action necessary; may increase opioid dose if needed)
Frequently drowsy, arousable, drifts off to sleep during conversation Unacceptable; monitor respiratory status and sedation level closely until sedation level is stable at <3 and respiratory status is satisfactory; decrease opioid dose 25% to 50%, or notifiy prescriber or anesthesiologist for orders; consider a non-sedation, opioid-sparing nonopioid if not contraindicated
Somnolent, minimal or no response to verbal and physical stimulation Unacceptable; stop opioid; consider administering naloxone; notifiy prescriber or anesthesiologist; monitor respiratory status and sedation level closely until sedation level is stable at <3 and respiratory status is acceptable
arm group label: Melatonin
arm group type: Active Comparator
description: 3 mg of liquid melatonin by oral route for 8 days. The 1st dose will be given 1-2 hours prior to the surgery, followed by bed time doses (between 7-9 pm) given on postoperative day (POD) 1 until discharge or for the first 7 days.
arm group label: Placebo Group
arm group type: Placebo Comparator
description: Similar looking/tasting 3 mg (5 ml) placebo syrup administered preoperatively by oral route and for the next 7 days or until discharge. The 1st dose will be given 1-2 hours prior to the surgery, followed by bed time doses (between 7-9 pm) given on postoperative day (POD) 1 until discharge or for the first 7 days.
intervention type: Other
intervention name: Liquid Melatonin
description: Melatonin is a natural supplement.
arm group label: Melatonin
intervention type: Other
intervention name: Placebo
description: Similar looking/tasting placebo syrup
arm group label: Placebo Group
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: No
last name: Toni Tidy, BHSc
phone: 905-525-9140
phone ext: 21737
email: tonitidy@mcmaster.ca
last name: Harsha Shanthanna, MD
phone: 905-522-1155
phone ext: 33853
email: shanthh@mcmaster.ca
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Sponsor
mesh term: Delirium
mesh term: Emergence Delirium
mesh term: Melatonin