<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/NCT03013790</url>
  </required_header>
  <id_info>
    <org_study_id>MICE</org_study_id>
    <nct_id>NCT03013790</nct_id>
  </id_info>
  <brief_title>Melatonin Use in the Intensive Care Elderly Population</brief_title>
  <acronym>MICE</acronym>
  <official_title>Melatonin Use in the Intensive Care Elderly Population</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>MICE Trial Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>MICE Trial Group</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators are studying the use of Melatonin in non-ventilated patients over the age&#xD;
      of 65. Primary endpoint will be assesments of delirium, with secondary endpoints to include&#xD;
      length of stay, use of anti-psychotic medications, and mortality&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Summary Melatonin is a naturally produced hormone involved in the synchronization of&#xD;
      circadian rhythms and the sleep-wake cycle in humans. It is often given as a sleep aid and is&#xD;
      generally well tolerated, with very few drug-drug interactions. Recent studies have shown&#xD;
      marginal benefit in increasing amount of sleep, but have proven benefit in decreasing&#xD;
      delirium in elderly patients on medical wards.&#xD;
&#xD;
      Delirium is a serious problem in hospitals and Intensive-Care Units (ICUs), contributing to&#xD;
      longer hospital stays as well as morbidity and mortality. Studies have shown that each&#xD;
      additional day of delirium increases mortality by 10%1. It is estimated that delirium costs&#xD;
      the US healthcare system $38-$152 billion annually, and the cost of treating a delirious&#xD;
      patient is 2.5 times higher than treating one without delirium. It is estimated that up to&#xD;
      one third of cases of delirium are preventable. Additionally, many of the medications given&#xD;
      in the ICU can worsen delirium, including narcotics, antipsychotics, and benzodiazepines.&#xD;
&#xD;
      Treatment of delirium consists mostly of prevention, by frequently re-orienting the&#xD;
      individual, letting in as much natural light as possible, frequent touching, and providing a&#xD;
      quiet place for rest. Pharmacological treatment consists mostly of antipsychotics, which&#xD;
      often have adverse effects and can worsen delirium.&#xD;
&#xD;
      Incidents of delirium are much higher in elderly patients, up to 80% in some cohorts, as well&#xD;
      as ICU patients. Multiple theories for this exist, including the lack of a true rest time at&#xD;
      night, multiple sedatives that can affect sleep-wake cycle, and large amounts of noise. It is&#xD;
      also known that elderly patients have less total sleep and more nighttime arousals, and that&#xD;
      ICUs in particular are quite loud, especially at night. The increase in ambient noise paired&#xD;
      with frequent interruptions in sleep for monitoring and blood draws exacerbates this problem&#xD;
      and likely leads to a delirious state.&#xD;
&#xD;
      To our knowledge, no study has looked at melatonin's effect on elderly, non-ventilated&#xD;
      patients in the ICU, which is the group most at risk for developing delirium. Recent studies&#xD;
      have indicated that delirium is decreased with melatonin use in a simulated ICU environment.2&#xD;
      This randomized, controlled study would aim to confirm these results in an actual ICU&#xD;
      environment.&#xD;
&#xD;
      Additionally, it is unknown what doses are most effective for treatment of delirium.&#xD;
      Literature has shown improvement with both 3 mg and 5 mg, but recent meta-analysis have not&#xD;
      shown benefit of one over the other. 3 Participants Multiple studies done on critically ill,&#xD;
      non-ventilated patients in the ICU show an incidence of delirium of at least 60%, and in some&#xD;
      cases up to 80%4. At Parkview, the highest incidence recorded was 55%, but this was with all&#xD;
      patients. It is likely that this percentage is much higher in the elderly. Assuming an&#xD;
      average incidence of 70%, and assuming the investigators would want to be able to detect a&#xD;
      20% decrease in this incidence with our intervention, the investigators would aim to enroll&#xD;
      600 patients (200 in each arm), with an interim analysis to be done at 300 patients to asses&#xD;
      for harm or efficacy. This will be done by analyzing the primary outcome for a P-value of&#xD;
      &lt;0.05.&#xD;
&#xD;
      Exclusion Criteria Patients with head trauma or Neurosurgical intervention Patients &lt;65 years&#xD;
      of age Patients with an expected life expectancy &lt;48 hours Blind patients Patients with a&#xD;
      seizure history Patients with uncontrolled hypertension Patients with a supratheraputic&#xD;
      (&gt;3.0) INR Patients on strong CYP1A2 inhibitors: ciprofloxacin, fluvoxamine, methoxsalen,&#xD;
      ofloxacin, primaquine Patients who do not speak English or Spanish&#xD;
&#xD;
      Design Upon admission to the ICU, all consecutive, eligible patients or their POA will be&#xD;
      presented with an informed consent describing the trial (Appendix A). All patients over 65&#xD;
      will be screened. Attending physicians as well as Critical Care Fellows will be allowed to&#xD;
      consent the patients. At the point of deciding to join the trial, an order will be put in the&#xD;
      computer for &quot;melatonin protocol&quot;. At this point, pharmacy will assign that patient to either&#xD;
      the placebo, 3mg, or 5mg arm of the study in a 1:1:1 fashion. Physicians, pharmacists, and&#xD;
      nursing staff will be blinded to the protocol. Melatonin dosages of 3 and 5mg will be used&#xD;
      for the study, as recent work with higher doses has been shown to have a &quot;carryover&quot; effect&#xD;
      into the following day. The placebo pill will be a small white tablet of similar size to the&#xD;
      3 and 5mg tablets of melatonin. It is sucrose and is regulated by the FDA as safe for human&#xD;
      consumption. Either placebo or melatonin will be administered at 9pm with evening&#xD;
      medications.&#xD;
&#xD;
      The treatment group will be given either the assigned dose or placebo nightly. Either PO or&#xD;
      PT would be acceptable. The protocol will run until the patient is discharged from the&#xD;
      hospital. Delirium will be assessed using the CAM-ICU evaluation tool in the ICU and bCAM on&#xD;
      the floor according to pre-existing protocols. These will be assessed every 12 hours per a&#xD;
      protocol already in place. These tools are the most widely used in the US, with multiple&#xD;
      studies showing reliable detection of delirium. The CAM scale is attached for reference.&#xD;
&#xD;
      If a patient deteriorates while in the ICU and requires intubation, they will be continued on&#xD;
      the protocol.&#xD;
&#xD;
      Melatonin is generally well-tolerated5, but the two most common side effects are headaches&#xD;
      and confusion. We hope to mitigate the confusion by using a lower dose of melatonin.&#xD;
      Incidence of headache will be tracked, and if deemed necessary by the attending physician,&#xD;
      melatonin therapy can be stopped. Melatonin has minor interactions with Warfarin and&#xD;
      dihydropyridine calcium channel blockers, but patient's INR (if they are on Warfarin) and BP&#xD;
      will be tracked routinely. Melatonin is metabolized by the CYP1A2 system, and so patients on&#xD;
      medications that are potent inhibitors of this enzyme will also be excluded from the study.&#xD;
      There is an interaction between Melatonin and Olanzipine, which is sometimes used for&#xD;
      treatment of delirium. There is the potential for increased sedation with this combination,&#xD;
      but patients will be monitored in an ICU setting while receiving these medications.&#xD;
&#xD;
      Primary outcome will be incidence of delirium (using the CAM-ICU and bCAM scores) in the&#xD;
      study population&#xD;
&#xD;
      Secondary outcomes will be:&#xD;
&#xD;
      ICU days Total Hospital days 30 and 90-day mortality Use of anti-psychotic medications for&#xD;
      treatment of delirium (Haloperidol, Ziprasidone, Olanzapine, Quetiapine) Average Richmond&#xD;
      Agitation and Sedation Scale (RASS) scores when delirium assessed&#xD;
&#xD;
      Hypothesis The investigators' hypothesis is that the use of melatonin will significantly&#xD;
      decrease the incidence of delirium in the elderly, non-ventilated patient. The investigators&#xD;
      will use an accepted P-value of &lt; 0.05 to determine significance. If the p-value doesn't meet&#xD;
      significance, the null hypothesis that melatonin does not decrease the incidence of delirium&#xD;
      in the elderly non-ventilated patient will be accepted.&#xD;
&#xD;
      Collection/Retention of information:&#xD;
&#xD;
      Patients' CAM-ICU scores are already documented in Meditech. Other variables (when patient&#xD;
      moves to floor, when the patient is discharged) are already routinely documented. Following&#xD;
      completion, these variables will be placed in a database and de-identified. The data will be&#xD;
      kept for an additional 3 years to allow for further analysis if required.&#xD;
&#xD;
      Nursing staff as well as house staff will undergo a brief in-service on the study principles&#xD;
      as well as a reminder of how to use the CAM-ICU scores.&#xD;
&#xD;
      Confidentiality:&#xD;
&#xD;
      Only the PI will see the patient's identified information before deidentifying it. To ensure&#xD;
      patient privacy, the informed consent discussion will happen in the patient's private room&#xD;
&#xD;
      Risks:&#xD;
&#xD;
      Melatonin has been proven to safe in every patient population by multiple studies. A&#xD;
      consensus statement by the World Sleep Foundation in 2000 confirms that there have been no&#xD;
      significant side-effects in healthy adults. Specifically, the use of melatonin in seizure&#xD;
      disorders is controversial, with some data showing detriment and some showing benefit. For&#xD;
      this reason, patients with a seizure disorder have been excluded from the study. The&#xD;
      investigators will be using USP (United States Pharmacopeia)- certified melatonin as well.&#xD;
      USP is a non-profit organization that regulates over-the-counter (OTC) supplements in the US.&#xD;
      Its seal verifies that the manufacturer adheres to good manufacturing practices.&#xD;
&#xD;
      The attending physician on the case can choose to withdraw the patient from the study at any&#xD;
      time if they feel that participation is adversely affecting the patient.&#xD;
&#xD;
      Compensation:&#xD;
&#xD;
      There will be no compensation provided for participation in this study.&#xD;
&#xD;
      Benefits:&#xD;
&#xD;
      Considering the multiple studies that have suggested safety and efficacy, critically ill&#xD;
      patients stand to benefit from a lack of delirium and possibly shorter hospital stays. This&#xD;
      would benefit Parkview Medical Center as well.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">January 2018</completion_date>
  <primary_completion_date type="Anticipated">January 2018</primary_completion_date>
  <phase>Phase 4</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>Prevention</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Delirium</measure>
    <time_frame>Length of Hospital Stay, Average of 1 week</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Use of Antipsychotic Medications</measure>
    <time_frame>Length of Hospital Stay, Average of 1 week</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average RASS Score</measure>
    <time_frame>Length of Hospital Stay, Average of 1 week</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU days</measure>
    <time_frame>Length of Hospital Stay, Average of 1 week</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Days</measure>
    <time_frame>Length of Hospital Stay, Average of 1 week</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>30 day mortality</measure>
    <time_frame>30 days post D/C</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>90 day mortality</measure>
    <time_frame>90 days post D/C</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">600</enrollment>
  <condition>Delirium</condition>
  <condition>Melatonin</condition>
  <arm_group>
    <arm_group_label>Melatonin 5mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will be given 5mg tablets of Melatonin nightly for the duration of their hospital stay</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Melatonin 3mg</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will be given 3mg tablets of Melatonin nightly for the duration of their hospital stay</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This arm will be given a Sucrose tablet nightly for the duration of their hospital stay</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melatonin</intervention_name>
    <description>Patients will receive Melatonin at 2 different doses or a placebo</description>
    <arm_group_label>Melatonin 3mg</arm_group_label>
    <arm_group_label>Melatonin 5mg</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Non-ventilated Patients over the age of 65&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with head trauma or Neurosurgical intervention&#xD;
&#xD;
          -  Patients &lt;65 years of age&#xD;
&#xD;
          -  Patients with an expected life expectancy &lt;48 hours&#xD;
&#xD;
          -  Blind patients&#xD;
&#xD;
          -  Patients with a seizure history&#xD;
&#xD;
          -  Patients with uncontrolled hypertension&#xD;
&#xD;
          -  Patients with a supratheraputic (&gt;3.0) INR&#xD;
&#xD;
          -  Patients on strong CYP1A2 inhibitors: ciprofloxacin, fluvoxamine, methoxsalen,&#xD;
             ofloxacin, primaquine&#xD;
&#xD;
          -  Patients who do not speak English or Spanish&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Mike Forte, DO</last_name>
    <phone>7195641542</phone>
    <email>mike_forte@parkviewmc.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Josh Gordon, DO</last_name>
    <phone>7195641542</phone>
    <email>joshiah_gordon@parkviewmc.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Parkview Medical Center</name>
      <address>
        <city>Pueblo</city>
        <state>Colorado</state>
        <zip>81003</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mike Forte, DO</last_name>
      <phone>719-564-1542</phone>
      <email>mike_forte@parkviewmc.com</email>
    </contact>
    <contact_backup>
      <last_name>Josh Gordon, DO</last_name>
      <phone>7195641542</phone>
      <email>joshiah_gordon@parkviewmc.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009 Dec 1;180(11):1092-7. doi: 10.1164/rccm.200904-0537OC. Epub 2009 Sep 10.</citation>
    <PMID>19745202</PMID>
  </reference>
  <reference>
    <citation>Huang HW, Zheng BL, Jiang L, Lin ZT, Zhang GB, Shen L, Xi XM. Effect of oral melatonin and wearing earplugs and eye masks on nocturnal sleep in healthy subjects in a simulated intensive care unit environment: which might be a more promising strategy for ICU sleep deprivation? Crit Care. 2015 Mar 19;19(1):124. doi: 10.1186/s13054-015-0842-8.</citation>
    <PMID>25887528</PMID>
  </reference>
  <reference>
    <citation>Chen S, Shi L, Liang F, Xu L, Desislava D, Wu Q, Zhang J. Exogenous Melatonin for Delirium Prevention: a Meta-analysis of Randomized Controlled Trials. Mol Neurobiol. 2016 Aug;53(6):4046-4053. doi: 10.1007/s12035-015-9350-8. Epub 2015 Jul 21.</citation>
    <PMID>26189834</PMID>
  </reference>
  <reference>
    <citation>Bourne RS, Mills GH. Melatonin: possible implications for the postoperative and critically ill patient. Intensive Care Med. 2006 Mar;32(3):371-9. doi: 10.1007/s00134-005-0061-x. Epub 2006 Feb 14.</citation>
    <PMID>16477412</PMID>
  </reference>
  <reference>
    <citation>Arendt J. In what circumstances is melatonin a useful sleep therapy? Consensus statement, WFSRS focus group, Dresden, November 1999. J Sleep Res. 2000 Dec;9(4):397-8. doi: 10.1111/j.1365-2869.2000.00229.x. No abstract available.</citation>
    <PMID>11123525</PMID>
  </reference>
  <reference>
    <citation>Artemiou P, Bily B, Bilecova-Rabajdova M, Sabol F, Torok P, Kolarcik P, Kolesar A. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients. Kardiochir Torakochirurgia Pol. 2015 Jun;12(2):126-33. doi: 10.5114/kitp.2015.52853. Epub 2015 Jun 30.</citation>
    <PMID>26336494</PMID>
  </reference>
  <reference>
    <citation>Bellapart J, Boots R. Potential use of melatonin in sleep and delirium in the critically ill. Br J Anaesth. 2012 Apr;108(4):572-80. doi: 10.1093/bja/aes035.</citation>
    <PMID>22419624</PMID>
  </reference>
  <reference>
    <citation>Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12(2):R52. doi: 10.1186/cc6871. Epub 2008 Apr 18.</citation>
    <PMID>18423009</PMID>
  </reference>
  <reference>
    <citation>Chakraborti D, Tampi DJ, Tampi RR. Melatonin and melatonin agonist for delirium in the elderly patients. Am J Alzheimers Dis Other Demen. 2015 Mar;30(2):119-29. doi: 10.1177/1533317514539379. Epub 2014 Jun 18.</citation>
    <PMID>24946785</PMID>
  </reference>
  <reference>
    <citation>Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, Nakamura H; DELIRIA-J Group. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014 Apr;71(4):397-403. doi: 10.1001/jamapsychiatry.2013.3320.</citation>
    <PMID>24554232</PMID>
  </reference>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>January 3, 2017</study_first_submitted>
  <study_first_submitted_qc>January 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 9, 2017</study_first_posted>
  <last_update_submitted>July 10, 2017</last_update_submitted>
  <last_update_submitted_qc>July 10, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">July 13, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>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/NCT03013790
org study id: MICE
nct id: NCT03013790
lead sponsor: 
has dmc: Yes
The investigators are studying the use of Melatonin in non-ventilated patients over the age
      of 65. Primary endpoint will be assesments of delirium, with secondary endpoints to include
      length of stay, use of anti-psychotic medications, and mortality
Summary Melatonin is a naturally produced hormone involved in the synchronization of
      circadian rhythms and the sleep-wake cycle in humans. It is often given as a sleep aid and is
      generally well tolerated, with very few drug-drug interactions. Recent studies have shown
      marginal benefit in increasing amount of sleep, but have proven benefit in decreasing
      delirium in elderly patients on medical wards.

      Delirium is a serious problem in hospitals and Intensive-Care Units (ICUs), contributing to
      longer hospital stays as well as morbidity and mortality. Studies have shown that each
      additional day of delirium increases mortality by 10%1. It is estimated that delirium costs
      the US healthcare system $38-$152 billion annually, and the cost of treating a delirious
      patient is 2.5 times higher than treating one without delirium. It is estimated that up to
      one third of cases of delirium are preventable. Additionally, many of the medications given
      in the ICU can worsen delirium, including narcotics, antipsychotics, and benzodiazepines.

      Treatment of delirium consists mostly of prevention, by frequently re-orienting the
      individual, letting in as much natural light as possible, frequent touching, and providing a
      quiet place for rest. Pharmacological treatment consists mostly of antipsychotics, which
      often have adverse effects and can worsen delirium.

      Incidents of delirium are much higher in elderly patients, up to 80% in some cohorts, as well
      as ICU patients. Multiple theories for this exist, including the lack of a true rest time at
      night, multiple sedatives that can affect sleep-wake cycle, and large amounts of noise. It is
      also known that elderly patients have less total sleep and more nighttime arousals, and that
      ICUs in particular are quite loud, especially at night. The increase in ambient noise paired
      with frequent interruptions in sleep for monitoring and blood draws exacerbates this problem
      and likely leads to a delirious state.

      To our knowledge, no study has looked at melatonin's effect on elderly, non-ventilated
      patients in the ICU, which is the group most at risk for developing delirium. Recent studies
      have indicated that delirium is decreased with melatonin use in a simulated ICU environment.2
      This randomized, controlled study would aim to confirm these results in an actual ICU
      environment.

      Additionally, it is unknown what doses are most effective for treatment of delirium.
      Literature has shown improvement with both 3 mg and 5 mg, but recent meta-analysis have not
      shown benefit of one over the other. 3 Participants Multiple studies done on critically ill,
      non-ventilated patients in the ICU show an incidence of delirium of at least 60%, and in some
      cases up to 80%4. At Parkview, the highest incidence recorded was 55%, but this was with all
      patients. It is likely that this percentage is much higher in the elderly. Assuming an
      average incidence of 70%, and assuming the investigators would want to be able to detect a
      20% decrease in this incidence with our intervention, the investigators would aim to enroll
      600 patients (200 in each arm), with an interim analysis to be done at 300 patients to asses
      for harm or efficacy. This will be done by analyzing the primary outcome for a P-value of
      <0.05.

      Exclusion Criteria Patients with head trauma or Neurosurgical intervention Patients <65 years
      of age Patients with an expected life expectancy <48 hours Blind patients Patients with a
      seizure history Patients with uncontrolled hypertension Patients with a supratheraputic
      (>3.0) INR Patients on strong CYP1A2 inhibitors: ciprofloxacin, fluvoxamine, methoxsalen,
      ofloxacin, primaquine Patients who do not speak English or Spanish

      Design Upon admission to the ICU, all consecutive, eligible patients or their POA will be
      presented with an informed consent describing the trial (Appendix A). All patients over 65
      will be screened. Attending physicians as well as Critical Care Fellows will be allowed to
      consent the patients. At the point of deciding to join the trial, an order will be put in the
      computer for "melatonin protocol". At this point, pharmacy will assign that patient to either
      the placebo, 3mg, or 5mg arm of the study in a 1:1:1 fashion. Physicians, pharmacists, and
      nursing staff will be blinded to the protocol. Melatonin dosages of 3 and 5mg will be used
      for the study, as recent work with higher doses has been shown to have a "carryover" effect
      into the following day. The placebo pill will be a small white tablet of similar size to the
      3 and 5mg tablets of melatonin. It is sucrose and is regulated by the FDA as safe for human
      consumption. Either placebo or melatonin will be administered at 9pm with evening
      medications.

      The treatment group will be given either the assigned dose or placebo nightly. Either PO or
      PT would be acceptable. The protocol will run until the patient is discharged from the
      hospital. Delirium will be assessed using the CAM-ICU evaluation tool in the ICU and bCAM on
      the floor according to pre-existing protocols. These will be assessed every 12 hours per a
      protocol already in place. These tools are the most widely used in the US, with multiple
      studies showing reliable detection of delirium. The CAM scale is attached for reference.

      If a patient deteriorates while in the ICU and requires intubation, they will be continued on
      the protocol.

      Melatonin is generally well-tolerated5, but the two most common side effects are headaches
      and confusion. We hope to mitigate the confusion by using a lower dose of melatonin.
      Incidence of headache will be tracked, and if deemed necessary by the attending physician,
      melatonin therapy can be stopped. Melatonin has minor interactions with Warfarin and
      dihydropyridine calcium channel blockers, but patient's INR (if they are on Warfarin) and BP
      will be tracked routinely. Melatonin is metabolized by the CYP1A2 system, and so patients on
      medications that are potent inhibitors of this enzyme will also be excluded from the study.
      There is an interaction between Melatonin and Olanzipine, which is sometimes used for
      treatment of delirium. There is the potential for increased sedation with this combination,
      but patients will be monitored in an ICU setting while receiving these medications.

      Primary outcome will be incidence of delirium (using the CAM-ICU and bCAM scores) in the
      study population

      Secondary outcomes will be:

      ICU days Total Hospital days 30 and 90-day mortality Use of anti-psychotic medications for
      treatment of delirium (Haloperidol, Ziprasidone, Olanzapine, Quetiapine) Average Richmond
      Agitation and Sedation Scale (RASS) scores when delirium assessed

      Hypothesis The investigators' hypothesis is that the use of melatonin will significantly
      decrease the incidence of delirium in the elderly, non-ventilated patient. The investigators
      will use an accepted P-value of < 0.05 to determine significance. If the p-value doesn't meet
      significance, the null hypothesis that melatonin does not decrease the incidence of delirium
      in the elderly non-ventilated patient will be accepted.

      Collection/Retention of information:

      Patients' CAM-ICU scores are already documented in Meditech. Other variables (when patient
      moves to floor, when the patient is discharged) are already routinely documented. Following
      completion, these variables will be placed in a database and de-identified. The data will be
      kept for an additional 3 years to allow for further analysis if required.

      Nursing staff as well as house staff will undergo a brief in-service on the study principles
      as well as a reminder of how to use the CAM-ICU scores.

      Confidentiality:

      Only the PI will see the patient's identified information before deidentifying it. To ensure
      patient privacy, the informed consent discussion will happen in the patient's private room

      Risks:

      Melatonin has been proven to safe in every patient population by multiple studies. A
      consensus statement by the World Sleep Foundation in 2000 confirms that there have been no
      significant side-effects in healthy adults. Specifically, the use of melatonin in seizure
      disorders is controversial, with some data showing detriment and some showing benefit. For
      this reason, patients with a seizure disorder have been excluded from the study. The
      investigators will be using USP (United States Pharmacopeia)- certified melatonin as well.
      USP is a non-profit organization that regulates over-the-counter (OTC) supplements in the US.
      Its seal verifies that the manufacturer adheres to good manufacturing practices.

      The attending physician on the case can choose to withdraw the patient from the study at any
      time if they feel that participation is adversely affecting the patient.

      Compensation:

      There will be no compensation provided for participation in this study.

      Benefits:

      Considering the multiple studies that have suggested safety and efficacy, critically ill
      patients stand to benefit from a lack of delirium and possibly shorter hospital stays. This
      would benefit Parkview Medical Center as well.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Care Provider)
measure: Delirium
time frame: Length of Hospital Stay, Average of 1 week
measure: Use of Antipsychotic Medications
time frame: Length of Hospital Stay, Average of 1 week
measure: Average RASS Score
time frame: Length of Hospital Stay, Average of 1 week
measure: ICU days
time frame: Length of Hospital Stay, Average of 1 week
measure: Hospital Days
time frame: Length of Hospital Stay, Average of 1 week
measure: 30 day mortality
time frame: 30 days post D/C
measure: 90 day mortality
time frame: 90 days post D/C
arm group label: Melatonin 5mg
arm group type: Active Comparator
description: This arm will be given 5mg tablets of Melatonin nightly for the duration of their hospital stay
arm group label: Melatonin 3mg
arm group type: Active Comparator
description: This arm will be given 3mg tablets of Melatonin nightly for the duration of their hospital stay
arm group label: Placebo
arm group type: Placebo Comparator
description: This arm will be given a Sucrose tablet nightly for the duration of their hospital stay
intervention type: Drug
intervention name: Melatonin
description: Patients will receive Melatonin at 2 different doses or a placebo
arm group label: Melatonin 3mg
arm group label: Melatonin 5mg
arm group label: Placebo
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Mike Forte, DO
phone: 7195641542
email: mike_forte@parkviewmc.com
last name: Josh Gordon, DO
phone: 7195641542
email: joshiah_gordon@parkviewmc.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
citation: Pisani MA, Kong SY, Kasl SV, Murphy TE, Araujo KL, Van Ness PH. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009 Dec 1;180(11):1092-7. doi: 10.1164/rccm.200904-0537OC. Epub 2009 Sep 10.
PMID: 19745202
citation: Huang HW, Zheng BL, Jiang L, Lin ZT, Zhang GB, Shen L, Xi XM. Effect of oral melatonin and wearing earplugs and eye masks on nocturnal sleep in healthy subjects in a simulated intensive care unit environment: which might be a more promising strategy for ICU sleep deprivation? Crit Care. 2015 Mar 19;19(1):124. doi: 10.1186/s13054-015-0842-8.
PMID: 25887528
citation: Chen S, Shi L, Liang F, Xu L, Desislava D, Wu Q, Zhang J. Exogenous Melatonin for Delirium Prevention: a Meta-analysis of Randomized Controlled Trials. Mol Neurobiol. 2016 Aug;53(6):4046-4053. doi: 10.1007/s12035-015-9350-8. Epub 2015 Jul 21.
PMID: 26189834
citation: Bourne RS, Mills GH. Melatonin: possible implications for the postoperative and critically ill patient. Intensive Care Med. 2006 Mar;32(3):371-9. doi: 10.1007/s00134-005-0061-x. Epub 2006 Feb 14.
PMID: 16477412
citation: Arendt J. In what circumstances is melatonin a useful sleep therapy? Consensus statement, WFSRS focus group, Dresden, November 1999. J Sleep Res. 2000 Dec;9(4):397-8. doi: 10.1111/j.1365-2869.2000.00229.x. No abstract available.
PMID: 11123525
citation: Artemiou P, Bily B, Bilecova-Rabajdova M, Sabol F, Torok P, Kolarcik P, Kolesar A. Melatonin treatment in the prevention of postoperative delirium in cardiac surgery patients. Kardiochir Torakochirurgia Pol. 2015 Jun;12(2):126-33. doi: 10.5114/kitp.2015.52853. Epub 2015 Jun 30.
PMID: 26336494
citation: Bellapart J, Boots R. Potential use of melatonin in sleep and delirium in the critically ill. Br J Anaesth. 2012 Apr;108(4):572-80. doi: 10.1093/bja/aes035.
PMID: 22419624
citation: Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12(2):R52. doi: 10.1186/cc6871. Epub 2008 Apr 18.
PMID: 18423009
citation: Chakraborti D, Tampi DJ, Tampi RR. Melatonin and melatonin agonist for delirium in the elderly patients. Am J Alzheimers Dis Other Demen. 2015 Mar;30(2):119-29. doi: 10.1177/1533317514539379. Epub 2014 Jun 18.
PMID: 24946785
citation: Hatta K, Kishi Y, Wada K, Takeuchi T, Odawara T, Usui C, Nakamura H; DELIRIA-J Group. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014 Apr;71(4):397-403. doi: 10.1001/jamapsychiatry.2013.3320.
PMID: 24554232
responsible party type: Sponsor
mesh term: Delirium
mesh term: Melatonin