<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/NCT01724424</url>
  </required_header>
  <id_info>
    <org_study_id>3/057/11</org_study_id>
    <nct_id>NCT01724424</nct_id>
  </id_info>
  <brief_title>Melatonin in Healthy Volunteers</brief_title>
  <acronym>DAMSEL1</acronym>
  <official_title>A Dose Escalation Study of Melatonin in Healthy Volunteers as a Potential Treatment for Sepsis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aberdeen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Aberdeen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Antioxidant therapy targeted at mitochondria has the potential to reduce inflammation,&#xD;
      mitochondrial damage and organ dysfunction in sepsis. Melatonin accumulates in mitochondria&#xD;
      and both it and its metabolites have potent antioxidant and anti-inflammatory activity,&#xD;
      preventing organ dysfunction in a rat model of sepsis. The investigators propose a study in&#xD;
      healthy volunteers to assess the tolerability and pharmacokinetics of exogenous melatonin and&#xD;
      its major metabolites and to relate these doses to ex vivo anti-inflammatory and antioxidant&#xD;
      activities. Groups of healthy subjects will receive increasing sequential doses of oral&#xD;
      melatonin in an open label dose escalation study. Ex vivo inflammatory responses, oxidative&#xD;
      stress and mitochondrial function at concentrations of melatonin identified in the dose&#xD;
      escalation study will be determined following exposure of whole blood to an inflammatory&#xD;
      insult. This will provide crucial information to inform a subsequent phase II clinical trial&#xD;
      of melatonin in patients with sepsis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Around 40,000 people die from sepsis in the UK each year. Although the Surviving Sepsis&#xD;
      Campaign -a performance improvement effort by hospitals across Europe, South America and the&#xD;
      United States- has improved outcomes, the mortality rate remains at 31% overall, and &gt;70% in&#xD;
      patients who develop sepsis-induced multiple organ failure.&#xD;
&#xD;
      Oxidative stress in patients with sepsis has been consistently described over the last 20&#xD;
      years by us and others (reviewed in [2]). Oxidative stress initiates inflammatory responses&#xD;
      via activation of the redox sensitive transcription factor nuclear factor kappa B (NFkB).&#xD;
      Mitochondrial dysfunction initiated by oxidative stress is generally accepted as a playing a&#xD;
      major role in sepsis induced organ failure.&#xD;
&#xD;
      Production of energy takes place in mitochondria resulting in production of reactive oxygen&#xD;
      species (ROS) as by-products. Although ROS are damaging, they are essential in cell&#xD;
      signalling and their activity is tightly regulated by a network of antioxidants. When&#xD;
      antioxidant defences are overwhelmed, oxidative stress results, causing damage to lipids,&#xD;
      proteins and nucleic acids within mitochondria and resulting in cell death.&#xD;
&#xD;
      It has been recognised that exogenous antioxidants may be useful in sepsis and more recently&#xD;
      the potential for antioxidants acting specifically in mitochondria has been highlighted.&#xD;
      Antioxidants targeted to mitochondria reduced organ damage in a rat model of sepsis. Although&#xD;
      endogenous melatonin is primarily recognised for regulation of the sleep-wake cycle, higher&#xD;
      concentrations have potent antioxidant activity with highest levels in mitochondria, and thus&#xD;
      stabilise the mitochondrial membrane. Metabolites of melatonin also have antioxidant activity&#xD;
      and products from the reactions with oxidant species are also antioxidants.&#xD;
&#xD;
      In clinical studies low doses (1-5mg) of exogenous melatonin are effective in normalising the&#xD;
      sleep-wake cycle in patients with sepsis. Our in vitro studies in a human endothelial cell&#xD;
      model of sepsis show that higher dose melatonin and its metabolites are equally effective. In&#xD;
      a rat model of sepsis melatonin reduces oxidative damage. The dose needed for antioxidant&#xD;
      actions is considerably higher than that used in sleep-wake cycle studies, but the actual&#xD;
      dose required is unclear. In some studies melatonin has been administered to patients at&#xD;
      larger doses. Melatonin (10mg/day) decreased interleukin-6 (IL-6) levels in patients with&#xD;
      cancer; 300mg/day decreased oxidative stress in patients with amyotrophic lateral sclerosis.&#xD;
      In children with muscular dystrophy, 70mg/day melatonin reduced cytokines and lipid&#xD;
      peroxidation. Melatonin is also likely to be beneficial in sepsis.&#xD;
&#xD;
      In several historical studies melatonin has been given to human volunteers with no reports of&#xD;
      toxicity. Waldhauser gave 80mg melatonin hourly for 4h to healthy men with no ill effects&#xD;
      other than drowsiness and in healthy women given 300mg/d for 4 months there were no side&#xD;
      effects. Adverse effects are rare at doses &lt;1g, but can include drowsiness, headache,&#xD;
      hypothermia, pruritis, abdominal cramps, and tachycardia. Oral bioavailability of low doses&#xD;
      was estimated at 15% of the parent compound but this makes no allowance for the known&#xD;
      bioactivity of metabolites. We propose to undertake a dose escalation study in healthy&#xD;
      volunteers to assess the tolerability of the doses proposed and to measure levels of&#xD;
      exogenous melatonin and the major metabolites. This will provide crucial information to&#xD;
      inform a subsequent application for a clinical trial of melatonin in patients with sepsis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2012</start_date>
  <completion_date type="Actual">May 2013</completion_date>
  <primary_completion_date type="Actual">May 2013</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants in each dose group with adverse events</measure>
    <time_frame>6h and 1 week</time_frame>
    <description>Adverse events : nausea, vomiting, diarrhoea, itching, headache, drowsiness and any other symptoms for 6h immediately after dosing and again after 1 week. Sleeping patterns will also be assessed after 1 week.&#xD;
Altered heart rate, oxygen saturation, ECG, blood pressure.&#xD;
Changes in biochemistry (sodium , potassium, urea, AST, creatinine, glucose) or haematology (WBC and differential counts).&#xD;
All events will be graded according to prospectively defined criteria.</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Sepsis</condition>
  <arm_group>
    <arm_group_label>melatonin 20mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>2 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>melatonin 30mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Melatonin 50mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Melatonin 100mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melatonin</intervention_name>
    <description>20 mg oral single dose</description>
    <arm_group_label>melatonin 20mg</arm_group_label>
    <other_name>N-acetyl-5-methoxytryptamine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melatonin</intervention_name>
    <description>30 mg oral single dose</description>
    <arm_group_label>melatonin 30mg</arm_group_label>
    <other_name>N-acetyl-5-methoxytryptamine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melatonin</intervention_name>
    <description>50mg oral single dose</description>
    <arm_group_label>Melatonin 50mg</arm_group_label>
    <other_name>N-acetyl-5-methoxytryptamine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Melatonin</intervention_name>
    <description>100mg oral single dose</description>
    <arm_group_label>Melatonin 100mg</arm_group_label>
    <other_name>N-acetyl-5-methoxytryptamine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  male&#xD;
&#xD;
          -  aged 18-30 years&#xD;
&#xD;
          -  less than 100kg body weight&#xD;
&#xD;
          -  non-smoker&#xD;
&#xD;
          -  no regular medication&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  female&#xD;
&#xD;
          -  over 100kg&#xD;
&#xD;
          -  under 18 years&#xD;
&#xD;
          -  over 30 years&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>30 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nigel Webster</last_name>
    <role>Study Director</role>
    <affiliation>University of Aberdeen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Aberdeen</name>
      <address>
        <city>Aberdeen</city>
        <state>Scoltand</state>
        <zip>AB25 2ZD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2013</verification_date>
  <study_first_submitted>June 14, 2012</study_first_submitted>
  <study_first_submitted_qc>November 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 9, 2012</study_first_posted>
  <last_update_submitted>May 7, 2013</last_update_submitted>
  <last_update_submitted_qc>May 7, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 9, 2013</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>Sepsis</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/NCT01724424
org study id: 3/057/11
nct id: NCT01724424
lead sponsor: 
has dmc: Yes
Antioxidant therapy targeted at mitochondria has the potential to reduce inflammation,
      mitochondrial damage and organ dysfunction in sepsis. Melatonin accumulates in mitochondria
      and both it and its metabolites have potent antioxidant and anti-inflammatory activity,
      preventing organ dysfunction in a rat model of sepsis. The investigators propose a study in
      healthy volunteers to assess the tolerability and pharmacokinetics of exogenous melatonin and
      its major metabolites and to relate these doses to ex vivo anti-inflammatory and antioxidant
      activities. Groups of healthy subjects will receive increasing sequential doses of oral
      melatonin in an open label dose escalation study. Ex vivo inflammatory responses, oxidative
      stress and mitochondrial function at concentrations of melatonin identified in the dose
      escalation study will be determined following exposure of whole blood to an inflammatory
      insult. This will provide crucial information to inform a subsequent phase II clinical trial
      of melatonin in patients with sepsis.
Around 40,000 people die from sepsis in the UK each year. Although the Surviving Sepsis
      Campaign -a performance improvement effort by hospitals across Europe, South America and the
      United States- has improved outcomes, the mortality rate remains at 31% overall, and >70% in
      patients who develop sepsis-induced multiple organ failure.

      Oxidative stress in patients with sepsis has been consistently described over the last 20
      years by us and others (reviewed in [2]). Oxidative stress initiates inflammatory responses
      via activation of the redox sensitive transcription factor nuclear factor kappa B (NFkB).
      Mitochondrial dysfunction initiated by oxidative stress is generally accepted as a playing a
      major role in sepsis induced organ failure.

      Production of energy takes place in mitochondria resulting in production of reactive oxygen
      species (ROS) as by-products. Although ROS are damaging, they are essential in cell
      signalling and their activity is tightly regulated by a network of antioxidants. When
      antioxidant defences are overwhelmed, oxidative stress results, causing damage to lipids,
      proteins and nucleic acids within mitochondria and resulting in cell death.

      It has been recognised that exogenous antioxidants may be useful in sepsis and more recently
      the potential for antioxidants acting specifically in mitochondria has been highlighted.
      Antioxidants targeted to mitochondria reduced organ damage in a rat model of sepsis. Although
      endogenous melatonin is primarily recognised for regulation of the sleep-wake cycle, higher
      concentrations have potent antioxidant activity with highest levels in mitochondria, and thus
      stabilise the mitochondrial membrane. Metabolites of melatonin also have antioxidant activity
      and products from the reactions with oxidant species are also antioxidants.

      In clinical studies low doses (1-5mg) of exogenous melatonin are effective in normalising the
      sleep-wake cycle in patients with sepsis. Our in vitro studies in a human endothelial cell
      model of sepsis show that higher dose melatonin and its metabolites are equally effective. In
      a rat model of sepsis melatonin reduces oxidative damage. The dose needed for antioxidant
      actions is considerably higher than that used in sleep-wake cycle studies, but the actual
      dose required is unclear. In some studies melatonin has been administered to patients at
      larger doses. Melatonin (10mg/day) decreased interleukin-6 (IL-6) levels in patients with
      cancer; 300mg/day decreased oxidative stress in patients with amyotrophic lateral sclerosis.
      In children with muscular dystrophy, 70mg/day melatonin reduced cytokines and lipid
      peroxidation. Melatonin is also likely to be beneficial in sepsis.

      In several historical studies melatonin has been given to human volunteers with no reports of
      toxicity. Waldhauser gave 80mg melatonin hourly for 4h to healthy men with no ill effects
      other than drowsiness and in healthy women given 300mg/d for 4 months there were no side
      effects. Adverse effects are rare at doses <1g, but can include drowsiness, headache,
      hypothermia, pruritis, abdominal cramps, and tachycardia. Oral bioavailability of low doses
      was estimated at 15% of the parent compound but this makes no allowance for the known
      bioactivity of metabolites. We propose to undertake a dose escalation study in healthy
      volunteers to assess the tolerability of the doses proposed and to measure levels of
      exogenous melatonin and the major metabolites. This will provide crucial information to
      inform a subsequent application for a clinical trial of melatonin in patients with sepsis.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Number of participants in each dose group with adverse events
time frame: 6h and 1 week
description: Adverse events : nausea, vomiting, diarrhoea, itching, headache, drowsiness and any other symptoms for 6h immediately after dosing and again after 1 week. Sleeping patterns will also be assessed after 1 week.
Altered heart rate, oxygen saturation, ECG, blood pressure.
Changes in biochemistry (sodium , potassium, urea, AST, creatinine, glucose) or haematology (WBC and differential counts).
All events will be graded according to prospectively defined criteria.
arm group label: melatonin 20mg
arm group type: Experimental
description: 2 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.
arm group label: melatonin 30mg
arm group type: Experimental
description: 3 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.
arm group label: Melatonin 50mg
arm group type: Experimental
description: 5 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.
arm group label: Melatonin 100mg
arm group type: Experimental
description: 10 x 10mg capsules of melatonin, single dose. Blood sampling and physiological measures (blood pressure, ECG, oxygen saturation) every 30 mins for 6 hours.
intervention type: Drug
intervention name: Melatonin
description: 20 mg oral single dose
arm group label: melatonin 20mg
other name: N-acetyl-5-methoxytryptamine
intervention type: Drug
intervention name: Melatonin
description: 30 mg oral single dose
arm group label: melatonin 30mg
other name: N-acetyl-5-methoxytryptamine
intervention type: Drug
intervention name: Melatonin
description: 50mg oral single dose
arm group label: Melatonin 50mg
other name: N-acetyl-5-methoxytryptamine
intervention type: Drug
intervention name: Melatonin
description: 100mg oral single dose
arm group label: Melatonin 100mg
other name: N-acetyl-5-methoxytryptamine
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 30 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Nigel Webster
role: Study Director
affiliation: University of Aberdeen
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Sepsis
mesh term: Melatonin