<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/NCT03266965</url>
  </required_header>
  <id_info>
    <org_study_id>20161186</org_study_id>
    <secondary_id>W81XWH-16-1-0462</secondary_id>
    <nct_id>NCT03266965</nct_id>
  </id_info>
  <brief_title>Histaminergic Basis of Central Fatigue in Multiple Sclerosis - A Novel Approach</brief_title>
  <official_title>Histaminergic Basis of Central Fatigue in Multiple Sclerosis - A Novel Approach</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Miami</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Miami</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The histaminergic system is phylogenetically one of the oldest parts of the nervous system&#xD;
      but it is a relatively recent discovery. It is involved with several vegetative functions&#xD;
      like sleep, attention and learning, feeding and satiety, working memory, cognition,&#xD;
      depression, and most of all arousal and energy&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Establish in an open label clinical trial the tolerability and safety of various doses&#xD;
           of l-histidine and lodosyn that may increase levels of l-histidine and histamine in the&#xD;
           serum and cerebrospinal fluid (CSF).&#xD;
&#xD;
        2. Perform pharmacokinetic studies in serum and CSF of study subjects the levels of&#xD;
           l-histidine and histamine after treatment with various combination of l-histidine and&#xD;
           lodosyn.&#xD;
&#xD;
        3. Preliminary information will also be collected on the effects of this intervention on&#xD;
           alleviation of fatigue.&#xD;
&#xD;
      The findings from this study go beyond the effects of histamine on fatigue. If central&#xD;
      histamine can be increased by the strategy outlined above, a number of other vegetative&#xD;
      hypothalamic functions intricately associated with fatigue including sleep, cognition and&#xD;
      satiety need to be examined in MS patients in future studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 23, 2018</start_date>
  <completion_date type="Actual">August 7, 2020</completion_date>
  <primary_completion_date type="Actual">August 7, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of adverse events experienced by participants.</measure>
    <time_frame>30 days</time_frame>
    <description>All adverse and serious adverse events reported during the study will be analyzed and tabulated. No quantitative statistical analysis will be performed. The primary goal of this study is to establish that this intervention is safe and possibly effective.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change extent of fatigue.</measure>
    <time_frame>Screening(0 day), baseline(15 days) and final visit(30 days)</time_frame>
    <description>At the conclusion of the study, each individual would have completed a screening and baseline visit without any intervention and two weekly visits during intervention with the study medications. The two evaluations off drug will be compared to the two evaluations on drug. A drop of the Fatigue Severity Scale (FSS) score by 1 point or more will be considered a response. Once the information is converted into a binary function of response / no response, the data is amenable to conditional logistic regression analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Quality of life.</measure>
    <time_frame>Screening(0 day), baseline(15 days) and final visit(30 days)</time_frame>
    <description>Multiple Sclerosis Quality of Life (MSQOL) scales will be used to measure the change in Quality of Life. Based on the scale, there will be a 0 to 100 with a higher score indicating a higher quality of life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of fatigue impact scale.</measure>
    <time_frame>Screening(0 day), baseline(15 days) and final visit(30 days)</time_frame>
    <description>Modified Fatigue Impact Scale (MFIS) scale will be used to evaluate the physical, cognitive and psychosocial scores. The score ranges from 0 to 84 with a lower score, lower side effects of fatigue.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of visual pain.</measure>
    <time_frame>Screening(0 day), baseline(15 days) and final visit(30 days)</time_frame>
    <description>Visual analogue scale to evaluate the pain by using a numerical scale for 0 to 10 with a lower score, less visual pain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of daytime sleepiness.</measure>
    <time_frame>Screening(0 day), baseline(15 days) and final visit(30 days)</time_frame>
    <description>Epworth sleep scale to rate the probability of falling asleep during daytime on a scale of 0 to 24 with a lower score the lower the symptoms of sleepness.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of hunger sensitivity.</measure>
    <time_frame>Screening(0 day), baseline(15 days) and final visit(30 days)</time_frame>
    <description>Hunger Satiety Scale to determine the extent of hunger and fullness by using a 1 to 10 score range with a higher score indicating a higher hunger sensitivity.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Multiple Sclerosis</condition>
  <arm_group>
    <arm_group_label>Histidine Intervention Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A total of 15 subjects will be recruited in batches of 5 until completed 15 subjects in the trial. If a subject withdraws the trial, the study will continue and enrolling subjects until 15 of them complete the trial. The subject composition (MS patient/Normal subject) 4 MS and 1 normal will be tested on a dose of L-Histidine 250 mg plus Lodosyn 50 mg BID for seven days. If there are no safety concerns, the next 5 patients will be recruited 4 MS and 1 normal to test the dose of 500 mg with Lodosyn 50 mg bid for seven days. If there are no safety concerns, then L-histidine 1,000 mg plus Lodosyn (Carbidopa) 50 mg bid will be tested in the next 5 subjects 4 MS and 1 normal for seven days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carbidopa</intervention_name>
    <description>All subjects will receive a fixed dose of 50mg of Lodosyn twice daily.</description>
    <arm_group_label>Histidine Intervention Group</arm_group_label>
    <other_name>Lodosyn</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L-Histidine</intervention_name>
    <description>Sequential Dose Escalation of 250mg to 500mg to 1000mg twice daily.</description>
    <arm_group_label>Histidine Intervention Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for Healthy Volunteers:&#xD;
&#xD;
          1. Male or female subjects between the ages of 18 and 60 will be eligible.&#xD;
&#xD;
          2. Subjects should be in good physical health without history of chronic illness and&#xD;
             should be generally considered healthy.&#xD;
&#xD;
          3. Spouses or caregivers of patients with MS would be encouraged to participate.&#xD;
&#xD;
        Inclusion Criteria for Patients with Multiple Sclerosis (MS):&#xD;
&#xD;
          1. Patients with MS regardless of the disease type, who experience severe fatigue will be&#xD;
             eligible to participate.&#xD;
&#xD;
          2. Fatigue Severity Score of &gt;/= 4.0 will qualify as long as all other inclusion /&#xD;
             exclusion criteria are met.&#xD;
&#xD;
          3. Established MS by McDonald Criteria - 2010 Revision (24). Relapse Remitting (RR) and&#xD;
             progressive forms of MS are eligible&#xD;
&#xD;
          4. Severe fatigue that has lasted greater than 6 months&#xD;
&#xD;
          5. Clinically stable on a current therapy with any Disease Modifying Therapy (DMT)&#xD;
&#xD;
        Exclusion Criteria for Healthy Volunteers:&#xD;
&#xD;
          1. Adults unable to give informed consent due to cognitive impairment or mental&#xD;
             disorders.&#xD;
&#xD;
          2. Children below the age of consent&#xD;
&#xD;
          3. Pregnant women&#xD;
&#xD;
          4. Prisoners&#xD;
&#xD;
          5. History of chronic disorders like hypertension, diabetes, hyperlipidemia, depression,&#xD;
             hypothyroidism etc. that require chronic treatment&#xD;
&#xD;
          6. Known chronic fatigue syndrome&#xD;
&#xD;
          7. Blood disorders or coagulopathy&#xD;
&#xD;
          8. Chronic allergies or history of asthma.&#xD;
&#xD;
          9. Using antihistamines, bronchodilators or H2 blockers for hyperacidity&#xD;
&#xD;
         10. Using medications for sleep, or known sleep disorders&#xD;
&#xD;
         11. Any medication or condition deemed unsuitable by the PI&#xD;
&#xD;
        Exclusion Criteria for Patients with Multiple Sclerosis (MS):&#xD;
&#xD;
          1. Adults unable to give informed consent due to cognitive impairment or mental&#xD;
             disorders.&#xD;
&#xD;
          2. Children below the age of consent&#xD;
&#xD;
          3. Pregnant women&#xD;
&#xD;
          4. Prisoners&#xD;
&#xD;
          5. Systemic disorders known to cause fatigue such as severe anemia, infections, chronic&#xD;
             systemic infectious or inflammatory disorders, including known autoimmune disorders.&#xD;
&#xD;
          6. Chronic fatigue syndrome&#xD;
&#xD;
          7. Hypothyroidism&#xD;
&#xD;
          8. Systemic malignancy&#xD;
&#xD;
          9. Undergoing chemotherapy&#xD;
&#xD;
         10. Depression&#xD;
&#xD;
         11. Sleep disorders including narcolepsy, excessive day-time sleep.&#xD;
&#xD;
         12. History of substance abuse&#xD;
&#xD;
         13. Excessive consumption of coffee or over-the-counter stimulants&#xD;
&#xD;
         14. Concomitant medications of amantadine, methylphenidate, amphetamines, pemoline,&#xD;
             barbiturates, tizanidine, Monoamine oxidase inhibitor (MAO) inhibitors,&#xD;
             benzodiazepines, barbiturates, tricyclic antidepressants, antihistamines, H2 blockers&#xD;
             for gastro-esophageal reflux disease (GERD), selective serotonin reuptake inhibitors&#xD;
             (SSRIs) and any other medication that in the opinion of the PI should be excluded.&#xD;
&#xD;
         15. Patients who were using modafinil for treatment of fatigues prior to the study may&#xD;
             participate but will be required to undergo a washout of 2 weeks prior to entry into&#xD;
             the trial.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kottil Rammohan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Miami</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>July 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 30, 2017</study_first_posted>
  <last_update_submitted>October 5, 2020</last_update_submitted>
  <last_update_submitted_qc>October 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Miami</investigator_affiliation>
    <investigator_full_name>Kottil W. Rammohan</investigator_full_name>
    <investigator_title>Professor Of Clinical Neurology</investigator_title>
  </responsible_party>
  <keyword>Fatigue</keyword>
  <keyword>Histamine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Fatigue</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carbidopa</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03266965
org study id: 20161186
secondary id: W81XWH-16-1-0462
nct id: NCT03266965
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The histaminergic system is phylogenetically one of the oldest parts of the nervous system
      but it is a relatively recent discovery. It is involved with several vegetative functions
      like sleep, attention and learning, feeding and satiety, working memory, cognition,
      depression, and most of all arousal and energy
1. Establish in an open label clinical trial the tolerability and safety of various doses
           of l-histidine and lodosyn that may increase levels of l-histidine and histamine in the
           serum and cerebrospinal fluid (CSF).

        2. Perform pharmacokinetic studies in serum and CSF of study subjects the levels of
           l-histidine and histamine after treatment with various combination of l-histidine and
           lodosyn.

        3. Preliminary information will also be collected on the effects of this intervention on
           alleviation of fatigue.

      The findings from this study go beyond the effects of histamine on fatigue. If central
      histamine can be increased by the strategy outlined above, a number of other vegetative
      hypothalamic functions intricately associated with fatigue including sleep, cognition and
      satiety need to be examined in MS patients in future studies.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of adverse events experienced by participants.
time frame: 30 days
description: All adverse and serious adverse events reported during the study will be analyzed and tabulated. No quantitative statistical analysis will be performed. The primary goal of this study is to establish that this intervention is safe and possibly effective.
measure: Change extent of fatigue.
time frame: Screening(0 day), baseline(15 days) and final visit(30 days)
description: At the conclusion of the study, each individual would have completed a screening and baseline visit without any intervention and two weekly visits during intervention with the study medications. The two evaluations off drug will be compared to the two evaluations on drug. A drop of the Fatigue Severity Scale (FSS) score by 1 point or more will be considered a response. Once the information is converted into a binary function of response / no response, the data is amenable to conditional logistic regression analysis.
measure: Change in Quality of life.
time frame: Screening(0 day), baseline(15 days) and final visit(30 days)
description: Multiple Sclerosis Quality of Life (MSQOL) scales will be used to measure the change in Quality of Life. Based on the scale, there will be a 0 to 100 with a higher score indicating a higher quality of life.
measure: Change of fatigue impact scale.
time frame: Screening(0 day), baseline(15 days) and final visit(30 days)
description: Modified Fatigue Impact Scale (MFIS) scale will be used to evaluate the physical, cognitive and psychosocial scores. The score ranges from 0 to 84 with a lower score, lower side effects of fatigue.
measure: Change of visual pain.
time frame: Screening(0 day), baseline(15 days) and final visit(30 days)
description: Visual analogue scale to evaluate the pain by using a numerical scale for 0 to 10 with a lower score, less visual pain.
measure: Change of daytime sleepiness.
time frame: Screening(0 day), baseline(15 days) and final visit(30 days)
description: Epworth sleep scale to rate the probability of falling asleep during daytime on a scale of 0 to 24 with a lower score the lower the symptoms of sleepness.
measure: Change of hunger sensitivity.
time frame: Screening(0 day), baseline(15 days) and final visit(30 days)
description: Hunger Satiety Scale to determine the extent of hunger and fullness by using a 1 to 10 score range with a higher score indicating a higher hunger sensitivity.
arm group label: Histidine Intervention Group
arm group type: Experimental
description: A total of 15 subjects will be recruited in batches of 5 until completed 15 subjects in the trial. If a subject withdraws the trial, the study will continue and enrolling subjects until 15 of them complete the trial. The subject composition (MS patient/Normal subject) 4 MS and 1 normal will be tested on a dose of L-Histidine 250 mg plus Lodosyn 50 mg BID for seven days. If there are no safety concerns, the next 5 patients will be recruited 4 MS and 1 normal to test the dose of 500 mg with Lodosyn 50 mg bid for seven days. If there are no safety concerns, then L-histidine 1,000 mg plus Lodosyn (Carbidopa) 50 mg bid will be tested in the next 5 subjects 4 MS and 1 normal for seven days.
intervention type: Drug
intervention name: Carbidopa
description: All subjects will receive a fixed dose of 50mg of Lodosyn twice daily.
arm group label: Histidine Intervention Group
other name: Lodosyn
intervention type: Dietary Supplement
intervention name: L-Histidine
description: Sequential Dose Escalation of 250mg to 500mg to 1000mg twice daily.
arm group label: Histidine Intervention Group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kottil Rammohan, MD
role: Principal Investigator
affiliation: University of Miami
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Miami
investigator full name: Kottil W. Rammohan
investigator title: Professor Of Clinical Neurology
mesh term: Multiple Sclerosis
mesh term: Sclerosis
mesh term: Fatigue
mesh term: Carbidopa
sharing ipd: No