<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/NCT03823638</url>
  </required_header>
  <id_info>
    <org_study_id>0346-17-HMO-CTIL</org_study_id>
    <nct_id>NCT03823638</nct_id>
  </id_info>
  <brief_title>Safety, Tolerability and Effects of Mannitol in Parkinson's Disease</brief_title>
  <acronym>PD-mannitol</acronym>
  <official_title>A Phase II Single Center, Randomized, Double Blind and Placebo Controlled Study Assessing the Safety, Tolerability and Effects of Progressively Increased Dose of Oral Mannitol in Parkinson's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hadassah Medical Organization</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hadassah Medical Organization</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>
      Parkinson's disease is a progressive neurodegenerative disease that causes disabling motor&#xD;
      and cognitive impairments. Currently, no disease-modifying therapy exists for this disease.&#xD;
      Mannitol, a naturally-occurring substance, which is commonly used as sweetener, was offered&#xD;
      as such agent. In this phase II, safety, tolerability-based dose finding, and efficacy study,&#xD;
      mannitol or placebo (dextrose) in escalating doses will be given to patients with Parkinson's&#xD;
      disease for 36 weeks.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 20, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of oral mannitol in Parkinson's disease as assessed by the number of mannitol-related adverse events, clinically significant changes in vital signs and clinically significant abnormalities in laboratory results.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Safety will be assessed by the number of treatment-related adverse events, number of patients with clinically significant change of vital signs (supine and standing blood pressure and pulse) and number of patients with clinically significant change in laboratory results (electrolytes, renal and liver functions, blood count).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tolerability of oral mannitol in Parkinson's disease as assessed by the maximal daily dose (in grams) of mannitol that does not cause discomfort.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Tolerability of oral mannitol in Parkinson's disease as assessed by the maximal daily dose (in grams, up to 18 grams per day) of mannitol that does not cause discomfort based on the subjective report by the patient.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time-interval for starting symptomatic therapy (in days) between baseline and week 36, in patients not receiving symptomatic therapy at baseline.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Median time interval will be reported. P-Values as assessed by Mann-Whitney test will be reported. Longer time interval will be considered as a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in levodopa-equivalent dose units between baseline and week 36.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Total levodopa-equivalent dose (LED units) will be calculated based on Tomlinson, Mov Disord 2010. P-Values as assessed by Mann-Whitney test will be reported. Smaller change will be considered as a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Brief Smell Identification Test (B-SIT) score between baseline and week 36.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Median and range of change will be reported. P-Values as assessed by Mann-Whitney test will be reported. Higher absolute positive value (reflecting improved smell) or lower absolute negative value (slower deterioration) will be considered as better outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in constipation assesment (CAS) score between baseline and week 36.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Median and range of change will be reported. Change in score will be reported. P-Values as assessed by Mann-Whitney test will be reported. Lower absolute positive value or higher absolute negative value will be considered as better outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Montreal Cognitive Assessment (MoCA) test score between baseline and week 36.</measure>
    <time_frame>36 weeks</time_frame>
    <description>P-Values as assessed by Mann-Whitney test will be reported. Higher absolute positive value or lower absolute negative value will be considered as better outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in non-motor symptoms of Parkinson's disease scale (NMSS) between baseline and week 36.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Median and range of change will be reported. P-Values as assessed by Mann-Whitney test will be reported. Lower absolute positive value or higher absolute negative value will be considered as better outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the ratio of total-to-proteinase K-resistant α-synuclein in red blood cells (RBC) measured by enzyme-linked immunosorbent assay (ELISA)between baseline and week 36.</measure>
    <time_frame>36 weeks</time_frame>
    <description>Median and range of change will be reported. P-Values as assessed by Mann-Whitney test will be reported. Higher absolute positive value or lower absolute negative value will be considered as better outcomes.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Parkinson Disease</condition>
  <arm_group>
    <arm_group_label>D-Mannitol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral Supplement of the investigated substance: D-Mannitol powder (manufacturer Roquette)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Oral Supplement of the placebo: Dextrose monohydrate powder (manufacturer Roquette)</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Oral D-Mannitol of Placebo</intervention_name>
    <description>Gradually increased doses of oral D-Mannitol of Placebo (Dextrose monohydrate)</description>
    <arm_group_label>D-Mannitol</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Ability to understand and signing of informed consent form.&#xD;
&#xD;
          2. Age 40-75 years at the day of visit 1.&#xD;
&#xD;
          3. Diagnosis of Parkinson's disease that is based on the United Kingdom brain bank&#xD;
             criteria diagnosed after the age of 40.&#xD;
&#xD;
          4. Stable regime of anti-parkinsonian medication for at least 4 weeks at the day of visit&#xD;
             1.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with motor deficits that require administration of symptomatic therapy more&#xD;
             than 4 times per day at the day of visit 1.&#xD;
&#xD;
          2. Patients on advanced therapy for Parkinson's disease (sub-cutaneous apomorphine, deep&#xD;
             brain stimulation or intra-jejunal levodopa infusion).&#xD;
&#xD;
          3. Patients with dementia reflected by a Mini-mental state examination (MoCA) ≥ 24.&#xD;
&#xD;
          4. Patient with legal guardian.&#xD;
&#xD;
          5. History of psychosis or use of dopamine receptor blocking agent on the year proceeding&#xD;
             at the visit 1. Quetiapine at dose lower or equal 50 mg per day prescribed for&#xD;
             indication other than psychosis is allowed.&#xD;
&#xD;
          6. Suspected Parkinsonian syndrome other than Parkinson's disease.&#xD;
&#xD;
          7. Use of medical marihuana on the month proceeding visit 1.&#xD;
&#xD;
          8. Pregnant or lactating women, or fertile woman who does not use contraceptive. Woman of&#xD;
             child-bearing potential must have a negative urine Human chorionic gonadotropin (hCG)&#xD;
             and will be monitored by repeated urine tests.&#xD;
&#xD;
          9. Patient with significantly impaired renal functions (urea or creatinine values 20%&#xD;
             above the upper norm limit).&#xD;
&#xD;
         10. Diabetes mellitus.&#xD;
&#xD;
         11. Clinical evidence for congestive heart failure.&#xD;
&#xD;
         12. Patient with symptomatic orthostatic hypotension.&#xD;
&#xD;
         13. Based on investigator's opinion, any medical condition that may progress due to&#xD;
             consumption of oral mannitol or glucose.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>David Arkadir, MD PhD</last_name>
    <phone>02-6777716</phone>
    <email>arkadir@hadassah.org.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anna Linetsky</last_name>
    <phone>02-6777716</phone>
    <email>annalin@hadassah.org.il</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hadassah Medical Center</name>
      <address>
        <city>Jerusalem</city>
        <zip>91120</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Arkadir, MD PhD</last_name>
      <phone>02-6777716</phone>
      <email>arkadir@hadassah.org.il</email>
    </contact>
    <contact_backup>
      <last_name>Anna Linetsky</last_name>
      <phone>02-6777716</phone>
      <email>annalin@hadassah.org.il</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>November 20, 2018</study_first_submitted>
  <study_first_submitted_qc>January 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <last_update_submitted>January 29, 2019</last_update_submitted>
  <last_update_submitted_qc>January 29, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 30, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hadassah Medical Organization</investigator_affiliation>
    <investigator_full_name>ARKADIR DAVID</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Parkinson Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mannitol</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/NCT03823638
org study id: 0346-17-HMO-CTIL
nct id: NCT03823638
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Parkinson's disease is a progressive neurodegenerative disease that causes disabling motor
      and cognitive impairments. Currently, no disease-modifying therapy exists for this disease.
      Mannitol, a naturally-occurring substance, which is commonly used as sweetener, was offered
      as such agent. In this phase II, safety, tolerability-based dose finding, and efficacy study,
      mannitol or placebo (dextrose) in escalating doses will be given to patients with Parkinson's
      disease for 36 weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Safety of oral mannitol in Parkinson's disease as assessed by the number of mannitol-related adverse events, clinically significant changes in vital signs and clinically significant abnormalities in laboratory results.
time frame: 36 weeks
description: Safety will be assessed by the number of treatment-related adverse events, number of patients with clinically significant change of vital signs (supine and standing blood pressure and pulse) and number of patients with clinically significant change in laboratory results (electrolytes, renal and liver functions, blood count).
measure: Tolerability of oral mannitol in Parkinson's disease as assessed by the maximal daily dose (in grams) of mannitol that does not cause discomfort.
time frame: 36 weeks
description: Tolerability of oral mannitol in Parkinson's disease as assessed by the maximal daily dose (in grams, up to 18 grams per day) of mannitol that does not cause discomfort based on the subjective report by the patient.
measure: Time-interval for starting symptomatic therapy (in days) between baseline and week 36, in patients not receiving symptomatic therapy at baseline.
time frame: 36 weeks
description: Median time interval will be reported. P-Values as assessed by Mann-Whitney test will be reported. Longer time interval will be considered as a better outcome.
measure: Change in levodopa-equivalent dose units between baseline and week 36.
time frame: 36 weeks
description: Total levodopa-equivalent dose (LED units) will be calculated based on Tomlinson, Mov Disord 2010. P-Values as assessed by Mann-Whitney test will be reported. Smaller change will be considered as a better outcome.
measure: Change of Brief Smell Identification Test (B-SIT) score between baseline and week 36.
time frame: 36 weeks
description: Median and range of change will be reported. P-Values as assessed by Mann-Whitney test will be reported. Higher absolute positive value (reflecting improved smell) or lower absolute negative value (slower deterioration) will be considered as better outcomes.
measure: Change in constipation assesment (CAS) score between baseline and week 36.
time frame: 36 weeks
description: Median and range of change will be reported. Change in score will be reported. P-Values as assessed by Mann-Whitney test will be reported. Lower absolute positive value or higher absolute negative value will be considered as better outcomes.
measure: Change in Montreal Cognitive Assessment (MoCA) test score between baseline and week 36.
time frame: 36 weeks
description: P-Values as assessed by Mann-Whitney test will be reported. Higher absolute positive value or lower absolute negative value will be considered as better outcomes.
measure: Change in non-motor symptoms of Parkinson's disease scale (NMSS) between baseline and week 36.
time frame: 36 weeks
description: Median and range of change will be reported. P-Values as assessed by Mann-Whitney test will be reported. Lower absolute positive value or higher absolute negative value will be considered as better outcomes.
measure: Change in the ratio of total-to-proteinase K-resistant α-synuclein in red blood cells (RBC) measured by enzyme-linked immunosorbent assay (ELISA)between baseline and week 36.
time frame: 36 weeks
description: Median and range of change will be reported. P-Values as assessed by Mann-Whitney test will be reported. Higher absolute positive value or lower absolute negative value will be considered as better outcomes.
arm group label: D-Mannitol
arm group type: Experimental
description: Oral Supplement of the investigated substance: D-Mannitol powder (manufacturer Roquette)
arm group label: Placebo
arm group type: Placebo Comparator
description: Oral Supplement of the placebo: Dextrose monohydrate powder (manufacturer Roquette)
intervention type: Dietary Supplement
intervention name: Oral D-Mannitol of Placebo
description: Gradually increased doses of oral D-Mannitol of Placebo (Dextrose monohydrate)
arm group label: D-Mannitol
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: No
last name: David Arkadir, MD PhD
phone: 02-6777716
email: arkadir@hadassah.org.il
last name: Anna Linetsky
phone: 02-6777716
email: annalin@hadassah.org.il
facility: 
status: Recruiting
contact: 
contact backup: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Hadassah Medical Organization
investigator full name: ARKADIR DAVID
investigator title: Principal Investigator
mesh term: Parkinson Disease
mesh term: Mannitol
sharing ipd: No