<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/NCT01729598</url>
  </required_header>
  <id_info>
    <org_study_id>12-0068-F6A</org_study_id>
    <nct_id>NCT01729598</nct_id>
  </id_info>
  <brief_title>Valproic Acid in Subjects With Intact Cognition - Proof of Concept Study</brief_title>
  <acronym>VPA</acronym>
  <official_title>Safety And Target Engagement Of Clu1 By Valproic Acid In Subjects With Intact Cognition: Proof Of Concept For The Development Of A Prevention Trial For Alzheimer's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gregory Jicha, 323-5550</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Kentucky</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kentucky Alzheimer's Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Kentucky</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety of administration and effects of valproic&#xD;
      acid on clusterin expression in cognitively-intact, healthy, elderly subjects. Clusterin&#xD;
      mutations have recently been identified as a risk factor for the development of Alzheimer's&#xD;
      Disease and changes in clusterin expression are seen in the elderly who develop Alzheimer's&#xD;
      disease irrespective of whether they carry these genetic mutations or not. Valproic acid may&#xD;
      prevent or reverse these changes.&#xD;
&#xD;
      Fourteen subjects with normal memory and thinking will participate in this study. Ten of&#xD;
      these subjects will receive valproic acid and 4 will receive a &quot;placebo&quot; capsule with no&#xD;
      active medicine. Participants will take study medication or placebo for 28 days and be&#xD;
      followed for a total 35 days in this trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a placebo-controlled, single-center, multiple ascending dose study. Seven healthy&#xD;
      volunteers will be enrolled into 2 sequential cohorts, for a total of 14 enrolled subjects.&#xD;
      The study will be conducted using two doses of valproate (250 mg PO bid, followed by 500 mg&#xD;
      PO bid). At each dose level, 7 cognitively intact normal elderly subjects will be entered&#xD;
      into the study with two subjects randomly selected to receive placebo while the other five&#xD;
      subjects receive the designated dose of valproate.&#xD;
&#xD;
      Study procedures will include routine assessment of adverse events, safety labs, baseline&#xD;
      MRI, physical and neurological exams, and cerebrospinal fluid collection.&#xD;
&#xD;
      Other investigational medication or devices are prohibited during this study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2012</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">October 2014</primary_completion_date>
  <phase>Early Phase 1</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>Basic Science</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Frequency of Adverse Events Over the Duration of the Study by Study Arm</measure>
    <time_frame>Day 35</time_frame>
    <description>Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests throughout the study. The incidence of observed toxicities and adverse events will be tabulated, the frequencies compared in participants who receive active medication and those who receive placebo, and reviewed for potential significance and clinical importance.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm</measure>
    <time_frame>Baseline and day 28</time_frame>
    <description>Change in cerebrospinal fluid amyloid-beta 1-42 levels in pg/ml from baseline to end of treatment (day 28)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Cerebrospinal Fluid P-tau Levels (pg/ml)</measure>
    <time_frame>Baseline and day 28</time_frame>
    <description>Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Free &amp; Cued Selective Reminding Test- Free Recall (Number of Items Correct)</measure>
    <time_frame>Baseline and day 28</time_frame>
    <description>Change in Free &amp; Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)</measure>
    <time_frame>Baseline and day 28</time_frame>
    <description>Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Alzheimer's Disease</condition>
  <arm_group>
    <arm_group_label>Valproic Acid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Valproic acid 250 mg or 500mg by mouth twice daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo capsule by mouth twice daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Valproic Acid</intervention_name>
    <description>generic valproic acid tablets packaged in placebo-matched capsules.</description>
    <arm_group_label>Valproic Acid</arm_group_label>
    <other_name>VPA</other_name>
    <other_name>Depakote</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Sugar pill</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men or women aged 65-90, inclusive.&#xD;
&#xD;
          2. English-speaking, to ensure compliance with cognitive testing and study visit&#xD;
             procedures.&#xD;
&#xD;
          3. Female participants must not be pregnant or of childbearing potential, i.e. either&#xD;
             surgically sterile or postmenopausal for &gt; 1 year.&#xD;
&#xD;
          4. Stable medical condition for three months prior to screening visit, with no clinically&#xD;
             significant abnormalities of hepatic, renal, and hematologic function defined as&#xD;
             follows:&#xD;
&#xD;
               -  Platelets &gt; 100,000&#xD;
&#xD;
               -  Serum creatinine ≤ 1.6 mg/dL&#xD;
&#xD;
               -  Liver function tests ≤ 1.5 upper limit of normal&#xD;
&#xD;
               -  No clinically significant abnormalities of other laboratory studies (blood&#xD;
                  counts, chemistry panel, urinalysis) as determined by the study physician&#xD;
&#xD;
          5. Stable medications for 4 weeks prior to screening visit.&#xD;
&#xD;
          6. Able to ingest oral medications.&#xD;
&#xD;
          7. No history of adverse drug reactions to VPA or similar agents.&#xD;
&#xD;
          8. Physically acceptable for this study as confirmed by medical history, physical exam,&#xD;
             neurological exam and clinical tests in the opinion of the study physician.&#xD;
&#xD;
          9. Not demented by Hachinski Ischemic Index (&lt; 4).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Significant neurologic disease such as Parkinson's disease, stroke, brain tumor,&#xD;
             multiple sclerosis or seizure disorder.&#xD;
&#xD;
          2. Major depression in past 12 months (DSM-IV criteria), major mental illness such as&#xD;
             schizophrenia, or recent (in past 12 months) alcohol or substance abuse by history.&#xD;
&#xD;
          3. History of invasive cancer within the past two years (excluding non-melanoma skin&#xD;
             cancer).&#xD;
&#xD;
          4. Contra-indications to lumbar puncture (bleeding disorder, platelet count &lt; 100,000,&#xD;
             anticoagulant treatment, major structural abnormality or sepsis in the area of the&#xD;
             lumbosacral spine that would make spinal fluid collection technically difficult).&#xD;
&#xD;
          5. Clinically significant MRI abnormalities that contraindicate lumber or suggest central&#xD;
             nervous system disease processes that could influence study outcomes in the opinion of&#xD;
             the PI.&#xD;
&#xD;
          6. Use of any investigational agents within 30 days prior to screening.&#xD;
&#xD;
          7. Major surgery within eight weeks prior to the Baseline Visit.&#xD;
&#xD;
          8. Severe unstable medical illnesses, including uncontrolled cardiac conditions or heart&#xD;
             failure (New York Heart Association Class III or IV) .&#xD;
&#xD;
          9. Antiretroviral therapy for human immunodeficiency virus (HIV).&#xD;
&#xD;
         10. Residence in a skilled nursing facility.&#xD;
&#xD;
         11. Blindness, deafness, language difficulties or any other disability which may prevent&#xD;
             the participant from participating or cooperating in the protocol.&#xD;
&#xD;
        Excluded Medications&#xD;
&#xD;
          1. Experimental drugs&#xD;
&#xD;
          2. Lamictal&#xD;
&#xD;
          3. Tricyclic antidepressants (amitriptyline/nortryptiline)&#xD;
&#xD;
          4. Carbamazepine/ oxcarbazepine&#xD;
&#xD;
          5. Benzodiazepines&#xD;
&#xD;
          6. Phenobarbital&#xD;
&#xD;
          7. Phenytoin&#xD;
&#xD;
          8. Tolbutamide&#xD;
&#xD;
          9. Topiramate&#xD;
&#xD;
         10. Warfarin&#xD;
&#xD;
         11. Zidovudine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steve Estus, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kentucky</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gregory Jicha, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Kentucky</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sander's Brown Center on Aging</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>May 14, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 20, 2012</study_first_posted>
  <results_first_submitted>March 8, 2017</results_first_submitted>
  <results_first_submitted_qc>October 7, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">October 9, 2019</results_first_posted>
  <last_update_submitted>October 7, 2019</last_update_submitted>
  <last_update_submitted_qc>October 7, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 9, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Kentucky</investigator_affiliation>
    <investigator_full_name>Gregory Jicha, 323-5550</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>cognitively normal elderly population</keyword>
  <keyword>safety and tolerability</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Valproic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>IPD will be shared with interested investigators that submit a data request to the UK Alzheimer Center Biostatistics Group upon publication of the primary manuscript from this study. The request will be reviewed for scientific validity and human subjects protection issues prior to approval for release. IPD that may be released includes all clinical data stripped of identifying information. Clinical Information will be assigned a blinded subject number that protects the identity and HIPAA protected information collected as part of this study. To request data, follow the instructions at the following link: http://www.uky.edu/coa/adc/investigators-research-resources</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>1/1/19 to 12/31/28</ipd_time_frame>
    <ipd_access_criteria>Access will be granted to any investigator upon provision of an acceptable project hypothesis and specification of data desired. Oversight by the project team will ensure that redundant projects do not result in competitive use of the resources. Project data access will be determined by the PI and investigator team at UK within these broad access terms. There will be no cost for data access. We stipulate that the parent grant UL1TR001998 should be cited by those with whom data is shared.</ipd_access_criteria>
    <ipd_url>http://www.uky.edu/coa/adc/investigators-research-resources</ipd_url>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Valproic Acid</title>
          <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Valproic Acid</title>
          <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="10"/>
            <count group_id="B2" value="4"/>
            <count group_id="B3" value="14"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="76" spread="7.3"/>
                    <measurement group_id="B2" value="81" spread="12.2"/>
                    <measurement group_id="B3" value="78" spread="8.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Frequency of Adverse Events Over the Duration of the Study by Study Arm</title>
        <description>Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests throughout the study. The incidence of observed toxicities and adverse events will be tabulated, the frequencies compared in participants who receive active medication and those who receive placebo, and reviewed for potential significance and clinical importance.</description>
        <time_frame>Day 35</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Valproic Acid</title>
            <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
          </group>
        </group_list>
        <measure>
          <title>Frequency of Adverse Events Over the Duration of the Study by Study Arm</title>
          <description>Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests throughout the study. The incidence of observed toxicities and adverse events will be tabulated, the frequencies compared in participants who receive active medication and those who receive placebo, and reviewed for potential significance and clinical importance.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm</title>
        <description>Change in cerebrospinal fluid amyloid-beta 1-42 levels in pg/ml from baseline to end of treatment (day 28)</description>
        <time_frame>Baseline and day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Valproic Acid</title>
            <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm</title>
          <description>Change in cerebrospinal fluid amyloid-beta 1-42 levels in pg/ml from baseline to end of treatment (day 28)</description>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="57.1" spread="28.4"/>
                    <measurement group_id="O2" value="44.7" spread="24.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.55</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Cerebrospinal Fluid P-tau Levels (pg/ml)</title>
        <description>Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28)</description>
        <time_frame>Baseline and day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Valproic Acid</title>
            <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cerebrospinal Fluid P-tau Levels (pg/ml)</title>
          <description>Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28)</description>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.7" spread="11.9"/>
                    <measurement group_id="O2" value="11.0" spread="25.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.19</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Free &amp; Cued Selective Reminding Test- Free Recall (Number of Items Correct)</title>
        <description>Change in Free &amp; Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28)</description>
        <time_frame>Baseline and day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Valproic Acid</title>
            <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Free &amp; Cued Selective Reminding Test- Free Recall (Number of Items Correct)</title>
          <description>Change in Free &amp; Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28)</description>
          <units>number of items recalled</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.4" spread="3.5"/>
                    <measurement group_id="O2" value="-4.5" spread="3.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.02</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)</title>
        <description>Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)</description>
        <time_frame>Baseline and day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Valproic Acid</title>
            <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)</title>
          <description>Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)</description>
          <units>pg/ml</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2610" spread="4373"/>
                    <measurement group_id="O2" value="201" spread="871"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.31</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>35 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Valproic Acid</title>
          <description>Valproic acid 250 mg or 500mg by mouth twice daily.&#xD;
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Placebo capsule by mouth twice daily.&#xD;
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (10.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>hypoglycemia</sub_title>
                <assessment>Systematic Assessment</assessment>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>fatigue</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="4"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="4"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Gregory A. Jicha</name_or_title>
      <organization>University of Kentucky</organization>
      <phone>859-323-5550</phone>
      <email>gregory.jicha@uky.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01729598
org study id: 12-0068-F6A
nct id: NCT01729598
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
The purpose of this study is to evaluate the safety of administration and effects of valproic
      acid on clusterin expression in cognitively-intact, healthy, elderly subjects. Clusterin
      mutations have recently been identified as a risk factor for the development of Alzheimer's
      Disease and changes in clusterin expression are seen in the elderly who develop Alzheimer's
      disease irrespective of whether they carry these genetic mutations or not. Valproic acid may
      prevent or reverse these changes.

      Fourteen subjects with normal memory and thinking will participate in this study. Ten of
      these subjects will receive valproic acid and 4 will receive a "placebo" capsule with no
      active medicine. Participants will take study medication or placebo for 28 days and be
      followed for a total 35 days in this trial.
This is a placebo-controlled, single-center, multiple ascending dose study. Seven healthy
      volunteers will be enrolled into 2 sequential cohorts, for a total of 14 enrolled subjects.
      The study will be conducted using two doses of valproate (250 mg PO bid, followed by 500 mg
      PO bid). At each dose level, 7 cognitively intact normal elderly subjects will be entered
      into the study with two subjects randomly selected to receive placebo while the other five
      subjects receive the designated dose of valproate.

      Study procedures will include routine assessment of adverse events, safety labs, baseline
      MRI, physical and neurological exams, and cerebrospinal fluid collection.

      Other investigational medication or devices are prohibited during this study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Triple (Participant, Care Provider, Investigator)
measure: Frequency of Adverse Events Over the Duration of the Study by Study Arm
time frame: Day 35
description: Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests throughout the study. The incidence of observed toxicities and adverse events will be tabulated, the frequencies compared in participants who receive active medication and those who receive placebo, and reviewed for potential significance and clinical importance.
measure: Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm
time frame: Baseline and day 28
description: Change in cerebrospinal fluid amyloid-beta 1-42 levels in pg/ml from baseline to end of treatment (day 28)
measure: Change in Cerebrospinal Fluid P-tau Levels (pg/ml)
time frame: Baseline and day 28
description: Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28)
measure: Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct)
time frame: Baseline and day 28
description: Change in Free & Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28)
measure: Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)
time frame: Baseline and day 28
description: Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)
arm group label: Valproic Acid
arm group type: Experimental
description: Valproic acid 250 mg or 500mg by mouth twice daily.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo capsule by mouth twice daily.
intervention type: Drug
intervention name: Valproic Acid
description: generic valproic acid tablets packaged in placebo-matched capsules.
arm group label: Valproic Acid
other name: VPA
other name: Depakote
intervention type: Drug
intervention name: Placebo
description: Placebo capsule without active study medication in identical capsules as experimental medicine.
arm group label: Placebo
other name: Sugar pill
criteria: 
gender: All
minimum age: 65 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Steve Estus, PhD
role: Principal Investigator
affiliation: University of Kentucky
last name: Gregory Jicha, MD
role: Principal Investigator
affiliation: University of Kentucky
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Kentucky
investigator full name: Gregory Jicha, 323-5550
investigator title: Professor
mesh term: Alzheimer Disease
mesh term: Valproic Acid
sharing ipd: Yes
ipd description: IPD will be shared with interested investigators that submit a data request to the UK Alzheimer Center Biostatistics Group upon publication of the primary manuscript from this study. The request will be reviewed for scientific validity and human subjects protection issues prior to approval for release. IPD that may be released includes all clinical data stripped of identifying information. Clinical Information will be assigned a blinded subject number that protects the identity and HIPAA protected information collected as part of this study. To request data, follow the instructions at the following link: http://www.uky.edu/coa/adc/investigators-research-resources
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: 1/1/19 to 12/31/28
ipd access criteria: Access will be granted to any investigator upon provision of an acceptable project hypothesis and specification of data desired. Oversight by the project team will ensure that redundant projects do not result in competitive use of the resources. Project data access will be determined by the PI and investigator team at UK within these broad access terms. There will be no cost for data access. We stipulate that the parent grant UL1TR001998 should be cited by those with whom data is shared.
ipd url: http://www.uky.edu/coa/adc/investigators-research-resources
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 