<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/NCT01703117</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 18-0623</org_study_id>
    <secondary_id>APE-0792</secondary_id>
    <nct_id>NCT01703117</nct_id>
  </id_info>
  <brief_title>Riluzole in Mild Alzheimer's Disease</brief_title>
  <official_title>Glutamatergic Dysfunction in Cognitive Aging: Riluzole in Mild Alzheimer's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Icahn School of Medicine at Mount Sinai</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rockefeller University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cognitive aging is a major source of disability in an increasingly aging population. The&#xD;
      paucity of effective treatments for cognitive aging disorders, and most importantly in&#xD;
      Alzheimer's disease instigates a need for further research into novel therapeutic&#xD;
      possibilities. Alzheimer's disease is the most common neurodegenerative disorder and its&#xD;
      prevalence steeply increases. Glutamate-mediated excitotoxicity in neuropsychiatric disorders&#xD;
      and in particular in Alzheimer's disease has been shown to cause significant cerebral damage.&#xD;
      Early effective therapeutic intervention in Alzheimer's disease is critical in order to&#xD;
      prevent or at least slow down neuropathological progression that will lead to widespread&#xD;
      irreversible neuronal loss and significant cognitive dysfunction. Riluzole, a glutamate&#xD;
      modulator agent, will be tested in mild Alzheimer's disease patients. Cognitive functional&#xD;
      changes along with two established in vivo biomarkers, namely, Magnetic Resonance&#xD;
      Spectroscopy (MRS) and Fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) will&#xD;
      be evaluated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A double-blinded, randomized, placebo-controlled study will be performed. Forty-two&#xD;
      individuals with a diagnosis of mild Alzheimer's disease between 50-95 years old will&#xD;
      complete the study. All forty-two individuals will have been on an acetylcholinesterase&#xD;
      inhibitor, which is FDA approved for the treatment of Alzheimer's disease, for at least 2&#xD;
      months prior to initiating the study, unless the medication was not previously tolerated.&#xD;
      Twenty to twenty-two mild Alzheimer's disease patients will receive riluzole and another&#xD;
      20-22 will receive a placebo. All patients will have a neurological evaluation and&#xD;
      neuropsychological tests performed to confirm that they meet criteria for probable&#xD;
      Alzheimer's disease set out by the National Institute on Aging - Alzheimer's disease&#xD;
      Association that recently revisited the NINCDS-ADRDA criteria along with FDG-PET biomarker&#xD;
      consistent with Alzheimer's disease.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 2013</start_date>
  <completion_date type="Actual">May 26, 2020</completion_date>
  <primary_completion_date type="Actual">May 26, 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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Imaging Biomarkers FDG-PET SUVR in Regions of Interest</measure>
    <time_frame>Change from baseline to 6 months</time_frame>
    <description>Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest.&#xD;
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS</measure>
    <time_frame>Changes from baseline to 6 months</time_frame>
    <description>N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Glutamate Levels Measured Through 1H MRS</measure>
    <time_frame>Change from baseline to 6 months</time_frame>
    <description>In vivo measurement of glutamate with 1H magnetic resonance spectroscopy (MRS) (a neuroimaging study) in posterior cingulate as a marker of target engagement at three and six months compared to baseline.In vivo brain levels of glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of glutamate and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog)</measure>
    <time_frame>baseline to 6 months</time_frame>
    <description>The ADAS comprises two subscales, cognitive and non-cognitive. The Cognitive Subscale (ADAScog) is a psychometric instrument that includes 11 tasks and evaluates memory, attention, reasoning, language, orientation, and praxis, scored from 0 to 70. The full ADAS total is scored by summing the number of errors made on each task on a range from 0 to 150 so that higher scores indicate worse performance.The non-cognitive component was not used in this study. Obtained for correlation with neuroimaging biomarkers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neuropsychiatry Inventory - NPI</measure>
    <time_frame>baseline to 6 months</time_frame>
    <description>NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 0 to 144; Higher scores indicate greater disease severity.&#xD;
Obtained for correlation with neuroimaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ADCS Activities of Daily Living</measure>
    <time_frame>baseline to 6 months</time_frame>
    <description>ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity.&#xD;
Obtained for correlation with neuroimaging</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Alzheimer's Disease</condition>
  <arm_group>
    <arm_group_label>age matched cohort 50-95 years old</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>20-22 subjects between the ages of 50-95 will receive riluzole</description>
  </arm_group>
  <arm_group>
    <arm_group_label>24 subjects between 50-95 years old</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>20-22 subjects between 50-95 will receive placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Riluzole</intervention_name>
    <description>20-22 subjects between the ages of 60-85 will receive study drug.</description>
    <arm_group_label>age matched cohort 50-95 years old</arm_group_label>
    <other_name>no other names</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>20-22 subjects between the ages of 60-85 will receive placebo</description>
    <arm_group_label>24 subjects between 50-95 years old</arm_group_label>
    <other_name>no other names</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female; 50 - 95 years old with mild Alzheimer's disease determined after&#xD;
             neurological and neuropsychological evaluation following the National Institute on&#xD;
             Aging - Alzheimer's disease Association criteria that recently revisited the&#xD;
             NINCDS-ADRDA criteria. For mild Alzheimer's disease, Clinical Dementia Ratings Scale&#xD;
             (CDR) should be 0.5 or 1 and Mini Mental State Examination (MMSS) between 19 and 27.&#xD;
&#xD;
          -  Must be on donepezil (Aricept®) or rivastigmine (Exelon®) or galantamine (Razadyne®)&#xD;
             at a consistent dose for at least 2 months. Patients will be considered for inclusion&#xD;
             if they were previously unable to tolerate acetylcholinesterase inhibitors and as a&#xD;
             result, are no longer on the medication for at least 2 months.&#xD;
&#xD;
          -  Must be fluent in English&#xD;
&#xD;
          -  The subject will appoint or have previously appointed a health care proxy specifically&#xD;
             designated for research consent and that this be documented.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Severe Alzheimer's disease and other dementias as determined by neuropsychological&#xD;
             testing and neurological evaluation.&#xD;
&#xD;
          -  Previous riluzole treatment.&#xD;
&#xD;
          -  MRI contraindication (severe claustrophobia, metal implants, shunts, pacemaker, joint&#xD;
             implants, metal valves).&#xD;
&#xD;
          -  Currently taking medications that either have evidence of glutamatergic activity or&#xD;
             has previous MRS evidence of effects on brain glutamate levels at the discretion of&#xD;
             the PI such as memantine, lamotrigine, lithium, opiates, bupropion, psychostimulants&#xD;
             such as amphetamines and methylphenidate, tricyclic antidepressants, benzodiazepines&#xD;
             and any other drug that the investigators judge might interfere with the study.&#xD;
             (subjects on those medications may still be included in the study however only the&#xD;
             values of NAA from MRS will be utilized and not the glutamate measurements).&#xD;
&#xD;
          -  Currently a user of the following illicit drugs: cocaine,&#xD;
             methylenedioxymethamphetamine (MDMA) (&quot;ecstasy&quot;), heroin and other opioids or has a&#xD;
             history of drug or alcohol abuse within the past 5 years.&#xD;
&#xD;
          -  Serum creatinine &gt;1.5 times the upper limit of normal.&#xD;
&#xD;
          -  Abnormal liver function test (greater than 2 times the upper limit of normal for&#xD;
             alanine aminotransferase (ALT) or aspartate aminotransferase (AST); or bilirubin &gt;1.5&#xD;
             times the upper limit of normal.&#xD;
&#xD;
          -  History of brain disease including Parkinson's Disease, severe brain trauma, seizures,&#xD;
             history of stroke, clinically significant lacunar infarct in a region important for&#xD;
             cognition or multiple lacunes or a cortical infarct or focal lesions of clinical&#xD;
             significance, multiple sclerosis, mental retardation, normal pressure hydrocephalus,&#xD;
             central nervous system (CNS) tumor, Huntington's disease, subdural hematoma or other&#xD;
             serious neurological disorder.&#xD;
&#xD;
          -  Uncontrolled diabetes mellitus (Hba1c higher than 7) or chronically uncontrolled&#xD;
             hypertension.&#xD;
&#xD;
          -  Subject must not be taking Namenda® (memantine) for 6-weeks prior to study entrance.&#xD;
&#xD;
          -  Currently taking any concomitant hepatotoxic drugs such as allopurinol, methyldopa and&#xD;
             sulfasalazine.&#xD;
&#xD;
          -  Any unstable serious co-existing medical condition(s) including but not limited to&#xD;
             myocardial infarction, coronary artery disease requiring coronary bypass surgery,&#xD;
             unstable angina, clinically evident congestive heart failure within 6 months prior to&#xD;
             the screening visit.&#xD;
&#xD;
          -  Current smoker or user of nicotine-containing products, such as chewing tobacco,&#xD;
             nicotine patch or gum for the past 2 months.&#xD;
&#xD;
          -  Current untreated major depression defined by Geriatric Depression Scale &gt; 20.&#xD;
&#xD;
          -  Participation in any investigational or marketed drug or device trial within 30 days&#xD;
             prior to the screening visit.&#xD;
&#xD;
          -  Significant neuropsychiatric illnesses such as bipolar disorder, schizophrenia,&#xD;
             moderate-severe anxiety, vascular dementia, Creutzfeldt-Jakob dementia, HIV dementia,&#xD;
             and dementia in other specified diseases.&#xD;
&#xD;
          -  Subjects who have been on donepezil for longer than 5 years.&#xD;
&#xD;
          -  Weight&gt; 300 pounds.&#xD;
&#xD;
          -  Lactose intolerance.&#xD;
&#xD;
          -  Any medical or social condition that, in the opinion of the Investigator, might pose&#xD;
             additional risk to the participant or confound the results of the study.&#xD;
&#xD;
          -  Positive Hepatitis Serology (Hep. B antigen+ or Hep. C antibody+)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>95 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ana Pereira, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Rockefeller University</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, Andrews RD, Lukic AS, Lee J, Hampilos N, Shafiian N, Sano M, David Mozley P, Fillit H, McEwen BS, Shungu DC, Pereira AC. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease. Brain. 2021 Dec 31;144(12):3742-3755. doi: 10.1093/brain/awab222.</citation>
    <PMID>34145880</PMID>
  </results_reference>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>October 4, 2012</study_first_submitted>
  <study_first_submitted_qc>October 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2012</study_first_posted>
  <results_first_submitted>May 26, 2021</results_first_submitted>
  <results_first_submitted_qc>August 26, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">September 22, 2021</results_first_posted>
  <last_update_submitted>August 26, 2021</last_update_submitted>
  <last_update_submitted_qc>August 26, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 22, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>Ana Pereira</investigator_full_name>
    <investigator_title>Principal Investigator; Assistant Professor of Neurology and Neuroscience</investigator_title>
  </responsible_party>
  <keyword>Alzheimer's Disease</keyword>
  <keyword>Dementia</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>Riluzole</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 18, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/17/NCT01703117/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Riluzole</title>
          <description>Riluzole 50mg twice a day</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Matching placebo twice a day</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
                <participants group_id="P2" count="24"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Placebo</title>
          <description>Matching placebo twice a day</description>
        </group>
        <group group_id="B2">
          <title>Riluzole</title>
          <description>Riluzole 50mg twice a day</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="20"/>
            <count group_id="B2" value="22"/>
            <count group_id="B3" value="42"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="74.6" spread="7.7"/>
                    <measurement group_id="B2" value="75.3" spread="5.8"/>
                    <measurement group_id="B3" value="74.98" spread="6.7"/>
                  </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="14"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Black or African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black/non-Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Latino/Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White/non-Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Education</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15.1" spread="3.1"/>
                    <measurement group_id="B2" value="15.9" spread="3.0"/>
                    <measurement group_id="B3" value="15.5" spread="3.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Imaging Biomarkers FDG-PET SUVR in Regions of Interest</title>
        <description>Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest.&#xD;
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.</description>
        <time_frame>Change from baseline to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo</title>
            <description>Matching placebo twice a day</description>
          </group>
          <group group_id="O2">
            <title>Riluzole</title>
            <description>Riluzole 50mg twice a day</description>
          </group>
        </group_list>
        <measure>
          <title>Imaging Biomarkers FDG-PET SUVR in Regions of Interest</title>
          <description>Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest.&#xD;
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.</description>
          <units>Standardized Uptake Value Ratios (SUVRs)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Posterior cingulate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.048" spread="0.035"/>
                    <measurement group_id="O2" value="-0.005" spread="0.035"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Precuneus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.032" spread="0.028"/>
                    <measurement group_id="O2" value="-0.007" spread="0.032"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Temporal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.023" spread="0.033"/>
                    <measurement group_id="O2" value="0.002" spread="0.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Frontal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.129" spread="0.066"/>
                    <measurement group_id="O2" value="-0.077" spread="0.072"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Parietal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.020" spread="0.027"/>
                    <measurement group_id="O2" value="-0.005" spread="0.024"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hippocampus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.018" spread="0.034"/>
                    <measurement group_id="O2" value="-0.002" spread="0.029"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right Hippocampus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.021" spread="0.036"/>
                    <measurement group_id="O2" value="0.002" spread="0.027"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AD Progression score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.579" spread="0.607"/>
                    <measurement group_id="O2" value="0.245" spread="0.558"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Post Cing - Precuneus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.041" spread="0.042"/>
                    <measurement group_id="O2" value="-0.006" spread="0.038"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Orbitofrontal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.019" spread="0.044"/>
                    <measurement group_id="O2" value="0.014" spread="0.036"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS</title>
        <description>N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.</description>
        <time_frame>Changes from baseline to 6 months</time_frame>
        <population>Some participants could not complete MRS study due to multiple reasons (eg could not tolerate lengthy exam, did not return to visit etc) or did complete it but quality control of the MRS spectra did not pass screening criteria for analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Riluzole</title>
            <description>Riluzole 50mg twice a day</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo twice a day</description>
          </group>
        </group_list>
        <measure>
          <title>Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS</title>
          <description>N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.</description>
          <population>Some participants could not complete MRS study due to multiple reasons (eg could not tolerate lengthy exam, did not return to visit etc) or did complete it but quality control of the MRS spectra did not pass screening criteria for analysis.</population>
          <units>Ratios</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BASELINE (NAA/W)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.3843874" spread="0.0815156"/>
                    <measurement group_id="O2" value="0.4274546" spread="0.0684472"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 MONTHS (NAA/W)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.3996655" spread="0.0927727"/>
                    <measurement group_id="O2" value="0.4248429" spread="0.0774599"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 MONTHS (NAA/W)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.3784181" spread="0.0758756"/>
                    <measurement group_id="O2" value="0.4415926" spread="0.1039630"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BASELINE (NAA/tCr)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.4488809" spread="0.1731644"/>
                    <measurement group_id="O2" value="1.4802620" spread="0.1412636"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 MONTHS (NAA/tCr)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.4271889" spread="0.1140340"/>
                    <measurement group_id="O2" value="1.4766125" spread="0.1304353"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 MONTHS (NAA/tCr)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.4594796" spread="0.1458860"/>
                    <measurement group_id="O2" value="1.4811814" spread="0.1474927"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Glutamate Levels Measured Through 1H MRS</title>
        <description>In vivo measurement of glutamate with 1H magnetic resonance spectroscopy (MRS) (a neuroimaging study) in posterior cingulate as a marker of target engagement at three and six months compared to baseline.In vivo brain levels of glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of glutamate and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.</description>
        <time_frame>Change from baseline to 6 months</time_frame>
        <population>Some participants could not complete MRS study due to multiple reasons (eg could not tolerate lengthy exam, did not return to visit etc) or did complete it but quality control of the MRS spectra did not pass screening criteria for analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Riluzole</title>
            <description>Riluzole 50mg twice a day</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo twice a day</description>
          </group>
        </group_list>
        <measure>
          <title>Glutamate Levels Measured Through 1H MRS</title>
          <description>In vivo measurement of glutamate with 1H magnetic resonance spectroscopy (MRS) (a neuroimaging study) in posterior cingulate as a marker of target engagement at three and six months compared to baseline.In vivo brain levels of glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of glutamate and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.</description>
          <population>Some participants could not complete MRS study due to multiple reasons (eg could not tolerate lengthy exam, did not return to visit etc) or did complete it but quality control of the MRS spectra did not pass screening criteria for analysis.</population>
          <units>Ratios</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BASELINE (Glu/W)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0598059" spread="0.0164069"/>
                    <measurement group_id="O2" value="0.0677906" spread="0.0133271"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 MONTHS (Glu/W)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0579899" spread="0.0181040"/>
                    <measurement group_id="O2" value="0.0646162" spread="0.0107094"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 MONTHS (Glu/W)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0609985" spread="0.0156960"/>
                    <measurement group_id="O2" value="0.0633453" spread="0.0147764"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>BASELINE (Glu/tCr)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2280186" spread="0.0543718"/>
                    <measurement group_id="O2" value="0.2367567" spread="0.0484442"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 MONTHS (Glu/tCr)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2080647" spread="0.0515160"/>
                    <measurement group_id="O2" value="0.2285644" spread="0.0441709"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 MONTHS (Glu/tCr)</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="17"/>
                    <count group_id="O2" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2339366" spread="0.0370164"/>
                    <measurement group_id="O2" value="0.2162526" spread="0.0426140"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog)</title>
        <description>The ADAS comprises two subscales, cognitive and non-cognitive. The Cognitive Subscale (ADAScog) is a psychometric instrument that includes 11 tasks and evaluates memory, attention, reasoning, language, orientation, and praxis, scored from 0 to 70. The full ADAS total is scored by summing the number of errors made on each task on a range from 0 to 150 so that higher scores indicate worse performance.The non-cognitive component was not used in this study. Obtained for correlation with neuroimaging biomarkers.</description>
        <time_frame>baseline to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Riluzole</title>
            <description>Riluzole 50mg twice a day</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo twice a day</description>
          </group>
        </group_list>
        <measure>
          <title>Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog)</title>
          <description>The ADAS comprises two subscales, cognitive and non-cognitive. The Cognitive Subscale (ADAScog) is a psychometric instrument that includes 11 tasks and evaluates memory, attention, reasoning, language, orientation, and praxis, scored from 0 to 70. The full ADAS total is scored by summing the number of errors made on each task on a range from 0 to 150 so that higher scores indicate worse performance.The non-cognitive component was not used in this study. Obtained for correlation with neuroimaging biomarkers.</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BASELINE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.4981818" spread="7.8875264"/>
                    <measurement group_id="O2" value="17.9005000" spread="7.4614719"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 MONTHS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.8022727" spread="9.7334313"/>
                    <measurement group_id="O2" value="18.8495000" spread="9.2608983"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Neuropsychiatry Inventory - NPI</title>
        <description>NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 0 to 144; Higher scores indicate greater disease severity.&#xD;
Obtained for correlation with neuroimaging</description>
        <time_frame>baseline to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Riluzole</title>
            <description>Riluzole 50mg twice a day</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo twice a day</description>
          </group>
        </group_list>
        <measure>
          <title>Neuropsychiatry Inventory - NPI</title>
          <description>NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 0 to 144; Higher scores indicate greater disease severity.&#xD;
Obtained for correlation with neuroimaging</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BASELINE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.6363636" spread="9.1627894"/>
                    <measurement group_id="O2" value="10.2000000" spread="11.1383642"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 MONTHS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.0909091" spread="6.6254135"/>
                    <measurement group_id="O2" value="14.0500000" spread="12.8082005"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>ADCS Activities of Daily Living</title>
        <description>ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity.&#xD;
Obtained for correlation with neuroimaging</description>
        <time_frame>baseline to 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Riluzole</title>
            <description>Riluzole 50mg twice a day</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Matching placebo twice a day</description>
          </group>
        </group_list>
        <measure>
          <title>ADCS Activities of Daily Living</title>
          <description>ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity.&#xD;
Obtained for correlation with neuroimaging</description>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>BASELINE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="68.3636364" spread="9.5096215"/>
                    <measurement group_id="O2" value="68.0500000" spread="9.3215935"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 MONTHS</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="65.5000000" spread="11.5377228"/>
                    <measurement group_id="O2" value="64.3000000" spread="10.7757037"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Riluzole</title>
          <description>Riluzole 50mg twice a day</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Matching placebo twice a day</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Blood disorder</sub_title>
                <description>laboratory abnormalities (thrombocytopenia) with study article discontinuation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac</sub_title>
                <description>bradycardia and pacemaker placement with study article discontinuation</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>GI</sub_title>
                <description>Gastrointestinal hemorrhage with hospitalization and study article discontinuation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>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="21" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Elevated liver enzymes</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Paranoia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="24"/>
              </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>
    <limitations_and_caveats>1.Sample size was relatively small, and results require replication in larger-sample studies. 2.lack of amyloid characterization. 3.MRS is unable to differentiate neurotransmitter or vesicular and metabolic pools of glutamate. Longitudinal MRS measurements can be subject to technical variability and head motion. 4. the study was not powered for neuropsychological outcome and clinical changes must be viewed only as directional/exploratory.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Ana Pereira</name_or_title>
      <organization>Icahn School of Medicine at Mount Sinai</organization>
      <phone>212-241-6984</phone>
      <email>ana.pereira@mssm.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/NCT01703117
org study id: GCO 18-0623
secondary id: APE-0792
nct id: NCT01703117
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
Cognitive aging is a major source of disability in an increasingly aging population. The
      paucity of effective treatments for cognitive aging disorders, and most importantly in
      Alzheimer's disease instigates a need for further research into novel therapeutic
      possibilities. Alzheimer's disease is the most common neurodegenerative disorder and its
      prevalence steeply increases. Glutamate-mediated excitotoxicity in neuropsychiatric disorders
      and in particular in Alzheimer's disease has been shown to cause significant cerebral damage.
      Early effective therapeutic intervention in Alzheimer's disease is critical in order to
      prevent or at least slow down neuropathological progression that will lead to widespread
      irreversible neuronal loss and significant cognitive dysfunction. Riluzole, a glutamate
      modulator agent, will be tested in mild Alzheimer's disease patients. Cognitive functional
      changes along with two established in vivo biomarkers, namely, Magnetic Resonance
      Spectroscopy (MRS) and Fluorodeoxyglucose (18F) positron emission tomography (FDG-PET) will
      be evaluated.
A double-blinded, randomized, placebo-controlled study will be performed. Forty-two
      individuals with a diagnosis of mild Alzheimer's disease between 50-95 years old will
      complete the study. All forty-two individuals will have been on an acetylcholinesterase
      inhibitor, which is FDA approved for the treatment of Alzheimer's disease, for at least 2
      months prior to initiating the study, unless the medication was not previously tolerated.
      Twenty to twenty-two mild Alzheimer's disease patients will receive riluzole and another
      20-22 will receive a placebo. All patients will have a neurological evaluation and
      neuropsychological tests performed to confirm that they meet criteria for probable
      Alzheimer's disease set out by the National Institute on Aging - Alzheimer's disease
      Association that recently revisited the NINCDS-ADRDA criteria along with FDG-PET biomarker
      consistent with Alzheimer's disease.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Imaging Biomarkers FDG-PET SUVR in Regions of Interest
time frame: Change from baseline to 6 months
description: Change from baseline to 6 months in cerebral glucose metabolism measured with FDG PET in posterior cingulate cortex, hippocampus, precuneus, and medial temporal, lateral temporal, inferior parietal, and frontal lobes, referred to collectively as our pre-specified regions of interest.
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an imaging procedure that measures glucose metabolism in the brain.It is a well-established Alzheimer's disease biomarker and predictor of disease progression. For each FDG PET scan, 5 mCi of fluorodeoxyglucose was administered followed by a 40 minute uptake period during which the participant was in a resting state. Images were acquired on a Siemens Biograph 64mCT scanner as a series of 4 frames of 5 minutes each. Using SPM12 (Wellcome Trust), motion correction was performed and frames averaged into a static image. Each 6 month scan was coregistered to the baseline FDG scan, which was co-registered to the participant's T1-weighted MRI scan.
measure: Imaging Biomarkers N-acetylaspartate (NAA) in Posterior Cingulate (PC) Measured Through 1H MRS
time frame: Changes from baseline to 6 months
description: N-acetylaspartate (NAA) is a neuronal viability marker measured through magnetic resonance spectroscopy (1H MRS).In vivo brain levels of NAA, glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex (PC) voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of NAA and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.
measure: Glutamate Levels Measured Through 1H MRS
time frame: Change from baseline to 6 months
description: In vivo measurement of glutamate with 1H magnetic resonance spectroscopy (MRS) (a neuroimaging study) in posterior cingulate as a marker of target engagement at three and six months compared to baseline.In vivo brain levels of glutamate, tCr and other major metabolites were obtained using 1H MRS and a 2x2x2-cm3 Posterior Cingulate Cortex voxel of interest in approximately 6.5 minutes using the constant-time point-resolved spectroscopy (CT-PRESS) technique with TE 30 ms, 129 constant-time increments (t1) of 0.8ms, and TR 1500 ms and a receive-only 8-channel phased-array head coil.The levels of glutamate and other metabolites were expressed semi-quantitatively as ratios of peak areas relative to that of the unsuppressed water signal (W) from the same voxels. For consistency with earlier MRS literature, levels of the same metabolites were also expressed as peak ratios relative to tCr area in the same voxel.
measure: Alzheimer's Disease Assessment Scale (ADAS) - Cognitive Subscale (ADAScog)
time frame: baseline to 6 months
description: The ADAS comprises two subscales, cognitive and non-cognitive. The Cognitive Subscale (ADAScog) is a psychometric instrument that includes 11 tasks and evaluates memory, attention, reasoning, language, orientation, and praxis, scored from 0 to 70. The full ADAS total is scored by summing the number of errors made on each task on a range from 0 to 150 so that higher scores indicate worse performance.The non-cognitive component was not used in this study. Obtained for correlation with neuroimaging biomarkers.
measure: Neuropsychiatry Inventory - NPI
time frame: baseline to 6 months
description: NPI assesses psychopathology in participants with dementia and other neurologic disorders. Information is obtained from a caregiver familiar with the participant's behavior. Total score ranges from 0 to 144; Higher scores indicate greater disease severity.
Obtained for correlation with neuroimaging
measure: ADCS Activities of Daily Living
time frame: baseline to 6 months
description: ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity.
Obtained for correlation with neuroimaging
arm group label: age matched cohort 50-95 years old
arm group type: Experimental
description: 20-22 subjects between the ages of 50-95 will receive riluzole
arm group label: 24 subjects between 50-95 years old
arm group type: Placebo Comparator
description: 20-22 subjects between 50-95 will receive placebo
intervention type: Drug
intervention name: Riluzole
description: 20-22 subjects between the ages of 60-85 will receive study drug.
arm group label: age matched cohort 50-95 years old
other name: no other names
intervention type: Drug
intervention name: Placebo
description: 20-22 subjects between the ages of 60-85 will receive placebo
arm group label: 24 subjects between 50-95 years old
other name: no other names
criteria: 
gender: All
minimum age: 50 Years
maximum age: 95 Years
healthy volunteers: No
last name: Ana Pereira, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
facility: 
facility: 
country: United States
citation: Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, Andrews RD, Lukic AS, Lee J, Hampilos N, Shafiian N, Sano M, David Mozley P, Fillit H, McEwen BS, Shungu DC, Pereira AC. Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease. Brain. 2021 Dec 31;144(12):3742-3755. doi: 10.1093/brain/awab222.
PMID: 34145880
responsible party type: Principal Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: Ana Pereira
investigator title: Principal Investigator; Assistant Professor of Neurology and Neuroscience
mesh term: Alzheimer Disease
mesh term: Riluzole
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: 1.Sample size was relatively small, and results require replication in larger-sample studies. 2.lack of amyloid characterization. 3.MRS is unable to differentiate neurotransmitter or vesicular and metabolic pools of glutamate. Longitudinal MRS measurements can be subject to technical variability and head motion. 4. the study was not powered for neuropsychological outcome and clinical changes must be viewed only as directional/exploratory.
point of contact: 