<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/NCT03748706</url>
  </required_header>
  <id_info>
    <org_study_id>PTI-125-03</org_study_id>
    <secondary_id>R44AG060878</secondary_id>
    <nct_id>NCT03748706</nct_id>
  </id_info>
  <brief_title>PTI-125 for Mild-to-moderate Alzheimer's Disease Patients</brief_title>
  <official_title>A Phase 2a, Open-label, Multiple Dose, Safety, Pharmacokinetic and Biomarker Study of PTl-125 in Mild-to-moderate Alzheimer's Disease Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Pain Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Cassava Sciences, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate Alzheimer's&#xD;
      disease patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD&#xD;
      patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the&#xD;
      study. Patients will receive 100 mg b.i.d. of PTI-125. The objectives of this study are to&#xD;
      investigate the safety, pharmacokinetics and effect on biomarkers of PTI-125 following 28-day&#xD;
      repeat-dose oral administration.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 7, 2019</start_date>
  <completion_date type="Actual">May 8, 2019</completion_date>
  <primary_completion_date type="Actual">May 8, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Plasma Concentration (Cmax)</measure>
    <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
    <description>Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to Maximum Plasma Concentration (Tmax)</measure>
    <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
    <description>Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Last Quantifiable Plasma Concentration (Clast)</measure>
    <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
    <description>Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to Last Quantifiable Plasma Concentration (Tlast)</measure>
    <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
    <description>Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area Under the Curve (AUClast)</measure>
    <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
    <description>AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Plasma Half-life (T1/2)</measure>
    <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
    <description>Assessment of the half-life in plasma of PTI-125</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>SavaDx (Biomarker)</measure>
    <time_frame>Study Day 1 and Day 28</time_frame>
    <description>Blood samples will be tested for the complementary diagnostic/biomarker for Alzheimer's disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF Biomarkers</measure>
    <time_frame>Change from Baseline to Day 28</time_frame>
    <description>A cerebrospinal fluid sample collection will be performed for Aβ42, tau, YKL40 and other potential CSF biomarkers</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>Simufilam (PTI-125)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Simufilam (PTI-125) 100 mg oral tablets administered twice daily (BID)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PTI-125, 100 mg tablets</intervention_name>
    <description>PTI-125, 100 mg tablets taken twice a day for 28 days</description>
    <arm_group_label>Simufilam (PTI-125)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ages &gt;= 50 and &lt;= 85 years&#xD;
&#xD;
          -  Informed consent form (ICF) signed by the subject or legally acceptable&#xD;
             representative.&#xD;
&#xD;
          -  Clinical diagnosis of dementia due to possible or probable Alzheimer's disease&#xD;
&#xD;
          -  Mini-Mental State Examination score &gt;= 16 and &lt;= 24 at screening&#xD;
&#xD;
          -  If female, postmenopausal for at least 1 year&#xD;
&#xD;
          -  Patient living at home, senior residential setting, or an institutional setting&#xD;
             without the need for continuous (i.e. 24-hour) nursing care&#xD;
&#xD;
          -  General health status acceptable for participation in the study&#xD;
&#xD;
          -  Fluency (oral and written) in English or Spanish&#xD;
&#xD;
          -  If receiving memantine, rivastigmine, galantamine or an AChEI, receiving a stable dose&#xD;
             for at least 3 months (90 days) before screening and with continuous dosing for at&#xD;
             least 3 months. If receiving donepezil, receiving any dose lower than 23 mg once&#xD;
             daily.&#xD;
&#xD;
          -  The patient is a non-smoker for at least 12 months.&#xD;
&#xD;
          -  The patient or legal representative must agree to comply with the drawing of blood&#xD;
             samples and with a lumbar puncture and the drawing of cerebrospinal fluid samples.&#xD;
&#xD;
          -  The patient has a ratio of total tau/Abeta42 in cerebrospinal fluid &gt;= 0.30.&#xD;
&#xD;
          -  Patient has a caregiver or legal representative responsible for administering the drug&#xD;
             and recording the time.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Exposure to an experimental drug, experimental biologic or experimental medical device&#xD;
             within the longer of 5 half-lives or 3 months before screening&#xD;
&#xD;
          -  Residence in a skilled nursing facility&#xD;
&#xD;
          -  Clinically significant laboratory test results&#xD;
&#xD;
          -  Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating&#xD;
             hormone level and thyroid supplementation dose must be stable for at least 6 months&#xD;
             before screening)&#xD;
&#xD;
          -  Insufficiently controlled diabetes mellitus or requiring insulin&#xD;
&#xD;
          -  Renal insufficiency (serum creatinine &gt;2.0 mg/dL)&#xD;
&#xD;
          -  Malignant tumor within 3 years before screening (except squamous and basal cell&#xD;
             carcinoma or cervical carcinoma in situ or localized prostate cancer or localized&#xD;
             stage 1 bladder cancer)&#xD;
&#xD;
          -  History of ischemic colitis or ischemic enterocolitis&#xD;
&#xD;
          -  Unstable medical condition that is clinically significant in the judgment of the&#xD;
             investigator&#xD;
&#xD;
          -  Alanine transaminase (ALT) or aspartate transaminase (AST) &gt;2 times the upper limit of&#xD;
             normal or total bilirubin greater than the upper limit of normal.&#xD;
&#xD;
          -  History of myocardial infarction or unstable angina within 6 months before screening&#xD;
&#xD;
          -  History of more than 1 myocardial infarction within 5 years before screening&#xD;
&#xD;
          -  Clinically significant cardiac arrhythmia (including atrial fibrillation),&#xD;
             cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are&#xD;
             acceptable)&#xD;
&#xD;
          -  Symptomatic hypotension, or uncontrolled hypertension&#xD;
&#xD;
          -  Clinically significant abnormality on screening electrocardiogram (ECG), including but&#xD;
             not necessarily limited to a confirmed corrected QT value &gt;= 450 msec for males or &gt;=&#xD;
             470 msec for females.&#xD;
&#xD;
          -  Stroke within 18 months before screening, or history of a stroke concomitant with&#xD;
             onset of dementia&#xD;
&#xD;
          -  History of brain tumor or other clinically significant space-occupying lesion on CT or&#xD;
             MRI&#xD;
&#xD;
          -  Head trauma with clinically significant loss of consciousness within 12 months before&#xD;
             screening or concurrent with the onset of dementia&#xD;
&#xD;
          -  Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or&#xD;
             resuscitation&#xD;
&#xD;
          -  Specific degenerative CNS disease diagnosis other than Alzheimer's disease (eg,&#xD;
             Huntington's disease, Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal&#xD;
             Dementia, Parkinson's disease)&#xD;
&#xD;
          -  Wernicke's encephalopathy&#xD;
&#xD;
          -  Active acute or chronic Central Nervous System infection&#xD;
&#xD;
          -  Donepezil 23 mg or greater quaque die currently or within 3 months prior to enrollment&#xD;
             in the study&#xD;
&#xD;
          -  Discontinued AChEI &lt; 30 days prior to enrollment in the study&#xD;
&#xD;
          -  Antipsychotics; low doses are allowed only if given for sleep disturbances, agitation&#xD;
             and/or aggression, and only if the subject has received a stable dose for at least 3&#xD;
             months before enrollment in the study&#xD;
&#xD;
          -  Tricyclic antidepressants and monoamine oxidase inhibitors; all other antidepressants&#xD;
             are allowed only if the subject has received a stable dose for at least 3 months&#xD;
             before enrollment in the study&#xD;
&#xD;
          -  Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses&#xD;
             for benign tremor); low doses of benzodiazepines and zolpidem are allowed only if&#xD;
             given for insomnia/sleep disturbance, and only if the subject has received a stable&#xD;
             dose for at least 3 months before enrollment in the study&#xD;
&#xD;
          -  Peripherally acting drugs with effects on cholinergic transmission&#xD;
&#xD;
          -  Immunosuppressants, including systemic corticosteroids, if taken in clinically&#xD;
             immunosuppressive doses (Steroid use for allergy or other inflammation is permitted.)&#xD;
&#xD;
          -  Antiepileptic medications if taken for control of seizures&#xD;
&#xD;
          -  Chronic intake of opioid-containing analgesics&#xD;
&#xD;
          -  Sedating H1 antihistamines&#xD;
&#xD;
          -  Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or&#xD;
             similar therapeutic agent within 30 days before screening&#xD;
&#xD;
          -  Clinically significant illness within 30 days of enrollment&#xD;
&#xD;
          -  History of significant neurological, hepatic, renal, endocrine, cardiovascular,&#xD;
             gastrointestinal, pulmonary, or metabolic disease&#xD;
&#xD;
          -  Positive serum hepatitis B surface antigen (HBsAg) or positive hepatitis C virus (HCV)&#xD;
             antibody test at screening&#xD;
&#xD;
          -  Positive HIV test at screening&#xD;
&#xD;
          -  Loss of a significant volume of blood (&gt; 450 mL) within 4 weeks prior to the study&#xD;
&#xD;
          -  Metformin or cimetidine.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lindsay Burns, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Cassava Sciences, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Insite Clinical Research</name>
      <address>
        <city>DeSoto</city>
        <state>Texas</state>
        <zip>75115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Trials of Texas</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.cassavasciences.com</url>
    <description>Cassava Sciences company website</description>
  </link>
  <reference>
    <citation>Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol Aging. 2017 Jul;55:99-114. doi: 10.1016/j.neurobiolaging.2017.03.016. Epub 2017 Mar 31.</citation>
    <PMID>28438486</PMID>
  </reference>
  <reference>
    <citation>Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan M, Shah SM, Burns LH. Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. doi: 10.1523/JNEUROSCI.0354-12.2012. Erratum In: J Neurosci. 2021 Dec 15;41(50):10405. J Neurosci. 2022 Jan 19;42(3):529.</citation>
    <PMID>22815492</PMID>
  </reference>
  <results_reference>
    <citation>Wang HY, Pei Z, Lee KC, Lopez-Brignoni E, Nikolov B, Crowley CA, Marsman MR, Barbier R, Friedmann N, Burns LH. PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients. J Prev Alzheimers Dis. 2020;7(4):256-264. doi: 10.14283/jpad.2020.6.</citation>
    <PMID>32920628</PMID>
  </results_reference>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>November 13, 2018</study_first_submitted>
  <study_first_submitted_qc>November 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <results_first_submitted>March 3, 2021</results_first_submitted>
  <results_first_submitted_qc>March 31, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">April 1, 2021</results_first_posted>
  <last_update_submitted>June 12, 2021</last_update_submitted>
  <last_update_submitted_qc>June 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 7, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 5, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/06/NCT03748706/Prot_ICF_001.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 16, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/06/NCT03748706/SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>PTI-125</title>
          <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>PTI-125</title>
          <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="13"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="67.8" lower_limit="56" upper_limit="81"/>
                  </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="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </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_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Plasma Concentration (Cmax)</title>
        <description>Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin.</description>
        <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Plasma Concentration (Cmax)</title>
          <description>Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin.</description>
          <units>ng/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="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1 Cmax</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1020" spread="442"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 28 Cmax</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1100" spread="417"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Time to Maximum Plasma Concentration (Tmax)</title>
        <description>Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax</description>
        <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Maximum Plasma Concentration (Tmax)</title>
          <description>Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax</description>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1 Tmax</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.00" lower_limit="1.00" upper_limit="3.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 28 Tmax</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.06" lower_limit="1.00" upper_limit="5.93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Last Quantifiable Plasma Concentration (Clast)</title>
        <description>Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected.</description>
        <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Last Quantifiable Plasma Concentration (Clast)</title>
          <description>Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected.</description>
          <units>ng/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="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1 Clast</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="176" spread="112"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 28 Clast</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="238" spread="168"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Time to Last Quantifiable Plasma Concentration (Tlast)</title>
        <description>Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma.</description>
        <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Last Quantifiable Plasma Concentration (Tlast)</title>
          <description>Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma.</description>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1 Tlast</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.0" spread="0.0150"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 28 Tlast</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.0" spread="0.0285"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Area Under the Curve (AUClast)</title>
        <description>AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration.</description>
        <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Curve (AUClast)</title>
          <description>AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration.</description>
          <units>h*ng/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="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1 AUClast</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5320" spread="2230"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 28 AUClast</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6700" spread="3240"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Plasma Half-life (T1/2)</title>
        <description>Assessment of the half-life in plasma of PTI-125</description>
        <time_frame>Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Half-life (T1/2)</title>
          <description>Assessment of the half-life in plasma of PTI-125</description>
          <units>hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Day 1 T1/2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.51" spread="2.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 28 T1/2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.35" spread="1.39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>SavaDx (Biomarker)</title>
        <description>Blood samples will be tested for the complementary diagnostic/biomarker for Alzheimer's disease.</description>
        <time_frame>Study Day 1 and Day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>SavaDx (Biomarker)</title>
          <description>Blood samples will be tested for the complementary diagnostic/biomarker for Alzheimer's disease.</description>
          <units>% change from baseline</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-39.8" spread="0.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>CSF Biomarkers</title>
        <description>A cerebrospinal fluid sample collection will be performed for Aβ42, tau, YKL40 and other potential CSF biomarkers</description>
        <time_frame>Change from Baseline to Day 28</time_frame>
        <group_list>
          <group group_id="O1">
            <title>PTI-125</title>
            <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</description>
          </group>
        </group_list>
        <measure>
          <title>CSF Biomarkers</title>
          <description>A cerebrospinal fluid sample collection will be performed for Aβ42, tau, YKL40 and other potential CSF biomarkers</description>
          <units>% change from baseline</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Total tau</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-19.8" spread="0.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abeta42</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.3" spread="0.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>p-tau181</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-34.4" spread="0.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neurogranin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-32" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neurofilament light chain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-22" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>YKL-40</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9" spread="0.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IL-6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14" spread="0.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IL-1 beta</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-11" spread="0.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TNF alpha</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5" spread="0.01"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Within the 28-day treatment period.</time_frame>
      <desc>Moderate; mild; severe Serious; not serious Unlikely; likely; possibly related to drug treatment</desc>
      <group_list>
        <group group_id="E1">
          <title>PTI-125</title>
          <description>PTI-125 100 mg oral tablets administered twice daily (BID)&#xD;
PTI-125, 100 mg tablets: PTI-125, 100 mg tablets taken twice a day for 28 days</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="13"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (Unspecified)</default_vocab>
        <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="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <description>Moderate severity; rated as unlikely to be related to treatment.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>B12 deficiency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal colic</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Flu</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
              </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>Top enrolling PIs are included as authors on Cassava publications, but no individual PI has the right to publish alone without Cassava authorization.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Lindsay Burns, SVP of Neuroscience</name_or_title>
      <organization>Cassava Sciences</organization>
      <phone>512-501-2484</phone>
      <email>lburns@cassavasciences.com</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/NCT03748706
org study id: PTI-125-03
secondary id: R44AG060878
nct id: NCT03748706
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate Alzheimer's
      disease patients.
This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD
      patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the
      study. Patients will receive 100 mg b.i.d. of PTI-125. The objectives of this study are to
      investigate the safety, pharmacokinetics and effect on biomarkers of PTI-125 following 28-day
      repeat-dose oral administration.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Plasma Concentration (Cmax)
time frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
description: Blood draws will be done to evaluate levels of PTI-125 in the plasma using non-compartmental methods in WinNonlin.
measure: Time to Maximum Plasma Concentration (Tmax)
time frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
description: Levels of PTI-125 will be assessed to determine how long it takes to reach the Cmax
measure: Last Quantifiable Plasma Concentration (Clast)
time frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
description: Levels of PTI-125 will be assessed to determine the last time point where PTI-125 can be detected.
measure: Time to Last Quantifiable Plasma Concentration (Tlast)
time frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
description: Levels of PTI-125 will be assessed to determine the elapsed time to where PTI-125 can last be detected in the plasma.
measure: Area Under the Curve (AUClast)
time frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
description: AUC for PTI-125 plasma concentration from time zero to the last quantifiable plasma concentration.
measure: Plasma Half-life (T1/2)
time frame: Study Day 1 and Day 28 at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-dose
description: Assessment of the half-life in plasma of PTI-125
measure: SavaDx (Biomarker)
time frame: Study Day 1 and Day 28
description: Blood samples will be tested for the complementary diagnostic/biomarker for Alzheimer's disease.
measure: CSF Biomarkers
time frame: Change from Baseline to Day 28
description: A cerebrospinal fluid sample collection will be performed for Aβ42, tau, YKL40 and other potential CSF biomarkers
arm group label: Simufilam (PTI-125)
arm group type: Experimental
description: Simufilam (PTI-125) 100 mg oral tablets administered twice daily (BID)
intervention type: Drug
intervention name: PTI-125, 100 mg tablets
description: PTI-125, 100 mg tablets taken twice a day for 28 days
arm group label: Simufilam (PTI-125)
criteria: 
gender: All
minimum age: 50 Years
maximum age: 85 Years
healthy volunteers: No
last name: Lindsay Burns, PhD
role: Study Director
affiliation: Cassava Sciences, Inc.
facility: 
facility: 
country: United States
url: http://www.cassavasciences.com
description: Cassava Sciences company website
citation: Wang HY, Lee KC, Pei Z, Khan A, Bakshi K, Burns LH. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol Aging. 2017 Jul;55:99-114. doi: 10.1016/j.neurobiolaging.2017.03.016. Epub 2017 Mar 31.
PMID: 28438486
citation: Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan M, Shah SM, Burns LH. Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. doi: 10.1523/JNEUROSCI.0354-12.2012. Erratum In: J Neurosci. 2021 Dec 15;41(50):10405. J Neurosci. 2022 Jan 19;42(3):529.
PMID: 22815492
citation: Wang HY, Pei Z, Lee KC, Lopez-Brignoni E, Nikolov B, Crowley CA, Marsman MR, Barbier R, Friedmann N, Burns LH. PTI-125 Reduces Biomarkers of Alzheimer's Disease in Patients. J Prev Alzheimers Dis. 2020;7(4):256-264. doi: 10.14283/jpad.2020.6.
PMID: 32920628
responsible party type: Sponsor
mesh term: Alzheimer Disease
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 