<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/NCT03757325</url>
  </required_header>
  <id_info>
    <org_study_id>DNLI-D-0002</org_study_id>
    <nct_id>NCT03757325</nct_id>
  </id_info>
  <brief_title>Study to Evaluate DNL747 in Subjects With Alzheimer's Disease</brief_title>
  <official_title>A Multicenter, Randomized, Placebo-Controlled, Double-Blind, Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL747 in Subjects With Alzheimer's Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Denali Therapeutics Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Denali Therapeutics Inc.</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and&#xD;
      pharmacodynamics of multiple oral doses of DNL747 in subjects with Alzheimer's disease when&#xD;
      administered for 29 days in a cross-over design&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 1b randomized, placebo-controlled, double-blind, crossover study to evaluate&#xD;
      the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL747 in&#xD;
      subjects with Alzheimer's disease (AD)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 13, 2019</start_date>
  <completion_date type="Actual">December 5, 2019</completion_date>
  <primary_completion_date type="Actual">December 5, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects with clinically significant neurological examination abnormalities</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Subjects with laboratory test abnormalities</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic measure of CSF concentrations of DNL747</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamic measure of pS166 in PBMCs</measure>
    <time_frame>Randomization - Day 86</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>DNL747 First, Placebo Second</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive DNL747 for 29 days for the first period and then will switch to placebo for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo First, DNL747 Second</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive placebo for 29 days for the first period and then will switch to DNL747 for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DNL747</intervention_name>
    <description>DNL747</description>
    <arm_group_label>DNL747 First, Placebo Second</arm_group_label>
    <arm_group_label>Placebo First, DNL747 Second</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>DNL747 First, Placebo Second</arm_group_label>
    <arm_group_label>Placebo First, DNL747 Second</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key Inclusion Criteria:&#xD;
&#xD;
          -  Women of non-childbearing potential and men, aged 55-85 years&#xD;
&#xD;
          -  AD diagnosis based on the 2011 National Institute on Aging-Alzheimer's Association&#xD;
             Guidelines&#xD;
&#xD;
          -  Supportive evidence for diagnosis of AD based upon positive CSF Aβ42 test, or&#xD;
             documented history of positive amyloid-specific PET scan&#xD;
&#xD;
          -  Screening MMSE score of 16-26 points&#xD;
&#xD;
          -  Screening CDR Global Score of 0.5-1.0&#xD;
&#xD;
          -  Availability of a person (&quot;caregiver&quot;) who, in the investigator's judgment, has&#xD;
             frequent and sufficient contact with the participant and is able to provide accurate&#xD;
             information regarding the participant's cognitive and functional abilities, agrees to&#xD;
             provide information at clinic visits that require input for scale completion, assists&#xD;
             the participant with compliance for at-home study treatment administration, and signs&#xD;
             the necessary consent form (note: the caregiver is not required to stay in the unit)&#xD;
&#xD;
          -  Approved AD treatments (acetylcholinesterase inhibitors ± memantine) and other&#xD;
             prescription medications must be stable for ≥1 month prior to screening and&#xD;
             anticipated to be stable over the duration of the study&#xD;
&#xD;
        Key Exclusion Criteria:&#xD;
&#xD;
          -  Clinical history within 2 years of the screening visit or current evidence of any&#xD;
             neurological or neurodegenerative disorder other than AD that is associated with&#xD;
             transient or sustained alterations in cognition&#xD;
&#xD;
          -  Magnetic resonance imaging (MRI) at screening (or within 1 year of screening visit)&#xD;
             consistent with any neurological or neurodegenerative disorder other than AD that is&#xD;
             associated with transient or sustained alterations in cognition&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Clinical Site(s)</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Site(s)</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Site(s)</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Site(s)</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84124</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Site(s)</name>
      <address>
        <city>Groningen</city>
        <zip>9713</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>November 27, 2018</study_first_submitted>
  <study_first_submitted_qc>November 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>February 25, 2020</last_update_submitted>
  <last_update_submitted_qc>February 25, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 26, 2020</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>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03757325
org study id: DNLI-D-0002
nct id: NCT03757325
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and
      pharmacodynamics of multiple oral doses of DNL747 in subjects with Alzheimer's disease when
      administered for 29 days in a cross-over design
This is a Phase 1b randomized, placebo-controlled, double-blind, crossover study to evaluate
      the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL747 in
      subjects with Alzheimer's disease (AD)
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
time frame: Randomization - Day 86
measure: Number of Subjects with clinically significant neurological examination abnormalities
time frame: Randomization - Day 86
measure: Number of Subjects with laboratory test abnormalities
time frame: Randomization - Day 86
measure: Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747
time frame: Randomization - Day 86
measure: Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747
time frame: Randomization - Day 86
measure: Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747
time frame: Randomization - Day 86
measure: Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747
time frame: Randomization - Day 86
measure: Pharmacokinetic measure of CSF concentrations of DNL747
time frame: Randomization - Day 86
measure: Pharmacodynamic measure of pS166 in PBMCs
time frame: Randomization - Day 86
arm group label: DNL747 First, Placebo Second
arm group type: Experimental
description: Subjects will receive DNL747 for 29 days for the first period and then will switch to placebo for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.
arm group label: Placebo First, DNL747 Second
arm group type: Experimental
description: Subjects will receive placebo for 29 days for the first period and then will switch to DNL747 for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods.
intervention type: Drug
intervention name: DNL747
description: DNL747
arm group label: DNL747 First, Placebo Second
arm group label: Placebo First, DNL747 Second
intervention type: Drug
intervention name: Placebo
description: Placebo
arm group label: DNL747 First, Placebo Second
arm group label: Placebo First, DNL747 Second
criteria: 
gender: All
minimum age: 55 Years
maximum age: 85 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
country: Netherlands
country: United States
responsible party type: Sponsor
mesh term: Alzheimer Disease
sharing ipd: No