<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/NCT03757351</url>
  </required_header>
  <id_info>
    <org_study_id>TDR16536</org_study_id>
    <secondary_id>DNLI-D-0003</secondary_id>
    <nct_id>NCT03757351</nct_id>
  </id_info>
  <brief_title>Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis</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 Amyotrophic Lateral Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sanofi</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Denali Therapeutics Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sanofi</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 Amyotrophic Lateral&#xD;
      Sclerosis in a cross-over design&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Due to change in Sanofi's development strategy for DNL747/SAR443060 - not due to any safety&#xD;
    concerns&#xD;
  </why_stopped>
  <start_date type="Actual">December 14, 2018</start_date>
  <completion_date type="Actual">June 18, 2020</completion_date>
  <primary_completion_date type="Actual">June 18, 2020</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>3</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Amyotrophic Lateral Sclerosis</condition>
  <arm_group>
    <arm_group_label>DNL747 First, Placebo Second</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo First, DNL747 Second</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Open-Label Extension</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Conducted in the Netherlands only.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DNL747</intervention_name>
    <description>Repeating oral dose</description>
    <arm_group_label>DNL747 First, Placebo Second</arm_group_label>
    <arm_group_label>Open-Label Extension</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>Repeating oral dose</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 (Double-Blind Part):&#xD;
&#xD;
          -  Women of non-childbearing potential and men, aged 21-80 years&#xD;
&#xD;
          -  Willingness and ability to complete all aspects of the study; participant should be&#xD;
             capable of completing assessments either alone or with help of a caregiver&#xD;
&#xD;
          -  Diagnosis of laboratory-supported probable, probable, or definite (sporadic or&#xD;
             familial) ALS according to the El Escorial World Federation of Neurology revised&#xD;
             research diagnostic criteria&#xD;
&#xD;
          -  Less than 3 years since symptom onset&#xD;
&#xD;
          -  Forced vital capacity (FVC) &gt;50% predicted measured within 30 days of screening&#xD;
&#xD;
          -  If subject is taking approved ALS treatments (riluzole and/or edaravone), doses must&#xD;
             be stable for ≥2 months prior to screening and subject is expected to stay on a stable&#xD;
             regimen throughout the study&#xD;
&#xD;
        Key Exclusion Criteria (Double-Blind Part):&#xD;
&#xD;
          -  History of a clinically significant non-ALS neurologic disorder (other than frontal&#xD;
             temporal lobe dementia), including, but not limited to, muscular dystrophy, spinal&#xD;
             stenosis, peripheral neuropathy, inherited neuropathies, AD, Parkinson's disease, Lewy&#xD;
             body dementia, vascular dementia, Huntington's disease, epilepsy, stroke, multiple&#xD;
             sclerosis, brain tumor, or brain infection or abscess&#xD;
&#xD;
          -  Unstable or poorly controlled comorbid disease process of any organ system currently&#xD;
             requiring active treatment or likely to require treatment adjustment during the study&#xD;
&#xD;
        Key Inclusion Criteria (Open-Label Extension):&#xD;
&#xD;
          -  Successful completion of both periods of the the double-blind, crossover part of the&#xD;
             study&#xD;
&#xD;
          -  Continued diagnosis of laboratory-supported probable, probable, or definite (sporadic&#xD;
             or familial) ALS according to the El Escorial World Federation of Neurology revised&#xD;
             research diagnostic criteria&#xD;
&#xD;
        Key Exclusion Criteria (Open-Label Extension):&#xD;
&#xD;
          -  Presence of laboratory abnormalities, physical examination findings, or AEs determined&#xD;
             to be clinically significant by the investigator from the double-blind part of the&#xD;
             study that have not resolved by the final follow-up visit as part of the double-blind&#xD;
             study period&#xD;
&#xD;
          -  New diagnosis of clinically significant neurological disorder (other than frontal&#xD;
             temporal lobe dementia)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Clinical Sciences &amp; Operations</last_name>
    <role>Study Director</role>
    <affiliation>Sanofi</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bioclinica</name>
      <address>
        <city>Orlando</city>
        <state>Florida</state>
        <zip>32806</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>PRA Health Sciences</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84124</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHDR</name>
      <address>
        <city>Leiden</city>
        <state>South Holland</state>
        <zip>2333</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2021</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>May 11, 2022</last_update_submitted>
  <last_update_submitted_qc>May 11, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 12, 2022</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>Motor Neuron Disease</mesh_term>
    <mesh_term>Amyotrophic Lateral Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org</ipd_description>
  </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/NCT03757351
org study id: TDR16536
secondary id: DNLI-D-0003
nct id: NCT03757351
lead sponsor: 
collaborator: 
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 Amyotrophic Lateral
      Sclerosis in a cross-over design
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
arm group label: Placebo First, DNL747 Second
arm group type: Experimental
arm group label: Open-Label Extension
arm group type: Experimental
description: Conducted in the Netherlands only.
intervention type: Drug
intervention name: DNL747
description: Repeating oral dose
arm group label: DNL747 First, Placebo Second
arm group label: Open-Label Extension
arm group label: Placebo First, DNL747 Second
intervention type: Drug
intervention name: Placebo
description: Repeating oral dose
arm group label: DNL747 First, Placebo Second
arm group label: Placebo First, DNL747 Second
criteria: 
gender: All
minimum age: 21 Years
maximum age: 80 Years
healthy volunteers: No
last name: Clinical Sciences & Operations
role: Study Director
affiliation: Sanofi
facility: 
facility: 
facility: 
country: Netherlands
country: United States
responsible party type: Sponsor
mesh term: Motor Neuron Disease
mesh term: Amyotrophic Lateral Sclerosis
mesh term: Sclerosis
sharing ipd: Yes
ipd description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org