<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/NCT02221622</url>
  </required_header>
  <id_info>
    <org_study_id>AlloPhase1</org_study_id>
    <secondary_id>1UF1AG046148</secondary_id>
    <nct_id>NCT02221622</nct_id>
  </id_info>
  <brief_title>Allopregnanolone for Mild Cognitive Impairment Due to Alzheimer's Disease or Mild AD</brief_title>
  <acronym>Allo</acronym>
  <official_title>Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase 1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Southern California</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Southern California</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and tolerability of allopregnanolone, a&#xD;
      naturally occurring brain steroid, in mild cognitive impairment and early Alzheimer's disease&#xD;
      participants. The primary goal is to determine the maximally tolerated dose.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1) Each dose group will be comprised of 8 participants (6 randomized to allopregnanolone; 2&#xD;
      randomized to placebo) administered one dose of allopregnanolone or placebo once per week for&#xD;
      12 weeks. A higher dose will be administered to the next group of participants when the lower&#xD;
      dose is shown to be safe and tolerable. 2) Pharmacokinetic analyses will be conducted on&#xD;
      blood samples taken from participants at the beginning and end of the trial. 3) The trial&#xD;
      will assess safety including via MRI brain imaging.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">February 2018</completion_date>
  <primary_completion_date type="Actual">February 2018</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety profile: Adverse events</measure>
    <time_frame>From Baseline to week 16</time_frame>
    <description>Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety profile: Clinical laboratory measurements</measure>
    <time_frame>From Baseline to week 13</time_frame>
    <description>Evaluating the proportion of subjects exceeding pre-established critical values per treatment arm:&#xD;
Alanine aminotransferase (ALT, U/L) &gt; 5 times upper normal limit Aspartate aminotransferase (AST, U/L) &gt; 5 times upper normal limit Total serum bilirubin (mg/dl) &gt; 2 times upper normal limit Serum creatinine (mg/dl) &gt; 2 times upper normal limit Serum creatine phosphokinase (U/L) &gt; 5 times upper normal limit</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety profile: ARIA</measure>
    <time_frame>From Baseline to week 13</time_frame>
    <description>MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety profile: Physical and neurological examination</measure>
    <time_frame>From Baseline to week 16</time_frame>
    <description>To evaluate the proportion of abnormal examination findings of subjects in each treatment arm.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tolerability - Maximum tolerated dose (MTD)</measure>
    <time_frame>From Baseline to week 12</time_frame>
    <description>Onset of sedation will define the upper most limit of drug dose</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax)</measure>
    <time_frame>Weeks: 1 and 12</time_frame>
    <description>Measurement of maximum concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax)</measure>
    <time_frame>Weeks: 1 and 12</time_frame>
    <description>Time to attain maximum concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC)</measure>
    <time_frame>Weeks: 1 and 12</time_frame>
    <description>Pharmacokinetic parameter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL)</measure>
    <time_frame>Weeks: 1 and 12</time_frame>
    <description>Pharmacokinetic parameter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss)</measure>
    <time_frame>Weeks: 1 and 12</time_frame>
    <description>Pharmacokinetic parameter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState)</measure>
    <time_frame>Baseline to Week 13</time_frame>
    <description>Alzheimer's disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog); Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Alzheimer's disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC); CogState 12-min battery (CogState)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain MRI volumetrics</measure>
    <time_frame>Baseline and Week 13</time_frame>
    <description>Gray matter, white matter and hippocampal volume measurements, including subfield analysis.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Mild Cognitive Impairment</condition>
  <condition>Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>Allopregnanolone 2 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Allopregnanolone 4 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Allopregnanolone 6-18 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Drug: Placebo injection (intravenous solution) once per week for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Allopregnanolone injection (intravenous solution)</intervention_name>
    <description>Allopregnanolone intravenous infusion</description>
    <arm_group_label>Allopregnanolone 2 mg</arm_group_label>
    <arm_group_label>Allopregnanolone 4 mg</arm_group_label>
    <arm_group_label>Allopregnanolone 6-18 mg</arm_group_label>
    <other_name>3α,5α-tetrahydroprogesterone</other_name>
    <other_name>3α-hydroxy-5α-pregnan-20-one</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo injection (intravenous solution)</intervention_name>
    <description>Placebo intravenous infusion</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men or postmenopausal women&#xD;
&#xD;
          -  55 years of age or older&#xD;
&#xD;
          -  Diagnosis of MCI due to AD or mild AD&#xD;
&#xD;
          -  MMSE &gt; 20 at screen&#xD;
&#xD;
          -  Capacity to provide informed consent&#xD;
&#xD;
          -  Residing in the community with a caregiver able to accompany the patient to clinic&#xD;
             visits&#xD;
&#xD;
          -  No medical contraindications to participation&#xD;
&#xD;
          -  Willingness to comply with study procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of benzodiazepines, sedative/hypnotics, anticonvulsants, antipsychotics, and other&#xD;
             drugs that might interact with the GABA-A receptor complex&#xD;
&#xD;
          -  Seizure disorder, history of stroke, focal brain lesion, traumatic brain injury,&#xD;
             substance abuse, malignancy&#xD;
&#xD;
          -  Clinically significant laboratory or ECG abnormality&#xD;
&#xD;
          -  MRI indicative of any other significant abnormality, including but not limited to&#xD;
             evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations,&#xD;
             subdural hematoma, or space occupying lesions&#xD;
&#xD;
          -  Any condition that would contraindicate an MRI such as the presence of metallic&#xD;
             objects in the eyes, skin, heart, or body&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Roberta D Brinton, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern California</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lon S Schneider, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southern California</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Southern California - Alzheimer Disease Research Center - Healthcare Consultation Center II</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>July 2, 2014</study_first_submitted>
  <study_first_submitted_qc>August 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 20, 2014</study_first_posted>
  <last_update_submitted>July 2, 2019</last_update_submitted>
  <last_update_submitted_qc>July 2, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Alzheimer's disease</keyword>
  <keyword>Mild Cognitive Impairment</keyword>
  <keyword>Dementia</keyword>
  <keyword>Regenerative therapeutic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pregnanolone</mesh_term>
    <mesh_term>Pharmaceutical Solutions</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02221622
org study id: AlloPhase1
secondary id: 1UF1AG046148
nct id: NCT02221622
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to evaluate the safety and tolerability of allopregnanolone, a
      naturally occurring brain steroid, in mild cognitive impairment and early Alzheimer's disease
      participants. The primary goal is to determine the maximally tolerated dose.
1) Each dose group will be comprised of 8 participants (6 randomized to allopregnanolone; 2
      randomized to placebo) administered one dose of allopregnanolone or placebo once per week for
      12 weeks. A higher dose will be administered to the next group of participants when the lower
      dose is shown to be safe and tolerable. 2) Pharmacokinetic analyses will be conducted on
      blood samples taken from participants at the beginning and end of the trial. 3) The trial
      will assess safety including via MRI brain imaging.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Safety profile: Adverse events
time frame: From Baseline to week 16
description: Incidence and severity of treatment emergent adverse events assessed weekly per treatment arm.
measure: Safety profile: Clinical laboratory measurements
time frame: From Baseline to week 13
description: Evaluating the proportion of subjects exceeding pre-established critical values per treatment arm:
Alanine aminotransferase (ALT, U/L) > 5 times upper normal limit Aspartate aminotransferase (AST, U/L) > 5 times upper normal limit Total serum bilirubin (mg/dl) > 2 times upper normal limit Serum creatinine (mg/dl) > 2 times upper normal limit Serum creatine phosphokinase (U/L) > 5 times upper normal limit
measure: Safety profile: ARIA
time frame: From Baseline to week 13
description: MRI based assessment of amyloid related imaging abnormalities (ARIA); proportion of subjects with ARIA
measure: Safety profile: Physical and neurological examination
time frame: From Baseline to week 16
description: To evaluate the proportion of abnormal examination findings of subjects in each treatment arm.
measure: Tolerability - Maximum tolerated dose (MTD)
time frame: From Baseline to week 12
description: Onset of sedation will define the upper most limit of drug dose
measure: Pharmacokinetic profile after single and multiple doses: Maximum Concentration (Cmax)
time frame: Weeks: 1 and 12
description: Measurement of maximum concentration
measure: Pharmacokinetic profile after single and multiple doses: time attain to Cmax (Tmax)
time frame: Weeks: 1 and 12
description: Time to attain maximum concentration.
measure: Pharmacokinetic profile after single and multiple doses: Area under the curve (AUC)
time frame: Weeks: 1 and 12
description: Pharmacokinetic parameter.
measure: Pharmacokinetic profile after single and multiple doses: Drug Clearance (CL)
time frame: Weeks: 1 and 12
description: Pharmacokinetic parameter.
measure: Pharmacokinetic profile after single and multiple doses: apparent volume of distribution at steady state (Vss)
time frame: Weeks: 1 and 12
description: Pharmacokinetic parameter.
measure: Cognitive tests (ADAS-Cog; MMSE/MoCA; ADCS-CGIC; CogState)
time frame: Baseline to Week 13
description: Alzheimer's disease Assessment Scale Cognitive Subscale 14 (ADAS-Cog); Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Alzheimer's disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC); CogState 12-min battery (CogState)
measure: Brain MRI volumetrics
time frame: Baseline and Week 13
description: Gray matter, white matter and hippocampal volume measurements, including subfield analysis.
arm group label: Allopregnanolone 2 mg
arm group type: Experimental
description: Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
arm group label: Allopregnanolone 4 mg
arm group type: Experimental
description: Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
arm group label: Allopregnanolone 6-18 mg
arm group type: Experimental
description: Drug: Allopregnanolone injection (intravenous solution) once per week for 12 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Drug: Placebo injection (intravenous solution) once per week for 12 weeks
intervention type: Drug
intervention name: Allopregnanolone injection (intravenous solution)
description: Allopregnanolone intravenous infusion
arm group label: Allopregnanolone 2 mg
arm group label: Allopregnanolone 4 mg
arm group label: Allopregnanolone 6-18 mg
other name: 3α,5α-tetrahydroprogesterone
other name: 3α-hydroxy-5α-pregnan-20-one
intervention type: Drug
intervention name: Placebo injection (intravenous solution)
description: Placebo intravenous infusion
arm group label: Placebo
criteria: 
gender: All
minimum age: 55 Years
maximum age: N/A
healthy volunteers: No
last name: Roberta D Brinton, Ph.D.
role: Principal Investigator
affiliation: University of Southern California
last name: Lon S Schneider, M.D.
role: Principal Investigator
affiliation: University of Southern California
facility: 
country: United States
responsible party type: Sponsor
mesh term: Alzheimer Disease
mesh term: Cognitive Dysfunction
mesh term: Pregnanolone
mesh term: Pharmaceutical Solutions