<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/NCT04452500</url>
  </required_header>
  <id_info>
    <org_study_id>MHBB-014-18S</org_study_id>
    <secondary_id>CX001917-01</secondary_id>
    <nct_id>NCT04452500</nct_id>
  </id_info>
  <brief_title>Phase IIa Trial of a Selective Glucocorticoid Receptor Antagonist in the Treatment of Veterans With Posttraumatic Stress Disorder (PTSD)</brief_title>
  <official_title>Phase IIa Trial of a Selective Glucocorticoid Receptor Antagonist in the Treatment of Veterans With Posttraumatic Stress Disorder (PTSD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      There is large body of evidence demonstrating that Posttraumatic Stress Disorder (PTSD) is&#xD;
      associated with alterations in the stress hormone cortisol. There is also evidence that&#xD;
      medications that block cortisol may be beneficial for treating PTSD and depression. The VA&#xD;
      recently completed a study of a mifepristone, a medication that blocks cortisol and&#xD;
      progesterone hormones, and found some benefit for Veterans who did not have a history of&#xD;
      traumatic brain injury. The proposal will test a medication from a new class of cortisol&#xD;
      blockers which have no effect on progesterone. The proposed study will test the drug&#xD;
      CORT108297 for treatment of PTSD and will establish a safety profile that will inform the&#xD;
      design of future studies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Posttraumatic stress disorder (PTSD) is a serious psychiatric disorder associated with&#xD;
      significant morbidity and mortality worldwide. There is an urgent unmet need to develop&#xD;
      effective pharmacologic treatments for Veterans with PTSD. The pathophysiology of PTSD is&#xD;
      associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and represents&#xD;
      a potential target for therapy. Glucocorticoid receptor (GR) antagonists have shown promise&#xD;
      for treating both PTSD and Major Depression. Glucocorticoid receptor antagonists such as&#xD;
      mifepristone are hypothesized to recalibrate the HPA axis through blockade of peripheral and&#xD;
      central GR and enhance central glucocorticoid signaling. In PTSD, enhanced central&#xD;
      glucocorticoid signaling and normalization of HPA axis regulation could constrain stress&#xD;
      responsive systems, such as the sympathetic nervous system, that are disrupted in PTSD&#xD;
      leading to clinical improvement. A recently completed trial of mifepristone, a GR antagonist&#xD;
      that can modulate dysregulation of the HPA axis, demonstrated clinical benefits at 4 weeks in&#xD;
      a sub-group of Veterans with PTSD without history of traumatic brain injury. Mifepristone&#xD;
      also antagonizes the progesterone receptor (PR) and has abortifacient effects, limiting its&#xD;
      potential for widespread use. CORT108297 is a second-generation glucocorticoid receptor&#xD;
      antagonist which has no affinity for the PR and is proposed for a Phase IIa clinical trial in&#xD;
      Veterans with PTSD. CORT108297 has been shown to have efficacy in preclinical CNS models, and&#xD;
      was well tolerated and safe in Phase I healthy volunteer studies making it a candidate for&#xD;
      further development. Thus, the goal will be to complete a Phase IIa proof of concept trial of&#xD;
      CORT108297 to focus on safety and tolerability, and obtain pilot efficacy data to inform the&#xD;
      design of future clinical trials.&#xD;
&#xD;
      The investigators propose a two-site parallel group, randomized, double-blind,&#xD;
      placebo-controlled Phase IIa clinical trial to test the efficacy and safety of CORT108297-&#xD;
      180mg daily for 7 days for PTSD symptoms in Veterans. The key outcome measures will be&#xD;
      obtained at baseline, day 7, 28, and day 56. Male and female Veterans between the ages of&#xD;
      18-69 who meet criteria for current full syndrome PTSD will be enrolled in a 2 site trial.&#xD;
      Each of the two sites will enroll 44 medically healthy male and female Veterans with chronic&#xD;
      PTSD who will be randomized (1:1 to either a) CORT108297 or b) placebo (n=22 per condition&#xD;
      per site) resulting in a final sample size of 88 participants over a 26-month enrollment&#xD;
      window.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 15, 2022</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The investigators propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IIa clinical trial to test the efficacy and safety of CORT108297- 180mg daily for 7 days for PTSD symptoms in Veterans.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinician Administered PTSD Scale for DSM-5 (CAPS)</measure>
    <time_frame>56 days</time_frame>
    <description>The CAPS is a 30-item interview that is the gold standard assessment for PTSD. The CAPS provides a dimensional and categorical measure of PTSD, and incorporates frequency and intensity of symptoms into a single severity score.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Frequency, Intensity, Burden of Side Effects (FIBSER)</measure>
    <time_frame>56 days</time_frame>
    <description>The FIBSER is a self-report 0-6 Likert-type scale that measures global frequency, intensity, and overall burden of side effects.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Columbia Suicide Severity Rating Scale</measure>
    <time_frame>56 days</time_frame>
    <description>The C-SSRS is FDA approved for assessing severity and change of suicidality in drug studies.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PTSD Checklist for DSM-5</measure>
    <time_frame>56 days</time_frame>
    <description>The PCL is a validated self-report scale assessing PTSD symptoms corresponding to DSM-5.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>World Health Organization Quality of Life (WHOQOL-BREF)</measure>
    <time_frame>56 days</time_frame>
    <description>The WHOQOL-BREF instrument comprises 26 items, which measure the following broad domains: physical health, psychological health, social relationships, and environment. The WHOQOL-BREF is a shorter version of the original WHOQOL-100 instrument and is more convenient for use in large research studies or clinical trials.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">88</enrollment>
  <condition>PTSD</condition>
  <arm_group>
    <arm_group_label>CORT108297</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CORT108297- 180mg daily for 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo- 180mg daily for 7 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CORT108297</intervention_name>
    <description>CORT108297- 180mg daily for 7 days</description>
    <arm_group_label>CORT108297</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo- 180mg daily for 7 days</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  History of US military service&#xD;
&#xD;
          -  Capable of reading and understanding English&#xD;
&#xD;
          -  Able to provide written informed consent&#xD;
&#xD;
          -  Criterion A event meets DSM-5 criteria and occurred during military service, including&#xD;
             combat and military sexual trauma&#xD;
&#xD;
          -  Chronic full syndromal PTSD diagnosis &gt;3 months duration as indexed by CAPS-5 at&#xD;
             screening, and CAPS-5 score &gt; 26 CAPS-5 total score for the past week at baseline&#xD;
&#xD;
          -  Participants (male or pre-menopausal females) agree to use two forms of reliable&#xD;
             contraception, one of which is a barrier method&#xD;
&#xD;
          -  Participants may be on a stable dose (8 weeks at minimum) of an SSRI or SNRI for&#xD;
             treatment of their PTSD&#xD;
&#xD;
          -  Participants may be on a stable dose of trazodone for sleep maintenance.&#xD;
&#xD;
          -  If pain medications are required (opiates), the dose must be stable for 4 weeks at&#xD;
             minimum&#xD;
&#xD;
          -  For participants who are in psychotherapy, treatment must be stable for 6 weeks&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  DSM-5 alcohol, marijuana, and/or other drug use disorder in the last 3 months&#xD;
&#xD;
               -  Mild alcohol and marijuana use not meeting criteria for use disorder will be&#xD;
                  allowed&#xD;
&#xD;
          -  Lifetime bipolar disorder I or II, schizophrenia, schizoaffective disorder,&#xD;
             obsessive-compulsive disorder, or major depressive disorder with psychotic features&#xD;
&#xD;
          -  Exposure to trauma in the last 3 months&#xD;
&#xD;
          -  Use of exclusionary antidepressant (mirtazapine, doxepin, tricyclics), mood&#xD;
             stabilizers (e.g., lithium), antipsychotic medication, benzodiazepines&#xD;
&#xD;
          -  Prominent suicidal or homicidal ideation or any suicidal behavior in the past 3 months&#xD;
             on the Columbia Suicide Severity Rating Scale (C-SSRS) or increased risk of suicide&#xD;
             that necessitates additional therapy or inpatient treatment&#xD;
&#xD;
          -  Pre-existing sleep apnea in the absence of adherence to effective treatment (such as&#xD;
             CPAP or oral device) or positive screen for sleep apnea by type III device&#xD;
&#xD;
          -  Veteran has a medical condition that requires the use of corticosteroids (oral or&#xD;
             inhaled)&#xD;
&#xD;
          -  Neurologic disorder or systemic illness affecting CNS function&#xD;
&#xD;
          -  Chronic or unstable medical illness including unstable angina, myocardial infarction&#xD;
             within the past 6 months, congestive heart failure, preexisting hypotension or&#xD;
             orthostatic hypotension&#xD;
&#xD;
               -  heart block or arrhythmia&#xD;
&#xD;
               -  chronic renal or hepatic failure, and pancreatitis&#xD;
&#xD;
               -  severe chronic obstructive pulmonary disease&#xD;
&#xD;
          -  History of hepatobiliary disease or an AST or ALT greater than 2x the upper limit of&#xD;
             normal, History of renal disease or an eGFR of less than 60 ml/min&#xD;
&#xD;
          -  A prolonged QTc &gt;450 msec on ECG at screening&#xD;
&#xD;
          -  History of additional risk factors for Torsades de pointes&#xD;
&#xD;
               -  e.g., heart failure, hypokalemia, family history of long QT syndrome&#xD;
&#xD;
          -  Participants who may require the use of concomitant medications that prolong the&#xD;
             QT/QTc interval&#xD;
&#xD;
          -  Use of concomitant medications that might increase the plasma concentration of&#xD;
             CORT108297&#xD;
&#xD;
               -  e.g., use of strong inhibitors of CYP3A such as Clarithromycin, telithromycin,&#xD;
                  nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir,&#xD;
                  lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir&#xD;
&#xD;
          -  Poorly controlled hypertension&#xD;
&#xD;
          -  Poorly controlled diabetes mellitus&#xD;
&#xD;
          -  History of moderate or severe traumatic brain injury&#xD;
&#xD;
          -  Mild cognitive impairment assessed by the Montreal Cognitive Assessment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>69 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thomas C. Neylan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>San Francisco VA Medical Center, San Francisco, CA</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jennifer A Hlavin, MS</last_name>
    <phone>(415) 221-4810</phone>
    <phone_ext>26624</phone_ext>
    <email>jennifer.hlavin@va.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Laura A Muratore, BA</last_name>
    <phone>(415) 802-5308</phone>
    <email>laura.muratore@va.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Tuscaloosa VA Medical Center, Tuscaloosa, AL</name>
      <address>
        <city>Tuscaloosa</city>
        <state>Alabama</state>
        <zip>35404</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Brittney Washington</last_name>
      <phone>205-554-2000</phone>
      <phone_ext>3839</phone_ext>
      <email>Brittney.washington@va.gov</email>
    </contact>
    <contact_backup>
      <last_name>Whitney Gay</last_name>
      <phone>2055542000</phone>
      <phone_ext>3267</phone_ext>
      <email>Whitney.gay@va.gov</email>
    </contact_backup>
  </location>
  <location>
    <facility>
      <name>San Francisco VA Medical Center, San Francisco, CA</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94121</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jennifer A Hlavin, MS</last_name>
      <phone>415-221-4810</phone>
      <phone_ext>26624</phone_ext>
      <email>jennifer.hlavin@va.gov</email>
    </contact>
    <investigator>
      <last_name>Thomas C. Neylan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>June 26, 2020</study_first_submitted>
  <study_first_submitted_qc>June 26, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 30, 2020</study_first_posted>
  <last_update_submitted>October 19, 2022</last_update_submitted>
  <last_update_submitted_qc>October 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Glucocorticoids</keyword>
  <keyword>Posttraumatic Stress Disorder</keyword>
  <keyword>Quality of Life</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stress Disorders, Traumatic</mesh_term>
    <mesh_term>Stress Disorders, Post-Traumatic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>For the proposed work final de-identified data from this project will be shared as widely as possible with the scientific community using UCSF DataShare (aka Dash). This self-service tool, available to any UCSF affiliated researcher, is a collaboration between University of California San Francisco's Library, and the UC Curation Center (UC3) at the California Digital Library and the UCSF Clinical and Translational Science Institute (CTSI).</ipd_description>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Within 1 year of the end of the funding period.</ipd_time_frame>
    <ipd_access_criteria>After the raw data is made available on the Dash site, anyone will also be able to view the descriptive metadata used to index the data set. This information is publicly available to allow for maximum discoverability. Individuals wishing to access the data must agree to terms of use for the data set via a Data Use Agreement, and may have to meet additional requirements as set forth by the PI. The data will be permanently archived and available through the California Digital Library.</ipd_access_criteria>
  </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/NCT04452500
org study id: MHBB-014-18S
secondary id: CX001917-01
nct id: NCT04452500
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
There is large body of evidence demonstrating that Posttraumatic Stress Disorder (PTSD) is
      associated with alterations in the stress hormone cortisol. There is also evidence that
      medications that block cortisol may be beneficial for treating PTSD and depression. The VA
      recently completed a study of a mifepristone, a medication that blocks cortisol and
      progesterone hormones, and found some benefit for Veterans who did not have a history of
      traumatic brain injury. The proposal will test a medication from a new class of cortisol
      blockers which have no effect on progesterone. The proposed study will test the drug
      CORT108297 for treatment of PTSD and will establish a safety profile that will inform the
      design of future studies.
Posttraumatic stress disorder (PTSD) is a serious psychiatric disorder associated with
      significant morbidity and mortality worldwide. There is an urgent unmet need to develop
      effective pharmacologic treatments for Veterans with PTSD. The pathophysiology of PTSD is
      associated with dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and represents
      a potential target for therapy. Glucocorticoid receptor (GR) antagonists have shown promise
      for treating both PTSD and Major Depression. Glucocorticoid receptor antagonists such as
      mifepristone are hypothesized to recalibrate the HPA axis through blockade of peripheral and
      central GR and enhance central glucocorticoid signaling. In PTSD, enhanced central
      glucocorticoid signaling and normalization of HPA axis regulation could constrain stress
      responsive systems, such as the sympathetic nervous system, that are disrupted in PTSD
      leading to clinical improvement. A recently completed trial of mifepristone, a GR antagonist
      that can modulate dysregulation of the HPA axis, demonstrated clinical benefits at 4 weeks in
      a sub-group of Veterans with PTSD without history of traumatic brain injury. Mifepristone
      also antagonizes the progesterone receptor (PR) and has abortifacient effects, limiting its
      potential for widespread use. CORT108297 is a second-generation glucocorticoid receptor
      antagonist which has no affinity for the PR and is proposed for a Phase IIa clinical trial in
      Veterans with PTSD. CORT108297 has been shown to have efficacy in preclinical CNS models, and
      was well tolerated and safe in Phase I healthy volunteer studies making it a candidate for
      further development. Thus, the goal will be to complete a Phase IIa proof of concept trial of
      CORT108297 to focus on safety and tolerability, and obtain pilot efficacy data to inform the
      design of future clinical trials.

      The investigators propose a two-site parallel group, randomized, double-blind,
      placebo-controlled Phase IIa clinical trial to test the efficacy and safety of CORT108297-
      180mg daily for 7 days for PTSD symptoms in Veterans. The key outcome measures will be
      obtained at baseline, day 7, 28, and day 56. Male and female Veterans between the ages of
      18-69 who meet criteria for current full syndrome PTSD will be enrolled in a 2 site trial.
      Each of the two sites will enroll 44 medically healthy male and female Veterans with chronic
      PTSD who will be randomized (1:1 to either a) CORT108297 or b) placebo (n=22 per condition
      per site) resulting in a final sample size of 88 participants over a 26-month enrollment
      window.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The investigators propose a two-site parallel group, randomized, double-blind, placebo-controlled Phase IIa clinical trial to test the efficacy and safety of CORT108297- 180mg daily for 7 days for PTSD symptoms in Veterans.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Clinician Administered PTSD Scale for DSM-5 (CAPS)
time frame: 56 days
description: The CAPS is a 30-item interview that is the gold standard assessment for PTSD. The CAPS provides a dimensional and categorical measure of PTSD, and incorporates frequency and intensity of symptoms into a single severity score.
measure: Frequency, Intensity, Burden of Side Effects (FIBSER)
time frame: 56 days
description: The FIBSER is a self-report 0-6 Likert-type scale that measures global frequency, intensity, and overall burden of side effects.
measure: Columbia Suicide Severity Rating Scale
time frame: 56 days
description: The C-SSRS is FDA approved for assessing severity and change of suicidality in drug studies.
measure: PTSD Checklist for DSM-5
time frame: 56 days
description: The PCL is a validated self-report scale assessing PTSD symptoms corresponding to DSM-5.
measure: World Health Organization Quality of Life (WHOQOL-BREF)
time frame: 56 days
description: The WHOQOL-BREF instrument comprises 26 items, which measure the following broad domains: physical health, psychological health, social relationships, and environment. The WHOQOL-BREF is a shorter version of the original WHOQOL-100 instrument and is more convenient for use in large research studies or clinical trials.
arm group label: CORT108297
arm group type: Experimental
description: CORT108297- 180mg daily for 7 days
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo- 180mg daily for 7 days
intervention type: Drug
intervention name: CORT108297
description: CORT108297- 180mg daily for 7 days
arm group label: CORT108297
intervention type: Drug
intervention name: Placebo
description: Placebo- 180mg daily for 7 days
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 69 Years
healthy volunteers: No
last name: Thomas C. Neylan, MD
role: Principal Investigator
affiliation: San Francisco VA Medical Center, San Francisco, CA
last name: Jennifer A Hlavin, MS
phone: (415) 221-4810
phone ext: 26624
email: jennifer.hlavin@va.gov
last name: Laura A Muratore, BA
phone: (415) 802-5308
email: laura.muratore@va.gov
facility: 
status: Recruiting
contact: 
contact backup: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Stress Disorders, Traumatic
mesh term: Stress Disorders, Post-Traumatic
sharing ipd: Yes
ipd description: For the proposed work final de-identified data from this project will be shared as widely as possible with the scientific community using UCSF DataShare (aka Dash). This self-service tool, available to any UCSF affiliated researcher, is a collaboration between University of California San Francisco's Library, and the UC Curation Center (UC3) at the California Digital Library and the UCSF Clinical and Translational Science Institute (CTSI).
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Within 1 year of the end of the funding period.
ipd access criteria: After the raw data is made available on the Dash site, anyone will also be able to view the descriptive metadata used to index the data set. This information is publicly available to allow for maximum discoverability. Individuals wishing to access the data must agree to terms of use for the data set via a Data Use Agreement, and may have to meet additional requirements as set forth by the PI. The data will be permanently archived and available through the California Digital Library.