<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/NCT01665950</url>
  </required_header>
  <id_info>
    <org_study_id>2011P002545</org_study_id>
    <nct_id>NCT01665950</nct_id>
  </id_info>
  <brief_title>Simvastatin Augmentation of Lithium Treatment in Bipolar Depression</brief_title>
  <official_title>Simvastatin Augmentation of Lithium Treatment in Bipolar Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary Aim: To estimate the antidepressant efficacy of simvastatin versus placebo as an&#xD;
      adjunct to lithium, valproate, and/or other atypical antipsychotic therapy among individuals&#xD;
      with bipolar I disorder in a nonpsychotic major depressive episode.&#xD;
&#xD;
      Hypothesis: Simvastatin will be superior to placebo in improvement of depressive symptoms&#xD;
      assessed by the Montgomery-Asberg Depression Rating Scale (MADRS).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      (see brief summary)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Lack of enrollment&#xD;
  </why_stopped>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">October 2014</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in MADRS (4 Weeks)</measure>
    <time_frame>Baseline vs week 4 (and, for placebo nonresponders in 1st 4 weeks, week 8 vs week 4)</time_frame>
    <description>Change in Montgomery-Asberg Depression Rating Scale (MADRS) in simvastatin-treated epochs versus placebo-treated epochs</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">4</enrollment>
  <condition>Bipolar Disorder</condition>
  <arm_group>
    <arm_group_label>Simvastatin-Simvastatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo-&gt;Simvastatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the next 4 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo-Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the subsequent 4 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Simvastatin</intervention_name>
    <description>The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: n=30 subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
    <arm_group_label>Placebo-&gt;Simvastatin</arm_group_label>
    <arm_group_label>Simvastatin-Simvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Subjects (n=15) are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
    <arm_group_label>Placebo-&gt;Simvastatin</arm_group_label>
    <arm_group_label>Placebo-Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion:&#xD;
&#xD;
          -  Age 18-65&#xD;
&#xD;
          -  written informed consent&#xD;
&#xD;
          -  meets Diagnostic and Statistical Manual - IV (DSM-IV) criteria (by Structured Clinical&#xD;
             Interview for DSM-IV (SCID-I/P)) for bipolar I disorder, current episode depressed&#xD;
&#xD;
          -  Montgomery-Asberg Depression Scale (MADRS) score of at least 20 (i.e., moderate&#xD;
             depression) and no greater than 34 (i.e., severe depression) at screen and baseline&#xD;
             visit&#xD;
&#xD;
          -  Young Mania Rating Scale (YMRS) score &lt; 12 at screen and baseline visit&#xD;
&#xD;
          -  currently treated with a lithium preparation (carbonate or citrate) at stable dose for&#xD;
             at least 4 wks with level &gt;0.4 and &lt;1.0; and/or valproate at stable dose for at least&#xD;
             4 wks at level &gt;60 and &lt;110; and/or other atypical antipsychotic at stable dose for at&#xD;
             least 4 weeks (at least minimum FDA-labeled dose).&#xD;
&#xD;
        Exclusion:&#xD;
&#xD;
          -  Psychotic features in the current episode, as assessed by YMRS item #8&gt;6&#xD;
&#xD;
          -  felt by the study clinician to require inpatient hospitalization for adequate&#xD;
             management&#xD;
&#xD;
          -  more than 3 failed pharmacologic interventions in the current major depressive&#xD;
             episode, exclusive of primary mood stabilizer&#xD;
&#xD;
          -  current substance use disorder other than nicotine, by SCID-I/P&#xD;
&#xD;
          -  pregnant women or women of child bearing potential who are not using a medically&#xD;
             accepted means of contraception (to include oral contraceptive or implant, condom,&#xD;
             diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy)&#xD;
&#xD;
          -  women who are breastfeeding&#xD;
&#xD;
          -  serious suicide or homicide risk, as assessed by evaluating clinician&#xD;
&#xD;
          -  other unstable medical illness including cardiovascular, hepatic, renal, respiratory,&#xD;
             endocrine, neurological, or hematological disease, based on review of medical history,&#xD;
             physical examination, and screening laboratory tests&#xD;
&#xD;
          -  patients who have taken an investigational psychotropic drug within the last 30 days&#xD;
&#xD;
          -  patients receiving additional anticonvulsant, antipsychotic, or antidepressant within&#xD;
             1 week prior to study entry&#xD;
&#xD;
          -  patients requiring continued treatment with excluded medications (see below).&#xD;
&#xD;
        Excluded medications: other statins, which could influence Wnt signaling; any other drug&#xD;
        known to interact with simvastatin, including potent inhibitors/inducers of CYP3A4 such as&#xD;
        itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin,&#xD;
        voriconazole, cyclosporine or danazol; gemfibrozil or other lipid-lowering drugs that can&#xD;
        cause myopathy when given alone; amiodarone, ranolazine, verapamil, diltiazem, or&#xD;
        amlodipine; niacin; digoxin; coumarin anticoagulants; colchicine; nefazodone; protease&#xD;
        inhibitors including ritonavir, indinavir, nelfinavir, or saquinavir.&#xD;
&#xD;
        Allowed: benzodiazepines and sedative-hypnotic agents if dosage has been stable for 2 weeks&#xD;
        prior to study entry; thyroid or estrogen replacement provided dosage has been stable for 1&#xD;
        month; antidepressants, antipsychotics, and anticonvulsants provided dosage has been stable&#xD;
        for 1 week prior to study entry.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Roy H Perlis, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>April 9, 2012</study_first_submitted>
  <study_first_submitted_qc>August 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 16, 2012</study_first_posted>
  <results_first_submitted>November 30, 2016</results_first_submitted>
  <results_first_submitted_qc>January 4, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">February 23, 2017</results_first_posted>
  <last_update_submitted>April 3, 2017</last_update_submitted>
  <last_update_submitted_qc>April 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 9, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Roy Perlis</investigator_full_name>
    <investigator_title>Associate Professor of Psychiatry</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bipolar Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Simvastatin</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Simvastatin-Simvastatin</title>
          <description>Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: Subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
        </group>
        <group group_id="P2">
          <title>Placebo-&gt;Simvastatin</title>
          <description>Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the next 4 wks&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: Subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results ar</description>
        </group>
        <group group_id="P3">
          <title>Placebo-Placebo</title>
          <description>Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the subsequent 4 weeks&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Simvastatin-Simvastatin</title>
          <description>Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: Subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
        </group>
        <group group_id="B2">
          <title>Placebo-&gt;Simvastatin</title>
          <description>Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the next 4 wks&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: Subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results ar</description>
        </group>
        <group group_id="B3">
          <title>Placebo-Placebo</title>
          <description>Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the subsequent 4 weeks&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
            <count group_id="B2" value="0"/>
            <count group_id="B3" value="2"/>
            <count group_id="B4" value="4"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="41.5" lower_limit="27" upper_limit="56"/>
                    <measurement group_id="B3" value="46.5" lower_limit="44" upper_limit="49"/>
                    <measurement group_id="B4" value="44" lower_limit="27" upper_limit="56"/>
                  </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="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in MADRS (4 Weeks)</title>
        <description>Change in Montgomery-Asberg Depression Rating Scale (MADRS) in simvastatin-treated epochs versus placebo-treated epochs</description>
        <time_frame>Baseline vs week 4 (and, for placebo nonresponders in 1st 4 weeks, week 8 vs week 4)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin-Simvastatin</title>
            <description>Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: Subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Placebo-&gt;Simvastatin</title>
            <description>Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the next 4 wks&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: Subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results ar</description>
          </group>
          <group group_id="O3">
            <title>Placebo-Placebo</title>
            <description>Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the subsequent 4 weeks&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in MADRS (4 Weeks)</title>
          <description>Change in Montgomery-Asberg Depression Rating Scale (MADRS) in simvastatin-treated epochs versus placebo-treated epochs</description>
          <units>units on a scale</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-20"/>
                    <measurement group_id="O3" value="-10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Simvastatin-Simvastatin</title>
          <description>Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
        </group>
        <group group_id="E2">
          <title>Placebo-&gt;Simvastatin</title>
          <description>Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the next 4 wks&#xD;
Simvastatin: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results ar</description>
        </group>
        <group group_id="E3">
          <title>Placebo-Placebo</title>
          <description>Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the subsequent 4 weeks&#xD;
Placebo: Subjects are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="1"/>
              </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>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The study was terminated early because delays in study initiation and insufficient recruitment. Our statisticians have advised us that this analysis is uninformative as it represents the change for one individual in 2 of the three arms of the study.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Roy Perlis</name_or_title>
      <organization>Massachusetts General Hospital, Center for Quantitative Health</organization>
      <phone>617-643-6310</phone>
      <email>rperlis@partners.org</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/NCT01665950
org study id: 2011P002545
nct id: NCT01665950
lead sponsor: 
has dmc: Yes
Primary Aim: To estimate the antidepressant efficacy of simvastatin versus placebo as an
      adjunct to lithium, valproate, and/or other atypical antipsychotic therapy among individuals
      with bipolar I disorder in a nonpsychotic major depressive episode.

      Hypothesis: Simvastatin will be superior to placebo in improvement of depressive symptoms
      assessed by the Montgomery-Asberg Depression Rating Scale (MADRS).
(see brief summary)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Change in MADRS (4 Weeks)
time frame: Baseline vs week 4 (and, for placebo nonresponders in 1st 4 weeks, week 8 vs week 4)
description: Change in Montgomery-Asberg Depression Rating Scale (MADRS) in simvastatin-treated epochs versus placebo-treated epochs
arm group label: Simvastatin-Simvastatin
arm group type: Experimental
description: Subjects will receive simvastatin in phase 1 (4 weeks) and phase 2 (4 weeks)
arm group label: Placebo->Simvastatin
arm group type: Experimental
description: Placebo non-responders after the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the next 4 weeks
arm group label: Placebo-Placebo
arm group type: Placebo Comparator
description: Placebo nonresponders for the 1st 4 weeks will be re-randomized 1:1 to placebo or simvastatin for the subsequent 4 weeks
intervention type: Drug
intervention name: Simvastatin
description: The study uses the Sequential Parallel Comparison design (SPCD), with two 4-week phases: n=30 subjects are randomized 1:1 to simvastatin versus placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 for a further 4 weeks. The SPCD will allow us to pool data from both phases to estimate the simvastatin treatment effect. Subjects who respond in phase 1, and all subjects who receive simvastatin in phase 1, continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.
arm group label: Placebo->Simvastatin
arm group label: Simvastatin-Simvastatin
intervention type: Drug
intervention name: Placebo
description: Subjects (n=15) are randomized to placebo add-on for 4 weeks, with the nonresponders re-randomized 1:1 to statin vs placebo for a further 4 weeks. Subjects who respond in phase 1 continue blinded treatment in phase 2 to preserve the blind, but only phase 1 results are analyzed. Dosage for simvastatin or matched placebo 20mg daily for 8 weeks.
arm group label: Placebo->Simvastatin
arm group label: Placebo-Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Roy H Perlis, MD, MSc
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Roy Perlis
investigator title: Associate Professor of Psychiatry
mesh term: Bipolar Disorder
mesh term: Simvastatin
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The study was terminated early because delays in study initiation and insufficient recruitment. Our statisticians have advised us that this analysis is uninformative as it represents the change for one individual in 2 of the three arms of the study.
point of contact: 