<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/NCT01706965</url>
  </required_header>
  <id_info>
    <org_study_id>6320</org_study_id>
    <nct_id>NCT01706965</nct_id>
  </id_info>
  <brief_title>Kuvan in People With Schizophrenia and Schizoaffective Disorder</brief_title>
  <official_title>6R-BH 4 in People With Schizophrenia and Schizoaffective Disorder</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>New York State Psychiatric Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Stanley Medical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>New York State Psychiatric Institute</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rater blinded trial of six weeks of Kuvan vs. multivitamin in 60 outpatients with&#xD;
      schizophrenia or schizoaffective disorder. The aims are to evaluate an anticipated clinical&#xD;
      response to Kuvan treatment including negative symptom and cognitive deficits, evaluate&#xD;
      safety of Kuvan treatment for schizophrenic patients and evaluate the relationship of changes&#xD;
      in plasma Kuvan levels and efficacy outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Tetrahydrobiopterin (BH4) is a vital central nervous system (CNS) cofactor that maintains&#xD;
      availability of amine neurotransmitters such as dopamine (DA) and serotonin (5HT), and&#xD;
      stimulates and modulates the glutamatergic system. Dysregulation of these neurotransmitter&#xD;
      systems has been implicated in the pathogenesis of schizophrenia (SZ). A central role of BH4&#xD;
      in schizophrenia is further supported by a study finding a relative deficit of 32% for SZ&#xD;
      patients as compared to controls. The observed BH4 deficit is comparable to that reported for&#xD;
      genetic BH4 deficiency disorders, supporting its characterization as having physiological&#xD;
      significance. This highly significant finding, along with: a) the known roles of BH4 in&#xD;
      neurotransmitter maintenance, b) dysregulation of CNS neurotransmitter synthesis observed in&#xD;
      human BH4 deficiencies, c) evidence that plasma biopterin levels are correlated with CNS&#xD;
      biopterin levels, and d) evidence that urinary biopterin excretion is not increased in SZ,&#xD;
      all support our hypothesis that dysregulation of BH4 biosynthesis is involved in the&#xD;
      pathophysiology of SZ. Moreover, additional data suggesting that mood stabilizer drugs can&#xD;
      moderately increase levels of biopterin in patients with psychiatric disorders, and the&#xD;
      reported efficacy of BH4 in pilot studies of neuropsychiatric disorders, suggest that&#xD;
      alleviation of the schizophrenia BH4 deficit via treatment with synthetic BH4 supplement&#xD;
      (Sapropterin dihydrochloride or Kuvan), may give rise to an improvement of the symptoms of&#xD;
      schizophrenia, including positive and negative symptoms as well as neurocognitive deficits.&#xD;
      Sapropterin dihydrochlorides, teh active pharmaceutical ingredient in Kuvan Tablets,is a&#xD;
      synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin&#xD;
      (BH4)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">June 2016</completion_date>
  <primary_completion_date type="Actual">June 2016</primary_completion_date>
  <phase>Phase 1/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>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Final Positive and Negative Symptom Scale (PANSS)</measure>
    <time_frame>Baseline (start of Kuvan) and at six weeks of treatment</time_frame>
    <description>This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Final MATRICS Cognitive Battery</measure>
    <time_frame>Baseline to week 6</time_frame>
    <description>MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Schizophrenia</condition>
  <condition>Schizoaffective Disorder</condition>
  <arm_group>
    <arm_group_label>Kuvan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Multivitamin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Daily multivitamin tablet</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Kuvan</intervention_name>
    <description>20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight</description>
    <arm_group_label>Kuvan</arm_group_label>
    <other_name>Sapropterin dihydrochloride</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Multivitamin</intervention_name>
    <description>Multi-vitamin will be used as an active control in this study. Will be dosed daily</description>
    <arm_group_label>Multivitamin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female outpatients with schizophrenia or schizoaffective disorder&#xD;
&#xD;
          -  Ages 18-64&#xD;
&#xD;
          -  A score of 45 or greater on PANSS&#xD;
&#xD;
          -  All oral and depot antipsychotics (with the exception of clozapine) are allowable.&#xD;
             Patients must be on their antipsychotic medication for 3 months and stable on dose of&#xD;
             antipsychotic and adjunctive medications for 2 weeks prior to study entry. If a&#xD;
             patient is on depot medication, they must be stable in dose for 2 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Organic brain disorder, including epilepsy; mental retardation; or a medical condition&#xD;
             whose pathology or treatment would likely alter the presentation or treatment of&#xD;
             schizophrenia&#xD;
&#xD;
          -  Participated in any investigational study or taken an investigational drug within 30&#xD;
             days&#xD;
&#xD;
          -  Current Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)&#xD;
             diagnosis of drug/alcohol abuse in last month and current DSM-IV diagnosis&#xD;
             drug/alcohol dependence in last 6 months. Subjects must have a negative drug screen at&#xD;
             baseline (with one retest allowed for suspected false positive based on clinical&#xD;
             judgement of the investigator)&#xD;
&#xD;
          -  Diagnosis of any known BH4 deficiency disorder (other than schizophrenia or&#xD;
             schizoaffective disorder), including dopa-responsive dystonia,phenylketonuria (PKU),&#xD;
             and autism&#xD;
&#xD;
          -  Current treatment with clozapine&#xD;
&#xD;
          -  In the investigator's judgment, a significant risk of suicide or violent behavior&#xD;
&#xD;
          -  Current use of levodopa and nitric oxide-mediated vasorelaxation or oral minoxidil&#xD;
&#xD;
          -  Women will be excluded if they are pregnant, lactating, or not either&#xD;
             surgically-sterile or using appropriate methods of birth control. Women must agree to&#xD;
             continue using applicable birth control throughout the trial. All women of&#xD;
             child-bearing potential must have a negative urine pregnancy test at the screening&#xD;
             visit and visit 2 (1 week before beginning study medication)&#xD;
&#xD;
          -  Absolute neutrophil count below 2.0 on screening&#xD;
&#xD;
          -  Any contraindication or allergic reaction to previous multi-vitamin or unwillingness&#xD;
             to stop use of current multi-vitamin during study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jeffrey A Lieberman, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>New York State Psychiatric</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>New York State Psychiatric Institute</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>October 10, 2012</study_first_submitted>
  <study_first_submitted_qc>October 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 15, 2012</study_first_posted>
  <results_first_submitted>July 10, 2017</results_first_submitted>
  <results_first_submitted_qc>August 14, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">September 13, 2017</results_first_posted>
  <last_update_submitted>August 14, 2017</last_update_submitted>
  <last_update_submitted_qc>August 14, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2017</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>Schizophrenia</mesh_term>
    <mesh_term>Psychotic Disorders</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Kuvan</title>
          <description>Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study&#xD;
Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight</description>
        </group>
        <group group_id="P2">
          <title>Multivitamin</title>
          <description>Daily multivitamin tablet&#xD;
Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Kuvan</title>
          <description>Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study&#xD;
Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight</description>
        </group>
        <group group_id="B2">
          <title>Multivitamin</title>
          <description>Daily multivitamin tablet&#xD;
Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily</description>
        </group>
        <group group_id="B3">
          <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="13"/>
            <count group_id="B2" value="12"/>
            <count group_id="B3" value="25"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40.15" spread="12.1"/>
                    <measurement group_id="B2" value="46.1" spread="8.0"/>
                    <measurement group_id="B3" value="43.0" spread="10.1"/>
                  </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="5"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Final Positive and Negative Symptom Scale (PANSS)</title>
        <description>This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse</description>
        <time_frame>Baseline (start of Kuvan) and at six weeks of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Kuvan</title>
            <description>Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study&#xD;
Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight</description>
          </group>
          <group group_id="O2">
            <title>Multivitamin</title>
            <description>Daily multivitamin tablet&#xD;
Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily</description>
          </group>
        </group_list>
        <measure>
          <title>Final Positive and Negative Symptom Scale (PANSS)</title>
          <description>This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse</description>
          <units>PANSS Total</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.4" spread="10.9"/>
                    <measurement group_id="O2" value="60.2" spread="13.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Univariate ANOVA, controlling for baseline PANSS total</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>.38</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Final MATRICS Cognitive Battery</title>
        <description>MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.</description>
        <time_frame>Baseline to week 6</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Kuvan</title>
            <description>Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study&#xD;
Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight</description>
          </group>
          <group group_id="O2">
            <title>Multivitamin</title>
            <description>Daily multivitamin tablet&#xD;
Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily</description>
          </group>
        </group_list>
        <measure>
          <title>Final MATRICS Cognitive Battery</title>
          <description>MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.</description>
          <units>Total MATRICS score</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.92" spread="17.1"/>
                    <measurement group_id="O2" value="35.0" spread="12.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>ANOVA, controlled for baseline MATRICS</non_inferiority_desc>
            <p_value>.99</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Kuvan</title>
          <description>Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study&#xD;
Kuvan: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight</description>
        </group>
        <group group_id="E2">
          <title>Multivitamin</title>
          <description>Daily multivitamin tablet&#xD;
Multivitamin: Multi-vitamin will be used as an active control in this study. Will be dosed daily</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="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye swelling</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Stomach disconfort</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>anorexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>urtiacia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>URI</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>stiffness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>hand pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>restlessnes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>auditory hallucinatiuons</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>nocturnal enuresis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Vaginal Yeast infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Difficulty speaking</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>sore throat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>bruising</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="12"/>
              </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>
    <point_of_contact>
      <name_or_title>Marlene Carlson</name_or_title>
      <organization>New York State Psychiatric Insititute</organization>
      <phone>646-774-8436</phone>
      <email>marlene.carlson@nyspi.columbia.edu</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/NCT01706965
org study id: 6320
nct id: NCT01706965
lead sponsor: 
collaborator: 
has dmc: No
Rater blinded trial of six weeks of Kuvan vs. multivitamin in 60 outpatients with
      schizophrenia or schizoaffective disorder. The aims are to evaluate an anticipated clinical
      response to Kuvan treatment including negative symptom and cognitive deficits, evaluate
      safety of Kuvan treatment for schizophrenic patients and evaluate the relationship of changes
      in plasma Kuvan levels and efficacy outcomes.
Tetrahydrobiopterin (BH4) is a vital central nervous system (CNS) cofactor that maintains
      availability of amine neurotransmitters such as dopamine (DA) and serotonin (5HT), and
      stimulates and modulates the glutamatergic system. Dysregulation of these neurotransmitter
      systems has been implicated in the pathogenesis of schizophrenia (SZ). A central role of BH4
      in schizophrenia is further supported by a study finding a relative deficit of 32% for SZ
      patients as compared to controls. The observed BH4 deficit is comparable to that reported for
      genetic BH4 deficiency disorders, supporting its characterization as having physiological
      significance. This highly significant finding, along with: a) the known roles of BH4 in
      neurotransmitter maintenance, b) dysregulation of CNS neurotransmitter synthesis observed in
      human BH4 deficiencies, c) evidence that plasma biopterin levels are correlated with CNS
      biopterin levels, and d) evidence that urinary biopterin excretion is not increased in SZ,
      all support our hypothesis that dysregulation of BH4 biosynthesis is involved in the
      pathophysiology of SZ. Moreover, additional data suggesting that mood stabilizer drugs can
      moderately increase levels of biopterin in patients with psychiatric disorders, and the
      reported efficacy of BH4 in pilot studies of neuropsychiatric disorders, suggest that
      alleviation of the schizophrenia BH4 deficit via treatment with synthetic BH4 supplement
      (Sapropterin dihydrochloride or Kuvan), may give rise to an improvement of the symptoms of
      schizophrenia, including positive and negative symptoms as well as neurocognitive deficits.
      Sapropterin dihydrochlorides, teh active pharmaceutical ingredient in Kuvan Tablets,is a
      synthetic preparation of the dihydrochloride salt of naturally occurring tetrahydrobiopterin
      (BH4)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: Final Positive and Negative Symptom Scale (PANSS)
time frame: Baseline (start of Kuvan) and at six weeks of treatment
description: This is a is a 30 item rating scale widely used in the assessment of schizophrenia ranging from 30-210. Higher scores are worse
measure: Final MATRICS Cognitive Battery
time frame: Baseline to week 6
description: MATRICS assessing 7 domains (Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. Raw scores are converted into a composite T-score (normative mean = 50; standard deviation = 10), where higher values indicated less impairment.
arm group label: Kuvan
arm group type: Experimental
description: Kuvan once-daily dosing initiated with 10mg/kg for the first week followed by 20mg/kg for the remaining weeks of the study
arm group label: Multivitamin
arm group type: Active Comparator
description: Daily multivitamin tablet
intervention type: Drug
intervention name: Kuvan
description: 20mg/kg using a daily dosing schedule. To increase tolerability, treatment will be initiated at 10mg/kg for the first week of the study. Given the short length of the trial, no dose adjustments will be made for changes in weight
arm group label: Kuvan
other name: Sapropterin dihydrochloride
intervention type: Drug
intervention name: Multivitamin
description: Multi-vitamin will be used as an active control in this study. Will be dosed daily
arm group label: Multivitamin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: No
last name: Jeffrey A Lieberman, M.D.
role: Principal Investigator
affiliation: New York State Psychiatric
facility: 
country: United States
responsible party type: Sponsor
mesh term: Schizophrenia
mesh term: Psychotic Disorders
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 