<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/NCT02197286</url>
  </required_header>
  <id_info>
    <org_study_id>S13-01127</org_study_id>
    <nct_id>NCT02197286</nct_id>
  </id_info>
  <brief_title>Targeted Vitamin D Treatment of Schizophrenia-Associated Hyperprolinemia</brief_title>
  <official_title>Vitamin-D Treatment Targeted to Hyperprolinemia-Associated Schizophrenia.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NYU Langone Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Stanley Medical Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>NYU Langone Health</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A ten week, blinded trial of vitamin D vs. placebo in 80 patients with schizophrenia or&#xD;
      schizoaffective disorder who have low blood levels of vitamin D and elevated blood levels of&#xD;
      the amino acid proline. The aims of the study are to evaluate an anticipated clinical&#xD;
      response to vitamin D supplementation including negative symptoms and cognitive deficits,&#xD;
      evaluate safety of vitamin D supplementation for schizophrenia patients and evaluate the&#xD;
      relationship of changes in plasma proline levels and efficacy outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has&#xD;
      long-been considered important in schizophrenia susceptibility. VitD supplementation has been&#xD;
      suggested for those at-risk, and recent studies have demonstrated that vitD insufficiency&#xD;
      extends into both adolescent and adult schizophrenia.&#xD;
&#xD;
      The mechanism by which vitD deficits confers risk is unknown. However, vitD is a&#xD;
      transcriptional regulator, and the investigators recently found that vitD significantly&#xD;
      up-regulates PRODH gene expression. This is important because the highest known genetic risk&#xD;
      of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which PRODH&#xD;
      maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism. Proline&#xD;
      is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been&#xD;
      associated with learning and memory deficits and neurotransmitter dysregulation in animal&#xD;
      models, and in humans, with decreased intelligence quotient (IQ), cognitive impairment, and&#xD;
      schizoaffective disorder. The investigators recently found that &gt;25% of schizophrenia&#xD;
      patients were hyperprolinemic and hypothesized a causal relationship between vitD, proline&#xD;
      elevation, and schizophrenia, such that vitD insufficiency causes decreased PRODH expression&#xD;
      and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in 64 patients and 90&#xD;
      controls, the investigators found that vitD insufficiency (&lt;30ng/ml) was significantly&#xD;
      associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively correlated with&#xD;
      proline (p=0.01), and vitD insufficient subjects had three times greater odds of&#xD;
      hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains &gt;37% of&#xD;
      the association between vitD insufficiency and schizophrenia, signifying that vitD&#xD;
      insufficiency increases schizophrenia risk, at least in part by elevating proline. These&#xD;
      findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating vitD&#xD;
      insufficiency, may improve symptoms including neurocognitive deficits.&#xD;
&#xD;
      The Specific Aims of this study are:&#xD;
&#xD;
      Aim 1) To Evaluate a clinical response to vitamin D3 (vitD3) treatment, targeting patients&#xD;
      with both vitD insufficiency and hyperprolinemia.&#xD;
&#xD;
      Aim 2) To Evaluate the relationship between fasting plasma proline change, PRODH expression,&#xD;
      and symptoms, for development of an efficacy biomarker.&#xD;
&#xD;
      The aims will be accomplished via a ten week, double-blind, placebo controlled trial, in&#xD;
      which schizophrenia or schizoaffective disorder subjects who are both vitD insufficient and&#xD;
      hyperprolinemic, will be randomized to vitD3 (4,000 international units (IU)/day n=40) or&#xD;
      placebo (n=40) as an adjunct to their antipsychotics.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Personnel changes at study site.&#xD;
  </why_stopped>
  <start_date>February 2015</start_date>
  <primary_completion_date type="Anticipated">December 2017</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical response to supplementation with vitamin D.</measure>
    <time_frame>Baseline (start of vitamin D supplementation) through ten weeks of treatment.</time_frame>
    <description>To evaluate an anticipated clinical response to supplementation with vitamin D including negative symptoms and cognitive deficits by the change in the Positive and Negative Symptom Scale (PANSS) total score and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive scale. Secondary outcomes will also involve investigation of individual domains of the PANSS and MATRICS.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Biological response to supplementation with vitamin D.</measure>
    <time_frame>Lead-in phase visit, baseline visit and then at biweekly visits through ten weeks of treatment.</time_frame>
    <description>Measure plasma proline levels and peripheral PRODH gene expression levels, and examine the relationship with clinical symptoms and cognitive deficits for efficacy biomarker development.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Length of hospital stay.</measure>
    <time_frame>Lead-in phase visit, baseline visit and then at biweekly visits until discharge, an expected average period from lead-in to discharge of seven weeks.</time_frame>
    <description>Firstly, compare the length of hospitalization between study arms. Secondly, measure plasma proline levels and peripheral gene expression, and examine the relationship via regression modeling, with the length of hospitalization.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of participants with adverse events as a measure of safety.</measure>
    <time_frame>Throughout 10 week treatment study period.</time_frame>
    <description>To evaluate the safety of vitamin D supplementation for schizophrenic or schizoaffective patients, by collecting data on all adverse events.</description>
  </other_outcome>
  <other_outcome>
    <measure>Clinical response to supplementation with vitamin D.</measure>
    <time_frame>Baseline (start of vitamin D supplementation) through ten weeks of treatment.</time_frame>
    <description>To evaluate a clinical response to vitamin D supplementation by the change in the Brief Ratings Psychiatric Scale.</description>
  </other_outcome>
  <other_outcome>
    <measure>Clinical response to supplementation with vitamin D.</measure>
    <time_frame>Baseline (start of vitamin D supplementation) through ten weeks of treatment.</time_frame>
    <description>To evaluate a clinical response to vitamin D supplementation by the change in the Wechsler Adult Intelligence scale.</description>
  </other_outcome>
  <other_outcome>
    <measure>Clinical response to supplementation with vitamin D.</measure>
    <time_frame>Baseline (start of vitamin D supplementation) through ten weeks of treatment.</time_frame>
    <description>To evaluate a clinical response to vitamin D supplementation by the change in the Clinical Global Impression scale.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Schizophrenia</condition>
  <condition>Schizoaffective Disorder</condition>
  <arm_group>
    <arm_group_label>Vitamin D (cholecalciferol)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention: Capsules containing the active ingredient, cholecalciferol @ 4,000 international units (IU). One capsule daily, oral administration for 10 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Daily matching placebo gelatin capsule (also contains microcrystalline cellulose).&#xD;
Capsules are identical in size, color and taste to experimental drug.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cholecalciferol</intervention_name>
    <description>One capsule containing 4,000 IU of Cholecalciferol, per day</description>
    <arm_group_label>Vitamin D (cholecalciferol)</arm_group_label>
    <other_name>Other name: Vitamin D3</other_name>
    <other_name>Trade name:Biotech Pharmacal, Inc: Vitamin D3-4,</other_name>
    <other_name>4,000 IU per day</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Daily dose of a single gelatin placebo capsule.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion Criteria for Recruitment&#xD;
&#xD;
          1. Male and Female, all racial/ethnic groups, aged 18-65 years.&#xD;
&#xD;
          2. Admission diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective&#xD;
             disorder.&#xD;
&#xD;
          3. Capability to give informed consent.&#xD;
&#xD;
        Inclusion Criteria for Randomization and Trial Entry&#xD;
&#xD;
          1. Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the&#xD;
             gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for&#xD;
             females and 327.6 uM for males).&#xD;
&#xD;
          2. 25(OH)D insufficiency (&lt;30ng/ml).&#xD;
&#xD;
          3. Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective&#xD;
             disorder.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Exclusion Criteria for Recruitment&#xD;
&#xD;
          1. Organic brain disorders.&#xD;
&#xD;
          2. Valproate treatment within 14 days, because of known proline up-regulatory effects.&#xD;
&#xD;
          3. Pregnant women or women of child-bearing potential, who are not surgically-sterile or&#xD;
             who are not using appropriate methods of birth control.&#xD;
&#xD;
          4. Amino acid metabolism disorder diagnosis.&#xD;
&#xD;
          5. Hypercalcemia (&gt;10.4mg/dL), hypercalciuria (&gt;0.20mg/mg), hyperthyroidism (&gt;65pg/ml) or&#xD;
             history of renal stones, kidney disease, atherosclerosis, sarcoidosis, histoplasmosis&#xD;
             and lymphoma.&#xD;
&#xD;
          6. Chart record of HIV positive status.&#xD;
&#xD;
          7. Treatment with clozapine, as this may reflect general treatment resistance.&#xD;
&#xD;
        Exclusion Criteria for Randomization and Trial Entry&#xD;
&#xD;
          1. Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium&#xD;
             &gt;10.4mg/dL), hypercalciuria (urine calcium/urine creatinine &gt;0.20 mg/mg), or&#xD;
             hyperthyroidism (parathyroid hormone (PTH) &gt; 65pg/ml).&#xD;
&#xD;
          2. Initiation of Valproate treatment.&#xD;
&#xD;
          3. Continued use of dietary supplementation, such as fish oil supplementation or vitamin&#xD;
             D supplements (&gt;400 IU/day).&#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>James D Clelland</last_name>
    <role>Principal Investigator</role>
    <affiliation>NYU Langone Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bellevue Hospital Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2015</verification_date>
  <study_first_submitted>July 16, 2014</study_first_submitted>
  <study_first_submitted_qc>July 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <last_update_submitted>October 7, 2015</last_update_submitted>
  <last_update_submitted_qc>October 7, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 12, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>NYU Langone Health</investigator_affiliation>
    <investigator_full_name>James D. Clelland</investigator_full_name>
    <investigator_title>Research Assistant Professor</investigator_title>
  </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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Ergocalciferols</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
    <mesh_term>Vitamins</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02197286
org study id: S13-01127
nct id: NCT02197286
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
A ten week, blinded trial of vitamin D vs. placebo in 80 patients with schizophrenia or
      schizoaffective disorder who have low blood levels of vitamin D and elevated blood levels of
      the amino acid proline. The aims of the study are to evaluate an anticipated clinical
      response to vitamin D supplementation including negative symptoms and cognitive deficits,
      evaluate safety of vitamin D supplementation for schizophrenia patients and evaluate the
      relationship of changes in plasma proline levels and efficacy outcomes.
25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has
      long-been considered important in schizophrenia susceptibility. VitD supplementation has been
      suggested for those at-risk, and recent studies have demonstrated that vitD insufficiency
      extends into both adolescent and adult schizophrenia.

      The mechanism by which vitD deficits confers risk is unknown. However, vitD is a
      transcriptional regulator, and the investigators recently found that vitD significantly
      up-regulates PRODH gene expression. This is important because the highest known genetic risk
      of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which PRODH
      maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism. Proline
      is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been
      associated with learning and memory deficits and neurotransmitter dysregulation in animal
      models, and in humans, with decreased intelligence quotient (IQ), cognitive impairment, and
      schizoaffective disorder. The investigators recently found that >25% of schizophrenia
      patients were hyperprolinemic and hypothesized a causal relationship between vitD, proline
      elevation, and schizophrenia, such that vitD insufficiency causes decreased PRODH expression
      and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in 64 patients and 90
      controls, the investigators found that vitD insufficiency (<30ng/ml) was significantly
      associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively correlated with
      proline (p=0.01), and vitD insufficient subjects had three times greater odds of
      hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains >37% of
      the association between vitD insufficiency and schizophrenia, signifying that vitD
      insufficiency increases schizophrenia risk, at least in part by elevating proline. These
      findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating vitD
      insufficiency, may improve symptoms including neurocognitive deficits.

      The Specific Aims of this study are:

      Aim 1) To Evaluate a clinical response to vitamin D3 (vitD3) treatment, targeting patients
      with both vitD insufficiency and hyperprolinemia.

      Aim 2) To Evaluate the relationship between fasting plasma proline change, PRODH expression,
      and symptoms, for development of an efficacy biomarker.

      The aims will be accomplished via a ten week, double-blind, placebo controlled trial, in
      which schizophrenia or schizoaffective disorder subjects who are both vitD insufficient and
      hyperprolinemic, will be randomized to vitD3 (4,000 international units (IU)/day n=40) or
      placebo (n=40) as an adjunct to their antipsychotics.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Clinical response to supplementation with vitamin D.
time frame: Baseline (start of vitamin D supplementation) through ten weeks of treatment.
description: To evaluate an anticipated clinical response to supplementation with vitamin D including negative symptoms and cognitive deficits by the change in the Positive and Negative Symptom Scale (PANSS) total score and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive scale. Secondary outcomes will also involve investigation of individual domains of the PANSS and MATRICS.
measure: Biological response to supplementation with vitamin D.
time frame: Lead-in phase visit, baseline visit and then at biweekly visits through ten weeks of treatment.
description: Measure plasma proline levels and peripheral PRODH gene expression levels, and examine the relationship with clinical symptoms and cognitive deficits for efficacy biomarker development.
measure: Length of hospital stay.
time frame: Lead-in phase visit, baseline visit and then at biweekly visits until discharge, an expected average period from lead-in to discharge of seven weeks.
description: Firstly, compare the length of hospitalization between study arms. Secondly, measure plasma proline levels and peripheral gene expression, and examine the relationship via regression modeling, with the length of hospitalization.
measure: Number of participants with adverse events as a measure of safety.
time frame: Throughout 10 week treatment study period.
description: To evaluate the safety of vitamin D supplementation for schizophrenic or schizoaffective patients, by collecting data on all adverse events.
measure: Clinical response to supplementation with vitamin D.
time frame: Baseline (start of vitamin D supplementation) through ten weeks of treatment.
description: To evaluate a clinical response to vitamin D supplementation by the change in the Brief Ratings Psychiatric Scale.
measure: Clinical response to supplementation with vitamin D.
time frame: Baseline (start of vitamin D supplementation) through ten weeks of treatment.
description: To evaluate a clinical response to vitamin D supplementation by the change in the Wechsler Adult Intelligence scale.
measure: Clinical response to supplementation with vitamin D.
time frame: Baseline (start of vitamin D supplementation) through ten weeks of treatment.
description: To evaluate a clinical response to vitamin D supplementation by the change in the Clinical Global Impression scale.
arm group label: Vitamin D (cholecalciferol)
arm group type: Experimental
description: Intervention: Capsules containing the active ingredient, cholecalciferol @ 4,000 international units (IU). One capsule daily, oral administration for 10 weeks.
arm group label: Placebo
arm group type: Placebo Comparator
description: Daily matching placebo gelatin capsule (also contains microcrystalline cellulose).
Capsules are identical in size, color and taste to experimental drug.
intervention type: Drug
intervention name: Cholecalciferol
description: One capsule containing 4,000 IU of Cholecalciferol, per day
arm group label: Vitamin D (cholecalciferol)
other name: Other name: Vitamin D3
other name: Trade name:Biotech Pharmacal, Inc: Vitamin D3-4,
other name: 4,000 IU per day
intervention type: Drug
intervention name: Placebo
description: Daily dose of a single gelatin placebo capsule.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: James D Clelland
role: Principal Investigator
affiliation: NYU Langone Health
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: NYU Langone Health
investigator full name: James D. Clelland
investigator title: Research Assistant Professor
mesh term: Schizophrenia
mesh term: Psychotic Disorders
mesh term: Vitamin D
mesh term: Ergocalciferols
mesh term: Cholecalciferol
mesh term: Vitamins