<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/NCT03790345</url>
  </required_header>
  <id_info>
    <org_study_id>B12B16study</org_study_id>
    <nct_id>NCT03790345</nct_id>
  </id_info>
  <brief_title>Vitamin B6 and B12 in the Treatment of Movement Disorders Induced by Antipsychotics</brief_title>
  <official_title>Effect of Vitamin B6 and B12 in the Treatment of Movement Disorders Induced by Antipsychotics</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      D2 dopaminergic receptor blockers, used to treat schizophrenia, can lead to the onset of&#xD;
      movement disorders. Drug-induced movement disorders encompass several syndromes.&#xD;
      Parkinsonism, dystonia, dyskinesia and akathisia are the most prevalent. All of them lead to&#xD;
      poor adherence to the treatment instituted, decrease in the quality of life, relapses and&#xD;
      hospitalizations. The pathophysiology of drug-induced movement disorders is complex and&#xD;
      poorly understood, but seems to be associated with oxidative stress, as a result of an&#xD;
      increase in free radicals generated from dopamine metabolism. Treatment strategies following&#xD;
      the onset of drug-induced movement disorders include neuroleptic discontinuation, use of&#xD;
      atypical antipsychotics and anticholinergics. A pre-clinical study showed that the&#xD;
      antioxidant properties of vitamins B6 and B12, alone or in combination, prevented the&#xD;
      development of orofacial dyskinesia induced by haloperidol. This clinical trial aims to&#xD;
      evaluate the effects of vitamins B6 and B12 on the treatment of patients diagnosed with&#xD;
      schizophrenia, schizoaffective or bipolar disorder who present with tardive dyskinesia,&#xD;
      dystonia and parkinsonism.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      D2 dopaminergic receptor blockers, used to treat schizophrenia, can lead to the onset of&#xD;
      drug-induced movement disorders, such as parkinsonism, dystonia, dyskinesia and akathisia.&#xD;
      They seem to be associated with oxidative stress, as a result of an increase in free radicals&#xD;
      generated from dopamine metabolism. A preclinical study showed that vitamin B6 (pyridoxine)&#xD;
      and B12 (cobalamin), alone or in combination, prevented the development of orofacial&#xD;
      dyskinesia induced by haloperidol in an animal model of schizophrenia.&#xD;
&#xD;
      Specific Aim1: To conduct a prospective, randomized, double-blind, placebo-controlled trial&#xD;
      to evaluate the efficacy of 12-week adjuvant treatment with 200mg of pyridoxine (B6) or 2mg&#xD;
      of cobalamin (B12) to treat drug-induced movement disorders of patients with schizophrenia,&#xD;
      schizoaffective or bipolar disorder. The investigators will randomly assign 45 patients into&#xD;
      three groups: placebo, B6 or B12 and check whether administration of vitamin B6 (pyridoxine)&#xD;
      or B12 (cobalamin) attenuates drug-induced movement disorders (IDDM) in patients with&#xD;
      diagnosis of schizophrenia, schizoaffective or bipolar disorder.&#xD;
&#xD;
      Specific Aim 2: To quantify changes in serum markers of inflammation and biomarkers of&#xD;
      oxidative stress in response to adjunctive treatment with B6 or B12. The hypothesis is that&#xD;
      changes in these biomarkers will mediate the clinical response to them.&#xD;
&#xD;
      Research Plan: The investigators will carry out a proof of concept 12-week prospective,&#xD;
      randomized, double-blind, controlled trial of vitamin B6 and B12, at doses of 200 mg/day and&#xD;
      2mg/day, respectively, or identical placebo tablets, added to ongoing antipsychotics in 45&#xD;
      stable patients (ages 18-60 years, 15 patients per group) with diagnosis of schizophrenia,&#xD;
      schizoaffective or bipolar disorder. The study will be conducted at the Drug Research and&#xD;
      Development Center (NPDM), at the Universidade Federal do Ceará, Fortaleza, Brazil. This&#xD;
      center has a long history of performing placebocontrolled trials in clinical medicine&#xD;
      (http://www.npdm.ufc.br/) and has the necessary infrastructure to successfully complete the&#xD;
      proposed study protocol. All participants will give written informed consent prior to study&#xD;
      enrollment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 3, 2019</start_date>
  <completion_date type="Anticipated">November 3, 2021</completion_date>
  <primary_completion_date type="Anticipated">June 3, 2020</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Proof of concept 12-week prospective, randomized, double-blind, controlled trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>10-item rating scale to assess extrapyramidal symptoms; each item is scored 0-4, yielding a total between 0 and 40.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in the Barnes Akathisia Rating Scale (BAS, BARS) scores</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness are rated on a 4-point scale from 0 - 3 and are summed yielding a total score ranging from 0 to 9. The Global Clinical Assessment of Akathisia uses a 5-point scale ranging from 0 - 4.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in the Abnormal Involuntary Movement Scale (AIMS) scores</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>10-item rating scale to assess involuntary movements; items are rated on a five-point scale of severity from 0-4, yielding a total between 0 and 40.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in the Brief Psychiatry Rating Scale (BPRS) scores</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>18-item rating scale to assess changes in psychopathology; each item is scored 0-6, yielding a total between 0 and 40.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Plasma Glutathione (GSH)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>GSH in ng/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Nitrite</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>Nitrite in nanomole/mililiter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Thiobarbituric acid reactive substances (TBARS)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>TBARS in mmol of malonaldehyde/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Interleukin 1 β (IL-1β)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>IL-1β in pg/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Interleukin-4</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>IL-4 in pg/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Interferon gamma (IFNγ)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>IFNγ in pg/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Tumor necrosis factor alpha (TNF-α)</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>TNF-α in pg/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity</measure>
    <time_frame>Baseline and 12 weeks</time_frame>
    <description>IDO activity in U IDO mol^-1/mg^-1</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">45</enrollment>
  <condition>Schizophrenia</condition>
  <condition>Drug Induced Movement Disorder, Unspecified</condition>
  <condition>Oxidative Stress</condition>
  <arm_group>
    <arm_group_label>Experimental group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 subjects will be randomly assigned to adjuvant treatment with 200mg of vitamin B6 (pyridoxine).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Experimental group 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>15 subjects will be randomly assigned to adjuvant treatment with 2mg of vitamin B12 (cobalamin).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo oral tablet</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>15 subjects will be randomly assigned to adjuvant treatment with placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pyridoxine</intervention_name>
    <description>Adjuvant daily treatment with 200mg of pyridoxine</description>
    <arm_group_label>Experimental group 1</arm_group_label>
    <other_name>Vitamin B6</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cobalamin</intervention_name>
    <description>Adjuvant daily treatment with 2mg of cobalamin</description>
    <arm_group_label>Experimental group 2</arm_group_label>
    <other_name>Vitamin B12</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Adjuvant daily treatment with placebo</description>
    <arm_group_label>Placebo oral tablet</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Capacity to provide informed consent;&#xD;
&#xD;
          -  Schizophrenia diagnosis (confirmed by Structured Clinical Interview (SCID);&#xD;
&#xD;
          -  Movement disorders induced by psychotropic drugs of at least moderate severity;&#xD;
&#xD;
          -  Exposure to psychotropic medication for at least three months prior of the appearance&#xD;
             of movement disorders;.&#xD;
&#xD;
          -  Disorders of movement for at least one year;&#xD;
&#xD;
          -  Stable psychotropic regimen for at least one month prior to study entry.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  6-month history of any drug or alcohol abuse or dependence;&#xD;
&#xD;
          -  Changes in psychotropic medications within the last 4 weeks;&#xD;
&#xD;
          -  General medical illness including autoimmune disorders, known chronic infections such&#xD;
             as HIV or hepatitis C, and liver or renal failure that could adversely impact on&#xD;
             patient outcome;&#xD;
&#xD;
          -  Women who are planning to become pregnant, are pregnant, or are breastfeeding.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lia LO Sanders, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Núcleo de Pesquisa e Desenvolvimento de Medicamentos</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lia LO Sanders, MD, PhD</last_name>
    <phone>+55(85)3366-8338</phone>
    <email>lia_sanders@hotmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Núcleo de Pesquisa e Desenvolvimento de Medicamentos - UFC</name>
      <address>
        <city>Fortaleza</city>
        <state>CE</state>
        <zip>60430-275</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lia LO Sanders, MD, PhD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 21, 2018</study_first_submitted>
  <study_first_submitted_qc>December 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 31, 2018</study_first_posted>
  <last_update_submitted>December 14, 2019</last_update_submitted>
  <last_update_submitted_qc>December 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Schizophrenia</keyword>
  <keyword>Cobalamin</keyword>
  <keyword>Pyridoxine</keyword>
  <keyword>Drug-induced movement disorder</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Movement Disorders</mesh_term>
    <mesh_term>Schizophrenia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamins</mesh_term>
    <mesh_term>Vitamin B 12</mesh_term>
    <mesh_term>Pyridoxine</mesh_term>
    <mesh_term>Vitamin B 6</mesh_term>
    <mesh_term>Vitamin B Complex</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/NCT03790345
org study id: B12B16study
nct id: NCT03790345
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
D2 dopaminergic receptor blockers, used to treat schizophrenia, can lead to the onset of
      movement disorders. Drug-induced movement disorders encompass several syndromes.
      Parkinsonism, dystonia, dyskinesia and akathisia are the most prevalent. All of them lead to
      poor adherence to the treatment instituted, decrease in the quality of life, relapses and
      hospitalizations. The pathophysiology of drug-induced movement disorders is complex and
      poorly understood, but seems to be associated with oxidative stress, as a result of an
      increase in free radicals generated from dopamine metabolism. Treatment strategies following
      the onset of drug-induced movement disorders include neuroleptic discontinuation, use of
      atypical antipsychotics and anticholinergics. A pre-clinical study showed that the
      antioxidant properties of vitamins B6 and B12, alone or in combination, prevented the
      development of orofacial dyskinesia induced by haloperidol. This clinical trial aims to
      evaluate the effects of vitamins B6 and B12 on the treatment of patients diagnosed with
      schizophrenia, schizoaffective or bipolar disorder who present with tardive dyskinesia,
      dystonia and parkinsonism.
D2 dopaminergic receptor blockers, used to treat schizophrenia, can lead to the onset of
      drug-induced movement disorders, such as parkinsonism, dystonia, dyskinesia and akathisia.
      They seem to be associated with oxidative stress, as a result of an increase in free radicals
      generated from dopamine metabolism. A preclinical study showed that vitamin B6 (pyridoxine)
      and B12 (cobalamin), alone or in combination, prevented the development of orofacial
      dyskinesia induced by haloperidol in an animal model of schizophrenia.

      Specific Aim1: To conduct a prospective, randomized, double-blind, placebo-controlled trial
      to evaluate the efficacy of 12-week adjuvant treatment with 200mg of pyridoxine (B6) or 2mg
      of cobalamin (B12) to treat drug-induced movement disorders of patients with schizophrenia,
      schizoaffective or bipolar disorder. The investigators will randomly assign 45 patients into
      three groups: placebo, B6 or B12 and check whether administration of vitamin B6 (pyridoxine)
      or B12 (cobalamin) attenuates drug-induced movement disorders (IDDM) in patients with
      diagnosis of schizophrenia, schizoaffective or bipolar disorder.

      Specific Aim 2: To quantify changes in serum markers of inflammation and biomarkers of
      oxidative stress in response to adjunctive treatment with B6 or B12. The hypothesis is that
      changes in these biomarkers will mediate the clinical response to them.

      Research Plan: The investigators will carry out a proof of concept 12-week prospective,
      randomized, double-blind, controlled trial of vitamin B6 and B12, at doses of 200 mg/day and
      2mg/day, respectively, or identical placebo tablets, added to ongoing antipsychotics in 45
      stable patients (ages 18-60 years, 15 patients per group) with diagnosis of schizophrenia,
      schizoaffective or bipolar disorder. The study will be conducted at the Drug Research and
      Development Center (NPDM), at the Universidade Federal do Ceará, Fortaleza, Brazil. This
      center has a long history of performing placebocontrolled trials in clinical medicine
      (http://www.npdm.ufc.br/) and has the necessary infrastructure to successfully complete the
      proposed study protocol. All participants will give written informed consent prior to study
      enrollment.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Proof of concept 12-week prospective, randomized, double-blind, controlled trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores
time frame: Baseline and 12 weeks
description: 10-item rating scale to assess extrapyramidal symptoms; each item is scored 0-4, yielding a total between 0 and 40.
measure: Change in the Barnes Akathisia Rating Scale (BAS, BARS) scores
time frame: Baseline and 12 weeks
description: Objective Akathisia, Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness are rated on a 4-point scale from 0 - 3 and are summed yielding a total score ranging from 0 to 9. The Global Clinical Assessment of Akathisia uses a 5-point scale ranging from 0 - 4.
measure: Change in the Abnormal Involuntary Movement Scale (AIMS) scores
time frame: Baseline and 12 weeks
description: 10-item rating scale to assess involuntary movements; items are rated on a five-point scale of severity from 0-4, yielding a total between 0 and 40.
measure: Change in the Brief Psychiatry Rating Scale (BPRS) scores
time frame: Baseline and 12 weeks
description: 18-item rating scale to assess changes in psychopathology; each item is scored 0-6, yielding a total between 0 and 40.
measure: Change in Plasma Glutathione (GSH)
time frame: Baseline and 12 weeks
description: GSH in ng/mL
measure: Change in serum level of Nitrite
time frame: Baseline and 12 weeks
description: Nitrite in nanomole/mililiter
measure: Change in serum level of Thiobarbituric acid reactive substances (TBARS)
time frame: Baseline and 12 weeks
description: TBARS in mmol of malonaldehyde/mL
measure: Change in serum level of Interleukin 1 β (IL-1β)
time frame: Baseline and 12 weeks
description: IL-1β in pg/mL
measure: Change in serum level of Interleukin-4
time frame: Baseline and 12 weeks
description: IL-4 in pg/mL
measure: Change in serum level of Interferon gamma (IFNγ)
time frame: Baseline and 12 weeks
description: IFNγ in pg/mL
measure: Change in serum level of Tumor necrosis factor alpha (TNF-α)
time frame: Baseline and 12 weeks
description: TNF-α in pg/mL
measure: Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity
time frame: Baseline and 12 weeks
description: IDO activity in U IDO mol^-1/mg^-1
arm group label: Experimental group 1
arm group type: Experimental
description: 15 subjects will be randomly assigned to adjuvant treatment with 200mg of vitamin B6 (pyridoxine).
arm group label: Experimental group 2
arm group type: Experimental
description: 15 subjects will be randomly assigned to adjuvant treatment with 2mg of vitamin B12 (cobalamin).
arm group label: Placebo oral tablet
arm group type: Sham Comparator
description: 15 subjects will be randomly assigned to adjuvant treatment with placebo.
intervention type: Drug
intervention name: Pyridoxine
description: Adjuvant daily treatment with 200mg of pyridoxine
arm group label: Experimental group 1
other name: Vitamin B6
intervention type: Drug
intervention name: Cobalamin
description: Adjuvant daily treatment with 2mg of cobalamin
arm group label: Experimental group 2
other name: Vitamin B12
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Adjuvant daily treatment with placebo
arm group label: Placebo oral tablet
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Lia LO Sanders, MD, PhD
role: Principal Investigator
affiliation: Núcleo de Pesquisa e Desenvolvimento de Medicamentos
last name: Lia LO Sanders, MD, PhD
phone: +55(85)3366-8338
email: lia_sanders@hotmail.com
facility: 
status: Recruiting
contact: 
country: Brazil
responsible party type: Sponsor
mesh term: Movement Disorders
mesh term: Schizophrenia
mesh term: Vitamins
mesh term: Vitamin B 12
mesh term: Pyridoxine
mesh term: Vitamin B 6
mesh term: Vitamin B Complex