<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/NCT03788759</url>
  </required_header>
  <id_info>
    <org_study_id>LipoicStudy</org_study_id>
    <nct_id>NCT03788759</nct_id>
  </id_info>
  <brief_title>Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia</brief_title>
  <official_title>Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia: A Randomized, Double-blind, Placebo-controlled Trial</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>
    <collaborator>
      <agency>Conselho Nacional de Desenvolvimento Científico e Tecnológico</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Schizophrenia is a devastating mental disorder with a prevalence of approximately 1%&#xD;
      worldwide. While effective in reducing positive symptoms, current treatments have limited&#xD;
      effects on cognitive and social cognition/processing deficits of schizophrenia, which are&#xD;
      closely linked to real-world dysfunction and lack of socio-occupational integration. There is&#xD;
      compelling evidence for impaired antioxidant defense system and inflammatory abnormalities in&#xD;
      schizophrenia. A new therapeutic approach to the disease might well be to hinder oxidative&#xD;
      damage, inflammation and its clinical sequelae. Alpha-lipoic acid (ALA) is a naturally&#xD;
      occurring compound, synthesized in the mitochondria, that is currently approved to treat&#xD;
      diabetic neuropathic pain. Drug repurposing is a fast, and cost-effective method that can&#xD;
      overcome drug discovery challenges of targeting neuropsychiatric disorders. In a pilot&#xD;
      investigation, adjunctive treatment with ALA led to robust improvement in negative and&#xD;
      cognitive symptoms of ten patients with schizophrenia. This project aims to investigate the&#xD;
      efficacy of ALA as a disease-modifying drug for the treatment of schizophrenia, by improving&#xD;
      sociability and cognition, as well as to correlate patients' response with biomarkers that&#xD;
      will shed light on the pathophysiology of this complex disease. It comprises 1) a&#xD;
      prospective, randomized, double-blind, placebo-controlled trial to evaluate efficacy of ALA&#xD;
      to treat cognitive and negative symptoms of patients with schizophrenia and 2) an&#xD;
      investigation of changes in biomarkers of oxidative stress in response to adjunctive&#xD;
      treatment with ALA. The proposed study could establish a new adjunctive treatment for&#xD;
      schizophrenia, recognize a novel pharmacological approach and help unveil the biological&#xD;
      basis of the disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The underlying pathogenesis of schizophrenia remains unknown, but aberrant&#xD;
      reduction-oxidation has gained increasing support as an hypothesis to help explain the&#xD;
      pathophysiology of the disease. Alpha-lipoic acid (ALA) is a naturally occurring antioxidant,&#xD;
      essential for the function of different enzymes of mitochondria's oxidative metabolism, that&#xD;
      is currently approved to treat diabetic neuropathic pain9. ALA and its reduced form,&#xD;
      dihydrolipoic acid (DHLA), have important advantages over other antioxidant agents such as&#xD;
      vitamin E and C, partly due to their amphiphilic properties, which confer antioxidant actions&#xD;
      in the membrane as well as in the cytosol. A preclinical study conducted in our lab showed&#xD;
      that ALA alone and combined with clozapine reverses schizophrenia associated symptoms and&#xD;
      pro-oxidant changes induced by ketamine in mice. Before the widespread use of antipsychotics,&#xD;
      two studies found that low doses of ALA relieved symptoms in patients with schizophrenia.&#xD;
&#xD;
      More recently, my colleagues and I conducted an open label proof of concept study that&#xD;
      provided encouraging evidence that low doses of ALA might be an effective adjunctive&#xD;
      treatment for schizophrenia. Based on promising preliminary results, the investigators will&#xD;
      now test ALA in a more rigorous placebo-controlled clinical study.&#xD;
&#xD;
      Specific Aim1: To conduct a prospective, randomized, double-blind, placebo-controlled trial&#xD;
      to evaluate the efficacy of adjuvant treatment with low doses (100mg) of ALA to treat&#xD;
      cognitive and negative symptoms of patients with schizophrenia. The investigators will&#xD;
      randomize 50 patients over 4 months.&#xD;
&#xD;
      Specific Aim 2: To quantify changes in biomarkers of oxidative stress in response to&#xD;
      adjunctive treatment with ALA. The hypothesis is that changes in these biomarkers will&#xD;
      mediate the clinical response to ALA.&#xD;
&#xD;
      Research Plan: To carry out a proof of concept 4-month prospective, randomized, double-blind,&#xD;
      controlled trial of alpha-lipoic acid, at doses of 100 mg/day or identical placebo tablets,&#xD;
      added to ongoing antipsychotics in 50 stable patients (ages 18-60 years, 25 patients per&#xD;
      group) with diagnosis of schizophrenia. 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>Completed</overall_status>
  <start_date type="Actual">September 1, 2019</start_date>
  <completion_date type="Actual">December 1, 2021</completion_date>
  <primary_completion_date type="Actual">December 1, 2021</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 4-month 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 Brief Psychiatry Rating Scale (BPRS) scores</measure>
    <time_frame>Baseline and 16 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 108.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores</measure>
    <time_frame>Baseline and 16 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>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain resting state activity</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Functional Magnetic Resonance Imaging (fMRI) scans before and after treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gut Microbiota Composition</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Analyses of patient's gut microbiota</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Body Mass Index (BMI)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Weight and height will be combined to report BMI in kg/m^2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Abdominal Circumference</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Abdominal Circumference in cm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in plasma Aspartate Aminotransferase (AST)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>AST in U/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>ALT in U/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Hemoglobin concentration (HC)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>HC in g/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Hematocrit (Ht)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Ht in %</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in White blood cell count (WBC)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>WBC in number per microliter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Neutrophil Count (NC)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>NC in number per microliter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Platelet Count (PC)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>PC in number per microliter</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Glycohemoglobin (HbA1c)</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>HbA1c in %</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Vitamin B12</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Vitamin B12 in pg/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Folic Acid</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Folic Acid in ng/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Plasma Glutathione (GSH)</measure>
    <time_frame>Baseline and 16 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 16 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 16 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 16 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 16 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 16 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 16 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 16 weeks</time_frame>
    <description>IDO activity in U IDO mol^-1/mg^-1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Eotaxin</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Eotaxin in ng/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Isoprostanes</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Isoprostanes in pg/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Calprotectin</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Serum Calprotectin in ng/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Serotonin</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Serotonin in ng/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Block Corsi Test</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>This test assesses visuo-spatial short term working memory. Participants are asked to mimick a researcher as he/she taps a sequence of up to nine identical spatially separated blocks. The test measures both the number of correct sequences and the longest sequence remembered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum level of Tryptophan</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Tryptophan in micrograms/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Trail Making Test</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Trail Making Test measured in time and number of errors. It tests visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. Provide information about visual search speed, scanning, speed of processing, mental flexibility, executive functioning.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Subtest Digit Span</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Individual tries to repeat digits forward, backward, and in ascending order. This test measures short term memory, working memory. The score is the maximum number of digits correctly remembered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Category (Animal) Fluency</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Participants have to produce as many words as possible from a category in a given time (usually 60 seconds). Performance measure is the total number of words</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>F-A-S test</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>It assesses phonemic fluency by requesting an individual to orally produce as many words as possible that begin with the letters F, A, and S within a prescribed time frame, usually 1 min.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rey Auditory Verbal Learning Test</measure>
    <time_frame>Baseline and 16 weeks</time_frame>
    <description>Participants are asked to repeat list of 15 unrelated words; another list of 15 unrelated words are given and participants must again repeat the original list of 15 words and then again after 30 minutes. Score range: 0-15</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>Schizophrenia</condition>
  <condition>Oxidative Stress</condition>
  <arm_group>
    <arm_group_label>Experimental group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>25 subjects will be randomized to 100mg of alpha-lipoic acid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>25 subjects will be randomized to placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Alpha-lipoic acid</intervention_name>
    <description>Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.</description>
    <arm_group_label>Experimental group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Administration of placebo, as an adjunct to antipsychotic medication.</description>
    <arm_group_label>Placebo group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Capacity to provide informed consent;&#xD;
&#xD;
          -  Schizophrenia diagnosis (made by research psychiatrists using the Structured Clinical&#xD;
             Interview, SCID-5, for Diagnostic and Statistical Manual of Mental Disorders);&#xD;
&#xD;
          -  Negative and/or cognitive symptoms despite adequate antipsychotic treatment;&#xD;
&#xD;
          -  Ages 18-60 years&#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;
          -  Actual valproate use (potential interaction with ALA);&#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>
  <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>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
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  </reference>
  <reference>
    <citation>Kanchanatawan B, Hemrungrojn S, Thika S, Sirivichayakul S, Ruxrungtham K, Carvalho AF, Geffard M, Anderson G, Maes M. Changes in Tryptophan Catabolite (TRYCAT) Pathway Patterning Are Associated with Mild Impairments in Declarative Memory in Schizophrenia and Deficits in Semantic and Episodic Memory Coupled with Increased False-Memory Creation in Deficit Schizophrenia. Mol Neurobiol. 2018 Jun;55(6):5184-5201. doi: 10.1007/s12035-017-0751-8. Epub 2017 Sep 5.</citation>
    <PMID>28875464</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>December 23, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 28, 2018</study_first_posted>
  <last_update_submitted>August 26, 2022</last_update_submitted>
  <last_update_submitted_qc>August 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 29, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara</investigator_affiliation>
    <investigator_full_name>Lia Sanders</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Schizophrenia</keyword>
  <keyword>Drug repurposing</keyword>
  <keyword>Alpha-lipoic acid</keyword>
  <keyword>Adjuvant treatment</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Schizophrenia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thioctic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03788759
org study id: LipoicStudy
nct id: NCT03788759
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Schizophrenia is a devastating mental disorder with a prevalence of approximately 1%
      worldwide. While effective in reducing positive symptoms, current treatments have limited
      effects on cognitive and social cognition/processing deficits of schizophrenia, which are
      closely linked to real-world dysfunction and lack of socio-occupational integration. There is
      compelling evidence for impaired antioxidant defense system and inflammatory abnormalities in
      schizophrenia. A new therapeutic approach to the disease might well be to hinder oxidative
      damage, inflammation and its clinical sequelae. Alpha-lipoic acid (ALA) is a naturally
      occurring compound, synthesized in the mitochondria, that is currently approved to treat
      diabetic neuropathic pain. Drug repurposing is a fast, and cost-effective method that can
      overcome drug discovery challenges of targeting neuropsychiatric disorders. In a pilot
      investigation, adjunctive treatment with ALA led to robust improvement in negative and
      cognitive symptoms of ten patients with schizophrenia. This project aims to investigate the
      efficacy of ALA as a disease-modifying drug for the treatment of schizophrenia, by improving
      sociability and cognition, as well as to correlate patients' response with biomarkers that
      will shed light on the pathophysiology of this complex disease. It comprises 1) a
      prospective, randomized, double-blind, placebo-controlled trial to evaluate efficacy of ALA
      to treat cognitive and negative symptoms of patients with schizophrenia and 2) an
      investigation of changes in biomarkers of oxidative stress in response to adjunctive
      treatment with ALA. The proposed study could establish a new adjunctive treatment for
      schizophrenia, recognize a novel pharmacological approach and help unveil the biological
      basis of the disease.
The underlying pathogenesis of schizophrenia remains unknown, but aberrant
      reduction-oxidation has gained increasing support as an hypothesis to help explain the
      pathophysiology of the disease. Alpha-lipoic acid (ALA) is a naturally occurring antioxidant,
      essential for the function of different enzymes of mitochondria's oxidative metabolism, that
      is currently approved to treat diabetic neuropathic pain9. ALA and its reduced form,
      dihydrolipoic acid (DHLA), have important advantages over other antioxidant agents such as
      vitamin E and C, partly due to their amphiphilic properties, which confer antioxidant actions
      in the membrane as well as in the cytosol. A preclinical study conducted in our lab showed
      that ALA alone and combined with clozapine reverses schizophrenia associated symptoms and
      pro-oxidant changes induced by ketamine in mice. Before the widespread use of antipsychotics,
      two studies found that low doses of ALA relieved symptoms in patients with schizophrenia.

      More recently, my colleagues and I conducted an open label proof of concept study that
      provided encouraging evidence that low doses of ALA might be an effective adjunctive
      treatment for schizophrenia. Based on promising preliminary results, the investigators will
      now test ALA in a more rigorous placebo-controlled clinical study.

      Specific Aim1: To conduct a prospective, randomized, double-blind, placebo-controlled trial
      to evaluate the efficacy of adjuvant treatment with low doses (100mg) of ALA to treat
      cognitive and negative symptoms of patients with schizophrenia. The investigators will
      randomize 50 patients over 4 months.

      Specific Aim 2: To quantify changes in biomarkers of oxidative stress in response to
      adjunctive treatment with ALA. The hypothesis is that changes in these biomarkers will
      mediate the clinical response to ALA.

      Research Plan: To carry out a proof of concept 4-month prospective, randomized, double-blind,
      controlled trial of alpha-lipoic acid, at doses of 100 mg/day or identical placebo tablets,
      added to ongoing antipsychotics in 50 stable patients (ages 18-60 years, 25 patients per
      group) with diagnosis of schizophrenia. 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 4-month prospective, randomized, double-blind, controlled trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in the Brief Psychiatry Rating Scale (BPRS) scores
time frame: Baseline and 16 weeks
description: 18-item rating scale to assess changes in psychopathology; each item is scored 0-6, yielding a total between 0 and 108.
measure: Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores
time frame: Baseline and 16 weeks
description: 10-item rating scale to assess extrapyramidal symptoms; each item is scored 0-4, yielding a total between 0 and 40.
measure: Brain resting state activity
time frame: Baseline and 16 weeks
description: Functional Magnetic Resonance Imaging (fMRI) scans before and after treatment
measure: Gut Microbiota Composition
time frame: Baseline and 16 weeks
description: Analyses of patient's gut microbiota
measure: Change in Body Mass Index (BMI)
time frame: Baseline and 16 weeks
description: Weight and height will be combined to report BMI in kg/m^2
measure: Change in Abdominal Circumference
time frame: Baseline and 16 weeks
description: Abdominal Circumference in cm
measure: Change in plasma Aspartate Aminotransferase (AST)
time frame: Baseline and 16 weeks
description: AST in U/L
measure: Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT)
time frame: Baseline and 16 weeks
description: ALT in U/L
measure: Change in Hemoglobin concentration (HC)
time frame: Baseline and 16 weeks
description: HC in g/dL
measure: Change in Hematocrit (Ht)
time frame: Baseline and 16 weeks
description: Ht in %
measure: Change in White blood cell count (WBC)
time frame: Baseline and 16 weeks
description: WBC in number per microliter
measure: Change in Neutrophil Count (NC)
time frame: Baseline and 16 weeks
description: NC in number per microliter
measure: Change in Platelet Count (PC)
time frame: Baseline and 16 weeks
description: PC in number per microliter
measure: Change in Glycohemoglobin (HbA1c)
time frame: Baseline and 16 weeks
description: HbA1c in %
measure: Change in serum level of Vitamin B12
time frame: Baseline and 16 weeks
description: Vitamin B12 in pg/mL
measure: Change in serum level of Folic Acid
time frame: Baseline and 16 weeks
description: Folic Acid in ng/mL
measure: Change in Plasma Glutathione (GSH)
time frame: Baseline and 16 weeks
description: GSH in ng/mL
measure: Change in serum level of Nitrite
time frame: Baseline and 16 weeks
description: Nitrite in nanomole/mililiter
measure: Change in serum level of Thiobarbituric acid reactive substances (TBARS)
time frame: Baseline and 16 weeks
description: TBARS in mmol of malonaldehyde/mL
measure: Change in serum level of Interleukin 1 β (IL-1β)
time frame: Baseline and 16 weeks
description: IL-1β in pg/mL
measure: Change in serum level of Interleukin-4
time frame: Baseline and 16 weeks
description: IL-4 in pg/mL
measure: Change in serum level of Interferon gamma (IFNγ)
time frame: Baseline and 16 weeks
description: IFNγ in pg/mL
measure: Change in serum level of Tumor necrosis factor alpha (TNF-α)
time frame: Baseline and 16 weeks
description: TNF-α in pg/mL
measure: Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity
time frame: Baseline and 16 weeks
description: IDO activity in U IDO mol^-1/mg^-1
measure: Change in serum level of Eotaxin
time frame: Baseline and 16 weeks
description: Eotaxin in ng/mL
measure: Change in serum level of Isoprostanes
time frame: Baseline and 16 weeks
description: Isoprostanes in pg/mL
measure: Change in serum level of Calprotectin
time frame: Baseline and 16 weeks
description: Serum Calprotectin in ng/mL
measure: Change in serum level of Serotonin
time frame: Baseline and 16 weeks
description: Serotonin in ng/mL
measure: Change in Block Corsi Test
time frame: Baseline and 16 weeks
description: This test assesses visuo-spatial short term working memory. Participants are asked to mimick a researcher as he/she taps a sequence of up to nine identical spatially separated blocks. The test measures both the number of correct sequences and the longest sequence remembered.
measure: Change in serum level of Tryptophan
time frame: Baseline and 16 weeks
description: Tryptophan in micrograms/mL
measure: Change in Trail Making Test
time frame: Baseline and 16 weeks
description: Trail Making Test measured in time and number of errors. It tests visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as quickly as possible while still maintaining accuracy. Provide information about visual search speed, scanning, speed of processing, mental flexibility, executive functioning.
measure: Change in Subtest Digit Span
time frame: Baseline and 16 weeks
description: Individual tries to repeat digits forward, backward, and in ascending order. This test measures short term memory, working memory. The score is the maximum number of digits correctly remembered.
measure: Category (Animal) Fluency
time frame: Baseline and 16 weeks
description: Participants have to produce as many words as possible from a category in a given time (usually 60 seconds). Performance measure is the total number of words
measure: F-A-S test
time frame: Baseline and 16 weeks
description: It assesses phonemic fluency by requesting an individual to orally produce as many words as possible that begin with the letters F, A, and S within a prescribed time frame, usually 1 min.
measure: Rey Auditory Verbal Learning Test
time frame: Baseline and 16 weeks
description: Participants are asked to repeat list of 15 unrelated words; another list of 15 unrelated words are given and participants must again repeat the original list of 15 words and then again after 30 minutes. Score range: 0-15
arm group label: Experimental group
arm group type: Experimental
description: 25 subjects will be randomized to 100mg of alpha-lipoic acid.
arm group label: Placebo group
arm group type: Placebo Comparator
description: 25 subjects will be randomized to placebo.
intervention type: Drug
intervention name: Alpha-lipoic acid
description: Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.
arm group label: Experimental group
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Administration of placebo, as an adjunct to antipsychotic medication.
arm group label: Placebo group
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
facility: 
country: Brazil
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PMID: 28875464
responsible party type: Principal Investigator
investigator affiliation: Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
investigator full name: Lia Sanders
investigator title: Principal Investigator
mesh term: Schizophrenia
mesh term: Thioctic Acid
sharing ipd: Undecided