Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03788759
Recruitment Status : Recruiting
First Posted : December 28, 2018
Last Update Posted : April 10, 2019
Sponsor:
Collaborator:
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Information provided by (Responsible Party):
Lia Sanders, Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Schizophrenia Oxidative Stress Drug: Alpha-lipoic acid Drug: Placebo Oral Tablet Phase 2 Phase 3

Detailed Description:

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Proof of concept 4-month prospective, randomized, double-blind, controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Alpha-lipoic Acid Adjunctive Therapy in Schizophrenia: A Randomized, Double-blind, Placebo-controlled Trial
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: Experimental group
25 subjects will be randomized to 100mg of alpha-lipoic acid.
Drug: Alpha-lipoic acid
Administration of ALA (100 mg/day) for 4 months, as an adjunct to antipsychotic medication.

Placebo Comparator: Placebo group
25 subjects will be randomized to placebo.
Drug: Placebo Oral Tablet
Administration of placebo, as an adjunct to antipsychotic medication.




Primary Outcome Measures :
  1. Change in the Brief Psychiatry Rating Scale (BPRS) scores [ Time Frame: Baseline and 16 weeks ]
    18-item rating scale to assess changes in psychopathology; each item is scored 0-6, yielding a total between 0 and 108.


Secondary Outcome Measures :
  1. Change in the Simpson-Angus Extrapyramidal Symptoms Scale (SAS) scores [ Time Frame: Baseline and 16 weeks ]
    10-item rating scale to assess extrapyramidal symptoms; each item is scored 0-4, yielding a total between 0 and 40.

  2. Brain resting state activity [ Time Frame: Baseline and 16 weeks ]
    Functional Magnetic Resonance Imaging (fMRI) scans before and after treatment

  3. Gut Microbiota Composition [ Time Frame: Baseline and 16 weeks ]
    Analyses of patient's gut microbiota

  4. Change in Body Mass Index (BMI) [ Time Frame: Baseline and 16 weeks ]
    Weight and height will be combined to report BMI in kg/m^2

  5. Change in Abdominal Circumference [ Time Frame: Baseline and 16 weeks ]
    Abdominal Circumference in cm

  6. Change in plasma Aspartate Aminotransferase (AST) [ Time Frame: Baseline and 16 weeks ]
    AST in U/L

  7. Change in plasma Aspartate Aminotransferase (AST) Alanine Aminotransferase (ALT) [ Time Frame: Baseline and 16 weeks ]
    ALT in U/L

  8. Change in Hemoglobin concentration (HC) [ Time Frame: Baseline and 16 weeks ]
    HC in g/dL

  9. Change in Hematocrit (Ht) [ Time Frame: Baseline and 16 weeks ]
    Ht in %

  10. Change in White blood cell count (WBC) [ Time Frame: Baseline and 16 weeks ]
    WBC in number per microliter

  11. Change in Neutrophil Count (NC) [ Time Frame: Baseline and 16 weeks ]
    NC in number per microliter

  12. Change in Platelet Count (PC) [ Time Frame: Baseline and 16 weeks ]
    PC in number per microliter

  13. Change in Glycohemoglobin (HbA1c) [ Time Frame: Baseline and 16 weeks ]
    HbA1c in %

  14. Change in serum level of Vitamin B12 [ Time Frame: Baseline and 16 weeks ]
    Vitamin B12 in pg/mL

  15. Change in serum level of Folic Acid [ Time Frame: Baseline and 16 weeks ]
    Folic Acid in ng/mL

  16. Change in Plasma Glutathione (GSH) [ Time Frame: Baseline and 16 weeks ]
    GSH in ng/mL

  17. Change in serum level of Nitrite [ Time Frame: Baseline and 16 weeks ]
    Nitrite in nanomole/mililiter

  18. Change in serum level of Thiobarbituric acid reactive substances (TBARS) [ Time Frame: Baseline and 16 weeks ]
    TBARS in mmol of malonaldehyde/mL

  19. Change in serum level of Interleukin 1 β (IL-1β) [ Time Frame: Baseline and 16 weeks ]
    IL-1β in pg/mL

  20. Change in serum level of Interleukin-4 [ Time Frame: Baseline and 16 weeks ]
    IL-4 in pg/mL

  21. Change in serum level of Interferon gamma (IFNγ) [ Time Frame: Baseline and 16 weeks ]
    IFNγ in pg/mL

  22. Change in serum level of Tumor necrosis factor alpha (TNF-α) [ Time Frame: Baseline and 16 weeks ]
    TNF-α in pg/mL

  23. Change in Indoleamine 2,3-dioxygenase (IDO) enzymatic activity [ Time Frame: Baseline and 16 weeks ]
    IDO activity in U IDO mol^-1/mg^-1

  24. Change in serum level of Eotaxin [ Time Frame: Baseline and 16 weeks ]
    Eotaxin in ng/mL

  25. Change in serum level of Isoprostanes [ Time Frame: Baseline and 16 weeks ]
    Isoprostanes in pg/mL

  26. Change in serum level of Calprotectin [ Time Frame: Baseline and 16 weeks ]
    Serum Calprotectin in ng/mL

  27. Change in serum level of Serotonin [ Time Frame: Baseline and 16 weeks ]
    Serotonin in ng/mL

  28. Change in Block Corsi Test [ Time Frame: Baseline and 16 weeks ]
    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.

  29. Change in serum level of Tryptophan [ Time Frame: Baseline and 16 weeks ]
    Tryptophan in micrograms/mL

  30. Change in Trail Making Test [ Time Frame: Baseline and 16 weeks ]
    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.

  31. Change in Subtest Digit Span [ Time Frame: Baseline and 16 weeks ]
    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.

  32. Category (Animal) Fluency [ Time Frame: Baseline and 16 weeks ]
    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

  33. F-A-S test [ Time Frame: Baseline and 16 weeks ]
    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.

  34. Rey Auditory Verbal Learning Test [ Time Frame: Baseline and 16 weeks ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Capacity to provide informed consent;
  • Schizophrenia diagnosis (made by research psychiatrists using the Structured Clinical Interview, SCID-5, for Diagnostic and Statistical Manual of Mental Disorders);
  • Negative and/or cognitive symptoms despite adequate antipsychotic treatment;
  • Ages 18-60 years

Exclusion Criteria:

  • 6-month history of any drug or alcohol abuse or dependence;
  • Changes in psychotropic medications within the last 4 weeks;
  • Actual valproate use (potential interaction with ALA);
  • General medical illness including autoimmune disorders, known chronic infections such as HIV or hepatitis C, and liver or renal failure that could adversely impact on patient outcome;
  • Women who are planning to become pregnant, are pregnant, or are breastfeeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03788759


Contacts
Layout table for location contacts
Contact: Lia LO Sanders, MD, PhD +55(85)3366-8338 lia_sanders@hotmail.com

Locations
Layout table for location information
Brazil
Núcleo de Pesquisa e Desenvolvimento de Medicamentos - UFC Recruiting
Fortaleza, CE, Brazil, 60430-275
Contact: Lia LO Sanders, MD, PhD         
Sponsors and Collaborators
Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Investigators
Layout table for investigator information
Principal Investigator: Lia LO Sanders, MD, PhD Núcleo de Pesquisa e Desenvolvimento de Medicamentos

Publications:

Layout table for additonal information
Responsible Party: Lia Sanders, Principal Investigator, Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara
ClinicalTrials.gov Identifier: NCT03788759     History of Changes
Other Study ID Numbers: LipoicStudy
First Posted: December 28, 2018    Key Record Dates
Last Update Posted: April 10, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Lia Sanders, Nucleo De Pesquisa E Desenvolvimento De Medicamentos Da Universidade Federal Do Ceara:
Schizophrenia
Drug repurposing
Alpha-lipoic acid
Adjuvant treatment
Additional relevant MeSH terms:
Layout table for MeSH terms
Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders
Thioctic Acid
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances