<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/NCT04502251</url>
  </required_header>
  <id_info>
    <org_study_id>70005317.5.0000.5307</org_study_id>
    <nct_id>NCT04502251</nct_id>
  </id_info>
  <brief_title>LDN and tDCS in Fibromyalgia</brief_title>
  <official_title>Association of Low Doses of Naltrexone and Transcranial Direct Current Stimulation in Fibromyalgia: Randomized Clinical Trial, Blind, Controlled With Placebo</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centro Universitario La Salle</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital de Clinicas de Porto Alegre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Centro Universitario La Salle</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>
      Fibromyalgia is a complex generalized and diffuse musculoskeletal chronic pain; and&#xD;
      pharmacological approaches are widely used to relieve pain and increase life quality. In this&#xD;
      context, low-dose naltrexone (LDN) was able to increase nociceptive threshold in patients&#xD;
      with fibromyalgia. Moreover, non-pharmacological techniques, like Transcranial Direct Current&#xD;
      Stimulation (tDCS), have been shown effective for pain management. This study aims to&#xD;
      evaluate the analgesic and neuromodulatory effect of combined LDN followed by tDCS in&#xD;
      fibromyalgia patients. This is a randomized, double-blinded, parallel,&#xD;
      placebo/sham-controlled trial, in which 92 (10% loss) women with fibromyalgia will be&#xD;
      included included and signed the informed consent. Patients will be allocated into 4 groups:&#xD;
      tDCS+LDN (n=21), Sham-tDCS+LDN (n=22), tDCS+Placebo (n=22), and Sham-tDCS+Placebo (n=21). LDN&#xD;
      or placebo (p.o.) intervention lasts 26 days, in the last five, tDCS will be applied (sham or&#xD;
      active, 20min, 2mA). Questionnaires assessed are: Sociodemographic, Visual Analog Pain Scale&#xD;
      (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia&#xD;
      Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Chronic Pain Profile Scale&#xD;
      (CPP). Also, pain measures were taken: Pain Pressure Threshold (PPT) and Conditioned Pain&#xD;
      Modulation (CPM). Blood samples will be collected to analyze Brain Derived Neurotrophic&#xD;
      Factor (BDNF) serum levels.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 1, 2018</start_date>
  <completion_date type="Actual">July 1, 2020</completion_date>
  <primary_completion_date type="Actual">August 1, 2019</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>A randomized, double-blinded, parallel, controlled with placebo and sham stimulation, clinical trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>This is a double-blinded study, in which the participants and the outcomes assessor, who is the same as the investigator and the care provider, are blinded</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Pain in VAS</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>Visual Analogue Scale (VAS) that goes from 0 cm (without pain) to 10cm (worst pain).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Depressive symptoms</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>Beck Depression Inventory (BDI-II) that goes from 0 (without depressive symptoms) to 63 (worst depressive symptoms)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anxiety levels</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>State-Trait Anxiety Inventory (STAI) divided into state anxiety (from 0 to 52, the higher the worse) and trait anxiety (from 0 to 48, the higher the worse)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Catastrophizing Thought</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>Pain Catastrophizing Scale (PCS): divided into rumination (from 0 to 16, the higher the worse), magnification (from 0 to 12, the higher the worse) and hopelessness (from 0 to 24, the higher the worse). Total goes from 0 to 52, the higher the worse</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Profile of Chronic Pain</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>Profile of Chronic Pain Scale (PCP:S): divided into Frequency and Intensity of Pain (from 0 to 30, the higher the worse), Pain Effect in Activities (from 0 to 36, the higher the worse) and Pain Effect in Emotions (from 0 to 25, the higher the worse)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain Pressure Threshold</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>Pain Pressure Threshold (PPT) measured using an electronic algometer applied in the right forearm; and patients need to report the first pain sensation (minimum pain) and maximum pain. Threshold goes from 0 to the maximum value the patient can hold, the higher the value, better is the result</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Conditioned Pain Modulation</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>Conditioned Pain Modulation (CPM) with an algometer (PPT task), the patient informed when felt a pain equal to 6 in the VAS. This pain level was applied in the right forearm for 30 seconds, while the left forearm (non-dominant hand) was submerged in water from 0˚C to 1.5˚C; after 30s, patients reported their pain in each of the arms. CPM = left forearm VAS - 6. (from -4 to 6, the value must be as closest to -4 as possible, meaning the higher the worse)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum BDNF</measure>
    <time_frame>Change between baseline and after association (26 days from baseline)</time_frame>
    <description>Blood sample collected and centrifuged, the supernatant aliquoted for BDNF analysis using ELISA technique, according to manufacturer's instructions (values start in 0, patients with fibromyalgia usually have higher levels of serum BDNF, therefore the higher the worse)</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">92</enrollment>
  <condition>Fibromyalgia</condition>
  <arm_group>
    <arm_group_label>LDN + tDCS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Low Dose Naltrexone and Transcranial Direct Current Stimulation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LDN + Sham tDCS</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Low Dose Naltrexone and Sham Transcranial Direct Current Stimulation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + tDCS</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo and Transcranial Direct Current Stimulation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo + Sham tDCS</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Placebo and Sham Transcranial Direct Current Stimulation</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Low-Dose Naltrexone</intervention_name>
    <description>4.5mg daily dose, orally, during 26 days</description>
    <arm_group_label>LDN + Sham tDCS</arm_group_label>
    <arm_group_label>LDN + tDCS</arm_group_label>
    <other_name>LDN</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Transcranial Direct Current Stimulation</intervention_name>
    <description>An anodal electrode was placed on the scalp above the primary motor cortex (M1), contralateral to the dominant cortex. The cathodal electrode was placed on the supraorbital contralateral area. The current used was 2mA during 20 minutes.</description>
    <arm_group_label>LDN + tDCS</arm_group_label>
    <arm_group_label>Placebo + tDCS</arm_group_label>
    <other_name>tDCS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The capsule presented the same format, size and color as LDN capsules, however the excipient used was starch.</description>
    <arm_group_label>Placebo + Sham tDCS</arm_group_label>
    <arm_group_label>Placebo + tDCS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham Transcranial Direct Current Stimulation</intervention_name>
    <description>Sham-tDCS stimulation consists of an active current during 30 seconds</description>
    <arm_group_label>LDN + Sham tDCS</arm_group_label>
    <arm_group_label>Placebo + Sham tDCS</arm_group_label>
    <other_name>Sham tDCS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  signed the consent form&#xD;
&#xD;
          -  women from 18 to 65 years&#xD;
&#xD;
          -  confirmed diagnosis of fibromyalgia according 2016 American College of Rheumatology&#xD;
             criteria&#xD;
&#xD;
          -  read and write&#xD;
&#xD;
          -  pain higher than 6 in the Visual Analogue Scale (VAS), in the last 3 months&#xD;
&#xD;
          -  chronic stable treatment in the last 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  in use of opioid drugs;&#xD;
&#xD;
          -  pregnancy or not using anticontraceptive&#xD;
&#xD;
          -  history of alcohol or drug abuse in the last 6 months&#xD;
&#xD;
          -  history of neurological pathologies&#xD;
&#xD;
          -  history of arrhythmia&#xD;
&#xD;
          -  history of use of drugs that might change vascular response&#xD;
&#xD;
          -  history of head trauma&#xD;
&#xD;
          -  history of neurosurgery&#xD;
&#xD;
          -  decompensated systemic diseases or chronic inflammatory diseases (lupus, rheumatoid&#xD;
             arthritis, Sjogren syndrome, Reiter syndrome)&#xD;
&#xD;
          -  history of non-compensated hypothyroidism&#xD;
&#xD;
          -  personal history of cancer.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Universidade La Salle</name>
      <address>
        <city>Canoas</city>
        <state>Rio Grande Do Sul</state>
        <zip>92010-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
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    <PMID>17559710</PMID>
  </reference>
  <verification_date>August 2020</verification_date>
  <study_first_submitted>July 25, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>August 3, 2020</last_update_submitted>
  <last_update_submitted_qc>August 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Centro Universitario La Salle</investigator_affiliation>
    <investigator_full_name>Andressa de Souza</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>tDCS</keyword>
  <keyword>LDN</keyword>
  <keyword>Transcranial Direct Current Stimulation</keyword>
  <keyword>Low Dose Naltrexone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fibromyalgia</mesh_term>
    <mesh_term>Myofascial Pain Syndromes</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naltrexone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol, Statistical Analysis Plan, and Informed Consent Form</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 13, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/51/NCT04502251/Prot_SAP_ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04502251
org study id: 70005317.5.0000.5307
nct id: NCT04502251
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Fibromyalgia is a complex generalized and diffuse musculoskeletal chronic pain; and
      pharmacological approaches are widely used to relieve pain and increase life quality. In this
      context, low-dose naltrexone (LDN) was able to increase nociceptive threshold in patients
      with fibromyalgia. Moreover, non-pharmacological techniques, like Transcranial Direct Current
      Stimulation (tDCS), have been shown effective for pain management. This study aims to
      evaluate the analgesic and neuromodulatory effect of combined LDN followed by tDCS in
      fibromyalgia patients. This is a randomized, double-blinded, parallel,
      placebo/sham-controlled trial, in which 92 (10% loss) women with fibromyalgia will be
      included included and signed the informed consent. Patients will be allocated into 4 groups:
      tDCS+LDN (n=21), Sham-tDCS+LDN (n=22), tDCS+Placebo (n=22), and Sham-tDCS+Placebo (n=21). LDN
      or placebo (p.o.) intervention lasts 26 days, in the last five, tDCS will be applied (sham or
      active, 20min, 2mA). Questionnaires assessed are: Sociodemographic, Visual Analog Pain Scale
      (VAS), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), Fibromyalgia
      Impact Questionnaire (FIQ), Beck Depression Inventory (BDI-II), Chronic Pain Profile Scale
      (CPP). Also, pain measures were taken: Pain Pressure Threshold (PPT) and Conditioned Pain
      Modulation (CPM). Blood samples will be collected to analyze Brain Derived Neurotrophic
      Factor (BDNF) serum levels.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: A randomized, double-blinded, parallel, controlled with placebo and sham stimulation, clinical trial.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: This is a double-blinded study, in which the participants and the outcomes assessor, who is the same as the investigator and the care provider, are blinded
measure: Pain in VAS
time frame: Change between baseline and after association (26 days from baseline)
description: Visual Analogue Scale (VAS) that goes from 0 cm (without pain) to 10cm (worst pain).
measure: Depressive symptoms
time frame: Change between baseline and after association (26 days from baseline)
description: Beck Depression Inventory (BDI-II) that goes from 0 (without depressive symptoms) to 63 (worst depressive symptoms)
measure: Anxiety levels
time frame: Change between baseline and after association (26 days from baseline)
description: State-Trait Anxiety Inventory (STAI) divided into state anxiety (from 0 to 52, the higher the worse) and trait anxiety (from 0 to 48, the higher the worse)
measure: Pain Catastrophizing Thought
time frame: Change between baseline and after association (26 days from baseline)
description: Pain Catastrophizing Scale (PCS): divided into rumination (from 0 to 16, the higher the worse), magnification (from 0 to 12, the higher the worse) and hopelessness (from 0 to 24, the higher the worse). Total goes from 0 to 52, the higher the worse
measure: Profile of Chronic Pain
time frame: Change between baseline and after association (26 days from baseline)
description: Profile of Chronic Pain Scale (PCP:S): divided into Frequency and Intensity of Pain (from 0 to 30, the higher the worse), Pain Effect in Activities (from 0 to 36, the higher the worse) and Pain Effect in Emotions (from 0 to 25, the higher the worse)
measure: Pain Pressure Threshold
time frame: Change between baseline and after association (26 days from baseline)
description: Pain Pressure Threshold (PPT) measured using an electronic algometer applied in the right forearm; and patients need to report the first pain sensation (minimum pain) and maximum pain. Threshold goes from 0 to the maximum value the patient can hold, the higher the value, better is the result
measure: Conditioned Pain Modulation
time frame: Change between baseline and after association (26 days from baseline)
description: Conditioned Pain Modulation (CPM) with an algometer (PPT task), the patient informed when felt a pain equal to 6 in the VAS. This pain level was applied in the right forearm for 30 seconds, while the left forearm (non-dominant hand) was submerged in water from 0˚C to 1.5˚C; after 30s, patients reported their pain in each of the arms. CPM = left forearm VAS - 6. (from -4 to 6, the value must be as closest to -4 as possible, meaning the higher the worse)
measure: Serum BDNF
time frame: Change between baseline and after association (26 days from baseline)
description: Blood sample collected and centrifuged, the supernatant aliquoted for BDNF analysis using ELISA technique, according to manufacturer's instructions (values start in 0, patients with fibromyalgia usually have higher levels of serum BDNF, therefore the higher the worse)
arm group label: LDN + tDCS
arm group type: Active Comparator
description: Low Dose Naltrexone and Transcranial Direct Current Stimulation
arm group label: LDN + Sham tDCS
arm group type: Sham Comparator
description: Low Dose Naltrexone and Sham Transcranial Direct Current Stimulation
arm group label: Placebo + tDCS
arm group type: Placebo Comparator
description: Placebo and Transcranial Direct Current Stimulation
arm group label: Placebo + Sham tDCS
arm group type: Other
description: Placebo and Sham Transcranial Direct Current Stimulation
intervention type: Drug
intervention name: Low-Dose Naltrexone
description: 4.5mg daily dose, orally, during 26 days
arm group label: LDN + Sham tDCS
arm group label: LDN + tDCS
other name: LDN
intervention type: Device
intervention name: Transcranial Direct Current Stimulation
description: An anodal electrode was placed on the scalp above the primary motor cortex (M1), contralateral to the dominant cortex. The cathodal electrode was placed on the supraorbital contralateral area. The current used was 2mA during 20 minutes.
arm group label: LDN + tDCS
arm group label: Placebo + tDCS
other name: tDCS
intervention type: Drug
intervention name: Placebo
description: The capsule presented the same format, size and color as LDN capsules, however the excipient used was starch.
arm group label: Placebo + Sham tDCS
arm group label: Placebo + tDCS
intervention type: Device
intervention name: Sham Transcranial Direct Current Stimulation
description: Sham-tDCS stimulation consists of an active current during 30 seconds
arm group label: LDN + Sham tDCS
arm group label: Placebo + Sham tDCS
other name: Sham tDCS
criteria: 
gender: Female
minimum age: 8 Years
maximum age: 65 Years
healthy volunteers: No
facility: 
country: Brazil
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PMID: 17559710
responsible party type: Principal Investigator
investigator affiliation: Centro Universitario La Salle
investigator full name: Andressa de Souza
investigator title: Principal Investigator
mesh term: Fibromyalgia
mesh term: Myofascial Pain Syndromes
mesh term: Naltrexone
sharing ipd: Undecided
provided document: 