<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/NCT03293394</url>
  </required_header>
  <id_info>
    <org_study_id>NP2743</org_study_id>
    <nct_id>NCT03293394</nct_id>
  </id_info>
  <brief_title>Rehabilitative Trial With tDCS in Amyotrophic Lateral Sclerosis</brief_title>
  <acronym>tDCS_MND</acronym>
  <official_title>Rehabilitative Trial With Transcranial Direct Current Stimulation (tDCS) in Amyotrophic Lateral Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which is a group of&#xD;
      neurological disorders that selectively affect motor neurons, the cells that control&#xD;
      voluntary muscles of the body. The disorder causes muscle weakness and atrophy throughout the&#xD;
      body due to the degeneration of the upper and lower motor neurons. Current drugs approved for&#xD;
      ALS treatment only modestly slow disease progression.&#xD;
&#xD;
      Transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been&#xD;
      demonstrated to modulate cerebral excitability in several neurodegenerative disorders and&#xD;
      modulate intracortical connectivity measures.&#xD;
&#xD;
      In this randomized, double-blind, sham-controlled study, the investigators will evaluate&#xD;
      whether a two-weeks' treatment with bilateral motor cortex anodal tDCS and spinal cathodal&#xD;
      tDCS can improve symptoms in patients with amyotrophic lateral sclerosis and modulate&#xD;
      intracortical connectivity, at short and long term.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which is a group of&#xD;
      neurological disorders that selectively affect motor neurons, the cells that control&#xD;
      voluntary muscles of the body. The disorder causes muscle weakness and atrophy throughout the&#xD;
      body due to the degeneration of the upper and lower motor neurons. Current drugs approved for&#xD;
      ALS treatment only modestly slow disease progression.&#xD;
&#xD;
      Transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been&#xD;
      demonstrated to modulate cerebral excitability in several neurodegenerative disorders and&#xD;
      modulate intracortical connectivity measures.&#xD;
&#xD;
      In this randomized, double-blind, sham-controlled study, the investigators will evaluate&#xD;
      whether a two-weeks' treatment with bilateral motor cortex anodal tDCS and spinal cathodal&#xD;
      tDCS can improve symptoms in patients with amyotrophic lateral sclerosis and modulate&#xD;
      intracortical connectivity, at short and long term.&#xD;
&#xD;
      Subjects will be randomized in two groups, one receiving a 10 day (5 days/week for 2 weeks)&#xD;
      treatment with anodal bilateral motor cortex tDCS and cathodal spinal tDCS and the other&#xD;
      receiving sham stimulation with identical parameters. After the intervention, patients will&#xD;
      be reassessed with a clinical and neurophysiological evaluation at 2 weeks, 2 months and 6&#xD;
      months after treatment. Furthermore, blood neurofilaments will be measured at each time&#xD;
      point.&#xD;
&#xD;
      Clinical evaluation will include the ALSFRS-R, ALSAQ-40, CBI, EQ-5D-5L, muscle strength&#xD;
      evaluated with the MRC scale.&#xD;
&#xD;
      Neurophysiological evaluation will include measures of intracortical connectivity, evaluated&#xD;
      with transcranial magnetic stimulation (TMS) as short interval intracortical inhibition&#xD;
      (SICI-ICF), long interval intracortical inhibition (LICI), short interval intracortical&#xD;
      facilitation (SICF).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2, 2017</start_date>
  <completion_date type="Actual">July 1, 2018</completion_date>
  <primary_completion_date type="Actual">June 20, 2018</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Muscle Strength From Baseline</measure>
    <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
    <description>A megascore is obtained by summing scores of single muscles (shoulder abductors, elbow flexors and extensors, wrist flexors, thumb opponent, hip flexors, knee flexors and extensors, and ankle dorsiflexors and extensors on both sides) manually evaluated according to the Medical Research Council (MRC) scale, which ranges from 0 (no movement) to 5 (normal contraction).&#xD;
The score for each muscle is summed, with scores ranging from 100 (no impairment) to 0 (most severe impairment).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Short-interval Intracortical Inhibition (SICI) From Baseline</measure>
    <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
    <description>By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on short-interval intracortical inhibition (SICI) from baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the ALSFRS-R Score From Baseline</measure>
    <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
    <description>Change in the ALS Functional Rating Scale (ALSFRS-R) score from baseline. The ALSFRS provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS includes ten questions that rate the patients level of functional impairment in performing one of ten common tasks. Each task is rated on a five-point scale from 0 (can't do) to 4 (normal ability). Individual item scores are summed to produce a reported score of between 40 (no impairment) and 0 (severe impairment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Quality of Life From Baseline: ALSAQ-40 Scale</measure>
    <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
    <description>Change of quality of life from baseline evaluated with the ALSAQ-40 scale. The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) is a patient self-report health status scale. The ALSAQ is specifically used to measure the subjective well-being of patients with amyotrophic lateral sclerosis. There are 40 items/questions with 5 discrete scales: physical mobility (10 items), activities of daily living and independence (10 items), eating and drinking (3 items), communication (7 items), emotional reactions (10 items). Patients are asked to think about the difficulties they may have experienced during the last two weeks (e.g. I have found it difficult to feed myself). Patients are asked to indicate the frequency of each event by selecting one of 5 options (Likert scale):&#xD;
never/rarely/sometimes/often/always or cannot do at all. The total ranges from 0 (no impairment) to 160 (severe impairment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Quality of Life From Baseline: EQ-5D-5L Scale</measure>
    <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
    <description>Change of quality of life from baseline evaluated with the EQ-5D-5L scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The scale ranges from 5 (no impairment) to 25 (severe impairment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Quality of Life From Baseline: EQ-VAS Scale</measure>
    <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
    <description>Change of quality of life from baseline evaluated with the EQ-VAS scale. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. The scale ranges from 0 (severe impairment) to 100 (no impairment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Caregiver Burden (CBI)</measure>
    <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
    <description>Change of quality of life from baseline evaluated with the CBI scale. The CBI scale is 24- item scale designed to assess the experience of caregivers of older people. The multidimensional instrument assesses five domains of burden (time-dependence, developmental, physical, social, and emotional). Items are scored on a 4-point scale, ranging from &quot;not at all descriptive&quot; to &quot;very descriptive&quot;. The scale ranges from 0 (no impairment) to 96 (severe impairment).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change Intracortical Facilitation (ICF) From Baseline</measure>
    <time_frame>Baseline - 2 weeks - 2 month - 6 months</time_frame>
    <description>By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on intracortical facilitation (ICF) from baseline</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Amyotrophic Lateral Sclerosis</condition>
  <arm_group>
    <arm_group_label>Real tDCS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham tDCS</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>10 days sham bilateral motor cortex and sham spinal tDCS</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Anodal bilateral motor cortex and cathodal spinal tDCS</intervention_name>
    <description>10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
    <arm_group_label>Real tDCS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham bilateral motor cortex and sham spinal tDCS</intervention_name>
    <description>10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
    <arm_group_label>Sham tDCS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with a diagnosis of probable, laboratory-supported probable, or definite&#xD;
             amyotrophic lateral sclerosis according to the El Escorial revised criteria&#xD;
&#xD;
          -  Disease duration ≤ 24 months&#xD;
&#xD;
          -  Disease progression in the past 3 months&#xD;
&#xD;
          -  Score ≥ 2 at the item &quot;swallowing&quot; of the ALS Functional Rating Scale Revised&#xD;
&#xD;
          -  Score ≥ 2 at the item &quot;walking&quot; of the ALS Functional Rating Scale Revised&#xD;
&#xD;
          -  Treatment with steady regimen of riluzole for a minimum of 1 month before study entry,&#xD;
             and desiring its continuation&#xD;
&#xD;
          -  Able to give informed consent&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Motor neuron diseases other than ALS&#xD;
&#xD;
          -  Severe head trauma in the past&#xD;
&#xD;
          -  History of seizures&#xD;
&#xD;
          -  History of ischemic stroke or hemorrhage&#xD;
&#xD;
          -  Pacemaker&#xD;
&#xD;
          -  Metal implants in the head/neck region&#xD;
&#xD;
          -  Severe comorbidity&#xD;
&#xD;
          -  Intake of illegal drugs&#xD;
&#xD;
          -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Barbara Borroni, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Azienda Ospedaliera Spedali Civili, Brescia</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Alberto Benussi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Università degli Studi di Brescia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>AO Spedali Civili</name>
      <address>
        <city>Brescia</city>
        <state>BS</state>
        <zip>25100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Quartarone A, Lang N, Rizzo V, Bagnato S, Morgante F, Sant'angelo A, Crupi D, Battaglia F, Messina C, Girlanda P. Motor cortex abnormalities in amyotrophic lateral sclerosis with transcranial direct-current stimulation. Muscle Nerve. 2007 May;35(5):620-4. doi: 10.1002/mus.20737.</citation>
    <PMID>17221883</PMID>
  </reference>
  <reference>
    <citation>Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, Cotelli M, De Ridder D, Ferrucci R, Langguth B, Marangolo P, Mylius V, Nitsche MA, Padberg F, Palm U, Poulet E, Priori A, Rossi S, Schecklmann M, Vanneste S, Ziemann U, Garcia-Larrea L, Paulus W. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017 Jan;128(1):56-92. doi: 10.1016/j.clinph.2016.10.087. Epub 2016 Oct 29.</citation>
    <PMID>27866120</PMID>
  </reference>
  <reference>
    <citation>Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S. Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol. 2015 May;14(5):478-84. doi: 10.1016/S1474-4422(15)00014-9. Epub 2015 Apr 3. Erratum In: Lancet Neurol. 2015 Jun;14(6):566.</citation>
    <PMID>25843898</PMID>
  </reference>
  <reference>
    <citation>Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor neuron dysfunction in frontotemporal dementia. Brain. 2011 Sep;134(Pt 9):2582-94. doi: 10.1093/brain/awr195. Epub 2011 Aug 11.</citation>
    <PMID>21840887</PMID>
  </reference>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>September 21, 2017</study_first_submitted>
  <study_first_submitted_qc>September 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 26, 2017</study_first_posted>
  <results_first_submitted>November 4, 2019</results_first_submitted>
  <results_first_submitted_qc>November 4, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">November 22, 2019</results_first_posted>
  <last_update_submitted>March 1, 2020</last_update_submitted>
  <last_update_submitted_qc>March 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</investigator_affiliation>
    <investigator_full_name>Barbara Borroni</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Amyotrophic Lateral Sclerosis</keyword>
  <keyword>Motor Neuron Disease</keyword>
  <keyword>Transcranial Direct Current Stimulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Motor Neuron Disease</mesh_term>
    <mesh_term>Amyotrophic Lateral Sclerosis</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 5, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03293394/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Real tDCS</title>
          <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
        </group>
        <group group_id="P2">
          <title>Sham tDCS</title>
          <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Intervention (2 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Follow-up (6 Months)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Baseline analysis are reported for 30 participants who completed the first intervention.</population>
      <group_list>
        <group group_id="B1">
          <title>Real tDCS</title>
          <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
        </group>
        <group group_id="B2">
          <title>Sham tDCS</title>
          <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
            <count group_id="B2" value="10"/>
            <count group_id="B3" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="60.5" spread="10.9"/>
                    <measurement group_id="B2" value="63.9" spread="11.3"/>
                    <measurement group_id="B3" value="61.7" spread="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Italy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Disease Duration</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2.1" spread="1.4"/>
                    <measurement group_id="B2" value="1.8" spread="1.0"/>
                    <measurement group_id="B3" value="2.0" spread="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Muscle Strength From Baseline</title>
        <description>A megascore is obtained by summing scores of single muscles (shoulder abductors, elbow flexors and extensors, wrist flexors, thumb opponent, hip flexors, knee flexors and extensors, and ankle dorsiflexors and extensors on both sides) manually evaluated according to the Medical Research Council (MRC) scale, which ranges from 0 (no movement) to 5 (normal contraction).&#xD;
The score for each muscle is summed, with scores ranging from 100 (no impairment) to 0 (most severe impairment).</description>
        <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Muscle Strength From Baseline</title>
          <description>A megascore is obtained by summing scores of single muscles (shoulder abductors, elbow flexors and extensors, wrist flexors, thumb opponent, hip flexors, knee flexors and extensors, and ankle dorsiflexors and extensors on both sides) manually evaluated according to the Medical Research Council (MRC) scale, which ranges from 0 (no movement) to 5 (normal contraction).&#xD;
The score for each muscle is summed, with scores ranging from 100 (no impairment) to 0 (most severe impairment).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="74.7" spread="0.0"/>
                    <measurement group_id="O2" value="74.7" spread="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="76.4" spread="0.2"/>
                    <measurement group_id="O2" value="74.5" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="76.4" spread="0.4"/>
                    <measurement group_id="O2" value="72.9" spread="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="75.9" spread="0.6"/>
                    <measurement group_id="O2" value="72.0" spread="0.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.001</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Short-interval Intracortical Inhibition (SICI) From Baseline</title>
        <description>By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on short-interval intracortical inhibition (SICI) from baseline</description>
        <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Short-interval Intracortical Inhibition (SICI) From Baseline</title>
          <description>By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on short-interval intracortical inhibition (SICI) from baseline</description>
          <units>millivolts</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.0" spread="0.1"/>
                    <measurement group_id="O2" value="1.0" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.4" spread="0.1"/>
                    <measurement group_id="O2" value="1.0" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.5" spread="0.1"/>
                    <measurement group_id="O2" value="0.9" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6" spread="0.1"/>
                    <measurement group_id="O2" value="1.0" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.011</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in the ALSFRS-R Score From Baseline</title>
        <description>Change in the ALS Functional Rating Scale (ALSFRS-R) score from baseline. The ALSFRS provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS includes ten questions that rate the patients level of functional impairment in performing one of ten common tasks. Each task is rated on a five-point scale from 0 (can't do) to 4 (normal ability). Individual item scores are summed to produce a reported score of between 40 (no impairment) and 0 (severe impairment).</description>
        <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change in the ALSFRS-R Score From Baseline</title>
          <description>Change in the ALS Functional Rating Scale (ALSFRS-R) score from baseline. The ALSFRS provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS includes ten questions that rate the patients level of functional impairment in performing one of ten common tasks. Each task is rated on a five-point scale from 0 (can't do) to 4 (normal ability). Individual item scores are summed to produce a reported score of between 40 (no impairment) and 0 (severe impairment).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baselin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.5" spread="0.0"/>
                    <measurement group_id="O2" value="31.5" spread="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.5" spread="0.2"/>
                    <measurement group_id="O2" value="31.8" spread="0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.0" spread="0.4"/>
                    <measurement group_id="O2" value="30.4" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.4" spread="0.5"/>
                    <measurement group_id="O2" value="29.7" spread="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.190</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change of Quality of Life From Baseline: ALSAQ-40 Scale</title>
        <description>Change of quality of life from baseline evaluated with the ALSAQ-40 scale. The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) is a patient self-report health status scale. The ALSAQ is specifically used to measure the subjective well-being of patients with amyotrophic lateral sclerosis. There are 40 items/questions with 5 discrete scales: physical mobility (10 items), activities of daily living and independence (10 items), eating and drinking (3 items), communication (7 items), emotional reactions (10 items). Patients are asked to think about the difficulties they may have experienced during the last two weeks (e.g. I have found it difficult to feed myself). Patients are asked to indicate the frequency of each event by selecting one of 5 options (Likert scale):&#xD;
never/rarely/sometimes/often/always or cannot do at all. The total ranges from 0 (no impairment) to 160 (severe impairment).</description>
        <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change of Quality of Life From Baseline: ALSAQ-40 Scale</title>
          <description>Change of quality of life from baseline evaluated with the ALSAQ-40 scale. The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) is a patient self-report health status scale. The ALSAQ is specifically used to measure the subjective well-being of patients with amyotrophic lateral sclerosis. There are 40 items/questions with 5 discrete scales: physical mobility (10 items), activities of daily living and independence (10 items), eating and drinking (3 items), communication (7 items), emotional reactions (10 items). Patients are asked to think about the difficulties they may have experienced during the last two weeks (e.g. I have found it difficult to feed myself). Patients are asked to indicate the frequency of each event by selecting one of 5 options (Likert scale):&#xD;
never/rarely/sometimes/often/always or cannot do at all. The total ranges from 0 (no impairment) to 160 (severe impairment).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.0" spread="0.0"/>
                    <measurement group_id="O2" value="45.0" spread="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40.1" spread="2.0"/>
                    <measurement group_id="O2" value="38.3" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.8" spread="1.8"/>
                    <measurement group_id="O2" value="41.0" spread="2.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.9" spread="2.2"/>
                    <measurement group_id="O2" value="42.4" spread="3.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.652</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change of Quality of Life From Baseline: EQ-5D-5L Scale</title>
        <description>Change of quality of life from baseline evaluated with the EQ-5D-5L scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The scale ranges from 5 (no impairment) to 25 (severe impairment).</description>
        <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change of Quality of Life From Baseline: EQ-5D-5L Scale</title>
          <description>Change of quality of life from baseline evaluated with the EQ-5D-5L scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The scale ranges from 5 (no impairment) to 25 (severe impairment).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.0" spread="0.0"/>
                    <measurement group_id="O2" value="13.0" spread="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.2" spread="0.5"/>
                    <measurement group_id="O2" value="13.6" spread="0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.6" spread="0.5"/>
                    <measurement group_id="O2" value="14.2" spread="0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.3" spread="0.6"/>
                    <measurement group_id="O2" value="14.3" spread="0.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.190</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change of Quality of Life From Baseline: EQ-VAS Scale</title>
        <description>Change of quality of life from baseline evaluated with the EQ-VAS scale. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. The scale ranges from 0 (severe impairment) to 100 (no impairment).</description>
        <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change of Quality of Life From Baseline: EQ-VAS Scale</title>
          <description>Change of quality of life from baseline evaluated with the EQ-VAS scale. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. The scale ranges from 0 (severe impairment) to 100 (no impairment).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="51.6" spread="0.0"/>
                    <measurement group_id="O2" value="51.6" spread="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="56.3" spread="2.0"/>
                    <measurement group_id="O2" value="46.1" spread="2.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.2" spread="2.2"/>
                    <measurement group_id="O2" value="42.7" spread="3.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.7" spread="2.9"/>
                    <measurement group_id="O2" value="40.2" spread="4.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.011</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Caregiver Burden (CBI)</title>
        <description>Change of quality of life from baseline evaluated with the CBI scale. The CBI scale is 24- item scale designed to assess the experience of caregivers of older people. The multidimensional instrument assesses five domains of burden (time-dependence, developmental, physical, social, and emotional). Items are scored on a 4-point scale, ranging from &quot;not at all descriptive&quot; to &quot;very descriptive&quot;. The scale ranges from 0 (no impairment) to 96 (severe impairment).</description>
        <time_frame>Baseline - 2 weeks - 2 months - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Caregiver Burden (CBI)</title>
          <description>Change of quality of life from baseline evaluated with the CBI scale. The CBI scale is 24- item scale designed to assess the experience of caregivers of older people. The multidimensional instrument assesses five domains of burden (time-dependence, developmental, physical, social, and emotional). Items are scored on a 4-point scale, ranging from &quot;not at all descriptive&quot; to &quot;very descriptive&quot;. The scale ranges from 0 (no impairment) to 96 (severe impairment).</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.7" spread="0.0"/>
                    <measurement group_id="O2" value="26.7" spread="0.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.6" spread="1.1"/>
                    <measurement group_id="O2" value="30.0" spread="1.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.0" spread="1.4"/>
                    <measurement group_id="O2" value="30.4" spread="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.8" spread="1.3"/>
                    <measurement group_id="O2" value="30.7" spread="1.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.003</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change Intracortical Facilitation (ICF) From Baseline</title>
        <description>By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on intracortical facilitation (ICF) from baseline</description>
        <time_frame>Baseline - 2 weeks - 2 month - 6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Real tDCS</title>
            <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
          <group group_id="O2">
            <title>Sham tDCS</title>
            <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
          </group>
        </group_list>
        <measure>
          <title>Change Intracortical Facilitation (ICF) From Baseline</title>
          <description>By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on intracortical facilitation (ICF) from baseline</description>
          <units>millivolts</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baselin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.8" spread="0.1"/>
                    <measurement group_id="O2" value="1.7" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Weeks</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.3" spread="0.0"/>
                    <measurement group_id="O2" value="1.7" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.4" spread="0.1"/>
                    <measurement group_id="O2" value="1.7" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 Months</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.6" spread="0.0"/>
                    <measurement group_id="O2" value="1.6" spread="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.001</p_value>
            <method>ANOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 Months follow-up</time_frame>
      <desc>Adverse event has been defined as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.</desc>
      <group_list>
        <group group_id="E1">
          <title>Real tDCS</title>
          <description>10 days anodal bilateral motor cortex and cathodal spinal tDCS&#xD;
Anodal bilateral motor cortex and cathodal spinal tDCS: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
        </group>
        <group group_id="E2">
          <title>Sham tDCS</title>
          <description>10 days sham bilateral motor cortex and sham spinal tDCS&#xD;
Sham bilateral motor cortex and sham spinal tDCS: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Worsening of Global Clinical Conditions</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Respiratory Failure</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Prof. Barbara Borroni</name_or_title>
      <organization>Spedali Civili di Brescia</organization>
      <phone>+39 0303995631</phone>
      <email>bborroni@inwind.it</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03293394
org study id: NP2743
nct id: NCT03293394
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which is a group of
      neurological disorders that selectively affect motor neurons, the cells that control
      voluntary muscles of the body. The disorder causes muscle weakness and atrophy throughout the
      body due to the degeneration of the upper and lower motor neurons. Current drugs approved for
      ALS treatment only modestly slow disease progression.

      Transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been
      demonstrated to modulate cerebral excitability in several neurodegenerative disorders and
      modulate intracortical connectivity measures.

      In this randomized, double-blind, sham-controlled study, the investigators will evaluate
      whether a two-weeks' treatment with bilateral motor cortex anodal tDCS and spinal cathodal
      tDCS can improve symptoms in patients with amyotrophic lateral sclerosis and modulate
      intracortical connectivity, at short and long term.
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, which is a group of
      neurological disorders that selectively affect motor neurons, the cells that control
      voluntary muscles of the body. The disorder causes muscle weakness and atrophy throughout the
      body due to the degeneration of the upper and lower motor neurons. Current drugs approved for
      ALS treatment only modestly slow disease progression.

      Transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been
      demonstrated to modulate cerebral excitability in several neurodegenerative disorders and
      modulate intracortical connectivity measures.

      In this randomized, double-blind, sham-controlled study, the investigators will evaluate
      whether a two-weeks' treatment with bilateral motor cortex anodal tDCS and spinal cathodal
      tDCS can improve symptoms in patients with amyotrophic lateral sclerosis and modulate
      intracortical connectivity, at short and long term.

      Subjects will be randomized in two groups, one receiving a 10 day (5 days/week for 2 weeks)
      treatment with anodal bilateral motor cortex tDCS and cathodal spinal tDCS and the other
      receiving sham stimulation with identical parameters. After the intervention, patients will
      be reassessed with a clinical and neurophysiological evaluation at 2 weeks, 2 months and 6
      months after treatment. Furthermore, blood neurofilaments will be measured at each time
      point.

      Clinical evaluation will include the ALSFRS-R, ALSAQ-40, CBI, EQ-5D-5L, muscle strength
      evaluated with the MRC scale.

      Neurophysiological evaluation will include measures of intracortical connectivity, evaluated
      with transcranial magnetic stimulation (TMS) as short interval intracortical inhibition
      (SICI-ICF), long interval intracortical inhibition (LICI), short interval intracortical
      facilitation (SICF).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Change in Muscle Strength From Baseline
time frame: Baseline - 2 weeks - 2 months - 6 months
description: A megascore is obtained by summing scores of single muscles (shoulder abductors, elbow flexors and extensors, wrist flexors, thumb opponent, hip flexors, knee flexors and extensors, and ankle dorsiflexors and extensors on both sides) manually evaluated according to the Medical Research Council (MRC) scale, which ranges from 0 (no movement) to 5 (normal contraction).
The score for each muscle is summed, with scores ranging from 100 (no impairment) to 0 (most severe impairment).
measure: Change in Short-interval Intracortical Inhibition (SICI) From Baseline
time frame: Baseline - 2 weeks - 2 months - 6 months
description: By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on short-interval intracortical inhibition (SICI) from baseline
measure: Change in the ALSFRS-R Score From Baseline
time frame: Baseline - 2 weeks - 2 months - 6 months
description: Change in the ALS Functional Rating Scale (ALSFRS-R) score from baseline. The ALSFRS provides a physician-generated estimate of the patient's degree of functional impairment, which can be evaluated serially to objectively assess any response to treatment or progression of disease. The ALSFRS includes ten questions that rate the patients level of functional impairment in performing one of ten common tasks. Each task is rated on a five-point scale from 0 (can't do) to 4 (normal ability). Individual item scores are summed to produce a reported score of between 40 (no impairment) and 0 (severe impairment).
measure: Change of Quality of Life From Baseline: ALSAQ-40 Scale
time frame: Baseline - 2 weeks - 2 months - 6 months
description: Change of quality of life from baseline evaluated with the ALSAQ-40 scale. The Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ) is a patient self-report health status scale. The ALSAQ is specifically used to measure the subjective well-being of patients with amyotrophic lateral sclerosis. There are 40 items/questions with 5 discrete scales: physical mobility (10 items), activities of daily living and independence (10 items), eating and drinking (3 items), communication (7 items), emotional reactions (10 items). Patients are asked to think about the difficulties they may have experienced during the last two weeks (e.g. I have found it difficult to feed myself). Patients are asked to indicate the frequency of each event by selecting one of 5 options (Likert scale):
never/rarely/sometimes/often/always or cannot do at all. The total ranges from 0 (no impairment) to 160 (severe impairment).
measure: Change of Quality of Life From Baseline: EQ-5D-5L Scale
time frame: Baseline - 2 weeks - 2 months - 6 months
description: Change of quality of life from baseline evaluated with the EQ-5D-5L scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. The scale ranges from 5 (no impairment) to 25 (severe impairment).
measure: Change of Quality of Life From Baseline: EQ-VAS Scale
time frame: Baseline - 2 weeks - 2 months - 6 months
description: Change of quality of life from baseline evaluated with the EQ-VAS scale. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. The scale ranges from 0 (severe impairment) to 100 (no impairment).
measure: Change in Caregiver Burden (CBI)
time frame: Baseline - 2 weeks - 2 months - 6 months
description: Change of quality of life from baseline evaluated with the CBI scale. The CBI scale is 24- item scale designed to assess the experience of caregivers of older people. The multidimensional instrument assesses five domains of burden (time-dependence, developmental, physical, social, and emotional). Items are scored on a 4-point scale, ranging from "not at all descriptive" to "very descriptive". The scale ranges from 0 (no impairment) to 96 (severe impairment).
measure: Change Intracortical Facilitation (ICF) From Baseline
time frame: Baseline - 2 weeks - 2 month - 6 months
description: By using transcranial magnetic stimulation (TMS), the investigators will evaluate the effects of tDCS on intracortical facilitation (ICF) from baseline
arm group label: Real tDCS
arm group type: Experimental
description: 10 days anodal bilateral motor cortex and cathodal spinal tDCS
arm group label: Sham tDCS
arm group type: Placebo Comparator
description: 10 days sham bilateral motor cortex and sham spinal tDCS
intervention type: Device
intervention name: Anodal bilateral motor cortex and cathodal spinal tDCS
description: 10 sessions of anodal bilateral motor cortex and cathodal spinal transcranial direct current stimulation (5 days/week for 2 weeks)
arm group label: Real tDCS
intervention type: Device
intervention name: Sham bilateral motor cortex and sham spinal tDCS
description: 10 sessions of sham bilateral motor cortex and sham spinal transcranial direct current stimulation (5 days/week for 2 weeks)
arm group label: Sham tDCS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Barbara Borroni, MD
role: Principal Investigator
affiliation: Azienda Ospedaliera Spedali Civili, Brescia
last name: Alberto Benussi, MD
role: Principal Investigator
affiliation: Università degli Studi di Brescia
facility: 
country: Italy
citation: Quartarone A, Lang N, Rizzo V, Bagnato S, Morgante F, Sant'angelo A, Crupi D, Battaglia F, Messina C, Girlanda P. Motor cortex abnormalities in amyotrophic lateral sclerosis with transcranial direct-current stimulation. Muscle Nerve. 2007 May;35(5):620-4. doi: 10.1002/mus.20737.
PMID: 17221883
citation: Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian F, Cotelli M, De Ridder D, Ferrucci R, Langguth B, Marangolo P, Mylius V, Nitsche MA, Padberg F, Palm U, Poulet E, Priori A, Rossi S, Schecklmann M, Vanneste S, Ziemann U, Garcia-Larrea L, Paulus W. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clin Neurophysiol. 2017 Jan;128(1):56-92. doi: 10.1016/j.clinph.2016.10.087. Epub 2016 Oct 29.
PMID: 27866120
citation: Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S. Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol. 2015 May;14(5):478-84. doi: 10.1016/S1474-4422(15)00014-9. Epub 2015 Apr 3. Erratum In: Lancet Neurol. 2015 Jun;14(6):566.
PMID: 25843898
citation: Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor neuron dysfunction in frontotemporal dementia. Brain. 2011 Sep;134(Pt 9):2582-94. doi: 10.1093/brain/awr195. Epub 2011 Aug 11.
PMID: 21840887
responsible party type: Principal Investigator
investigator affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
investigator full name: Barbara Borroni
investigator title: Professor
mesh term: Motor Neuron Disease
mesh term: Amyotrophic Lateral Sclerosis
mesh term: Sclerosis
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 