<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/NCT01733407</url>
  </required_header>
  <id_info>
    <org_study_id>FD-R-04127-01</org_study_id>
    <nct_id>NCT01733407</nct_id>
  </id_info>
  <brief_title>L-Serine Supplementation in Hereditary Sensory Neuropathy Type 1</brief_title>
  <official_title>A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of L-Serine in Subjects With Hereditary Sensory Neuropathy Type 1</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In hereditary sensory and autonomic neuropathy type 1 (HSAN1) the investigators recently&#xD;
      discovered the accumulation of two neurotoxic sphingolipids. It appears that these lipids&#xD;
      arise as the mutant enzyme has a reduced affinity for its normal preferred substrate&#xD;
      L-serine. The investigators now plan to perform a two year study of L-serine supplementation&#xD;
      to correct the biochemistry and neurological disease in humans with HSAN1. In the course the&#xD;
      investigators will also establish correlations between an existing neurological rating scale&#xD;
      of sensory neuropathy and intraepidermal nerve fiber density.&#xD;
&#xD;
      Funding Source - FDA OOPD&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study objective is to evaluate the efficacy of L-serine in subjects with hereditary&#xD;
      sensory neuropathy type 1 (HSAN1). Hereditary sensory and autonomic neuropathy type I (HSAN1)&#xD;
      is a progressive and debilitating illness for which currently no treatment exists. The&#xD;
      investigators recently identified two novel deoxysphingoid bases (DSB) that accumulate in&#xD;
      plasma of HSAN1 patients and mutant transgenic HSAN1 mice. The disease is caused by missense&#xD;
      mutations in the SPTLC1 gene encoding a subunit of the enzyme serine palmitoyltransferase&#xD;
      (SPT). In normal circumstances the SPT enzyme catalyzes the reaction of palmitoyl-CoA with&#xD;
      serine to form sphinganine. The two newly identified DSB, deoxysphinganine and&#xD;
      deoxymethylsphinganine, arise from condensation of palmitoyl-CoA with alanine and glycine&#xD;
      respectively, suggesting that HSAN1 mutations alter amino acid selectivity of SPT. In support&#xD;
      of this hypothesis the investigators have shown that levels of DSB in humans and mice can be&#xD;
      lowered by supplementation with the enzyme's normal substrate, serine.&#xD;
&#xD;
      In this randomized, double-blind, placebo-controlled cross over study the investigators will&#xD;
      enroll 20 research participants with HSAN1 with 10 subjects assigned to L-serine (400mg/kg/d)&#xD;
      and 10 assigned to placebo who are each treated for 12 months. The 10 subjects assigned to&#xD;
      placebo will then be crossed over to active L-serine for the remaining 12 months. The&#xD;
      progression of HSAN1 will be measured by the change in an established clinical rating scale&#xD;
      and measures of intraepidermal nerve fiber density (IENFD) on skin biopsy. L-serine levels&#xD;
      will be measured using 24-hour pharmacokinetic blood sample at 12-month intervals. The&#xD;
      investigators will assess the percentage of failures (clinical decline of &gt; 1 point on CMTNS&#xD;
      or &gt; 30% decrease in IENFD) at 6 month intervals. Regardless of CMTNS score, all subjects who&#xD;
      are on placebo for the first year will be switched to active study drug in year two.&#xD;
&#xD;
      After the 2 year period subjects will be given the option of being re-consented for the open&#xD;
      label extension. All consented subjects will then be treated with L-serine (400 mg/kg/d) for&#xD;
      an additional year.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2013</start_date>
  <completion_date type="Actual">July 2017</completion_date>
  <primary_completion_date type="Actual">May 2016</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Charcot Marie Tooth Neuropathy Score</measure>
    <time_frame>48 Weeks</time_frame>
    <description>The Charcot Marie Tooth Neuropathy Score (CMTNS) is a 0 to 36 point composite scoring assessment that is used to measure disease severity in Charcot Marie Tooth Neuropathy and other sensory and motor neuropathies. The CMTNS is composed of 9 items that evaluate functions related to disease progression. These 9 parameters include reviewing sensory symptoms, motor symptoms (arms and legs), pinprick sensibility, vibration, leg strength, arm strength, and nerve conduction tests. Each item is scored from 0 to 4, with the lower scores representing less severe symptoms and higher scores representing more severe symptoms.The 9 individual item scores are then totaled to provide a global measure of disease severity. For example the lowest possible total score is 0 which represents an asymptomatic individual and the highest score possible is a 36 which represents an individual with severe disease progression. There are sub scores that can be assessed but sub scores were not utilized in this study</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intraepidermal Nerve Fiber Density (IENFD)</measure>
    <time_frame>48 Weeks</time_frame>
    <description>Counts of nerve fibers per unit area in skin biopsies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS)</measure>
    <time_frame>48 Weeks</time_frame>
    <description>Autonomic Function Testing (AFT) tests the effectiveness of your autonomic nervous system which regulates important functions such as blood pressure, heart rate, and respiration. AFT results are quantified using the composite autonomic severity score scale (CASS) which is a scale from 0 to 10 that is the sum of three sub scores (cardiovagal, adrenergic, and sudomotor). Cardiovagal is scored from 0 to 3, sudomotor is scored from 0 to 3, and adrenergic is scored from 0 to 4. The tests include deep breathing, Valsalva maneuver, head-up tilt, and a sweat test. The three subscores are then summed. This total represents the CASS which classifies autonomic function as normal functioning (total score 0), mild (total score 1-3), moderate (total score 4-6), or severe (total score 7-10).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nerve Conduction Testing</measure>
    <time_frame>48 Weeks</time_frame>
    <description>Evaluates the functioning of electrical conduction of the motor and sensory nerves of the human body.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>1-deoxy-sphinganine</measure>
    <time_frame>48 Weeks</time_frame>
    <description>Plasma levels of the deoxysphingoid lipid 1-deoxy-sphinganine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>1-deoxy-sphingosine</measure>
    <time_frame>48 weeks</time_frame>
    <description>Plasma levels of the deoxysphingoid lipid 1-deoxy-sphingosine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Hereditary Sensory and Autonomic Neuropathy Type I</condition>
  <arm_group>
    <arm_group_label>Sugar pill</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo arm</description>
  </arm_group>
  <arm_group>
    <arm_group_label>L-serine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>amino acid supplementation with L-serine</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>L-serine</intervention_name>
    <description>400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
    <arm_group_label>L-serine</arm_group_label>
    <other_name>amino acid supplementation with L-serine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>400mg/kg/d divided TID for year 1 only.</description>
    <arm_group_label>Sugar pill</arm_group_label>
    <other_name>sugar pill</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HSAN1 patients with prominent sensory loss with foot ulcers or shooting pains and&#xD;
             con-firmed mutations in SPTLC1.&#xD;
&#xD;
          -  Males and females of 18 years or older&#xD;
&#xD;
          -  All patients will be able to provide informed consent and comply with oral dietary&#xD;
             supple-mentation and study activities. Compliance with supplementation will be&#xD;
             monitored through measurement of DSB levels.&#xD;
&#xD;
          -  Subjects must not have taken L-serine for at least 30 days prior to randomization&#xD;
             (L-serine-naïve subjects are permitted in the study).&#xD;
&#xD;
          -  Women must not become pregnant for the duration of the study and must be willing to&#xD;
             use two contraceptive therapies and have a negative pregnancy test throughout the&#xD;
             course of the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any cause of neuropathy other than HSAN1 (such as diabetes or drug-induced&#xD;
             neuropathy), medical history of kidney stones, or history of poliomyelitis or&#xD;
             radiotherapy.&#xD;
&#xD;
          -  Pregnant women, breastfeeding, or not using adequate contraception; for women&#xD;
             included, an accepted method of contraception will be used throughout the study.&#xD;
&#xD;
          -  Active drug or alcohol use or dependence that, in the opinion of the site&#xD;
             investigator, would interfere with adherence to study requirements.&#xD;
&#xD;
          -  Patients on blood-thinners such as warfarin (Coumadin) or heparin will not be biopsied&#xD;
             until they have held the medication for 5 days. Following the biopsy they will resume&#xD;
             the maintenance dose of their medication.&#xD;
&#xD;
          -  Serious illness (requiring systemic treatment and/or hospitalization) until subject&#xD;
             either completes therapy or is clinically stable on therapy, in the opinion of the&#xD;
             site investigator, for at least 10 days prior to study entry.&#xD;
&#xD;
          -  The presence of unstable psychiatric disease, cognitive impairment, or dementia that&#xD;
             would impair ability of the subject to provide informed consent, according to PI&#xD;
             judgment, or a history of active substance abuse within the prior year.&#xD;
&#xD;
          -  Subjects who are non-ambulatory.&#xD;
&#xD;
          -  Subjects with uncontrolled diabetes.&#xD;
&#xD;
          -  Patients who are unable or unwilling to give consent will not be enrolled in the&#xD;
             study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Florian S Eichler, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UMass Medical Center</name>
      <address>
        <city>Worcester</city>
        <state>Massachusetts</state>
        <zip>01605</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest. 2011 Dec;121(12):4735-45. doi: 10.1172/JCI57549.</citation>
    <PMID>22045570</PMID>
  </reference>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>September 19, 2012</study_first_submitted>
  <study_first_submitted_qc>November 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 27, 2012</study_first_posted>
  <results_first_submitted>May 3, 2018</results_first_submitted>
  <results_first_submitted_qc>August 14, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">September 12, 2018</results_first_posted>
  <last_update_submitted>August 14, 2018</last_update_submitted>
  <last_update_submitted_qc>August 14, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">September 12, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Florian Eichler</investigator_full_name>
    <investigator_title>Assistant Professor of Neurology</investigator_title>
  </responsible_party>
  <keyword>inherited neuropathies</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peripheral Nervous System Diseases</mesh_term>
    <mesh_term>Hereditary Sensory and Autonomic Neuropathies</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Sugar Pill</title>
          <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
        </group>
        <group group_id="P2">
          <title>L-serine</title>
          <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Sugar Pill</title>
          <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
        </group>
        <group group_id="B2">
          <title>L-serine</title>
          <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</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="9"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="18"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</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>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="49.9" spread="16.9"/>
                    <measurement group_id="B2" value="45.8" spread="11.0"/>
                    <measurement group_id="B3" value="47.8" spread="14.0"/>
                  </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="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="6"/>
                  </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="9"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="18"/>
                  </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>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Canada</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Charcot-Marie-Tooth Neuropathy Score</title>
          <description>The Charcot Marie Tooth Neuropathy Score (CMTNS) is a 36-point composite scoring assessment that assesses disease severity in neuropathies. It is composed of 9 items that evaluate functions related to disease progression including assessing sensory symptoms, motor symptoms, pinprick sensibility, vibration, leg strength, arm strength, and nerve conduction tests. Each item is scored from 0 to 4 with the lower scores representing less severe symptoms and higher scores representing more severe symptoms.The individual item scores are then totaled to provide a global measure of disease severity</description>
          <units>scores on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24.6" spread="7.0"/>
                    <measurement group_id="B2" value="20.6" spread="10.0"/>
                    <measurement group_id="B3" value="22.6" spread="8.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Charcot Marie Tooth Neuropathy Score</title>
        <description>The Charcot Marie Tooth Neuropathy Score (CMTNS) is a 0 to 36 point composite scoring assessment that is used to measure disease severity in Charcot Marie Tooth Neuropathy and other sensory and motor neuropathies. The CMTNS is composed of 9 items that evaluate functions related to disease progression. These 9 parameters include reviewing sensory symptoms, motor symptoms (arms and legs), pinprick sensibility, vibration, leg strength, arm strength, and nerve conduction tests. Each item is scored from 0 to 4, with the lower scores representing less severe symptoms and higher scores representing more severe symptoms.The 9 individual item scores are then totaled to provide a global measure of disease severity. For example the lowest possible total score is 0 which represents an asymptomatic individual and the highest score possible is a 36 which represents an individual with severe disease progression. There are sub scores that can be assessed but sub scores were not utilized in this study</description>
        <time_frame>48 Weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sugar Pill</title>
            <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
          </group>
          <group group_id="O2">
            <title>L-serine</title>
            <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Charcot Marie Tooth Neuropathy Score</title>
          <description>The Charcot Marie Tooth Neuropathy Score (CMTNS) is a 0 to 36 point composite scoring assessment that is used to measure disease severity in Charcot Marie Tooth Neuropathy and other sensory and motor neuropathies. The CMTNS is composed of 9 items that evaluate functions related to disease progression. These 9 parameters include reviewing sensory symptoms, motor symptoms (arms and legs), pinprick sensibility, vibration, leg strength, arm strength, and nerve conduction tests. Each item is scored from 0 to 4, with the lower scores representing less severe symptoms and higher scores representing more severe symptoms.The 9 individual item scores are then totaled to provide a global measure of disease severity. For example the lowest possible total score is 0 which represents an asymptomatic individual and the highest score possible is a 36 which represents an individual with severe disease progression. There are sub scores that can be assessed but sub scores were not utilized in this study</description>
          <units>scores 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="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.67" spread="6.69"/>
                    <measurement group_id="O2" value="20.22" spread="10.10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Intraepidermal Nerve Fiber Density (IENFD)</title>
        <description>Counts of nerve fibers per unit area in skin biopsies</description>
        <time_frame>48 Weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sugar Pill</title>
            <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
          </group>
          <group group_id="O2">
            <title>L-serine</title>
            <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Intraepidermal Nerve Fiber Density (IENFD)</title>
          <description>Counts of nerve fibers per unit area in skin biopsies</description>
          <units>nerve fibers per micrometer^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Upper Thigh</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34.67" spread="35.12"/>
                    <measurement group_id="O2" value="49.56" spread="43.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lower Calf</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.89" spread="2.67"/>
                    <measurement group_id="O2" value="13.89" spread="24.10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS)</title>
        <description>Autonomic Function Testing (AFT) tests the effectiveness of your autonomic nervous system which regulates important functions such as blood pressure, heart rate, and respiration. AFT results are quantified using the composite autonomic severity score scale (CASS) which is a scale from 0 to 10 that is the sum of three sub scores (cardiovagal, adrenergic, and sudomotor). Cardiovagal is scored from 0 to 3, sudomotor is scored from 0 to 3, and adrenergic is scored from 0 to 4. The tests include deep breathing, Valsalva maneuver, head-up tilt, and a sweat test. The three subscores are then summed. This total represents the CASS which classifies autonomic function as normal functioning (total score 0), mild (total score 1-3), moderate (total score 4-6), or severe (total score 7-10).</description>
        <time_frame>48 Weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sugar Pill</title>
            <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
          </group>
          <group group_id="O2">
            <title>L-serine</title>
            <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS)</title>
          <description>Autonomic Function Testing (AFT) tests the effectiveness of your autonomic nervous system which regulates important functions such as blood pressure, heart rate, and respiration. AFT results are quantified using the composite autonomic severity score scale (CASS) which is a scale from 0 to 10 that is the sum of three sub scores (cardiovagal, adrenergic, and sudomotor). Cardiovagal is scored from 0 to 3, sudomotor is scored from 0 to 3, and adrenergic is scored from 0 to 4. The tests include deep breathing, Valsalva maneuver, head-up tilt, and a sweat test. The three subscores are then summed. This total represents the CASS which classifies autonomic function as normal functioning (total score 0), mild (total score 1-3), moderate (total score 4-6), or severe (total score 7-10).</description>
          <units>scores 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="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.56" spread="1.24"/>
                    <measurement group_id="O2" value="2.22" spread="1.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Nerve Conduction Testing</title>
        <description>Evaluates the functioning of electrical conduction of the motor and sensory nerves of the human body.</description>
        <time_frame>48 Weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sugar Pill</title>
            <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
          </group>
          <group group_id="O2">
            <title>L-serine</title>
            <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
          </group>
        </group_list>
        <measure>
          <title>Nerve Conduction Testing</title>
          <description>Evaluates the functioning of electrical conduction of the motor and sensory nerves of the human body.</description>
          <units>microvolts</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Sensrory Right Median Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.34" spread="4.03"/>
                    <measurement group_id="O2" value="5.51" spread="9.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sensory Right Antebrach Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.31" spread="3.94"/>
                    <measurement group_id="O2" value="5.89" spread="9.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sensory Right Superficial Radial Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.56" spread="10.17"/>
                    <measurement group_id="O2" value="10.84" spread="20.11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sensory Right Sural Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.52" spread="1.57"/>
                    <measurement group_id="O2" value="1.07" spread="2.61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sensory Right Superficial Peroneal Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.00" spread="0.00"/>
                    <measurement group_id="O2" value="0.00" spread="0.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Motor Right Median (Wrist) Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.34" spread="4.52"/>
                    <measurement group_id="O2" value="4.21" spread="4.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Motor Right Ulnar (Wrist) Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.49" spread="3.60"/>
                    <measurement group_id="O2" value="4.37" spread="4.80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Motor Right Peroneal EDB (Ankle) Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.54" spread="1.52"/>
                    <measurement group_id="O2" value="0.24" spread="0.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Motor Right Peroneal Tib (Below) Amplitude</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.29" spread="0.47"/>
                    <measurement group_id="O2" value="1.39" spread="2.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>1-deoxy-sphinganine</title>
        <description>Plasma levels of the deoxysphingoid lipid 1-deoxy-sphinganine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups</description>
        <time_frame>48 Weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sugar Pill</title>
            <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
          </group>
          <group group_id="O2">
            <title>L-serine</title>
            <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
          </group>
        </group_list>
        <measure>
          <title>1-deoxy-sphinganine</title>
          <description>Plasma levels of the deoxysphingoid lipid 1-deoxy-sphinganine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups</description>
          <units>micromole per liter</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.338" spread="0.191"/>
                    <measurement group_id="O2" value="0.112" spread="0.042"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>1-deoxy-sphingosine</title>
        <description>Plasma levels of the deoxysphingoid lipid 1-deoxy-sphingosine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups</description>
        <time_frame>48 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Sugar Pill</title>
            <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
          </group>
          <group group_id="O2">
            <title>L-serine</title>
            <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
          </group>
        </group_list>
        <measure>
          <title>1-deoxy-sphingosine</title>
          <description>Plasma levels of the deoxysphingoid lipid 1-deoxy-sphingosine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups</description>
          <units>micromole per liter</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.698" spread="0.306"/>
                    <measurement group_id="O2" value="0.337" spread="0.132"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Sugar Pill</title>
          <description>Placebo arm&#xD;
placebo: 400mg/kg/d divided TID for year 1 only.</description>
        </group>
        <group group_id="E2">
          <title>L-serine</title>
          <description>amino acid supplementation with L-serine&#xD;
L-serine: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-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="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Esophageal Cancer</sub_title>
                <description>Subject developed esophageal cancer</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>MRSA Staff Infection</sub_title>
                <assessment>Systematic Assessment</assessment>
                <description>Hospitalized for MRSA Staff Infection</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>ABDOMINAL PAIN UPPER</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Clostridium Difficile Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Nail Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Osteomyelitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Staphylococcal Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Localized Infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Burns Second Degree</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Foot Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Frostbite</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Tendon Injury</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Thermal Burn</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood Sodium Decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Vitamin D Deficiency</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bunion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Bursitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Pain in Extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Tendonitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Peripheral Sensory Neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Blister</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
              <event>
                <sub_title>Skin Ulcer</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Finger Amputation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="9"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Dr. Florian Eichler</name_or_title>
      <organization>Massachusetts General Hospital</organization>
      <phone>617-643-3799</phone>
      <email>Feichler@partners.org</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/NCT01733407
org study id: FD-R-04127-01
nct id: NCT01733407
lead sponsor: 
has dmc: Yes
In hereditary sensory and autonomic neuropathy type 1 (HSAN1) the investigators recently
      discovered the accumulation of two neurotoxic sphingolipids. It appears that these lipids
      arise as the mutant enzyme has a reduced affinity for its normal preferred substrate
      L-serine. The investigators now plan to perform a two year study of L-serine supplementation
      to correct the biochemistry and neurological disease in humans with HSAN1. In the course the
      investigators will also establish correlations between an existing neurological rating scale
      of sensory neuropathy and intraepidermal nerve fiber density.

      Funding Source - FDA OOPD
The study objective is to evaluate the efficacy of L-serine in subjects with hereditary
      sensory neuropathy type 1 (HSAN1). Hereditary sensory and autonomic neuropathy type I (HSAN1)
      is a progressive and debilitating illness for which currently no treatment exists. The
      investigators recently identified two novel deoxysphingoid bases (DSB) that accumulate in
      plasma of HSAN1 patients and mutant transgenic HSAN1 mice. The disease is caused by missense
      mutations in the SPTLC1 gene encoding a subunit of the enzyme serine palmitoyltransferase
      (SPT). In normal circumstances the SPT enzyme catalyzes the reaction of palmitoyl-CoA with
      serine to form sphinganine. The two newly identified DSB, deoxysphinganine and
      deoxymethylsphinganine, arise from condensation of palmitoyl-CoA with alanine and glycine
      respectively, suggesting that HSAN1 mutations alter amino acid selectivity of SPT. In support
      of this hypothesis the investigators have shown that levels of DSB in humans and mice can be
      lowered by supplementation with the enzyme's normal substrate, serine.

      In this randomized, double-blind, placebo-controlled cross over study the investigators will
      enroll 20 research participants with HSAN1 with 10 subjects assigned to L-serine (400mg/kg/d)
      and 10 assigned to placebo who are each treated for 12 months. The 10 subjects assigned to
      placebo will then be crossed over to active L-serine for the remaining 12 months. The
      progression of HSAN1 will be measured by the change in an established clinical rating scale
      and measures of intraepidermal nerve fiber density (IENFD) on skin biopsy. L-serine levels
      will be measured using 24-hour pharmacokinetic blood sample at 12-month intervals. The
      investigators will assess the percentage of failures (clinical decline of > 1 point on CMTNS
      or > 30% decrease in IENFD) at 6 month intervals. Regardless of CMTNS score, all subjects who
      are on placebo for the first year will be switched to active study drug in year two.

      After the 2 year period subjects will be given the option of being re-consented for the open
      label extension. All consented subjects will then be treated with L-serine (400 mg/kg/d) for
      an additional year.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Charcot Marie Tooth Neuropathy Score
time frame: 48 Weeks
description: The Charcot Marie Tooth Neuropathy Score (CMTNS) is a 0 to 36 point composite scoring assessment that is used to measure disease severity in Charcot Marie Tooth Neuropathy and other sensory and motor neuropathies. The CMTNS is composed of 9 items that evaluate functions related to disease progression. These 9 parameters include reviewing sensory symptoms, motor symptoms (arms and legs), pinprick sensibility, vibration, leg strength, arm strength, and nerve conduction tests. Each item is scored from 0 to 4, with the lower scores representing less severe symptoms and higher scores representing more severe symptoms.The 9 individual item scores are then totaled to provide a global measure of disease severity. For example the lowest possible total score is 0 which represents an asymptomatic individual and the highest score possible is a 36 which represents an individual with severe disease progression. There are sub scores that can be assessed but sub scores were not utilized in this study
measure: Intraepidermal Nerve Fiber Density (IENFD)
time frame: 48 Weeks
description: Counts of nerve fibers per unit area in skin biopsies
measure: Autonomic Function Testing (AFT) Composite Autonomic Severity Score (CASS)
time frame: 48 Weeks
description: Autonomic Function Testing (AFT) tests the effectiveness of your autonomic nervous system which regulates important functions such as blood pressure, heart rate, and respiration. AFT results are quantified using the composite autonomic severity score scale (CASS) which is a scale from 0 to 10 that is the sum of three sub scores (cardiovagal, adrenergic, and sudomotor). Cardiovagal is scored from 0 to 3, sudomotor is scored from 0 to 3, and adrenergic is scored from 0 to 4. The tests include deep breathing, Valsalva maneuver, head-up tilt, and a sweat test. The three subscores are then summed. This total represents the CASS which classifies autonomic function as normal functioning (total score 0), mild (total score 1-3), moderate (total score 4-6), or severe (total score 7-10).
measure: Nerve Conduction Testing
time frame: 48 Weeks
description: Evaluates the functioning of electrical conduction of the motor and sensory nerves of the human body.
measure: 1-deoxy-sphinganine
time frame: 48 Weeks
description: Plasma levels of the deoxysphingoid lipid 1-deoxy-sphinganine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups
measure: 1-deoxy-sphingosine
time frame: 48 weeks
description: Plasma levels of the deoxysphingoid lipid 1-deoxy-sphingosine measured by liquid chromatography/mass spectrometry after hydrolyzing the N-acyl and O-linked headgroups
arm group label: Sugar pill
arm group type: Placebo Comparator
description: Placebo arm
arm group label: L-serine
arm group type: Active Comparator
description: amino acid supplementation with L-serine
intervention type: Drug
intervention name: L-serine
description: 400mg/kg/d L-serine or placebo divided TID for year 1, then crossover of placebo arm so that all patients on 400mg/kg/d L-serine divided TID for year 2.
arm group label: L-serine
other name: amino acid supplementation with L-serine
intervention type: Drug
intervention name: placebo
description: 400mg/kg/d divided TID for year 1 only.
arm group label: Sugar pill
other name: sugar pill
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Florian S Eichler, MD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
facility: 
country: United States
citation: Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest. 2011 Dec;121(12):4735-45. doi: 10.1172/JCI57549.
PMID: 22045570
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Florian Eichler
investigator title: Assistant Professor of Neurology
mesh term: Peripheral Nervous System Diseases
mesh term: Hereditary Sensory and Autonomic Neuropathies
sharing ipd: Undecided
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 