<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/NCT02970162</url>
  </required_header>
  <id_info>
    <org_study_id>LMS-003</org_study_id>
    <nct_id>NCT02970162</nct_id>
  </id_info>
  <brief_title>Phase 3 Study to Evaluate Efficacy of Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS)</brief_title>
  <official_title>A Phase 3, Double-Blind, Placebo-controlled, Randomized, Parallel-Group Study to Evaluate the Efficacy and Safety of Amifampridine Phosphate in Patients With Lambert-Eaton Myasthenic Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Catalyst Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Catalyst Pharmaceuticals, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the effect of withdrawing amifampridine phosphate treatment from&#xD;
      patients with LEMS. One half of the patients will continue to receive amifampridine phosphate&#xD;
      and the other half will receive placebo, during this double-blind study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a randomized (1:1), double-blind, placebo-controlled, parallel-group, withdrawal&#xD;
      study designed to evaluate the efficacy and safety of amifampridine phosphate in patients&#xD;
      diagnosed with LEMS. The study was planned to include approximately 28 male and female&#xD;
      patients.&#xD;
&#xD;
      Prior to the study, patients were receiving unblinded treatment in the expanded access&#xD;
      program (EAP-001). Patients had to be on a stable dose and frequency of amifampridine&#xD;
      phosphate for at least 1 week prior to randomization into LMS-003. Screening and&#xD;
      randomization (Day 0) may have been into a single visit.&#xD;
&#xD;
      Patients who met eligibility criteria were randomized 1:1 to amifampridine phosphate (at the&#xD;
      patient's optimal dose) or placebo on Day 0.&#xD;
&#xD;
      Baseline assessments were obtained on Study Day 0, while the patient has been on open-label&#xD;
      amifampridine phosphate and in relationship to the usual dosing schedule. Patients took&#xD;
      blinded study medication on Day 1 through Day 3. On Day 4, a dose of blinded study medication&#xD;
      was administered by the site study personnel. This was the same medication that the patient&#xD;
      took on Day 1 through Day 3. The assessments listed below were performed following either the&#xD;
      second, third, or fourth dose of medication taken on Day 4, and this should be the same dose&#xD;
      after which Day 0 assessments were performed. For example, if the patient took their second&#xD;
      dose of amifampridine in the clinic on Day 0 and had assessments started 40 minutes later,&#xD;
      then on Day 4, that patient should be assessed after taking their second dose of&#xD;
      investigational product (IP).&#xD;
&#xD;
      Beginning with the next dose after all Day 0 baseline assessments were completed, the patient&#xD;
      received IP through Day 4, with a clinic visit on the last day (Day 4) for assessments.&#xD;
&#xD;
      The planned duration of participation for each patient was up to 12 days, including screening&#xD;
      (up to 7 days), Day 0 assessments and randomization, and IP administration (Day 1 through Day&#xD;
      4).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2016</start_date>
  <completion_date type="Actual">October 2017</completion_date>
  <primary_completion_date type="Actual">October 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>Yes</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Quantitative Myasthenia Gravis (QMG) Score</measure>
    <time_frame>change from baseline in QMG score at end of day 4</time_frame>
    <description>The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Subject Global Impression (SGI) Score</measure>
    <time_frame>change from baseline in SGI score at end of day 4</time_frame>
    <description>The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline</measure>
    <time_frame>change from baseline in CGI-I score at end of day 4</time_frame>
    <description>The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Triple Timed Up and Go Walk Test (3TUG)</measure>
    <time_frame>change from baseline in 3TUG at end of day 4</time_frame>
    <description>The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Lambert-Eaton Myasthenic Syndrome</condition>
  <arm_group>
    <arm_group_label>amifampridine phosphate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo (for amifampridine phosphate)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo by mouth 3 to 4 times per day for 4 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amifampridine Phosphate</intervention_name>
    <arm_group_label>amifampridine phosphate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <arm_group_label>placebo (for amifampridine phosphate)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female ≥18 years of age and currently receiving amifampridine phosphate for&#xD;
             LEMS.&#xD;
&#xD;
          2. Diagnosis of LEMS by antibody testing or electromyography (EMG).&#xD;
&#xD;
          3. Completion of anti-cancer treatment at least 3 months (90 days) prior to Screening.&#xD;
&#xD;
          4. If receiving peripherally acting cholinesterase inhibitors (e.g. pyridostigmine), a&#xD;
             stable dose of cholinesterase inhibitors is required for at least 7 days prior to&#xD;
             randomization and throughout the study.&#xD;
&#xD;
          5. If receiving permitted oral immunosuppressants (prednisone or other corticosteroid), a&#xD;
             stable dose is required for at least 30 days prior to randomization and throughout the&#xD;
             study.&#xD;
&#xD;
          6. Female patients of childbearing potential must practice an effective, reliable&#xD;
             contraceptive regimen during the study.&#xD;
&#xD;
          7. Able to perform all study procedures and assessments.&#xD;
&#xD;
          8. Willing and able to travel to study site and attend all clinic study visits.&#xD;
&#xD;
          9. Willing and able to provide written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Clinically significant long corrected QT (QTc) interval on ECG in previous 12 months.&#xD;
&#xD;
          2. Seizure disorder.&#xD;
&#xD;
          3. Active brain metastases.&#xD;
&#xD;
          4. Unable to ambulate.&#xD;
&#xD;
          5. Pregnant or lactating females.&#xD;
&#xD;
          6. Any other condition which, in the opinion of the Investigator, might interfere with&#xD;
             the patient's participation in the study or confound the assessment of the patient.&#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>Perry Shieh, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, Los Angeles</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCLA</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>November 16, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <results_first_submitted>September 24, 2018</results_first_submitted>
  <results_first_submitted_qc>December 20, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">December 24, 2018</results_first_posted>
  <last_update_submitted>December 20, 2018</last_update_submitted>
  <last_update_submitted_qc>December 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 24, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>LEMS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lambert-Eaton Myasthenic Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Amifampridine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 27, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/62/NCT02970162/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 12, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/62/NCT02970162/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Amifampridine Phosphate</title>
          <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days&#xD;
Amifampridine Phosphate</description>
        </group>
        <group group_id="P2">
          <title>Placebo (for Amifampridine Phosphate)</title>
          <description>placebo by mouth 3 to 4 times per day for 4 days&#xD;
Placebo Oral Tablet</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="13"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="13"/>
              </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_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Amifampridine Phosphate</title>
          <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days&#xD;
Amifampridine Phosphate</description>
        </group>
        <group group_id="B2">
          <title>Placebo (for Amifampridine Phosphate)</title>
          <description>placebo by mouth 3 to 4 times per day for 4 days&#xD;
Placebo Oral Tablet</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="13"/>
            <count group_id="B2" value="13"/>
            <count group_id="B3" value="26"/>
          </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="54.9" spread="11.51"/>
                    <measurement group_id="B2" value="53.4" spread="13.46"/>
                    <measurement group_id="B3" value="54.2" spread="12.30"/>
                  </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="9"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="21"/>
                  </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>Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="77.62" spread="20.312"/>
                    <measurement group_id="B2" value="93.95" spread="15.449"/>
                    <measurement group_id="B3" value="85.78" spread="19.545"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Quantitative Myasthenia Gravis (QMG) Score</title>
        <description>The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome.</description>
        <time_frame>change from baseline in QMG score at end of day 4</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Amifampridine Phosphate</title>
            <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days&#xD;
Amifampridine Phosphate</description>
          </group>
          <group group_id="O2">
            <title>Placebo (for Amifampridine Phosphate)</title>
            <description>placebo by mouth 3 to 4 times per day for 4 days&#xD;
Placebo Oral Tablet</description>
          </group>
        </group_list>
        <measure>
          <title>Quantitative Myasthenia Gravis (QMG) Score</title>
          <description>The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome.</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="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.8" spread="4.20"/>
                    <measurement group_id="O2" value="8.5" spread="5.43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.9" spread="4.94"/>
                    <measurement group_id="O2" value="15.0" spread="5.90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.1" spread="3.07"/>
                    <measurement group_id="O2" value="6.5" spread="4.82"/>
                  </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>0.0004</p_value>
            <p_value_desc>LS means</p_value_desc>
            <method>Least square means</method>
            <method_desc>Fixed effects treatment and QMG at Baseline. Between-treatment difference in LS means (95% CI) -6.54 (-9.78, -3.29).</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Subject Global Impression (SGI) Score</title>
        <description>The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement.</description>
        <time_frame>change from baseline in SGI score at end of day 4</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Amifampridine Phosphate</title>
            <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days&#xD;
Amifampridine Phosphate</description>
          </group>
          <group group_id="O2">
            <title>Placebo (for Amifampridine Phosphate)</title>
            <description>placebo by mouth 3 to 4 times per day for 4 days&#xD;
Placebo Oral Tablet</description>
          </group>
        </group_list>
        <measure>
          <title>Subject Global Impression (SGI) Score</title>
          <description>The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement.</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="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.1" spread="0.86"/>
                    <measurement group_id="O2" value="5.8" spread="0.90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Day 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.3" spread="1.65"/>
                    <measurement group_id="O2" value="2.4" spread="1.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change from baseline to Day 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.8" spread="1.74"/>
                    <measurement group_id="O2" value="-3.5" spread="2.18"/>
                  </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>0.0003</p_value>
            <p_value_desc>CFB for SGI score was modeled as the response, with fixed effects terms for treatment and SGI at Baseline</p_value_desc>
            <method>Fixed effects linear model</method>
            <method_desc>This statistical test applies to the change from baseline SGI scores to Day 4 values row.</method_desc>
            <param_type>LS means</param_type>
            <param_value>2.95</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.53</ci_lower_limit>
            <ci_upper_limit>4.38</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline</title>
        <description>The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome.</description>
        <time_frame>change from baseline in CGI-I score at end of day 4</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Amifampridine Phosphate</title>
            <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days&#xD;
Amifampridine Phosphate</description>
          </group>
          <group group_id="O2">
            <title>Placebo (for Amifampridine Phosphate)</title>
            <description>placebo by mouth 3 to 4 times per day for 4 days&#xD;
Placebo Oral Tablet</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline</title>
          <description>The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome.</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="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.8" spread="0.8"/>
                    <measurement group_id="O2" value="5.5" spread="1.27"/>
                  </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>0.0020</p_value>
            <method>Wilcoxon Rank Sum Test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Triple Timed Up and Go Walk Test (3TUG)</title>
        <description>The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint.</description>
        <time_frame>change from baseline in 3TUG at end of day 4</time_frame>
        <population>The number and proportion of patients with a ≥20% increase in 3TUG average time</population>
        <group_list>
          <group group_id="O1">
            <title>Amifampridine Phosphate</title>
            <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days&#xD;
Amifampridine Phosphate</description>
          </group>
          <group group_id="O2">
            <title>Placebo (for Amifampridine Phosphate)</title>
            <description>placebo by mouth 3 to 4 times per day for 4 days&#xD;
Placebo Oral Tablet</description>
          </group>
        </group_list>
        <measure>
          <title>Triple Timed Up and Go Walk Test (3TUG)</title>
          <description>The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint.</description>
          <population>The number and proportion of patients with a ≥20% increase in 3TUG average time</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="13"/>
                <count group_id="O2" value="13"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="8"/>
                  </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>0.0112</p_value>
            <method>Fisher Exact</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>All AEs were observed for each patient from enrollment until study completion (up to 12 days per patient).</time_frame>
      <desc>Treatment-emergent AEs (TEAEs) were summarized using system organ class and PT by treatment and overall for all patients in the safety population.</desc>
      <group_list>
        <group group_id="E1">
          <title>Amifampridine Phosphate</title>
          <description>amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days&#xD;
Amifampridine Phosphate</description>
        </group>
        <group group_id="E2">
          <title>Placebo (for Amifampridine Phosphate)</title>
          <description>placebo by mouth 3 to 4 times per day for 4 days&#xD;
Placebo Oral Tablet</description>
        </group>
      </group_list>
      <serious_events>
        <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="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 13.1</default_vocab>
        <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="3" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>myocardial ischemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>motion sickness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>diplopia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>eyelid ptosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>hypoaesthesia, oral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>impaired gastric emptying</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>oral disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>asthenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>feeling hot</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>muscular weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>limb discomfort</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>muscle spasm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>musculoskeletal stiffness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>balance disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>eyelid ptosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>facial nerve disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>movement disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>somnolence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>speech disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>insomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>dysphonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
              <event>
                <sub_title>dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>dermatitis contact</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="13"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="13"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Gary Ingenito</name_or_title>
      <organization>Catalyst Pharmaceuticals, Inc.</organization>
      <phone>305-420-3200</phone>
      <email>gingenito@catalystpharma.com</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/NCT02970162
org study id: LMS-003
nct id: NCT02970162
lead sponsor: 
has dmc: No
This study evaluates the effect of withdrawing amifampridine phosphate treatment from
      patients with LEMS. One half of the patients will continue to receive amifampridine phosphate
      and the other half will receive placebo, during this double-blind study.
This was a randomized (1:1), double-blind, placebo-controlled, parallel-group, withdrawal
      study designed to evaluate the efficacy and safety of amifampridine phosphate in patients
      diagnosed with LEMS. The study was planned to include approximately 28 male and female
      patients.

      Prior to the study, patients were receiving unblinded treatment in the expanded access
      program (EAP-001). Patients had to be on a stable dose and frequency of amifampridine
      phosphate for at least 1 week prior to randomization into LMS-003. Screening and
      randomization (Day 0) may have been into a single visit.

      Patients who met eligibility criteria were randomized 1:1 to amifampridine phosphate (at the
      patient's optimal dose) or placebo on Day 0.

      Baseline assessments were obtained on Study Day 0, while the patient has been on open-label
      amifampridine phosphate and in relationship to the usual dosing schedule. Patients took
      blinded study medication on Day 1 through Day 3. On Day 4, a dose of blinded study medication
      was administered by the site study personnel. This was the same medication that the patient
      took on Day 1 through Day 3. The assessments listed below were performed following either the
      second, third, or fourth dose of medication taken on Day 4, and this should be the same dose
      after which Day 0 assessments were performed. For example, if the patient took their second
      dose of amifampridine in the clinic on Day 0 and had assessments started 40 minutes later,
      then on Day 4, that patient should be assessed after taking their second dose of
      investigational product (IP).

      Beginning with the next dose after all Day 0 baseline assessments were completed, the patient
      received IP through Day 4, with a clinic visit on the last day (Day 4) for assessments.

      The planned duration of participation for each patient was up to 12 days, including screening
      (up to 7 days), Day 0 assessments and randomization, and IP administration (Day 1 through Day
      4).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Quantitative Myasthenia Gravis (QMG) Score
time frame: change from baseline in QMG score at end of day 4
description: The QMG is a physician-rated test including 13 assessments such as facial strength, swallowing, grip strength, and duration of time that limbs can be maintained in outstretched positions. Each assessment is graded as 0 (none), 1 (mild), 2 (moderate), or 3 (severe), for a total range of 0-39. A higher total score indicates a worse outcome.
measure: Subject Global Impression (SGI) Score
time frame: change from baseline in SGI score at end of day 4
description: The SGI is a 7-point scale on which the patient rates their global impression of the effects of a study treatment (1=terrible to 7=delighted). The SGI was assessed by the patient or the patient's parent/guardian/caregiver if the patient was unable to complete the SGI. The SGI has demonstrated concordance with the physician's assessment of improvement.
measure: Change in Clinician's Global Impression of Improvement (CGI-I) at Day 4 Compared to Baseline
time frame: change from baseline in CGI-I score at end of day 4
description: The CGI-I captures the Investigator's global impression of the patient's improvement or worsening from baseline status. The 7-point scale is scored by the Investigator based on changes in symptoms, behavior, and functional abilities. Each symptom is rated as 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very much worse). The total score can range from 0 to 49. A higher score indicates a worse outcome.
measure: Triple Timed Up and Go Walk Test (3TUG)
time frame: change from baseline in 3TUG at end of day 4
description: The 3TUG is a functional mobility test that requires a patient to stand up from a straight-backed armchair, walk 3 meters, turn around, walk back, and sit down in the chair. A modification of this is where the individual performs the test 3 times without pause, and the measurement is the average time required to complete each of the 3 repetitions. Based upon literature reports that a significant change in gait for a similar walk-test is an increase in time of more than 20%, this has been incorporated into the endpoint.
arm group label: amifampridine phosphate
arm group type: Experimental
description: amifampridine phosphate 10 mg (amifampridine equivalent) by mouth, 30 to 80 mg total daily dose, 3 to 4 times per day for 4 days
arm group label: placebo (for amifampridine phosphate)
arm group type: Placebo Comparator
description: placebo by mouth 3 to 4 times per day for 4 days
intervention type: Drug
intervention name: Amifampridine Phosphate
arm group label: amifampridine phosphate
intervention type: Drug
intervention name: Placebo Oral Tablet
arm group label: placebo (for amifampridine phosphate)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Perry Shieh, MD, PhD
role: Principal Investigator
affiliation: University of California, Los Angeles
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lambert-Eaton Myasthenic Syndrome
mesh term: Syndrome
mesh term: Amifampridine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 