<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/NCT03781479</url>
  </required_header>
  <id_info>
    <org_study_id>SMA-001</org_study_id>
    <nct_id>NCT03781479</nct_id>
  </id_info>
  <brief_title>Controlled Trial to Evaluate Amifampridine Phosphate in Spinal Muscular Atrophy Type 3 Patients</brief_title>
  <official_title>A Randomized, Placebo-Controlled, Crossover Study to Evaluate the Safety and Efficacy of Amifampridine Phosphate in Ambulatory Patients With Spinal Muscular Atrophy (SMA) Type 3</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>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A two-period, two-treatment, crossover study to evaluate the safety, tolerability and&#xD;
      efficacy of amifampridine phosphate in ambulatory patients diagnosed with spinal muscular&#xD;
      atrophy (SMA) Type 3.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This randomized (1:1), double-blind, placebo-controlled, 2-period, 2-treatment, crossover,&#xD;
      outpatient study is designed to evaluate the safety, tolerability and efficacy of&#xD;
      amifampridine phosphate in ambulatory patients diagnosed with SMA Type 3. The study is&#xD;
      planned to include approximately 12 male and female SMA Type 3 patients. The planned duration&#xD;
      of participation for each patient is approximately 2 months, based upon length of dose&#xD;
      titration and excluding the screening period, which can last up to 14 days. Patients should&#xD;
      only be taking the assigned investigational product (amifampridine phosphate 10 mg tablets or&#xD;
      matching placebo tablets), no new therapies are permitted during the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 21, 2019</start_date>
  <completion_date type="Actual">July 23, 2020</completion_date>
  <primary_completion_date type="Actual">July 23, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis</measure>
    <time_frame>Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28</time_frame>
    <description>Hammersmith Functional Motor Scale Expanded (HFMSE) assesses motor function by functional item in order of progressive difficulty, with higher values showing higher function abilities. Each item is scored on a scale of 0-2 with 2 representing item achieved unaided and 0 representing inability to achieve item. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28. The total HFMSE score was calculated as the sum of each item score, with a maximum score of 66 (all items achieved unaided) and minimum score of 0 (all items failed). Change from baseline (CFB) will be assessed from Day 0 to Day 28. A mixed effects liner model was fit with the HFMSE change from baseline (CFB) scores at Day 28 as a response and treatment, sequence, and treatment by sequence as fixed effect terms and patient as a random effect.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Muscular Atrophy, Spinal</condition>
  <arm_group>
    <arm_group_label>Amifampridine Phosphate - Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo - Amifampridine Phosphate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amifampridine Phosphate</intervention_name>
    <description>Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.</description>
    <arm_group_label>Amifampridine Phosphate - Placebo</arm_group_label>
    <arm_group_label>Placebo - Amifampridine Phosphate</arm_group_label>
    <other_name>3,4 diaminopyridine phosphate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Placebo Oral Tablet</description>
    <arm_group_label>Amifampridine Phosphate - Placebo</arm_group_label>
    <arm_group_label>Placebo - Amifampridine Phosphate</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Willing and able to provide written informed consent after the nature of the study has&#xD;
             been explained and before the start of any research-related procedures.&#xD;
&#xD;
          2. Male or female between the ages of 6 and 50 years.&#xD;
&#xD;
          3. Genetically confirmed diagnosis of SMA Type 3.&#xD;
&#xD;
          4. Able to walk independently for at least 30 meters.&#xD;
&#xD;
          5. Not taking Nusinersen for the treatment of SMA (Nusinersen should be stopped at least&#xD;
             6 months before screening). Salbutamol is permitted only if the dose has been stable&#xD;
             during the 6 months before screening.&#xD;
&#xD;
          6. Able to swallow oral medication.&#xD;
&#xD;
          7. Female patients of childbearing potential must have a negative pregnancy test (serum&#xD;
             human chorionic gonadotropin [HCG] at Screening); and must practice an effective,&#xD;
             reliable contraceptive regimen during the study and for up to 30 days following&#xD;
             discontinuation of treatment.&#xD;
&#xD;
          8. Ability to participate in the study based on overall health of the patient and disease&#xD;
             prognosis, as applicable, in the opinion of the Investigator; and able to comply with&#xD;
             all requirements of the protocol, including completion of study questionnaires.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Epilepsy and currently on medication for epilepsy.&#xD;
&#xD;
          2. Concomitant use of medicinal products with a known potential to cause QTc&#xD;
             prolongation.&#xD;
&#xD;
          3. Patients with long QT syndromes.&#xD;
&#xD;
          4. An electrocardiogram (ECG) within 6 months before starting treatment that shows&#xD;
             clinically significant abnormalities, in the opinion of the Investigator.&#xD;
&#xD;
          5. Breastfeeding or pregnant at Screening or planning to become pregnant at any time&#xD;
             during the study.&#xD;
&#xD;
          6. Treatment with an investigational drug (other than amifampridine), device, or&#xD;
             biological agent within 6 months prior to Screening or while participating in this&#xD;
             study.&#xD;
&#xD;
          7. Surgery for scoliosis or joint contractures within the previous 6 months.&#xD;
&#xD;
          8. Any medical condition that, in the opinion of the Investigator, might interfere with&#xD;
             the patient's participation in the study, poses an added risk for the patient, or&#xD;
             confound the assessment of the patient.&#xD;
&#xD;
          9. History of drug allergy to any pyridine-containing substances or any amifampridine&#xD;
             excipient(s).&#xD;
&#xD;
         10. Less than a 3-point improvement in HFSME from start of the Open label Run -in period&#xD;
             to end of Run-in (Day 0).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lorenzo Maggi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Carlo Besta Institute, Milan, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Neurological Institute Carlo Besta</name>
      <address>
        <city>Milano</city>
        <state>Lombardy</state>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <results_first_submitted>April 6, 2021</results_first_submitted>
  <results_first_submitted_qc>May 28, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">June 1, 2021</results_first_posted>
  <last_update_submitted>May 28, 2021</last_update_submitted>
  <last_update_submitted_qc>May 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Type 3</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscular Atrophy</mesh_term>
    <mesh_term>Muscular Atrophy, Spinal</mesh_term>
    <mesh_term>Atrophy</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>September 27, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03781479/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>May 11, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03781479/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>The study was conducted from 14 January 2019 - 17 September 2020 at two sites in Europe.</recruitment_details>
      <pre_assignment_details>A screening visit was conducted to ensure that each patient met inclusion/exclusion criteria for the study. Those patients successfully completing screening had procedures/assessments conducted at the start of the Run-in period (Day 1, before starting study medication) and during Run-in, until stable dose and frequency of amifampridine was established for at least 7 days, and at least a 3-point improvement in HFMSE score was achieved from start of Run-in to be eligible for randomization (Day 0).</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Amifampridine Phosphate - Placebo</title>
          <description>Each patient participated in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate was achieved for 7 days. After this phase, half of the subjects were randomized to receive amifampridine in Period 1 and then crossed over to receive placebo in Period 2. Each randomized treatment period was 14 days in duration.&#xD;
Dosing was up to 80 mg per day and frequency was between 3-4 times per day.&#xD;
Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.&#xD;
Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.</description>
        </group>
        <group group_id="P2">
          <title>Placebo - Amifampridine Phosphate</title>
          <description>Each patient participated in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate was achieved for 7 days. After this phase, half of the subjects were randomized to receive placebo in Period 1 and then crossed over to receive amifampridine in Period 2. Each randomized treatment period was 14 days in duration.&#xD;
Dosing was up to 80 mg per day and frequency was between 3-4 times per day.&#xD;
Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.&#xD;
Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.</description>
        </group>
        <group group_id="P3">
          <title>Not Randomized</title>
          <description>Patients receiving amifampridine during the open-label run-in period but were not randomized to receive treatment.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The analysis of baseline characteristics included all patients in the Safety population, who are those patients who enrolled and received at least one dose of amifampridine. Patients who began the Run-in period regardless of whether they were randomized to double blind medication on Day 0 belong to the Safety population.</population>
      <group_list>
        <group group_id="B1">
          <title>Amifampridine Phosphate - Placebo</title>
          <description>Each patient participated in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate was achieved for 7 days. After this phase, half of the subjects were randomized to receive amifampridine in Period 1 and then crossed over to receive placebo in Period 2. Each randomized treatment period was 14 days in duration.&#xD;
Dosing was up to 80 mg per day and frequency was between 3-4 times per day. Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.&#xD;
Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.</description>
        </group>
        <group group_id="B2">
          <title>Placebo - Amifampridine Phosphate</title>
          <description>Each patient participated in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate was achieved for 7 days. After this phase, half of the subjects were randomized to receive placebo in Period 1 and then crossed over to receive amifampridine in Period 2. Each randomized treatment period was 14 days in duration.&#xD;
Dosing was up to 80 mg per day and frequency was between 3-4 times per day. Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.&#xD;
Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.</description>
        </group>
        <group group_id="B3">
          <title>Not Randomized</title>
          <description>Patients receiving amifampridine during the open-label run-in period but were not randomized to receive treatment.</description>
        </group>
        <group group_id="B4">
          <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="6"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="1"/>
            <count group_id="B4" value="13"/>
          </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="37.2" spread="8.5"/>
                    <measurement group_id="B2" value="30.2" spread="13.5"/>
                    <measurement group_id="B3" value="45.0"/>
                    <measurement group_id="B4" value="34.5" spread="11.3"/>
                  </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="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="8"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                  </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 group_id="B4" 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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="12"/>
                  </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 group_id="B4" 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 group_id="B4" 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="64.7" spread="9.3"/>
                    <measurement group_id="B2" value="67.8" spread="11.8"/>
                    <measurement group_id="B3" value="76.9"/>
                    <measurement group_id="B4" value="67.0" spread="10.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>cm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="169.3" spread="9.0"/>
                    <measurement group_id="B2" value="174.8" spread="6.1"/>
                    <measurement group_id="B3" value="170.0"/>
                    <measurement group_id="B4" value="171.9" spread="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BMI</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22.5" spread="1.4"/>
                    <measurement group_id="B2" value="22.3" spread="4.3"/>
                    <measurement group_id="B3" value="26.6"/>
                    <measurement group_id="B4" value="22.7" spread="3.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis</title>
        <description>Hammersmith Functional Motor Scale Expanded (HFMSE) assesses motor function by functional item in order of progressive difficulty, with higher values showing higher function abilities. Each item is scored on a scale of 0-2 with 2 representing item achieved unaided and 0 representing inability to achieve item. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28. The total HFMSE score was calculated as the sum of each item score, with a maximum score of 66 (all items achieved unaided) and minimum score of 0 (all items failed). Change from baseline (CFB) will be assessed from Day 0 to Day 28. A mixed effects liner model was fit with the HFMSE change from baseline (CFB) scores at Day 28 as a response and treatment, sequence, and treatment by sequence as fixed effect terms and patient as a random effect.</description>
        <time_frame>Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28</time_frame>
        <population>The analysis of primary outcome data was based on the Full Analysis Set population, which included all randomized patients who received at least one dose of study medication (amifampridine or placebo) and had at least one post-treatment efficacy assessment. Patients are compared for efficacy according to the treatment to which they were randomized, regardless of the treatment actually received.</population>
        <group_list>
          <group group_id="O1">
            <title>Amifampridine Phosphate</title>
            <description>Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects were randomized to receive amifampridine in Period 1 and then crossed over to receive placebo in Period 2 and the other were randomized to receive placebo in Period 1 and then crossed over to receive amifampridine in Period 2.&#xD;
Each randomized treatment period is 14 days in duration.&#xD;
Dosing was up to 80 mg per day and frequency was between 3-4 times per day.&#xD;
Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.&#xD;
Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.&#xD;
The Amifampridine study arm includes all patients in the FAS population who received Amifampridine during the treatment period, regardless of which Period the treatment was administered.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each patient will participate in an open-label unblinded drug escalation/treatment run-in phase for up to 4 weeks until stable dose and frequency of amifampridine phosphate is achieved for 7 days. After this phase, half of the subjects were randomized to receive amifampridine in Period 1 and then crossed over to receive placebo in Period 2 and the other were randomized to receive placebo in Period 1 and then crossed over to receive amifampridine in Period 2.&#xD;
Each randomized treatment period is 14 days in duration.&#xD;
Dosing was up to 80 mg per day and frequency was between 3-4 times per day.&#xD;
Amifampridine Phosphate: Amifampridine phosphate tablets 10 mg were provided in round, white-scored tablets, and contained amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.&#xD;
Placebo: A placebo equivalent was provided as tablets indistinguishable from the amifampridine phosphate tablets. The placebo was administered consistent with the dose and dose regimen of amifampridine phosphate.&#xD;
The Placebo study arm includes all patients in the FAS population who received Placebo during the treatment period, regardless of which Period the treatment was administered.</description>
          </group>
        </group_list>
        <measure>
          <title>Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis</title>
          <description>Hammersmith Functional Motor Scale Expanded (HFMSE) assesses motor function by functional item in order of progressive difficulty, with higher values showing higher function abilities. Each item is scored on a scale of 0-2 with 2 representing item achieved unaided and 0 representing inability to achieve item. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28. The total HFMSE score was calculated as the sum of each item score, with a maximum score of 66 (all items achieved unaided) and minimum score of 0 (all items failed). Change from baseline (CFB) will be assessed from Day 0 to Day 28. A mixed effects liner model was fit with the HFMSE change from baseline (CFB) scores at Day 28 as a response and treatment, sequence, and treatment by sequence as fixed effect terms and patient as a random effect.</description>
          <population>The analysis of primary outcome data was based on the Full Analysis Set population, which included all randomized patients who received at least one dose of study medication (amifampridine or placebo) and had at least one post-treatment efficacy assessment. Patients are compared for efficacy according to the treatment to which they were randomized, regardless of the treatment actually received.</population>
          <units>Overall Score</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
                <count group_id="O2" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.208" spread="0.326"/>
                    <measurement group_id="O2" value="-0.583" spread="0.326"/>
                  </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>
            <groups_desc>A mixed effects liner model was fit with the HFMSE change from baseline (CFB) scores at Day 28 as a response and treatment, sequence, and treatment by sequence as fixed effect terms and patient as a random effect.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0083</p_value>
            <method>Mixed Models Analysis</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.792</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.22</ci_lower_limit>
            <ci_upper_limit>1.37</ci_upper_limit>
            <estimate_desc>Results show the LSMeans for the estimated difference between treatments along with a 95% confidence interval for this difference.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Serious adverse events (SAEs) were recorded for each patient from the time informed consent was obtained at Screening and continued through four weeks after the last visit or at the early discontinuation visit, for a total of approximately 14 weeks. Non-serious AEs were recorded for each patient after the first administration of study drug through the termination visit or at the early termination visit, for a total of approximately 10 weeks.</time_frame>
      <desc>Serious classification based on the FDA regulatory definition of a serious AE.</desc>
      <group_list>
        <group group_id="E1">
          <title>Amifampridine</title>
          <description>Treatment administered to the patient at the time of onset of the AE.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Treatment administered to the patient at the time of onset of the AE.</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="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (19.0)</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="5" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Hypoaesthesia oral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Paraesthesia oral</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </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="12"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Transaminases increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </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="12"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Intranasal Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Gary Ingenito</name_or_title>
      <organization>Catalyst Pharmaceuticals, Inc.</organization>
      <phone>3054203200</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/NCT03781479
org study id: SMA-001
nct id: NCT03781479
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
A two-period, two-treatment, crossover study to evaluate the safety, tolerability and
      efficacy of amifampridine phosphate in ambulatory patients diagnosed with spinal muscular
      atrophy (SMA) Type 3.
This randomized (1:1), double-blind, placebo-controlled, 2-period, 2-treatment, crossover,
      outpatient study is designed to evaluate the safety, tolerability and efficacy of
      amifampridine phosphate in ambulatory patients diagnosed with SMA Type 3. The study is
      planned to include approximately 12 male and female SMA Type 3 patients. The planned duration
      of participation for each patient is approximately 2 months, based upon length of dose
      titration and excluding the screening period, which can last up to 14 days. Patients should
      only be taking the assigned investigational product (amifampridine phosphate 10 mg tablets or
      matching placebo tablets), no new therapies are permitted during the study.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Hammersmith Functional Motor Scale Expanded (HFMSE) Summary Statistics and Mixed Model Analysis
time frame: Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28
description: Hammersmith Functional Motor Scale Expanded (HFMSE) assesses motor function by functional item in order of progressive difficulty, with higher values showing higher function abilities. Each item is scored on a scale of 0-2 with 2 representing item achieved unaided and 0 representing inability to achieve item. Each item was assessed by the patient at Screening, the first (Day 1) and last day (Day 0) of the Run-in period, during Period 1 at Day 7 and Day 14, and during Period 2 at Day 21 and Day 28. The total HFMSE score was calculated as the sum of each item score, with a maximum score of 66 (all items achieved unaided) and minimum score of 0 (all items failed). Change from baseline (CFB) will be assessed from Day 0 to Day 28. A mixed effects liner model was fit with the HFMSE change from baseline (CFB) scores at Day 28 as a response and treatment, sequence, and treatment by sequence as fixed effect terms and patient as a random effect.
arm group label: Amifampridine Phosphate - Placebo
arm group type: Experimental
description: Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks
arm group label: Placebo - Amifampridine Phosphate
arm group type: Experimental
description: Oral tablets, 30 to 80 mg per day in divided doses 3 to 4 times a day for 4 weeks
intervention type: Drug
intervention name: Amifampridine Phosphate
description: Amifampridine phosphate tablets 10 mg will be provided in round, white-scored tablets, and containing amifampridine phosphate formulated to be the equivalent of 10 mg amifampridine base per tablet.
arm group label: Amifampridine Phosphate - Placebo
arm group label: Placebo - Amifampridine Phosphate
other name: 3,4 diaminopyridine phosphate
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Placebo Oral Tablet
arm group label: Amifampridine Phosphate - Placebo
arm group label: Placebo - Amifampridine Phosphate
criteria: 
gender: All
minimum age: 6 Years
maximum age: 50 Years
healthy volunteers: No
last name: Lorenzo Maggi, MD
role: Principal Investigator
affiliation: Carlo Besta Institute, Milan, Italy
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Muscular Atrophy
mesh term: Muscular Atrophy, Spinal
mesh term: Atrophy
mesh term: Amifampridine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 