xml: <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/NCT06003166</url>
    </required_header>
    <id_info>
      <org_study_id>00002665</org_study_id>
      <secondary_id>R01NS111293</secondary_id>
      <nct_id>NCT06003166</nct_id>
    </id_info>
    <brief_title>4-AP Peripheral Nerve Crossover Trial</brief_title>
    <official_title>Pharmaco-Diagnostic Crossover Trial for Peripheral Nerve Continuity After Trauma</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Arizona</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
        <agency_class>NIH</agency_class>
      </collaborator>
    </sponsors>
    <source>University of Arizona</source>
    <oversight_info>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The purpose of this study is to evaluate the role of single dose 4-aminopyridine (4-AP) on&#xD;
        the diagnosis of severing vs non-severing nerve injury after peripheral nerve traction and/or&#xD;
        crush injury. The investigational treatment will be used to test the hypothesis that&#xD;
        4-aminopyridine can speed the determination of nerve continuity after peripheral nerve&#xD;
        traction and/or crush injuries allowing the identification of incomplete injuries earlier&#xD;
        than standard electrodiagnostic (EDX) and clinical assessment.&#xD;
  &#xD;
        Participants will be randomized to one of two groups to determine the order of treatment they&#xD;
        receive (drug and placebo vs placebo and drug). Participants will undergo baseline testing&#xD;
        for nerve assessment, receive either drug or placebo based on randomization and undergo&#xD;
        hourly sensory and motor evaluation, EDX testing and serum 4AP levels for three hours after&#xD;
        dosing. Participants will then repeat this with the crossover arm.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is a single-center study that will be conducted at the University of Arizona College of&#xD;
        Medicine, Tuscon. It is a double-blind, randomized, crossover trial design. Group A will&#xD;
        receive the study drug followed by the placebo on the main trial day, and Group B will&#xD;
        receive placebo first followed by the study drug. These groups will exist for both aims (both&#xD;
        types of included patients).&#xD;
  &#xD;
        Patients are randomized for the order (drug and placebo vs placebo and drug) of treatment&#xD;
        they receive. Eligible, consented patients will present for testing from one of three&#xD;
        locations (emergency department, inpatient ward, or home). Patients will undergo testing&#xD;
        under the direction of trial personnel. Testing will be initiated by patients undergoing a&#xD;
        high-resolution ultrasound for anatomic nerve assessment. Patients will then undergo a&#xD;
        thorough sensory and motor evaluation and establish an intravenous line for blood sampling. A&#xD;
        baseline blood sample and EDX study (prior to drug and placebo) and sensorimotor examination&#xD;
        will be performed. These tests comprise part of a standardized array of tests performed&#xD;
        hourly. This array of tests (serum 4AP level, EDX study, and sensorimotor examination) will&#xD;
        be repeated every hour after treatment for three hours (Figure 1) during which the drug will&#xD;
        have decreased to a level low enough to have no expected effect. The final hourly test is the&#xD;
        return to baseline test. It is likely going to occur at the third hourly posttest, but is&#xD;
        depicted separately for clarity. Only three tests after dosing will be necessary, based on&#xD;
        our expectations from known pharmacokinetic data. Patients will then repeat this with the&#xD;
        crossover arm (drug vs placebo).&#xD;
  &#xD;
        Finally, testing is concluded at the end of this period. Research subjects will be provided a&#xD;
        diary and asked to record symptoms as instructed. The subjects will be asked to maintain the&#xD;
        diary for 20 weeks and the diaries will be reviewed at each follow up visit and collected at&#xD;
        or after the final 20 week visit.&#xD;
  &#xD;
        Following the initial testing, subjects will be seen for a period of 20 weeks after injury to&#xD;
        monitor recovery and progress. Subjects will return for follow-up visits at 2, 6, 12, 18, and&#xD;
        20 weeks post injury. Subjects will receive a physical exam at all follow-up visit. EDX&#xD;
        testing will be completed at 6, 12, and 18 week visits only. Subjects will complete a&#xD;
        telephone interview at 9 and 15 weeks post injury at which time subjective motor and sensory&#xD;
        function will be assessed by asking 1) Can you move your (affected extremity)? Yes or No 2)&#xD;
        Can you feel your (affected extremity)? Yes or No. Review of the subject diary will also be&#xD;
        completed. The 9, 15, and 20 week visits are not part of standard of care and are being done&#xD;
        for research purposes only. Each visit or phone interview will last approximately 30 minutes.&#xD;
        Subjects will be instructed to bring the research diary to their follow-up appointments and&#xD;
        will be reviewed and evaluated by study personnel. At the final 20 week visit the diary will&#xD;
        be collected. Additional follow up might be considered beyond standard of care for diary&#xD;
        completion if required.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 2023</start_date>
    <completion_date type="Anticipated">July 2028</completion_date>
    <primary_completion_date type="Anticipated">December 2027</primary_completion_date>
    <phase>Phase 3</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>Diagnostic</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Subjective return of sensation</measure>
      <time_frame>During dosing of drug intervention and 2, 6, 9, 12, 15, 20 weeks post injury</time_frame>
      <description>Return of lost sensation after nerve injury attributable to circulating 4AP. Subjective return of sensation in the injured limb or portion of the limb.&#xD;
  Patients for this trial are not able to sense in portions of their limbs. The measure will be sensation, measured on the binary scale of yes or no (able to feel the extremity versus unable to feel). This is assessed through clinical examination of the injured limb.</description>
    </primary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">68</enrollment>
    <condition>Peripheral Nerve Injury</condition>
    <condition>Crush Injury</condition>
    <arm_group>
      <arm_group_label>4AP then placebo (Group A)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Subjects randomized to this group will receive the study drug (4AP) followed by the placebo.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo then 4AP (Group B)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Subjects randomized to this group will receive the placebo first followed by the study drug (4AP)</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>4-Aminopyridine</intervention_name>
      <description>Study drug will be a one time dose of 5mg immediate release 4 aminopyridine</description>
      <arm_group_label>4AP then placebo (Group A)</arm_group_label>
      <arm_group_label>Placebo then 4AP (Group B)</arm_group_label>
      <other_name>4AP</other_name>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Matched placebo</description>
      <arm_group_label>4AP then placebo (Group A)</arm_group_label>
      <arm_group_label>Placebo then 4AP (Group B)</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients with trauma involving two or less limbs where the continuity of a given&#xD;
               peripheral nerve or nerves is unclear on presenting physical examination.&#xD;
  &#xD;
            -  Closed soft tissue envelope obscuring direct observation of the continuity of the&#xD;
               affected nerve.&#xD;
  &#xD;
            -  Cognitive ability to report sensory and motor deficit during examination.&#xD;
  &#xD;
            -  Able to complete single day dosing within seven days (168 hours) of nerve injury&#xD;
               diagnosis.&#xD;
  &#xD;
            -  Eligible for standard of care plan of monitoring vs surgical exploration of the nerve.&#xD;
  &#xD;
            -  Adults subject aged 18-90&#xD;
  &#xD;
            -  Known limb trauma which resulted in nerve injury (aim 1) or post-operative/post&#xD;
               intervention nerve injury (aim 2).&#xD;
  &#xD;
            -  Ability to give written informed consent.&#xD;
  &#xD;
            -  Capable of safely undergoing electrodiagnostic testing (EDX).&#xD;
  &#xD;
            -  Availability for all testing days and main trial day.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Not able to complete dosing within seven days (168 hours) of nerve injury diagnosis&#xD;
  &#xD;
            -  Distracting injury which prevents adequate examination.&#xD;
  &#xD;
            -  Plan for surgical exploration of the nerve during the ensuing 48 hours.&#xD;
  &#xD;
            -  Plan for surgical exploration of the nerve as part of another surgical procedure&#xD;
               within 48 hours of evaluation.&#xD;
  &#xD;
            -  Intoxication during examination or evidence of cognitive deficit that emerges during&#xD;
               examination.&#xD;
  &#xD;
            -  History of multiple sclerosis, stroke or any other diagnosed neurological disorder&#xD;
  &#xD;
            -  History of hypersensitivity to AMPYRA® or 4-aminopyridine&#xD;
  &#xD;
            -  Current use of aminopyridine medications, including other compounded 4-AP&#xD;
  &#xD;
            -  Renal impairment based on calculated GFR (GFR&lt;80 mL/min). This laboratory value is&#xD;
               measured in all inpatient trauma patients as part of the standard of care.&#xD;
  &#xD;
            -  History of difficult compliance with timely follow up or plan to seek care at another&#xD;
               institution closer to home.&#xD;
  &#xD;
            -  Patients outside the age range or unable to consent.&#xD;
  &#xD;
            -  Patients with a known history of a seizure disorder (4AP overdose can, in selected&#xD;
               cases, result in limited seizure activity).&#xD;
  &#xD;
            -  Patients with a concomitant traumatic brain injury.&#xD;
  &#xD;
            -  Patients unable to communicate return or loss of sensation.&#xD;
  &#xD;
            -  Patients unable to exhibit motor control on the affected limb at baseline.&#xD;
  &#xD;
            -  Patients unwilling to complete the study requirements.&#xD;
  &#xD;
            -  Patients with injuries too extensive to isolate a single nerve(s) for testing.&#xD;
  &#xD;
            -  Patients currently taking organic cat-ion transporter 2 (OCT2) inhibitors, e.g.&#xD;
               Cimetidine.&#xD;
  &#xD;
            -  Pregnancy, breastfeeding or incarcerated individuals.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>90 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>John Elfar, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University of Arizona</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Andrea Horne</last_name>
      <phone>520-626-6456</phone>
      <email>ahh@arizona.edu</email>
    </overall_contact>
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    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 9, 2023</study_first_submitted>
    <study_first_submitted_qc>August 18, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 21, 2023</study_first_posted>
    <last_update_submitted>August 18, 2023</last_update_submitted>
    <last_update_submitted_qc>August 18, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 21, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of Arizona</investigator_affiliation>
      <investigator_full_name>John Elfar</investigator_full_name>
      <investigator_title>Tenured Professor, Chairman, Department of Orthopaedic Surgery</investigator_title>
    </responsible_party>
    <keyword>4 aminopyridine</keyword>
    <keyword>peripheral nerve</keyword>
    <keyword>crush injury</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Peripheral Nerve Injuries</mesh_term>
      <mesh_term>Wounds and Injuries</mesh_term>
      <mesh_term>Crush Injuries</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>4-Aminopyridine</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06003166
  org study id: 00002665
  secondary id: R01NS111293
  nct id: NCT06003166
  lead sponsor: 
  collaborator: 
  is fda regulated drug: Yes
  is fda regulated device: No
  The purpose of this study is to evaluate the role of single dose 4-aminopyridine (4-AP) on
        the diagnosis of severing vs non-severing nerve injury after peripheral nerve traction and/or
        crush injury. The investigational treatment will be used to test the hypothesis that
        4-aminopyridine can speed the determination of nerve continuity after peripheral nerve
        traction and/or crush injuries allowing the identification of incomplete injuries earlier
        than standard electrodiagnostic (EDX) and clinical assessment.
  
        Participants will be randomized to one of two groups to determine the order of treatment they
        receive (drug and placebo vs placebo and drug). Participants will undergo baseline testing
        for nerve assessment, receive either drug or placebo based on randomization and undergo
        hourly sensory and motor evaluation, EDX testing and serum 4AP levels for three hours after
        dosing. Participants will then repeat this with the crossover arm.
  This is a single-center study that will be conducted at the University of Arizona College of
        Medicine, Tuscon. It is a double-blind, randomized, crossover trial design. Group A will
        receive the study drug followed by the placebo on the main trial day, and Group B will
        receive placebo first followed by the study drug. These groups will exist for both aims (both
        types of included patients).
  
        Patients are randomized for the order (drug and placebo vs placebo and drug) of treatment
        they receive. Eligible, consented patients will present for testing from one of three
        locations (emergency department, inpatient ward, or home). Patients will undergo testing
        under the direction of trial personnel. Testing will be initiated by patients undergoing a
        high-resolution ultrasound for anatomic nerve assessment. Patients will then undergo a
        thorough sensory and motor evaluation and establish an intravenous line for blood sampling. A
        baseline blood sample and EDX study (prior to drug and placebo) and sensorimotor examination
        will be performed. These tests comprise part of a standardized array of tests performed
        hourly. This array of tests (serum 4AP level, EDX study, and sensorimotor examination) will
        be repeated every hour after treatment for three hours (Figure 1) during which the drug will
        have decreased to a level low enough to have no expected effect. The final hourly test is the
        return to baseline test. It is likely going to occur at the third hourly posttest, but is
        depicted separately for clarity. Only three tests after dosing will be necessary, based on
        our expectations from known pharmacokinetic data. Patients will then repeat this with the
        crossover arm (drug vs placebo).
  
        Finally, testing is concluded at the end of this period. Research subjects will be provided a
        diary and asked to record symptoms as instructed. The subjects will be asked to maintain the
        diary for 20 weeks and the diaries will be reviewed at each follow up visit and collected at
        or after the final 20 week visit.
  
        Following the initial testing, subjects will be seen for a period of 20 weeks after injury to
        monitor recovery and progress. Subjects will return for follow-up visits at 2, 6, 12, 18, and
        20 weeks post injury. Subjects will receive a physical exam at all follow-up visit. EDX
        testing will be completed at 6, 12, and 18 week visits only. Subjects will complete a
        telephone interview at 9 and 15 weeks post injury at which time subjective motor and sensory
        function will be assessed by asking 1) Can you move your (affected extremity)? Yes or No 2)
        Can you feel your (affected extremity)? Yes or No. Review of the subject diary will also be
        completed. The 9, 15, and 20 week visits are not part of standard of care and are being done
        for research purposes only. Each visit or phone interview will last approximately 30 minutes.
        Subjects will be instructed to bring the research diary to their follow-up appointments and
        will be reviewed and evaluated by study personnel. At the final 20 week visit the diary will
        be collected. Additional follow up might be considered beyond standard of care for diary
        completion if required.
  allocation: Randomized
  intervention model: Crossover Assignment
  primary purpose: Diagnostic
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: Subjective return of sensation
  time frame: During dosing of drug intervention and 2, 6, 9, 12, 15, 20 weeks post injury
  description: Return of lost sensation after nerve injury attributable to circulating 4AP. Subjective return of sensation in the injured limb or portion of the limb.
  Patients for this trial are not able to sense in portions of their limbs. The measure will be sensation, measured on the binary scale of yes or no (able to feel the extremity versus unable to feel). This is assessed through clinical examination of the injured limb.
  arm group label: 4AP then placebo (Group A)
  arm group type: Experimental
  description: Subjects randomized to this group will receive the study drug (4AP) followed by the placebo.
  arm group label: Placebo then 4AP (Group B)
  arm group type: Experimental
  description: Subjects randomized to this group will receive the placebo first followed by the study drug (4AP)
  intervention type: Drug
  intervention name: 4-Aminopyridine
  description: Study drug will be a one time dose of 5mg immediate release 4 aminopyridine
  arm group label: 4AP then placebo (Group A)
  arm group label: Placebo then 4AP (Group B)
  other name: 4AP
  intervention type: Other
  intervention name: Placebo
  description: Matched placebo
  arm group label: 4AP then placebo (Group A)
  arm group label: Placebo then 4AP (Group B)
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 90 Years
  healthy volunteers: No
  last name: John Elfar, MD
  role: Principal Investigator
  affiliation: University of Arizona
  last name: Andrea Horne
  phone: 520-626-6456
  email: ahh@arizona.edu
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  responsible party type: Principal Investigator
  investigator affiliation: University of Arizona
  investigator full name: John Elfar
  investigator title: Tenured Professor, Chairman, Department of Orthopaedic Surgery
  mesh term: Peripheral Nerve Injuries
  mesh term: Wounds and Injuries
  mesh term: Crush Injuries
  mesh term: 4-Aminopyridine
  sharing ipd: No