<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/NCT03780829</url>
  </required_header>
  <id_info>
    <org_study_id>B2848-R</org_study_id>
    <nct_id>NCT03780829</nct_id>
  </id_info>
  <brief_title>AIH for Spinal Cord Repair</brief_title>
  <official_title>Repetitive Acute Intermittent Hypoxia for Spinal Cord Repair</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>VA Office of Research and Development</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>VA Office of Research and Development</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Contusive cervical spinal cord injury (cSCI) impairs upper limb function (reach-and-grasp)&#xD;
      which limits daily-life activities and thus decreases the quality of life. Promoting&#xD;
      neuroplasticity may support upper limb recovery after SCI. Repetitive exposure to acute&#xD;
      intermittent hypoxia (rAIH) combined with motor training promotes recovery of motor function&#xD;
      after SCI; however, the overall effects of rAIH/training are limited. The investigators will&#xD;
      use an adult rat model of long-term contusive cSCI to study novel approaches to enhance the&#xD;
      effect of rAIH/training on forelimb function and study the neuronal substrate underlying the&#xD;
      effects. The findings will be used to direct the development of more effective rAIH/training&#xD;
      approaches for people with contusive, functionally incomplete, cSCI. Because deficits in&#xD;
      upper limb function are a major problem after stroke, amyotrophic lateral sclerosis, multiple&#xD;
      sclerosis, and other motor disorders, this work may also be relevant for patients with other&#xD;
      types of central nervous system (CNS) lesions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The overall goal is to develop effective, clinically applicable, approaches to restore upper&#xD;
      limb function (reach-and-grasp) after chronic contusive cervical spinal cord injury (cSCI).&#xD;
      Impairments in upper limb function significantly reduce the quality of life for people with&#xD;
      cSCI. Reach-and-grasp actions in animals and humans are largely controlled by the&#xD;
      corticospinal tract (CST). The investigators argue that promoting plasticity within the CST&#xD;
      may support the recovery of upper limb function after cSCI. Repetitive exposure to acute&#xD;
      intermittent hypoxia (rAIH) combined with motor training is a safe, minimally invasive,&#xD;
      treatment that elicits neuroplasticity resulting in improved recovery after cSCI, but its&#xD;
      overall effects remain limited. The main goals are to: 1) enhance rAIH/training-induced&#xD;
      aftereffects on forelimb function and increase the understanding of the neuronal substrates&#xD;
      in an adult rat model of chronic contusive cSCI, and 2) use this knowledge to guide the&#xD;
      development of more effective rAIH/training approaches to improve upper limb function in&#xD;
      humans with chronic contusive cSCI.&#xD;
&#xD;
      In Specific Aim 1, using an adult rat model of chronic contusive cSCI, the investigators will&#xD;
      investigate the effects of rAIH frequency and dose on rAIH/training-mediated functional&#xD;
      recovery of the impaired forelimb. Also, the investigators will combine rAIH/training with&#xD;
      N-methyl-D-aspartate receptor (NMDA)-mediated synaptic plasticity through D-cycloserine&#xD;
      treatment and study the effects on recovery of forelimb function. Immunocytochemistry with&#xD;
      imaging techniques will be used to assess structural neuronal plasticity in the CST after&#xD;
      rAIH/training. In Specific Aim 2, in people with chronic incomplete cSCI, guided by the&#xD;
      findings in Specific Aim 1, the investigators will study the effects of rAIH frequency and&#xD;
      concurrent D-cycloserine treatment on rAIH/training-mediated upper limb function recovery.&#xD;
      The investigators will comprehensively analyze the effects of rAIH on the strength of&#xD;
      electrophysiological and functional aftereffects in the upper limb.&#xD;
&#xD;
      The proposed research will provide new knowledge on rAIH/training-mediated functional and&#xD;
      anatomical aftereffects (Specific Aim 1), which will be used to develop effective&#xD;
      rAIH/training protocols for people with contusive, functionally incomplete, cSCI (Specific&#xD;
      Aim 2). The data from the investigators' experiments may lead to clinically applicable&#xD;
      approaches that improve arm and hand function recovery after chronic contusive cSCI, which&#xD;
      would positively impact the quality of life of Veterans with cSCI. The relevance of this&#xD;
      proposal is emphasized by the limited efficacy of current strategies to improve upper limb&#xD;
      function after cSCI.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 25, 2020</start_date>
  <completion_date type="Anticipated">January 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2024</primary_completion_date>
  <phase>Early Phase 1</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>
    <intervention_model_description>repetitive intermittent hypoxia treatment combined with exercise and/or NMDA agonist</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>participants and some research personnel will be blinded</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in grip strength</measure>
    <time_frame>baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week</time_frame>
    <description>Grip strength will be measured using a hand-held dynamometer, with an average force (measured in dynes) taken over the course of three trials. A rest break is provided between trials. Strength testing will be completed bilaterally.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in pinch strength</measure>
    <time_frame>baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week</time_frame>
    <description>Pinch strength will be assessed using a digital pinch gauge (unit of Force= Newton). The minimum value of zero will be assigned when a participant cannot actively squeeze the pinch meter between the thumb and index finger. The mean value of total of 3 trials will be assessed, with a rest break provided between trials.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in motor evoked potential size</measure>
    <time_frame>30 minutes before and 30 minutes after intervention</time_frame>
    <description>Resting and active motor thresholds (RMT and AMT) will be tested in each of the muscles using a stimulator.</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">90</enrollment>
  <condition>SCI</condition>
  <arm_group>
    <arm_group_label>hypoxia plus training</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>combined hypoxia treatment with exercise training</description>
  </arm_group>
  <arm_group>
    <arm_group_label>sham hypoxia plus training</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>combined sham hypoxia treatment with exercise training</description>
  </arm_group>
  <arm_group>
    <arm_group_label>hypoxia plus training plus NMDA agonist</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>combined hypoxia treatment with exercise training and with NMDA agonist treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>hypoxia plus training plus sham NMDA agonist</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>combined hypoxia treatment with exercise training and with sham NMDA agonist treatment</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>hypoxia</intervention_name>
    <description>intermittent cycles of normoxia-hypoxia</description>
    <arm_group_label>hypoxia plus training</arm_group_label>
    <arm_group_label>hypoxia plus training plus NMDA agonist</arm_group_label>
    <arm_group_label>hypoxia plus training plus sham NMDA agonist</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>sham hypoxia</intervention_name>
    <description>intermittent cycles of sham hypoxia</description>
    <arm_group_label>sham hypoxia plus training</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>D-cycloserine</intervention_name>
    <description>NMDA agonist treatment</description>
    <arm_group_label>hypoxia plus training plus NMDA agonist</arm_group_label>
    <other_name>NMDA agonist</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>sham-NMDA agonist</intervention_name>
    <description>sham-NMDA agonist treatment</description>
    <arm_group_label>hypoxia plus training plus sham NMDA agonist</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>exercise training</intervention_name>
    <description>bimanual massed practice training</description>
    <arm_group_label>hypoxia plus training</arm_group_label>
    <arm_group_label>hypoxia plus training plus NMDA agonist</arm_group_label>
    <arm_group_label>hypoxia plus training plus sham NMDA agonist</arm_group_label>
    <arm_group_label>sham hypoxia plus training</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and females Veterans between 18-85 years&#xD;
&#xD;
          -  Chronic cSCI (1 yr of injury)&#xD;
&#xD;
          -  Cervical injury at C8 or above&#xD;
&#xD;
          -  Sensory function: impaired (score of 1) but not absent (score of 0) or intact (score&#xD;
             of 2) innervations in dermatomes C6, C7 and C8 during light touch and pin prick&#xD;
             stimulus using the International Standards for Neurological Classification of Spinal&#xD;
             Cord Injury (ISNCSCI) sensory scores&#xD;
&#xD;
          -  Motor function: Able to grasp small objects with one hand and able to perform a&#xD;
             visible precision grasp between the index finger and thumb&#xD;
&#xD;
          -  Motor scores ISNCSCI: 1 to 4 but not 5 on finger flexors and finger abductors on the&#xD;
             hand tested.&#xD;
&#xD;
               -  These criteria were selected to ensure that hand impairment will not interfere&#xD;
                  with the ability to perform training and proposed tests&#xD;
&#xD;
        Inclusion criteria for controls:&#xD;
&#xD;
          -  Male and females (18-80 years)&#xD;
&#xD;
          -  Right handed&#xD;
&#xD;
          -  Able to complete precision and power grips&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled medical problems including pulmonary, cardiovascular or orthopedic&#xD;
             disease&#xD;
&#xD;
          -  Any debilitating disease prior to the SCI that caused exercise intolerance&#xD;
&#xD;
          -  Premorbid, ongoing major depression or psychosis, altered cognitive status&#xD;
&#xD;
          -  History of head injury or stroke&#xD;
&#xD;
          -  Metal plate in skull&#xD;
&#xD;
          -  History of seizures&#xD;
&#xD;
          -  Receiving drugs acting primarily on the central nervous system, which lower the&#xD;
             seizure threshold such as antipsychotic drugs&#xD;
&#xD;
               -  chlorpromazine&#xD;
&#xD;
               -  clozapine&#xD;
&#xD;
               -  or tricyclic antidepressants&#xD;
&#xD;
          -  Pregnant females&#xD;
&#xD;
          -  Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal&#xD;
             cord disease as spinal stenosis, spina bifida or herniated cervical disk&#xD;
&#xD;
          -  AIH Exclusion Criteria (in addition to the above listed exclusion criteria):&#xD;
&#xD;
               -  resting heart rate &gt; 120 bpm&#xD;
&#xD;
               -  resting systolic blood pressure &gt;180 mmHg&#xD;
&#xD;
               -  resting diastolic blood pressure &gt;100 mmHg&#xD;
&#xD;
               -  self-reported history of unstable angina or myocardial infarction within the&#xD;
                  previous month&#xD;
&#xD;
               -  resting SpO2 &gt; or equal to 95%&#xD;
&#xD;
               -  cardiopulmonary complications such as COPD&#xD;
&#xD;
        Exclusion criteria for healthy controls:&#xD;
&#xD;
          -  Same as for SCI individuals&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Martin Oudega, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Edward Hines Jr. VA Hospital, Hines, IL</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Martin Oudega, PhD</last_name>
    <phone>(305) 575-7000</phone>
    <email>moudega@sralab.org</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Monica A Perez, PhD</last_name>
    <phone>(312) 238-2886</phone>
    <email>mperez04@sralab.org</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Edward Hines Jr. VA Hospital, Hines, IL</name>
      <address>
        <city>Hines</city>
        <state>Illinois</state>
        <zip>60141-3030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Meghan Morrow, OTR</last_name>
      <phone>248-721-0663</phone>
      <email>Meghan.Morrow@va.gov</email>
    </contact>
    <investigator>
      <last_name>Martin Oudega, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>January 27, 2023</last_update_submitted>
  <last_update_submitted_qc>January 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>spinal cord injury</keyword>
  <keyword>hypoxia</keyword>
  <keyword>plasticity</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cycloserine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03780829
org study id: B2848-R
nct id: NCT03780829
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Contusive cervical spinal cord injury (cSCI) impairs upper limb function (reach-and-grasp)
      which limits daily-life activities and thus decreases the quality of life. Promoting
      neuroplasticity may support upper limb recovery after SCI. Repetitive exposure to acute
      intermittent hypoxia (rAIH) combined with motor training promotes recovery of motor function
      after SCI; however, the overall effects of rAIH/training are limited. The investigators will
      use an adult rat model of long-term contusive cSCI to study novel approaches to enhance the
      effect of rAIH/training on forelimb function and study the neuronal substrate underlying the
      effects. The findings will be used to direct the development of more effective rAIH/training
      approaches for people with contusive, functionally incomplete, cSCI. Because deficits in
      upper limb function are a major problem after stroke, amyotrophic lateral sclerosis, multiple
      sclerosis, and other motor disorders, this work may also be relevant for patients with other
      types of central nervous system (CNS) lesions.
The overall goal is to develop effective, clinically applicable, approaches to restore upper
      limb function (reach-and-grasp) after chronic contusive cervical spinal cord injury (cSCI).
      Impairments in upper limb function significantly reduce the quality of life for people with
      cSCI. Reach-and-grasp actions in animals and humans are largely controlled by the
      corticospinal tract (CST). The investigators argue that promoting plasticity within the CST
      may support the recovery of upper limb function after cSCI. Repetitive exposure to acute
      intermittent hypoxia (rAIH) combined with motor training is a safe, minimally invasive,
      treatment that elicits neuroplasticity resulting in improved recovery after cSCI, but its
      overall effects remain limited. The main goals are to: 1) enhance rAIH/training-induced
      aftereffects on forelimb function and increase the understanding of the neuronal substrates
      in an adult rat model of chronic contusive cSCI, and 2) use this knowledge to guide the
      development of more effective rAIH/training approaches to improve upper limb function in
      humans with chronic contusive cSCI.

      In Specific Aim 1, using an adult rat model of chronic contusive cSCI, the investigators will
      investigate the effects of rAIH frequency and dose on rAIH/training-mediated functional
      recovery of the impaired forelimb. Also, the investigators will combine rAIH/training with
      N-methyl-D-aspartate receptor (NMDA)-mediated synaptic plasticity through D-cycloserine
      treatment and study the effects on recovery of forelimb function. Immunocytochemistry with
      imaging techniques will be used to assess structural neuronal plasticity in the CST after
      rAIH/training. In Specific Aim 2, in people with chronic incomplete cSCI, guided by the
      findings in Specific Aim 1, the investigators will study the effects of rAIH frequency and
      concurrent D-cycloserine treatment on rAIH/training-mediated upper limb function recovery.
      The investigators will comprehensively analyze the effects of rAIH on the strength of
      electrophysiological and functional aftereffects in the upper limb.

      The proposed research will provide new knowledge on rAIH/training-mediated functional and
      anatomical aftereffects (Specific Aim 1), which will be used to develop effective
      rAIH/training protocols for people with contusive, functionally incomplete, cSCI (Specific
      Aim 2). The data from the investigators' experiments may lead to clinically applicable
      approaches that improve arm and hand function recovery after chronic contusive cSCI, which
      would positively impact the quality of life of Veterans with cSCI. The relevance of this
      proposal is emphasized by the limited efficacy of current strategies to improve upper limb
      function after cSCI.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: repetitive intermittent hypoxia treatment combined with exercise and/or NMDA agonist
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: participants and some research personnel will be blinded
measure: Change in grip strength
time frame: baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week
description: Grip strength will be measured using a hand-held dynamometer, with an average force (measured in dynes) taken over the course of three trials. A rest break is provided between trials. Strength testing will be completed bilaterally.
measure: Change in pinch strength
time frame: baseline, 1st week, 2nd week, 4th week, 8th week, and 12th week
description: Pinch strength will be assessed using a digital pinch gauge (unit of Force= Newton). The minimum value of zero will be assigned when a participant cannot actively squeeze the pinch meter between the thumb and index finger. The mean value of total of 3 trials will be assessed, with a rest break provided between trials.
measure: Change in motor evoked potential size
time frame: 30 minutes before and 30 minutes after intervention
description: Resting and active motor thresholds (RMT and AMT) will be tested in each of the muscles using a stimulator.
arm group label: hypoxia plus training
arm group type: Experimental
description: combined hypoxia treatment with exercise training
arm group label: sham hypoxia plus training
arm group type: Sham Comparator
description: combined sham hypoxia treatment with exercise training
arm group label: hypoxia plus training plus NMDA agonist
arm group type: Experimental
description: combined hypoxia treatment with exercise training and with NMDA agonist treatment
arm group label: hypoxia plus training plus sham NMDA agonist
arm group type: Placebo Comparator
description: combined hypoxia treatment with exercise training and with sham NMDA agonist treatment
intervention type: Behavioral
intervention name: hypoxia
description: intermittent cycles of normoxia-hypoxia
arm group label: hypoxia plus training
arm group label: hypoxia plus training plus NMDA agonist
arm group label: hypoxia plus training plus sham NMDA agonist
intervention type: Behavioral
intervention name: sham hypoxia
description: intermittent cycles of sham hypoxia
arm group label: sham hypoxia plus training
intervention type: Drug
intervention name: D-cycloserine
description: NMDA agonist treatment
arm group label: hypoxia plus training plus NMDA agonist
other name: NMDA agonist
intervention type: Drug
intervention name: sham-NMDA agonist
description: sham-NMDA agonist treatment
arm group label: hypoxia plus training plus sham NMDA agonist
intervention type: Behavioral
intervention name: exercise training
description: bimanual massed practice training
arm group label: hypoxia plus training
arm group label: hypoxia plus training plus NMDA agonist
arm group label: hypoxia plus training plus sham NMDA agonist
arm group label: sham hypoxia plus training
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Martin Oudega, PhD
role: Principal Investigator
affiliation: Edward Hines Jr. VA Hospital, Hines, IL
last name: Martin Oudega, PhD
phone: (305) 575-7000
email: moudega@sralab.org
last name: Monica A Perez, PhD
phone: (312) 238-2886
email: mperez04@sralab.org
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Cycloserine
sharing ipd: No