<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/NCT04437056</url>
  </required_header>
  <id_info>
    <org_study_id>EK 2319/2019</org_study_id>
    <nct_id>NCT04437056</nct_id>
  </id_info>
  <brief_title>Nerve Transfers in Post-stroke Spasticity</brief_title>
  <official_title>Outcome Measurements After Cognitive Nerve Transfers to Spastic Muscles in Stroke Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Vienna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Shirley Ryan AbilityLab</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Medical University of Vienna</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Stroke is nowadays a leading cause of disability with devastating sequelae. Upper limb&#xD;
      spasticity is one of them. Nevertheless, not all the muscles are equally affected, as some&#xD;
      may turn spastic or paretic and other remain intact. This unique pathophysiological mosaic&#xD;
      dictates a precise therapeutic plan. Existing spasticity treatment has significant drawbacks&#xD;
      due to its unspecific targeting and short duration. A causal, life-lasting treatment,&#xD;
      precisely adapted to every single patient's needs and to disease pattern, is currently&#xD;
      missing. Hyperselective muscle denervation and subsequent cognitive reinnervation with&#xD;
      appropriate unaffected donor nerves may break the pathological spastic circuit and provide&#xD;
      volitional muscle control. With this pioneering study we will perform cognitive nerve&#xD;
      transfers to spastic muscles and will prospectively investigate their effects on clinical,&#xD;
      electrophysiological, molecular-biological and histological level. Accurate donor nerve&#xD;
      selection will be for the first time quantified through motor unit number estimation with&#xD;
      high-density needle electromyography. This revolutionary concept can open the window to a new&#xD;
      era of therapeutic possibilities for stroke victims.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">September 1, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Chedoke Arm and Hand Activity Inventory (CAHAI-9) score</measure>
    <time_frame>0-24 months</time_frame>
    <description>Patients can reach a score for CAHAI 9 between 9 to 63. The lower the score, the greater impairment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Modified Ashworth Scale</measure>
    <time_frame>0-24 months</time_frame>
    <description>A score of 1 indicates no resistance, and 5 indicates rigidity. A 1+ scoring category indicates resistance through less than half of the movement. Scores range from 0-4, with 6 choices .</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in electrophysiological muscle activity after nerve transfers</measure>
    <time_frame>0-24 months</time_frame>
    <description>Low frequency-dependent depression of H-wave (in mV)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in muscle satellite cell population (%) in spastic muscles and comparison with healthy control group</measure>
    <time_frame>During surgery- 24 months</time_frame>
    <description>Muscle biopsies from spastic muscles will be obtained during the surgery of nerve transfers. The muscle satellite cell population (%) will be calculated with the use of Flow Cytometry and be compared to the one of healthy muscles of control group. There will be no recruitment procedure for the control group. Routinely, when we carry out surgery for ulnar nerve release in the elbow and nerve transposition, a part of the flexor carpi ulnaris muscle needs to be excised and discarded. After obtaining informed consent from patients for further use of their biological material, we will collect these muscles and use them as control group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Action Research Arm Test (ARAT)</measure>
    <time_frame>0-24 months</time_frame>
    <description>The total score on the ARAT ranges from 0 to 57, with the lowest score indicating that no movements can be performed, and the upper score indicating normal performance.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Disabilities of the Arm, Shoulder and Hand (DASH) score</measure>
    <time_frame>0-24 months</time_frame>
    <description>Scores range from 0 (no disability) to 100 (most severe disability).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Motor Unit Number Estimation of donor and spastic muscles</measure>
    <time_frame>0-24 months</time_frame>
    <description>High density electromyography with fine needle electrodes will be applied to allow an accurate estimation of motor units (absolute number) in donor muscles, in spastic muscles and in newly-innervated muscles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of collagen content between spastic and healthy muscles</measure>
    <time_frame>During surgery- 12 months</time_frame>
    <description>Muscle biopsies from spastic muscles will be obtained during the surgery of nerve transfers. Collagen content of spastic muscles (%) will be calculated with the use of Picrosirius red staining and bright field light microscopy and be compared with healthy muscles of control group. There will be no recruitment procedure for the control group. Routinely, when we carry out surgery for ulnar nerve release in the elbow and nerve transposition, a part of the flexor carpi ulnaris muscle needs to be excised and discarded. After obtaining informed consent from patients for further use of their biological material, we will collect these muscles and use them as control group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in sarcomere length (μm) in spastic muscles</measure>
    <time_frame>During surgery- 12 months</time_frame>
    <description>Biopsy of a muscle fascicle from spastic muscles will be obtained during the surgery of nerve transfers with the use of dedicated clamps and will be fixed in formalin. The sarcomere length will be calculated with the use of fractional laser. The sarcomere length of spastic muscles will be compared with the sarcomere length of healthy control group muscles.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Spasticity as Sequela of Stroke</condition>
  <condition>Nerve Transfers</condition>
  <arm_group>
    <arm_group_label>Stroke patients with upper limb spasticity</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients with post-stroke upper limb spasticity will be operated for cognitive nerve transfers to spastic muscles to allow for volitional muscle reinnervation and disrupture of spasticity. Adequate healthy nerve donors from the ipsilateral arm will be determined clinically and electrophysiologically.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Cognitive nerve transfers to spastic upper extremity muscles in stroke patients</intervention_name>
    <description>Based on the fact that upper motor neuron syndrome after stroke is presented with variable clinical features, usually without affecting in the same way the entire upper extremity, we aim to investigate the efficacy of nerve transfers to spastic muscles after stroke using as donor nerves that innervate unaffected ipsilateral volitionally controlled muscles.</description>
    <arm_group_label>Stroke patients with upper limb spasticity</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Are undergoing nerve transfers&#xD;
&#xD;
          -  Age from 18 to 75 years old&#xD;
&#xD;
          -  Minimum of 1 year interval after stroke&#xD;
&#xD;
          -  Are able to understand German or English&#xD;
&#xD;
          -  Medical Research Council (MRC) Muscle scale for donor nerves: M4 or M5&#xD;
&#xD;
          -  Walking patients, with or without crutches&#xD;
&#xD;
          -  Good general health condition and social support&#xD;
&#xD;
        For the control group:&#xD;
&#xD;
          -  Age 18-75 years old&#xD;
&#xD;
          -  Indication for ulnar nerve release and submuscular transposition for compression&#xD;
             neuropathy in the elbow&#xD;
&#xD;
          -  No other neurological disorders&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Stroke earlier than 3 years at the time of first consultation&#xD;
&#xD;
          -  Lower limb spasticity and patients mobile with wheel chair&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Oskar Aszmann, Prof</last_name>
    <role>Study Director</role>
    <affiliation>Department of Surgery, Medical University of Vienna</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>General Hospital of Vienna</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <reference>
    <citation>Urban PP, Wolf T, Uebele M, Marx JJ, Vogt T, Stoeter P, Bauermann T, Weibrich C, Vucurevic GD, Schneider A, Wissel J. Occurence and clinical predictors of spasticity after ischemic stroke. Stroke. 2010 Sep;41(9):2016-20. doi: 10.1161/STROKEAHA.110.581991. Epub 2010 Aug 12.</citation>
    <PMID>20705930</PMID>
  </reference>
  <reference>
    <citation>Wissel J, Manack A, Brainin M. Toward an epidemiology of poststroke spasticity. Neurology. 2013 Jan 15;80(3 Suppl 2):S13-9. doi: 10.1212/WNL.0b013e3182762448.</citation>
    <PMID>23319481</PMID>
  </reference>
  <reference>
    <citation>Sommerfeld DK, Gripenstedt U, Welmer AK. Spasticity after stroke: an overview of prevalence, test instruments, and treatments. Am J Phys Med Rehabil. 2012 Sep;91(9):814-20. doi: 10.1097/PHM.0b013e31825f13a3.</citation>
    <PMID>22760104</PMID>
  </reference>
  <reference>
    <citation>Zheng MX, Hua XY, Feng JT, Li T, Lu YC, Shen YD, Cao XH, Zhao NQ, Lyu JY, Xu JG, Gu YD, Xu WD. Trial of Contralateral Seventh Cervical Nerve Transfer for Spastic Arm Paralysis. N Engl J Med. 2018 Jan 4;378(1):22-34. doi: 10.1056/NEJMoa1615208. Epub 2017 Dec 20.</citation>
    <PMID>29262271</PMID>
  </reference>
  <reference>
    <citation>Qiu YQ, Du MX, Yu BF, Jiang S, Feng JT, Shen YD, Xu WD. Contralateral Lumbar to Sacral Nerve Rerouting for Hemiplegic Patients After Stroke: A Clinical Pilot Study. World Neurosurg. 2019 Jan;121:12-18. doi: 10.1016/j.wneu.2018.09.118. Epub 2018 Sep 26.</citation>
    <PMID>30266703</PMID>
  </reference>
  <reference>
    <citation>Khalifeh JM, Dibble CF, Van Voorhis A, Doering M, Boyer MI, Mahan MA, Wilson TJ, Midha R, Yang LJS, Ray WZ. Nerve transfers in the upper extremity following cervical spinal cord injury. Part 1: Systematic review of the literature. J Neurosurg Spine. 2019 Jul 12:1-12. doi: 10.3171/2019.4.SPINE19173. Online ahead of print.</citation>
    <PMID>31299644</PMID>
  </reference>
  <reference>
    <citation>Faturi FM, Lopes Santos G, Ocamoto GN, Russo TL. Structural muscular adaptations in upper limb after stroke: a systematic review. Top Stroke Rehabil. 2019 Jan;26(1):73-79. doi: 10.1080/10749357.2018.1517511. Epub 2018 Sep 17.</citation>
    <PMID>30222075</PMID>
  </reference>
  <reference>
    <citation>Smith LR, Pichika R, Meza RC, Gillies AR, Baliki MN, Chambers HG, Lieber RL. Contribution of extracellular matrix components to the stiffness of skeletal muscle contractures in patients with cerebral palsy. Connect Tissue Res. 2021 May;62(3):287-298. doi: 10.1080/03008207.2019.1694011. Epub 2019 Nov 28.</citation>
    <PMID>31779492</PMID>
  </reference>
  <reference>
    <citation>Mandeville RM, Brown JM, Sheean GL. Semi-quantitative electromyography as a predictor of nerve transfer outcome. Clin Neurophysiol. 2019 May;130(5):701-706. doi: 10.1016/j.clinph.2019.02.008. Epub 2019 Feb 28.</citation>
    <PMID>30875537</PMID>
  </reference>
  <reference>
    <citation>Barreca S, Gowland CK, Stratford P, Huijbregts M, Griffiths J, Torresin W, Dunkley M, Miller P, Masters L. Development of the Chedoke Arm and Hand Activity Inventory: theoretical constructs, item generation, and selection. Top Stroke Rehabil. 2004 Fall;11(4):31-42. doi: 10.1310/JU8P-UVK6-68VW-CF3W.</citation>
    <PMID>15592988</PMID>
  </reference>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>June 1, 2020</study_first_submitted>
  <study_first_submitted_qc>June 16, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 18, 2020</study_first_posted>
  <last_update_submitted>April 4, 2022</last_update_submitted>
  <last_update_submitted_qc>April 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of Vienna</investigator_affiliation>
    <investigator_full_name>Olga Politikou</investigator_full_name>
    <investigator_title>MD, Principal Investigator, PhD Student Clinical Laboratory for Bionic Extremity Reconstruction</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscle Spasticity</mesh_term>
    <mesh_term>Stroke</mesh_term>
  </condition_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/NCT04437056
org study id: EK 2319/2019
nct id: NCT04437056
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Stroke is nowadays a leading cause of disability with devastating sequelae. Upper limb
      spasticity is one of them. Nevertheless, not all the muscles are equally affected, as some
      may turn spastic or paretic and other remain intact. This unique pathophysiological mosaic
      dictates a precise therapeutic plan. Existing spasticity treatment has significant drawbacks
      due to its unspecific targeting and short duration. A causal, life-lasting treatment,
      precisely adapted to every single patient's needs and to disease pattern, is currently
      missing. Hyperselective muscle denervation and subsequent cognitive reinnervation with
      appropriate unaffected donor nerves may break the pathological spastic circuit and provide
      volitional muscle control. With this pioneering study we will perform cognitive nerve
      transfers to spastic muscles and will prospectively investigate their effects on clinical,
      electrophysiological, molecular-biological and histological level. Accurate donor nerve
      selection will be for the first time quantified through motor unit number estimation with
      high-density needle electromyography. This revolutionary concept can open the window to a new
      era of therapeutic possibilities for stroke victims.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Chedoke Arm and Hand Activity Inventory (CAHAI-9) score
time frame: 0-24 months
description: Patients can reach a score for CAHAI 9 between 9 to 63. The lower the score, the greater impairment.
measure: Modified Ashworth Scale
time frame: 0-24 months
description: A score of 1 indicates no resistance, and 5 indicates rigidity. A 1+ scoring category indicates resistance through less than half of the movement. Scores range from 0-4, with 6 choices .
measure: Changes in electrophysiological muscle activity after nerve transfers
time frame: 0-24 months
description: Low frequency-dependent depression of H-wave (in mV)
measure: Changes in muscle satellite cell population (%) in spastic muscles and comparison with healthy control group
time frame: During surgery- 24 months
description: Muscle biopsies from spastic muscles will be obtained during the surgery of nerve transfers. The muscle satellite cell population (%) will be calculated with the use of Flow Cytometry and be compared to the one of healthy muscles of control group. There will be no recruitment procedure for the control group. Routinely, when we carry out surgery for ulnar nerve release in the elbow and nerve transposition, a part of the flexor carpi ulnaris muscle needs to be excised and discarded. After obtaining informed consent from patients for further use of their biological material, we will collect these muscles and use them as control group.
measure: The Action Research Arm Test (ARAT)
time frame: 0-24 months
description: The total score on the ARAT ranges from 0 to 57, with the lowest score indicating that no movements can be performed, and the upper score indicating normal performance.
measure: The Disabilities of the Arm, Shoulder and Hand (DASH) score
time frame: 0-24 months
description: Scores range from 0 (no disability) to 100 (most severe disability).
measure: Motor Unit Number Estimation of donor and spastic muscles
time frame: 0-24 months
description: High density electromyography with fine needle electrodes will be applied to allow an accurate estimation of motor units (absolute number) in donor muscles, in spastic muscles and in newly-innervated muscles
measure: Comparison of collagen content between spastic and healthy muscles
time frame: During surgery- 12 months
description: Muscle biopsies from spastic muscles will be obtained during the surgery of nerve transfers. Collagen content of spastic muscles (%) will be calculated with the use of Picrosirius red staining and bright field light microscopy and be compared with healthy muscles of control group. There will be no recruitment procedure for the control group. Routinely, when we carry out surgery for ulnar nerve release in the elbow and nerve transposition, a part of the flexor carpi ulnaris muscle needs to be excised and discarded. After obtaining informed consent from patients for further use of their biological material, we will collect these muscles and use them as control group.
measure: Changes in sarcomere length (μm) in spastic muscles
time frame: During surgery- 12 months
description: Biopsy of a muscle fascicle from spastic muscles will be obtained during the surgery of nerve transfers with the use of dedicated clamps and will be fixed in formalin. The sarcomere length will be calculated with the use of fractional laser. The sarcomere length of spastic muscles will be compared with the sarcomere length of healthy control group muscles.
arm group label: Stroke patients with upper limb spasticity
arm group type: Other
description: Patients with post-stroke upper limb spasticity will be operated for cognitive nerve transfers to spastic muscles to allow for volitional muscle reinnervation and disrupture of spasticity. Adequate healthy nerve donors from the ipsilateral arm will be determined clinically and electrophysiologically.
intervention type: Procedure
intervention name: Cognitive nerve transfers to spastic upper extremity muscles in stroke patients
description: Based on the fact that upper motor neuron syndrome after stroke is presented with variable clinical features, usually without affecting in the same way the entire upper extremity, we aim to investigate the efficacy of nerve transfers to spastic muscles after stroke using as donor nerves that innervate unaffected ipsilateral volitionally controlled muscles.
arm group label: Stroke patients with upper limb spasticity
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Oskar Aszmann, Prof
role: Study Director
affiliation: Department of Surgery, Medical University of Vienna
facility: 
country: Austria
citation: Urban PP, Wolf T, Uebele M, Marx JJ, Vogt T, Stoeter P, Bauermann T, Weibrich C, Vucurevic GD, Schneider A, Wissel J. Occurence and clinical predictors of spasticity after ischemic stroke. Stroke. 2010 Sep;41(9):2016-20. doi: 10.1161/STROKEAHA.110.581991. Epub 2010 Aug 12.
PMID: 20705930
citation: Wissel J, Manack A, Brainin M. Toward an epidemiology of poststroke spasticity. Neurology. 2013 Jan 15;80(3 Suppl 2):S13-9. doi: 10.1212/WNL.0b013e3182762448.
PMID: 23319481
citation: Sommerfeld DK, Gripenstedt U, Welmer AK. Spasticity after stroke: an overview of prevalence, test instruments, and treatments. Am J Phys Med Rehabil. 2012 Sep;91(9):814-20. doi: 10.1097/PHM.0b013e31825f13a3.
PMID: 22760104
citation: Zheng MX, Hua XY, Feng JT, Li T, Lu YC, Shen YD, Cao XH, Zhao NQ, Lyu JY, Xu JG, Gu YD, Xu WD. Trial of Contralateral Seventh Cervical Nerve Transfer for Spastic Arm Paralysis. N Engl J Med. 2018 Jan 4;378(1):22-34. doi: 10.1056/NEJMoa1615208. Epub 2017 Dec 20.
PMID: 29262271
citation: Qiu YQ, Du MX, Yu BF, Jiang S, Feng JT, Shen YD, Xu WD. Contralateral Lumbar to Sacral Nerve Rerouting for Hemiplegic Patients After Stroke: A Clinical Pilot Study. World Neurosurg. 2019 Jan;121:12-18. doi: 10.1016/j.wneu.2018.09.118. Epub 2018 Sep 26.
PMID: 30266703
citation: Khalifeh JM, Dibble CF, Van Voorhis A, Doering M, Boyer MI, Mahan MA, Wilson TJ, Midha R, Yang LJS, Ray WZ. Nerve transfers in the upper extremity following cervical spinal cord injury. Part 1: Systematic review of the literature. J Neurosurg Spine. 2019 Jul 12:1-12. doi: 10.3171/2019.4.SPINE19173. Online ahead of print.
PMID: 31299644
citation: Faturi FM, Lopes Santos G, Ocamoto GN, Russo TL. Structural muscular adaptations in upper limb after stroke: a systematic review. Top Stroke Rehabil. 2019 Jan;26(1):73-79. doi: 10.1080/10749357.2018.1517511. Epub 2018 Sep 17.
PMID: 30222075
citation: Smith LR, Pichika R, Meza RC, Gillies AR, Baliki MN, Chambers HG, Lieber RL. Contribution of extracellular matrix components to the stiffness of skeletal muscle contractures in patients with cerebral palsy. Connect Tissue Res. 2021 May;62(3):287-298. doi: 10.1080/03008207.2019.1694011. Epub 2019 Nov 28.
PMID: 31779492
citation: Mandeville RM, Brown JM, Sheean GL. Semi-quantitative electromyography as a predictor of nerve transfer outcome. Clin Neurophysiol. 2019 May;130(5):701-706. doi: 10.1016/j.clinph.2019.02.008. Epub 2019 Feb 28.
PMID: 30875537
citation: Barreca S, Gowland CK, Stratford P, Huijbregts M, Griffiths J, Torresin W, Dunkley M, Miller P, Masters L. Development of the Chedoke Arm and Hand Activity Inventory: theoretical constructs, item generation, and selection. Top Stroke Rehabil. 2004 Fall;11(4):31-42. doi: 10.1310/JU8P-UVK6-68VW-CF3W.
PMID: 15592988
responsible party type: Principal Investigator
investigator affiliation: Medical University of Vienna
investigator full name: Olga Politikou
investigator title: MD, Principal Investigator, PhD Student Clinical Laboratory for Bionic Extremity Reconstruction
mesh term: Muscle Spasticity
mesh term: Stroke
sharing ipd: No