<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/NCT03009500</url>
  </required_header>
  <id_info>
    <org_study_id>16-5927</org_study_id>
    <nct_id>NCT03009500</nct_id>
  </id_info>
  <brief_title>Randomized Controlled Trial of Efficacy and Safety of Local Anesthetics and Steroids for Chronic Peripheral Post-traumatic Neuropathic Pain</brief_title>
  <acronym>RESPERIST</acronym>
  <official_title>A Multi-center Randomized Controlled Trial of Efficacy and Safety of Perineural Local Anesthetics and Steroids for Chronic Peripheral Post-traumatic Neuropathic Pain: The Resperist Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate three different injectable solutions used to block&#xD;
      ankle nerves to manage ankle pain. The current standard of medical care is to inject a&#xD;
      combination of local anesthetics and steroids around injured nerves. There is evidence that&#xD;
      injection of local anesthetic (without the steroid) can calm the injured nerve and provide&#xD;
      pain relief from a few days up to a few months. Injection of sterile salt water also has the&#xD;
      potential to provide pain relief by breaking scar tissue around the nerve thereby relieving&#xD;
      compression. Injections of local anesthetic and steroids around injured nerves have been used&#xD;
      for many years to provide relief of pain but the specific reason is not well known for this&#xD;
      benefit.&#xD;
&#xD;
      There are three possibilities: 1) Steroids can reduce inflammation and calm the nerves, 2)&#xD;
      local anesthetics can have similar actions but with shorter duration (few days), and 3)&#xD;
      injection of any solution can break scarring around an injured/compressed nerve.&#xD;
&#xD;
      The study will compare pain relief and possible adverse effects from these three different&#xD;
      solutions. This study will help provide definitive answers regarding pain relief and possible&#xD;
      adverse effects of the three solutions. This, in turn, will determine the best possible&#xD;
      option for injection in patients with nerve-related injury pain.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This project is a randomized controlled trial with the aim of comparing efficacy of image&#xD;
      (ultrasound)-guided administration of perineural combination of steroids and local anesthetic&#xD;
      (current standard of care) against perineural local anesthetic (LA) or saline in providing&#xD;
      sustained analgesic benefit in people with chronic neuropathic pain (NP) of the foot and&#xD;
      ankle.&#xD;
&#xD;
      The study design will be multi-center, prospective, concealed, blinded, parallel group trial&#xD;
      with three groups, block randomization (blocks of six participants) and allocation in a 2:2:2&#xD;
      ratio. Study participants and outcome evaluators will be blinded to treatment assignments.&#xD;
&#xD;
      Participants will be randomly assigned to one of the three groups to receive two US-guided&#xD;
      injections (at an interval of one to two weeks) of one of the following around one or more of&#xD;
      the five nerves innervating the foot and ankle:&#xD;
&#xD;
      The initial procedure will be repeated after one to two weeks unless clinical circumstances&#xD;
      dictate otherwise (that is, the patient declined a second injection because of increase in&#xD;
      pain or satisfaction with pain relief). The rationale for the repeat procedure is to allow&#xD;
      possible benefit from a cumulative effect of the procedures and/or the injectates. Between&#xD;
      the first injection and first follow-up visit, no patient will be allowed any additional&#xD;
      therapeutic interventions. Nerves to be targeted by the injection will be decided by the&#xD;
      treating physician based on area of the foot and ankle that displays features of neuropathic&#xD;
      pain. Each injection of study medications will be preceded by subcutaneous injections of 1&#xD;
      mLs of LA (2% lidocaine) at each of the injection sites. This will reduce discomfort of the&#xD;
      study participants from the injections. The subcutaneous LA will also cause numbness of the&#xD;
      skin and this will ensure blinding of participants to their group allocation. Two&#xD;
      ultrasound-guided procedures will be performed at weekly intervals over two weeks. The&#xD;
      US-guided technique for performing these procedures has been described in previous studies&#xD;
      from our center.22 Conservative measures (oral analgesics, physiotherapy) will continue&#xD;
      during the study. Fasting blood glucose will be measured at baseline and at one month&#xD;
      following the interventions. Systolic and diastolic blood pressure (with participant sitting&#xD;
      for at least 5 minutes prior to the measurement) values will be recoded as a mean of three&#xD;
      consecutive readings at baseline and at one month following the interventions.&#xD;
      Cross-sectional area (CSA) of tibial nerve at 3 cm proximal to cephalad edge of medial&#xD;
      malleolus will also be measured prior to the first procedure and prior to the second&#xD;
      procedure in participants with pain in distribution of the tibial nerve. Change in CSA (if&#xD;
      any) will be correlated with analgesic response to perineural injections because decrease in&#xD;
      CSA may indicate reduction in edema of the nerve.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2017</start_date>
  <completion_date type="Actual">June 2019</completion_date>
  <primary_completion_date type="Actual">March 2018</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>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Determination of Numerical Rating Scores (NRS) (range 0-10) for foot and ankle pain</measure>
    <time_frame>One month after intervention</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Measuring NRS (range 0-10) for foot and ankle pain</measure>
    <time_frame>Three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring changes in the PCS (Pain Catastrophizing Scale) Questionnaire</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring changes in the Douleur Neuropathique (DN4) Questionnaire</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in the NPSI (Neuropathic Pain Symptom Inventory) Questionnaire</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in the Anxiety and Depression component scores on the Hospital Anxiety and Depression Scale (HADS)</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in Depression scores on the Patient Health Questionnaire (PHQ-9)</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in Brief Pain Inventory interference with activities (BPI-I) score</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in Short Form-12 (SF-12) score</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in Lower Extremity Function Score (LEFS)</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in pain (cold pain and heat pain) thresholds as determined by quantitative sensory testing (QST)</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring change in sensory (cold and hot detection) thresholds as determined by quantitative sensory testing (QST)</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of the cross-sectional area of tibial nerve for neural edema between interventions</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measuring incidence of adverse effects</measure>
    <time_frame>One month and three months after intervention compared to pre-intervention</time_frame>
    <description>Hyperglycemia (change in blood glucose levels) and hypertension (change in blood pressure levels)&#xD;
Infections at the injection site, skin discolouration or atrophy at the injection site, fractures, and evidence of myopathy</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Neuralgia</condition>
  <condition>Peripheral Neuropathic Pain</condition>
  <arm_group>
    <arm_group_label>Local Anesthetic</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Injection of 2-6 cc of LA (0.25% bupivacaine) per nerve to a maximum of 20 cc</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Local Anesthetic with steroids</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Injection of 2-6 cc of LA (0.25% bupivacaine) per nerve containing steroids (methylprednisolone (Depo-Medrol) 4 mg per cc) to a maximum of 20 cc</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Injection of 2-6 cc of saline (0.9% sodium chloride) per nerve to a maximum of 20 cc</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bupivacaine</intervention_name>
    <arm_group_label>Local Anesthetic</arm_group_label>
    <arm_group_label>Local Anesthetic with steroids</arm_group_label>
    <other_name>Marcaine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Depo-Medrol Injectable Product</intervention_name>
    <arm_group_label>Local Anesthetic with steroids</arm_group_label>
    <other_name>Methylprednisone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Saline (Sodium Chloride) solution</intervention_name>
    <arm_group_label>Saline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lidocaine</intervention_name>
    <description>Each injection of study medications will be preceded by subcutaneous injections of 1 mLs of 2% lidocaine at each injection site to reduce discomfort of the study participants from the injections</description>
    <arm_group_label>Local Anesthetic</arm_group_label>
    <arm_group_label>Local Anesthetic with steroids</arm_group_label>
    <arm_group_label>Saline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Pain in foot in neuro-anatomically congruent location following trauma (including&#xD;
             surgery) for more than three months&#xD;
&#xD;
          2. Physician-reported DN4 scoring confirming neuropathic pain (score &gt;3/10)&#xD;
&#xD;
          3. Average intensity of pain more than 3/10 on numerical rating score&#xD;
&#xD;
          4. Failed trial of appropriate doses of first line medications for neuropathic pain&#xD;
             (anticonvulsants and/or antidepressants) for six weeks&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt; 18 or Age &gt; 80 years&#xD;
&#xD;
          2. Perineural or intra-articular steroid injections in the last 6 months&#xD;
&#xD;
          3. Allergy to local anesthetics or steroids&#xD;
&#xD;
          4. Ongoing litigation issues related to the patient's pain&#xD;
&#xD;
          5. Pregnancy&#xD;
&#xD;
          6. Coagulopathy or systemic infection&#xD;
&#xD;
          7. Peripheral neuropathy or myopathy, central neuropathic pain (e.g. post-stroke pain)&#xD;
&#xD;
          8. Infection in the ankle or foot&#xD;
&#xD;
          9. An unstable medical or psychiatric condition&#xD;
&#xD;
         10. Significant catastrophizing as indicated by pain catastrophizing scale (PCS) score&#xD;
             equal to or more than 30/52.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anuj Bhatia, MD FRCPC</last_name>
    <role>Principal Investigator</role>
    <affiliation>UHN</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Toronto Western Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5T 2S8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 4, 2017</study_first_posted>
  <last_update_submitted>March 23, 2020</last_update_submitted>
  <last_update_submitted_qc>March 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Health Network, Toronto</investigator_affiliation>
    <investigator_full_name>Anuj Bhatia</investigator_full_name>
    <investigator_title>Director, Anesthesia Chronic Pain Clinical Services</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuralgia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylprednisolone</mesh_term>
    <mesh_term>Methylprednisolone Acetate</mesh_term>
    <mesh_term>Methylprednisolone Hemisuccinate</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Prednisolone acetate</mesh_term>
    <mesh_term>Lidocaine</mesh_term>
    <mesh_term>Bupivacaine</mesh_term>
    <mesh_term>Prednisolone hemisuccinate</mesh_term>
    <mesh_term>Prednisolone phosphate</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/NCT03009500
org study id: 16-5927
nct id: NCT03009500
lead sponsor: 
has dmc: No
The purpose of this study is to evaluate three different injectable solutions used to block
      ankle nerves to manage ankle pain. The current standard of medical care is to inject a
      combination of local anesthetics and steroids around injured nerves. There is evidence that
      injection of local anesthetic (without the steroid) can calm the injured nerve and provide
      pain relief from a few days up to a few months. Injection of sterile salt water also has the
      potential to provide pain relief by breaking scar tissue around the nerve thereby relieving
      compression. Injections of local anesthetic and steroids around injured nerves have been used
      for many years to provide relief of pain but the specific reason is not well known for this
      benefit.

      There are three possibilities: 1) Steroids can reduce inflammation and calm the nerves, 2)
      local anesthetics can have similar actions but with shorter duration (few days), and 3)
      injection of any solution can break scarring around an injured/compressed nerve.

      The study will compare pain relief and possible adverse effects from these three different
      solutions. This study will help provide definitive answers regarding pain relief and possible
      adverse effects of the three solutions. This, in turn, will determine the best possible
      option for injection in patients with nerve-related injury pain.
This project is a randomized controlled trial with the aim of comparing efficacy of image
      (ultrasound)-guided administration of perineural combination of steroids and local anesthetic
      (current standard of care) against perineural local anesthetic (LA) or saline in providing
      sustained analgesic benefit in people with chronic neuropathic pain (NP) of the foot and
      ankle.

      The study design will be multi-center, prospective, concealed, blinded, parallel group trial
      with three groups, block randomization (blocks of six participants) and allocation in a 2:2:2
      ratio. Study participants and outcome evaluators will be blinded to treatment assignments.

      Participants will be randomly assigned to one of the three groups to receive two US-guided
      injections (at an interval of one to two weeks) of one of the following around one or more of
      the five nerves innervating the foot and ankle:

      The initial procedure will be repeated after one to two weeks unless clinical circumstances
      dictate otherwise (that is, the patient declined a second injection because of increase in
      pain or satisfaction with pain relief). The rationale for the repeat procedure is to allow
      possible benefit from a cumulative effect of the procedures and/or the injectates. Between
      the first injection and first follow-up visit, no patient will be allowed any additional
      therapeutic interventions. Nerves to be targeted by the injection will be decided by the
      treating physician based on area of the foot and ankle that displays features of neuropathic
      pain. Each injection of study medications will be preceded by subcutaneous injections of 1
      mLs of LA (2% lidocaine) at each of the injection sites. This will reduce discomfort of the
      study participants from the injections. The subcutaneous LA will also cause numbness of the
      skin and this will ensure blinding of participants to their group allocation. Two
      ultrasound-guided procedures will be performed at weekly intervals over two weeks. The
      US-guided technique for performing these procedures has been described in previous studies
      from our center.22 Conservative measures (oral analgesics, physiotherapy) will continue
      during the study. Fasting blood glucose will be measured at baseline and at one month
      following the interventions. Systolic and diastolic blood pressure (with participant sitting
      for at least 5 minutes prior to the measurement) values will be recoded as a mean of three
      consecutive readings at baseline and at one month following the interventions.
      Cross-sectional area (CSA) of tibial nerve at 3 cm proximal to cephalad edge of medial
      malleolus will also be measured prior to the first procedure and prior to the second
      procedure in participants with pain in distribution of the tibial nerve. Change in CSA (if
      any) will be correlated with analgesic response to perineural injections because decrease in
      CSA may indicate reduction in edema of the nerve.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Double (Participant, Outcomes Assessor)
measure: Determination of Numerical Rating Scores (NRS) (range 0-10) for foot and ankle pain
time frame: One month after intervention
measure: Measuring NRS (range 0-10) for foot and ankle pain
time frame: Three months after intervention compared to pre-intervention
measure: Measuring changes in the PCS (Pain Catastrophizing Scale) Questionnaire
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring changes in the Douleur Neuropathique (DN4) Questionnaire
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in the NPSI (Neuropathic Pain Symptom Inventory) Questionnaire
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in the Anxiety and Depression component scores on the Hospital Anxiety and Depression Scale (HADS)
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in Depression scores on the Patient Health Questionnaire (PHQ-9)
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in Brief Pain Inventory interference with activities (BPI-I) score
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in Short Form-12 (SF-12) score
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in Lower Extremity Function Score (LEFS)
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in pain (cold pain and heat pain) thresholds as determined by quantitative sensory testing (QST)
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring change in sensory (cold and hot detection) thresholds as determined by quantitative sensory testing (QST)
time frame: One month and three months after intervention compared to pre-intervention
measure: Measurement of the cross-sectional area of tibial nerve for neural edema between interventions
time frame: One month and three months after intervention compared to pre-intervention
measure: Measuring incidence of adverse effects
time frame: One month and three months after intervention compared to pre-intervention
description: Hyperglycemia (change in blood glucose levels) and hypertension (change in blood pressure levels)
Infections at the injection site, skin discolouration or atrophy at the injection site, fractures, and evidence of myopathy
arm group label: Local Anesthetic
arm group type: Active Comparator
description: Injection of 2-6 cc of LA (0.25% bupivacaine) per nerve to a maximum of 20 cc
arm group label: Local Anesthetic with steroids
arm group type: Active Comparator
description: Injection of 2-6 cc of LA (0.25% bupivacaine) per nerve containing steroids (methylprednisolone (Depo-Medrol) 4 mg per cc) to a maximum of 20 cc
arm group label: Saline
arm group type: Placebo Comparator
description: Injection of 2-6 cc of saline (0.9% sodium chloride) per nerve to a maximum of 20 cc
intervention type: Drug
intervention name: Bupivacaine
arm group label: Local Anesthetic
arm group label: Local Anesthetic with steroids
other name: Marcaine
intervention type: Drug
intervention name: Depo-Medrol Injectable Product
arm group label: Local Anesthetic with steroids
other name: Methylprednisone
intervention type: Other
intervention name: Saline (Sodium Chloride) solution
arm group label: Saline
intervention type: Drug
intervention name: Lidocaine
description: Each injection of study medications will be preceded by subcutaneous injections of 1 mLs of 2% lidocaine at each injection site to reduce discomfort of the study participants from the injections
arm group label: Local Anesthetic
arm group label: Local Anesthetic with steroids
arm group label: Saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Anuj Bhatia, MD FRCPC
role: Principal Investigator
affiliation: UHN
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: University Health Network, Toronto
investigator full name: Anuj Bhatia
investigator title: Director, Anesthesia Chronic Pain Clinical Services
mesh term: Neuralgia
mesh term: Methylprednisolone
mesh term: Methylprednisolone Acetate
mesh term: Methylprednisolone Hemisuccinate
mesh term: Prednisolone
mesh term: Prednisolone acetate
mesh term: Lidocaine
mesh term: Bupivacaine
mesh term: Prednisolone hemisuccinate
mesh term: Prednisolone phosphate
sharing ipd: No