<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/NCT02208778</url>
  </required_header>
  <id_info>
    <org_study_id>13124</org_study_id>
    <nct_id>NCT02208778</nct_id>
  </id_info>
  <brief_title>Imaging Pain Relief in Osteoarthritis</brief_title>
  <acronym>IPRO</acronym>
  <official_title>Functional Brain Imaging to Understand the Mechanisms of Pain Relief in Knee Osteoarthritis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Nottingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Arthritis Research UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Nottingham</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Osteoarthritis (OA) is a degenerative joint disease and is the most common form of arthritis.&#xD;
      Pain reduction and functional recovery are the key elements of the clinical management of OA.&#xD;
      Current treatment guidelines recommend a combination of pharmacological and&#xD;
      non-pharmacological treatments. However, these are not always effective, with nearly 20% of&#xD;
      patients not responding to any standard therapy, including joint replacement.&#xD;
&#xD;
      The mechanisms of pain relief are not well understood and are complicated by the remarkably&#xD;
      large placebo effect, and inter-individual variation. There is no objective criteria for&#xD;
      predicting whether a patient will respond to a given treatment&#xD;
&#xD;
      Duloxetine, an antidepressant drug, has proven effectiveness in various chronic pain&#xD;
      syndromes including knee OA. The effect is however limited and only clinically relevant in&#xD;
      around half of the trial patients. Importantly, it is currently unclear how and in whom&#xD;
      duloxetine alleviates chronic pain.&#xD;
&#xD;
      Advanced MRI techniques use strong magnetic fields and radio frequency signals to generate&#xD;
      metabolic, anatomical and functional brain images (fMRI).&#xD;
&#xD;
      Remifentanil is a potent analgesic agent whose analgesic effect has been well characterised&#xD;
      in healthy volunteers, including fMRI studies showing modulation of activation of regions in&#xD;
      the brain related to pain processing. Nevertheless, the neural correlates of remifentanil&#xD;
      effects have not yet been investigated in chronic pain patients.&#xD;
&#xD;
      The aim of this research is to use a combination of multimodal MRI, genetic and psychometric&#xD;
      assessments to identify the mechanisms of pain relief in knee OA patients, following&#xD;
      treatments with duloxetine and remifentanil, in a placebo controlled condition. With this we&#xD;
      also aim to identify genetic, anatomical and brain activity predictors of treatment outcomes.&#xD;
&#xD;
      The main hypotheses are:&#xD;
&#xD;
        -  Analgesic response to duloxetine treatment can be predicted using a range of baseline&#xD;
           brain imaging markers and QST.&#xD;
&#xD;
        -  Analgesic response to duloxetine is mediated by modulation of neural networks&#xD;
           underpinning emotional control.&#xD;
&#xD;
        -  Duloxetine-induced changes in brain activation differ between responders and&#xD;
           non-responders.&#xD;
&#xD;
      This study is expected to last for two years. It is funded by Arthritis Research United&#xD;
      Kingdom and forms part of a wider scientific investigation, using translational&#xD;
      methodologies, to enhance the understanding of arthritis pain and to improve its treatment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>December 2014</start_date>
  <completion_date type="Actual">June 2016</completion_date>
  <primary_completion_date type="Actual">June 2016</primary_completion_date>
  <phase>Phase 4</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>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction in nociceptive brain response after duloxetine</measure>
    <time_frame>Baseline, week six</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Neural network change (resting condition) induced by duloxetine</measure>
    <time_frame>Baseline, week six</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis</measure>
    <time_frame>Baseline, week six</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences in brain response and network change between responders and non-responders</measure>
    <time_frame>Baseline, week six</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Identification of QST and questionnaire parameters that predict response to duloxetine</measure>
    <time_frame>Baseline, week six</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between baseline CPM and TS with brain activity and connectivity changes</measure>
    <time_frame>Baseline, week six</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Group differences in brain activity and structure in pain processing, limbic and modulatory pathways changes following duloxetine treatment in comparison to placebo</measure>
    <time_frame>Baseline, week six</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Determination of gene variations that can be linked with duloxetine treatment response</measure>
    <time_frame>Baseline, week six</time_frame>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">77</enrollment>
  <condition>Osteoarthritis</condition>
  <condition>Chronic Pain</condition>
  <arm_group>
    <arm_group_label>Duloxetine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (for Duloxetine)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Remifentanil</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo (for Remifentanil)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Intravenous infusion of normal saline, during less than 20 min</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Duloxetine</intervention_name>
    <description>54 participants will be allocated for duloxetine treatment</description>
    <arm_group_label>Duloxetine</arm_group_label>
    <other_name>Cymbalta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Remifentanil</intervention_name>
    <description>27 participants will be allocated to Remifentanil infusion</description>
    <arm_group_label>Remifentanil</arm_group_label>
    <other_name>Remifentanil hydrochloride</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo (for Remifentanil)</intervention_name>
    <description>Placebo comparator to Remifentanil treatment. 27 participants will be allocated to this arm</description>
    <arm_group_label>Placebo (for Remifentanil)</arm_group_label>
    <other_name>Sodium chloride</other_name>
    <other_name>Normal saline</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo (for Duloxetine)</intervention_name>
    <description>Sugar pill manufactured to mimic Duloxetine 30mg. 27 participants will be allocated to this intervention</description>
    <arm_group_label>Placebo (for Duloxetine)</arm_group_label>
    <other_name>Sugar pill</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Radiographically defined OA knee changes with knee pain&#xD;
&#xD;
          -  Must have self-reported knee pain&#xD;
&#xD;
          -  Able to give informed consent&#xD;
&#xD;
          -  Over 35 years old&#xD;
&#xD;
          -  Male or female&#xD;
&#xD;
          -  Females not pregnant or lactating and using effective contraception&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  People with any known contraindication to MRI like&#xD;
&#xD;
               -  Intraocular metallic foreign bodies;&#xD;
&#xD;
               -  Intracranial aneurysm clips;&#xD;
&#xD;
               -  Cardiac pacemakers and defibrillators;&#xD;
&#xD;
               -  Cochlear implants;&#xD;
&#xD;
          -  People with a significant head tremor;&#xD;
&#xD;
          -  People with potential metal foreign bodies due to previous accidents;&#xD;
&#xD;
          -  Breastfeeding or pregnancy, confirmed by pregnancy test;&#xD;
&#xD;
          -  People that are felt to be unfit for the MRI scan according to the judgement of&#xD;
             medically qualified personnel, either on the research team, or the patient's clinical&#xD;
             team. (eg. due to back pain, claustrophobia, acute sickness etc.) This includes&#xD;
             patients with signs of impaired temperature regulation such as an extremely high&#xD;
             fever;&#xD;
&#xD;
          -  Patients with large tattoos, specifically in the head, neck or shoulder region;&#xD;
&#xD;
          -  Persons that do not have the capacity to consent;&#xD;
&#xD;
          -  Aged less than 35;&#xD;
&#xD;
          -  Major medical, neurological and psychiatric co-morbidities;&#xD;
&#xD;
          -  Other significant medical condition;&#xD;
&#xD;
          -  Metallic agents embedded within the body (ie. Shrapnel, surgical pins);&#xD;
&#xD;
          -  Refusal by participant to general practitioner (GP) being informed;&#xD;
&#xD;
          -  Have uncontrolled narrow-angle glaucoma;&#xD;
&#xD;
          -  Have recently taken monoamine oxidase inhibitor (MAOI) or Mellaril® (thioridazine);&#xD;
&#xD;
          -  Taking fluvoxamine, ciprofloxacin or enoxacin;&#xD;
&#xD;
          -  Taking St. John's Wort, a herbal treatment (Hypericum perforatum);&#xD;
&#xD;
          -  Taking other medicines containing duloxetine;&#xD;
&#xD;
          -  Have liver disease or severe kidney disease;&#xD;
&#xD;
          -  Currently on antidepressant treatment, including treatment for pain with tricyclic&#xD;
             agents such as amitryptiline;&#xD;
&#xD;
          -  Have recently taken monoamine oxidase inhibitor (MAOI) or Mellaril® (thioridazine);&#xD;
&#xD;
          -  Taking tramadol;&#xD;
&#xD;
          -  Known hypersensitivity, allergy or intolerance to one of duloxetine's components;&#xD;
&#xD;
          -  Unwillingness to take caution in relation to use of other centrally active substances&#xD;
             such as alcohol and sedative drugs;&#xD;
&#xD;
          -  Current treatment with potent inhibitors of CYP1A2 like fluvoxamine;&#xD;
&#xD;
        Participants undergoing acute treatment (remifentanil or placebo) have, in addition to the&#xD;
        stated above, the following exclusion criteria:&#xD;
&#xD;
          -  Taking morphine&#xD;
&#xD;
          -  Known hypersensitivity, allergy or intolerance to one of remifentanil's components or&#xD;
             other fentanyl - analogues&#xD;
&#xD;
          -  Current treatment with cardiac depressant drugs such as beta-blockers and calcium&#xD;
             channel blocking agents&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dorothee P Auer, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Nottingham</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Nottingham - School of Medicine - Radiological Sciences</name>
      <address>
        <city>Nottingham</city>
        <state>Nottinghamshire</state>
        <zip>NG7 2UH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>August 4, 2014</study_first_submitted>
  <study_first_submitted_qc>August 4, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 5, 2014</study_first_posted>
  <last_update_submitted>November 23, 2017</last_update_submitted>
  <last_update_submitted_qc>November 23, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 27, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Osteoarthritis</keyword>
  <keyword>Chronic Pain</keyword>
  <keyword>Pain relief</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Chronic Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Remifentanil</mesh_term>
    <mesh_term>Duloxetine Hydrochloride</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02208778
org study id: 13124
nct id: NCT02208778
lead sponsor: 
collaborator: 
has dmc: No
Osteoarthritis (OA) is a degenerative joint disease and is the most common form of arthritis.
      Pain reduction and functional recovery are the key elements of the clinical management of OA.
      Current treatment guidelines recommend a combination of pharmacological and
      non-pharmacological treatments. However, these are not always effective, with nearly 20% of
      patients not responding to any standard therapy, including joint replacement.

      The mechanisms of pain relief are not well understood and are complicated by the remarkably
      large placebo effect, and inter-individual variation. There is no objective criteria for
      predicting whether a patient will respond to a given treatment

      Duloxetine, an antidepressant drug, has proven effectiveness in various chronic pain
      syndromes including knee OA. The effect is however limited and only clinically relevant in
      around half of the trial patients. Importantly, it is currently unclear how and in whom
      duloxetine alleviates chronic pain.

      Advanced MRI techniques use strong magnetic fields and radio frequency signals to generate
      metabolic, anatomical and functional brain images (fMRI).

      Remifentanil is a potent analgesic agent whose analgesic effect has been well characterised
      in healthy volunteers, including fMRI studies showing modulation of activation of regions in
      the brain related to pain processing. Nevertheless, the neural correlates of remifentanil
      effects have not yet been investigated in chronic pain patients.

      The aim of this research is to use a combination of multimodal MRI, genetic and psychometric
      assessments to identify the mechanisms of pain relief in knee OA patients, following
      treatments with duloxetine and remifentanil, in a placebo controlled condition. With this we
      also aim to identify genetic, anatomical and brain activity predictors of treatment outcomes.

      The main hypotheses are:

        -  Analgesic response to duloxetine treatment can be predicted using a range of baseline
           brain imaging markers and QST.

        -  Analgesic response to duloxetine is mediated by modulation of neural networks
           underpinning emotional control.

        -  Duloxetine-induced changes in brain activation differ between responders and
           non-responders.

      This study is expected to last for two years. It is funded by Arthritis Research United
      Kingdom and forms part of a wider scientific investigation, using translational
      methodologies, to enhance the understanding of arthritis pain and to improve its treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Reduction in nociceptive brain response after duloxetine
time frame: Baseline, week six
measure: Neural network change (resting condition) induced by duloxetine
time frame: Baseline, week six
measure: Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis
time frame: Baseline, week six
measure: Differences in brain response and network change between responders and non-responders
time frame: Baseline, week six
measure: Identification of QST and questionnaire parameters that predict response to duloxetine
time frame: Baseline, week six
measure: Correlation between baseline CPM and TS with brain activity and connectivity changes
time frame: Baseline, week six
measure: Group differences in brain activity and structure in pain processing, limbic and modulatory pathways changes following duloxetine treatment in comparison to placebo
time frame: Baseline, week six
measure: Determination of gene variations that can be linked with duloxetine treatment response
time frame: Baseline, week six
arm group label: Duloxetine
arm group type: Experimental
description: Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth
arm group label: Placebo (for Duloxetine)
arm group type: Placebo Comparator
description: Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth
arm group label: Remifentanil
arm group type: Experimental
description: Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes
arm group label: Placebo (for Remifentanil)
arm group type: Placebo Comparator
description: Intravenous infusion of normal saline, during less than 20 min
intervention type: Drug
intervention name: Duloxetine
description: 54 participants will be allocated for duloxetine treatment
arm group label: Duloxetine
other name: Cymbalta
intervention type: Drug
intervention name: Remifentanil
description: 27 participants will be allocated to Remifentanil infusion
arm group label: Remifentanil
other name: Remifentanil hydrochloride
intervention type: Drug
intervention name: Placebo (for Remifentanil)
description: Placebo comparator to Remifentanil treatment. 27 participants will be allocated to this arm
arm group label: Placebo (for Remifentanil)
other name: Sodium chloride
other name: Normal saline
intervention type: Drug
intervention name: Placebo (for Duloxetine)
description: Sugar pill manufactured to mimic Duloxetine 30mg. 27 participants will be allocated to this intervention
arm group label: Placebo (for Duloxetine)
other name: Sugar pill
criteria: 
gender: All
minimum age: 35 Years
maximum age: N/A
healthy volunteers: No
last name: Dorothee P Auer, PhD
role: Principal Investigator
affiliation: University of Nottingham
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Osteoarthritis
mesh term: Chronic Pain
mesh term: Remifentanil
mesh term: Duloxetine Hydrochloride