xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05986513</url>
    </required_header>
    <id_info>
      <org_study_id>OAKneeMRI</org_study_id>
      <nct_id>NCT05986513</nct_id>
    </id_info>
    <brief_title>Brain MRI for Knee OA</brief_title>
    <official_title>Investigating Brain Abnormalities in People With Knee Osteoarthritis Using MRI: a Nociplastic Pain Mechanism Based Assessment</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Toronto Rehabilitation Institute</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>McMaster University</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Toronto Rehabilitation Institute</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>
        It has been estimated that 300 million people worldwide have osteoarthritis (OA), and this&#xD;
        has increased by 97% over the past 25 years. OA is degenerative joint disease that has joint&#xD;
        cartilage break down and causes the surrounding bone to change and rub. The pain and loss of&#xD;
        mobility experienced by people with knee OA can seriously reduce quality of life, while pain&#xD;
        management causes significant healthcare spending. Unfortunately, the pain associated with OA&#xD;
        is complex and difficult to treat other than to have a total knee replacement surgery to&#xD;
        replace the damaged bone and surrounding tissues with artificial ones. Our research study&#xD;
        plans to use advanced magnetic resonance imaging techniques and novel analysis methods to&#xD;
        determine if specific parts of the brain are responsible for difficult to describe and&#xD;
        diagnose aspects of chronic pain. This study will help us better understand the effects of&#xD;
        chronic pain in the brain and the results will help guide future research into new&#xD;
        therapeutic options that would focus on relieving the brain dysfunction caused by chronic&#xD;
        pain.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Chronic pain and knee osteoarthritis - context and gap&#xD;
  &#xD;
        Chronic pain is a debilitating concern that can affect the health, employment, and lifestyle&#xD;
        of individuals and puts a tremendous strain on the healthcare system. The prevalence of&#xD;
        osteoarthritis (OA) is estimated at over 650 million worldwide, and people with knee OA&#xD;
        account for 80% of the total burden (Cui et al. 2020). Globally in 2017, knee OA had a&#xD;
        prevalence of 263,086,500 and incidence of 12,888,400 (James et al. 2018). A recent study&#xD;
        also found that between 19%-43% of adults 40 years and older had knee OA markers, detected&#xD;
        using magnetic resonance imaging (MRI), but were asymptomatic (Culvenor et al. 2019). It is&#xD;
        estimated that more than 10 million Canadians will have knee OA by the year 2040 (Bombardier&#xD;
        et al. 2011) significantly contributing to OA healthcare costs of 1.45 trillion (Bombardier&#xD;
        et al. 2011; Sharif et al. 2017). The severity of pain and its impact on function have been&#xD;
        identified by people living with knee OA as two of the most important effects of the disease&#xD;
        (Smith et al. 2014), contributing to reduced quality of life (Neogi et al. 2013).&#xD;
        Uncontrolled OA joint pain is associated with increased healthcare use, therefore improving&#xD;
        pain management for OA in Canada may result in a significant healthcare expenditure savings&#xD;
        of up to $488 billion (Bombardier et al. 2011). The pain experience and its associated&#xD;
        mechanisms in people with knee OA are known to be complex, with alterations in pain&#xD;
        signalling (Fingleton et al. 2015) a major factor in susceptibility to the development of&#xD;
        persistent pain (Carlesso et al. 2019). Changes in nervous system sensitization do not&#xD;
        necessarily correlate with changes in pain, demonstrating that other factors modulating pain,&#xD;
        a top-down process, are at play (Skou et al. 2016; Edwards et la. 2016). Interestingly,&#xD;
        between 10-20% of knee OA patients continue to experience intense pain even after a total&#xD;
        knee replacement indicating that mechanisms beyond those involving joint structures are&#xD;
        likely contributing to a complex pain process (Baker et la. 2007; Lundblad et al. 2008; Rice&#xD;
        et al. 2018). In a disease where the joint is viewed as an organ in failure (Loeser et al.&#xD;
        2012), phenotyping is necessary to make sense of the heterogeneity. Specific to knee&#xD;
        osteoarthritis (OA), pain is associated with changes in the joint structure due to&#xD;
        inflammation (e.g., synovitis)(Dainese et al. 2022) or bone marrow lesions (Aso et al. 2021),&#xD;
        but the underlying mechanisms are not fully understood (Gwilym et al. 2008).&#xD;
  &#xD;
        Nociceptive, neuropathic, and nociplastic pain&#xD;
  &#xD;
        In general, pain of known origin falls under two categories based on the cause: (i)&#xD;
        nociceptive: pain caused by damage to a bodily tissue; (ii) neuropathic: pain caused by&#xD;
        damage to a nerve or nervous system. However, chronic pain that is present without&#xD;
        discernable nociceptive or neuropathic components is classified as nociplastic pain (IASP&#xD;
        2022). A recent study by Kosek et al. (2021) developed a simple scale for nociplastic pain&#xD;
        diagnosis for clinical pain assessment based on i) the duration/regionality/type of pain, ii)&#xD;
        history of hypersensitivities, iii) comorbidity identification, and iv) evoked pain&#xD;
        hypersensitivity (Kosek et al 2021). As a visual representation, the Michigan Body Map (MBM)&#xD;
        has been validated as a rapid and reliable tool for patients to identify general bodily&#xD;
        regions where they experience chronic pain (Brummett et al. 2016). The MBM is a useful and&#xD;
        simple tool to determine if pain is localized (i.e., likely nociceptive or neuropathic pain)&#xD;
        or widespread (i.e., likely nociplastic pain)(Brummett et al. 2016). To address the unknown&#xD;
        chronic pain mechanisms and pain presenting beyond nociceptive or neuropathic injuries,&#xD;
        research has been focused on the theory of central sensitization as a phenomenon of&#xD;
        nociplastic pain (Fitzcharles et al. 2021; Walsh 2021). The concept of central sensitization&#xD;
        is that dysfunction in the central nervous system results in hypersensitivity to noxious and&#xD;
        innocuous stimuli (de Boer et al. 2019; Neblett et al. 2013).&#xD;
  &#xD;
        Current methods for nociplastic pain assessment&#xD;
  &#xD;
        One method being used to examine nociceptive pain is functional magnetic resonance imaging&#xD;
        (fMRI) data to measure the neurologic pain signature (NPS)(Han et al. 2022; Wager et al.&#xD;
        2013). The data collected from fMRIs is the brain's blood-oxygen level dependent (BOLD)&#xD;
        signal which is closely connected to neurophysiological activation of the brain, and the&#xD;
        signal fluctuates based on diamagnetic properties of deoxygenated blood and changes to blood&#xD;
        flow and volume to activated or deactivated parts of the brain (Ogawa et al. 1990). The NPS&#xD;
        has been shown to be a robust metric for quantitatively assessing the brain's activation in&#xD;
        response to pain (Han et al. 2022; Wager et al. 2013). Based on the NPS, humans have several&#xD;
        brain regions with key involvement in nociceptive pain interpretation that have&#xD;
        proportionately increased or decreased activity relative to an individual's pain (Wager et&#xD;
        al. 2013). The activation pattern of the NPS has been shown to be responsive to different&#xD;
        forms of quantitative sensory testing (QST) such as thermal, mechanical (Wager et al. 2013),&#xD;
        and electrical perturbations (Choi et al. 2011; Rütgen et al. 2015).&#xD;
  &#xD;
        In women with chronic joint pain, there is evidence of cortical thinning related to chronic&#xD;
        pain that exceeds that of normal aging, especially in the hippocampus, thalamus, and anterior&#xD;
        cingulate cortex (de Kruijf et al. 2016). Within the context of OA, several studies have&#xD;
        explored the effects of knee OA on fMRI activation changes (López-Solà et al. 2022; Pujol et&#xD;
        al. 2017; Yue et al. 2018; Zunhammer et al. 2018). In summary, the studies indicate the BOLD&#xD;
        signal is regionally elevated in patients with knee OA, but can be reduced by non-steroidal&#xD;
        anti-inflammatory drugs (López-Solà et al. 2022) and analgesics (Yue et al. 2018). Spreading&#xD;
        pain and heightened widespread pain sensitivity with corresponding brain abnormalities are&#xD;
        commonly found in patients with knee OA (Pujol et al. 2017), and these pain-related brain&#xD;
        abnormalities are distinct from potential psychological biases of placebos (Zunhammer et al.&#xD;
        2018).&#xD;
  &#xD;
        To address the challenges of identifying the underlying pain mechanisms and providing&#xD;
        patient-focused results, our research group has developed an analysis method for resting&#xD;
        state fMRI (rsfMRI) and diffusion tensor imaging (DTI) that applies a personalized analysis.&#xD;
        Based on the previous research using the NPS, the investigators expect to find regional brain&#xD;
        alterations caused by pain that could improve our understanding of chronic pain that are also&#xD;
        unique to each patient with knee OA. With our novel analysis, each patient with knee OA will&#xD;
        have their MRI data compared to over 88 age- and sex-matched controls and a Z-scoring&#xD;
        methodology can identify and objectively quantify abnormal brain regions. This can be applied&#xD;
        as a compliment to clinical pain tests and more standard group-wise MRI analyses such as the&#xD;
        NPS and functional networks.&#xD;
  &#xD;
        While MRI has been useful in indicating brain regions altered by pain, inflammation and&#xD;
        excitotoxicity may be underlying pathophysiologies behind nociplastic pain. A possible&#xD;
        mechanistic pathway is that of kynurenine, having been linked to several inflammatory&#xD;
        conditions, that can be neuroprotective if metabolized into kynurenic acid but neurotoxic if&#xD;
        metabolized into quinolinic acid (Savitz 2020; Schwarcz and Stone 2017). Kynurenine is a&#xD;
        metabolite of tryptophan and is detectable peripherally using the 13C-Tryptophan Breath Test&#xD;
        (13C-TBT)(Teraishi et al. 2015). Although kynurenine has been researched for depression&#xD;
        (Teraishi et al. 2015), there is mechanistic overlap at N-methyl-D-aspartate (NMDA) receptors&#xD;
        between chronic pain and depression (Savitz 2020; Teraishi et al. 2015; Brandl et al. 2022).&#xD;
        Two metabolomic studies of OA patients found decreased tryptophan concentrations (Abdelrazig&#xD;
        et al. 2021; Van Pevenage et al. 2022), thus forming the possibility that the kynurenine&#xD;
        pathways may be a useful bioindicator for OA.&#xD;
  &#xD;
        Our solution for chronic nociplastic pain assessment&#xD;
  &#xD;
        This proposed study will be a quantitative examination of nociplastic pain in patients with&#xD;
        knee OA. Therefore, the primary objective for this study is to determine if chronic pain,&#xD;
        more specifically chronic nociplastic pain, causes neuroplastic brain alterations. It is&#xD;
        hypothesized that people with localized chronic pain (OA-Knee) and widespread chronic pain&#xD;
        (OA-Knee+Body) exhibit abnormal brain function (e.g., network connectivity and ROI&#xD;
        complexity) and reduced microstructural integrity of brain white matter (e.g., decreased&#xD;
        fractional anisotropy), that would also be proportionately associated with pain sensitivity&#xD;
        and mental state, in comparison to similarly aged individuals with knee osteoarthritis&#xD;
        without chronic pain.&#xD;
  &#xD;
        The cohort of participants will be separated into three patient groups: the control group&#xD;
        will include participants with knee OA but no pain (Osteoarthritis - pain free (OA-PF)), the&#xD;
        first exploratory group would include participants with knee OA with pain at the knee&#xD;
        (OA-Knee), and the second exploratory group, indicative of chronic nociplastic pain would&#xD;
        include people with knee OA with knee and widespread body pain (OA-Knee+Body). Participants&#xD;
        in the OA-Knee+Body group will be representative of chronic pain patients presenting with&#xD;
        nociplastic pain based on several clinical pain tests (e.g., Nociplastic pain criteria (Kosek&#xD;
        et al. 2021), Michigan Body Map (Brummett et al. 2016), knee and wrist QST). Widespread&#xD;
        bodily pain will be determined by identifying pain in &gt;3 body regions on the Michigan Body&#xD;
        Map and experiencing pain the knee and wrist pain pressure test. This study is designed to&#xD;
        acquire resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) MRI data at&#xD;
        baseline and after experimentally induced pain (i.e., Cold Pressor Gel Test (Lapotka et al.&#xD;
        2017)), and compare the MRI data to clinical pain test results. The exploratory outcomes are&#xD;
        to examine if there neuroinflammatory group differences based on the results of the 13C-TBT&#xD;
        data.&#xD;
  &#xD;
        Study Design&#xD;
  &#xD;
        Study participants will be asked to complete a screening appointment over the phone prior to&#xD;
        a data collection visit. Prospective participants will be notified of our study by their&#xD;
        rheumatologist (i.e., Dr. Adachi) and will contact Dr. Danielli via email if they are&#xD;
        interested in participating. Prospective participants will then contact Dr. Danielli to&#xD;
        arrange a phone call to verbally obtain consent and perform the screening questions to&#xD;
        determine eligibility. The screening visit will take about 30 minutes with Dr. Danielli. As&#xD;
        part of the screening process prospective participants will be asked to complete the&#xD;
        Nociplastic Pain Criteria (Kosek et al. 2021), the DSM-V Alcohol Use Disorder questionnaire,&#xD;
        provide demographic information (i.e., to have balanced age and sex recruitment), and&#xD;
        identify possible MRI contraindications. If someone is eligible to participate, an&#xD;
        appointment will be then booked for the data collection study visit. All prospective&#xD;
        participants will have been diagnosed with knee OA by their rheumatologist and the screening&#xD;
        visit will be done to categorize participants into one of three study groups and efficiently&#xD;
        book a data collection visit.&#xD;
  &#xD;
        Informed written consent will be obtained in accordance with the World Medical Association&#xD;
        Declaration of Helsinki prior to any data collection at the data collection study visit. All&#xD;
        participants will receive the same data collection protocols. Depending on the preference of&#xD;
        the participants, screening and data will be collected at either the Imaging Research Centre&#xD;
        (IRC) at St. Joseph's Healthcare Hamilton or the Joint Department of Medical Imaging (JDMI)&#xD;
        at Toronto Western Hospital. The questionnaires (i.e., the Depression Anxiety Stress Scale&#xD;
        (DASS42)(Crawford et al. 2003), Intermittent and Constant Osteoarthritis Pain (ICOAP)(Hawker&#xD;
        et al. 2008; Hawker et al. 2011), and Brief Pain Inventory (BPI)(Cleeland et al. 1991)), and&#xD;
        participants will also have a wrist and knee pressure pain threshold tests; these will take&#xD;
        about 15 minutes to complete. The baseline and secondary MRI acquisitions would take about 45&#xD;
        minutes each. Participants will be given 5-10 minutes between MRI scan sessions to take a&#xD;
        break and stretch their legs. The data collection study visit will last about 2 hours.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">August 31, 2025</completion_date>
    <primary_completion_date type="Anticipated">May 1, 2025</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>Adults who have been clinically diagnosed with knee osteoarthritis (pain free, localized knee pain, or knee and widespread pain) will all receive the same intervention and study protocol.</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Single (Outcomes Assessor)</masking>
      <masking_description>The MRI analysis methods are quantitative and unbiased by convention. Furthermore, they will require the researcher to input the age and sex of the participant and indicate if the participant was a healthy control or experimental to allow for group comparisons, but that will not influence the analyses or outcomes.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Group and individual differences at baseline and post-intervention</measure>
      <time_frame>2 hours</time_frame>
      <description>The primary objective is to determine if chronic pain, more specifically chronic nociplastic pain, causes neuroplastic brain alterations. It is hypothesized that people with localized chronic pain (OA-Knee) and widespread chronic pain (OA-Knee+Body) would exhibit abnormal brain function (e.g., network connectivity and ROI complexity) and reduced microstructural integrity of brain white matter, that would also be proportionately associated with pain sensitivity and mental state, in comparison to similarly aged individuals with knee osteoarthritis without chronic pain.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Presence of neuroinflammation</measure>
      <time_frame>2 hours</time_frame>
      <description>The exploratory objective of this study involves peripherally measuring neuroinflammation using the 13C Tryptophan Breath Test (13C-TBT). This test allows our research team to collect exhaled breath samples at multiple time intervals during the data collection study visit after oral consumption of the L-[1-13C]tryptophan and water solution, which based on the metabolism of the labelled tryptophan is a peripheral bioindicator for the presence of neuroinflammation.</description>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">66</enrollment>
    <condition>Chronic Pain</condition>
    <condition>Central Sensitisation</condition>
    <condition>Knee Osteoarthritis</condition>
    <arm_group>
      <arm_group_label>OA-PF</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Individuals with knee OA without knee or bodily pain. All participants will complete the same study protocol with pre- post-perturbation MRI scans and pain assessment questionnaires, as well as breath samples collected at multiple time points during the study visit.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>OA-Knee</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Individuals with knee OA with localized knee pain. All participants will complete the same study protocol with pre- post-perturbation MRI scans and pain assessment questionnaires, as well as breath samples collected at multiple time points during the study visit.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>OA-Knee+Body</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Individuals with knee OA with localized knee pain and widespread bodily pain. All participants will complete the same study protocol with pre- post-perturbation MRI scans and pain assessment questionnaires, as well as breath samples collected at multiple time points during the study visit.</description>
    </arm_group>
    <intervention>
      <intervention_type>Behavioral</intervention_type>
      <intervention_name>Cold Pressor Gel Test</intervention_name>
      <description>This test will allow the research team to induce a painful sensation in participants in a safe, non-invasive, standardized, and short-lasting manner. The protocol for the cold pressor gel test is simple: participants will place their non-dominant hand in the container of cold water for as long as they can up to a maximum of two minutes. If it becomes too painful or uncomfortable during those two minutes, participants can remove their hand from the container. It should be noted again that this is not a treatment for knee OA or chronic pain and will be used to investigate the effects of acute pain in the brain of individuals with a chronic pain condition.</description>
      <arm_group_label>OA-Knee</arm_group_label>
      <arm_group_label>OA-Knee+Body</arm_group_label>
      <arm_group_label>OA-PF</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Clinical diagnosis and radiographic evidence of knee OA (by rheumatologist).&#xD;
  &#xD;
            2. For the two experimental groups (Groups OA-Knee and OA-Knee+Body), participants must&#xD;
               have experienced chronic pain related to their knee OA (&gt;3 months) on most days of&#xD;
               each month.&#xD;
  &#xD;
            3. Participants in Group OA-Knee+Body must:&#xD;
  &#xD;
                 -  Exhibit chronic knee pain and widespread bodily pain at &gt;3 Michigan Body Map&#xD;
                    regions.&#xD;
  &#xD;
                 -  Meet the Kosek criteria for nociplastic pain: i) the duration/regionality/type of&#xD;
                    pain, ii) history of hypersensitivities, iii) comorbidity identification, and iv)&#xD;
                    evoked pain hypersensitivity [19]&#xD;
  &#xD;
            4. Participants must be able to speak and understand English.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Unable to provide consent (e.g., poor English language skills, etc.)&#xD;
  &#xD;
            2. History of liver or kidney disease&#xD;
  &#xD;
            3. MRI contraindications:&#xD;
  &#xD;
                 -  Pacemaker&#xD;
  &#xD;
                 -  Stent&#xD;
  &#xD;
                 -  Joint prothesis&#xD;
  &#xD;
                 -  Implanted devices&#xD;
  &#xD;
                 -  Claustrophobia&#xD;
  &#xD;
                 -  Pregnant&#xD;
  &#xD;
                 -  Permanent piercings&#xD;
  &#xD;
            4. Chronic/abusive use of alcohol and/or illicit drugs&#xD;
  &#xD;
            5. Previous clinical diagnosis of fibromyalgia, a multisite pain disorder, a systemic&#xD;
               inflammatory disorder (e.g., rheumatoid arthritis, myopathy), depression,&#xD;
               post-traumatic stress disorder&#xD;
  &#xD;
            6. Previous stroke or moderate/severe traumatic brain injury, subarachnoid hemorrhage, or&#xD;
               intracranial hemorrhage&#xD;
  &#xD;
            7. Use of psychotropic medications&#xD;
  &#xD;
            8. Control subjects (Group OA-PF) also cannot have a history of chronic pain or knee pain&#xD;
               caused by osteoporosis or osteoarthritis&#xD;
  &#xD;
            9. Total knee replacement&#xD;
  &#xD;
           10. Pregnant or chance of being pregnant&#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>Dinesh Kumbhare, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>University Health Network, Toronto</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Michael D Noseworthy, PhD, PEng</last_name>
      <role>Principal Investigator</role>
      <affiliation>McMaster University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Dinesh Kumbhare, MD, PhD</last_name>
      <phone>416 597 3422</phone>
      <phone_ext>4612</phone_ext>
      <email>dinesh.kumbhare@uhn.ca</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Ethan Danielli, PhD</last_name>
      <email>ethan.danielli@uhn.ca</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Imaging Research Centre, St. Joseph's Healthcare Hamilton</name>
        <address>
          <city>Hamilton</city>
          <state>Ontario</state>
          <zip>L8P 2J5</zip>
          <country>Canada</country>
        </address>
      </facility>
      <contact>
        <last_name>Ethan Danielli, PhD</last_name>
        <email>ethan.danielli@uhn.ca</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>Toronto Rehabilitation Institute</name>
        <address>
          <city>Toronto</city>
          <state>Ontario</state>
          <zip>M5G 2A2</zip>
          <country>Canada</country>
        </address>
      </facility>
      <contact>
        <last_name>Ethan Danielli, PhD</last_name>
        <email>ethan.danielli@uhn.ca</email>
      </contact>
    </location>
    <location_countries>
      <country>Canada</country>
    </location_countries>
    <link>
      <url>https://www.arthritisalliance.ca/en/initiativesen/impact-of-arthritis</url>
      <description>Bombardier C, Hawker G, Mosher D. (2011) The impact of arthritis in Canada: today and over the next 30 years. The Arthritis Alliance of Canada.</description>
    </link>
    <link>
      <url>http://www.iasp-pain.org/resources/terminology/</url>
      <description>International Association for the Study of Pain (IASP). IASP Terminology. [Accessed on 30 November 2022].</description>
    </link>
    <reference>
      <citation>Cui A, Li H, Wang D, Zhong J, Chen Y, Lu H. Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. EClinicalMedicine. 2020 Nov 26;29-30:100587. doi: 10.1016/j.eclinm.2020.100587. eCollection 2020 Dec.</citation>
      <PMID>34505846</PMID>
    </reference>
    <reference>
      <citation>GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018 Nov 10;392(10159):1789-1858. doi: 10.1016/S0140-6736(18)32279-7. Epub 2018 Nov 8. Erratum In: Lancet. 2019 Jun 22;393(10190):e44.</citation>
      <PMID>30496104</PMID>
    </reference>
    <reference>
      <citation>Culvenor AG, Oiestad BE, Hart HF, Stefanik JJ, Guermazi A, Crossley KM. Prevalence of knee osteoarthritis features on magnetic resonance imaging in asymptomatic uninjured adults: a systematic review and meta-analysis. Br J Sports Med. 2019 Oct;53(20):1268-1278. doi: 10.1136/bjsports-2018-099257. Epub 2018 Jun 9.</citation>
      <PMID>29886437</PMID>
    </reference>
    <reference>
      <citation>Sharif B, Kopec JA, Wong H, Anis AH. Distribution and Drivers of Average Direct Cost of Osteoarthritis in Canada From 2003 to 2010. Arthritis Care Res (Hoboken). 2017 Feb;69(2):243-251. doi: 10.1002/acr.22933.</citation>
      <PMID>27159532</PMID>
    </reference>
    <reference>
      <citation>Smith TO, Purdy R, Lister S, Salter C, Fleetcroft R, Conaghan P. Living with osteoarthritis: a systematic review and meta-ethnography. Scand J Rheumatol. 2014;43(6):441-52. doi: 10.3109/03009742.2014.894569. Epub 2014 Jun 2.</citation>
      <PMID>24882107</PMID>
    </reference>
    <reference>
      <citation>Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage. 2013 Sep;21(9):1145-53. doi: 10.1016/j.joca.2013.03.018.</citation>
      <PMID>23973124</PMID>
    </reference>
    <reference>
      <citation>Fingleton C, Smart K, Moloney N, Fullen BM, Doody C. Pain sensitization in people with knee osteoarthritis: a systematic review and meta-analysis. Osteoarthritis Cartilage. 2015 Jul;23(7):1043-56. doi: 10.1016/j.joca.2015.02.163. Epub 2015 Mar 5.</citation>
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    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 3, 2023</study_first_submitted>
    <study_first_submitted_qc>August 3, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 15, 2023</last_update_submitted>
    <last_update_submitted_qc>August 15, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 18, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Toronto Rehabilitation Institute</investigator_affiliation>
      <investigator_full_name>Dinesh Kumbhare</investigator_full_name>
      <investigator_title>Scientist</investigator_title>
    </responsible_party>
    <keyword>functional magnetic resonance imaging</keyword>
    <keyword>diffusion tensor imaging</keyword>
    <keyword>nociplastic pain</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Osteoarthritis</mesh_term>
      <mesh_term>Osteoarthritis, Knee</mesh_term>
      <mesh_term>Chronic Pain</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>The data collected for this study will not be shared with researchers outside of the research team.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05986513
  org study id: OAKneeMRI
  nct id: NCT05986513
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  It has been estimated that 300 million people worldwide have osteoarthritis (OA), and this
        has increased by 97% over the past 25 years. OA is degenerative joint disease that has joint
        cartilage break down and causes the surrounding bone to change and rub. The pain and loss of
        mobility experienced by people with knee OA can seriously reduce quality of life, while pain
        management causes significant healthcare spending. Unfortunately, the pain associated with OA
        is complex and difficult to treat other than to have a total knee replacement surgery to
        replace the damaged bone and surrounding tissues with artificial ones. Our research study
        plans to use advanced magnetic resonance imaging techniques and novel analysis methods to
        determine if specific parts of the brain are responsible for difficult to describe and
        diagnose aspects of chronic pain. This study will help us better understand the effects of
        chronic pain in the brain and the results will help guide future research into new
        therapeutic options that would focus on relieving the brain dysfunction caused by chronic
        pain.
  Chronic pain and knee osteoarthritis - context and gap
  
        Chronic pain is a debilitating concern that can affect the health, employment, and lifestyle
        of individuals and puts a tremendous strain on the healthcare system. The prevalence of
        osteoarthritis (OA) is estimated at over 650 million worldwide, and people with knee OA
        account for 80% of the total burden (Cui et al. 2020). Globally in 2017, knee OA had a
        prevalence of 263,086,500 and incidence of 12,888,400 (James et al. 2018). A recent study
        also found that between 19%-43% of adults 40 years and older had knee OA markers, detected
        using magnetic resonance imaging (MRI), but were asymptomatic (Culvenor et al. 2019). It is
        estimated that more than 10 million Canadians will have knee OA by the year 2040 (Bombardier
        et al. 2011) significantly contributing to OA healthcare costs of 1.45 trillion (Bombardier
        et al. 2011; Sharif et al. 2017). The severity of pain and its impact on function have been
        identified by people living with knee OA as two of the most important effects of the disease
        (Smith et al. 2014), contributing to reduced quality of life (Neogi et al. 2013).
        Uncontrolled OA joint pain is associated with increased healthcare use, therefore improving
        pain management for OA in Canada may result in a significant healthcare expenditure savings
        of up to $488 billion (Bombardier et al. 2011). The pain experience and its associated
        mechanisms in people with knee OA are known to be complex, with alterations in pain
        signalling (Fingleton et al. 2015) a major factor in susceptibility to the development of
        persistent pain (Carlesso et al. 2019). Changes in nervous system sensitization do not
        necessarily correlate with changes in pain, demonstrating that other factors modulating pain,
        a top-down process, are at play (Skou et al. 2016; Edwards et la. 2016). Interestingly,
        between 10-20% of knee OA patients continue to experience intense pain even after a total
        knee replacement indicating that mechanisms beyond those involving joint structures are
        likely contributing to a complex pain process (Baker et la. 2007; Lundblad et al. 2008; Rice
        et al. 2018). In a disease where the joint is viewed as an organ in failure (Loeser et al.
        2012), phenotyping is necessary to make sense of the heterogeneity. Specific to knee
        osteoarthritis (OA), pain is associated with changes in the joint structure due to
        inflammation (e.g., synovitis)(Dainese et al. 2022) or bone marrow lesions (Aso et al. 2021),
        but the underlying mechanisms are not fully understood (Gwilym et al. 2008).
  
        Nociceptive, neuropathic, and nociplastic pain
  
        In general, pain of known origin falls under two categories based on the cause: (i)
        nociceptive: pain caused by damage to a bodily tissue; (ii) neuropathic: pain caused by
        damage to a nerve or nervous system. However, chronic pain that is present without
        discernable nociceptive or neuropathic components is classified as nociplastic pain (IASP
        2022). A recent study by Kosek et al. (2021) developed a simple scale for nociplastic pain
        diagnosis for clinical pain assessment based on i) the duration/regionality/type of pain, ii)
        history of hypersensitivities, iii) comorbidity identification, and iv) evoked pain
        hypersensitivity (Kosek et al 2021). As a visual representation, the Michigan Body Map (MBM)
        has been validated as a rapid and reliable tool for patients to identify general bodily
        regions where they experience chronic pain (Brummett et al. 2016). The MBM is a useful and
        simple tool to determine if pain is localized (i.e., likely nociceptive or neuropathic pain)
        or widespread (i.e., likely nociplastic pain)(Brummett et al. 2016). To address the unknown
        chronic pain mechanisms and pain presenting beyond nociceptive or neuropathic injuries,
        research has been focused on the theory of central sensitization as a phenomenon of
        nociplastic pain (Fitzcharles et al. 2021; Walsh 2021). The concept of central sensitization
        is that dysfunction in the central nervous system results in hypersensitivity to noxious and
        innocuous stimuli (de Boer et al. 2019; Neblett et al. 2013).
  
        Current methods for nociplastic pain assessment
  
        One method being used to examine nociceptive pain is functional magnetic resonance imaging
        (fMRI) data to measure the neurologic pain signature (NPS)(Han et al. 2022; Wager et al.
        2013). The data collected from fMRIs is the brain's blood-oxygen level dependent (BOLD)
        signal which is closely connected to neurophysiological activation of the brain, and the
        signal fluctuates based on diamagnetic properties of deoxygenated blood and changes to blood
        flow and volume to activated or deactivated parts of the brain (Ogawa et al. 1990). The NPS
        has been shown to be a robust metric for quantitatively assessing the brain's activation in
        response to pain (Han et al. 2022; Wager et al. 2013). Based on the NPS, humans have several
        brain regions with key involvement in nociceptive pain interpretation that have
        proportionately increased or decreased activity relative to an individual's pain (Wager et
        al. 2013). The activation pattern of the NPS has been shown to be responsive to different
        forms of quantitative sensory testing (QST) such as thermal, mechanical (Wager et al. 2013),
        and electrical perturbations (Choi et al. 2011; Rütgen et al. 2015).
  
        In women with chronic joint pain, there is evidence of cortical thinning related to chronic
        pain that exceeds that of normal aging, especially in the hippocampus, thalamus, and anterior
        cingulate cortex (de Kruijf et al. 2016). Within the context of OA, several studies have
        explored the effects of knee OA on fMRI activation changes (López-Solà et al. 2022; Pujol et
        al. 2017; Yue et al. 2018; Zunhammer et al. 2018). In summary, the studies indicate the BOLD
        signal is regionally elevated in patients with knee OA, but can be reduced by non-steroidal
        anti-inflammatory drugs (López-Solà et al. 2022) and analgesics (Yue et al. 2018). Spreading
        pain and heightened widespread pain sensitivity with corresponding brain abnormalities are
        commonly found in patients with knee OA (Pujol et al. 2017), and these pain-related brain
        abnormalities are distinct from potential psychological biases of placebos (Zunhammer et al.
        2018).
  
        To address the challenges of identifying the underlying pain mechanisms and providing
        patient-focused results, our research group has developed an analysis method for resting
        state fMRI (rsfMRI) and diffusion tensor imaging (DTI) that applies a personalized analysis.
        Based on the previous research using the NPS, the investigators expect to find regional brain
        alterations caused by pain that could improve our understanding of chronic pain that are also
        unique to each patient with knee OA. With our novel analysis, each patient with knee OA will
        have their MRI data compared to over 88 age- and sex-matched controls and a Z-scoring
        methodology can identify and objectively quantify abnormal brain regions. This can be applied
        as a compliment to clinical pain tests and more standard group-wise MRI analyses such as the
        NPS and functional networks.
  
        While MRI has been useful in indicating brain regions altered by pain, inflammation and
        excitotoxicity may be underlying pathophysiologies behind nociplastic pain. A possible
        mechanistic pathway is that of kynurenine, having been linked to several inflammatory
        conditions, that can be neuroprotective if metabolized into kynurenic acid but neurotoxic if
        metabolized into quinolinic acid (Savitz 2020; Schwarcz and Stone 2017). Kynurenine is a
        metabolite of tryptophan and is detectable peripherally using the 13C-Tryptophan Breath Test
        (13C-TBT)(Teraishi et al. 2015). Although kynurenine has been researched for depression
        (Teraishi et al. 2015), there is mechanistic overlap at N-methyl-D-aspartate (NMDA) receptors
        between chronic pain and depression (Savitz 2020; Teraishi et al. 2015; Brandl et al. 2022).
        Two metabolomic studies of OA patients found decreased tryptophan concentrations (Abdelrazig
        et al. 2021; Van Pevenage et al. 2022), thus forming the possibility that the kynurenine
        pathways may be a useful bioindicator for OA.
  
        Our solution for chronic nociplastic pain assessment
  
        This proposed study will be a quantitative examination of nociplastic pain in patients with
        knee OA. Therefore, the primary objective for this study is to determine if chronic pain,
        more specifically chronic nociplastic pain, causes neuroplastic brain alterations. It is
        hypothesized that people with localized chronic pain (OA-Knee) and widespread chronic pain
        (OA-Knee+Body) exhibit abnormal brain function (e.g., network connectivity and ROI
        complexity) and reduced microstructural integrity of brain white matter (e.g., decreased
        fractional anisotropy), that would also be proportionately associated with pain sensitivity
        and mental state, in comparison to similarly aged individuals with knee osteoarthritis
        without chronic pain.
  
        The cohort of participants will be separated into three patient groups: the control group
        will include participants with knee OA but no pain (Osteoarthritis - pain free (OA-PF)), the
        first exploratory group would include participants with knee OA with pain at the knee
        (OA-Knee), and the second exploratory group, indicative of chronic nociplastic pain would
        include people with knee OA with knee and widespread body pain (OA-Knee+Body). Participants
        in the OA-Knee+Body group will be representative of chronic pain patients presenting with
        nociplastic pain based on several clinical pain tests (e.g., Nociplastic pain criteria (Kosek
        et al. 2021), Michigan Body Map (Brummett et al. 2016), knee and wrist QST). Widespread
        bodily pain will be determined by identifying pain in >3 body regions on the Michigan Body
        Map and experiencing pain the knee and wrist pain pressure test. This study is designed to
        acquire resting state functional MRI (rsfMRI) and diffusion tensor imaging (DTI) MRI data at
        baseline and after experimentally induced pain (i.e., Cold Pressor Gel Test (Lapotka et al.
        2017)), and compare the MRI data to clinical pain test results. The exploratory outcomes are
        to examine if there neuroinflammatory group differences based on the results of the 13C-TBT
        data.
  
        Study Design
  
        Study participants will be asked to complete a screening appointment over the phone prior to
        a data collection visit. Prospective participants will be notified of our study by their
        rheumatologist (i.e., Dr. Adachi) and will contact Dr. Danielli via email if they are
        interested in participating. Prospective participants will then contact Dr. Danielli to
        arrange a phone call to verbally obtain consent and perform the screening questions to
        determine eligibility. The screening visit will take about 30 minutes with Dr. Danielli. As
        part of the screening process prospective participants will be asked to complete the
        Nociplastic Pain Criteria (Kosek et al. 2021), the DSM-V Alcohol Use Disorder questionnaire,
        provide demographic information (i.e., to have balanced age and sex recruitment), and
        identify possible MRI contraindications. If someone is eligible to participate, an
        appointment will be then booked for the data collection study visit. All prospective
        participants will have been diagnosed with knee OA by their rheumatologist and the screening
        visit will be done to categorize participants into one of three study groups and efficiently
        book a data collection visit.
  
        Informed written consent will be obtained in accordance with the World Medical Association
        Declaration of Helsinki prior to any data collection at the data collection study visit. All
        participants will receive the same data collection protocols. Depending on the preference of
        the participants, screening and data will be collected at either the Imaging Research Centre
        (IRC) at St. Joseph's Healthcare Hamilton or the Joint Department of Medical Imaging (JDMI)
        at Toronto Western Hospital. The questionnaires (i.e., the Depression Anxiety Stress Scale
        (DASS42)(Crawford et al. 2003), Intermittent and Constant Osteoarthritis Pain (ICOAP)(Hawker
        et al. 2008; Hawker et al. 2011), and Brief Pain Inventory (BPI)(Cleeland et al. 1991)), and
        participants will also have a wrist and knee pressure pain threshold tests; these will take
        about 15 minutes to complete. The baseline and secondary MRI acquisitions would take about 45
        minutes each. Participants will be given 5-10 minutes between MRI scan sessions to take a
        break and stretch their legs. The data collection study visit will last about 2 hours.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  intervention model description: Adults who have been clinically diagnosed with knee osteoarthritis (pain free, localized knee pain, or knee and widespread pain) will all receive the same intervention and study protocol.
  primary purpose: Basic Science
  masking: Single (Outcomes Assessor)
  masking description: The MRI analysis methods are quantitative and unbiased by convention. Furthermore, they will require the researcher to input the age and sex of the participant and indicate if the participant was a healthy control or experimental to allow for group comparisons, but that will not influence the analyses or outcomes.
  measure: Group and individual differences at baseline and post-intervention
  time frame: 2 hours
  description: The primary objective is to determine if chronic pain, more specifically chronic nociplastic pain, causes neuroplastic brain alterations. It is hypothesized that people with localized chronic pain (OA-Knee) and widespread chronic pain (OA-Knee+Body) would exhibit abnormal brain function (e.g., network connectivity and ROI complexity) and reduced microstructural integrity of brain white matter, that would also be proportionately associated with pain sensitivity and mental state, in comparison to similarly aged individuals with knee osteoarthritis without chronic pain.
  measure: Presence of neuroinflammation
  time frame: 2 hours
  description: The exploratory objective of this study involves peripherally measuring neuroinflammation using the 13C Tryptophan Breath Test (13C-TBT). This test allows our research team to collect exhaled breath samples at multiple time intervals during the data collection study visit after oral consumption of the L-[1-13C]tryptophan and water solution, which based on the metabolism of the labelled tryptophan is a peripheral bioindicator for the presence of neuroinflammation.
  arm group label: OA-PF
  arm group type: Active Comparator
  description: Individuals with knee OA without knee or bodily pain. All participants will complete the same study protocol with pre- post-perturbation MRI scans and pain assessment questionnaires, as well as breath samples collected at multiple time points during the study visit.
  arm group label: OA-Knee
  arm group type: Experimental
  description: Individuals with knee OA with localized knee pain. All participants will complete the same study protocol with pre- post-perturbation MRI scans and pain assessment questionnaires, as well as breath samples collected at multiple time points during the study visit.
  arm group label: OA-Knee+Body
  arm group type: Experimental
  description: Individuals with knee OA with localized knee pain and widespread bodily pain. All participants will complete the same study protocol with pre- post-perturbation MRI scans and pain assessment questionnaires, as well as breath samples collected at multiple time points during the study visit.
  intervention type: Behavioral
  intervention name: Cold Pressor Gel Test
  description: This test will allow the research team to induce a painful sensation in participants in a safe, non-invasive, standardized, and short-lasting manner. The protocol for the cold pressor gel test is simple: participants will place their non-dominant hand in the container of cold water for as long as they can up to a maximum of two minutes. If it becomes too painful or uncomfortable during those two minutes, participants can remove their hand from the container. It should be noted again that this is not a treatment for knee OA or chronic pain and will be used to investigate the effects of acute pain in the brain of individuals with a chronic pain condition.
  arm group label: OA-Knee
  arm group label: OA-Knee+Body
  arm group label: OA-PF
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: No
  last name: Dinesh Kumbhare, MD, PhD
  role: Principal Investigator
  affiliation: University Health Network, Toronto
  last name: Michael D Noseworthy, PhD, PEng
  role: Principal Investigator
  affiliation: McMaster University
  last name: Dinesh Kumbhare, MD, PhD
  phone: 416 597 3422
  phone ext: 4612
  email: dinesh.kumbhare@uhn.ca
  last name: Ethan Danielli, PhD
  email: ethan.danielli@uhn.ca
  facility: 
  contact: 
  facility: 
  contact: 
  country: Canada
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  responsible party type: Principal Investigator
  investigator affiliation: Toronto Rehabilitation Institute
  investigator full name: Dinesh Kumbhare
  investigator title: Scientist
  mesh term: Osteoarthritis
  mesh term: Osteoarthritis, Knee
  mesh term: Chronic Pain
  sharing ipd: No
  ipd description: The data collected for this study will not be shared with researchers outside of the research team.