<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/NCT03262051</url>
  </required_header>
  <id_info>
    <org_study_id>2016-02232</org_study_id>
    <nct_id>NCT03262051</nct_id>
  </id_info>
  <brief_title>Impact of Acute and Chronic Inflammation on Cytochromes P450 Activity Measured With Dried Blood Spot</brief_title>
  <official_title>Impact of Acute and Chronic Inflammation on Cytochromes P450 Activity Measured With Dried Blood Spot</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Geneva</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Geneva</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>
      Cytochromes P450, main enzymes of drug metabolism, play a prominent role in the first-pass&#xD;
      metabolism of oral substances. Inter-individual variability in their activity due to genetic&#xD;
      and environmental factors has been observed and may be associated with adverse therapeutic&#xD;
      outcomes (ineffectiveness or toxicity). The inflammation, whether acute or chronic, can&#xD;
      theoretically modulate the pharmacokinetics of drugs by modulating enzyme activity. Indeed,&#xD;
      in vitro data and animal models, as well as more limited data in humans, indicate a&#xD;
      down-regulation of CYP in the context of inflammation.&#xD;
&#xD;
      The cocktail approach developed and validated in Geneva (&quot;cocktail Geneva&quot;) measures the&#xD;
      activity of several CYP simultaneously using micro-doses of probe drugs and facilitating&#xD;
      sampling (10uL capillary blood) on a dried blood spot.&#xD;
&#xD;
      We intend to measure the activity of CYP in an acute inflammation model (hip surgery and&#xD;
      SARS-CoV-2 infection) and chronic inflammation (rheumatoid arthritis, RA). The effect of the&#xD;
      biological agent tocilizumab (anti IL-6 receptor) in a treated patient subgroup (patients&#xD;
      treated regardless of our study) will be measured after 3 months of treatment.&#xD;
&#xD;
      The main objective is to determine if interleukin 6 levels are correlated with the activity&#xD;
      of CYP450 in patients with acute (orthopedic surgery - hip or SARS-CoV-2 infection) or&#xD;
      chronic inflammation (RA).&#xD;
&#xD;
      Secondary objectives are:&#xD;
&#xD;
        -  To correlate CYPs activities with the levels of other inflammatory markers (CRP, TNF-α,&#xD;
           IL-1β, IFN-γ);&#xD;
&#xD;
        -  To assess correlation between markers of inflammation, CYP activities and the intensity&#xD;
           of fatigue and pain;&#xD;
&#xD;
        -  To assess if tocilizumab reverse CYP activity in patients with RA after 3 months&#xD;
           treatment;&#xD;
&#xD;
        -  To assess if SARS-CoV-2 infection modify pharmacokinetic parameters of concomitant&#xD;
           medications which are CYPs substrates&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Anticipated">September 1, 2021</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluate the impact of IL6 levels on the activity of CYPs in patients with acute (post orthopaedic surgery -hip or post SARS-CoV-2 infection) and chronic (rheumatoid arthritis) inflammation.</measure>
    <time_frame>1 week</time_frame>
    <description>The phenotyping probe drugs used in this study will be given as 2 capsules: one capsule of Omeprazole 10 mg and one capsule containing the remaining probe 'cocktail' drugs (caffeine 50 mg, flurbiprofen 10 mg, dextromethorphan 10 mg, midazolam 1 mg, bupropion 20 mg).&#xD;
The enzymatic activities of the following CYP will be assessed by specific metabolite/probe single point concentration ratios (metabolic ratios-MR) in capillary blood:&#xD;
CYP1A2&#xD;
CYP2B6&#xD;
CYP2C9&#xD;
CYP2C19&#xD;
CYP2D6&#xD;
CYP3A4</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluate the correlation between the activity of CYPs and CRP levels</measure>
    <time_frame>1 week or 3 months</time_frame>
    <description>The routine concentration of the inflammatory marker C-reactive protein (CRP) will be measured in blood</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the correlation between the activity of CYPs and TNF-α levels</measure>
    <time_frame>1 week or 3 months</time_frame>
    <description>TNF-α blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the correlation between the activity of CYPs and IL-1β levels</measure>
    <time_frame>1 week</time_frame>
    <description>IL-1β blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the correlation between the activity of CYPs and IFN-γ levels</measure>
    <time_frame>1 week</time_frame>
    <description>IFN-γ blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess if tocilizumab reverse the activity of CYP in patients with RA after 3 months of treatment</measure>
    <time_frame>3 months</time_frame>
    <description>Comparison of CYP function before and 3 months after the beginning of the Tocilizumab treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess if SARS-CoV-2 infection modify pharmacokinetic parameters of concomitant medications which are CYPs substrates</measure>
    <time_frame>3 months</time_frame>
    <description>Comparison of plasma concentrations of CYPs substrates, when COVID-19 patients received any CYPs substrates</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the correlation between inflammatory markers, CYP function and intensity of fatigue (MFI) and pain (NRS)</measure>
    <time_frame>1 week</time_frame>
    <description>Function and intensity of fatigue will be measured with the validated French version of the Multidimensional Fatigue Inventory; pain will be measured with the numeric rating scale (NRS) 0 to 10 (0 = no pain and 10 = worst pain imaginable).</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">106</enrollment>
  <condition>Inflammation</condition>
  <arm_group>
    <arm_group_label>Patient with acute inflammation (surgery)</arm_group_label>
    <description>patients undergoing hip surgery</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Patient with chronic inflammation</arm_group_label>
    <description>patients with rheumatoid arthritis</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Patient with acute inflammation (SARS-CoV-2 infection)</arm_group_label>
    <description>patients with SARS-CoV-2 infection</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>CYP phenotyping</intervention_name>
    <description>Phenotyping using a simplified version of the Geneva cocktail</description>
    <arm_group_label>Patient with acute inflammation (SARS-CoV-2 infection)</arm_group_label>
    <arm_group_label>Patient with acute inflammation (surgery)</arm_group_label>
    <arm_group_label>Patient with chronic inflammation</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Patients included in the study will be patients with either chronic inflammation (patients&#xD;
        with rheumatoid arthritis) or with acute inflammation (patients undergoing hip surgery or&#xD;
        with COVID-19). All patients will be recruited at the Geneva University Hospitals.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        --&gt; Inclusion Criteria: For hip surgery and chronic inflammation groups&#xD;
&#xD;
          -  Male and female patients diagnosed with rheumatoid arthritis or undergoing an elective&#xD;
             hip surgery&#xD;
&#xD;
          -  Age &gt; 18 years old&#xD;
&#xD;
          -  Understanding of French language and ability to give a written inform consent&#xD;
&#xD;
        For SARS-CoV-2 infection group&#xD;
&#xD;
          -  Male and female patients diagnosed with SARS-CoV-2 infection (positive RT-PCR) and CRP&#xD;
             &gt; 30 mg/L&#xD;
&#xD;
          -  Age &gt; 18 years old&#xD;
&#xD;
          -  Understanding of French language and ability to give a written inform consent&#xD;
&#xD;
             --&gt; Exclusion Criteria: For hip surgery and chronic inflammation groups&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Severe cardiac failure, severe edema or ascites&#xD;
&#xD;
          -  Severe COPD or pulmonary embolism requiring oxygen&#xD;
&#xD;
          -  Uncontrolled infection&#xD;
&#xD;
          -  Active cancer&#xD;
&#xD;
          -  HIV infection&#xD;
&#xD;
          -  Renal impairment (defined as serum creatinine concentrations &gt; 1.5 x ULN)&#xD;
&#xD;
          -  Hepatic impairment (alteration of hepatic tests AST, ALT, bilirubin, GGT &gt;2 x ULN)&#xD;
&#xD;
          -  Inability to give blood samples&#xD;
&#xD;
          -  Sensitivity to any of the drugs used&#xD;
&#xD;
          -  Intake of drugs altering CYPs activity (based on [1]) except for tocilizumab&#xD;
&#xD;
        For SARS-CoV-2 infection group&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Hospitalized in intensive care unit at time of inclusion&#xD;
&#xD;
          -  Hospitalized in intermediate care unit at time of inclusion&#xD;
&#xD;
          -  Active cancer&#xD;
&#xD;
          -  HIV infection&#xD;
&#xD;
          -  Renal impairment (glomerular filtration rate &lt; 30 mL/min/1.73m2)&#xD;
&#xD;
          -  Hepatic impairment (Child-Pugh score B and C)&#xD;
&#xD;
          -  Inability to give blood samples&#xD;
&#xD;
          -  Sensitivity to any of the drugs used&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Caroline Samer, MD</last_name>
    <phone>+41 22 382 99 47</phone>
    <email>caroline.samer@hcuge.ch</email>
  </overall_contact>
  <location>
    <facility>
      <name>Geneva University Hospitals, HUG</name>
      <address>
        <city>Genève</city>
        <country>Switzerland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Caroline Samer</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>August 21, 2017</study_first_submitted>
  <study_first_submitted_qc>August 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <last_update_submitted>March 2, 2021</last_update_submitted>
  <last_update_submitted_qc>March 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Geneva</investigator_affiliation>
    <investigator_full_name>Caroline Samer</investigator_full_name>
    <investigator_title>Doctor, University Hospital, Geneva</investigator_title>
  </responsible_party>
  <keyword>cytochromes P450</keyword>
  <keyword>chronic inflammation</keyword>
  <keyword>genotyping</keyword>
  <keyword>phenotyping</keyword>
  <keyword>acute inflammation</keyword>
  <keyword>rheumatoid arthritis</keyword>
  <keyword>surgery</keyword>
  <keyword>COVID-19</keyword>
  <keyword>SARS-CoV-2 infection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
  </condition_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/NCT03262051
org study id: 2016-02232
nct id: NCT03262051
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Cytochromes P450, main enzymes of drug metabolism, play a prominent role in the first-pass
      metabolism of oral substances. Inter-individual variability in their activity due to genetic
      and environmental factors has been observed and may be associated with adverse therapeutic
      outcomes (ineffectiveness or toxicity). The inflammation, whether acute or chronic, can
      theoretically modulate the pharmacokinetics of drugs by modulating enzyme activity. Indeed,
      in vitro data and animal models, as well as more limited data in humans, indicate a
      down-regulation of CYP in the context of inflammation.

      The cocktail approach developed and validated in Geneva ("cocktail Geneva") measures the
      activity of several CYP simultaneously using micro-doses of probe drugs and facilitating
      sampling (10uL capillary blood) on a dried blood spot.

      We intend to measure the activity of CYP in an acute inflammation model (hip surgery and
      SARS-CoV-2 infection) and chronic inflammation (rheumatoid arthritis, RA). The effect of the
      biological agent tocilizumab (anti IL-6 receptor) in a treated patient subgroup (patients
      treated regardless of our study) will be measured after 3 months of treatment.

      The main objective is to determine if interleukin 6 levels are correlated with the activity
      of CYP450 in patients with acute (orthopedic surgery - hip or SARS-CoV-2 infection) or
      chronic inflammation (RA).

      Secondary objectives are:

        -  To correlate CYPs activities with the levels of other inflammatory markers (CRP, TNF-α,
           IL-1β, IFN-γ);

        -  To assess correlation between markers of inflammation, CYP activities and the intensity
           of fatigue and pain;

        -  To assess if tocilizumab reverse CYP activity in patients with RA after 3 months
           treatment;

        -  To assess if SARS-CoV-2 infection modify pharmacokinetic parameters of concomitant
           medications which are CYPs substrates
observational model: Cohort
time perspective: Prospective
measure: Evaluate the impact of IL6 levels on the activity of CYPs in patients with acute (post orthopaedic surgery -hip or post SARS-CoV-2 infection) and chronic (rheumatoid arthritis) inflammation.
time frame: 1 week
description: The phenotyping probe drugs used in this study will be given as 2 capsules: one capsule of Omeprazole 10 mg and one capsule containing the remaining probe 'cocktail' drugs (caffeine 50 mg, flurbiprofen 10 mg, dextromethorphan 10 mg, midazolam 1 mg, bupropion 20 mg).
The enzymatic activities of the following CYP will be assessed by specific metabolite/probe single point concentration ratios (metabolic ratios-MR) in capillary blood:
CYP1A2
CYP2B6
CYP2C9
CYP2C19
CYP2D6
CYP3A4
measure: Evaluate the correlation between the activity of CYPs and CRP levels
time frame: 1 week or 3 months
description: The routine concentration of the inflammatory marker C-reactive protein (CRP) will be measured in blood
measure: Evaluate the correlation between the activity of CYPs and TNF-α levels
time frame: 1 week or 3 months
description: TNF-α blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.
measure: Evaluate the correlation between the activity of CYPs and IL-1β levels
time frame: 1 week
description: IL-1β blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.
measure: Evaluate the correlation between the activity of CYPs and IFN-γ levels
time frame: 1 week
description: IFN-γ blood concentrations will be measured by using the Fluorokine MAP Cytokine Multiplex Elisa.
measure: Assess if tocilizumab reverse the activity of CYP in patients with RA after 3 months of treatment
time frame: 3 months
description: Comparison of CYP function before and 3 months after the beginning of the Tocilizumab treatment.
measure: Assess if SARS-CoV-2 infection modify pharmacokinetic parameters of concomitant medications which are CYPs substrates
time frame: 3 months
description: Comparison of plasma concentrations of CYPs substrates, when COVID-19 patients received any CYPs substrates
measure: Evaluate the correlation between inflammatory markers, CYP function and intensity of fatigue (MFI) and pain (NRS)
time frame: 1 week
description: Function and intensity of fatigue will be measured with the validated French version of the Multidimensional Fatigue Inventory; pain will be measured with the numeric rating scale (NRS) 0 to 10 (0 = no pain and 10 = worst pain imaginable).
arm group label: Patient with acute inflammation (surgery)
description: patients undergoing hip surgery
arm group label: Patient with chronic inflammation
description: patients with rheumatoid arthritis
arm group label: Patient with acute inflammation (SARS-CoV-2 infection)
description: patients with SARS-CoV-2 infection
intervention type: Diagnostic Test
intervention name: CYP phenotyping
description: Phenotyping using a simplified version of the Geneva cocktail
arm group label: Patient with acute inflammation (SARS-CoV-2 infection)
arm group label: Patient with acute inflammation (surgery)
arm group label: Patient with chronic inflammation
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Caroline Samer, MD
phone: +41 22 382 99 47
email: caroline.samer@hcuge.ch
facility: 
status: Recruiting
contact: 
country: Switzerland
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Geneva
investigator full name: Caroline Samer
investigator title: Doctor, University Hospital, Geneva
mesh term: Inflammation