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/NCT06033469</url>
    </required_header>
    <id_info>
      <org_study_id>RC 01/17</org_study_id>
      <nct_id>NCT06033469</nct_id>
    </id_info>
    <brief_title>Therapeutic Monitoring of Infliximab and Adalimumab</brief_title>
    <official_title>Therapeutic Monitoring of Infliximab and Adalimumab in Pediatric Chronic Inflammatory Diseases: Innovative Pharmacological Strategies for Predicting Response and Adverse Effects</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>IRCCS Burlo Garofolo</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>IRCCS Burlo Garofolo</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Anti tumor necrosis factor (TNF agents), particularly infliximab and adalimumab, changed the&#xD;
        way chronic inflammatory bowel disease (IBD) refractory to conventional therapies is treated,&#xD;
        including in pediatric patients. However, approximately 10-30% of patients do not respond to&#xD;
        initial therapy and up to 50% lose response over time. Variability in response to therapy may&#xD;
        be influenced by multiple interacting factors at different levels. Recent studies showed that&#xD;
        measurement of serum infliximab concentrations during induction therapy predicts treatment&#xD;
        effects at one year. Therefore, therapeutic monitoring of infliximab is proposed as a useful&#xD;
        strategy to improve clinical outcomes and optimize healthcare resources.&#xD;
  &#xD;
        Most commercially available methods for infliximab quantification are based on the ELISA&#xD;
        assay, which has an assay time of at least 8 hours. Recently, commercial point-of-care&#xD;
        devices became available with assay times of less than one hour, enabling real-time&#xD;
        therapeutic drug monitoring; however, validation of these devices in clinical settings and&#xD;
        comparison with standard assays are still needed, particularly in pediatric patients. In&#xD;
        addition, some studies suggest that loss of response in patients treated with anti-TNFs may&#xD;
        be partly due to the emergence of specific anti-drug antibodies (AAFs). A limitation of the&#xD;
        most widely used ELISA assays is the inability to quantify drug and AAF when they are&#xD;
        simultaneously present. Recently, innovative ELISA assays have become available to overcome&#xD;
        this problem. However, there is a lack of comparative studies between the classical and the&#xD;
        specific method in terms of clinical response in pediatric patients. In patients who do not&#xD;
        respond to infliximab, especially if they have high levels of AAF, guidelines call for the&#xD;
        use of adalimumab. For this drug, the evidence in the literature regarding therapeutic&#xD;
        monitoring of adalimumab concentrations and association with response in pediatric patients&#xD;
        is still very preliminary. This study, carried out in in pediatric patients with IBD, aims&#xD;
        to:&#xD;
  &#xD;
          1. validate the &quot;point of care&quot; infliximab assay by comparing it with reference ELISA&#xD;
             assays;&#xD;
  &#xD;
          2. evaluate the correlation of infliximab and AAF levels, as measured by the innovative&#xD;
             ELISA assays, with response to therapy, compared to traditional assays.&#xD;
  &#xD;
          3. evaluate the association between adalimumab and AAF levels and response to therapy&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Anti-TNF agents, particularly infliximab and adalimumab, changed the way chronic inflammatory&#xD;
        bowel disease (IBD) refractory to conventional therapies is treated, including in pediatric&#xD;
        patients. These biologic agents also appear promising as first-line treatment even in the&#xD;
        early stages of the disease. However, approximately 10-30% of patients do not respond to&#xD;
        initial therapy and up to 50% lose response over time. In addition, the widespread use of&#xD;
        these drugs is limited by serious side effects and the high cost of therapy. Variability in&#xD;
        response to therapy may be influenced by multiple interacting factors at different levels.&#xD;
        Recent studies showed that measurement of serum infliximab concentrations during induction&#xD;
        therapy predicts treatment effects at one year: in particular, patients with infliximab&#xD;
        concentrations below 3 ug/ml at the end of induction (pre-dose IV infusion) have a reduced&#xD;
        probability of response. Therefore, therapeutic monitoring of infliximab is proposed as a&#xD;
        useful strategy to improve clinical outcomes and optimize healthcare resources.&#xD;
  &#xD;
        Currently, most commercially available methods for infliximab quantification are based on the&#xD;
        ELISA assay, which has an assay time of at least 8 hours, delaying therapeutic adjustment to&#xD;
        the next drug infusion. Recently, commercial point-of-care devices became available with&#xD;
        assay times of less than one hour, enabling real-time therapeutic drug monitoring; however,&#xD;
        validation of these devices in clinical settings and comparison with standard assays are&#xD;
        still needed, particularly in pediatric patients. In addition, some studies suggest that loss&#xD;
        of response in patients treated with anti-TNFs, infliximab and adalimumab, may be partly due&#xD;
        to the emergence of specific anti-drug antibodies (AAFs). A limitation of the most widely&#xD;
        used ELISA assays is the inability to quantify drug and AAF when they are simultaneously&#xD;
        present. Data from the literature suggest that in patients who lose response to anti-TNFs,&#xD;
        classical ELISA assays may overestimate the percentage of patients with low levels of both&#xD;
        drug and AAF; the use of specific ELISA assays allows accurate quantification of drug and AAF&#xD;
        levels even in these patients, allowing the clinician to modify therapy accordingly.&#xD;
        Recently, innovative ELISA assays have become available to overcome this problem. However,&#xD;
        there is a lack of comparative studies between the classical and the specific method in terms&#xD;
        of clinical response in pediatric patients. In patients who do not respond to infliximab,&#xD;
        especially if they have high levels of AAF, guidelines call for the use of adalimumab. For&#xD;
        this drug, the evidence in the literature regarding therapeutic monitoring of adalimumab&#xD;
        concentrations and association with response in pediatric patients is still very preliminary.&#xD;
        Thus, the research objectives are three, of equal importance:&#xD;
  &#xD;
          1. to validate the &quot;point of care&quot; infliximab assay by comparing it with reference ELISA&#xD;
             assays in pediatric patients with IBD;&#xD;
  &#xD;
          2. to evaluate the correlation of infliximab and AAF levels, as measured by the above&#xD;
             innovative ELISA assays, with response to therapy, compared to traditional assays, in&#xD;
             pediatric patients with IBD.&#xD;
  &#xD;
          3. to evaluate the association between adalimumab and AAF levels and response to therapy in&#xD;
             pediatric patients with IBD.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">March 15, 2018</start_date>
    <completion_date type="Anticipated">April 15, 2024</completion_date>
    <primary_completion_date type="Anticipated">April 15, 2024</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Other</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Infliximab concentration</measure>
      <time_frame>Through study completion, an average of 5 years</time_frame>
      <description>Assessed with the point-of-care assay and with the ELISA assay</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Adalimumab concentration</measure>
      <time_frame>Through study completion, an average of 5 years</time_frame>
      <description>Assessed with ELISA assay</description>
    </primary_outcome>
    <primary_outcome>
      <measure>AAF concentration</measure>
      <time_frame>Through study completion, an average of 5 years</time_frame>
      <description>Assessed by the novel ELISA assays</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Response to therapy assessed with validated score</measure>
      <time_frame>Through study completion, an average of 5 years</time_frame>
      <description>Assessed by Pediatric Crohn's disease activity index (PCDAI) and Pediatric UlcerativeColitis Activity Index (PUCAI). PCDAI ranges from 0 to 100; higher scores indicate more active disease. Clinical remission was defined as PCDAI ≤ 10. PUCAI score ranges from 0 to 85, with disease remission less than 10, mild disease activity between 10-35, moderate disease activity from 35-65, and severe disease activity above 65</description>
    </primary_outcome>
    <number_of_groups>1</number_of_groups>
    <enrollment type="Anticipated">100</enrollment>
    <condition>Inflammatory Bowel Diseases</condition>
    <arm_group>
      <arm_group_label>IBD group</arm_group_label>
      <description>Pediatric patients with IBD</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Infliximab</intervention_name>
      <description>Pediatric patients with IBD suitable for treatment with infliximab</description>
      <arm_group_label>IBD group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Adalimumab</intervention_name>
      <description>Pediatric patients with IBD suitable for treatment with adalimumab</description>
      <arm_group_label>IBD group</arm_group_label>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          Pediatric subjects with IBD suitable for treatment with infliximab or adalimumab&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Non-Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  IBD subjects&#xD;
  &#xD;
            -  age between 0 and 17 years&#xD;
  &#xD;
            -  suitable for treatment with infliximab or adalimumab&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Pediatric subjects with IBD not suitable for treatment with infliximab or adalimumab&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>1 Year</minimum_age>
      <maximum_age>17 Years</maximum_age>
    </eligibility>
    <overall_official>
      <last_name>Gabriele Stocco, MSC</last_name>
      <role>Principal Investigator</role>
      <affiliation>IRCCS materno infantile Burlo Garofolo</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Giuliana Decorti, MD</last_name>
      <phone>+390403785111</phone>
      <email>giuliana.decorti@burlo.trieste.it</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Gabriele Stocco, MSC</last_name>
      <phone>+390403785111</phone>
      <email>gabriele.stocco@burlo.trieste.it</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>IRCCS Burlo Garofolo</name>
        <address>
          <city>Trieste</city>
          <zip>34137</zip>
          <country>Italy</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Giuliana Decorti</last_name>
      </contact>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>September 5, 2023</study_first_submitted>
    <study_first_submitted_qc>September 5, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 13, 2023</study_first_posted>
    <last_update_submitted>September 5, 2023</last_update_submitted>
    <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Infliximab</keyword>
    <keyword>Adalimumab</keyword>
    <keyword>Inflammatory Bowel Diseases</keyword>
    <keyword>Pharmacokinetics</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Intestinal Diseases</mesh_term>
      <mesh_term>Inflammatory Bowel Diseases</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Adalimumab</mesh_term>
      <mesh_term>Infliximab</mesh_term>
    </intervention_browse>
    <!-- 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/NCT06033469
  org study id: RC 01/17
  nct id: NCT06033469
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  Anti tumor necrosis factor (TNF agents), particularly infliximab and adalimumab, changed the
        way chronic inflammatory bowel disease (IBD) refractory to conventional therapies is treated,
        including in pediatric patients. However, approximately 10-30% of patients do not respond to
        initial therapy and up to 50% lose response over time. Variability in response to therapy may
        be influenced by multiple interacting factors at different levels. Recent studies showed that
        measurement of serum infliximab concentrations during induction therapy predicts treatment
        effects at one year. Therefore, therapeutic monitoring of infliximab is proposed as a useful
        strategy to improve clinical outcomes and optimize healthcare resources.
  
        Most commercially available methods for infliximab quantification are based on the ELISA
        assay, which has an assay time of at least 8 hours. Recently, commercial point-of-care
        devices became available with assay times of less than one hour, enabling real-time
        therapeutic drug monitoring; however, validation of these devices in clinical settings and
        comparison with standard assays are still needed, particularly in pediatric patients. In
        addition, some studies suggest that loss of response in patients treated with anti-TNFs may
        be partly due to the emergence of specific anti-drug antibodies (AAFs). A limitation of the
        most widely used ELISA assays is the inability to quantify drug and AAF when they are
        simultaneously present. Recently, innovative ELISA assays have become available to overcome
        this problem. However, there is a lack of comparative studies between the classical and the
        specific method in terms of clinical response in pediatric patients. In patients who do not
        respond to infliximab, especially if they have high levels of AAF, guidelines call for the
        use of adalimumab. For this drug, the evidence in the literature regarding therapeutic
        monitoring of adalimumab concentrations and association with response in pediatric patients
        is still very preliminary. This study, carried out in in pediatric patients with IBD, aims
        to:
  
          1. validate the "point of care" infliximab assay by comparing it with reference ELISA
             assays;
  
          2. evaluate the correlation of infliximab and AAF levels, as measured by the innovative
             ELISA assays, with response to therapy, compared to traditional assays.
  
          3. evaluate the association between adalimumab and AAF levels and response to therapy
  Anti-TNF agents, particularly infliximab and adalimumab, changed the way chronic inflammatory
        bowel disease (IBD) refractory to conventional therapies is treated, including in pediatric
        patients. These biologic agents also appear promising as first-line treatment even in the
        early stages of the disease. However, approximately 10-30% of patients do not respond to
        initial therapy and up to 50% lose response over time. In addition, the widespread use of
        these drugs is limited by serious side effects and the high cost of therapy. Variability in
        response to therapy may be influenced by multiple interacting factors at different levels.
        Recent studies showed that measurement of serum infliximab concentrations during induction
        therapy predicts treatment effects at one year: in particular, patients with infliximab
        concentrations below 3 ug/ml at the end of induction (pre-dose IV infusion) have a reduced
        probability of response. Therefore, therapeutic monitoring of infliximab is proposed as a
        useful strategy to improve clinical outcomes and optimize healthcare resources.
  
        Currently, most commercially available methods for infliximab quantification are based on the
        ELISA assay, which has an assay time of at least 8 hours, delaying therapeutic adjustment to
        the next drug infusion. Recently, commercial point-of-care devices became available with
        assay times of less than one hour, enabling real-time therapeutic drug monitoring; however,
        validation of these devices in clinical settings and comparison with standard assays are
        still needed, particularly in pediatric patients. In addition, some studies suggest that loss
        of response in patients treated with anti-TNFs, infliximab and adalimumab, may be partly due
        to the emergence of specific anti-drug antibodies (AAFs). A limitation of the most widely
        used ELISA assays is the inability to quantify drug and AAF when they are simultaneously
        present. Data from the literature suggest that in patients who lose response to anti-TNFs,
        classical ELISA assays may overestimate the percentage of patients with low levels of both
        drug and AAF; the use of specific ELISA assays allows accurate quantification of drug and AAF
        levels even in these patients, allowing the clinician to modify therapy accordingly.
        Recently, innovative ELISA assays have become available to overcome this problem. However,
        there is a lack of comparative studies between the classical and the specific method in terms
        of clinical response in pediatric patients. In patients who do not respond to infliximab,
        especially if they have high levels of AAF, guidelines call for the use of adalimumab. For
        this drug, the evidence in the literature regarding therapeutic monitoring of adalimumab
        concentrations and association with response in pediatric patients is still very preliminary.
        Thus, the research objectives are three, of equal importance:
  
          1. to validate the "point of care" infliximab assay by comparing it with reference ELISA
             assays in pediatric patients with IBD;
  
          2. to evaluate the correlation of infliximab and AAF levels, as measured by the above
             innovative ELISA assays, with response to therapy, compared to traditional assays, in
             pediatric patients with IBD.
  
          3. to evaluate the association between adalimumab and AAF levels and response to therapy in
             pediatric patients with IBD.
  observational model: Other
  time perspective: Prospective
  measure: Infliximab concentration
  time frame: Through study completion, an average of 5 years
  description: Assessed with the point-of-care assay and with the ELISA assay
  measure: Adalimumab concentration
  time frame: Through study completion, an average of 5 years
  description: Assessed with ELISA assay
  measure: AAF concentration
  time frame: Through study completion, an average of 5 years
  description: Assessed by the novel ELISA assays
  measure: Response to therapy assessed with validated score
  time frame: Through study completion, an average of 5 years
  description: Assessed by Pediatric Crohn's disease activity index (PCDAI) and Pediatric UlcerativeColitis Activity Index (PUCAI). PCDAI ranges from 0 to 100; higher scores indicate more active disease. Clinical remission was defined as PCDAI ≤ 10. PUCAI score ranges from 0 to 85, with disease remission less than 10, mild disease activity between 10-35, moderate disease activity from 35-65, and severe disease activity above 65
  arm group label: IBD group
  description: Pediatric patients with IBD
  intervention type: Drug
  intervention name: Infliximab
  description: Pediatric patients with IBD suitable for treatment with infliximab
  arm group label: IBD group
  intervention type: Drug
  intervention name: Adalimumab
  description: Pediatric patients with IBD suitable for treatment with adalimumab
  arm group label: IBD group
  study pop: 
  sampling method: Non-Probability Sample
  criteria: 
  gender: All
  minimum age: 1 Year
  maximum age: 17 Years
  last name: Gabriele Stocco, MSC
  role: Principal Investigator
  affiliation: IRCCS materno infantile Burlo Garofolo
  last name: Giuliana Decorti, MD
  phone: +390403785111
  email: giuliana.decorti@burlo.trieste.it
  last name: Gabriele Stocco, MSC
  phone: +390403785111
  email: gabriele.stocco@burlo.trieste.it
  facility: 
  status: Recruiting
  contact: 
  country: Italy
  responsible party type: Sponsor
  mesh term: Intestinal Diseases
  mesh term: Inflammatory Bowel Diseases
  mesh term: Adalimumab
  mesh term: Infliximab