<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/NCT04490551</url>
  </required_header>
  <id_info>
    <org_study_id>AMC_MDL_161</org_study_id>
    <nct_id>NCT04490551</nct_id>
  </id_info>
  <brief_title>Combining Risk Factors and Faecal Immunochemical Testing in Colorectal Cancer Screening: a Randomized Controlled Trial</brief_title>
  <official_title>Combining Risk Factors and Faecal Immunochemical Testing in Colorectal Cancer Screening: a Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</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>
      Colorectal Carcinoma (CRC) is the third most frequent diagnosed cancer worldwide, with 1.4&#xD;
      million new cases every year. In an attempt to reduce this number many countries have&#xD;
      implemented a nationwide screening programme targeted at detecting CRC in an early phase&#xD;
      using fecal immunochemical tests (FITs). People with an elevated level of blood in their&#xD;
      stool are offered a colonoscopy, an invasive medical procedure where CRCs and premalignant&#xD;
      lesions (together also referred to as advanced neoplasia) can be detected accurately.&#xD;
&#xD;
      However, the current screening method using FIT is not optimal. In FIT-based CRC screening&#xD;
      studies, 1 in 4 participants with CRC and 2 in 3 participants with advanced neoplasia receive&#xD;
      a negative FIT result. In contrast, an estimated 1 in 2 FIT-positives have advanced neoplasia&#xD;
      at colonoscopy.&#xD;
&#xD;
      Recent studies have demonstrated that a risk model that takes into account the FIT result and&#xD;
      other risk factors for CRC could enhance the effectiveness of a FIT-based CRC screening&#xD;
      programme.&#xD;
&#xD;
      The objective of this study is to assess the yield of advanced neoplasia in the colon and&#xD;
      rectum of a FIT-based risk model at colonoscopy, compared to that of a FIT-only CRC screening&#xD;
      strategy. Our hypothesis is that a risk-based model yields significantly more advanced&#xD;
      neoplasia at colonoscopy than the FIT by itself, and that it does not affect participation&#xD;
      rate.&#xD;
&#xD;
      To assess this hypothesis, the investigators have designed a clinical trial in which the&#xD;
      investigators randomize 23,000 asymptomatic individuals between the age of 55 and 75 years&#xD;
      old to either risk-based screening (intervention group) or FIT-only screening (control&#xD;
      group). The intervention group will receive a questionnaire on risk factors of CRC (e.g.&#xD;
      smoking, family history of CRC), and a FIT. The control group will only receive the FIT. The&#xD;
      positivity threshold of the FIT in both groups will be set at 15 micrograms haemoglobin per&#xD;
      gram faeces. The positivity threshold of the risk-based model in the intervention group will&#xD;
      be set at 0.10 (out of a range of 0 to 1), a threshold that is calculated with a goal to&#xD;
      match the positivity rate of the control group.&#xD;
&#xD;
      Participants with a result that is above the thresholds of the FIT and/or the risk-based&#xD;
      model will be invited to undergo a colonoscopy according protocol of the Dutch national&#xD;
      screening program. After the study has ended, the investigators will compare both groups to&#xD;
      assess our hypotheses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION AND RATIONALE Colorectal Cancer (CRC) is the third most frequent diagnosed&#xD;
      cancer worldwide, with 1.4 million new cases every year. Mortality of CRC is estimated at&#xD;
      around 40%. To reduce the incidence of CRC and to abate the negative consequences associated&#xD;
      with CRC, methods for early detection of (pre)malignant colorectal lesions have extensively&#xD;
      been researched and implemented. Colonoscopy is the reference standard for the detection of&#xD;
      advanced neoplasia, but it requires trained endoscopists, carries a high burden, harbours a&#xD;
      risk for complications in patients, and increases societal costs.&#xD;
&#xD;
      Most screening programs use methods to select screening participants with a high risk of&#xD;
      advanced neoplasia for colonoscopy. One such method is the detection of blood in stool with&#xD;
      faecal immunochemical tests (FITs).&#xD;
&#xD;
      Multiple nation-wide screening programs have now been implemented using FIT, including one in&#xD;
      the Netherlands. In the Dutch CRC screening program, using a FIT threshold of 47 µg Hb/g&#xD;
      faeces, the sensitivity of FIT in detecting CRC is 85.5%. The sensitivity of FIT in detecting&#xD;
      advanced neoplasia (AN) is however substantially lower: 38%.&#xD;
&#xD;
      FIT-based screening also generates a high number of false positives, leading to unnecessary&#xD;
      colonoscopies and distress for those patients. Approximately 1 in 2 FIT-positives has&#xD;
      advanced neoplasia; the first round of the Dutch CRC screening program, using a FIT threshold&#xD;
      of 47 µg Hb/g faeces, reached a positive predictive value of 54%.&#xD;
&#xD;
      Previous studies have demonstrated the existence of clinical risk factors for CRC, such as&#xD;
      male gender, age, family history of CRC, and smoking. In a ZonMW sponsored project (ZonMW&#xD;
      50-50115-96-521) our group has shown that higher age, male sex, a family history with close&#xD;
      relatives in whom CRC was diagnosed, and active smoking were all associated with the presence&#xD;
      of advanced neoplasia (Stegeman et al, Gut, 2014).&#xD;
&#xD;
      Multiple CRC risk models have been developed using these risk factors, but most show only&#xD;
      weak discriminatory power. Others have proposed risk models that additionally included&#xD;
      molecular markers, increasing performance and discriminatory power, but these markers can be&#xD;
      cumbersome to collect and can be costly in respect to the relative cheap FIT test. the&#xD;
      investigators propose to combine CRC risk factors with the quantitative FIT result. FIT is a&#xD;
      quantitative test with a variable cut-off level, and individuals with higher values of faecal&#xD;
      haemoglobin are at higher risk of having advanced neoplasia at the cost of a lower&#xD;
      specificity. Therefore, the quantitative result can be used as a weight-factor in a risk&#xD;
      model.&#xD;
&#xD;
      Based on information on these risk factors for CRC and the quantitative FIT-result, our&#xD;
      FIT-based risk model for CRC screening calculates the personal risk of having advanced&#xD;
      neoplasia at colonoscopy. Inviting screening participants with elevated risk for colonoscopy,&#xD;
      rather than those whose FIT result exceeds a pre-specified threshold, has the potential to&#xD;
      increase the effectiveness and efficiency of FIT-based CRC screening. However, this requires&#xD;
      participants to complete the questions about risk.&#xD;
&#xD;
      Our hypothesis is that integration of FIT score with known risk factors (age, gender,&#xD;
      smoking, and family history of CRC) improves the number of participants in whom advanced&#xD;
      neoplasia is detected, relative to the number of invitees. The investigators will compare a&#xD;
      risk-based approach to screening, as described above, to the conventional FIT-only screening&#xD;
      in a randomized controlled screening trial.&#xD;
&#xD;
      OBJECTIVES The study hypothesis is that risk-based CRC screening significantly outperforms&#xD;
      FIT-only CRC screening in terms of the relative number of invitees in whom advanced neoplasia&#xD;
      is detected at colonoscopy.&#xD;
&#xD;
      Primary Research Question: does risk-based CRC screening result in a higher relative number&#xD;
      of invitees in whom advanced neoplasia is detected at colonoscopy compared to FIT-only CRC&#xD;
      screening?&#xD;
&#xD;
      Secondary Research Questions:&#xD;
&#xD;
      i) Does risk-based CRC screening result in a higher standardized screening yield in whom&#xD;
      advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening? ii) Is the&#xD;
      participation rate of risk-based CRC screening non-inferior compared to FIT-only screening?&#xD;
      iii) Does risk-based CRC screening result in a higher relative number of invitees in whom&#xD;
      advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening at higher&#xD;
      FIT-positivity thresholds (from 15 µg Hb /g faeces)? iv) Does risk-based CRC screening result&#xD;
      in a higher relative number of invitees in whom proximally located advanced neoplasia is&#xD;
      detected at colonoscopy compared to FIT-only CRC screening?&#xD;
&#xD;
      METHODS The investigators will perform a randomized controlled trial in 23,000 randomly&#xD;
      selected men and women (aged 55 to 75 years) eligible for participation in the national CRC&#xD;
      screening programme. All eligible participants will be second time invitees, living within a&#xD;
      25 km radius from the colonoscopy centre Bergman Clinics Amsterdam, which is accredited for&#xD;
      the national population screening program.&#xD;
&#xD;
      Eligible individuals are randomly allocated on a 1:1 basis to an invitation for either&#xD;
      risk-based CRC screening (intervention group) or FIT-only screening (control group).&#xD;
      Randomization per household will be done before invitation. Study invitations are sent out by&#xD;
      Foundation of Population Screening Mid-West (BoMW) early November 2019 before sending the FIT&#xD;
      sample kit of the national screening program to the study cohort from January 2020 to April&#xD;
      2020. The study invitation is combined with a leaflet containing information on study&#xD;
      participation. It will also contain an informed consent form, and a one-page questionnaire&#xD;
      (if allocated to the intervention arm) with a self-addressed envelope to the research&#xD;
      facility. The informed consent form will bear a unique study identification code.&#xD;
&#xD;
      The model that the investigators will use in this study for risk-based screening is derived&#xD;
      from a model developed in a primary colonoscopy screening trial (Stegeman et al, Gut, 2014).&#xD;
      The investigators have re-evaluated our multivariable risk model for CRC, with the aim to&#xD;
      simplify it for daily practice. A number of risk factors (such as elements from diet) added&#xD;
      little to the performance of the model, whereas collecting the necessary information proved&#xD;
      rather tedious. The quantitative FIT result, age, sex, family history and smoking behaviour&#xD;
      were the most decisive factors in the model.&#xD;
&#xD;
      This simplified FIT-based risk model had a performance like that of the extended model in the&#xD;
      development dataset. In this study the investigators will calculate the risk of harbouring&#xD;
      advanced neoplasia with our simplified FIT-based risk model, based on the quantitative FIT&#xD;
      result, age, sex, family history and smoking behaviour (see below). The threshold and&#xD;
      expected positivity rate of the risk-based model will be matched to the expected positivity&#xD;
      rate of the FIT-only group.&#xD;
&#xD;
      Regression equation of the updated model:&#xD;
&#xD;
      ln(odds AN) = -4.955073942+0.9196052173*Smoking+0.3364761549* √FIT+0.370575346*family history&#xD;
      of CRC-0.006934851*FIT+0.0228752117*age+0.070972656*gender&#xD;
&#xD;
      Probability of advanced neoplasia:&#xD;
&#xD;
      P (AN)=e^((odds AN))/(1+e^((odds AN))) If invitees that are allocated to the intervention&#xD;
      group (i.e. questionnaire and FIT) only return the questionnaire, they do not qualify for a&#xD;
      colonoscopy. When consenting invitees in the intervention group prefer not to complete the&#xD;
      questionnaire, FIT tests will be analysed at a cut-off of 15 µg Hb/g faeces.&#xD;
&#xD;
      The type of FIT that will be used is the one used in the Dutch national screening programme:&#xD;
      FOB-Gold (Sentinel, Italy). FIT-analyses and sending of FIT results will be performed&#xD;
      according to the logistics as being used in the national screening. The FIT result and the&#xD;
      result of the questionnaire will be entered in a database, to calculate the participant's&#xD;
      risk. All FIT positives (≥15 µg Hb/g faeces) will be referred for consultation for&#xD;
      colonoscopy at regional endoscopic centres. For the purpose of this study, FIT-negative but&#xD;
      risk-positive participants (i.e. the combination of the results of the questionnaire and the&#xD;
      quantitative FIT result) will also be invited for consultation for colonoscopy.&#xD;
&#xD;
      Colonoscopy will be performed by endoscopists accredited for our national screening programme&#xD;
      and according to national and international quality guidelines. Quality indicators and&#xD;
      endoscopic findings will be systematically recorded in a database, according to the standards&#xD;
      of the national screening programme. Lesions will be immediately removed, if possible, and&#xD;
      otherwise biopsies will be obtained. Histopathological assessment of these tissue samples&#xD;
      will provide a definitive diagnosis. Data on location, size, macroscopic aspect, morphology&#xD;
      and polypectomy will be recorded for all colonic lesions, which will be collected and&#xD;
      evaluated by an accredited GI-pathologist according to the Vienna criteria. Advanced adenomas&#xD;
      are defined as adenomas larger than 10 mm, adenomas with high-grade dysplasia or adenomas&#xD;
      with a villous component of at least 25%. Advice regarding surveillance colonoscopy after&#xD;
      removal of adenomatous polyps, large (≥10 mm) serrated lesions or cancer will be given to the&#xD;
      clients according to the Dutch CBO consensus.&#xD;
&#xD;
      Screening invitees can leave the study at any time for any reason if they wish to do so&#xD;
      without any consequences. The investigator can decide to withdraw a screening invitee from&#xD;
      the study for urgent medical reasons.&#xD;
&#xD;
      STATISTICAL ANALYSIS&#xD;
&#xD;
      Primary outcome The difference in screening yield will be estimated and expressed as an&#xD;
      absolute difference per 1,000 invitees, with 95% confidence intervals. The investigators will&#xD;
      test the null hypothesis of no difference in yield between the intervention and control group&#xD;
      using the chi-square test.&#xD;
&#xD;
      Secondary outcome The standardized screening yield will be calculated by ranking participants&#xD;
      according to their calculated risk (in risk-based screening) and comparing the yield of&#xD;
      risk-based screening for the number of positives that matches the number of FIT-positives&#xD;
      with FIT-only screening with a chi-square test. Additionally, the investigators will use the&#xD;
      McNemar test statistic to test the null hypothesis of no gain in screening yield in the&#xD;
      intervention group only, where the investigators can compare referrals based on FIT only with&#xD;
      referrals based on FIT and calculated risk.&#xD;
&#xD;
      The participation rate will be calculated through the number of participants relative to the&#xD;
      number of invitees in each arm. Differences in participation rate will be assessed using the&#xD;
      chi square test. The difference in screening yield of proximally located advanced neoplasia&#xD;
      between both arms will be estimated and expressed as an absolute difference per 1,000&#xD;
      invitees (with 95% confidence intervals). The null hypothesis of no difference in yield will&#xD;
      be tested using the chi square test.&#xD;
&#xD;
      Statistical significance level P-values of lower than 0.05 will be considered statistically&#xD;
      significant. All analysis between both arms are based on the intention-to-screen principle,&#xD;
      unless stated otherwise. Statistical analyses will be performed using R.&#xD;
&#xD;
      Additional outcomes Model performance in comparison to the FIT will be assessed with the net&#xD;
      reclassification improvement (NRI). In addition, the yield of the FIT-based risk model and&#xD;
      the FIT will be assessed at a broad range of FIT thresholds and will be estimated and&#xD;
      expressed as the number of detected advanced neoplasia per 1,000 invitees&#xD;
      (intention-to-screen) and per 1,000 colonoscopies (per protocol). Differences in the yield&#xD;
      will be tested using a chi square test. Any missing data that was intended to be used as&#xD;
      input for the risk-model, will be classified as '0'.&#xD;
&#xD;
      ETHICAL CONSIDERATIONS The study will be conducted according to the principles of the&#xD;
      Declaration of Helsinki (Version October 2008) and the Population Screening Act (WBO).&#xD;
      Permission to conduct this study has been granted by the Dutch Health Council and the Dutch&#xD;
      Minister of Healthcare.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 5, 2019</start_date>
  <completion_date type="Actual">June 1, 2021</completion_date>
  <primary_completion_date type="Actual">December 31, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The researchers conduct a parallel group randomized controlled trial. Asymptomatic individuals will be randomized to either risk-based screening or FIT-only screening.</intervention_model_description>
    <primary_purpose>Screening</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Yield of Advanced Neoplasia</measure>
    <time_frame>10 weeks</time_frame>
    <description>The primary outcome is the yield of advanced neoplasia, defined as the relative number of invitees in whom advanced neoplasia is detected at colonoscopy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Standardized Screening Yield</measure>
    <time_frame>10 weeks</time_frame>
    <description>standardized screening yield: ranking the number of participants according to their calculated risk and comparing the yield of risk-based screening for the number of positives that matches the number of FIT-positives with FIT-only screening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Participation Rate</measure>
    <time_frame>10 weeks</time_frame>
    <description>participation rate, defined as the relative number of invitees participating in screening.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Yield of Advanced Neoplasia at Other Thresholds</measure>
    <time_frame>10 weeks</time_frame>
    <description>yield of advanced neoplasia, defined as the relative number of invitees with advanced neoplasia detected at colonoscopy, at FIT-positivity thresholds of 15 µg Hb/g faeces and higher.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Yield of Proximally Located Advanced Neoplasia</measure>
    <time_frame>10 weeks</time_frame>
    <description>yield of proximally located advanced neoplasia, defined as the relative number of referred participants in whom proximally located advanced neoplasia is detected at colonoscopy.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">6753</enrollment>
  <condition>Colorectal Cancer</condition>
  <condition>Colorectal Carcinoma</condition>
  <condition>Colorectal Neoplasms</condition>
  <condition>Colorectal Adenoma</condition>
  <condition>Colorectal Adenoma and Carcinoma</condition>
  <arm_group>
    <arm_group_label>Intervention group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This group will be screened with the risk-based model. The input of the model will be gathered with the FIT, a validated questionnaire, and from data of the Dutch general population registry. The threshold of the model will be set at a calculated risk of 0.10. To comply with ethical guidelines, all participants in this group with a FIT result of &gt;=15 mcg Hb/g faeces and a calculated risk of &lt;0.10 will also be offered a colonoscopy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This group will be screened with the FIT. The threshold of the FIT will be set at &gt;= 15 mcg Hb/g faeces.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Risk-based logistic regression model</intervention_name>
    <description>The intervention will be a risk-based logistic regression model that takes multiple variables into account to calculate the risk of advanced neoplasia as an outcome.</description>
    <arm_group_label>Intervention group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>FIT</intervention_name>
    <description>FIT is a stool-based test that detects human blood in faeces.</description>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Intervention group</arm_group_label>
    <other_name>Faecal Immunochemic Test</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        In order to be eligible to participate in this study, a screening invitee must meet the&#xD;
        following criteria:&#xD;
&#xD;
          1. The screening invitee must be at least 55 years old, and no older than 75 years old,&#xD;
             at the day of invitation by the Foundation of Population Screening Mid-West&#xD;
&#xD;
          2. The screening invitee must be eligible for participation in the second round of the&#xD;
             Dutch CRC Population Screening Programme&#xD;
&#xD;
          3. The screening invitee must return a signed informed consent form&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        A potential screening invitee who meets any of the following criteria will be excluded from&#xD;
        participation in this study:&#xD;
&#xD;
          1. if he or she receives active treatment for CRC and/or AN, including palliative care.&#xD;
&#xD;
          2. if he or she fails to return a sample that is adequate for FIT testing.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Male and Females</gender_description>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Evelien Dekker, PhD MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Amsterdam UMC, locatie Academisch Medisch Centrum</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord-Holland</state>
        <zip>1105 AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
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  <verification_date>August 2021</verification_date>
  <study_first_submitted>July 13, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 29, 2020</study_first_posted>
  <last_update_submitted>August 12, 2021</last_update_submitted>
  <last_update_submitted_qc>August 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</investigator_affiliation>
    <investigator_full_name>Prof. Evelien Dekker, MD, PhD</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Colorectal Cancer</keyword>
  <keyword>Screening</keyword>
  <keyword>Model</keyword>
  <keyword>Faecal Immunochemic Test</keyword>
  <keyword>FIT</keyword>
  <keyword>Occult Blood</keyword>
  <keyword>Risk Factors</keyword>
  <keyword>Logistic Regression</keyword>
  <keyword>Advanced Neoplasia</keyword>
  <keyword>Advanced Adenoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Adenoma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Conditional on the permission of the Dutch government, anonymized research data may be shared after publication of the results in a peer-reviewed paper.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04490551
org study id: AMC_MDL_161
nct id: NCT04490551
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Colorectal Carcinoma (CRC) is the third most frequent diagnosed cancer worldwide, with 1.4
      million new cases every year. In an attempt to reduce this number many countries have
      implemented a nationwide screening programme targeted at detecting CRC in an early phase
      using fecal immunochemical tests (FITs). People with an elevated level of blood in their
      stool are offered a colonoscopy, an invasive medical procedure where CRCs and premalignant
      lesions (together also referred to as advanced neoplasia) can be detected accurately.

      However, the current screening method using FIT is not optimal. In FIT-based CRC screening
      studies, 1 in 4 participants with CRC and 2 in 3 participants with advanced neoplasia receive
      a negative FIT result. In contrast, an estimated 1 in 2 FIT-positives have advanced neoplasia
      at colonoscopy.

      Recent studies have demonstrated that a risk model that takes into account the FIT result and
      other risk factors for CRC could enhance the effectiveness of a FIT-based CRC screening
      programme.

      The objective of this study is to assess the yield of advanced neoplasia in the colon and
      rectum of a FIT-based risk model at colonoscopy, compared to that of a FIT-only CRC screening
      strategy. Our hypothesis is that a risk-based model yields significantly more advanced
      neoplasia at colonoscopy than the FIT by itself, and that it does not affect participation
      rate.

      To assess this hypothesis, the investigators have designed a clinical trial in which the
      investigators randomize 23,000 asymptomatic individuals between the age of 55 and 75 years
      old to either risk-based screening (intervention group) or FIT-only screening (control
      group). The intervention group will receive a questionnaire on risk factors of CRC (e.g.
      smoking, family history of CRC), and a FIT. The control group will only receive the FIT. The
      positivity threshold of the FIT in both groups will be set at 15 micrograms haemoglobin per
      gram faeces. The positivity threshold of the risk-based model in the intervention group will
      be set at 0.10 (out of a range of 0 to 1), a threshold that is calculated with a goal to
      match the positivity rate of the control group.

      Participants with a result that is above the thresholds of the FIT and/or the risk-based
      model will be invited to undergo a colonoscopy according protocol of the Dutch national
      screening program. After the study has ended, the investigators will compare both groups to
      assess our hypotheses.
INTRODUCTION AND RATIONALE Colorectal Cancer (CRC) is the third most frequent diagnosed
      cancer worldwide, with 1.4 million new cases every year. Mortality of CRC is estimated at
      around 40%. To reduce the incidence of CRC and to abate the negative consequences associated
      with CRC, methods for early detection of (pre)malignant colorectal lesions have extensively
      been researched and implemented. Colonoscopy is the reference standard for the detection of
      advanced neoplasia, but it requires trained endoscopists, carries a high burden, harbours a
      risk for complications in patients, and increases societal costs.

      Most screening programs use methods to select screening participants with a high risk of
      advanced neoplasia for colonoscopy. One such method is the detection of blood in stool with
      faecal immunochemical tests (FITs).

      Multiple nation-wide screening programs have now been implemented using FIT, including one in
      the Netherlands. In the Dutch CRC screening program, using a FIT threshold of 47 µg Hb/g
      faeces, the sensitivity of FIT in detecting CRC is 85.5%. The sensitivity of FIT in detecting
      advanced neoplasia (AN) is however substantially lower: 38%.

      FIT-based screening also generates a high number of false positives, leading to unnecessary
      colonoscopies and distress for those patients. Approximately 1 in 2 FIT-positives has
      advanced neoplasia; the first round of the Dutch CRC screening program, using a FIT threshold
      of 47 µg Hb/g faeces, reached a positive predictive value of 54%.

      Previous studies have demonstrated the existence of clinical risk factors for CRC, such as
      male gender, age, family history of CRC, and smoking. In a ZonMW sponsored project (ZonMW
      50-50115-96-521) our group has shown that higher age, male sex, a family history with close
      relatives in whom CRC was diagnosed, and active smoking were all associated with the presence
      of advanced neoplasia (Stegeman et al, Gut, 2014).

      Multiple CRC risk models have been developed using these risk factors, but most show only
      weak discriminatory power. Others have proposed risk models that additionally included
      molecular markers, increasing performance and discriminatory power, but these markers can be
      cumbersome to collect and can be costly in respect to the relative cheap FIT test. the
      investigators propose to combine CRC risk factors with the quantitative FIT result. FIT is a
      quantitative test with a variable cut-off level, and individuals with higher values of faecal
      haemoglobin are at higher risk of having advanced neoplasia at the cost of a lower
      specificity. Therefore, the quantitative result can be used as a weight-factor in a risk
      model.

      Based on information on these risk factors for CRC and the quantitative FIT-result, our
      FIT-based risk model for CRC screening calculates the personal risk of having advanced
      neoplasia at colonoscopy. Inviting screening participants with elevated risk for colonoscopy,
      rather than those whose FIT result exceeds a pre-specified threshold, has the potential to
      increase the effectiveness and efficiency of FIT-based CRC screening. However, this requires
      participants to complete the questions about risk.

      Our hypothesis is that integration of FIT score with known risk factors (age, gender,
      smoking, and family history of CRC) improves the number of participants in whom advanced
      neoplasia is detected, relative to the number of invitees. The investigators will compare a
      risk-based approach to screening, as described above, to the conventional FIT-only screening
      in a randomized controlled screening trial.

      OBJECTIVES The study hypothesis is that risk-based CRC screening significantly outperforms
      FIT-only CRC screening in terms of the relative number of invitees in whom advanced neoplasia
      is detected at colonoscopy.

      Primary Research Question: does risk-based CRC screening result in a higher relative number
      of invitees in whom advanced neoplasia is detected at colonoscopy compared to FIT-only CRC
      screening?

      Secondary Research Questions:

      i) Does risk-based CRC screening result in a higher standardized screening yield in whom
      advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening? ii) Is the
      participation rate of risk-based CRC screening non-inferior compared to FIT-only screening?
      iii) Does risk-based CRC screening result in a higher relative number of invitees in whom
      advanced neoplasia is detected at colonoscopy compared to FIT-only CRC screening at higher
      FIT-positivity thresholds (from 15 µg Hb /g faeces)? iv) Does risk-based CRC screening result
      in a higher relative number of invitees in whom proximally located advanced neoplasia is
      detected at colonoscopy compared to FIT-only CRC screening?

      METHODS The investigators will perform a randomized controlled trial in 23,000 randomly
      selected men and women (aged 55 to 75 years) eligible for participation in the national CRC
      screening programme. All eligible participants will be second time invitees, living within a
      25 km radius from the colonoscopy centre Bergman Clinics Amsterdam, which is accredited for
      the national population screening program.

      Eligible individuals are randomly allocated on a 1:1 basis to an invitation for either
      risk-based CRC screening (intervention group) or FIT-only screening (control group).
      Randomization per household will be done before invitation. Study invitations are sent out by
      Foundation of Population Screening Mid-West (BoMW) early November 2019 before sending the FIT
      sample kit of the national screening program to the study cohort from January 2020 to April
      2020. The study invitation is combined with a leaflet containing information on study
      participation. It will also contain an informed consent form, and a one-page questionnaire
      (if allocated to the intervention arm) with a self-addressed envelope to the research
      facility. The informed consent form will bear a unique study identification code.

      The model that the investigators will use in this study for risk-based screening is derived
      from a model developed in a primary colonoscopy screening trial (Stegeman et al, Gut, 2014).
      The investigators have re-evaluated our multivariable risk model for CRC, with the aim to
      simplify it for daily practice. A number of risk factors (such as elements from diet) added
      little to the performance of the model, whereas collecting the necessary information proved
      rather tedious. The quantitative FIT result, age, sex, family history and smoking behaviour
      were the most decisive factors in the model.

      This simplified FIT-based risk model had a performance like that of the extended model in the
      development dataset. In this study the investigators will calculate the risk of harbouring
      advanced neoplasia with our simplified FIT-based risk model, based on the quantitative FIT
      result, age, sex, family history and smoking behaviour (see below). The threshold and
      expected positivity rate of the risk-based model will be matched to the expected positivity
      rate of the FIT-only group.

      Regression equation of the updated model:

      ln(odds AN) = -4.955073942+0.9196052173*Smoking+0.3364761549* √FIT+0.370575346*family history
      of CRC-0.006934851*FIT+0.0228752117*age+0.070972656*gender

      Probability of advanced neoplasia:

      P (AN)=e^((odds AN))/(1+e^((odds AN))) If invitees that are allocated to the intervention
      group (i.e. questionnaire and FIT) only return the questionnaire, they do not qualify for a
      colonoscopy. When consenting invitees in the intervention group prefer not to complete the
      questionnaire, FIT tests will be analysed at a cut-off of 15 µg Hb/g faeces.

      The type of FIT that will be used is the one used in the Dutch national screening programme:
      FOB-Gold (Sentinel, Italy). FIT-analyses and sending of FIT results will be performed
      according to the logistics as being used in the national screening. The FIT result and the
      result of the questionnaire will be entered in a database, to calculate the participant's
      risk. All FIT positives (≥15 µg Hb/g faeces) will be referred for consultation for
      colonoscopy at regional endoscopic centres. For the purpose of this study, FIT-negative but
      risk-positive participants (i.e. the combination of the results of the questionnaire and the
      quantitative FIT result) will also be invited for consultation for colonoscopy.

      Colonoscopy will be performed by endoscopists accredited for our national screening programme
      and according to national and international quality guidelines. Quality indicators and
      endoscopic findings will be systematically recorded in a database, according to the standards
      of the national screening programme. Lesions will be immediately removed, if possible, and
      otherwise biopsies will be obtained. Histopathological assessment of these tissue samples
      will provide a definitive diagnosis. Data on location, size, macroscopic aspect, morphology
      and polypectomy will be recorded for all colonic lesions, which will be collected and
      evaluated by an accredited GI-pathologist according to the Vienna criteria. Advanced adenomas
      are defined as adenomas larger than 10 mm, adenomas with high-grade dysplasia or adenomas
      with a villous component of at least 25%. Advice regarding surveillance colonoscopy after
      removal of adenomatous polyps, large (≥10 mm) serrated lesions or cancer will be given to the
      clients according to the Dutch CBO consensus.

      Screening invitees can leave the study at any time for any reason if they wish to do so
      without any consequences. The investigator can decide to withdraw a screening invitee from
      the study for urgent medical reasons.

      STATISTICAL ANALYSIS

      Primary outcome The difference in screening yield will be estimated and expressed as an
      absolute difference per 1,000 invitees, with 95% confidence intervals. The investigators will
      test the null hypothesis of no difference in yield between the intervention and control group
      using the chi-square test.

      Secondary outcome The standardized screening yield will be calculated by ranking participants
      according to their calculated risk (in risk-based screening) and comparing the yield of
      risk-based screening for the number of positives that matches the number of FIT-positives
      with FIT-only screening with a chi-square test. Additionally, the investigators will use the
      McNemar test statistic to test the null hypothesis of no gain in screening yield in the
      intervention group only, where the investigators can compare referrals based on FIT only with
      referrals based on FIT and calculated risk.

      The participation rate will be calculated through the number of participants relative to the
      number of invitees in each arm. Differences in participation rate will be assessed using the
      chi square test. The difference in screening yield of proximally located advanced neoplasia
      between both arms will be estimated and expressed as an absolute difference per 1,000
      invitees (with 95% confidence intervals). The null hypothesis of no difference in yield will
      be tested using the chi square test.

      Statistical significance level P-values of lower than 0.05 will be considered statistically
      significant. All analysis between both arms are based on the intention-to-screen principle,
      unless stated otherwise. Statistical analyses will be performed using R.

      Additional outcomes Model performance in comparison to the FIT will be assessed with the net
      reclassification improvement (NRI). In addition, the yield of the FIT-based risk model and
      the FIT will be assessed at a broad range of FIT thresholds and will be estimated and
      expressed as the number of detected advanced neoplasia per 1,000 invitees
      (intention-to-screen) and per 1,000 colonoscopies (per protocol). Differences in the yield
      will be tested using a chi square test. Any missing data that was intended to be used as
      input for the risk-model, will be classified as '0'.

      ETHICAL CONSIDERATIONS The study will be conducted according to the principles of the
      Declaration of Helsinki (Version October 2008) and the Population Screening Act (WBO).
      Permission to conduct this study has been granted by the Dutch Health Council and the Dutch
      Minister of Healthcare.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The researchers conduct a parallel group randomized controlled trial. Asymptomatic individuals will be randomized to either risk-based screening or FIT-only screening.
primary purpose: Screening
masking: None (Open Label)
measure: Yield of Advanced Neoplasia
time frame: 10 weeks
description: The primary outcome is the yield of advanced neoplasia, defined as the relative number of invitees in whom advanced neoplasia is detected at colonoscopy.
measure: Standardized Screening Yield
time frame: 10 weeks
description: standardized screening yield: ranking the number of participants according to their calculated risk and comparing the yield of risk-based screening for the number of positives that matches the number of FIT-positives with FIT-only screening.
measure: Participation Rate
time frame: 10 weeks
description: participation rate, defined as the relative number of invitees participating in screening.
measure: Yield of Advanced Neoplasia at Other Thresholds
time frame: 10 weeks
description: yield of advanced neoplasia, defined as the relative number of invitees with advanced neoplasia detected at colonoscopy, at FIT-positivity thresholds of 15 µg Hb/g faeces and higher.
measure: Yield of Proximally Located Advanced Neoplasia
time frame: 10 weeks
description: yield of proximally located advanced neoplasia, defined as the relative number of referred participants in whom proximally located advanced neoplasia is detected at colonoscopy.
arm group label: Intervention group
arm group type: Experimental
description: This group will be screened with the risk-based model. The input of the model will be gathered with the FIT, a validated questionnaire, and from data of the Dutch general population registry. The threshold of the model will be set at a calculated risk of 0.10. To comply with ethical guidelines, all participants in this group with a FIT result of >=15 mcg Hb/g faeces and a calculated risk of <0.10 will also be offered a colonoscopy.
arm group label: Control group
arm group type: Active Comparator
description: This group will be screened with the FIT. The threshold of the FIT will be set at >= 15 mcg Hb/g faeces.
intervention type: Diagnostic Test
intervention name: Risk-based logistic regression model
description: The intervention will be a risk-based logistic regression model that takes multiple variables into account to calculate the risk of advanced neoplasia as an outcome.
arm group label: Intervention group
intervention type: Diagnostic Test
intervention name: FIT
description: FIT is a stool-based test that detects human blood in faeces.
arm group label: Control group
arm group label: Intervention group
other name: Faecal Immunochemic Test
criteria: 
gender: All
gender based: Yes
gender description: Male and Females
minimum age: 55 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Evelien Dekker, PhD MD
role: Principal Investigator
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
facility: 
country: Netherlands
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responsible party type: Principal Investigator
investigator affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
investigator full name: Prof. Evelien Dekker, MD, PhD
investigator title: Professor
mesh term: Carcinoma
mesh term: Colorectal Neoplasms
mesh term: Adenoma
sharing ipd: No
ipd description: Conditional on the permission of the Dutch government, anonymized research data may be shared after publication of the results in a peer-reviewed paper.