<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/NCT02208544</url>
  </required_header>
  <id_info>
    <org_study_id>KUN 2014-6514</org_study_id>
    <secondary_id>NL50166.091.14</secondary_id>
    <nct_id>NCT02208544</nct_id>
  </id_info>
  <brief_title>FDG-PET/CT in Evaluation of Cytological Indeterminate Thyroid Nodules to Prevent Unnecessary Surgery (EfFECTS)</brief_title>
  <acronym>EfFECTS</acronym>
  <official_title>Efficacy of [18F]-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (FDG-PET) in Evaluation of Cytological Indeterminate Thyroid Nodules Prior to Surgery: a Multicentre Cost-effectiveness Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dutch Cancer Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether the use of molecular imaging using&#xD;
      FDG-PET/CT could prevent unnecessary diagnostic thyroid surgery in case of indeterminate&#xD;
      cytology during fine-needle aspiration biopsy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: Only about ¼ of patients with thyroid nodules with indeterminate cytology are&#xD;
      proven to suffer from a malignancy at diagnostic hemithyroidectomy. Therefore ~¾ is operated&#xD;
      upon unbeneficially. Recent studies using FDG-PET/CT have suggested that it can decrease the&#xD;
      fraction of unbeneficial procedures from ~73% to ~40%. Thereby the direct costs per patient,&#xD;
      the number of hospitalization and average sick leave days might decrease and the experienced&#xD;
      HRQoL might increase. A study will be undertaken to show the additional value of FDG-PET/CT&#xD;
      after indeterminate cytology with respect to unbeneficial procedures, costs and utilities.&#xD;
&#xD;
      Main objective: To determine the impact of FDG-PET/CT on decreasing the fraction of patients&#xD;
      with cytologically indeterminate thyroid nodules undergoing unbeneficial patient management.&#xD;
&#xD;
      Study design: A prospective, multicentre, randomized, stratified controlled blinded trial&#xD;
      with an experimental study-arm (FDG-PET/CT-driven) and a control study-arm (diagnostic&#xD;
      hemithyroidectomy, independent of FDG-PET/CT-result).&#xD;
&#xD;
      Study population: Adult patients with a cytologically indeterminate thyroid nodule, without&#xD;
      exclusion criteria, in 15 (university and regional) hospitals distributed over the&#xD;
      Netherlands.&#xD;
&#xD;
      Intervention: One single FDG-PET/low-dose non-contrast enhanced CT of the head and neck is&#xD;
      performed in all patients. Patient management depends on allocation and results of this&#xD;
      FDG-PET/CT.&#xD;
&#xD;
      Main study parameters/endpoints: The number of unbeneficial interventions, i.e. surgery for&#xD;
      benign disease or watchful-waiting for malignancy.&#xD;
&#xD;
      Secondary objectives: complication rate, consequences of incidental PET-findings, number of&#xD;
      hospitalisation and sick leave days, volumes of healthcare consumed, experienced&#xD;
      health-related quality-of-life (HRQoL), genetic, cytological and (immuno)histopathological&#xD;
      features of the nodules.&#xD;
&#xD;
      Sample size calculation/data analysis: Based on above-mentioned estimated reduction in&#xD;
      unbeneficial interventions from ~73% to ~40%, at least 90 patients with nodules&gt;10 mm need to&#xD;
      be analyzed (2:1 allocation, α=0.05, power=0.90, single-sided Fisher's exact test). After&#xD;
      correction for nodule size and data-attrition, 132 patients need to be included in total.&#xD;
      Intention-to-treat analysis will be performed. Incremental Net Monetary Benefit based on the&#xD;
      total direct costs per patients and the gain in HRQoL-adjusted survival years are computed.&#xD;
      Cytological, histological and genetic parameters for FDG-avidity will be described.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness: All patients undergo one FDG-PET/CT scan of head/neck (effective dose: &lt;3.5 mSv)&#xD;
      and are asked to fill in 6 questionnaires at 4 timepoints. FDG-PET/CT negative patients in&#xD;
      the experimental arm will undergo a single confirmatory US (±FNAC). An interim/posterior&#xD;
      analysis of the control subjects is performed to ensure oncological safety. In case of an&#xD;
      unexpected high false-negative ratio in this control arm, all patients will be advised to&#xD;
      undergo surgery.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 16, 2015</start_date>
  <completion_date type="Actual">February 15, 2022</completion_date>
  <primary_completion_date type="Actual">January 1, 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>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Fraction of unbeneficial treatment</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>Unbeneficial treatment is defined as either:&#xD;
surgery in benign disease&#xD;
watchful waiting in malignant disease&#xD;
benign or malignant disease is defined on final histology (after surgery) or 12 month follow-up including confirmatory neck ultrasonography.&#xD;
This parameter is compared between both study arms based on intention-to-treat.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Fraction Complications</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO1b: To determine the effect of incorporation of FDG-PET/CT on the complication-ratio.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction False-Negative FDG-PET/CT's</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO1c: To determine the false-negative fraction of FDG-PET/CT in this population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lesion and Patient Characteristics</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO1d: To determine the influence of lesion size, pathological classification and patient characteristics on the diagnostic accuracy of FDG-PET/CT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction Incidental FDG-PET/CT Findings</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO1e: To determine whether incorporation of FDG-PET/CT of the head and neck lead to overdiagnosis in non-thyroidal incidental findings.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall and Disease Free Survival</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO1f: To determine the short-term overall and disease free survival in both study arms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FDG-PET/CT Implementation-hampering Factors</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO1g: To determine which factors hamper implementation of this modality for this indication (structured interviews).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction of Patients being operated despite negative FDG-PET/CT</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO1h: To determine the fraction of patients that cannot be reassured by a negative PET-scan (experimental arm only) despite careful selection of patients (implementability).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HRQoL-scores according to SF36-II, EQ-5D-5L, SF-HLQ and ThyPRO including changes</measure>
    <time_frame>Baseline, 2 months, 6 months and 12 months after inclusion</time_frame>
    <description>SO2a: To determine the impact on the experienced HRQoL between the group with and without FDG-PET/CT according to 4 different questionnaires at 4 timepoints during the first 12 months after FDG-PET/CT.&#xD;
SO2b: To determine whether patients in the experimental arm with negative PET-findings have a different HRQoL than those who receive surgery independent of the FDG-PET/CT results.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Direct Costs</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO3a: To determine the effect of incorporation of FDG-PET/CT on the mean direct costs (=volume of care multiplied by activity based costs) per patient during the first 12 months after FDG-PET/CT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Hospitalisation Days</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO3b: To determine the effect of incorporation of FDG-PET/CT on the average length of hospital stay for treatment of (complications of) thyroid lesions?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Sick Leave Days</measure>
    <time_frame>3 months after inclusions</time_frame>
    <description>SO3c: To determine the total number of sick leave days for the first three months in the patients? Do these differ between both study arms?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>incremental Net Monetary Benefit</measure>
    <time_frame>12 months after inclusion</time_frame>
    <description>SO3d: To determine the incremental Net Monetary Benefit of incorporation of FDG-PET/CT with respect to quality-adjusted life-years (QALYs, based on EQ-5D-5L index and overall survival) saved including sensitivity analysis.&#xD;
SO3e: To determine the incremental Net Monetary Benefit of incorporation of FDG-PET/CT with respect to decrease in unbeneficial treatment.&#xD;
Sensitivity analysis will be performed. A mere description will be given as there is no &quot;accepted&quot; value for this kind of analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tissue Protein- and Gene-expression profile</measure>
    <time_frame>12 months after inclusion of last patient</time_frame>
    <description>SO4a: Are there potential protein- or gene-expression profiles, capable of determining the nature of the FNAC-indeterminate nodes (cytology) SO4b: What is the interaction/correlation between the parameters mentioned in SO4a and the results of the FDG-PET/CT scan and the final diagnosis?</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Molecular biomarkers in relation to FDG-PET/CT</measure>
    <time_frame>12 months after inclusion of last patient</time_frame>
    <description>SO4b: What is the interaction/correlation between the parameters mentioned in SO4a and the results of the FDG-PET/CT scan and the final diagnosis?&#xD;
Can these tissue molecular biomarkers help in selecting the patients that benefit most from FDG-PET, or vice versa?&#xD;
Can higher pre-operative diagnostic accuracy be achieved by combining FDG-PET and molecular biomarkers?&#xD;
Are molecular biomarkers related to false-positive or false-negative FDG-PET/CT results?</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">132</enrollment>
  <condition>Thyroid Nodule</condition>
  <condition>Thyroid Neoplasms</condition>
  <arm_group>
    <arm_group_label>FDG-PET/CT-driven</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Following treatment based on FDG-PET/CT:&#xD;
negative: watchful waiting including confirmatory ultrasound&#xD;
positive: diagnostic thyroid surgery as planned</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Current Practice</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>diagnostic thyroid surgery despite results of FDG-PET/CT</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Diagnostic Thyroid Surgery</intervention_name>
    <description>Diagnostic Thyroid Surgery</description>
    <arm_group_label>Current Practice</arm_group_label>
    <arm_group_label>FDG-PET/CT-driven</arm_group_label>
    <other_name>Thyroid Lobectomy</other_name>
    <other_name>Hemithyroidectomy</other_name>
    <other_name>Thyroidectomy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Ultrasound of the head and neck</intervention_name>
    <description>Confirmatory Neck Ultrasonography in FDG-PET/CT negative patient in the experimental arm</description>
    <arm_group_label>FDG-PET/CT-driven</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>FDG-PET/CT</intervention_name>
    <description>Head and Neck FDG-PET/CT</description>
    <arm_group_label>Current Practice</arm_group_label>
    <arm_group_label>FDG-PET/CT-driven</arm_group_label>
    <other_name>fluorodeoxyglucose positron emission tomography</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Documented history of a solitary thyroid nodule or a dominant nodule within&#xD;
             multinodular disease, with (US-guided) FNAC performed by a dedicated radiologist or&#xD;
             experienced endocrinologist or pathologist, demonstrating an indeterminate cytological&#xD;
             examination (i.e. Bethesda category III or IV) according to the local pathologist and&#xD;
             confirmed after central review;&#xD;
&#xD;
          2. Scheduled for surgical excision (preferably) within 2 months of the inclusion date;&#xD;
&#xD;
          3. Age ≥ 18 years;&#xD;
&#xD;
          4. Euthyroid state with a serum thyrotropin (TSH) or a free T4 level within the&#xD;
             institutional upper and lower limits of normal, measured within 2 months of&#xD;
             registration. In case of a suppressed TSH: a negative 123I, 131I or 99mTcO4-&#xD;
             scintigraphy must be available (&quot;cold nodule&quot;);&#xD;
&#xD;
          5. In patients with multinodular disease and a dominant nodule, the nuclear medicine&#xD;
             physician responsible for FDG-PET/CT scan interpretation must determine whether the&#xD;
             nodule is likely to be discriminated on FDG-PET/CT imaging prior to enrolment;&#xD;
&#xD;
          6. Willing to participate in all aspects of the study;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. High a priori probability of malignancy:&#xD;
&#xD;
               -  FNAC Bethesda category V or VI during local reading or central review;&#xD;
&#xD;
               -  Prior radiation exposure / radiotherapy to the thyroid;&#xD;
&#xD;
               -  Prior neck surgery or radiation that in the opinion of the PI has disrupted&#xD;
                  tissue architecture of the thyroid;&#xD;
&#xD;
               -  New unexplained hoarseness, change of voice, stridor or paralysis of a vocal&#xD;
                  cord;&#xD;
&#xD;
                    -  In case a benign reason has been found (e.g. vocal cord edema), the patient&#xD;
                       is eligible;&#xD;
&#xD;
               -  Thyroid nodule discovered as a FDG-PET positive incidentaloma&#xD;
&#xD;
               -  New cervical lymphadenopathy highly suspicious for malignancy;&#xD;
&#xD;
                    -  In case malignancy is excluded, patient is eligible;&#xD;
&#xD;
               -  Previous treatment for thyroid carcinoma or current diagnosis of any other&#xD;
                  malignancy that is known to metastasize to the thyroid;&#xD;
&#xD;
               -  Known metastases of thyroid carcinoma;&#xD;
&#xD;
               -  Known genetic predisposition for thyroid carcinoma:&#xD;
&#xD;
                    -  Familiar Non-Medullary Thyroid Cancer (NMTC)&#xD;
&#xD;
                    -  Familiar Papillary Thyroid Cancer (FPTC)&#xD;
&#xD;
                    -  Familiar Adenomatoid Polyposis Coli syndrome (FAP, Gardner syndrome,&#xD;
                       APC-gene mutations on chromosome 5q21)&#xD;
&#xD;
                    -  Morbus Cowden (PTEN mutation on chromosome 10q23.3)&#xD;
&#xD;
                    -  PTC / nodular thyroid hyperplasia / papillary renal tumours. Linked to locus&#xD;
                       1q21.&#xD;
&#xD;
          2. Proven benign disease or insufficient material for a cytological diagnosis:&#xD;
&#xD;
               -  FNAC Bethesda category I or II during local reading or central review&#xD;
&#xD;
          3. Performance of non-routine additional diagnostic tests that alter the patients&#xD;
             treatment policy (e.g. mutation analysis on cytology)&#xD;
&#xD;
          4. Inability to undergo randomization:&#xD;
&#xD;
               -  Any patient that will receive thyroid surgery for other reasons (e.g. mechanical&#xD;
                  or cosmetic complaints).&#xD;
&#xD;
          5. Inability to undergo treatment:&#xD;
&#xD;
               -  Inability to undergo surgery in the opinion of the surgeon / anaesthetist.&#xD;
&#xD;
          6. Contra-indications for FDG-PET/CT:&#xD;
&#xD;
               -  Patient has evidence of infection localized to the neck in the 14 days prior to&#xD;
                  the FDG-PET/CT scan;&#xD;
&#xD;
               -  Inability to tolerate lying supine for the duration of an FDG-PET/CT examination&#xD;
                  (~10-15min);&#xD;
&#xD;
               -  Poorly regulated diabetes mellitus (see next item);&#xD;
&#xD;
               -  Hyperglycaemia at time of FDG injection prior to PET/CT (fasting serum glucose&#xD;
                  &gt;200mg/dL [&gt;11.1 mmol/L]);&#xD;
&#xD;
                    -  The use of short-acting insulins within 4 hours of the PET scan is not&#xD;
                       allowed&#xD;
&#xD;
               -  If female and fertile: signs and symptoms of pregnancy or a positive pregnancy&#xD;
                  test / breast-feeding;&#xD;
&#xD;
                    -  A formal negative pregnancy test is not obligatory&#xD;
&#xD;
               -  (severe) claustrophobia;&#xD;
&#xD;
                    -  Low dose benzodiazepines are allowed&#xD;
&#xD;
          7. General contra-indications:&#xD;
&#xD;
               -  Inability to give informed consent;&#xD;
&#xD;
               -  Severe psychiatric disorder;&#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_official>
    <last_name>Lioe-Fee de Geus-Oei, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Leiden University Medical Center, Leiden, the Netherlands</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Dennis Vriens, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Leiden University Medical Center, Leiden, the Netherlands</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lisanne de Koster, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Radboud University Medical Centre, Nijmegen, the Netherlands</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Radboudumc</name>
      <address>
        <city>Nijmegen</city>
        <state>Gelderland</state>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MUMC</name>
      <address>
        <city>Maastricht</city>
        <state>Limburg</state>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AMC</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord-Holland</state>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>VUmc</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord-Holland</state>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MeanderMC</name>
      <address>
        <city>Amersfoort</city>
        <state>Utrecht</state>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>LUMC</name>
      <address>
        <city>Leiden</city>
        <state>Zuid-Holland</state>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ErasmusMC</name>
      <address>
        <city>Rotterdam</city>
        <state>Zuid-Holland</state>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Onze Lieve Vrouwe Gasthuis</name>
      <address>
        <city>Amsterdam</city>
        <zip>1091AC</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rijnstate</name>
      <address>
        <city>Arnhem</city>
        <zip>6800TA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Reinier de Graaf Ziekenhuis</name>
      <address>
        <city>Delft</city>
        <zip>2625 AD</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UMCG</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Antonius</name>
      <address>
        <city>Nieuwegein</city>
        <zip>3430EM</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HagaZiekenhuis</name>
      <address>
        <city>The Hague</city>
        <zip>2566MJ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UMCU</name>
      <address>
        <city>Utrecht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Isala Klinieken</name>
      <address>
        <city>Zwolle</city>
        <zip>8025AB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <reference>
    <citation>de Geus-Oei LF, Pieters GF, Bonenkamp JJ, Mudde AH, Bleeker-Rovers CP, Corstens FH, Oyen WJ. 18F-FDG PET reduces unnecessary hemithyroidectomies for thyroid nodules with inconclusive cytologic results. J Nucl Med. 2006 May;47(5):770-5.</citation>
    <PMID>16644746</PMID>
  </reference>
  <reference>
    <citation>Vriens D, de Wilt JH, van der Wilt GJ, Netea-Maier RT, Oyen WJ, de Geus-Oei LF. The role of [18F]-2-fluoro-2-deoxy-d-glucose-positron emission tomography in thyroid nodules with indeterminate fine-needle aspiration biopsy: systematic review and meta-analysis of the literature. Cancer. 2011 Oct 15;117(20):4582-94. doi: 10.1002/cncr.26085. Epub 2011 Mar 22.</citation>
    <PMID>21432844</PMID>
  </reference>
  <reference>
    <citation>Vriens D, Adang EM, Netea-Maier RT, Smit JW, de Wilt JH, Oyen WJ, de Geus-Oei LF. Cost-effectiveness of FDG-PET/CT for cytologically indeterminate thyroid nodules: a decision analytic approach. J Clin Endocrinol Metab. 2014 Sep;99(9):3263-74. doi: 10.1210/jc.2013-3483. Epub 2014 May 29.</citation>
    <PMID>24873995</PMID>
  </reference>
  <reference>
    <citation>de Koster EJ, de Geus-Oei LF, Dekkers OM, van Engen-van Grunsven I, Hamming J, Corssmit EPM, Morreau H, Schepers A, Smit J, Oyen WJG, Vriens D. Diagnostic Utility of Molecular and Imaging Biomarkers in Cytological Indeterminate Thyroid Nodules. Endocr Rev. 2018 Apr 1;39(2):154-191. doi: 10.1210/er.2017-00133.</citation>
    <PMID>29300866</PMID>
  </reference>
  <results_reference>
    <citation>de Koster EJ, de Geus-Oei LF, Brouwers AH, van Dam EWCM, Dijkhorst-Oei LT, van Engen-van Grunsven ACH, van den Hout WB, Klooker TK, Netea-Maier RT, Snel M, Oyen WJG, Vriens D; EfFECTS trial study group. [18F]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial. Eur J Nucl Med Mol Imaging. 2022 May;49(6):1970-1984. doi: 10.1007/s00259-021-05627-2. Epub 2022 Jan 4.</citation>
    <PMID>34981165</PMID>
  </results_reference>
  <results_reference>
    <citation>de Koster EJ, Noortman WA, Mostert JM, Booij J, Brouwer CB, de Keizer B, de Klerk JMH, Oyen WJG, van Velden FHP, de Geus-Oei LF, Vriens D; EfFECTS trial study group. Quantitative classification and radiomics of [18F]FDG-PET/CT in indeterminate thyroid nodules. Eur J Nucl Med Mol Imaging. 2022 Jun;49(7):2174-2188. doi: 10.1007/s00259-022-05712-0. Epub 2022 Feb 9.</citation>
    <PMID>35138444</PMID>
  </results_reference>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>July 22, 2014</study_first_submitted>
  <study_first_submitted_qc>August 4, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 5, 2014</study_first_posted>
  <last_update_submitted>April 27, 2022</last_update_submitted>
  <last_update_submitted_qc>April 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Thyroid Nodule</keyword>
  <keyword>Indeterminate Cytology</keyword>
  <keyword>FDG-PET/CT</keyword>
  <keyword>Diagnostic Thyroid Surgery</keyword>
  <keyword>Efficacy</keyword>
  <keyword>Cost-Effectiveness</keyword>
  <keyword>Quality-of-Life</keyword>
  <keyword>Thyroidectomy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thyroid Nodule</mesh_term>
    <mesh_term>Thyroid Neoplasms</mesh_term>
    <mesh_term>Thyroid Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fluorodeoxyglucose F18</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The study protocol and datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Data requestors will need to sign a data access agreement and in keeping with patient consent for secondary use, obtain ethical approval for any new analyses.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>Starting 2023.</ipd_time_frame>
    <ipd_access_criteria>The study protocol and datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Data requestors will need to sign a data access agreement and in keeping with patient consent for secondary use, obtain ethical approval for any new analyses.</ipd_access_criteria>
  </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/NCT02208544
org study id: KUN 2014-6514
secondary id: NL50166.091.14
nct id: NCT02208544
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of this study is to determine whether the use of molecular imaging using
      FDG-PET/CT could prevent unnecessary diagnostic thyroid surgery in case of indeterminate
      cytology during fine-needle aspiration biopsy.
Rationale: Only about ¼ of patients with thyroid nodules with indeterminate cytology are
      proven to suffer from a malignancy at diagnostic hemithyroidectomy. Therefore ~¾ is operated
      upon unbeneficially. Recent studies using FDG-PET/CT have suggested that it can decrease the
      fraction of unbeneficial procedures from ~73% to ~40%. Thereby the direct costs per patient,
      the number of hospitalization and average sick leave days might decrease and the experienced
      HRQoL might increase. A study will be undertaken to show the additional value of FDG-PET/CT
      after indeterminate cytology with respect to unbeneficial procedures, costs and utilities.

      Main objective: To determine the impact of FDG-PET/CT on decreasing the fraction of patients
      with cytologically indeterminate thyroid nodules undergoing unbeneficial patient management.

      Study design: A prospective, multicentre, randomized, stratified controlled blinded trial
      with an experimental study-arm (FDG-PET/CT-driven) and a control study-arm (diagnostic
      hemithyroidectomy, independent of FDG-PET/CT-result).

      Study population: Adult patients with a cytologically indeterminate thyroid nodule, without
      exclusion criteria, in 15 (university and regional) hospitals distributed over the
      Netherlands.

      Intervention: One single FDG-PET/low-dose non-contrast enhanced CT of the head and neck is
      performed in all patients. Patient management depends on allocation and results of this
      FDG-PET/CT.

      Main study parameters/endpoints: The number of unbeneficial interventions, i.e. surgery for
      benign disease or watchful-waiting for malignancy.

      Secondary objectives: complication rate, consequences of incidental PET-findings, number of
      hospitalisation and sick leave days, volumes of healthcare consumed, experienced
      health-related quality-of-life (HRQoL), genetic, cytological and (immuno)histopathological
      features of the nodules.

      Sample size calculation/data analysis: Based on above-mentioned estimated reduction in
      unbeneficial interventions from ~73% to ~40%, at least 90 patients with nodules>10 mm need to
      be analyzed (2:1 allocation, α=0.05, power=0.90, single-sided Fisher's exact test). After
      correction for nodule size and data-attrition, 132 patients need to be included in total.
      Intention-to-treat analysis will be performed. Incremental Net Monetary Benefit based on the
      total direct costs per patients and the gain in HRQoL-adjusted survival years are computed.
      Cytological, histological and genetic parameters for FDG-avidity will be described.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: All patients undergo one FDG-PET/CT scan of head/neck (effective dose: <3.5 mSv)
      and are asked to fill in 6 questionnaires at 4 timepoints. FDG-PET/CT negative patients in
      the experimental arm will undergo a single confirmatory US (±FNAC). An interim/posterior
      analysis of the control subjects is performed to ensure oncological safety. In case of an
      unexpected high false-negative ratio in this control arm, all patients will be advised to
      undergo surgery.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: Triple (Participant, Care Provider, Outcomes Assessor)
measure: Fraction of unbeneficial treatment
time frame: 12 months after inclusion
description: Unbeneficial treatment is defined as either:
surgery in benign disease
watchful waiting in malignant disease
benign or malignant disease is defined on final histology (after surgery) or 12 month follow-up including confirmatory neck ultrasonography.
This parameter is compared between both study arms based on intention-to-treat.
measure: Fraction Complications
time frame: 12 months after inclusion
description: SO1b: To determine the effect of incorporation of FDG-PET/CT on the complication-ratio.
measure: Fraction False-Negative FDG-PET/CT's
time frame: 12 months after inclusion
description: SO1c: To determine the false-negative fraction of FDG-PET/CT in this population.
measure: Lesion and Patient Characteristics
time frame: 12 months after inclusion
description: SO1d: To determine the influence of lesion size, pathological classification and patient characteristics on the diagnostic accuracy of FDG-PET/CT.
measure: Fraction Incidental FDG-PET/CT Findings
time frame: 12 months after inclusion
description: SO1e: To determine whether incorporation of FDG-PET/CT of the head and neck lead to overdiagnosis in non-thyroidal incidental findings.
measure: Overall and Disease Free Survival
time frame: 12 months after inclusion
description: SO1f: To determine the short-term overall and disease free survival in both study arms.
measure: FDG-PET/CT Implementation-hampering Factors
time frame: 12 months after inclusion
description: SO1g: To determine which factors hamper implementation of this modality for this indication (structured interviews).
measure: Fraction of Patients being operated despite negative FDG-PET/CT
time frame: 12 months after inclusion
description: SO1h: To determine the fraction of patients that cannot be reassured by a negative PET-scan (experimental arm only) despite careful selection of patients (implementability).
measure: HRQoL-scores according to SF36-II, EQ-5D-5L, SF-HLQ and ThyPRO including changes
time frame: Baseline, 2 months, 6 months and 12 months after inclusion
description: SO2a: To determine the impact on the experienced HRQoL between the group with and without FDG-PET/CT according to 4 different questionnaires at 4 timepoints during the first 12 months after FDG-PET/CT.
SO2b: To determine whether patients in the experimental arm with negative PET-findings have a different HRQoL than those who receive surgery independent of the FDG-PET/CT results.
measure: Direct Costs
time frame: 12 months after inclusion
description: SO3a: To determine the effect of incorporation of FDG-PET/CT on the mean direct costs (=volume of care multiplied by activity based costs) per patient during the first 12 months after FDG-PET/CT.
measure: Number of Hospitalisation Days
time frame: 12 months after inclusion
description: SO3b: To determine the effect of incorporation of FDG-PET/CT on the average length of hospital stay for treatment of (complications of) thyroid lesions?
measure: Number of Sick Leave Days
time frame: 3 months after inclusions
description: SO3c: To determine the total number of sick leave days for the first three months in the patients? Do these differ between both study arms?
measure: incremental Net Monetary Benefit
time frame: 12 months after inclusion
description: SO3d: To determine the incremental Net Monetary Benefit of incorporation of FDG-PET/CT with respect to quality-adjusted life-years (QALYs, based on EQ-5D-5L index and overall survival) saved including sensitivity analysis.
SO3e: To determine the incremental Net Monetary Benefit of incorporation of FDG-PET/CT with respect to decrease in unbeneficial treatment.
Sensitivity analysis will be performed. A mere description will be given as there is no "accepted" value for this kind of analysis.
measure: Tissue Protein- and Gene-expression profile
time frame: 12 months after inclusion of last patient
description: SO4a: Are there potential protein- or gene-expression profiles, capable of determining the nature of the FNAC-indeterminate nodes (cytology) SO4b: What is the interaction/correlation between the parameters mentioned in SO4a and the results of the FDG-PET/CT scan and the final diagnosis?
measure: Molecular biomarkers in relation to FDG-PET/CT
time frame: 12 months after inclusion of last patient
description: SO4b: What is the interaction/correlation between the parameters mentioned in SO4a and the results of the FDG-PET/CT scan and the final diagnosis?
Can these tissue molecular biomarkers help in selecting the patients that benefit most from FDG-PET, or vice versa?
Can higher pre-operative diagnostic accuracy be achieved by combining FDG-PET and molecular biomarkers?
Are molecular biomarkers related to false-positive or false-negative FDG-PET/CT results?
arm group label: FDG-PET/CT-driven
arm group type: Experimental
description: Following treatment based on FDG-PET/CT:
negative: watchful waiting including confirmatory ultrasound
positive: diagnostic thyroid surgery as planned
arm group label: Current Practice
arm group type: Other
description: diagnostic thyroid surgery despite results of FDG-PET/CT
intervention type: Procedure
intervention name: Diagnostic Thyroid Surgery
description: Diagnostic Thyroid Surgery
arm group label: Current Practice
arm group label: FDG-PET/CT-driven
other name: Thyroid Lobectomy
other name: Hemithyroidectomy
other name: Thyroidectomy
intervention type: Device
intervention name: Ultrasound of the head and neck
description: Confirmatory Neck Ultrasonography in FDG-PET/CT negative patient in the experimental arm
arm group label: FDG-PET/CT-driven
intervention type: Radiation
intervention name: FDG-PET/CT
description: Head and Neck FDG-PET/CT
arm group label: Current Practice
arm group label: FDG-PET/CT-driven
other name: fluorodeoxyglucose positron emission tomography
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lioe-Fee de Geus-Oei, MD, PhD
role: Study Chair
affiliation: Leiden University Medical Center, Leiden, the Netherlands
last name: Dennis Vriens, MD, PhD
role: Study Director
affiliation: Leiden University Medical Center, Leiden, the Netherlands
last name: Lisanne de Koster, MD
role: Principal Investigator
affiliation: Radboud University Medical Centre, Nijmegen, the Netherlands
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country: Netherlands
citation: de Geus-Oei LF, Pieters GF, Bonenkamp JJ, Mudde AH, Bleeker-Rovers CP, Corstens FH, Oyen WJ. 18F-FDG PET reduces unnecessary hemithyroidectomies for thyroid nodules with inconclusive cytologic results. J Nucl Med. 2006 May;47(5):770-5.
PMID: 16644746
citation: Vriens D, de Wilt JH, van der Wilt GJ, Netea-Maier RT, Oyen WJ, de Geus-Oei LF. The role of [18F]-2-fluoro-2-deoxy-d-glucose-positron emission tomography in thyroid nodules with indeterminate fine-needle aspiration biopsy: systematic review and meta-analysis of the literature. Cancer. 2011 Oct 15;117(20):4582-94. doi: 10.1002/cncr.26085. Epub 2011 Mar 22.
PMID: 21432844
citation: Vriens D, Adang EM, Netea-Maier RT, Smit JW, de Wilt JH, Oyen WJ, de Geus-Oei LF. Cost-effectiveness of FDG-PET/CT for cytologically indeterminate thyroid nodules: a decision analytic approach. J Clin Endocrinol Metab. 2014 Sep;99(9):3263-74. doi: 10.1210/jc.2013-3483. Epub 2014 May 29.
PMID: 24873995
citation: de Koster EJ, de Geus-Oei LF, Dekkers OM, van Engen-van Grunsven I, Hamming J, Corssmit EPM, Morreau H, Schepers A, Smit J, Oyen WJG, Vriens D. Diagnostic Utility of Molecular and Imaging Biomarkers in Cytological Indeterminate Thyroid Nodules. Endocr Rev. 2018 Apr 1;39(2):154-191. doi: 10.1210/er.2017-00133.
PMID: 29300866
citation: de Koster EJ, de Geus-Oei LF, Brouwers AH, van Dam EWCM, Dijkhorst-Oei LT, van Engen-van Grunsven ACH, van den Hout WB, Klooker TK, Netea-Maier RT, Snel M, Oyen WJG, Vriens D; EfFECTS trial study group. [18F]FDG-PET/CT to prevent futile surgery in indeterminate thyroid nodules: a blinded, randomised controlled multicentre trial. Eur J Nucl Med Mol Imaging. 2022 May;49(6):1970-1984. doi: 10.1007/s00259-021-05627-2. Epub 2022 Jan 4.
PMID: 34981165
citation: de Koster EJ, Noortman WA, Mostert JM, Booij J, Brouwer CB, de Keizer B, de Klerk JMH, Oyen WJG, van Velden FHP, de Geus-Oei LF, Vriens D; EfFECTS trial study group. Quantitative classification and radiomics of [18F]FDG-PET/CT in indeterminate thyroid nodules. Eur J Nucl Med Mol Imaging. 2022 Jun;49(7):2174-2188. doi: 10.1007/s00259-022-05712-0. Epub 2022 Feb 9.
PMID: 35138444
responsible party type: Sponsor
mesh term: Thyroid Nodule
mesh term: Thyroid Neoplasms
mesh term: Thyroid Diseases
mesh term: Fluorodeoxyglucose F18
sharing ipd: Yes
ipd description: The study protocol and datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Data requestors will need to sign a data access agreement and in keeping with patient consent for secondary use, obtain ethical approval for any new analyses.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Clinical Study Report (CSR)
ipd time frame: Starting 2023.
ipd access criteria: The study protocol and datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Data requestors will need to sign a data access agreement and in keeping with patient consent for secondary use, obtain ethical approval for any new analyses.