<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/NCT04470440</url>
  </required_header>
  <id_info>
    <org_study_id>THYRONIVO (29BRC19.0228)</org_study_id>
    <nct_id>NCT04470440</nct_id>
  </id_info>
  <brief_title>Thyroid Dysfunction and Nivolumab Reponse in NSCLC</brief_title>
  <acronym>THYRONIVO</acronym>
  <official_title>Thyroid Biological Toxicity and Tumor Response in Patients Treated With NIVOLUMAB 2nd Line in Non-small Cell Bronchopulmonary Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Brest</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Brest</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>
      This is an observational, retrospective and monocentric study, conducted at the university&#xD;
      Hospital of Brest The primary objective is to assess the association between the occurrence&#xD;
      of thyroid dysfunction in patients treated with Nivolumab® for a non-small cell lung cancer&#xD;
      and prognosis and therapeutic response The second objective is to assess prognosis and&#xD;
      therapeutic response according to severity and subtype of thyroid dysfunction&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cohort characteristics&#xD;
&#xD;
      The patients' characteristics were collected from medicals records: age, gender, smoking&#xD;
      status (absent, current or weaned), WHO performance index, neoplastic characteristics (tumor&#xD;
      histology, history of brain metastasis, prior radiotherapy treatment, prior therapy lines&#xD;
      (defined by the number of chemotherapy or immunotherapy regimens used before Nivolumab®&#xD;
      treatment) We also recorded data about expression of tumor PD-L1, LDH levels and the&#xD;
      lymphocyte to neutrophil ratio (dNLR) summarized in the LIPI score (Lung immune prognostic&#xD;
      index), which distinguishes three categories: good prognosis (normal LDH, dNLR &lt;3),&#xD;
      intermediate prognosis (abnormal LDH or dNLR&gt; 3), poor prognosis (abnormal LDH and dNLR&gt; 3),&#xD;
&#xD;
      Treatment schedule and morphological monitoring&#xD;
&#xD;
      Nivolumab® (3mg/kg mg) was administered as an IV infusion for 30 minutes every 2 weeks until&#xD;
      disease progression, unacceptable toxicity, or death. Tumor assessment was performed every 2&#xD;
      months until disease progression. Tumor assessment was based on the results of the&#xD;
      computerized tomodensitometry (CT) + injection of a radioiodine contrast agent and/or&#xD;
      18F-fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) (18FDG-PET/CT), according&#xD;
      to the RECIST 1.1 or iRECIST 1.1 ((immune) Response Evaluation Criteria in Solid Tumors)&#xD;
      criterion. In case of a dissociated response (response of a lesion associated with a&#xD;
      progression of another lesion) or in case of suspicion of pseudo-progression (increase in&#xD;
      size or appearance of new lesions linked to the influx of immune cells within the tumor), a&#xD;
      new morphological evaluation after two additional cycles was taken into account.&#xD;
&#xD;
      Thyroid function screening and classification of thyroid dysfunction&#xD;
&#xD;
      Thyroid function screening was performed before (&lt;3 months) and during treatment with&#xD;
      Nivolumab® (TSH, free T4 (fT4), free T3 (fT3) ± Anti-thyroid peroxidase antibodies (TPOAb)&#xD;
      and/or TSH receptor antibodies (TRAbs) were measured by electrochemiluminescence (Reference&#xD;
      laboratory values were: TSH, 0.27-4.20 mIU/L; fT4, 11.6-22.0 pmol/L; fT3, 4.0-6.8 pmol/L;&#xD;
      TPOAb, &lt;34 kIU/L; and TRAb, &lt;1.75 U/L&#xD;
&#xD;
      For classification of thyroid dysfunction, the CTCAE classification was not taken into&#xD;
      account because it is not adapted to thyroid dysfunction that is often asymptomatic. Only&#xD;
      abnormalities of the thyroid function tests were considered as follow:&#xD;
&#xD;
        1. Patients with abnormalities of TSH level were classified in the group &quot;Thyroid&#xD;
           Dysfunction +&quot; and those with normal TSH level were classified in the group &quot;Thyroid&#xD;
           Dysfunction -&quot;. In case of normal TSH with isolated abnormality of peripherical hormone&#xD;
           fT4 and/or fT3, the patient was classified in the &quot;Thyroid Dysfunction -&quot; group;&#xD;
&#xD;
        2. Depending on the level of peripheral thyroid hormones (i.e. fT3 and fT4): subclinical&#xD;
           thyroid dysfunction was defined by an abnormal TSH without abnormality of the peripheral&#xD;
           hormones and overt thyroid dysfunction was defined by an abnormal TSH associated with at&#xD;
           least one abnormality of the peripheral hormones T3 or T4L;&#xD;
&#xD;
        3. Depending on the TSH level: moderate thyroid dysfunction was defined by a TSH level&#xD;
           between 0.1 mIU/L and 0.27 mIU/L or between 4.2 mIU/L and 10 mIU/L, and severe thyroid&#xD;
           dysfunction was defined in case of TSH ≤ 0.1 mUI/L or ≥ 10 mUI/L, respectively for&#xD;
           hyperthyroidism and hypothyroidism;&#xD;
&#xD;
        4. Depending on the type of thyroid dysfunction, we classified each patient in three&#xD;
           categories isolated hypothyroidism, isolated thyrotoxicosis and thyroiditis&#xD;
           (thyrotoxicosis then hypothyroidism).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 22, 2019</start_date>
  <completion_date type="Actual">November 5, 2019</completion_date>
  <primary_completion_date type="Actual">November 5, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>overall survival</measure>
    <time_frame>up to 48 months</time_frame>
    <description>OS was defined as the time between the introduction of Nivolumab® and death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>objective response rate (ORR)</measure>
    <time_frame>up to 48 months</time_frame>
    <description>The ORR was defined as a partial or complete response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>disease control rate (DCR)</measure>
    <time_frame>up to 48 months</time_frame>
    <description>DCR was defined as stability or as an objective response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>up to 48 months</time_frame>
    <description>PFS is defined as the time between the introduction of Nivolumab® and the date of progression or death.</description>
  </secondary_outcome>
  <enrollment type="Actual">134</enrollment>
  <condition>Non Small Cell Lung Cancer Metastatic</condition>
  <condition>Treatment Adverse Effect</condition>
  <condition>Thyroid Dysfunction</condition>
  <condition>Immune Checkpoint Inhibitor</condition>
  <condition>Prognosis</condition>
  <eligibility>
    <study_pop>
      <textblock>
        patients treated with Nivolumab® for a non-small cell lung cancer as a second line&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients at least 18 years old and had histologically confirmed locally advanced stage&#xD;
             (IIIB) or metastatic (IV) non-small cell lung cancer with disease progression;&#xD;
&#xD;
          -  treated with Nivolumab® as second or more therapeutic line&#xD;
&#xD;
          -  in the oncologic department university hospital of Brest&#xD;
&#xD;
          -  during the inclusion period between July 20, 2015 to June 30, 2018.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  patients whose primary tumor was not from bronchopulmonary origin&#xD;
&#xD;
          -  patients with a history of total thyroidectomy and/or having previously treated with&#xD;
             levothyroxine and/or having a thyroid dysfunction previously to the introduction of&#xD;
             Nivolumab®&#xD;
&#xD;
          -  patients not having any thyroid monitoring during Nivolumab® treatment, and those for&#xD;
             which data were missing&#xD;
&#xD;
          -  patients who expressed their opposition to participate in the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>CHRU de Brest</name>
      <address>
        <city>Brest</city>
        <zip>2909</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 7, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 14, 2020</study_first_posted>
  <last_update_submitted>July 9, 2020</last_update_submitted>
  <last_update_submitted_qc>July 9, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thyroid Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All collected data that underlie results in a publication</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>Data will be available beginning trois month and ending five year following the end of the study</ipd_time_frame>
    <ipd_access_criteria>Data access requests will be reviewed by the internal committee of Brest UH. Requestors will be required to sign and complete a data access agreement.</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/NCT04470440
org study id: THYRONIVO (29BRC19.0228)
nct id: NCT04470440
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is an observational, retrospective and monocentric study, conducted at the university
      Hospital of Brest The primary objective is to assess the association between the occurrence
      of thyroid dysfunction in patients treated with Nivolumab® for a non-small cell lung cancer
      and prognosis and therapeutic response The second objective is to assess prognosis and
      therapeutic response according to severity and subtype of thyroid dysfunction
Cohort characteristics

      The patients' characteristics were collected from medicals records: age, gender, smoking
      status (absent, current or weaned), WHO performance index, neoplastic characteristics (tumor
      histology, history of brain metastasis, prior radiotherapy treatment, prior therapy lines
      (defined by the number of chemotherapy or immunotherapy regimens used before Nivolumab®
      treatment) We also recorded data about expression of tumor PD-L1, LDH levels and the
      lymphocyte to neutrophil ratio (dNLR) summarized in the LIPI score (Lung immune prognostic
      index), which distinguishes three categories: good prognosis (normal LDH, dNLR <3),
      intermediate prognosis (abnormal LDH or dNLR> 3), poor prognosis (abnormal LDH and dNLR> 3),

      Treatment schedule and morphological monitoring

      Nivolumab® (3mg/kg mg) was administered as an IV infusion for 30 minutes every 2 weeks until
      disease progression, unacceptable toxicity, or death. Tumor assessment was performed every 2
      months until disease progression. Tumor assessment was based on the results of the
      computerized tomodensitometry (CT) + injection of a radioiodine contrast agent and/or
      18F-fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) (18FDG-PET/CT), according
      to the RECIST 1.1 or iRECIST 1.1 ((immune) Response Evaluation Criteria in Solid Tumors)
      criterion. In case of a dissociated response (response of a lesion associated with a
      progression of another lesion) or in case of suspicion of pseudo-progression (increase in
      size or appearance of new lesions linked to the influx of immune cells within the tumor), a
      new morphological evaluation after two additional cycles was taken into account.

      Thyroid function screening and classification of thyroid dysfunction

      Thyroid function screening was performed before (<3 months) and during treatment with
      Nivolumab® (TSH, free T4 (fT4), free T3 (fT3) ± Anti-thyroid peroxidase antibodies (TPOAb)
      and/or TSH receptor antibodies (TRAbs) were measured by electrochemiluminescence (Reference
      laboratory values were: TSH, 0.27-4.20 mIU/L; fT4, 11.6-22.0 pmol/L; fT3, 4.0-6.8 pmol/L;
      TPOAb, <34 kIU/L; and TRAb, <1.75 U/L

      For classification of thyroid dysfunction, the CTCAE classification was not taken into
      account because it is not adapted to thyroid dysfunction that is often asymptomatic. Only
      abnormalities of the thyroid function tests were considered as follow:

        1. Patients with abnormalities of TSH level were classified in the group "Thyroid
           Dysfunction +" and those with normal TSH level were classified in the group "Thyroid
           Dysfunction -". In case of normal TSH with isolated abnormality of peripherical hormone
           fT4 and/or fT3, the patient was classified in the "Thyroid Dysfunction -" group;

        2. Depending on the level of peripheral thyroid hormones (i.e. fT3 and fT4): subclinical
           thyroid dysfunction was defined by an abnormal TSH without abnormality of the peripheral
           hormones and overt thyroid dysfunction was defined by an abnormal TSH associated with at
           least one abnormality of the peripheral hormones T3 or T4L;

        3. Depending on the TSH level: moderate thyroid dysfunction was defined by a TSH level
           between 0.1 mIU/L and 0.27 mIU/L or between 4.2 mIU/L and 10 mIU/L, and severe thyroid
           dysfunction was defined in case of TSH ≤ 0.1 mUI/L or ≥ 10 mUI/L, respectively for
           hyperthyroidism and hypothyroidism;

        4. Depending on the type of thyroid dysfunction, we classified each patient in three
           categories isolated hypothyroidism, isolated thyrotoxicosis and thyroiditis
           (thyrotoxicosis then hypothyroidism).
observational model: Cohort
time perspective: Retrospective
measure: overall survival
time frame: up to 48 months
description: OS was defined as the time between the introduction of Nivolumab® and death
measure: objective response rate (ORR)
time frame: up to 48 months
description: The ORR was defined as a partial or complete response
measure: disease control rate (DCR)
time frame: up to 48 months
description: DCR was defined as stability or as an objective response
measure: Progression-free survival
time frame: up to 48 months
description: PFS is defined as the time between the introduction of Nivolumab® and the date of progression or death.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: France
responsible party type: Sponsor
mesh term: Thyroid Diseases
sharing ipd: Yes
ipd description: All collected data that underlie results in a publication
ipd info type: Study Protocol
ipd time frame: Data will be available beginning trois month and ending five year following the end of the study
ipd access criteria: Data access requests will be reviewed by the internal committee of Brest UH. Requestors will be required to sign and complete a data access agreement.