<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/NCT03815838</url>
  </required_header>
  <id_info>
    <org_study_id>SPON1592-17</org_study_id>
    <nct_id>NCT03815838</nct_id>
  </id_info>
  <brief_title>Molecular Imaging of Pituitary Adenomas</brief_title>
  <acronym>MIMOPA</acronym>
  <official_title>Molecular Imaging of Pituitary Adenomas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cardiff University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cardiff and Vale University Health Board</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Cardiff University</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>
      Background: Pituitary adenomas affect 10% of the population. Surgery offers the most&#xD;
      cost-effective treatment modality but cure rates are only 40-70%, in part due to the&#xD;
      limitations of Magnetic Resonance Imaging (MRI) in visualising small tumours (up to 40% are&#xD;
      undetected) and discriminating adenomatous tissue from healthy pituitary or post-surgical&#xD;
      change. Positron emission tomography (PET) imaging may improve localisation but current&#xD;
      tracers have short half-lives and are unsuitable for routine use. The dopaminergic system&#xD;
      regulates pituitary growth and function, as evidenced by the use of dopamine D2 receptor&#xD;
      agonists as medical therapy. Dopaminergic PET tracers, including 18F-FDOPA&#xD;
      (6-[18F]-L-fluoro-L-3,4-dihydroxyphenylalanine) and 18F (fluorine 18)-Fallypride (which binds&#xD;
      to D2/D3 receptors), might thus improve management by enhancing tumour discrimination and&#xD;
      quantifying D2 receptor expression.&#xD;
&#xD;
      Aim: To establish whether imaging changes in dopaminergic transmission and receptor function&#xD;
      has the potential to improve localisation of pituitary adenomas.&#xD;
&#xD;
      Methods: Subjects with pituitary adenomas will undergo 18F-FDOPA and 18F-Fallypride PET scans&#xD;
      in addition to standard pituitary MRI. Quantification of binding potential combined with MRI&#xD;
      co-registration to provide enhanced anatomical definition will be applied. In vivo D2&#xD;
      receptor binding will be correlated with ex vivo D2 receptor mRNA (messenger ribonucleic&#xD;
      acid) and protein expression from tumour samples removed at surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aim: In this proof-of-concept study, the investigators will seek to establish whether imaging&#xD;
      changes in Dopaminergic transmission and receptor function has the potential to improve&#xD;
      localisation and management of pituitary adenomas.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      Patients will be recruited from the general endocrine and pituitary multidisciplinary clinics&#xD;
      at the University Hospital of Wales. Patients will comprise those with a confirmed pituitary&#xD;
      adenoma for whom pituitary imaging is indicated as part of standard clinical management.&#xD;
      Tumour functionality (Cushing's syndrome, Acromegaly, Prolactinoma, TSHoma) and&#xD;
      hypopituitarism will be established in accordance with established clinical practice.&#xD;
      Detailed surgical, pathological and post-operative data will be collected in each case, in&#xD;
      order to facilitate correlation of PET/MRI findings with key clinical outcomes.&#xD;
&#xD;
      Histopathological examination:&#xD;
&#xD;
      Surgical specimens will be fixed in 10% neutral buffered formalin and embedded in paraffin as&#xD;
      per standard clinical practice. Histopathological confirmation of the presence and type of&#xD;
      pituitary adenoma will be established by typical microscopic appearances of an adenoma&#xD;
      supported by immunohistochemical staining for the relevant hormone (Growth hormone, ACTH&#xD;
      [Adrenocorticotrophic Hormone], Prolactin, TSH [Thyroid Stimulating Hormone], LH/FSH&#xD;
      [Luteinising hormone/Follicle Stimulating Hormone]). Tumour will also be stored snap frozen&#xD;
      for subsequent RNA and protein extraction, in order to quantify dopamine D2 short and long&#xD;
      isoform receptor expression. This will allow comparison of ex vivo receptor expression levels&#xD;
      with in vivo 18F-fallypride uptake.&#xD;
&#xD;
      PET-CT imaging:&#xD;
&#xD;
      Subjects will undergo 18F-FDOPA and 18F-Fallypride imaging according to established protocols&#xD;
      in the PET imaging centre (PETIC) at the University Hospital of Wales. Both compounds will be&#xD;
      synthesised in compliance with good manufacturing practice, and have been produced and&#xD;
      validated for human use in PETIC since 2015. Subjects will refrain from taking alcohol and&#xD;
      caffeine for 4 hours before the PET scanning session. PET scans will be acquired using a&#xD;
      PET-CT (Positron Emission Tomography-Computed Tomography) scanner with Time of Flight and a&#xD;
      64 slice CT in 3D list mode. Patients will be placed in the scanner in the supine position,&#xD;
      with the brain centred in the axial field of view. A CT scout view will be acquired to aid in&#xD;
      positioning of the patient following which the head will be fixed using a piece of surgical&#xD;
      tape.&#xD;
&#xD;
      18F-FDOPA protocol: For 18F-FDOPA, participants will be pre-treated with 150 mg (milligrams)&#xD;
      carbidopa and 400 mg entacapone 1 hour prior to radioisotope administration in order to block&#xD;
      peripheral metabolism of FDOPA and enhance specific signal detection. A low dose CT scan will&#xD;
      be acquired for positioning and attenuation correction. A single position Dynamic PET scan&#xD;
      will be acquired as 26 time-frames over 94.5 minutes (1 × 30 sec, 4 × 1 min, 3 × 2 min, 3 × 3&#xD;
      min, and 15 × 5 min). Immediately after the scan commences 111 MBq (Megabecquerels) of&#xD;
      18F-DOPA in normal saline will be administered via a long connecting tube as an intravenous&#xD;
      bolus at the start of scanning (avoiding brain stimuli). Data will be reconstructed using&#xD;
      OSEM (ordered-subsets expectation maximisation) following corrections for attenuation,&#xD;
      normalisation, scatter and patient movement. The cerebellum will be used to represent the&#xD;
      reference region for the data analysis and enable the generation of binding potential&#xD;
      parametric images using Logan plots.&#xD;
&#xD;
      18 F-Fallypride protocol: Dynamic acquisition of the PET scan will be started with a 30&#xD;
      second bolus administration of 18F Fallypride (2.6 MBq/kg body weight). Patients will undergo&#xD;
      3 hours of dynamic imaging (3 × 20 s, 3 × 1 min, 3 × 2 min, 3 × 3 min, 21 × 5 min, 2 × 8 min&#xD;
      and 4 × 10 min; 180 min in total)(with rest periods during the scan to reduce discomfort and&#xD;
      allow urinary voiding to reduce radiation dose to the bladder wall). Data will be&#xD;
      reconstructed using OSEM following corrections for attenuation, normalisation, scatter and&#xD;
      patient movement. The cerebellum will be used to represent the reference region for the data&#xD;
      analysis and enable the generation of binding potential parametric images using Logan plots.&#xD;
&#xD;
      Standard and 3D gradient echo MRI:&#xD;
&#xD;
      MR imaging will be performed on a 1.5T (Tesla) MRI unit. High resolution coronal T2-weighted&#xD;
      images and coronal and sagittal T1-weighted spin echo (SE) images of the pituitary gland will&#xD;
      be obtained before contrast injection. After intravenous injection of gadopentetate&#xD;
      dimeglumine contrast the investigators will repeat the acquisition of the coronal and&#xD;
      sagittal T1-weighted SE images of the pituitary gland and will also record a high resolution&#xD;
      T1-weighted spoiled gradient (SPGR) acquisition sequence of the whole head to optimise&#xD;
      co-registration with the PET/CT data.&#xD;
&#xD;
      Image processing and analysis:&#xD;
&#xD;
      Image analysis techniques to include detailed profiling of tracer uptake across the sella&#xD;
      will be applied. Image processing will be performed using commercially available software&#xD;
      packages.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">April 23, 2018</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PET uptake</measure>
    <time_frame>3 hours</time_frame>
    <description>Quantification of tracer binding potential combined with MRI co-registration</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Pituitary Adenoma</condition>
  <arm_group>
    <arm_group_label>PET imaging</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>18F-FDOPA and 18F-Fallypride PET imaging</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>PET imaging</intervention_name>
    <description>Positron emission tomography imaging using 18F-Fallypride and 18F-FDOPA</description>
    <arm_group_label>PET imaging</arm_group_label>
    <other_name>Fallypride</other_name>
    <other_name>F-DOPA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed pituitary adenoma for whom pituitary imaging is indicated as part of&#xD;
             standard clinical management&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy, breastfeeding and any contraindications to MRI or intravenous contrast&#xD;
             administration&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Aled Rees, MB BCh, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cardiff University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Aled Rees, MB BCh, PhD</last_name>
    <phone>+44(0)2920 742309</phone>
    <email>reesda@cf.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>University Hospital of Wales</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 4XW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aled Rees, MB BCh, PhD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 23, 2019</study_first_submitted>
  <study_first_submitted_qc>January 23, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>January 24, 2019</last_update_submitted>
  <last_update_submitted_qc>January 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 25, 2019</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>Adenoma</mesh_term>
    <mesh_term>Pituitary Neoplasms</mesh_term>
    <mesh_term>Pituitary Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fallypride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03815838
org study id: SPON1592-17
nct id: NCT03815838
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Background: Pituitary adenomas affect 10% of the population. Surgery offers the most
      cost-effective treatment modality but cure rates are only 40-70%, in part due to the
      limitations of Magnetic Resonance Imaging (MRI) in visualising small tumours (up to 40% are
      undetected) and discriminating adenomatous tissue from healthy pituitary or post-surgical
      change. Positron emission tomography (PET) imaging may improve localisation but current
      tracers have short half-lives and are unsuitable for routine use. The dopaminergic system
      regulates pituitary growth and function, as evidenced by the use of dopamine D2 receptor
      agonists as medical therapy. Dopaminergic PET tracers, including 18F-FDOPA
      (6-[18F]-L-fluoro-L-3,4-dihydroxyphenylalanine) and 18F (fluorine 18)-Fallypride (which binds
      to D2/D3 receptors), might thus improve management by enhancing tumour discrimination and
      quantifying D2 receptor expression.

      Aim: To establish whether imaging changes in dopaminergic transmission and receptor function
      has the potential to improve localisation of pituitary adenomas.

      Methods: Subjects with pituitary adenomas will undergo 18F-FDOPA and 18F-Fallypride PET scans
      in addition to standard pituitary MRI. Quantification of binding potential combined with MRI
      co-registration to provide enhanced anatomical definition will be applied. In vivo D2
      receptor binding will be correlated with ex vivo D2 receptor mRNA (messenger ribonucleic
      acid) and protein expression from tumour samples removed at surgery.
Aim: In this proof-of-concept study, the investigators will seek to establish whether imaging
      changes in Dopaminergic transmission and receptor function has the potential to improve
      localisation and management of pituitary adenomas.

      Methods:

      Patients will be recruited from the general endocrine and pituitary multidisciplinary clinics
      at the University Hospital of Wales. Patients will comprise those with a confirmed pituitary
      adenoma for whom pituitary imaging is indicated as part of standard clinical management.
      Tumour functionality (Cushing's syndrome, Acromegaly, Prolactinoma, TSHoma) and
      hypopituitarism will be established in accordance with established clinical practice.
      Detailed surgical, pathological and post-operative data will be collected in each case, in
      order to facilitate correlation of PET/MRI findings with key clinical outcomes.

      Histopathological examination:

      Surgical specimens will be fixed in 10% neutral buffered formalin and embedded in paraffin as
      per standard clinical practice. Histopathological confirmation of the presence and type of
      pituitary adenoma will be established by typical microscopic appearances of an adenoma
      supported by immunohistochemical staining for the relevant hormone (Growth hormone, ACTH
      [Adrenocorticotrophic Hormone], Prolactin, TSH [Thyroid Stimulating Hormone], LH/FSH
      [Luteinising hormone/Follicle Stimulating Hormone]). Tumour will also be stored snap frozen
      for subsequent RNA and protein extraction, in order to quantify dopamine D2 short and long
      isoform receptor expression. This will allow comparison of ex vivo receptor expression levels
      with in vivo 18F-fallypride uptake.

      PET-CT imaging:

      Subjects will undergo 18F-FDOPA and 18F-Fallypride imaging according to established protocols
      in the PET imaging centre (PETIC) at the University Hospital of Wales. Both compounds will be
      synthesised in compliance with good manufacturing practice, and have been produced and
      validated for human use in PETIC since 2015. Subjects will refrain from taking alcohol and
      caffeine for 4 hours before the PET scanning session. PET scans will be acquired using a
      PET-CT (Positron Emission Tomography-Computed Tomography) scanner with Time of Flight and a
      64 slice CT in 3D list mode. Patients will be placed in the scanner in the supine position,
      with the brain centred in the axial field of view. A CT scout view will be acquired to aid in
      positioning of the patient following which the head will be fixed using a piece of surgical
      tape.

      18F-FDOPA protocol: For 18F-FDOPA, participants will be pre-treated with 150 mg (milligrams)
      carbidopa and 400 mg entacapone 1 hour prior to radioisotope administration in order to block
      peripheral metabolism of FDOPA and enhance specific signal detection. A low dose CT scan will
      be acquired for positioning and attenuation correction. A single position Dynamic PET scan
      will be acquired as 26 time-frames over 94.5 minutes (1 × 30 sec, 4 × 1 min, 3 × 2 min, 3 × 3
      min, and 15 × 5 min). Immediately after the scan commences 111 MBq (Megabecquerels) of
      18F-DOPA in normal saline will be administered via a long connecting tube as an intravenous
      bolus at the start of scanning (avoiding brain stimuli). Data will be reconstructed using
      OSEM (ordered-subsets expectation maximisation) following corrections for attenuation,
      normalisation, scatter and patient movement. The cerebellum will be used to represent the
      reference region for the data analysis and enable the generation of binding potential
      parametric images using Logan plots.

      18 F-Fallypride protocol: Dynamic acquisition of the PET scan will be started with a 30
      second bolus administration of 18F Fallypride (2.6 MBq/kg body weight). Patients will undergo
      3 hours of dynamic imaging (3 × 20 s, 3 × 1 min, 3 × 2 min, 3 × 3 min, 21 × 5 min, 2 × 8 min
      and 4 × 10 min; 180 min in total)(with rest periods during the scan to reduce discomfort and
      allow urinary voiding to reduce radiation dose to the bladder wall). Data will be
      reconstructed using OSEM following corrections for attenuation, normalisation, scatter and
      patient movement. The cerebellum will be used to represent the reference region for the data
      analysis and enable the generation of binding potential parametric images using Logan plots.

      Standard and 3D gradient echo MRI:

      MR imaging will be performed on a 1.5T (Tesla) MRI unit. High resolution coronal T2-weighted
      images and coronal and sagittal T1-weighted spin echo (SE) images of the pituitary gland will
      be obtained before contrast injection. After intravenous injection of gadopentetate
      dimeglumine contrast the investigators will repeat the acquisition of the coronal and
      sagittal T1-weighted SE images of the pituitary gland and will also record a high resolution
      T1-weighted spoiled gradient (SPGR) acquisition sequence of the whole head to optimise
      co-registration with the PET/CT data.

      Image processing and analysis:

      Image analysis techniques to include detailed profiling of tracer uptake across the sella
      will be applied. Image processing will be performed using commercially available software
      packages.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: PET uptake
time frame: 3 hours
description: Quantification of tracer binding potential combined with MRI co-registration
arm group label: PET imaging
arm group type: Experimental
description: 18F-FDOPA and 18F-Fallypride PET imaging
intervention type: Diagnostic Test
intervention name: PET imaging
description: Positron emission tomography imaging using 18F-Fallypride and 18F-FDOPA
arm group label: PET imaging
other name: Fallypride
other name: F-DOPA
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Aled Rees, MB BCh, PhD
role: Principal Investigator
affiliation: Cardiff University
last name: Aled Rees, MB BCh, PhD
phone: +44(0)2920 742309
email: reesda@cf.ac.uk
facility: 
status: Recruiting
contact: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Adenoma
mesh term: Pituitary Neoplasms
mesh term: Pituitary Diseases
mesh term: Fallypride
sharing ipd: No