xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06014398</url>
    </required_header>
    <id_info>
      <org_study_id>23-127</org_study_id>
      <nct_id>NCT06014398</nct_id>
    </id_info>
    <brief_title>Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours</brief_title>
    <official_title>Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Royal College of Surgeons, Ireland</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Beaumont Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Royal College of Surgeons, Ireland</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:&#xD;
  &#xD;
        Approximately 480 primary, non-pituitary, brain tumours were diagnosed in Ireland each year&#xD;
        between 1994 and 2013. Recent developments in treatment have greatly improved survival for&#xD;
        younger patients in the 15-54 age range. The Irish National Neurosurgical Centre and the St&#xD;
        Luke's Radiation Oncology Centre at Beaumont Hospital and treat approximately 200 patients&#xD;
        with brain tumours per year with a combination of surgery, radiotherapy (RT) and chemotherapy&#xD;
        with RT being the most commonly used treatment modality. With improved survivorship, the&#xD;
        prospect of individuals living for several decades with co-morbidities induced by the tumour&#xD;
        itself or surgical and RT treatments, raises new and complex issues for patients and&#xD;
        clinicians.&#xD;
  &#xD;
        The hypothalamus and pituitary gland in the brain are the key regulators of hormone action.&#xD;
        They control several hormone systems including reproductive function (FSH, LH) growth (growth&#xD;
        hormone), thyroid (TSH) and adrenal function (ACTH) as well as many other homeostatic&#xD;
        mechanisms. It has long been recognised that therapeutic cranial RT to the pituitary gland&#xD;
        causes hypothalamic-pituitary dysfunction (hypopituitarism). Traditionally, high-risk groups&#xD;
        for post-irradiation hypopituitarism were considered to be patients with pituitary tumours,&#xD;
        survivors of childhood cancer and patients who received high-dose RT to treat nasopharyngeal&#xD;
        cancers. The potential for cranial radiotherapy to cause significant pituitary dysfunction in&#xD;
        adult patients with brain tumours has received little attention. The assumption has been that&#xD;
        the hypothalamic-pituitary axis is more resistant in adults than in children to the effect of&#xD;
        cranial RT. However, it is likely that the higher doses of RT, used to treat primary brain&#xD;
        tumours in adults, causes significant hypothalamic-pituitary dysfunction resulting in&#xD;
        hypopituitarism. Preliminary data from the National Pituitary Centre in Beaumont Hospital has&#xD;
        revealed that adult patients, treated with cranial radiotherapy for primary, non-pituitary&#xD;
        brain tumours, are at risk of hypopituitarism. Approximately 40% of patients had pituitary&#xD;
        deficiencies in at least one hormone axis, while 25% of patients had deficiencies in multiple&#xD;
        hormone axes. Hypopituitarism confers significant morbidity and increased mortality to&#xD;
        patients. At present, adult survivors of brain tumours are referred to the pituitary service&#xD;
        for assessment on an ad-hoc basis meaning that many patients with hypopituitarism may go&#xD;
        undiagnosed.&#xD;
  &#xD;
        In addition to the challenges caused by hypopituitarism, long-term neuropsychological&#xD;
        outcomes following a brain tumour cause significant functional impairments and reduced&#xD;
        HR-QOL. Patients can present with impairments in specific cognitive domains such as memory&#xD;
        and executive functioning or more global systems such as attention as well as significant&#xD;
        issues with fatigue. In addition to these primary deficits, patients can also present with&#xD;
        significant distress, fluctuant mood and anxiety. Despite the impact of brain tumours can&#xD;
        exert, the National Cancer Control Program's National Survivorship Needs Assessment Review&#xD;
        (2019) did not identify any studies reporting the needs of adult survivors of brain tumours&#xD;
        in Ireland.&#xD;
  &#xD;
        There is an urgent need to understand the impact of hypopituitarism and its treatment on&#xD;
        HR-QOL and neuropsychological functioning. The proposed study will add to the limited&#xD;
        existing literature on the prevalence of hypopituitarism in adult survivors of brain tumours&#xD;
        treated with radiotherapy and generate detailed information on deficiency rates for&#xD;
        individual pituitary hormones and how these deficiencies emerge over time. This will also be&#xD;
        the first study to examine if treatment of radiotherapy-induced hypopituitarism (as part of&#xD;
        routine clinical care) is associated with improved HR-QOL and neuropsychological functioning.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Hypothesis Adult survivors of primary, non-pituitary brain tumours have an increased risk of&#xD;
        hypopituitarism and experience impairments in HR-QOL and neuropsychological functioning. We&#xD;
        hypothesise that diagnosis of these deficiencies and the subsequent active replacement of&#xD;
        pituitary hormone deficits (as part of routine clinical care) will lead to an improvement in&#xD;
        neuropsychological functioning and HR-QOL in adult survivors of primary brain tumours.&#xD;
  &#xD;
        Objectives:&#xD;
  &#xD;
          1. To examine the impact of radiotherapy on pituitary hormone function in adult survivors&#xD;
             of primary, non-pituitary brain tumours.&#xD;
  &#xD;
          2. To assess HR-QOL and neuropsychological functioning in adult survivors of primary,&#xD;
             non-pituitary brain tumours.&#xD;
  &#xD;
          3. To examine the impact of pituitary hormone replacement and optimisation (as part of&#xD;
             routine clinical care) on HR-QOL and neuropsychological functioning in adult survivors&#xD;
             of primary, non-pituitary brain tumours.&#xD;
  &#xD;
             Methods&#xD;
  &#xD;
             Study Design &amp; Setting:&#xD;
  &#xD;
             A cross-sectional study will be conducted in the RCSI clinical research centre, located&#xD;
             on the Beaumont Hospital campus. The study will be conducted over three years from&#xD;
             September 2023 to September 2025.&#xD;
  &#xD;
             Participants:&#xD;
  &#xD;
             The study population will consist of adults who have previously received cranial&#xD;
             radiotherapy for a primary, non-pituitary brain tumour.&#xD;
  &#xD;
             Patient Recruitment:&#xD;
  &#xD;
               -  Participants will be identified in Professor Clare Faul's, Dr David Fitzpatrick's&#xD;
                  and Dr Nazmi ElBeltagi's clinic in St Luke's Radiation Oncology Centre at Beaumont&#xD;
                  Hospital.&#xD;
  &#xD;
               -  Patients will be approached by the research fellow during routine clinical&#xD;
                  consultations.&#xD;
  &#xD;
               -  The nature, purpose, benefits and risks of the study will be discussed with&#xD;
                  potential participants. They will be given the opportunity ask questions about the&#xD;
                  study. The patients' medical history will be reviewed to ensure they meet the study&#xD;
                  inclusion criteria.&#xD;
  &#xD;
               -  Patients will be given a patient information leaflet and asked to read this at&#xD;
                  home.&#xD;
  &#xD;
               -  The research fellow will follow up with a phone call within 72 hours and offer&#xD;
                  patients the opportunity to participate in the study. A first research study visit&#xD;
                  will be arranged for those who agree to participate.&#xD;
  &#xD;
             Study Procedure&#xD;
  &#xD;
             Study Visit One:&#xD;
  &#xD;
             Consent:&#xD;
  &#xD;
               -  Participants will be asked to attend study visit one in the RCSI Clinical Research&#xD;
                  Centre (CRC).&#xD;
  &#xD;
               -  Participants will be given the opportunity to ask questions and to have any&#xD;
                  concerns addressed by the research team.&#xD;
  &#xD;
               -  They will then be asked by the research fellow to provide their informed consent to&#xD;
                  (i) participate in the study and (ii) allow their data to be processed by the&#xD;
                  research team.&#xD;
  &#xD;
             Assessments:&#xD;
  &#xD;
               -  Participants will be asked to fast from midnight the previous evening as per&#xD;
                  Beaumont Hospital protocol for dynamic testing of pituitary function.&#xD;
  &#xD;
               -  They will be advised to take their usual medications with a small sip of water on&#xD;
                  the morning of the test.&#xD;
  &#xD;
               -  The research fellow will assess the participants' blood pressure, height, weight&#xD;
                  and body composition (using the bioimpedance technique with the Tanita® BC-418&#xD;
                  segmental body composition analyser).&#xD;
  &#xD;
               -  Women of childbearing age will be questioned to ensure they are not pregnancy. If&#xD;
                  there is any uncertainty, they will be asked to take a pregnancy test.&#xD;
  &#xD;
             Baseline blood sampling:&#xD;
  &#xD;
               -  A fasting 9am blood sample will be taken to assess pituitary function [ACTH,&#xD;
                  cortisol, FSH, LH, oestrogen (in females), testosterone (in males), sex hormone&#xD;
                  binding globulin, thyroid function tests, prolactin, IGF-1] and metabolic phenotype&#xD;
                  [full blood count, renal/ liver profile, cholesterol, HbA1c, homeostatic model&#xD;
                  assessment for insulin resistance (HOMA-IR)].&#xD;
  &#xD;
             Dynamic testing of pituitary function:&#xD;
  &#xD;
             • Patients will undergo dynamic testing of the ACTH and growth hormone axes using a&#xD;
             glucagon stimulation test (GST).&#xD;
  &#xD;
             • The Beaumont Hospital GST protocol will be followed throughout.&#xD;
  &#xD;
             • A cannula will be inserted into the patient's forearm. Baseline serum samples for&#xD;
             glucose, cortisol and growth hormone will be drawn from the cannula.&#xD;
  &#xD;
               -  Glucagon will then be injected into the lateral aspect of the mid quadriceps&#xD;
                  (vastus lateralis) by the research nurse/ fellow. A glucagon dose of 1mg will be&#xD;
                  used in adults less than 90kg and 1.5mg in adults greater than 90kg.&#xD;
  &#xD;
               -  Serum samples will be drawn from the cannula for glucose, cortisol and GH at 90,&#xD;
                  120, 150 and 180 minutes.&#xD;
  &#xD;
             Neuropsychological assessment:&#xD;
  &#xD;
             • A battery of neuropsychological tests to assess for cognitive, memory, language and&#xD;
             visuo-spatial dysfunction will be performed. These tests are fully validated and have&#xD;
             been widely used in the research setting.&#xD;
  &#xD;
               -  Cognitive dysfunction: Stroop colour-word test, phonemic verbal fluency, backward&#xD;
                  digital span&#xD;
  &#xD;
               -  Language dysfunction: Boston naming test&#xD;
  &#xD;
               -  Memory dysfunction: Logical memory, verbal paired associate and auditory delayed&#xD;
                  recognition task&#xD;
  &#xD;
               -  Visuo-spatial dysfunction Rey-osterrieth complex figure test&#xD;
  &#xD;
             HR-QOL assessment:&#xD;
  &#xD;
               -  Participants' HR-QOL will be measured using extensively validated assessment tools&#xD;
                  including the Short Form-36 (SF-36), Nottingham Health Profile and EQ-5D-5L.&#xD;
  &#xD;
               -  The SF-36 is a widely used HR-QOL assessment tool consisting of 4 physical and 4&#xD;
                  mental domains which are combined to give physical and mental component summary&#xD;
                  scores. The Nottingham Health Profile consists of two components; a subjective&#xD;
                  assessment of their general health and the impact on their activities of daily&#xD;
                  living. The EQ-5D-5L assesses level of difficulty with five aspects of daily&#xD;
                  living.&#xD;
  &#xD;
               -  The research fellow will ask participants the assessment questions, document their&#xD;
                  responses and calculate the overall scores (where necessary).&#xD;
  &#xD;
             Study visit one is then complete.&#xD;
  &#xD;
             Review of Pituitary Assessments:&#xD;
  &#xD;
             • Baseline and dynamic test results will be reviewed after study visit one by the&#xD;
             principal investigator and research fellow.&#xD;
  &#xD;
             • Selected patients whose GST identifies cortisol deficiency will be asked to attend the&#xD;
             RCSI-CRC for an additional study visit to undergo a short synacthen test (SST). This is&#xD;
             to confirm adrenal insufficiency as the GST has a false positive rate of approximately&#xD;
             20% for ACTH deficiency.&#xD;
  &#xD;
               -  A SST involves a cannula being inserted into the forearm and baseline serum samples&#xD;
                  for ACTH and cortisol being taken. Synacthen® 250mcg will then be administered&#xD;
                  intravenously. A second cortisol sample will be taken after 30 mins.&#xD;
  &#xD;
               -  Patients diagnosed with hypopituitarism will have their hormone deficits replaced&#xD;
                  as per best clinical practice by the endocrinology service. In the event of a&#xD;
                  patient being diagnosed with growth hormone deficiency, growth hormone replacement&#xD;
                  will be discussed with the radiation oncology team is not appropriate in all types&#xD;
                  of brain tumours.&#xD;
  &#xD;
               -  Patients will be counselled on the diagnosis of hypopituitarism and any questions&#xD;
                  or concerns addressed.&#xD;
  &#xD;
               -  Follow up blood tests may be required to assess the adequacy of pituitary hormone&#xD;
                  replacement, as per routine clinical practice.&#xD;
  &#xD;
             Treatment History and Radiotherapy Dose Calculation:&#xD;
  &#xD;
             • The patient's tumour histology, staging and neurosurgical treatment history will be&#xD;
             obtained from their physical and electronic medical records in Beaumont Hospital and St&#xD;
             Luke's Centre Radiation Oncology at Beaumont Hospital.&#xD;
  &#xD;
             • The type, dose, dose per fraction of radiotherapy received by the hypothalamus/&#xD;
             pituitary (which will be estimated from planning scans using the biological equivalent&#xD;
             dose) will be recorded in collaboration with Professor Clare Faul, Dr David&#xD;
             Fitzpatrick's and Dr Nazmi ElBeltagi's in St Luke's Radiation Oncology Centre at&#xD;
             Beaumont Hospital.&#xD;
  &#xD;
             Study Visit Two • All study participants will be asked to return for a second study&#xD;
             visit, four months after their first visit.&#xD;
  &#xD;
               -  Repeat measurements will be taken including:&#xD;
  &#xD;
                  o Weight, blood pressure and body composition.&#xD;
  &#xD;
                  o Fasting 9am blood samples to assess baseline pituitary function and metabolic&#xD;
                  phenotype [as previously outlined].&#xD;
  &#xD;
               -  All patients will have their HR-QOL and neuropsychological functioning reassessed&#xD;
                  to measure the change over the course of the study.&#xD;
  &#xD;
             End of study&#xD;
  &#xD;
             • Patients diagnosed with hypopituitarism during the study will be followed up in the&#xD;
             endocrinology clinic in Beaumont Hospital (as is the case for all patients with&#xD;
             hypopituitarism).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">September 1, 2025</completion_date>
    <primary_completion_date type="Anticipated">September 1, 2025</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>Prevalence of radiotherapy-induced hypopituitarism</measure>
      <time_frame>Assessed at Baseline</time_frame>
      <description>Prevalence of pituitary hormone deficiencies in adult survivors of primary, non-pituitary brain tumours, previously treated with radiotherapy.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>HR-QOL</measure>
      <time_frame>Assessed at baseline</time_frame>
      <description>The Short Form-36 will be used to assess HR-QOL in the study population relative to a published normative population. The SF-36 is a generic questionnaire consisting of 8 domains; physical function, bodily pain, role physical, general health, vitality, social functioning, role emotional, mental health. Each domain is scored form 0-100, with higher scores indicating better quality of life.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in HR-QOL</measure>
      <time_frame>Assessed at 4 months</time_frame>
      <description>HR-QOL will be reassessed at 16 weeks using the SF-36 in (i) participants with hypopituitarism and (ii) participants with normal pituitary function. The SF-36 is a generic questionnaire consisting of 8 domains; physical function, bodily pain, role physical, general health, vitality, social functioning, role emotional, mental health. Each domain is scored form 0-100, with higher scores indicating better quality of life.</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">50</enrollment>
    <condition>Hypopituitarism</condition>
    <condition>Radiotherapy-Induced Hypopituitarism</condition>
    <condition>Brain Tumor</condition>
    <arm_group>
      <arm_group_label>Study investigation</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>All enrolled patients will undergo standardised pituitary hormone assessments.</description>
    </arm_group>
    <intervention>
      <intervention_type>Diagnostic Test</intervention_type>
      <intervention_name>Dynamic testing of Pituitary Function</intervention_name>
      <description>Pituitary Function Assessment:&#xD;
  Baseline assessment of pituitary function by measuring ACTH, cortisol, FSH, LH, oestrogen (in females), testosterone (in males), sex hormone binding globulin, thyroid function tests, prolactin and IGF-1].&#xD;
  Dynamic testing of pituitary function:&#xD;
  Patients will undergo dynamic testing of the ACTH and growth hormone axes using a glucagon stimulation test (GST).&#xD;
  Patients whose GST identifies cortisol deficiency will undergo a short synacthen test to confirm adrenal insufficiency as the GST has a false positive rate of approximately 20% for ACTH deficiency.</description>
      <arm_group_label>Study investigation</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Adults (at least 18 years old) with a history of a primary, non-pituitary brain tumour&#xD;
               which was previously treated with radiotherapy.&#xD;
  &#xD;
            -  Participants must have been at least 16 years old at the time of undergoing&#xD;
               radiotherapy.&#xD;
  &#xD;
            -  A minimum of one year has elapsed since radiotherapy was completed.&#xD;
  &#xD;
            -  Capacity and willingness to provide informed consent.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Diagnosed with malignant astrocytic brain tumour with life expectancy of less than six&#xD;
               months.&#xD;
  &#xD;
            -  Brain tumour infiltration of the hypothalamus or pituitary pre-operatively.&#xD;
  &#xD;
            -  Previously diagnosis of hypopituitarism.&#xD;
  &#xD;
            -  Oral glucocorticoid use within the last three months.&#xD;
  &#xD;
            -  Pregnant or breastfeeding women at the time of recruitment.&#xD;
  &#xD;
            -  Unable to provide informed consent for inclusion in this study.&#xD;
  &#xD;
            -  Opinion of the radiation oncology or research team that participation in the study is&#xD;
               not in the best interest of the patient for any reason.&#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_contact>
      <last_name>Mark Sherlock, MD PhD</last_name>
      <phone>01-809 2811</phone>
      <email>marksherlock@rcsi.ie</email>
    </overall_contact>
    <location>
      <facility>
        <name>Beaumont Hospital</name>
        <address>
          <city>Dublin</city>
          <country>Ireland</country>
        </address>
      </facility>
      <contact>
        <last_name>Mark Sherlock, MD PhD</last_name>
        <phone>01-809 2811</phone>
        <email>marksherlock@rcsi.com</email>
      </contact>
    </location>
    <location>
      <facility>
        <name>St Luke's Radiation oncology Centre, Beaumont Hopsital</name>
        <address>
          <city>Dublin</city>
          <country>Ireland</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Ireland</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 24, 2023</study_first_submitted>
    <study_first_submitted_qc>August 22, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 28, 2023</study_first_posted>
    <last_update_submitted>August 22, 2023</last_update_submitted>
    <last_update_submitted_qc>August 22, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 28, 2023</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>Brain Neoplasms</mesh_term>
      <mesh_term>Hypopituitarism</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06014398
  org study id: 23-127
  nct id: NCT06014398
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Background:
  
        Approximately 480 primary, non-pituitary, brain tumours were diagnosed in Ireland each year
        between 1994 and 2013. Recent developments in treatment have greatly improved survival for
        younger patients in the 15-54 age range. The Irish National Neurosurgical Centre and the St
        Luke's Radiation Oncology Centre at Beaumont Hospital and treat approximately 200 patients
        with brain tumours per year with a combination of surgery, radiotherapy (RT) and chemotherapy
        with RT being the most commonly used treatment modality. With improved survivorship, the
        prospect of individuals living for several decades with co-morbidities induced by the tumour
        itself or surgical and RT treatments, raises new and complex issues for patients and
        clinicians.
  
        The hypothalamus and pituitary gland in the brain are the key regulators of hormone action.
        They control several hormone systems including reproductive function (FSH, LH) growth (growth
        hormone), thyroid (TSH) and adrenal function (ACTH) as well as many other homeostatic
        mechanisms. It has long been recognised that therapeutic cranial RT to the pituitary gland
        causes hypothalamic-pituitary dysfunction (hypopituitarism). Traditionally, high-risk groups
        for post-irradiation hypopituitarism were considered to be patients with pituitary tumours,
        survivors of childhood cancer and patients who received high-dose RT to treat nasopharyngeal
        cancers. The potential for cranial radiotherapy to cause significant pituitary dysfunction in
        adult patients with brain tumours has received little attention. The assumption has been that
        the hypothalamic-pituitary axis is more resistant in adults than in children to the effect of
        cranial RT. However, it is likely that the higher doses of RT, used to treat primary brain
        tumours in adults, causes significant hypothalamic-pituitary dysfunction resulting in
        hypopituitarism. Preliminary data from the National Pituitary Centre in Beaumont Hospital has
        revealed that adult patients, treated with cranial radiotherapy for primary, non-pituitary
        brain tumours, are at risk of hypopituitarism. Approximately 40% of patients had pituitary
        deficiencies in at least one hormone axis, while 25% of patients had deficiencies in multiple
        hormone axes. Hypopituitarism confers significant morbidity and increased mortality to
        patients. At present, adult survivors of brain tumours are referred to the pituitary service
        for assessment on an ad-hoc basis meaning that many patients with hypopituitarism may go
        undiagnosed.
  
        In addition to the challenges caused by hypopituitarism, long-term neuropsychological
        outcomes following a brain tumour cause significant functional impairments and reduced
        HR-QOL. Patients can present with impairments in specific cognitive domains such as memory
        and executive functioning or more global systems such as attention as well as significant
        issues with fatigue. In addition to these primary deficits, patients can also present with
        significant distress, fluctuant mood and anxiety. Despite the impact of brain tumours can
        exert, the National Cancer Control Program's National Survivorship Needs Assessment Review
        (2019) did not identify any studies reporting the needs of adult survivors of brain tumours
        in Ireland.
  
        There is an urgent need to understand the impact of hypopituitarism and its treatment on
        HR-QOL and neuropsychological functioning. The proposed study will add to the limited
        existing literature on the prevalence of hypopituitarism in adult survivors of brain tumours
        treated with radiotherapy and generate detailed information on deficiency rates for
        individual pituitary hormones and how these deficiencies emerge over time. This will also be
        the first study to examine if treatment of radiotherapy-induced hypopituitarism (as part of
        routine clinical care) is associated with improved HR-QOL and neuropsychological functioning.
  Hypothesis Adult survivors of primary, non-pituitary brain tumours have an increased risk of
        hypopituitarism and experience impairments in HR-QOL and neuropsychological functioning. We
        hypothesise that diagnosis of these deficiencies and the subsequent active replacement of
        pituitary hormone deficits (as part of routine clinical care) will lead to an improvement in
        neuropsychological functioning and HR-QOL in adult survivors of primary brain tumours.
  
        Objectives:
  
          1. To examine the impact of radiotherapy on pituitary hormone function in adult survivors
             of primary, non-pituitary brain tumours.
  
          2. To assess HR-QOL and neuropsychological functioning in adult survivors of primary,
             non-pituitary brain tumours.
  
          3. To examine the impact of pituitary hormone replacement and optimisation (as part of
             routine clinical care) on HR-QOL and neuropsychological functioning in adult survivors
             of primary, non-pituitary brain tumours.
  
             Methods
  
             Study Design & Setting:
  
             A cross-sectional study will be conducted in the RCSI clinical research centre, located
             on the Beaumont Hospital campus. The study will be conducted over three years from
             September 2023 to September 2025.
  
             Participants:
  
             The study population will consist of adults who have previously received cranial
             radiotherapy for a primary, non-pituitary brain tumour.
  
             Patient Recruitment:
  
               -  Participants will be identified in Professor Clare Faul's, Dr David Fitzpatrick's
                  and Dr Nazmi ElBeltagi's clinic in St Luke's Radiation Oncology Centre at Beaumont
                  Hospital.
  
               -  Patients will be approached by the research fellow during routine clinical
                  consultations.
  
               -  The nature, purpose, benefits and risks of the study will be discussed with
                  potential participants. They will be given the opportunity ask questions about the
                  study. The patients' medical history will be reviewed to ensure they meet the study
                  inclusion criteria.
  
               -  Patients will be given a patient information leaflet and asked to read this at
                  home.
  
               -  The research fellow will follow up with a phone call within 72 hours and offer
                  patients the opportunity to participate in the study. A first research study visit
                  will be arranged for those who agree to participate.
  
             Study Procedure
  
             Study Visit One:
  
             Consent:
  
               -  Participants will be asked to attend study visit one in the RCSI Clinical Research
                  Centre (CRC).
  
               -  Participants will be given the opportunity to ask questions and to have any
                  concerns addressed by the research team.
  
               -  They will then be asked by the research fellow to provide their informed consent to
                  (i) participate in the study and (ii) allow their data to be processed by the
                  research team.
  
             Assessments:
  
               -  Participants will be asked to fast from midnight the previous evening as per
                  Beaumont Hospital protocol for dynamic testing of pituitary function.
  
               -  They will be advised to take their usual medications with a small sip of water on
                  the morning of the test.
  
               -  The research fellow will assess the participants' blood pressure, height, weight
                  and body composition (using the bioimpedance technique with the Tanita® BC-418
                  segmental body composition analyser).
  
               -  Women of childbearing age will be questioned to ensure they are not pregnancy. If
                  there is any uncertainty, they will be asked to take a pregnancy test.
  
             Baseline blood sampling:
  
               -  A fasting 9am blood sample will be taken to assess pituitary function [ACTH,
                  cortisol, FSH, LH, oestrogen (in females), testosterone (in males), sex hormone
                  binding globulin, thyroid function tests, prolactin, IGF-1] and metabolic phenotype
                  [full blood count, renal/ liver profile, cholesterol, HbA1c, homeostatic model
                  assessment for insulin resistance (HOMA-IR)].
  
             Dynamic testing of pituitary function:
  
             • Patients will undergo dynamic testing of the ACTH and growth hormone axes using a
             glucagon stimulation test (GST).
  
             • The Beaumont Hospital GST protocol will be followed throughout.
  
             • A cannula will be inserted into the patient's forearm. Baseline serum samples for
             glucose, cortisol and growth hormone will be drawn from the cannula.
  
               -  Glucagon will then be injected into the lateral aspect of the mid quadriceps
                  (vastus lateralis) by the research nurse/ fellow. A glucagon dose of 1mg will be
                  used in adults less than 90kg and 1.5mg in adults greater than 90kg.
  
               -  Serum samples will be drawn from the cannula for glucose, cortisol and GH at 90,
                  120, 150 and 180 minutes.
  
             Neuropsychological assessment:
  
             • A battery of neuropsychological tests to assess for cognitive, memory, language and
             visuo-spatial dysfunction will be performed. These tests are fully validated and have
             been widely used in the research setting.
  
               -  Cognitive dysfunction: Stroop colour-word test, phonemic verbal fluency, backward
                  digital span
  
               -  Language dysfunction: Boston naming test
  
               -  Memory dysfunction: Logical memory, verbal paired associate and auditory delayed
                  recognition task
  
               -  Visuo-spatial dysfunction Rey-osterrieth complex figure test
  
             HR-QOL assessment:
  
               -  Participants' HR-QOL will be measured using extensively validated assessment tools
                  including the Short Form-36 (SF-36), Nottingham Health Profile and EQ-5D-5L.
  
               -  The SF-36 is a widely used HR-QOL assessment tool consisting of 4 physical and 4
                  mental domains which are combined to give physical and mental component summary
                  scores. The Nottingham Health Profile consists of two components; a subjective
                  assessment of their general health and the impact on their activities of daily
                  living. The EQ-5D-5L assesses level of difficulty with five aspects of daily
                  living.
  
               -  The research fellow will ask participants the assessment questions, document their
                  responses and calculate the overall scores (where necessary).
  
             Study visit one is then complete.
  
             Review of Pituitary Assessments:
  
             • Baseline and dynamic test results will be reviewed after study visit one by the
             principal investigator and research fellow.
  
             • Selected patients whose GST identifies cortisol deficiency will be asked to attend the
             RCSI-CRC for an additional study visit to undergo a short synacthen test (SST). This is
             to confirm adrenal insufficiency as the GST has a false positive rate of approximately
             20% for ACTH deficiency.
  
               -  A SST involves a cannula being inserted into the forearm and baseline serum samples
                  for ACTH and cortisol being taken. Synacthen® 250mcg will then be administered
                  intravenously. A second cortisol sample will be taken after 30 mins.
  
               -  Patients diagnosed with hypopituitarism will have their hormone deficits replaced
                  as per best clinical practice by the endocrinology service. In the event of a
                  patient being diagnosed with growth hormone deficiency, growth hormone replacement
                  will be discussed with the radiation oncology team is not appropriate in all types
                  of brain tumours.
  
               -  Patients will be counselled on the diagnosis of hypopituitarism and any questions
                  or concerns addressed.
  
               -  Follow up blood tests may be required to assess the adequacy of pituitary hormone
                  replacement, as per routine clinical practice.
  
             Treatment History and Radiotherapy Dose Calculation:
  
             • The patient's tumour histology, staging and neurosurgical treatment history will be
             obtained from their physical and electronic medical records in Beaumont Hospital and St
             Luke's Centre Radiation Oncology at Beaumont Hospital.
  
             • The type, dose, dose per fraction of radiotherapy received by the hypothalamus/
             pituitary (which will be estimated from planning scans using the biological equivalent
             dose) will be recorded in collaboration with Professor Clare Faul, Dr David
             Fitzpatrick's and Dr Nazmi ElBeltagi's in St Luke's Radiation Oncology Centre at
             Beaumont Hospital.
  
             Study Visit Two • All study participants will be asked to return for a second study
             visit, four months after their first visit.
  
               -  Repeat measurements will be taken including:
  
                  o Weight, blood pressure and body composition.
  
                  o Fasting 9am blood samples to assess baseline pituitary function and metabolic
                  phenotype [as previously outlined].
  
               -  All patients will have their HR-QOL and neuropsychological functioning reassessed
                  to measure the change over the course of the study.
  
             End of study
  
             • Patients diagnosed with hypopituitarism during the study will be followed up in the
             endocrinology clinic in Beaumont Hospital (as is the case for all patients with
             hypopituitarism).
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Diagnostic
  masking: None (Open Label)
  measure: Prevalence of radiotherapy-induced hypopituitarism
  time frame: Assessed at Baseline
  description: Prevalence of pituitary hormone deficiencies in adult survivors of primary, non-pituitary brain tumours, previously treated with radiotherapy.
  measure: HR-QOL
  time frame: Assessed at baseline
  description: The Short Form-36 will be used to assess HR-QOL in the study population relative to a published normative population. The SF-36 is a generic questionnaire consisting of 8 domains; physical function, bodily pain, role physical, general health, vitality, social functioning, role emotional, mental health. Each domain is scored form 0-100, with higher scores indicating better quality of life.
  measure: Change in HR-QOL
  time frame: Assessed at 4 months
  description: HR-QOL will be reassessed at 16 weeks using the SF-36 in (i) participants with hypopituitarism and (ii) participants with normal pituitary function. The SF-36 is a generic questionnaire consisting of 8 domains; physical function, bodily pain, role physical, general health, vitality, social functioning, role emotional, mental health. Each domain is scored form 0-100, with higher scores indicating better quality of life.
  arm group label: Study investigation
  arm group type: Experimental
  description: All enrolled patients will undergo standardised pituitary hormone assessments.
  intervention type: Diagnostic Test
  intervention name: Dynamic testing of Pituitary Function
  description: Pituitary Function Assessment:
  Baseline assessment of pituitary function by measuring ACTH, cortisol, FSH, LH, oestrogen (in females), testosterone (in males), sex hormone binding globulin, thyroid function tests, prolactin and IGF-1].
  Dynamic testing of pituitary function:
  Patients will undergo dynamic testing of the ACTH and growth hormone axes using a glucagon stimulation test (GST).
  Patients whose GST identifies cortisol deficiency will undergo a short synacthen test to confirm adrenal insufficiency as the GST has a false positive rate of approximately 20% for ACTH deficiency.
  arm group label: Study investigation
  criteria: 
  gender: All
  minimum age: 16 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Mark Sherlock, MD PhD
  phone: 01-809 2811
  email: marksherlock@rcsi.ie
  facility: 
  contact: 
  facility: 
  country: Ireland
  responsible party type: Sponsor
  mesh term: Brain Neoplasms
  mesh term: Hypopituitarism
  sharing ipd: No