<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/NCT03815006</url>
  </required_header>
  <id_info>
    <org_study_id>B00373</org_study_id>
    <nct_id>NCT03815006</nct_id>
  </id_info>
  <brief_title>Flash-glucose Monitoring in Sub-optimally Controlled Type 1 Diabetes (FLASH-UK)</brief_title>
  <acronym>FLASH-UK</acronym>
  <official_title>An Open-label, Multi-centre, Randomised, Parallel Design Study to Assess the Efficacy of Flash Glucose Monitoring in Adults With Sub-optimally Controlled Type 1 Diabetes.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Manchester University NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospitals of Derby and Burton NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Portsmouth Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital Birmingham NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Norfolk and Norwich University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Manchester</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Diabetes UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Clinical Trials Unit, Manchester</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>BHR Limited</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>East Suffolk and North Essex NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Adam Practice, Dorset</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Manchester University NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      FreeStyle Libre (FSL2) is a novel glucose monitoring device (Flash glucose monitoring) in the&#xD;
      form of a disc worn on the arm for 14 days, and a hand-held reader which is designed to&#xD;
      largely replace the recommended 4-10 painful finger-stick blood glucose tests required each&#xD;
      day for the self-management of type 1 diabetes. The purpose of this study is to determine&#xD;
      whether flash glucose monitoring with FSL2 device will improve HbA1c over 24 weeks compared&#xD;
      to self-monitoring of blood glucose in adults and adolescents (16 or older) with&#xD;
      sub-optimally controlled (HbA1c 7.5% to 11%) type 1 diabetes.&#xD;
&#xD;
      This is an open-label, multi-centre, randomised, parallel design study, involving a 2-week&#xD;
      run-in period, followed by a 24-week study period during which participants will use either&#xD;
      FSL2 or continue usual finger-stick glucose monitoring in random order. A total of up to 156&#xD;
&#xD;
      randomised participants from up to 180 recruited aged 16 years and older with T1D on insulin&#xD;
      pump therapy or multiple daily injection therapy were recruited through diabetes clinics in&#xD;
      participating centres.&#xD;
&#xD;
      Participants will receive appropriate training to maximise the benefits of FSL2 and&#xD;
      finger-stick glucose levels in self-management. The primary outcome is the difference in&#xD;
      HbA1c between the two groups at 24 weeks. Secondary outcomes are time spent with glucose&#xD;
      levels above and below target, as recorded by FSL2, and other flash glucose-based metrics.&#xD;
      Impact on quality of life, diabetes distress, mood, needle burden, disordered eating and&#xD;
      treatment satisfaction will also be undertaken. Relative cost-effectiveness of FSL2 device&#xD;
      compared with self-monitoring will also be assessed from a UK NHS perspective.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Design:&#xD;
&#xD;
      An open-label, multi-centre, randomised, parallel study, in adults and adolescents (16 years&#xD;
      and older) with type 1 diabetes and sub-optimal glycaemic control (HbA1c 7.5% to 11%), either&#xD;
      on insulin pump treatment or multiple daily injections, contrasting flash glucose monitoring&#xD;
      using FreeStyle Libre 2 device with traditional finger-stick glucose monitoring for 24 weeks.&#xD;
      Expecting approximately 15% to 20% dropout rate recruitment will aim for 180 participants&#xD;
      aiming for 156 randomised and 128 completed participants.&#xD;
&#xD;
      Participant Recruitment:&#xD;
&#xD;
      This is a UK multi-centre and recruitment will take place at the following centres:&#xD;
&#xD;
        1. Diabetes Centres within Manchester University Foundation Trust&#xD;
&#xD;
        2. Royal Derby Hospital, Derby&#xD;
&#xD;
        3. Queen Elizabeth Hospital, Birmingham&#xD;
&#xD;
        4. Addenbrookes Hospital, Cambridge&#xD;
&#xD;
        5. Norfolk and Norwich University Hospital, Norwich&#xD;
&#xD;
        6. Queen Alexandra Hospital, Portsmouth&#xD;
&#xD;
        7. Ipswich Hospital&#xD;
&#xD;
        8. The Adam Practice, Dorset&#xD;
&#xD;
      Each centre will aim to recruit between 25 to 30 participants. Additional diabetes centres&#xD;
      surrounding above hospitals may act as participant identification centres. Potential&#xD;
      participants will be identified by their treating clinicians and invited to contact the&#xD;
      research team. They will be sent the study information leaflets and an invitation by post or&#xD;
      in-person to join the study by the research team at least one day before the recruitment&#xD;
      visit. The study may also be advertised via social media.&#xD;
&#xD;
      After recruitment, consent, subjects will be randomised for 24-weeks home use of&#xD;
      flash-glucose monitoring or 24-weeks use finger-stick glucose monitoring.&#xD;
&#xD;
      Study Visits:&#xD;
&#xD;
      The study includes up to 7 visits for participants completing the study. Maximum time in&#xD;
      study is 30 weeks. Each study visit can be scheduled with +/- 2 weeks of the planned visit&#xD;
      date.&#xD;
&#xD;
      Visit 1: Recruitment Visit and Screening Assessment&#xD;
&#xD;
      Once the participants have agreed to participate in the study, they will be invited for the&#xD;
      recruitment visit, and given a participant ID, when the following activities will be&#xD;
      performed by the research team:&#xD;
&#xD;
        -  written informed consent/assent&#xD;
&#xD;
        -  checking inclusion and exclusion criteria&#xD;
&#xD;
        -  medical and diabetes history including the presence of diabetes complications and&#xD;
           hypoglycaemia burden&#xD;
&#xD;
        -  ethnicity, body weight and height measurement; calculation of BMI&#xD;
&#xD;
        -  record of current insulin therapy&#xD;
&#xD;
        -  urine or blood pregnancy test (females of child-bearing potential)&#xD;
&#xD;
        -  record of occupation and educational attainment&#xD;
&#xD;
        -  any history of disordered eating or needle phobia&#xD;
&#xD;
        -  previous participation in structured education, the status of carb counting, use of&#xD;
           bolus calculator&#xD;
&#xD;
      Screening Blood Sampling&#xD;
&#xD;
      Blood samples will be taken to measure HbA1c (measured at the local laboratory if not done&#xD;
      within the last two weeks). Renal and Thyroid function will also be evaluated (if not done in&#xD;
      last one year). Less than 15 ml of whole blood will be taken from each participant.&#xD;
&#xD;
      Questionnaires at screening&#xD;
&#xD;
      Evaluation of participants' responses in terms of quality of life, diabetes distress, needle&#xD;
      burden, disordered eating, depression and diabetes treatment satisfaction using&#xD;
&#xD;
        1. EQ-5DL-5L questionnaire&#xD;
&#xD;
        2. Type 1 Diabetes Distress Scale (DDS),&#xD;
&#xD;
        3. Diabetes fear of injecting and self-testing (D-FISQ) questionnaire,&#xD;
&#xD;
        4. Diabetes Eating Problem Survey (DEPS-R),&#xD;
&#xD;
        5. Diabetes Treatment Satisfaction Questionnaire (DTSQ),&#xD;
&#xD;
        6. Patient Health Questionnaire (PHQ-9) and&#xD;
&#xD;
        7. The Glucose Monitoring Satisfaction Survey (GMSS).&#xD;
&#xD;
        8. Hypoglycaemia burden will be assessed using Clarke questionnaire and Gold score.&#xD;
&#xD;
      Visit 2: Insertion of the blinded glucose monitoring device&#xD;
&#xD;
      Purpose of visit 2 is to insert a blinded glucose monitor (FreeStyle Libre Pro device). The&#xD;
      participant will be provided with instructions about using this device for the next two&#xD;
      weeks. Visit two may be combined with visit 1.&#xD;
&#xD;
      Visit 3: Adherence assessment, randomisation and the start of study treatment&#xD;
&#xD;
      During Visit 3, participant's adherence/tolerance of using the flash-CGM over preceding 14&#xD;
      days will be assessed. To proceed with the study participant should have worn the blinded&#xD;
      glucose monitoring device for at least ten days' during the last 14 days of the run-in&#xD;
      period. If the participant fails to demonstrate adherence or develops any significant allergy&#xD;
      or intolerance to the glucose sensor, the study will be terminated, and the participant will&#xD;
      be removed from the study. Participant randomisation for the treatment intervention will take&#xD;
      place during visit 3.&#xD;
&#xD;
      Initiation of study treatment The participant will arrive at the clinical facility or clinic&#xD;
      at the agreed time. Body weight measurement will be made. Participants will be provided with&#xD;
      necessary training on the use of study devices according to randomisation.&#xD;
&#xD;
      Training session Participants randomised to flash-glucose monitoring arm will receive&#xD;
      education and training about insertion and initiation of the sensor as well as how to use&#xD;
      flash-glucose monitoring data for treatment optimisation. They will be encouraged to download&#xD;
      data at home to identify pattern recognition. This session will be conducted by a&#xD;
      professional diabetes educator or a member of the study team. Education will be tailored to&#xD;
      meet the needs of the individual. Participants randomised to conventional finger-stick&#xD;
      glucose monitoring arm will be encouraged to use finger-stick glucose levels to optimise&#xD;
      treatment and will receive education about insulin dose adjustments using finger-stick&#xD;
      glucose levels. The study will try to mimic real-life conditions by continuing participants&#xD;
      pre-study diabetes treatment unchanged and finger-stick glucose testing frequency as&#xD;
      determined by the participant as required. Participants in both arms will also receive&#xD;
      training on sick day rules and dealing with hypo and hyperglycaemia. Participants will be&#xD;
      provided with a paper diary to collect information about insulin doses and carbohydrate&#xD;
      intake in the last three days of each study month.&#xD;
&#xD;
      Visit 4: (+4 weeks since randomisation): Review data and treatment optimisation Purpose of&#xD;
      this visit is to review data from Flash-glucose monitoring and finger-stick glucose&#xD;
      monitoring to further optimise treatment. Study devices will be downloaded. Information about&#xD;
      insulin doses and any adverse events will be collected.&#xD;
&#xD;
      Visit 5: (+12 weeks since randomisation): Review data and treatment optimisation&#xD;
&#xD;
      Purpose of this visit is to review data from Flash-glucose monitoring and finger-stick&#xD;
      glucose monitoring to further optimise treatment. Study devices will be downloaded.&#xD;
      Information about insulin doses, participant diaries and any adverse events will be&#xD;
      collected. A blood sample will be collected for HbA1c.&#xD;
&#xD;
      Visit 6: (+22 weeks since randomisation): Finger-stick glucose monitoring arm only&#xD;
&#xD;
      Participants randomised to finger-stick glucose monitoring arm will have an extra visit ten&#xD;
      weeks after visit 5 to insert a blinded glucose sensor for data capture.&#xD;
&#xD;
      Visit 7: (+24 weeks since randomisation): End of randomised study treatment&#xD;
&#xD;
      The participant will be invited to attend the research centre approximately 12 weeks after&#xD;
      Visit 5. This would be the end of 24 weeks randomised study period. All study devices will be&#xD;
      downloaded. Insulin usage data will be recorded and diaries collected. The participant will&#xD;
      have a blood test for the HbA1c. Body weight measurement will be made. The participant will&#xD;
      be asked to complete the same questionnaires completed at Visit 1. In addition, participants&#xD;
      in the FSL2 arm will be asked to complete a additional questionnaire exploring expectations&#xD;
      and experience of using FSL2 during the study. A subset of participants (n=40 aiming for 25&#xD;
      completed questionnaires) in the FSL2 arm and subset of researchers (n=10) will also be asked&#xD;
      to complete additional questionnaires to help with the process evaluation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 9, 2020</start_date>
  <completion_date type="Actual">October 10, 2021</completion_date>
  <primary_completion_date type="Actual">October 10, 2021</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>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>HbA1c Level at 24 weeks</measure>
    <time_frame>24 weeks</time_frame>
    <description>The primary outcome is difference in HbA1c between the two groups at 24 weeks.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>HbA1c Level at 12 weeks</measure>
    <time_frame>12 weeks</time_frame>
    <description>This is the difference in HbA1c between the two groups at 12 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 12 weeks</measure>
    <time_frame>12 weeks</time_frame>
    <description>This is the comparison between arms of percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 12 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 24 weeks</measure>
    <time_frame>24 weeks</time_frame>
    <description>This is the comparison between arms of percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 24 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - Time spent in the target glucose range between 3.9 to 10.0 mmol/l</measure>
    <time_frame>24 weeks</time_frame>
    <description>Time spent in the target glucose range between 3.9 to 10.0 mmol/l (70 to 180mg/dl).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - Time spent below target glucose (&lt;3.9mmol/l)</measure>
    <time_frame>24 weeks</time_frame>
    <description>Time spent below target glucose (&lt;3.9mmol/l) (&lt;70mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - Time spent above target glucose (10.0 mmol/l)</measure>
    <time_frame>24 weeks</time_frame>
    <description>Time spent above target glucose (10.0 mmol/l) (180 mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - Average glucose levels</measure>
    <time_frame>24 weeks</time_frame>
    <description>Average glucose levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - Standard deviation glucose levels</measure>
    <time_frame>24 weeks</time_frame>
    <description>Standard deviation glucose levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - Coefficient of variation glucose levels</measure>
    <time_frame>24 weeks</time_frame>
    <description>Coefficient of variation glucose levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - time with sensor glucose levels &lt; 3.5 mmol/l</measure>
    <time_frame>24 weeks</time_frame>
    <description>The time with sensor glucose levels &lt; 3.5 mmol/l (63 mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - time with sensor glucose levels &lt; 3.5 mmol/l</measure>
    <time_frame>24 weeks</time_frame>
    <description>The time with sensor glucose levels &lt; 3.0 (54mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - time with sensor glucose levels &lt; 2.8 mmol/l</measure>
    <time_frame>24 weeks</time_frame>
    <description>The time with sensor glucose levels &lt; 2.8 mmol/l (50 mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - time with sensor glucose levels in the significant hyperglycaemia</measure>
    <time_frame>24 weeks</time_frame>
    <description>The time with sensor glucose levels in the significant hyperglycaemia (glucose levels &gt; 16.7 mmol/l) (300mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sensor based - AUC of glucose below 3.0mmol/l</measure>
    <time_frame>24 weeks</time_frame>
    <description>AUC of glucose below 3.0mmol/l (54mg/dl)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total daily average insulin dose</measure>
    <time_frame>24 weeks</time_frame>
    <description>Comparison between arms of Total daily average insulin dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily average basal insulin dose</measure>
    <time_frame>24 weeks</time_frame>
    <description>Comparison between arms of Daily average basal insulin dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Daily average bolus dose</measure>
    <time_frame>24 weeks</time_frame>
    <description>Comparison between arms of Daily average bolus dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average number of boluses of rapid acting insulin</measure>
    <time_frame>24 weeks</time_frame>
    <description>Average number of boluses of rapid acting insulin per day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Freestyle Libre scans per day</measure>
    <time_frame>24 weeks</time_frame>
    <description>Number of Freestyle Libre scans per day in the intervention arm only</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of severe hypoglycaemic episodes</measure>
    <time_frame>24 weeks</time_frame>
    <description>Frequency of severe hypoglycaemic episodes as defined by American Diabetes Association</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of significant ketosis events</measure>
    <time_frame>24 weeks</time_frame>
    <description>Frequency of significant ketosis events (plasma ketones &gt;3mmol/l)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Nature and severity of other adverse events</measure>
    <time_frame>24 weeks</time_frame>
    <description>Nature and severity of other adverse events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Type 1 Diabetes Distress Scale Score</measure>
    <time_frame>24 weeks</time_frame>
    <description>Type 1 Diabetes Distress Scale score compared between arms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EQ-5D-5L Quality of Life questionnaire Score</measure>
    <time_frame>24 weeks</time_frame>
    <description>EQ-5D-5L Quality of Life questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Health Questionnaire Score</measure>
    <time_frame>24 weeks</time_frame>
    <description>Patient Health Questionnaire: score of 5-9 would be minimal symptoms. any score large than 20 would be categorised as severe major depression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diabetes fear of injecting and self-testing questionnaire Score</measure>
    <time_frame>24 weeks</time_frame>
    <description>Diabetes fear of injecting and self-testing questionnaire: 15 questions, 6 for Fear of Self injecting, 9 for fear of self testing.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The revised Diabetes Eating Problem Survey score</measure>
    <time_frame>24 weeks</time_frame>
    <description>The revised Diabetes Eating Problem Survey</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Average number of days of Libre usage per week</measure>
    <time_frame>24 weeks</time_frame>
    <description>Average number of days of usage per week</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Diabetes Treatment Satisfaction Questionnaire score</measure>
    <time_frame>24 weeks</time_frame>
    <description>Diabetes Treatment Satisfaction Questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Glucose Monitoring Satisfaction Survey score</measure>
    <time_frame>24 weeks</time_frame>
    <description>Glucose Monitoring Satisfaction Survey: 15 questions ranging from 1-5.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">156</enrollment>
  <condition>Diabetes Mellitus, Type 1</condition>
  <arm_group>
    <arm_group_label>Free Style Libre 2 device</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>At the start, a blood sample will be taken for the measurement of HbA1c. Training and education on the use of FSL2 will be provided by the research team. Participants will be advised to use flash glucose monitoring continuously for the next 24 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Self-monitoring of blood glucose</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>At the start, a blood sample will be taken for the measurement of HbA1c. Masked FSL will be applied for two weeks, during the last two weeks of control period. Education will focus on using fingerstick measurement for treatment optimisation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Free Style Libre 2</intervention_name>
    <description>FreeStyle Libre 2 (FSL2) is a novel glucose monitoring device (Flash glucose monitoring) in the form of a disc worn on the arm for 14 days and a hand-held reader which is designed to largely replace the recommended 4-10 painful finger-stick blood glucose tests required each day for the self-management of type 1 diabetes (T1D).</description>
    <arm_group_label>Free Style Libre 2 device</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  The participant is ≥16 years old&#xD;
&#xD;
          -  The participant has type 1 diabetes, as defined by WHO for at least 1 year or is&#xD;
             confirmed C-peptide negative if duration of diabetes is &lt; 1 years&#xD;
&#xD;
          -  Participant is treated with insulin pump or multiple daily injection for at least 12&#xD;
             weeks and no plans to change treatment modality during next 28 weeks&#xD;
&#xD;
          -  The participant is literate in English for safe study conduct&#xD;
&#xD;
          -  Screening HbA1c ≥ 7.5% (58.5mmol/mol) and ≤ 11% (97 mmol/mol) based on analysis from&#xD;
             local laboratory&#xD;
&#xD;
          -  The participant is willing to wear study glucose sensor and scan for glucose levels at&#xD;
             regular intervals&#xD;
&#xD;
          -  The participant is willing to follow study specific instructions and improve glucose&#xD;
             control&#xD;
&#xD;
          -  Female participants of child bearing age should be on effective contraception and must&#xD;
             have a negative blood or urine pregnancy test at screening.&#xD;
&#xD;
          -  The participant adopting a virtual pathway through the trial is able and willing to&#xD;
             post study devices, questionnaires and blood collection kits back to the research team&#xD;
             or to the laboratory using pre-paid postal services.&#xD;
&#xD;
          -  The participant adopting a virtual pathway through the trial has internet connection,&#xD;
             appropriate videoconferencing software and supporting devices to undertake video&#xD;
             consultations where necessary.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Key exclusion criteria:&#xD;
&#xD;
          -  Non-type 1 diabetes mellitus including those secondary to chronic disease&#xD;
&#xD;
          -  Any other physical disease or people with known severe mental illness (psychotic&#xD;
             disorder, bipolar disorder, dementia, substance and alcohol dependence, learning&#xD;
             disabilities, depression with active suicidal ideation) which are likely to interfere&#xD;
             with the normal conduct of the study and interpretation of the study results as judged&#xD;
             by the investigator&#xD;
&#xD;
          -  Current users of real-time glucose monitoring sensors or flash-glucose monitoring for&#xD;
             more than 4 weeks within last 12 weeks&#xD;
&#xD;
          -  Current treatment with drugs known to interfere with glucose metabolism, e.g. systemic&#xD;
             corticosteroids, SGLT2 inhibitors, GLP-1 agonists, Pramlinatide, non-selective&#xD;
             beta-blockers and MAO inhibitors etc.(patients on stable metformin is not an&#xD;
             exclusion)&#xD;
&#xD;
          -  Known or suspected allergy against insulin&#xD;
&#xD;
          -  Severe visual impairment&#xD;
&#xD;
          -  Complete loss of hypoglycaemia awareness&#xD;
&#xD;
          -  Significant renal impairment eGFR&lt;30 within previous one year or on dialysis or active&#xD;
             retinopathy (defined as presence of maculopathy or proliferative changes) as judged by&#xD;
             the investigator&#xD;
&#xD;
          -  More than one episode of severe hypoglycaemia as defined by American Diabetes&#xD;
             Association (30) in preceding 24 weeks&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>The Adam Practice</name>
      <address>
        <city>Poole</city>
        <state>Dorset</state>
        <zip>BH16 5PW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>College of Medical and Dental Sciences University of Birmingham</name>
      <address>
        <city>Birmingham</city>
        <zip>B152TT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <zip>CB20QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals of Derby and Burton NHS Foundation Trust</name>
      <address>
        <city>Derby</city>
        <zip>DE223NE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ipswich Hospital</name>
      <address>
        <city>Ipswich</city>
        <zip>IP4 5PD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Manchester University NHS Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <zip>M139WL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norfolk and Norwich University Hospitals NHS Foundation Trust</name>
      <address>
        <city>Norwich</city>
        <zip>NR47UY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Alexandra Hospital</name>
      <address>
        <city>Portsmouth</city>
        <zip>PO63LY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Leelarathna L, Wilmot EG. Flash forward: a review of flash glucose monitoring. Diabet Med. 2018 Apr;35(4):472-482. doi: 10.1111/dme.13584. Epub 2018 Feb 27.</citation>
    <PMID>29356072</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>January 11, 2019</study_first_submitted>
  <study_first_submitted_qc>January 18, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 24, 2019</study_first_posted>
  <last_update_submitted>August 19, 2022</last_update_submitted>
  <last_update_submitted_qc>August 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2022</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>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual participant data that underlie the results reported in the primary study manuscript after deidentification (text, tables, figures, and appendices).</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>Beginning 6 months and ending 3 years following article publication</ipd_time_frame>
    <ipd_access_criteria>Researchers who provide a methodologically sound proposal not overlapping with any planned secondary publications from the research team.</ipd_access_criteria>
  </patient_data>
  <pending_results>
    <submitted>December 13, 2022</submitted>
  </pending_results>
  <!-- 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/NCT03815006
org study id: B00373
nct id: NCT03815006
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
FreeStyle Libre (FSL2) is a novel glucose monitoring device (Flash glucose monitoring) in the
      form of a disc worn on the arm for 14 days, and a hand-held reader which is designed to
      largely replace the recommended 4-10 painful finger-stick blood glucose tests required each
      day for the self-management of type 1 diabetes. The purpose of this study is to determine
      whether flash glucose monitoring with FSL2 device will improve HbA1c over 24 weeks compared
      to self-monitoring of blood glucose in adults and adolescents (16 or older) with
      sub-optimally controlled (HbA1c 7.5% to 11%) type 1 diabetes.

      This is an open-label, multi-centre, randomised, parallel design study, involving a 2-week
      run-in period, followed by a 24-week study period during which participants will use either
      FSL2 or continue usual finger-stick glucose monitoring in random order. A total of up to 156

      randomised participants from up to 180 recruited aged 16 years and older with T1D on insulin
      pump therapy or multiple daily injection therapy were recruited through diabetes clinics in
      participating centres.

      Participants will receive appropriate training to maximise the benefits of FSL2 and
      finger-stick glucose levels in self-management. The primary outcome is the difference in
      HbA1c between the two groups at 24 weeks. Secondary outcomes are time spent with glucose
      levels above and below target, as recorded by FSL2, and other flash glucose-based metrics.
      Impact on quality of life, diabetes distress, mood, needle burden, disordered eating and
      treatment satisfaction will also be undertaken. Relative cost-effectiveness of FSL2 device
      compared with self-monitoring will also be assessed from a UK NHS perspective.
Study Design:

      An open-label, multi-centre, randomised, parallel study, in adults and adolescents (16 years
      and older) with type 1 diabetes and sub-optimal glycaemic control (HbA1c 7.5% to 11%), either
      on insulin pump treatment or multiple daily injections, contrasting flash glucose monitoring
      using FreeStyle Libre 2 device with traditional finger-stick glucose monitoring for 24 weeks.
      Expecting approximately 15% to 20% dropout rate recruitment will aim for 180 participants
      aiming for 156 randomised and 128 completed participants.

      Participant Recruitment:

      This is a UK multi-centre and recruitment will take place at the following centres:

        1. Diabetes Centres within Manchester University Foundation Trust

        2. Royal Derby Hospital, Derby

        3. Queen Elizabeth Hospital, Birmingham

        4. Addenbrookes Hospital, Cambridge

        5. Norfolk and Norwich University Hospital, Norwich

        6. Queen Alexandra Hospital, Portsmouth

        7. Ipswich Hospital

        8. The Adam Practice, Dorset

      Each centre will aim to recruit between 25 to 30 participants. Additional diabetes centres
      surrounding above hospitals may act as participant identification centres. Potential
      participants will be identified by their treating clinicians and invited to contact the
      research team. They will be sent the study information leaflets and an invitation by post or
      in-person to join the study by the research team at least one day before the recruitment
      visit. The study may also be advertised via social media.

      After recruitment, consent, subjects will be randomised for 24-weeks home use of
      flash-glucose monitoring or 24-weeks use finger-stick glucose monitoring.

      Study Visits:

      The study includes up to 7 visits for participants completing the study. Maximum time in
      study is 30 weeks. Each study visit can be scheduled with +/- 2 weeks of the planned visit
      date.

      Visit 1: Recruitment Visit and Screening Assessment

      Once the participants have agreed to participate in the study, they will be invited for the
      recruitment visit, and given a participant ID, when the following activities will be
      performed by the research team:

        -  written informed consent/assent

        -  checking inclusion and exclusion criteria

        -  medical and diabetes history including the presence of diabetes complications and
           hypoglycaemia burden

        -  ethnicity, body weight and height measurement; calculation of BMI

        -  record of current insulin therapy

        -  urine or blood pregnancy test (females of child-bearing potential)

        -  record of occupation and educational attainment

        -  any history of disordered eating or needle phobia

        -  previous participation in structured education, the status of carb counting, use of
           bolus calculator

      Screening Blood Sampling

      Blood samples will be taken to measure HbA1c (measured at the local laboratory if not done
      within the last two weeks). Renal and Thyroid function will also be evaluated (if not done in
      last one year). Less than 15 ml of whole blood will be taken from each participant.

      Questionnaires at screening

      Evaluation of participants' responses in terms of quality of life, diabetes distress, needle
      burden, disordered eating, depression and diabetes treatment satisfaction using

        1. EQ-5DL-5L questionnaire

        2. Type 1 Diabetes Distress Scale (DDS),

        3. Diabetes fear of injecting and self-testing (D-FISQ) questionnaire,

        4. Diabetes Eating Problem Survey (DEPS-R),

        5. Diabetes Treatment Satisfaction Questionnaire (DTSQ),

        6. Patient Health Questionnaire (PHQ-9) and

        7. The Glucose Monitoring Satisfaction Survey (GMSS).

        8. Hypoglycaemia burden will be assessed using Clarke questionnaire and Gold score.

      Visit 2: Insertion of the blinded glucose monitoring device

      Purpose of visit 2 is to insert a blinded glucose monitor (FreeStyle Libre Pro device). The
      participant will be provided with instructions about using this device for the next two
      weeks. Visit two may be combined with visit 1.

      Visit 3: Adherence assessment, randomisation and the start of study treatment

      During Visit 3, participant's adherence/tolerance of using the flash-CGM over preceding 14
      days will be assessed. To proceed with the study participant should have worn the blinded
      glucose monitoring device for at least ten days' during the last 14 days of the run-in
      period. If the participant fails to demonstrate adherence or develops any significant allergy
      or intolerance to the glucose sensor, the study will be terminated, and the participant will
      be removed from the study. Participant randomisation for the treatment intervention will take
      place during visit 3.

      Initiation of study treatment The participant will arrive at the clinical facility or clinic
      at the agreed time. Body weight measurement will be made. Participants will be provided with
      necessary training on the use of study devices according to randomisation.

      Training session Participants randomised to flash-glucose monitoring arm will receive
      education and training about insertion and initiation of the sensor as well as how to use
      flash-glucose monitoring data for treatment optimisation. They will be encouraged to download
      data at home to identify pattern recognition. This session will be conducted by a
      professional diabetes educator or a member of the study team. Education will be tailored to
      meet the needs of the individual. Participants randomised to conventional finger-stick
      glucose monitoring arm will be encouraged to use finger-stick glucose levels to optimise
      treatment and will receive education about insulin dose adjustments using finger-stick
      glucose levels. The study will try to mimic real-life conditions by continuing participants
      pre-study diabetes treatment unchanged and finger-stick glucose testing frequency as
      determined by the participant as required. Participants in both arms will also receive
      training on sick day rules and dealing with hypo and hyperglycaemia. Participants will be
      provided with a paper diary to collect information about insulin doses and carbohydrate
      intake in the last three days of each study month.

      Visit 4: (+4 weeks since randomisation): Review data and treatment optimisation Purpose of
      this visit is to review data from Flash-glucose monitoring and finger-stick glucose
      monitoring to further optimise treatment. Study devices will be downloaded. Information about
      insulin doses and any adverse events will be collected.

      Visit 5: (+12 weeks since randomisation): Review data and treatment optimisation

      Purpose of this visit is to review data from Flash-glucose monitoring and finger-stick
      glucose monitoring to further optimise treatment. Study devices will be downloaded.
      Information about insulin doses, participant diaries and any adverse events will be
      collected. A blood sample will be collected for HbA1c.

      Visit 6: (+22 weeks since randomisation): Finger-stick glucose monitoring arm only

      Participants randomised to finger-stick glucose monitoring arm will have an extra visit ten
      weeks after visit 5 to insert a blinded glucose sensor for data capture.

      Visit 7: (+24 weeks since randomisation): End of randomised study treatment

      The participant will be invited to attend the research centre approximately 12 weeks after
      Visit 5. This would be the end of 24 weeks randomised study period. All study devices will be
      downloaded. Insulin usage data will be recorded and diaries collected. The participant will
      have a blood test for the HbA1c. Body weight measurement will be made. The participant will
      be asked to complete the same questionnaires completed at Visit 1. In addition, participants
      in the FSL2 arm will be asked to complete a additional questionnaire exploring expectations
      and experience of using FSL2 during the study. A subset of participants (n=40 aiming for 25
      completed questionnaires) in the FSL2 arm and subset of researchers (n=10) will also be asked
      to complete additional questionnaires to help with the process evaluation.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: HbA1c Level at 24 weeks
time frame: 24 weeks
description: The primary outcome is difference in HbA1c between the two groups at 24 weeks.
measure: HbA1c Level at 12 weeks
time frame: 12 weeks
description: This is the difference in HbA1c between the two groups at 12 weeks
measure: Percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 12 weeks
time frame: 12 weeks
description: This is the comparison between arms of percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 12 weeks
measure: Percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 24 weeks
time frame: 24 weeks
description: This is the comparison between arms of percentage with HbA1c ≤ 53 mmol/mol (7.0%) at 24 weeks
measure: Sensor based - Time spent in the target glucose range between 3.9 to 10.0 mmol/l
time frame: 24 weeks
description: Time spent in the target glucose range between 3.9 to 10.0 mmol/l (70 to 180mg/dl).
measure: Sensor based - Time spent below target glucose (<3.9mmol/l)
time frame: 24 weeks
description: Time spent below target glucose (<3.9mmol/l) (<70mg/dl)
measure: Sensor based - Time spent above target glucose (10.0 mmol/l)
time frame: 24 weeks
description: Time spent above target glucose (10.0 mmol/l) (180 mg/dl)
measure: Sensor based - Average glucose levels
time frame: 24 weeks
description: Average glucose levels
measure: Sensor based - Standard deviation glucose levels
time frame: 24 weeks
description: Standard deviation glucose levels
measure: Sensor based - Coefficient of variation glucose levels
time frame: 24 weeks
description: Coefficient of variation glucose levels
measure: Sensor based - time with sensor glucose levels < 3.5 mmol/l
time frame: 24 weeks
description: The time with sensor glucose levels < 3.5 mmol/l (63 mg/dl)
measure: Sensor based - time with sensor glucose levels < 3.5 mmol/l
time frame: 24 weeks
description: The time with sensor glucose levels < 3.0 (54mg/dl)
measure: Sensor based - time with sensor glucose levels < 2.8 mmol/l
time frame: 24 weeks
description: The time with sensor glucose levels < 2.8 mmol/l (50 mg/dl)
measure: Sensor based - time with sensor glucose levels in the significant hyperglycaemia
time frame: 24 weeks
description: The time with sensor glucose levels in the significant hyperglycaemia (glucose levels > 16.7 mmol/l) (300mg/dl)
measure: Sensor based - AUC of glucose below 3.0mmol/l
time frame: 24 weeks
description: AUC of glucose below 3.0mmol/l (54mg/dl)
measure: Total daily average insulin dose
time frame: 24 weeks
description: Comparison between arms of Total daily average insulin dose
measure: Daily average basal insulin dose
time frame: 24 weeks
description: Comparison between arms of Daily average basal insulin dose
measure: Daily average bolus dose
time frame: 24 weeks
description: Comparison between arms of Daily average bolus dose
measure: Average number of boluses of rapid acting insulin
time frame: 24 weeks
description: Average number of boluses of rapid acting insulin per day
measure: Number of Freestyle Libre scans per day
time frame: 24 weeks
description: Number of Freestyle Libre scans per day in the intervention arm only
measure: Frequency of severe hypoglycaemic episodes
time frame: 24 weeks
description: Frequency of severe hypoglycaemic episodes as defined by American Diabetes Association
measure: Frequency of significant ketosis events
time frame: 24 weeks
description: Frequency of significant ketosis events (plasma ketones >3mmol/l)
measure: Nature and severity of other adverse events
time frame: 24 weeks
description: Nature and severity of other adverse events.
measure: Type 1 Diabetes Distress Scale Score
time frame: 24 weeks
description: Type 1 Diabetes Distress Scale score compared between arms
measure: EQ-5D-5L Quality of Life questionnaire Score
time frame: 24 weeks
description: EQ-5D-5L Quality of Life questionnaire
measure: Patient Health Questionnaire Score
time frame: 24 weeks
description: Patient Health Questionnaire: score of 5-9 would be minimal symptoms. any score large than 20 would be categorised as severe major depression
measure: Diabetes fear of injecting and self-testing questionnaire Score
time frame: 24 weeks
description: Diabetes fear of injecting and self-testing questionnaire: 15 questions, 6 for Fear of Self injecting, 9 for fear of self testing.
measure: The revised Diabetes Eating Problem Survey score
time frame: 24 weeks
description: The revised Diabetes Eating Problem Survey
measure: Average number of days of Libre usage per week
time frame: 24 weeks
description: Average number of days of usage per week
measure: Diabetes Treatment Satisfaction Questionnaire score
time frame: 24 weeks
description: Diabetes Treatment Satisfaction Questionnaire
measure: Glucose Monitoring Satisfaction Survey score
time frame: 24 weeks
description: Glucose Monitoring Satisfaction Survey: 15 questions ranging from 1-5.
arm group label: Free Style Libre 2 device
arm group type: Experimental
description: At the start, a blood sample will be taken for the measurement of HbA1c. Training and education on the use of FSL2 will be provided by the research team. Participants will be advised to use flash glucose monitoring continuously for the next 24 weeks.
arm group label: Self-monitoring of blood glucose
arm group type: No Intervention
description: At the start, a blood sample will be taken for the measurement of HbA1c. Masked FSL will be applied for two weeks, during the last two weeks of control period. Education will focus on using fingerstick measurement for treatment optimisation.
intervention type: Device
intervention name: Free Style Libre 2
description: FreeStyle Libre 2 (FSL2) is a novel glucose monitoring device (Flash glucose monitoring) in the form of a disc worn on the arm for 14 days and a hand-held reader which is designed to largely replace the recommended 4-10 painful finger-stick blood glucose tests required each day for the self-management of type 1 diabetes (T1D).
arm group label: Free Style Libre 2 device
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United Kingdom
citation: Leelarathna L, Wilmot EG. Flash forward: a review of flash glucose monitoring. Diabet Med. 2018 Apr;35(4):472-482. doi: 10.1111/dme.13584. Epub 2018 Feb 27.
PMID: 29356072
responsible party type: Sponsor
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
sharing ipd: Yes
ipd description: Individual participant data that underlie the results reported in the primary study manuscript after deidentification (text, tables, figures, and appendices).
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: Beginning 6 months and ending 3 years following article publication
ipd access criteria: Researchers who provide a methodologically sound proposal not overlapping with any planned secondary publications from the research team.
submitted: December 13, 2022