Closing the Loop in Children and Adolescents With Type 1 Diabetes in the Home Setting
Condition: Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Endocrine System Diseases; Autoimmune Diseases
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Metabolic Diseases; Glucose Metabolism Disorders; Endocrine System Diseases; Autoimmune Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      Type 1 diabetes (T1D) is one of the most common chronic childhood diseases requiring lifelong
      insulin therapy. Children and adolescents with T1D need regular insulin injections or the
      continuous insulin delivery using an insulin pump in order to keep blood glucose levels
      normal. We know that keeping blood sugars in the normal range will help prevent longterm
      diabetes-related complications involving the eyes, kidneys and heart. However, achieving
      treatment goals can be very difficult as the tighter we try to control blood glucose levels,
      the greater the risk to develop symptoms and signs of low glucose levels (hypoglycaemia).
      This is a particular problem at night and one solution is to develop a system whereby the
      amount of insulin injected is controlled by a computer and is very closely matched to the
      blood sugar levels on a continuous basis. This can be achieved by what is known as a
      "closed-loop system" where a small glucose sensor placed under the skin communicates with a
      computer containing an algorithm that drives an insulin pump. We have been testing such a
      system in Cambridge over the last five years in children and have found that this system is
      effective at maintaining tight glucose control and preventing nocturnal hypoglycaemia. More
      recently the system has been tested in real life conditions in the home setting for three
      weeks during a pilot single-centre study.

      The next step is to extend the evaluation of closed-loop over a prolonged period of three
      months. In the present study we are planning to study 24 young people aged 6-18 years on
      insulin pump therapy. During three months glucose will be controlled by the computer and
      during the other three months the subjects will make their own adjustments to the insulin
      therapy using real-time continuous glucose monitoring.

      We aim to determine the effect of the computer algorithm in keeping glucose levels between
      3.9 and 8 mmol/L (normal levels). Safety evaluation comprises assessment of the frequency of
      severe hypoglycaemic episodes. Participants' response to the use of the system in terms of
      lifestyle change, daily diabetes management and fear of hypoglycaemia will be assessed. We
      will also test for longer term glucose control by measuring glycated haemoglobin (HbA1c).
    

Detailed description: 
      Purpose of the study

      The purpose of this research is to evaluate the efficacy, safety and utility of the overnight
      automated closed-loop system in the home setting on consecutive nights over a 3-month period,
      as compared to the use of real-time continuous glucose monitoring (CGM) alone.

      Design

      The study is designed in the form of an open-label, cross-over study and it involves two
      3-month-long home studies during which overnight glucose levels will be controlled either by
      a closed-loop (CL) system combined with a real-time continuous subcutaneous glucose
      monitoring (CGM) or by real-time continuous glucose monitoring alone, in random order.

      The study will take place within the home setting where, initially, overnight supervision of
      the closed-loop system will be undertaken by a research nurse either at home or at an
      in-patient facility.

      Three UK centres will be involved in the study: Addenbrooke's Hospital, Cambridge, University
      College London Hospital (UCLH), London, Leeds Teaching Hospitals, Leeds

      Population

      A total of 30 children and adolescents with T1D between 6 and 18 years of age on insulin pump
      therapy will be recruited from the Paediatric Diabetes Outpatient Clinics at the three
      investigation centres to allow for 24 evaluable subjects. Each investigation centre will
      recruit at least three subjects to achieve balanced representation of study population.

      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 to join
      the study by the research team. They will have the opportunity to read and discuss the
      information. If they agree to participate in the study, informed consent and/or assent will
      be taken by a member of the research team who has a good working knowledge of the aims and
      practicalities of the study. The person taking consent will use language that is easy to
      understand and free from medical jargon.

      Experimental Procedures

      The study will consist of up to 10 visits, including two study periods (closed-loop vs.
      conventional pump therapy + continuous glucose monitoring). The study periods will last 3
      months each. The order of the two interventions will be random.

      Once the subjects have agreed to participate in the study, they will be invited for the
      recruitment visit, when participants' body weight and height, demographics, medical and
      diabetes history, and their previous days insulin therapy will be recorded. Urine pregnancy
      test will also be performed in females of children-bearing age.

      Once consent has been obtained and if all the inclusion and exclusion criteria are met the
      subject will be included in the study and allocated a sequential subject number.

      Blood samples will be taken for the baseline measurement of random C-peptide, glucose and
      HbA1c. Eligible subjects will also undergo a baseline evaluation where a blood sample for
      renal, liver, thyroid function, full blood count and anti-transglutaminase antibodies with
      IgA levels will be taken (if not done in the previous 3 months).

      Validated questionnaires will be distributed to assess both the user friendliness of the
      devices used by study participants and fear of hypoglycaemia before entering the study. Study
      participants will also be invited to participate in a semi-structured qualitative interview
      conducted by trained staff, which will occur face-to-face or via telephone, within 2-4 weeks
      (during the training period), to determine their expectations of the diabetes treatments to
      be used in the study.

      All eligible subjects who will have signed informed consent will be invited to a training
      session on the use of the devices which will be employed in the study.

        -  Two to four weeks prior to the first study night the subjects will be switched from
           their regular insulin pump to the study subcutaneous insulin infusion pump for the
           period of the study. Local diabetes clinic guidelines for switching insulin pumps will
           be followed. Subjects will be given training on the functionality of the pump by the
           research team and standard operational procedures, as well as the pump user manual, will
           be provided. The research and paediatric diabetes team will be available by telephone to
           assist with any concerns that the subjects may have regarding the pump.

        -  A training session on Continuous Glucose Monitoring (CGM) will take place about two to
           four weeks before the study starts. Subjects will be trained on the use of the study CGM
           system. Subjects will be trained at home/clinic by the research nurse to insert a
           subcutaneous glucose sensor and will be provided with the study CGM system to wear at
           home for at least three consecutive 5-day-sensor sessions (at least 12 days of use) or
           until subjects become confident with the device, namely with the performance of sensor
           insertion and calibrations. During the two to four week training period the CGM display
           may be masked so that subjects will not be able to see their glucose values. For
           subjects who use CGM as part of their normal diabetes care, the CGM display will not be
           masked during this training period. At the end of the training period the sensor data
           will be downloaded by the research team and will be used to optimise insulin therapy
           prior to the start of the study. This will be done in collaboration with the paediatrics
           diabetes team. The CGM readings recorded during this training period will used to assess
           baseline glucose control.

      At the end of the training session, a competency assessment tool will be used to evaluate
      subjects' competency in the use of both devices. Subjects' compliance in diabetes management
      will also be evaluated in terms of time wearing the continuous glucose monitoring device. A
      minimum of 12 days of continuous glucose monitor readings should be recorded over the time of
      use of the device. Competency and compliance evaluations will determine participants'
      eligibility before randomisation.

      Eligible subjects, who have completed the training session on the use of both the study
      subcutaneous insulin pump and the study CGM device and gained confidence in the use of both
      devices as assessed by the research team, will be randomised to one of the 2 intervention
      arms:

        1. Real-time CGM + overnight CL

        2. Real-time CGM alone Three to four weeks after the completion of each intervention arm,
           subjects will cross over to alternative intervention: those who were allocated to the
           CGM+CL intervention will be switched to CGM alone intervention, whereas those who
           completed the CGM alone intervention will be allocated to the CGM+CL intervention.
           During this three-to-four-weeks wash out period, real-time CGM may be used.

      Additional training on the use of real-time CGM will be provided at the beginning of the
      first intervention arm. This involves training on how to interpret the data displayed on the
      real-time CGM device screen and how to perform insulin therapy adjustments according to
      glucose reports. Written guidelines on the use of both real-time and retrospective
      information will be provided to all subjects.

      At the beginning of the closed-loop intervention, subjects will be provided with specific
      training on the use of the closed-loop system. Closed-loop training will be carried out in
      two consecutive stages:

        1. Supervised Closed Loop: the closed-loop system will be started in the evening or at
           bedtime and will remain in operation until the following morning.

           Each subject will be supervised in starting the closed-loop system by the research
           nurse/doctor for one night at home or at an in-patient facility, with the option of a
           second supervised night at the start of the closed-loop intervention, until the subject
           is confident to use the equipment. For subjects who were supervised in using the
           closed-loop system at the in-patient facility, the research nurse/clinician may provide
           assistance and supervision in setting up the closed-loop system for the first night at
           home.

        2. Unsupervised Closed Loop: Subjects will use the closed-loop system overnight at home for
           a total duration of 12 weeks. The subcutaneous CGM sensor will be replaced every 5 days
           by the subjects. Support and telephone advice will be provided by the research team for
           the duration of the study to deal with any concerns that may arise with the use of the
           closed-loop system components.

      Cross-over procedures:

      Having completed the first intervention arm, all subjects will cross over to the other
      intervention arm after a wash-out period of three to four weeks. Blood sampling for the
      determination of HbA1c will be taken to investigate any changes in metabolic control.
      Validated questionnaires will be distributed to evaluate the impact and satisfaction as well
      as the user friendliness of the devices employed in the completed arm of the study. A
      questionnaire evaluating fear of hypoglycaemia will also be distributed to both parents and
      children. Study participants will be invited to participate in a semi-structured qualitative
      interview conducted by trained staff within 0-4 weeks of completing the Closed Loop
      intervention arm, including their views on the diabetes treatment experienced. The second
      intervention treatment arm will start three to four weeks after the end of the first arm. In
      between the two intervention arms, subjects will resume their usual insulin regimen, using
      either the study insulin pump or usual patient's insulin pump. Real-time CGM may be used as
      part of their standard diabetes management.

      End of study:

      Having completed the second intervention arm of the study, subjects will revert to their
      conventional insulin pump therapy by switching to the insulin pump they were using before
      entering the study. Blood sampling for the determination of HbA1c will be taken to
      investigate any changes in metabolic control. Validated questionnaires will be distributed to
      evaluate the impact and satisfaction as well as the user friendliness of the devices employed
      in the completed arm of the study.
    

Intervention name(s): Overnight closed-loop; Real-time CGM alone
Intervention type(s): Device; Device
Intervention description(s): The closed-loop system is purpose-built and comprises a hand-held computer containing a model predictive control (MPC) based glucose control algorithm and communicating with the CGM device and the insulin pump.; Subject glucose level controlled by usual insulin pump therapy in conjunction with real time continuous glucose monitoring (CGM)
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Type 1 diabetes; Closed-loop glucose control; Artificial Pancreas; Continuous subcutaneous insulin infusion; Continuous glucose monitoring