Closing the Loop in Adults With Type 1 Diabetes Under Free Living Conditions
Closing the Loop in Adults With Type 1 Diabetes Under Free Living Conditions
The main objective of this study is to determine whether home use of day and night closed
 loop insulin delivery under free living conditions applying faster insulin aspart (FiAsp) is
 non-inferior to home use of closed-loop applying standard insulin aspart.

 This is a double-blind, multi-centre, randomised, crossover design study, involving a run-in
 period followed by two study periods during which glucose levels will be controlled either by
 an automated closed-loop system using standard rapid acting insulin analogue or by an
 automated closed-loop system using faster insulin aspart in random order.

 Subjects will receive appropriate training in the safe use of closed-loop insulin delivery
 system. Subjects will have regular contact with the study team during the home study phase
 including 24/7 telephone support.

 The primary outcome is time spent in target range between 3.9 and 10.0 mmol/L as recorded by
 CGM during home stay. Secondary outcomes are the HbA1c, time spent with glucose levels above
 and below target, as recorded by CGM, and other CGM based metrics.
Purpose of clinical trial The purpose is to determine whether home use of day and night
 closed loop applying faster insulin aspart is not inferior to home use of closed loop
 applying standard insulin aspart.

 Study objectives The study objective is to compare day and night automated closed-loop
 glucose control using faster acting insulin aspart with closed loop control using standard
 insulin aspart.

 1. EFFICACY: The objective is to assess the efficacy of day and night automated closed-loop
 glucose control applying standard rapid-acting insulin analogue in maintaining CGM
 glucose levels within the target range from 3.9 to 10.0 mmol/l, as compared to day and
 night closed-loop using faster acting insulin aspart

 2. SAFETY: The objective is to evaluate the safety of day and night automated closed-loop
 glucose control in terms of episodes of severe hypoglycaemia, hyperglycaemia and other
 adverse events and adverse device effects.

 3. UTILITY: The objective is to determine the percentage of time when closed-loop was
 operational, and usability and acceptance of the closed-loop system.

 Study Design A double-blind, multi-centre, randomised, two-period crossover study,
 contrasting day and night automated closed-loop glucose control applying standard rapid
 acting insulin analogue with day and night closed-loop control applying faster acting insulin
 aspart.

 Study Efficacy Endpoints The primary outcome is the time spent in the target glucose range
 from 3.9 to 10.0 mmol/l based on CGM glucose levels during the free living phase.

 Secondary outcomes include time spent above and below the target glucose range, based on CGM
 levels.

 Safety Evaluation Frequency of severe hypoglycaemic episodes as defined by American Diabetes
 Association, frequency of severe hyperglycaemia (>20 mmol/l) and / or significant ketosis
 (plasma ketones >3mmol/l) and nature and severity of other adverse events.

 Utility Evaluation Percentage of time spent in closed-loop. Usability and acceptance of the
 closed-loop system will be assessed using a patient experience questionnaire at the end of
 the second intervention. Additionally, human factor questionnaires will be administered
 following recruitment and at the end of each intervention arm.

 Sample Size 24 adults completing the study. Up to 30 subjects will be recruited to allow for
 dropouts.

 Maximum duration of study for a subject 20 weeks (5 months)

 Recruitment The subjects will be recruited through the adult diabetes outpatient clinics or
 other established methods at participating centres.

 Consent Participants will be asked to provide written informed consent.

 Baseline Assessment Eligible subjects will undergo a baseline evaluation including a blood
 sample for the measurement of HbA1c, renal, liver functions, full blood count, thyroid
 functions and coeliac antibody screen (if not done in the previous 3 months). Urine pregnancy
 test will be done in females. Additional centre specific assessments will also be undertaken.
 Human factor questionnaires will be administered.

 Study Training and Run-in Period Training sessions on the use of study CGM, insulin pump and
 closed-loop system will be provided by the research team. During the 2-4 weeks run-in period,
 subjects will use study CGM and insulin pump and will have regular contact with the research
 team. At the end of the run-in period, for compliance and to assess the ability of the
 subject to use the CGM and study pump safely, before the start of the first home study phase,
 at least 7 days of CGM data need to be recorded and safe use of study insulin pump
 demonstrated. CGM and insulin pump data during the run-in period will be used to assess
 baseline glucose control and optimise treatment before the start of the first home study
 phase.

 Competency Assessment Competency on the use of study insulin pump, study CGM and closed-loop
 system will be evaluated using a competency assessment tool developed by the research team.
 Further training may be delivered as required.

 Randomisation Eligible subjects will be randomised using randomisation software to the use of
 closed-loop with faster acting aspart or to closed-loop with standard insulin aspart.

 Automated closed-loop Training on the use of closed-loop will be provided by the research
 team. Automated closed-loop control will be commenced and during the 2-3 hour training the
 participant will operate the system under the supervision of the clinical team. Competency on
 the use of closed-loop system will be evaluated. Subjects will be advised to use automated
 closed-loop system for next 8 weeks

 Cross-over Assessment At the end of the first intervention human factor questionnaires will
 be administered.

 There will be no washout period in phase 3 extension.

 End of study assessments A patient experience questionnaire will be given at the end of the
 second intervention. Additionally human factor questionnaires will be administered.

 Procedures for safety monitoring during trial Standard operating procedures for monitoring
 and reporting of all adverse events and adverse device events will be in place, including
 serious adverse events (SAE), serious adverse device effects (SADE) and specific adverse
 events (AE) such as severe hypoglycaemia.

 Subjects will be asked to test and record blood ketones if their finger-stick glucose is
 above 14 mmol/l as part of the safety assessment for hyperglycaemia.

 A data monitoring and ethics committee (DMEC) will be informed of all serious adverse events
 and any unanticipated adverse device/method effects that occur during the study and will
 review compiled adverse event data at periodic intervals.

 Criteria for withdrawal of patients on safety grounds

 A subject may terminate participation in the study at any time without necessarily giving a
 reason and without any personal disadvantage. An investigator can stop the participation of a
 subject after consideration of the benefit/risk ratio. Possible reasons are:

 -  Serious adverse events

 -  Significant protocol violation or noncompliance

 -  Failure to satisfy competency assessment

 -  Decision by the investigator, or the sponsor, that termination is in the subject's best
 medical interest

 -  Pregnancy, planned pregnancy, or breast feeding

 -  Allergic reaction to insulin

 -  Technical grounds (e.g. subject relocates)
Inclusion Criteria:

 1. The subject has type 1 diabetes as defined by WHO

 2. The subject is 18 years of age or older

 3. The subject will have been on an insulin pump for at least 6 months with good
 knowledge of insulin self-adjustment including carbohydrate counting

 4. The subject is treated with one of the rapid acting or ultra-rapid acting insulin
 analogues (Insulin Aspart, faster acting insulin Aspart, Insulin Lispro or Insulin
 Glulisine)

 5. HbA1c <10% (86mmol/mol) for phase 3, based on analysis from central laboratory or
 equivalent

 6. The subject is willing to perform regular finger-prick blood glucose monitoring, with
 at least 2 measurements per day

 7. The subject is willing to wear closed-loop system at home and at work place

 8. The subject is willing to follow study specific instructions including the use of
 bolus calculator for all meals / snacks

 9. The subject is willing to upload pump and CGM data at regular intervals

 10. Female subjects of child bearing age should be on effective contraception and must
 have a negative urine-HCG pregnancy test at screening.

 Exclusion Criteria:

 1. Non-type 1 diabetes mellitus

 2. Subjects who are living alone

 3. Any other physical or psychological disease or condition likely to interfere with the
 normal conduct of the study and interpretation of the study results

 4. Current treatment with drugs known to have significant interference with glucose
 metabolism, such as systemic corticosteroids, as judged by the investigator

 5. Known or suspected allergy against insulin or previous reaction to FiAsp

 6. Subjects with clinically significant nephropathy (eGFR < 45ml/min), neuropathy or
 active retinopathy (defined as presence of maculopathy or more than background
 diabetic retinopathy changes) as judged by the investigator

 7. More than one episode of severe hypoglycaemia as defined by American Diabetes
 Association (42) in preceding 12 months (Severe hypoglycaemia is defined as an event
 requiring assistance of another person to actively administer carbohydrates, glucagon,
 or take other corrective actions including episodes of hypoglycaemia severe enough to
 cause unconsciousness, seizures or attendance at hospital.)

 8. Total daily insulin dose > 2 IU/kg/day

 9. Subject is pregnant or breast feeding or planning pregnancy within next 10 months

 10. Severe visual impairment

 11. Severe hearing impairment

 12. Lack of reliable telephone facility for contact

 13. Subject not proficient in English (UK), French (Switzerland) or German (Germany,
 Switzerland and Austria)

 Additional exclusion criteria specific for Austria

 1. Positive results on urine drug screen (amphetamines/metamphetamines, barbiturates,
 benzodiazepines, cannabinoids, cocaine, opiates).

 2. Positive alcohol breath test.

 3. Positive reaction to any of the following tests: hepatitis B surface (HBs) antigen,
 anti-hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus (HIV)
 1 antibodies, anti-HIV2 antibodies.