Study Design An open-label, single-centre, randomised, 2-period cross-over study, in adults
(18 years and older) with type 1 diabetes on insulin pump treatment.
It is expected that up to 26 adults with type 1 diabetes will be recruited, aiming for 19
completed participants. The study flow chart is outlined in Figure 2.
Study Subjects Study Population This is a single centre study and recruitment will take place
at the Manchester Diabetes Centre, Manchester Royal Infirmary, Manchester University NHS
Foundation Trust. Up to a total of 26 adults aged 18 years and older with type 1 diabetes on
insulin pump therapy will be recruited aiming for 19 completed participants. 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.
Randomisation Eligible subjects will be randomised by the clinical researcher up to 14 days
prior to first in-patient stay using Sealed Envelope randomisation software to undertake
closed-loop studies in one of two possible random sequences; ultrarapid-acting lispro
followed by insulin lispro, or insulin lispro followed by ultrarapid-acting insulin lispro.
Study Schedule Overview The study will be co-ordinated from the Manchester Diabetes Centre,
Manchester Royal Infirmary, Manchester. The study will consist of five Visits including two
9-hour stays at the MCRF, Manchester Royal Infirmary, Manchester. Visits 1 and 2 may be
combined. Tables 1 and 2 summarise the study visits.
Recruitment Visit and Baseline Assessment (Visit 1)
Once the subjects have agreed to participate in the study, they will be invited for the
recruitment visit, when the following activities will be performed by the research team:
Written informed consent
Checking inclusion and exclusion criteria
Medical (diabetes) history
Body weight and height measurement; calculation of BMI
Record of current insulin therapy
Serum pregnancy test (females of child-bearing potential) Baseline Blood Sampling During
Visit 1 consented participants will undergo a baseline evaluation where blood samples
for HbA1c and serum beta HCG (pregnancy test) in females of child-bearing potential will
be collected. Less than 15 ml of whole blood will be taken from each participant. In the
event the laboratory HbA1c returns below 48 mmol/mol or above 86 mmol/mol the
participant will be withdrawn.
Training Session on Continuous Glucose Monitoring (Visit 2) This session will cover key
aspects of the study CGM and attention will be paid to the following areas. This visit could
be combined with visit 1.
Written easy to use guidelines for the operation of CGM device will be provided. This session
will be conducted by a professional pump educator / study nurse and possibly a member of the
study team. Competency on the use of CGM will be assessed and additional training will be
provided if deemed necessary by the Competency Assessment Form.
Visit 3 - Optimisation During Visit 3, after a 2 to 3 weeks' run-in period, glucose control
will be optimised, if required, by the study team with special focus on insulin to
carbohydrate ratios.
Manchester Diabetes Centre is the largest insulin pump centre in UK. We expect most of the
participants in the study to be already well optimised. However, we will ensure this further
by reviewing insulin, glucose and carbohydrate data during the two-week run-in period.
Particular attention will be on the insulin carbohydrate ratio to see whether it is over
aggressive. If the insulin to carb ratio is over aggressive this could potentially reduce the
difference between Lispro and Lyumjev during the study. Participants whose glucose levels
drops (those who develop hypoglycaemia within 2 to 3 hours of meal bolus) carb ratio will be
adjusted to avoid this drop. Participants will also be randomised at visit 3.
Visit 4 will follow within 2 weeks of Visit 3. Participants will be advised to avoid
strenuous exercise 24 hours prior to each in-patient stay to avoid any bias arising from
changes in insulin sensitivity.
Activities during 9-hour in-patient stay (Visits 4 and 5, Figure 3) There will be two
in-patient study days, performed within 1-6 weeks of each other. On each Study Day,
participants will arrive at the study centre at approximately 08.30 and will be discharged by
18.00 the same day.
Participants will be advised to insert a new CGM sensor 48 hours before the planned
admission. A new insulin infusion cannula will be inserted on admission to the clinical
research facility. In addition, participant will be advised to change their usual insulin to
the corresponding study visit insulin formulation, 24 hours prior to admission. (For example;
if the participant is on insulin lispro, this will be changed to ultra rapid-acting lispro
24-hour prior to the admission for closed loop with ultrarapid-acting lispro and vice versa.)
Participants will be requested to fast from 12 midnight prior to admission (carbohydrate-free
liquids are allowed). Participants will be requested to check their glucose between 05:00 and
07:00. If the glucose level is, or anticipated to be, < 4 mmol/l during this period,
additional carbohydrate can be taken to aim for arrival glucose between 4 and 10 mmols.
Correction insulin doses may be given if arrival glucose is anticipated to be above range
(>10 mmol/l). Study visits may be rescheduled if participants develop significant
hypoglycaemia (<3.0 mmol) or significant hyperglycaemia (glucose >20 mmol/l and/or ketones
>0.6 mmol/l) 6 hours prior to or on arrival. On arrival, participant's usual insulin pump
will be changed to study insulin pump. Closed-loop with either ultrarapid-acting lispro or
insulin lispro will commence between 09:00 and 17:00 hours.
A 60g meal will be served at 11:00 with no meal bolus to mimic a missed meal bolus.
The study will end at 17.00. Patients will be switched back to their usual insulin pump
therapy at the end of the study. Standard operating procedures will be in place for treatment
of hypo and hyperglycaemia. Figure 3 summarises activities during the 9 hour in-patient stay.