Glucose control through a bihormonal artificial pancreas in patients after total pancreatectomy for cancer (PANORAMA): multicenter randomized controlled cross-over trial - Dutch Pancreatic Cancer Group (DPCG)

The feasibility of the BIHAP was tested in the clinical research center (CRC)
and at home (APPEL 1-3 study). Although the prototypes were bulky, these
studies showed that closed loop glucose control was similar to standard open
loop control. To make the closed loop system suitable for daily use at home,
all components were integrated into one wearable device. This miniaturized
prototype was tested for three days at home in eleven patients with type 1
diabetes (APPEL 4 study).The median glucose level for closed loop and open loop
therapy was comparable, while the time spent in range
(3.9-10 mmol/l) was higher for closed loop.
The results of the APPEL 4 study15 were used as input for risk management,
after which the system was further developed. The performance and safety of
this updated BIHAP was assessed in the APPEL 5 study.5 In this study, 23
patients were included in the data analysis. The participants used the DHFCL
system for 2 weeks at home, preceded by a 4-day training period. The patients
also completed a 2-week control period, which was open
loop control with their own insulin pump, with or without a glucose sensor. The
APPEL 4 and the APPEL 5 study have shown that the device is capable of a solid
improvement in glycemic control.

Most recently the APPEL 5+ study was carried out. In this blind-randomized
monocenter trial, 10 patients with TPD were randomized into BIHAP or standard
diabetes treatment for 7 days. Patients received blinded CGMs. Time spent in
euglycemia was significantly higher with BIHAP treatment (71-82% versus
52-81%). Also, hypoglycemia occurred less often (0% [IQR 0.0-0.0] vs 1.6% [IQR
0.8-3.8], p=0.004).

To assess the efficacy of the BIHAP (AP® 5, Inreda Diabetic BV) using glucagon
and insulin during a three-months period. It is hypothesized that treatment
with BIHAP provides better glucose control than current diabetes treatment.
Main parameter to evaluate glucose control is time spent in euglycemia (glucose
value 3.9-10.0 mmol/l or 70-180mg/dL).

This study is a randomized, multicenter cross-over trial in an outpatient
setting. The design is chosen because of the reduced influence of confounding
covariates and the requirement of less patients compared to other designs. The
duration of the study per patient is three months with current diabetes care
and five training days followed by three months BIHAP treatment (or in reversed
order). Between both arms there is a wash-out period of three months. The total
duration of the study will therefore be approximately ten months.

Prior to the start of the intervention period, the patients must attend an
instruction day at a central location. This training will be given by trained
personnel from Inreda Diabetic BV, simultaneously the BIHAP will be attached.
Afterwards, patients will be sent home and the five-day training period starts.
During this period, the settings and algorithm of the BIHAP will be
individually adjusted and patients will be monitored closely. After successful
completion of the five-day training period, the main study can start.
The investigational device is a dual-hormonal fully closed loop system (BIHAP;
industrial name AP® 5, Inreda Diabetic B.V.) which aims at optimally
controlling plasma glucose levels. This BIHAP contains of two pumps for
subcutaneous infusion of either insulin or glucagon via an infusion set, two
subcutaneously placed glucose-sensors and an algorithm driving pump infusion
rates based on the sensor input. In this way, the algorithm can maintain blood
glucose level within the target limits, i.e., between 3.9 and 10.0 mmol/l.
Daily self-measurements of blood glucose
(SMBGs; Accu-Chek Instant, Roche) are needed for calibration of the glucose
sensors. The BIHAP-system has to be worn continuously, except while showering.

During the control period of the trial, patients will continue their usual
diabetes therapy (CSII therapy or subcutaneous insulin injections). All
patients will wear an open glucose sensor (Freestyle Libre Pro IQ, Abbott) for
data collection. Patients are asked to scan their glucose level with FSL at
least three times a day during the study period, so that we have 24 hours of
glucose levels. More frequent scans will be performed according to the
patients* own judgement. The measured glucose levels will be automatically
transferred to an online database of Abbott. No calibrations are required for
the glucose sensor Furthermore, the patients may perform SMBG according to
their own insight.

All patients undergoing total pancreatectomy will develop insulin dependent
diabetes. Glucose control in TPD-patients is highly challenging due to the
complete loss of pancreatic endocrine parenchyma, which predisposes to severe
postoperative hypo- and hyperglycemia. TPD-patients have no endogenous
production of either insulin or glucagon. TPD patients are therefore the target
population to benefit from the BIHAP.