THE EFFECTS OF REAL-TIME CONTINUOUS GLUCOSE MONITORING ON GLYCEMIA AND QUALITY OF LIFE IN PATIENTS WITH TYPE 1 DIABETES MELLITUS AND IMPAIRED HYPOGLYCEMIA AWARENESS

Intensive insulin therapy in patients with type 1 diabetes (T1DM) reduces
microvascular and macrovascular complications but is also associated with an
increased rate of hypoglycemia. Recurrent hypoglycemia may lead to the
development of impaired hypoglycemia awareness (IHA) or hypoglycemia
unawareness (HU). Meticulous avoidance of hypoglycemia can restore the
concomitantly attenuated hypoglycemia counterregulatory mechanisms. The
recently developed technology of real-time continuous glucose monitoring
(RT-CGM) may help patients with T1DM to achieve better glycemic control with
less hypoglycemic episodes. Accordingly, one may hypothesize that particularly
T1DM patients with IHA will profit most from this novel technology as it may be
expected to lead to improvements in their quality of life. However, to date
there are no studies using RT-CGM specifically in T1DM patients with IHA.

Primary objective:
To assess the mean difference in time spent in the euglycemic range
(interstitial glucose >3.9-<10.0 mmol/L), expressed as hours/day, between the
two 16-week intervention periods, i.e. RT-CGM versus masked CGM, in patients
with T1DM and IHA.

Secondary objectives:
To measure:
1. (Diabetes-specific) markers of QoL, as assessed with questionnaires,
covering diabetes distress (PAID-5), fear of hypoglycemia (HFS-2),
self-efficacy (CIDS), health status (EQ-5D) and emotional well-being (WHO-5)
2. other glycemia variables, including HbA1c and time spent in hypo- and
hyperglycemia ranges, expressed in hours/day, averaged over 16 weeks of data
gathering during the intervention period, spent as or below an interstitial
glucose level of 3.9 or above an interstitial glucose level of 10.0 mmol/L,
respectively, as determined by (RT-)CGM data during the respective intervention
periods.
3. the incidence and duration of hypoglycemic episodes, expressed in
minutes/day, averaged over 16 weeks of data gathering during the intervention
period, during which the patients* (RT-)CGM-measured interstitial glucose
values are 3.9 mmol/L or below 3.9 mmol/L, according to (RT-)CGM data during
the respective intervention periods.
4. changes in hypoglycemia awareness score according to Gold et al. (reference:
Gold AE, MacLeod KM, Frier BM. Frequency of severe hypoglycemia in patients
with type I diabetes with impaired awareness of hypoglycemia. Diabetes Care
1994 Jul;17(7):697-703.)

Exploratory objectives
To explore:
1. RT-CGM derived measures of glucose variability
2. the autonomic nervous system balance
3. the duration of wear of the RT-CGM device
4. patients* therapy adjustments during the interventions
5. hypoglycemia awareness scores according to Clarke et al. (reference: Clarke
WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced
awareness of hypoglycemia in adults with IDDM. A prospective study of
hypoglycemic frequency and associated symptoms. Diabetes Care 1995
Apr;18(4):517-22.)
6. satisfaction with use of CGM (reference: Youth and parent satisfaction with
clinical use of the GlucoWatch G2 Biographer in the management of pediatric
type 1 diabetes. Diabetes Care 2005 Aug;28(8):1929-35.)
7. the number of contact moments not planned according to the study schedule
8. absence of work of patient (and spouse)
9. the global estimated costs of use of health care (hospital admissions,
ambulance- and house calls, etc.)

This is a randomized, two intervention periods, separated by a 12-week wash-out
period, cross-over study. After a 5-week run-in period, during which patients
receive global diabetes education and training in using CGM, patients will be
randomized to either 16 weeks of use of RT-CGM or a 16-week period of CGM. Both
interventions are additional to usual care and to performing self-measurements
of blood glucose (SMBG) according to the protocol. Depending on the order of
intervention, after the wash-out period patients will cross over to 16 weeks of
the other intervention.

Depending on the order, 16 weeks of use of real-time continuous glucose
monitoring (RT-CGM) and a 16-week period of masked continuous glucose
monitoring (CGM),.Both interventions are additional to usual care and to
performing self-measurements of blood glucose (SMBG) according to the protocol.

There will be 14 visits, 1 optional visit and13 telephone consultations in a
total study duration of 45 weeks. The duration of visits ranges from approx. 45
minutes (for follow-up visits) to approx. 2 hours (in case of endpoint
measurements).

A total amount of 45 mL blood will be collected for hematological and
biochemical (safety and end-point) assessments during the entire study period.
The maximum blood volume to be obtained during one visit is 13 mL. The
venipuncture may be painful.

During the screening, subjects will receive an extensive physical examination
(incl. e.g. length and weight measurement, vital parameters, examination of
heart, lungs and abdomen), during follow-up physical examination will be
limited to measuring vital parameters.

Four times cardiovascular autonomic functioning tests will be performed (each
time 20 min in total), and participants will be asked to fill out
questionnaires (approx. 30-50 min in total).

Participants will be asked to fill out questionnaires five times (taking
approx. 30-60 minutes). These concern hypoglycemia awareness or quality of
life. Two times participants will be asked to complete a 5-day diary concerning
intake, insulin use and sports.

Wearing of the continuous glucose monitors may case discomfort. Inserting a
sensor may cause bleeding, swelling, irritation and/or infection at the site of
insertion. Real-time glucose information will not be visible when participating
in the CGM-phase. Alarms from the RT-CGM may be perceived to be inconvenient.