Improving preconceptional suboptimal glycaemic control in type 1 diabetes using RealTime Continuous Glucose Monitoring: a randomised trial

Despite major advances in diabetes care the incidence of adverse pregnancy
outcomes in women with type 1 diabetes mellitus is still significantly higher
than in non-diabetic pregnancies. It is known that suboptimal glucose
regulation is associated with adverse pregnancy outcomes: suboptimal control in
the periconceptional period is associated with the development of congenital
malformations.
There is general consensus that prepregnancy care and optimal glycaemic control
is mandatory to achieve the best possible pregnancy outcome in these women with
HbA1c as the parameter reflecting the quality of glycaemic control. The latest
guidelines state that we should aim for a preconceptional HbA1c-level as near
the normal range as possible to achieve the best outcomes but at least an HbA1c
< 7.0% (53 mmol/mol).
With lowering of the HbA1c-level towards the normal range, the risk of
hypoglycaemia and severe hypoglycaemia increases, currently posing a barrier to
reach best control.
The current mainstay of monitoring glycaemic control (self-measurement of blood
glucose levels by finger stick) only provides snapshot images, limiting the
possibilities to improve glycaemic control.
Real-Time Continuous Glucose Monitoring System (RT-CGMS) allows instantaneous
display of actual glucose values combined with an alert-function when glucose
levels or changes in levels fall outside preset individualised limits. Studies
have shown that RT-CGMS can improve glycaemic control in patients with type 1
diabetes but these were heterogenic and no studies have been done with RT-CGMS
during the preconceptional or pregnant period in the specific patient group of
preconceptional women with suboptimal regulated type 1 diabetes .
Glycaemic variability is a new concept in diabetes care and it has been
suggested that the degree of glucose variability may be linked to adverse
outcomes. Rt-CGMS may also decrease glucosevariability.

This study is designed to investigate whether it is possible to achieve
substantial improvement of HbA1c values in preconceptional suboptimal regulated
type 1 diabetes mellitus (which is HbA1c 7.0-7.7%).

Primary outcome
- Absolute reduction in HbA1c

Secondary outcomes
- Incidence of severe hypoglycaemia
- Percentage of women with a fall in HbA1c of >= 0.5% (>= 5 mmol/mol)
- Percentage f women that reach target HbA1c (< 7.0% or < 53 mmol/mol)
- Time to reach target HbA1c
- number of consultations (by telephone, internet and in out-patient clinic)
- Change in glycaemic variability
- Composite end point: reduction of HbA1 >= 0.5% (>= 5 mmol/mol) without an
episode of severe hypoglycaemia
- Frequency of use RT-CGMS
- Fear of hypoglycaemia
- Quality-of-life
- Satisfaction with the device

Randomised controlled parallel-arm single centre trial for 16 weeks

This is a 16-week randomized controlled parallel-arm single centre trial
comparing the use of RT-CGMS with standard extensive care in preconceptional
setting in women with suboptimal regulated type 1 diabetes mellitus.

Setting:
The study will be carried out in the setting of the already longstanding
collaborative group of the UMC Utrecht Departments of Internal Medicine and
*Vrouw en Baby*. This group has founded in the nineties a joint
Obstetrics-Internal Medicine clinic for pregnant patients with any kind of
diabetes which has served as a role model for other institutions.

Recrutation:
Consecutively approach of patients: every women with suboptimal regulated type
1 diabetes mellitus who is treated at the out-patient clinic for Diabetology of
the UMC Utrecht and who has a child wish will be approached for this study
Other centra will be asked to to tell patients, of this specific population,
about this study. With aprovel of the patient the researcher will contact her
for more explanation and potential inclusion.

Randomisation
By a list, made in forehand by a independent person (unknown to the researcher
until the patient has signed for informed consent)

Intervention
Intervention group:
- Standard medical consultation by:
=> Diabetes nurse educator (scheduled every two weeks, plus possibility of
24h a day by telephone or email)
=> Diabetes specialist (scheduled week 0, week 1, week 4, week 8, week 12,
week 16)
Every therapy change will be made under supervision (from nurse to research
physician to supervising physician) and noted
- Standard therapy:
=> Insulin pump therapy (replaced by RT_CGMS: insulin pump and glucose sensor
in one)
=> SMBG at least 5 times a day for at least 5 days a week
- Standard blood controls:
=> HbA1c and fructosamine every 4 weeks
TSH and FT4, cholesterol, Hb, Kreatinine and urinesediment at baseline
- Research related:
=> Questionnaires every 4 weeks
=> RT-CGMS during 7 consecutive days every other week (in total: 8 of 16
weeks)
Results will be used for counseling / treatment adjustments
=> 2 times blinded RT-CGMS for 48 hours conform the control group in week 1
and 12st
- Post study:
=> Patients will be offered to use RT-CGMS after end of study

Control group:
- Standard medical consultation as in intervention group
Every therapy change will be made under supervision (from nurse to research
physician to supervising physician) and noted
- Standard therapy:
=> Insulin pump therapy continues
=> SMBG as in intervention group
- Standard blood controls:
=> Blood samples as in intervention group
- Research related:
=> Questionnaires as in intervention group
=> 2 times Blinded RT-CGMS as in intervention group. However,
results will not be revealed to participating control group of women nor to
the treating team except when CGMS analysis is clinically required.
- Post study:
=> Patients will be offered to use RT-CGMS after end of study

Intervention group:
- Insulin pump therapy will be continued
RT-CGMS during 7 consecutive days every other week (in total: 8 of 16 weeks).
Results will be used for counseling / treatment adjustments
- 2 times blinded RT-CGMS for 48 hours conform the control group in week 1 and
12st (when patient is not using RT-CGMS)

Control group:
- Insulin pump therapy will be continued
- 2 times Blinded RT-CGMS as in intervention group. However, results will not
be revealed to participating control group of women nor to the treating team
except when CGMS analysis is clinically required.

Participation with this trial can be a burden on some fronts:
- Some patients have to change physician (namely the research-physician with
supervision of the specialist who is concerned with the diabetic care of
pregnant women). However, when they get pregnant (although not participating
this study) they then also become under the supervision of the named specialist.
- The use of RT-CGMS can be a burden because the alert-function, besides the
advantage of the warning possibilities, causes unpredictable disturbances of
daily (meetings, visits, shopping etc) or nocturnal (sleeping) activities.
- Patients will have to connect the RT-CGMS themselves (every other week) and
will have to replace the needle after 3 days of use
- Patients always have to confirm glucose values given from the RT-CGMS with
SMBG before making therapy adjustments
- Former studies showed some possible skin irritative adverse affects from
(RT-)CMGS use
- We will ask patients to fill in some questionnaires every 4 weeks

Risk of hypoglycaemic events
It is possible that the incidence of hypoglycaemic events increases during this
trial compared to the period before participation. However, we expect that the
incidence is as high (or even less high) in the intervention group as in the
control group. Indeed the alertfunction of the RT-CGMS could theoretically
prevent an hypoglycemic episode. The higher incidence is being expected because
of the goals set by guidelines for women with diabetes type 1 who want to get
pregnant: lowering HbA1c as far as possible but at least under 7.0% (53
mmol/mol).
A systematic review of 7 RCT studies using devices which are still on the
market (not published yet) describes that 6 of 7 studies did not show an
increase in hypoglycaemic events. One study did show an increase in severe
hypoglycaemia (however the authors doubt if there was a relation with using the
device. Two studies showed a decrease in HbA1c in absence of severe or
non-severe hypoglycemia in the RT-CGMS group. No study was powered enough to
demonstrate a decrease in hypoglycaemic events.