Automated insulin Delivery Amongst Pregnant women with Type 1 diabetes

Current primary outcome measure as of 16/02/2022:

Percentage of time spent with glucose levels between 3.5-7.8 mmol/L based on CGM levels between 16 weeks gestation and delivery. Data for the intervention group will be collected as part of the data collection from the AiD closed-loop system. Data for the control group will be collected using software provided by the CGM manufacturer.
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Previous primary outcome measure:
The percentage of time spent with glucose levels between 3.9-7.8 mmol/L based on CGM levels at 24 and 34 weeks gestation. Data for the intervention group will be collected as part of the data collection from the AiD closed-loop system. The control group and those who have withdrawn from the intervention group will have a subcutaneous glucose sensor inserted by the clinical research team and will be instructed to wear it at home for 7-10 days. They will be asked to calibrate the CGM according to manufacturer instructions and to return for CGM sensor downloading within 14 days; Timepoint(s): End of the study

Current secondary outcome measures as of 16/02/2022:

The following will be measured using CGM measures:
1. The time spent with CGM glucose levels above and below target range (TAR>7.8mmol/L, TBR<3.5mmol/L), mean CGM glucose and CGM glucose variability measures (CV, SD)
2. The frequency and severity of hypoglycaemia episodes defined as CGM glucose levels TBR <3.5 mmol/L (level 1 hypoglycaemia) and TBR <3.0 mmol/L (level 2 hypoglycaemia) for at least 15 min. Distinct episodes must be separated for at least 30 min.
3. The international consensus targets for glycaemic assessment; TIR 3.5-7.8 mmol/L >70% (16hr 48 min), TAR >7.8mmol/L <25% (6 h), TBR <3.5 mmol/L <4% (1 h), and TBR <3.0 mmol/L <1% (15 min)
4. The Low Blood Glucose Index (LBGI) and High Blood Glucose Index (HBGI) measures
5. Where possible, blood samples will be collected at baseline, 24-26 weeks, 34-36 weeks for HbA1c testing to assess the change in the maternal level. Samples will be stored for further metabolic studies (optional).
6. CGM glucose levels during the first (<12 weeks 6 days gestation), second (13-27 weeks 6 days gestation) and third trimesters (28 weeks until delivery)
7. CGM glucose levels during the 24 h (midnight to midnight) and overnight time 23.00-07.00

Maternal obstetric outcomes (from hospital records):
1. Gestational weight gain (weight gain from booking visit to 36 weeks)
2. Maternal hypertensive disorders (gestational, worsening of pre-existing hypertension or preeclampsia)
3. Fetal growth (ultrasound estimated fetal weight, head and abdominal circumference measurements)
4. The mode of delivery (vaginal, instrumental, elective caesarean section and emergency caesarean section)
5. The gestational age at delivery and indication for any preterm delivery (<37 weeks)
6. Adverse events including pregnancy loss <24 weeks, stillbirth, neonatal death
7. Maternal hospital admissions (all admissions including the delivery admission)
8. Hospital length of stay (all admissions including the delivery admission)

Infant outcomes (from hospital records):
1. Neonatal morbidity including treatment for neonatal hypoglycaemia, neonatal jaundice and respiratory distress between the time of infant delivery and discharge from hospital
2. Infant birth weight (customised birth weight percentile, incidence of large for gestational age (LGA), and small for gestational age (SGA)
3. Neonatal intensive care unit (NICU) admission >24 h
4. Infant feeding at hospital discharge, 8-12 weeks postpartum, and 24 weeks postpartum (breast, bottle, both)
5. Hospital length of stay (from delivery until hospital discharge), including re-admissions >24 h within the first 7 days from birth

The following safety measures will be recorded on occurrence during the trial (from hospital records):
1. The frequency and severity of diabetic ketoacidosis during the period of inclusion in the trial
2. The number and severity of episodes of severe hypoglycaemia during the period of inclusion in the trial
3. The number and severity of episodes of adverse device effect

Psychosocial outcomes:
1. Questionnaires completed at baseline and 34-36 weeks
2. Qualitative interviews: 25 women randomized to the AiD arm will be interviewed post-randomization and again at 34-36 weeks; up to 25 staff from the trial sites will be interviewed
3. Postpartum: self-reported diabetes and treatment-related experience as described through descriptive writing using free text

Health economic outcomes
1. Cost of the closed-loop (study pump, CGM, and CamAPSCamAPS® FX) and control-arm (CGM and insulin delivery) glucose monitoring and insulin delivery systems including device training costs for intervention and control arm participants
2. Maternity health care use including NHS antenatal clinic visits, and between visit contacts which will be grouped as questions around
2.1. Diabetes management
2.2. Technical device issues
2.3.. Both diabetes and device issues
3. Antenatal hospital admissions (number and total length of hospital stay) including the delivery admission length of hospital stay
4. Neonatal health care use including costs of delivery, costs associated with any complications of delivery, and neonatal complications
5. Neonatal intensive care unit admissions (level of care and duration of admission) and total neonatal length of hospital stay
6. The EQ-5D Health-Related Quality of Life Questionnaire. The cost-effectiveness of the closed loop system will be estimated using the study primary outcome measure of time spent with glucose levels between 3.5-7.8 mmol/L. This cost-effectiveness study will estimate any additional cost per additional week of target glucose control. Additionally, collection of the EQ-5D will enable estimation of quality adjusted life years (QALYs) for a cost-utility analysis.

Key postpartum outcome analysis:
The key analysis will evaluate the change in the time spent in the target glucose range (CGM TIR 3.9 – 10.0 mmol/l) between the intervention and control arm between delivery and 6 months postpartum.

Post-partum exploratory outcomes:
1. Percentage time spent with CGM <3.0 mmol/l to quantify maternal moderate hypoglycaemia
2. Mean CGM glucose
3. Percentage time spent with CGM <3.9 mmol/l to quantify borderline hypoglycaemia
4. Percentage time spent at CGM >10.0 mmol/l to quantify hyperglycaemia
5. Standard deviation (SD) of CGM glucose to quantify the glucose variability
6. Coefficient of variation (CV), of CGM glucose to quantify the glucose variability
7. Insulin delivered (basal, bolus, and total) to assess insulin needs
8. Mild-moderate episodes of hypoglycaemia <3.9 (level 1) and <3.0 (level 2) from CGM data
defined as AUC <3.9 or AUC ≤3.0 for 15 minutes duration
9. Nocturnal hypoglycaemia (NH): CGM glucose <3.9 (level 1) and <3.0 (level 2) between 23:00 and 07:00

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Previous secondary outcome measures:
The following will be measured at 24 weeks and 34 weeks gestation:
1. Time spent with glucose levels between 3.9-7.8 mmol/L
2. Time spent with glucose levels above and below target range
3. Frequency and severity of hypoglycaemia episodes
4. Low and High Blood Glucose Index
5. Change in HbA1c level

The following will be measured following delivery;
1. Gestational weight gain
2. Gestational hypertension or preeclampsia
3. Mode of delivery
4. Gestational age at delivery and indication for any preterm delivery
5. Adverse events
6. Maternal hospital admissions
7. Hospital length of stay (both maternal and neonatal)
8. Neonatal morbidity
9. Infant birth weight
10. Neonatal intensive care unit (NICU) admission >24 hours
11. Infant feeding at hospital discharge (breast, bottle, both)

The following safety measures will be recorded on occurrence during the trial:
1. Frequency and severity of diabetic ketoacidosis
2. Number and severity of episodes of severe hypoglycaemia
3. Number and severity of episodes of adverse device effect