Title: Evaluation of the biomedical and psychosocial impact of automated Closed-Loop (Artificial Pancreas) insulin delivery in women with type 1 diabetes during pregnancy
Funder: Medical Research Council

Abstract: Poorly controlled type 1 diabetes has severe consequences for the woman, her infant and the NHS. National surveys confirm that most pregnant women with type 1 diabetes cannot achieve tight enough glucose control for healthy babies without themselves risking dangerously low glucose levels. _x000D_ _x000D_ HIGHER GLUCOSE levels contribute to larger babies with ONE in TWO babies born overweight or obese and ONE in THREE delivered prematurely. FOUR in TEN are admitted to neonatal intensive care units, each costing the NHS £3000-£5000. Too much insulin causes LOW GLUCOSE levels in the mother, which if dangerously low, can lead to coma, seizure and hospital admission. _x000D_ _x000D_ Currently, STANDARD insulin delivery is by injections using a pen (every 12-24 hours) & before meals or by a patient-directed insulin pump which delivers pre-programmed basal insulin (typically at 4-6 hourly intervals) & before meals. Manual correction doses are given when glucose levels are above target, but these take 3-4 hours to restore target glucose levels. Thus women using STANDARD patient-directed pumps or pens spend only 12 HOURS per day with glucose levels in target, with 10 HOURS too HIGH and 2 HOURS too LOW. Only 15% mothers achieve good overall glucose control and 10% are admitted to hospital with dangerously low glucose levels. _x000D_ _x000D_ Our study will use a novel ARTIFICIAL PANCREAS or Closed-Loop In Pregnancy (CLIP) system. CLIP includes 3 devices, a Continuous Glucose Monitor (CGM), which measures glucose, an insulin PUMP which delivers insulin and a mobile PHONE which contains a set of instructions specific for pregnancy to calculate & AUTOMATICALLY adjust insulin dose every 12 MINUTES. CLIP helps pregnant women to spend more time (16-18 HOURS) within target glucose levels with minimal time too low (<20 minutes). _x000D_ _x000D_ The CLIP system is EXPENSIVE but may be more EFFECTIVE & SAFER than standard insulin pumps or pens. There are strong economic and clinical arguments for TEMPORARILY using expensive technology for six months during type 1 diabetes PREGNANCY. CLIP has the potential to substantially improve glucose control and mother/infant health outcomes, but has not yet been tested in clinical NHS settings._x000D_ _x000D_ We will perform a high quality randomised trial to establish for women, clinicians and NHS commissioners whether there is an added benefit of CLIP over standard insulin delivery systems in pregnancy. The trial will include 124 women (62 for CLIP, 62 for pens or pumps) from 10 NHS sites. We expect each site to include 12-13 women over 24 months (6-7 per year) and have 3 stand-by sites if needed._x000D_ _x000D_ Women will be aiming to spend as much time as possible within the target glucose range of 3.9-7.8mmol/l (time-in-target). Training will be provided to ensure that CLIP is used appropriately in women from diverse social backgrounds, including in women without pump experience._x000D_ _x000D_ The major outcome is the percentage of time mothers' spend with target glucose levels (time-in-target), measured in day-to-day living at 34 weeks of pregnancy. Also important are high and low glucose episodes, the number of clinic visits and mother/infant health outcomes. Detailed questionnaires and interviews will help us understand pregnant women’s and NHS staff's experiences to ensure that if effective, future CLIP implementation is woman-centred._x000D_ _x000D_ The trial will be conducted in NHS maternity units (England, Scotland, Northern Ireland) in clinical settings to provide relevant results across the UK.

Lay abstract: Aim: To compare the biomedical and psychosocial effectiveness outcomes of STANDARD patient-directed and AUTOMATED Closed-Loop insulin delivery in pregnant women with type 1 diabetes._x000D_ _x000D_ Design: Open label two-arm multicentre randomised controlled trial (RCT)._x000D_ _x000D_ Target Population: n=124 pregnant women with type 1 diabetes (T1D), age 18-45 years, 7-14 weeks gestation, standard patient-directed insulin delivery (pen or pump), HbA1c 48-86 mmol/mol. _x000D_ _x000D_ Setting: 10 NHS antenatal diabetes clinics. Each will recruit 6-7 women per year (12-13 over 2 yrs) based on CONCEPTT recruitment._x000D_ _x000D_ Treatments being assessed: Two forms of insulin delivery each aiming to optimise the time spent within the NICE recommended target glucose range (3.5-7.8mmol/L)._x000D_ _x000D_ Intervention: An automated closed-loop insulin delivery (AiD) system comprising a Continuous Glucose Monitor (CGM), an insulin PUMP, and a mobile PHONE hosting the computer-based model predictive control (MPC) algorithm. _x000D_ Control: A standard insulin delivery system which is either insulin pump (Continuous Subcutaneous Insulin Infusion - CSII) or multiple daily injections (MDI) without closed-loop_x000D_ _x000D_ Planned outcome measures: Maternal CGM measures from trial entry to delivery. Maternal assessments at baseline, 24 & 34 weeks gestation & hospital discharge. Neonatal assessment at delivery & hospital discharge. _x000D_ _x000D_ PRIMARY OUTCOME: The time spent with glucose levels between 3.5-7.8 mmol/L based on CGM measures (Time In Range TIR 3.5-7.8mmol/L) from 16 weeks gestation until delivery._x000D_ _x000D_ SECONDARY OUTCOMES: _x000D_ Maternal Glycaemic Outcomes _x000D_ 1. 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)._x000D_ 2. 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 minutes_x000D_ 3. International consensus targets for glycaemic assessment; TIR 3.5-7.8mmol/L >70% (16hr 48 min), TAR >7.8mmol/L <25% (6hr), TBR <3.5mmol/L <4% (1hr), and TBR <3.0mmol/L <1% (15min) _x000D_ 4. Low Blood Glucose Index (LBGI) and High Blood Glucose Index (HBGI) measures_x000D_ 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). _x000D_ 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)._x000D_ 7. CGM glucose levels during the 24 hours (midnight to midnight) and overnight time 23.00-07.00hr_x000D_ _x000D_ Maternal Obstetric Outcomes_x000D_ 1. Gestational weight gain (weight gain from booking visit to 36 weeks)_x000D_ 2. Maternal hypertensive disorders (Gestational, worsening of pre-existing hypertension or preeclampsia) _x000D_ 3. Fetal growth (ultrasound estimated fetal weight, head and abdominal circumference measurements) _x000D_ 4. Mode of delivery (vaginal, instrumental, elective caesarean section and emergency caesarean section)_x000D_ 5. Gestational age at delivery and indication for any preterm delivery (<37 weeks)_x000D_ 6. Adverse events including pregnancy loss <24 weeks, stillbirth, neonatal death_x000D_ 7. Maternal hospital admissions (all admissions including the delivery admission)_x000D_ 8. Hospital length of stay (all admissions including the delivery admission)_x000D_ _x000D_ Infant Outcomes_x000D_ 1. Neonatal morbidity including treatment for neonatal hypoglycaemia, neonatal jaundice and respiratory distress between the time of infant delivery and discharge from hospital._x000D_ 2. Infant birth weight (customised birth weight percentile, incidence of large for gestational age (LGA), and small for gestational age (SGA)_x000D_ 3. Neonatal intensive care unit (NICU) admission >24 hours_x000D_ 4. Infant feeding at hospital discharge, 8-12 weeks postpartum, and 24 weeks postpartum (breast, bottle, both)_x000D_ 5. Hospital length of stay (from delivery until hospital discharge), including re-admissions >24h within the first seven days from birth_x000D_ _x000D_ Safety Outcomes_x000D_ 1. Frequency and severity of diabetic ketoacidosis _x000D_ 2. Number and severity of episodes of severe hypoglycaemia _x000D_ 3. Number and severity of episodes of adverse device effect_x000D_ _x000D_ Psychosocial Outcomes_x000D_ The following questionnaires will be completed at Baseline and 34-36 weeks: Insulin Delivery Systems: Perspectives, Ideas, Reflections and Expectations (INSPIRE), EQ-5D Health-Related Quality of Life Questionnaire; Diabetes Distress Scale (DDS), Hypoglycaemia Fear Survey Questionnaire II (HFSQ II) (Worry scale only), Pittsburgh Sleep Quality Index (PSQI)_x000D_ _x000D_ Qualitative interviews will be conducted with a smaller sample of trial participants who provide additional consent for a qualitative interview:_x000D_ 1. 25 women randomized to the AiD arm will be interviewed post randomization and again at 34-36 weeks_x000D_ 2. Up to 25 staff from the trial sites will be interviewed_x000D_ _x000D_ Health economic outcomes_x000D_ 1. Cost of the AiD closed-loop system _x000D_ 2. Cost of the control-arm glucose monitoring and insulin delivery_x000D_ 3. Training costs for AiD and control arms_x000D_ 4. Maternity health care use for AiD and control arms, including NHS antenatal clinic visits, between visit contacts, antenatal hospital admissions, length of hospital stay_x000D_ 5. Neonatal health care use for AiD and control arms, including costs of delivery vaginally or by caesarean section, costs associated with any complication of delivery, and neonatal complications, neonatal intensive care unit admissions, total neonatal length of hospital stay._x000D_ 6. The EQ-5D Health-Related Quality of Life Questionnaire_x000D_ _x000D_ Analyses: Intention to treat (ITT), with secondary per protocol analyses. Primary endpoint is the comparison between the two treatment arms based on a linear mixed effects model. Randomisation is stratified for centre and insulin delivery (pen or pump). _x000D_ _x000D_ Sample size information: It is accepted that a difference of 10% in CGM time-in-target (2.4hrs/day) is clinically worthwhile. To detect a clinically relevant difference of 10% with a SD of 15% at 90% power and 5% two sided significance requires a sample size of 98 or 124 total to allow for up to 10% drop outs and 10% pregnancy loss before 34 weeks gestation. _x000D_ _x000D_ Team expertise: diabetes, device trials, engineering, qualitative methodology, obstetrics, psychology, service users, statistics._x000D_ _x000D_ Timetable: set-up 0-6/12, all sites activated 12/12, recruitment ends 36/12, final mother/infant data 44/12, analyses/reports 48/12.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH