Title: Evaluation of the biomedical and psychosocial impact of Automated insulin Delivery Among Pregnant women with Type 1 diabetes
Funder: Department of Health and Social Care

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. Design: Open label two-arm multicentre randomised controlled trial (RCT). Target Population: n=124 pregnant women with type 1 diabetes (T1D), age 18-45 years, 8-14 weeks gestation, standard patient-directed insulin delivery (pen or pump), HbA1c 48-86 mmol/mol. Setting: 10 NHS antenatal diabetes clinics. Each will recruit 6-7 women per year (12-13 over 2 yrs) based on CONCEPTT recruitment. Treatments being assessed: Two forms of insulin delivery each aiming to optimise the time spent within the NICE recommended target glucose range (3.9-7.8mmol/L). Intervention: AUTOMATED Closed-Loop In Pregnancy (CLIP) system. The CLIP system includes a Continuous Glucose Monitor (CGM), an insulin PUMP and a mobile PHONE. Control: Standard PATIENT-DIRECTED insulin delivery (pen or pump). Planned outcome measures: Maternal assessments at baseline, 24 & 34 weeks gestation & hospital discharge. Neonatal assessment at delivery & hospital discharge. Consent will be taken for potential metabolic and National Pregnancy in Diabetes (NPID) linkage studies. PRIMARY OUTCOME: Maternal glucose control assessed by CGM time in target (3.9-7.8mmol/L) at 34 weeks gestation. SECONDARY OUTCOMES: Maternal biomedical: 1. Glucose control assessed by CGM (mean glucose, % time above & below NICE target, frequency & duration of glucose excursions, glucose variability measures) at 24 & 34 weeks gestation 2. Maternal HbA1c level & proportion of women with HbA1c < 48mmol/mol at 24 & 34 weeks gestation 3. Severe hypoglycaemia (third party assistance, seizure, coma) 4. Diabetic ketoacidosis 5. Device deficiency (device or user error) 6. Face-to-face contacts, antenatal admissions & hospital length of stay Obstetric & Neonatal: 1. Cord blood C-peptide 2. Gestational age at birth, % preterm <37 weeks 3. Infant birth weight, % Large, % Small for Gestational Age (LGA, SGA) 4. Neonatal morbidity (hypoglycaemia, jaundice, respiratory distress) 5. Neonatal Intensive Care Unit (NICU) admission 6. Adverse events (pregnancy loss, stillbirth, neonatal death) 7. Hospital length of stay Psychosocial: Mixed methods process evaluation with longitudinal, in-depth interviews with women & trial staff across sites. Questionnaires to assess treatment satisfaction (IDSRQ), anxiety (HADS), diabetes distress (DDS), fear of hypoglycaemia (HFS II) & psychosocial aspects of technology (INSPIRE). 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). 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. Team expertise: diabetes, device trials, engineering, qualitative methodology, obstetrics, psychology, service users, statistics. 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.

Lay 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. 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. 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. 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). 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. 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. 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. 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. The trial will be conducted in NHS maternity units (England, Scotland, Northern Ireland) in clinical settings to provide relevant results across the UK.

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