Efficacy and Mechanism Evaluation (Apr 2024)
Automated closed-loop insulin delivery for the management of type 1 diabetes during pregnancy: the AiDAPT RCT
Abstract
Background There are over 2000 pregnancies annually in women with type 1 diabetes in the UK. Despite recent improvements in diabetes technology, most women cannot achieve and maintain the recommended pregnancy glucose targets. Thus, one in two babies experience complications requiring neonatal care unit admission. Recent studies demonstrate that hybrid closed-loop therapy, in which algorithms adjust insulin delivery according to continuous glucose measurements, is effective for managing type 1 diabetes outside of pregnancy, but efficacy during pregnancy is unclear. Objective To examine the clinical efficacy of hybrid closed-loop compared to standard insulin therapy in pregnant women with type 1 diabetes. Design A multicentre, parallel-group, open-label, randomised, controlled trial in pregnant women with type 1 diabetes. Setting Nine antenatal diabetes clinics in England, Scotland and Northern Ireland. Participants Pregnant women with type 1 diabetes and above-target glucose levels, defined as glycated haemoglobin A1c of ≥ 48 mmol/mol (6.5%) in early pregnancy. Interventions A hybrid closed-loop system compared to standard insulin delivery (via insulin pump or multiple daily injections) with continuous glucose monitoring. Outcome measures The primary outcome is the difference between the intervention and control groups in percentage time spent in the pregnancy glucose target range (3.5–7.8 mmol/l) as measured by continuous glucose monitoring from 16 weeks’ gestation until delivery. Secondary outcomes include overnight time in range, time above range (> 7.8 mmol/l), glycated haemoglobin A1c, safety outcomes (diabetic ketoacidosis, severe hypoglycaemia, adverse device events), psychosocial functioning obstetric and neonatal outcomes. Results The percentage of time that maternal glucose levels were within target range was higher with closed-loop than standard insulin therapy: 68.2 ± 10.5 in closed-loop and 55.6 ± 12.5 in the control group (mean‑adjusted difference 10.5 percentage points, 95% confidence interval 7.0 to 14.0; p 10 mmol/l). The primary outcome was the percentage of time spent with CGM glucose levels between 3.5 and 7.8 mmol/l between 16 weeks’ gestation and delivery. Safety outcomes included the number and severity of diabetic ketoacidosis (DKA), severe hypoglycaemia (SH) and adverse device events. Patient-reported outcomes were reported at around 34–36 weeks’ gestation using the following validated questionnaires: Insulin Delivery Systems: Perspectives, Ideas, Reflections and Expectations (INSPIRE); EuroQol-5 Dimensions health-related quality-of-life questionnaire (EQ-5D), Diabetes Distress Scale (DDS), hypoglycaemia fear survey II (HFS – worry scale only) and Pittsburgh Sleep Quality Index (PSQI). Maternal and neonatal outcomes were documented at hospital discharge following delivery. Protocol amendments implemented during the COVID-19 pandemic allowed participants the option to continue using CGM with standard or closed-loop insulin delivery as per their initial randomisation for up to 6 months post partum. Outcomes for those who participated in the observational post-partum extension study will be reported separately. Details of the clinical study protocol are published. Primary outcome analysis was by intention-to-treat using a linear mixed-effects regression model adjusted for baseline CGM TIR, insulin delivery and clinical site. Missing primary end-point data were handled using multiple imputation (Rubins and direct likelihood methods) with all randomised participants included. For secondary outcomes, analyses were similar to the primary analysis, without imputation. False discovery rate (FDR)-adjusted p-values were calculated for selected secondary outcomes (overall, overnight, and by-trimester sensor glucose metrics, HbA1c, insulin doses, subgroup analyses, questionnaires) using Benjamini–Hochberg methods. For attainment of sensor glucose targets, a mixed-effects logistic regression model was fitted adjusting for baseline TIR, insulin delivery and clinical site as a random effect. All p-values are two-tailed. Analyses were performed using SAS® 9.4 (SAS Institute Inc., Cary, NC, USA; SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS Institute Inc. in the USA and other countries.® indicates USA registration). Results Participants Between September 2019 and May 2022, 334 participants were assessed for eligibility, with 126 enrolled and 124 randomised: 61 to the closed-loop intervention group and 63 to the standard care control group. Participants were from nine NHS maternity clinics and spanned a range of maternal age, body weight and glycaemic categories. Almost all (98%) were using CGM and approximately half were using insulin pump therapy at enrolment. Participants in the closed-loop group had more previous pregnancies, while those in the standard care group reported more previous DKA events. Two participants switched from their randomised allocation group: one intervention participant for whom lockdown restrictions prevented closed-loop training and one standard care participant who procured closed-loop (CamAPS FX) outside of the trial. Seven participants in each group discontinued their allocated treatment. Despite the impact of the COVID-19 pandemic, the proportion of completed study visits was high (approximately 95%). Participants in the standard care group had more additional clinic visits (1.5 vs. 1.1) and more unscheduled contacts (9.6 vs. 6.1), mostly for pregnancy and diabetes-related reasons. The frequency of sensor use was consistently high: median 97% across both treatment groups. The frequency of closed-loop use was high (median 96%) and remained > 95% throughout pregnancy. Primary efficacy end point The mean (± standard deviation) percentage of time that maternal glucose levels were within the pregnancy target range increased from 47.8 ± 16.4% to 68.2 ± 10.5% in the closed-loop group and from 44.5 ± 14.4% to 55.6 ± 12.5% in the control group [mean‑adjusted difference 10.5 percentage points, 95% confidence interval (CI) 7.0 to 14.0 percentage points; p 6.7 mmol/l) and more pronounced (> 10.0 mmol/l) categories, as well as lower mean glucose and lower HbA1c (mean difference −0.31%, 95% CI −0.50% to −0.12%; p 70% time (16 hours 48 minutes) within the pregnancy-specific range was achieved by 28 (47%) closed-loop and 7 (11%) standard care participants. Attainment of the sensor glucose target of 95%) throughout pregnancy, and without apparent safety problems, including among those new to insulin pump therapy. Indeed, participants who continued standard care had more clinic visits and more unscheduled contacts, suggesting that beyond initial training, closed-loop use did not require additional healthcare professional input. Recent trials have demonstrated the benefits of CamAPS FX to those with newly diagnosed type 1 diabetes and young children, and these results further extend the evidence for closed-loop therapy to pregnant women. During pregnancy, women in the closed-loop group increased the percentage of time with near-target glucose levels (3.5–10.0 mmol/l) from 71 to 87%. This is, to the best of our knowledge, the tightest glycaemic control yet achieved through use of closed-loop therapy. Alongside women’s motivation to minimise pregnancy complications, closed-loop use facilitated attainment of 70% time in pregnancy-specific target range throughout gestation. This suggests that tighter glycaemic control could also be feasible outside of pregnancy, when clinically warranted. Given the rapid increases in TIR observed within 1 week of therapy initiation in this trial, and within 1 day in a recent trial, we speculate that further benefits may be obtained from starting closed-loop before pregnancy, or as soon as possible, after pregnancy is confirmed. The current trial participants gained an additional 10% TIR above and beyond the 10% increment achieved by CGM and standard insulin therapy across pregnancy. Previous studies demonstrated that every 5% increased TIR is associated with improved obstetric and neonatal outcomes. Our trial was not powered for pregnancy outcomes, but we infer that this additional 10% time in the pregnancy target range would be expected to have additional health benefits for mothers and their babies. The strengths of our trial include its parallel-group, randomised controlled design, generalisability of our patient population, including those naive to insulin pump therapy and a large proportion who initiated therapy during the first trimester, and a flexible pragmatic trial protocol that facilitated virtual or in-person visits. There was no evidence of increased clinical contacts, frequently observed in investigational device trials. This trial had certain limitations. We did not undertake a health economic evaluation and the current sample size did not provide definitive data on maternal and neonatal health outcomes. Furthermore, our data are applicable only to the CamAPS FX closed-loop system and cannot be extrapolated to systems with higher glucose targets. Closed-loop therapy was effective in type 1 diabetes pregnancy, safely accommodating the marked gestational changes in insulin doses across a range of maternal body weight and glycaemic categories. It gave additional clinical advantage above and beyond that which can be achieved by CGM and standard insulin therapy, supporting NICE guideline recommendations that hybrid closed-loop therapy should be offered to all pregnant women with type 1 diabetes. Trial registration This trial is registered as ISRCTN56898625. Funding This award was funded by the National Institute of Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 16/35/01) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 7. See the NIHR Funding and Awards website for further award information. Dexcom supplied the continuous glucose monitoring systems used by AiDAPT intervention- and control-arm participants at reduced cost.
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