Closed-loop in adults with T2D requiring dialysis (AP-Renal)
Research type
Research Study
Full title
An open-label, multi-centre, multi-national, randomised, 2-period crossover study to assess the efficacy, safety and utility of fully closed-loop insulin delivery in comparison with standard care, in adults with type 2 diabetes requiring maintenance dialysis.
IRAS ID
261016
Contact name
Roman Hovorka
Contact email
Sponsor organisation
Cambridge University Hospitals NHS Foundation Trust jointly with University of Cambridge
Clinicaltrials.gov Identifier
NCT0402575
Duration of Study in the UK
1 years, 8 months, 30 days
Research summary
The main objective of this study is to determine the efficacy, safety and utility of fully automated closed-loop glucose control in the home setting over a 20 day period in adults with type 2 diabetes (T2D) requiring maintenance dialysis. This study builds on previous and on-going studies of closed-loop systems that have been performed in Cambridge in adults with type 1 diabetes in the home setting, and in adults with type 2 diabetes in the inpatient setting.
Lay Summary of Results:
Phase 1: In this open-label, multinational, two-center, randomized crossover trial, 26 adults with type 2 diabetes requiring dialysis (17 men, 9 women, average age 68 years, average diabetes duration of 20 years) underwent two 20-day periods of unrestricted living, comparing the Cambridge fully closed-loop system using faster insulin aspart (‘closed-loop’) with standard insulin therapy and a masked continuous glucose monitor (‘control’) in random order. The primary endpoint was time in target glucose range (5.6–10.0 mmol/L).
The proportion of time in target glucose range (5.6–10.0 mmol/L; primary endpoint) was 52.8 ± 12.5% with closed-loop versus 37.7 ± 20.5% with control; mean difference, 15.1 percentage points (95% CI 8.0–22.2; P < 0.001). Mean glucose was lower with closed-loop than control (10.1 ± 1.3 versus 11.6 ± 2.8 mmol/L; P = 0.003). Time in hypoglycemia
Institute of Metabolic Science
(<3.9 mmol/L) was reduced with closed-loop versus control (median (IQR) 0.1 (0.0–0.4%) versus 0.2 (0.0–0.9%); P = 0.040). No severe hypoglycemia events occurred during the control period, whereas one severe hypoglycemic event occurred during the closed-loop period, but not during closed-loop operation.
Fully closed-loop improved glucose control and reduced hypoglycemia compared with standard insulin therapy in adult outpatients with type 2 diabetes requiring dialysis.
Phase 2:
In this open-label, single-center, randomized crossover study, 26 adults with type 2 diabetes (7 women and 19 men; mean age 59 years; baseline glycated hemoglobin (HbA1c), 75 ± 15 mmol mol-/L (9.0% ± 1.4%)) underwent two 8-week periods to compare the CamAPS HX fully closed-loop app with standard insulin therapy and a masked glucose sensor (control) in random order, with a 2-week to 4-week washout between periods. The primary endpoint was proportion of time in target glucose range (3.9-10.0 mmol/L). Analysis was by intention to treat.
Thirty participants were recruited between 16 December 2020 and 24 November 2021, of whom 28 were randomized to two groups (14 to closed-loop therapy first and 14 to control therapy first). Proportion of time in target glucose range (mean ± s.d.) was 66.3% ± 14.9% with closed-loop therapy versus 32.3% ± 24.7% with control therapy (mean difference, 35.3 percentage points; 95% confidence interval (CI), 28.0-42.6 percentage points; P < 0.001). Time > 10.0 mmol/L was 33.2% ± 14.8% with closed-loop therapy versus 67.0% ± 25.2% with control therapy (mean difference, -35.2 percentage points; 95% CI, -42.8 to -27.5 percentage points; P < 0.001). Mean glucose was lower during the closed-loop therapy period than during the control therapy period (9.2 ± 1.2 mmol/L versus 12.6 ± 3.0 mmol/L, respectively; mean difference, -3.6 mmol/L; 95% CI, -4.6 to -2.5 mmol/L; P < 0.001). HbA1c was lower following closed-loop therapy (57 ± 9 mmol/mol (7.3% ± 0.8%)) than following control therapy (72 ± 13 mmol/mol (8.7% ± 1.2%); mean difference, -15 mmol/mol; 95% CI, -11 to -20 mmol/L (mean difference, -1.4%; 95% CI, -1.0 to -1.8%); P < 0.001). Time < 3.9 mmol/L was similar between treatments (a median of 0.44% (interquartile range, 0.19-0.81%) during the closed-loop therapy period versus a median of 0.08% (interquartile range, 0.00-1.05%) during the control therapy period; P = 0.43). No severe hypoglycemia events occurred in either period. One treatment-related serious adverse event occurred during the closed-loop therapy period.
Fully closed-loop insulin delivery improved glucose control without increasing hypoglycemia compared with standard insulin therapy and may represent a safe and efficacious method to improve outcomes in adults with type 2 diabetes.
Dissemination:
Phase 1 was published in the high impact peer-reviewed journal Nature Medicine (Boughton CK, Tripyla A, Hartnell S, et al. Fully automated closed-loop glucose control compared with standard insulin therapy in adults with type 2 diabetes requiring dialysis: an open-label, randomized crossover trial. Nat Med. 2021 Aug;27(8):1471-1476.) and the data has been included in presentations at numerous National and International Diabetes Conferences.
Phase 2 was published in the high impact peer-reviewed journal Nature Medicine (Daly AB, Boughton CK, Nwokolo M, et al. Fully automated closed-loop insulin delivery in adults with type 2 diabetes: an open-label, single-center, randomized crossover trial. Nat Med. 2023 Jan;29(1):203-208.) and presented at the European Association for the Study of Diabetes Conference in addition to the data being included in presentations at numerous National and International Diabetes Conferences.These studies also received widespread media attention with news stories reaching over 500 million individuals globally.
This is an open-label, two-centre, randomised, cross-over study, involving two home study periods during which glucose levels will be controlled either by a fully automated closed-loop system or by participants’ usual therapy in random order. Each treatment arm is 20 days long with a 2-4 week washout period between treatments. A total of up to 20 adults with T2D requiring maintenance dialysis will be recruited through the dialysis unit, to allow for 16 completed participants available for assessment.
Participants will receive appropriate training by the research team on the safe use of the study devices (insulin pump and continuous glucose monitoring (CGM) and closed-loop insulin delivery system. Participants in the control arm will continue with standard therapy and will wear a blinded CGM system.
The primary outcome is time spent with glucose levels in the target range between 5.6 and 10.0 mmol/L as recorded by CGM. Secondary outcomes are the time spent with glucose levels above and below target, as recorded by CGM, and other CGM-based metrics in addition to insulin requirements. Safety evaluation comprises the tabulation of severe hypoglycaemic episodes.
REC name
London - Stanmore Research Ethics Committee
REC reference
19/LO/0728
Date of REC Opinion
19 Jun 2019
REC opinion
Further Information Favourable Opinion