A comparison of two hybrid closed-loop systems in adolescents and young adults with type 1 diabetes (FLAIR): a multicentre, randomised, crossover trial

Richard M Bergenstal, Revital Nimri, Roy W Beck, Amy Criego, Lori Laffel, Desmond Schatz, Tadej Battelino, Thomas Danne, Stuart A Weinzimer, Judy Sibayan, Mary L Johnson, Ryan J Bailey, Peter Calhoun, Anders Carlson, Elvira Isganaitis, Rachel Bello, Anastasia Albanese-O'Neill, Klemen Dovc, Torben Biester, Kate Weyman, Korey Hood, Moshe Phillip, FLAIR Study Group, Richard M Bergenstal, Revital Nimri, Roy W Beck, Amy Criego, Lori Laffel, Desmond Schatz, Tadej Battelino, Thomas Danne, Stuart A Weinzimer, Judy Sibayan, Mary L Johnson, Ryan J Bailey, Peter Calhoun, Anders Carlson, Elvira Isganaitis, Rachel Bello, Anastasia Albanese-O'Neill, Klemen Dovc, Torben Biester, Kate Weyman, Korey Hood, Moshe Phillip, FLAIR Study Group

Abstract

Background: Management of type 1 diabetes is challenging. We compared outcomes using a commercially available hybrid closed-loop system versus a new investigational system with features potentially useful for adolescents and young adults with type 1 diabetes.

Methods: In this multinational, randomised, crossover trial (Fuzzy Logic Automated Insulin Regulation [FLAIR]), individuals aged 14-29 years old, with a clinical diagnosis of type 1 diabetes with a duration of at least 1 year, using either an insulin pump or multiple daily insulin injections, and glycated haemoglobin (HbA1c) levels of 7·0-11·0% (53-97 mmol/mol) were recruited from seven academic-based endocrinology practices, four in the USA, and one each in Germany, Israel, and Slovenia. After a run-in period to teach participants how to use the study pump and continuous glucose monitor, participants were randomly assigned (1:1) using a computer-generated sequence, with a permuted block design (block sizes of two and four), stratified by baseline HbA1c and use of a personal MiniMed 670G system (Medtronic) at enrolment, to either use of a MiniMed 670G hybrid closed-loop system (670G) or the investigational advanced hybrid closed-loop system (Medtronic) for the first 12-week period, and then participants were crossed over with no washout period, to the other group for use for another 12 weeks. Masking was not possible due to the nature of the systems used. The coprimary outcomes, measured with continuous glucose monitoring, were proportion of time that glucose levels were above 180 mg/dL (>10·0 mmol/L) during 0600 h to 2359 h (ie, daytime), tested for superiority, and proportion of time that glucose levels were below 54 mg/dL (<3·0 mmol/L) calculated over a full 24-h period, tested for non-inferiority (non-inferiority margin 2%). Analysis was by intention to treat. Safety was assessed in all participants randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT03040414, and is now complete.

Findings: Between June 3 and Aug 22, 2019, 113 individuals were enrolled into the trial. Mean age was 19 years (SD 4) and 70 (62%) of 113 participants were female. Mean proportion of time with daytime glucose levels above 180 mg/dL (>10·0 mmol/L) was 42% (SD 13) at baseline, 37% (9) during use of the 670G system, and 34% (9) during use of the advanced hybrid closed-loop system (mean difference [advanced hybrid closed-loop system minus 670G system] -3·00% [95% CI -3·97 to -2·04]; p<0·0001). Mean 24-h proportion of time with glucose levels below 54 mg/dL (<3·0 mmol/L) was 0·46% (SD 0·42) at baseline, 0·50% (0·35) during use of the 670G system, and 0·46% (0·33) during use of the advanced hybrid closed-loop system (mean difference [advanced hybrid closed-loop system minus 670G system] -0·06% [95% CI -0·11 to -0·02]; p<0·0001 for non-inferiority). One severe hypoglycaemic event occurred in the advanced hybrid closed-loop system group, determined to be unrelated to study treatment, and none occurred in the 670G group.

Interpretation: Hyperglycaemia was reduced without increasing hypoglycaemia in adolescents and young adults with type 1 diabetes using the investigational advanced hybrid closed-loop system compared with the commercially available MiniMed 670G system. Testing an advanced hybrid closed-loop system in populations that are underserved due to socioeconomic factors and testing during pregnancy and in individuals with impaired awareness of hypoglycaemia would advance the effective use of this technology FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Cumulative Distribution of Time in…
Figure 1.. Cumulative Distribution of Time in Range 70–180 mg/dL (3·9–10·0 mmol/L)
Figure 1 shows the cumulative distribution of the percentage of time that the glucose level was within the range of 70 to 180 mg per dL (3·9 to 10·0 mmol per liter), as measured by continuous glucose monitoring, for baseline and during each treatment arm.
Figure 2.. Time in Range 70–180 mg/dL…
Figure 2.. Time in Range 70–180 mg/dL (3·9–10·0 mmol/L) By Hour Over 24 Hours
Figure 2 shows an envelope plot of the percentage of time that the glucose level was within the range of 70 to 180 mg per dL (3·9 to 10·0 mmol per liter), as measured by continuous glucose monitoring, according to the time of day. Symbols denote the hourly median values, and the shaded regions are defined by the 25th and 75th percentiles.
Figure 3.. Average Insulin Delivery By Hour…
Figure 3.. Average Insulin Delivery By Hour Over 24 Hours
Figure 3 shows a stacked bar chart with bars representing the average insulin delivered during each hour of the day. The blue regions show the units of automated basal insulin delivered, the red regions show user-initiated bolus delivered, and the green regions show auto-correction bolus delivered.

References

    1. Martin CT, Criego AB, Carlson AL, Bergenstal RM. Advanced Technology in the Management of Diabetes: Which Comes First-Continuous Glucose Monitor or Insulin Pump? Curr Diab Rep 2019; 19(8): 50.
    1. Beck RW, Bergenstal RM, Laffel LM, Pickup JC. Advances in technology for management of type 1 diabetes. Lancet 2019; 394(10205): 1265–73.
    1. Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a Hybrid Closed-Loop Insulin Delivery System in Patients With Type 1 Diabetes. JAMA 2016; 316(13): 1407–8.
    1. Brown SA, Kovatchev BP, Raghinaru D, et al. Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N Engl J Med 2019; 381(18): 1707–17.
    1. Breton MD, Kanapka LG, Beck RW, et al. A Randomized Trial of Closed-Loop Control in Children with Type 1 Diabetes. N Engl J Med 2020; 383: 836–45.
    1. Garg SK, Weinzimer SA, Tamborlane WV, et al. Glucose Outcomes with the In-Home Use of a Hybrid Closed-Loop Insulin Delivery System in Adolescents and Adults with Type 1 Diabetes. Diabetes Technol Ther 2017; 19(3): 155–63.
    1. Isganaitis E, Raghinaru D, Ambler-Osborn L, et al. Closed-loop control (CLC) in teens and young adults improves glycemic control: Results from the International Diabetes Closed-Loop (iDCL) Trial. J Diabetes Sci Technol 2020; 14(2): A53.
    1. Atlas E, Nimri R, Miller S, Grunberg EA, Phillip M. MD-logic artificial pancreas system: a pilot study in adults with type 1 diabetes. Diabetes care 2010; 33(5): 1072–6.
    1. Nimri R, Muller I, Atlas E, et al. MD-Logic overnight control for 6 weeks of home use in patients with type 1 diabetes: randomized crossover trial. Diabetes care 2014; 37(11): 3025–32.
    1. Phillip M, Battelino T, Atlas E, et al. Nocturnal glucose control with an artificial pancreas at a diabetes camp. N Engl J Med 2013; 368(9): 824–33.
    1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329(14): 977–86.
    1. Battelino T, Danne T, Bergenstal RM, et al. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes care 2019; 42(8): 1593–603.
    1. Polonsky WH, Fisher L, Hessler D, Edelman SV. Development of a New Measure for Assessing Glucose Monitoring Device-Related Treatment Satisfaction and Quality of Life. Diabetes Technol Ther 2015; 17(9): 657–63.
    1. Benjamini Y, Hochberg Y. On the adaptive control of the false discovery rate in multiple testing with indepentdent statistics. Journal of Educational and Behavioral Statistics 2000; 25(1): 60–83.
    1. Akturk HK, Giordano D, Champakanath A, Brackett S, Garg S, Snell-Bergeon J. Long-term real-life glycaemic outcomes with a hybrid closed-loop system compared with sensor-augmented pump therapy in patients with type 1 diabetes. Diabetes Obes Metab 2020; 22(4): 583–9.
    1. Berget C, Messer LH, Vigers T, et al. Six months of hybrid closed loop in the real-world: An evaluation of children and young adults using the 670G system. Pediatr Diabetes 2020; 21(2): 310–8.
    1. Duffus SH, Ta’ani ZA, Slaughter JC, Niswender KD, Gregory JM. Increased proportion of time in hybrid closed-loop “Auto Mode” is associated with improved glycaemic control for adolescent and young patients with adult type 1 diabetes using the MiniMed 670G insulin pump. Diabetes Obes Metab 2019.
    1. Lal RA, Basina M, Maahs DM, Hood K, Buckingham B, Wilson DM. One Year Clinical Experience of the First Commercial Hybrid Closed-Loop System. Diabetes care 2019; 42(12): 2190–6.
    1. Messer LH, Berget C, Vigers T, et al. Real world hybrid closed-loop discontinuation: Predictors and perceptions of youth discontinuing the 670G system in the first 6 months. Pediatr Diabetes 2020; 21(2): 319–27.
    1. Beck RW, Bergenstal RM, Riddlesworth TD, et al. Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials. Diabetes care 2019; 42(3): 400–5.
    1. Carlson A, Bode BW, Brazg RL, et al. Safety and glycemic outcomes of the MiniMed Advanced Hybrid Closed-Loop (AHCL) system in subjects with T1D. Diabetes 2020; 69(Suppl 1): 97-LB.
    1. Collyns O, Meier R, Betts Z, et al. Improved glycemic outcomes with Medtronic Minimed Advanced Hybrid Closed-Loop delivery: Results from a randomized crossover trial comparing automated insulin delivery with predictive low glucose suspend in people with type 1 diabetes. Diabetes 2020; 69(Suppl 1): 199-OR.
    1. Tauschmann M, Thabit H, Bally L, et al. Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial. Lancet 2018; 392(10155): 1321–9.

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