Safety and Feasibility of the PEPPER Adaptive Bolus Advisor and Safety System: A Randomized Control Study

Background: The Patient Empowerment through Predictive Personalized Decision Support (PEPPER) system provides personalized bolus advice for people with type 1 diabetes. The system incorporates an adaptive insulin recommender system (based on case-based reasoning, an artificial intelligence methodology), coupled with a safety system, which includes predictive glucose alerts and alarms, predictive low-glucose suspend, personalized carbohydrate recommendations, and dynamic bolus insulin constraint. We evaluated the safety and efficacy of the PEPPER system compared to a standard bolus calculator. Methods: This was an open-labeled multicenter randomized controlled crossover study. Following 4-week run-in, participants were randomized to PEPPER/Control or Control/PEPPER in a 1:1 ratio for 12 weeks. Participants then crossed over after a washout period. The primary end-point was percentage time in range (TIR, 3.9-10.0 mmol/L [70-180 mg/dL]). Secondary outcomes included glycemic variability, quality of life, and outcomes on the safety system and insulin recommender. Results: Fifty-four participants on multiple daily injections (MDI) or insulin pump completed the run-in period, making up the intention-to-treat analysis. Median (interquartile range) age was 41.5 (32.3-49.8) years, diabetes duration 21.0 (11.5-26.0) years, and HbA1c 61.0 (58.0-66.1) mmol/mol. No significant difference was observed for percentage TIR between the PEPPER and Control groups (62.5 [52.1-67.8] % vs. 58.4 [49.6-64.3] %, respectively, P = 0.27). For quality of life, participants reported higher perceived hypoglycemia with the PEPPER system despite no objective difference in time spent in hypoglycemia. Conclusions: The PEPPER system was safe, but did not change glycemic outcomes, compared to control. There is wide scope for integrating PEPPER into routine diabetes management for pump and MDI users. Further studies are required to confirm overall effectiveness. Clinical trial registration: ClinicalTrials.gov NCT03849755 The work outlined in this manuscript was developed with the support of the awarded distinction by the Generalitat de Catalunya 2017 SGR 1551, and the European Union’s Horizon 2020 research and innovation programme under grant agreement No 689810 (PEPPER)