Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial

Background Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population. Methods We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1: 1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials. gov, number NCT01787903. Findings Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65.0% (95% CI 62.8-67.3) versus 55.4% (53.1-57.7; mean difference 9.6%, 95% CI 8 . 0-11.2; p < 0.0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose <= 3.9 mmol/L [6.8% vs 11.4%, mean difference 4.7%, 3.4-5.9; p < 0.0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28.2% vs 33.2%, mean difference 5.0%, 3.1-6.9; p< 0. 0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0.033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention. Interpretation CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population.