Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.
Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.
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DOI：
10.1016/s0140-6736(18)31947-0
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发表时间：
2018-10-13
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通讯作者：
APCam11 Consortium
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作者：
Tauschmann M;Thabit H;Bally L;Allen JM;Hartnell S;Wilinska ME;Ruan Y;Sibayan J;Kollman C;Cheng P;Beck RW;Acerini CL;Evans ML;Dunger DB;Elleri D;Campbell F;Bergenstal RM;Criego A;Shah VN;Leelarathna L;Hovorka R;APCam11 Consortium
对于1型糖尿病患者来说，血糖控制的实现仍然具有挑战性。我们评估了昼夜混合型闭环胰岛素输送与传感器增强泵治疗在6岁及以上控制欠佳的1型糖尿病患者中的有效性。在这项开放标签、多中心、多国、单期、平行随机对照试验中，参与者从英国四家医院和美国两家中心的糖尿病门诊诊所招募。我们随机分配接受胰岛素泵治疗且血糖控制欠佳（糖化血红蛋白[HbA1c] 7.5 - 10%）的6岁及以上1型糖尿病患者，在12周的自由生活中接受混合型闭环治疗或传感器增强泵治疗。在为期4周的磨合期内，对研究胰岛素泵和连续血糖监测进行了培训。使用中央随机化软件随机分配符合条件的受试者。两个研究组的分配采用非盲法，根据低（< 8.5%）或高（≥8.5%）的HbA1c在中心内进行随机分层。主要终点是随机化后12周葡萄糖浓度在3.9 - 10.0 mmol/L目标范围内的时间比例。对所有随机患者的主要结局和安全措施进行了分析。该试验已在ClinicalTrials.gov注册，编号NCT02523131，并已结束累积。从2016年5月12日至2017年11月17日，筛选114例患者，并随机分配86例符合条件的患者接受混合闭环治疗（n=46）或传感器增强泵治疗（n=40；对照组）。闭环组葡萄糖浓度在目标范围内的时间比例（65%,SD 8）明显高于对照组（54%,SD 9；平均变化差10.8个百分点，95% CI 8.2 ~ 13.5; p< 0.0001）。在闭环组中，HbA1c在4周的磨合后从筛查值8.3% （SD 0.6）降至筛查值8.0% (SD 0.6)，在12周的干预期后降至筛查值7.4% （SD 0.6）。对照组筛查时HbA1c值为8.2% (SD 0.5)，磨合后为7.8% (SD 0.6)，干预后为7.7% (SD 0.5)；与对照组相比，闭环组HbA1c百分比的降低明显更大（变化的平均差异为0.36%，95% CI为0.19至0.53;p< 0.0001）。葡萄糖浓度低于3.9 mmol/L（平均变化差值为- 0.83个百分点，- 1.40至- 0.16,p= 0.0013）和高于10.0 mmol/L（平均变化差值为- 10.3个百分点，- 13.2至- 7.5,p< 0.0001）时，闭环组花费的时间比对照组短。传感器测量的葡萄糖的变异系数在干预之间没有差异（变化的平均差异为- 0.4%，95% CI为- 1.4%至0.7%;p= 0.50）。同样，每日总胰岛素剂量没有差异（变化的平均差异为0.031 U/kg /天，95% CI为- 0.005至0.067,p= 0.09），体重也没有差异（变化的平均差异为0.68 kg， 95% CI为- 0.34至1.69,p= 0.19）。未发生严重低血糖。闭环组因输液器失效发生1例糖尿病酮症酸中毒。每个研究组有2名受试者出现了明显的高血糖，闭环组有13例其他不良事件，对照组有3例。混合型闭环胰岛素输送改善了血糖控制，同时降低了控制欠佳的1型糖尿病患者的低血糖风险。JDRF， NIHR和Wellcome Trust。
The achievement of glycaemic control remains challenging for patients with type 1 diabetes. We assessed the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older. In this open-label, multicentre, multinational, single-period, parallel randomised controlled trial, participants were recruited from diabetes outpatient clinics at four hospitals in the UK and two centres in the USA. We randomly assigned participants with type 1 diabetes aged 6 years and older treated with insulin pump and with suboptimal glycaemic control (glycated haemoglobin [HbA1c] 7·5–10·0%) to receive either hybrid closed-loop therapy or sensor-augmented pump therapy over 12 weeks of free living. Training on study insulin pump and continuous glucose monitoring took place over a 4-week run-in period. Eligible subjects were randomly assigned using central randomisation software. Allocation to the two study groups was unblinded, and randomisation was stratified within centre by low (<8·5%) or high (≥8·5%) HbA1c. The primary endpoint was the proportion of time that glucose concentration was within the target range of 3·9–10·0 mmol/L at 12 weeks post randomisation. Analyses of primary outcome and safety measures were done in all randomised patients. The trial is registered with ClinicalTrials.gov, number NCT02523131, and is closed to accrual. From May 12, 2016, to Nov 17, 2017, 114 individuals were screened, and 86 eligible patients were randomly assigned to receive hybrid closed-loop therapy (n=46) or sensor-augmented pump therapy (n=40; control group). The proportion of time that glucose concentration was within the target range was significantly higher in the closed-loop group (65%, SD 8) compared with the control group (54%, SD 9; mean difference in change 10·8 percentage points, 95% CI 8·2 to 13·5; p<0·0001). In the closed-loop group, HbA1c was reduced from a screening value of 8·3% (SD 0·6) to 8·0% (SD 0·6) after the 4-week run-in, and to 7·4% (SD 0·6) after the 12-week intervention period. In the control group, the HbA1c values were 8·2% (SD 0·5) at screening, 7·8% (SD 0·6) after run-in, and 7·7% (SD 0·5) after intervention; reductions in HbA1c percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0·36%, 95% CI 0·19 to 0·53; p<0·0001). The time spent with glucose concentrations below 3·9 mmol/L (mean difference in change −0·83 percentage points, −1·40 to −0·16; p=0·0013) and above 10·0 mmol/L (mean difference in change −10·3 percentage points, −13·2 to −7·5; p<0·0001) was shorter in the closed-loop group than the control group. The coefficient of variation of sensor-measured glucose was not different between interventions (mean difference in change −0·4%, 95% CI −1·4% to 0·7%; p=0·50). Similarly, total daily insulin dose was not different (mean difference in change 0·031 U/kg per day, 95% CI −0·005 to 0·067; p=0·09) and bodyweight did not differ (mean difference in change 0·68 kg, 95% CI −0·34 to 1·69; p=0·19). No severe hypoglycaemia occurred. One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure. Two participants in each study group had significant hyperglycaemia, and there were 13 other adverse events in the closed-loop group and three in the control group. Hybrid closed-loop insulin delivery improves glucose control while reducing the risk of hypoglycaemia across a wide age range in patients with suboptimally controlled type 1 diabetes. JDRF, NIHR, and Wellcome Trust.