Utilizing an RCT Approach to Compare the Efficacy and Sustainability of Technological and Psycho-Educational Interventions to Improve Impaired Awareness of Hypoglycemia in Type 1 Diabetes.

摘要 对低血糖(IAH)的认识受损仍然是1型糖尿病(T1D)的一个主要问题，影响约30% 在所有患有T1D的成年人中，他们都是严重低血糖的高危人群。包括混合闭环在内的干预措施 (HCL)和教育已经发展起来，它们减少了低血糖的时间，希望IAH将 颠倒了。所有这些都显示出了好处，但许多人没有做出回应。我们的目标是找出最 根据具体的临床特点进行有效的治疗。 我们将进行两个多中心、双臂、平行分组的随机对照试验(RCT) 超过12个月，磨合2-4周(持续随访24个月)。我们的试验干预是， 血糖意识训练(BGAT)，恢复长期低血糖意识 坚持1型糖尿病“低血糖”和低血糖意识恢复计划 成人1型糖尿病和有问题的低血糖，尽管优化了自我护理‘HARPdoc’。 我们将评估这些干预措施对恢复受损的交感-肾上腺反应的影响。 实验性低血糖和临床低血糖意识在T1D的恢复。试验1是一项随机对照试验 那些患有IAH的患者，HCL天真，在两个治疗组(HCL与BGAT)。6个月后，BGAT小组将 两组均给予盐酸，分别于术后12~24个月进行随访。试验2是IAH持续存在的随机对照试验 尽管使用了至少6个月的盐酸，并随机服用了6个月的HypoCOMPaSS或BGAT。在6点 几个月后，那些恢复知觉的人将在两个手臂上再继续生活6个月，然后在 12-24个月。持续6个月的IAH的参与者将进入一项探索性研究并接受 HARPdoc为期6个月，评估时间为12个月和24个月。试验1和试验2总共将招募至少1000人 10个中心的参与者，年龄在18岁到85岁之间，为期一年的IAH，包括10%-15%的 老年人(70岁和/或患有心血管疾病)，将随机接受所有干预 不包括葡萄糖钳夹，并将通过问卷评估IAH。 两项研究的主要结果是在夹闭葡萄糖为45 mg/dL时的肾上腺素反应。 随机化后6个月的两个试验中的ARM。次级结果(基线、6个月、12个月和24个月) 包括额外反调节激素反应、连续血糖监测(CGM)指标、C- 肽、糖化血红蛋白、患者报告的预后指标(PROMS)，包括IAH评分、严重低血糖和 安全数据。所有参与者将通过问卷测量CGM指标、IAH，并报告低血糖， 超过2年的PROMS和其他数据，以衡量“真实世界”的可持续性，但不会重复降血糖 24个月时夹闭，除非IAH的其他指标被证明不能可靠地反映受损的肾上腺素 12个月后回复。总体而言，这些研究将使未来在制定具体干预措施方面的研究成为可能 治疗IAH，并导致更有效的治疗途径。

Abstract Impaired awareness of hypoglycemia (IAH) remains a major issue in type 1 diabetes (T1D) affecting ~30% of all adults with T1D who are at high risk of severe hypoglycemia. Interventions including hybrid closed-loop (HCL) and education have been developed, which reduce time in hypoglycemia in the hope that IAH will be reversed. All have shown benefit, but many individuals do not respond. Our objective is to identify the most effective treatments according to specific clinical characteristics. We will run two multi-center, unblinded, two-arm, parallel-group randomized controlled trials (RCTs) over 12 months with a 2-4 week run-in (with continued follow-up for 24 months). Our trial interventions are, HCL, blood glucose awareness training (BGAT), Recovery of Hypoglycemia Awareness in Long- Standing Type 1 Diabetes ‘HypoCOMPaSS’ and Hypoglycemia Awareness Restoration Program for adults with type 1 diabetes and problematic hypoglycemia despite optimized self-care ‘HARPdoc’. We will assess the impact of these interventions on restoration of impaired sympatho-adrenal responses to experimental hypoglycemia and restoration of clinical hypoglycemia awareness in T1D. Trial 1 is an RCT in those with IAH, HCL naïve, in two treatment arms (HCL vs. BGAT). At 6 months, the BGAT group will be provided with HCL, both groups then followed-up at 12 & 24 months. Trial 2 is an RCT in IAH persisting despite using HCL for at least 6 months with randomization to HypoCOMPaSS or BGAT for 6 months. At 6 months, those with restored awareness will continue in both arms for a further 6 months and then assessed at 12 & 24 months. Participants with persistent IAH at 6 months will enter an exploratory study and receive HARPdoc for 6 months with assessments at 12 & 24 months. Trials 1 and 2 will recruit in total at least 1000 participants across 10 centers, aged 18 to 85 years old, T1D >1 year duration with IAH, including 10-15% of older adults (³70 years and/or with cardiovascular disease) who will be randomized to all interventions excluding glucose clamps and will be assessed for IAH by questionnaires. The primary outcome is epinephrine response at a clamped glucose of 45 mg/dL comparing the two study arms in both trials at 6 months post-randomization. Secondary outcomes (at baseline, 6, 12 and 24 months) include additional counter-regulatory hormone responses, continuous glucose monitoring (CGM) metrics, C- peptide, HbA1c, patient reported outcome measures (PROMs) including IAH scales, severe hypoglycemia and safety data. All participants will measure CGM metrics, IAH by questionnaire, and report hypoglycemia, PROMs and other data over 2 years to measure ‘real world’ sustainability but will not repeat hypoglycemic clamps at 24 months unless other measures of IAH prove unreliable in reflecting impaired epinephrine responses at 12 months. Overall, these studies will enable future research in developing specific interventions for IAH and lead to more effective therapeutic pathways.