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 低血糖意识受损（IAH）仍然是1型糖尿病（T1D）的一个主要问题，影响约30% 所有T1D成人患者中严重低血糖的高风险人群。包括混合闭环在内的干预措施 (HCL)和教育，这减少了低血糖的时间，希望IAH将是 颠倒了所有这些都显示出益处，但许多人没有反应。我们的目标是找出 根据具体的临床特征进行有效的治疗。 我们将进行两项多中心、非盲、双臂、平行组随机对照试验（RCT） 12个月以上，导入期为2 - 4周（持续随访24个月）。我们的试验干预是， HCL，血糖意识训练（BGAT），长期低血糖意识恢复， 站立1型糖尿病"HypoCOMPaSS"和Hypoprotein意识恢复计划， 1型糖尿病和有问题的低血糖成人，尽管优化自我护理'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， 实验性低血糖和恢复临床低血糖意识的T1D。试验1是一项RCT， 两个治疗组（HCL vs. BGAT）中未接受过HCL治疗的IAH患者。6个月时，BGAT组将 两组均给予HCL治疗，并于12~24个月进行随访。试验2是一项治疗IAH持续性 尽管使用HCL至少6个月，随机分配至HypoCOMPaSS或BGAT 6个月。6点 6个月后，恢复意识的患者将继续接受两组治疗6个月，然后在 12和24个月。6个月时持续IAH的参与者将进入探索性研究并接受 HARPdoc 6个月，12和24个月时进行评估。试验1和2将总共招募至少1000人 10个中心的受试者，年龄18 - 85岁，T1D> 1年IAH持续时间，包括10 - 15%的 将随机接受所有干预措施的老年人（≥ 70岁和/或患有心血管疾病） 不包括葡萄糖钳夹，并将通过问卷调查评估IAH。 主要结果是在45 mg/dL的葡萄糖钳夹下肾上腺素反应，比较两项研究 随机化后6个月时，两项试验中的两组。次要结局（基线、6、12和24个月） 包括额外反调节激素反应、连续葡萄糖监测（CGM）指标、C- 肽、HbA1c、患者报告结局指标（PROM），包括IAH量表、重度低血糖和 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， PROM和其他数据超过2年，以衡量"真实的世界"的可持续性，但不会重复低血糖 24个月时钳夹，除非IAH的其他测量结果证明在反映肾上腺素受损方面不可靠 12个月的回答总的来说，这些研究将使未来的研究在发展具体的干预措施 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.