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. - 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.