Closed Loop and Education for Hypoglycemia Awareness Restoration

Individuals with IAH exhibit blunted symptomatic and CR hormonal responses to hypoglycemia and, as such, have an impaired ability to respond to hypoglycemia. Thus, rates of severe hypoglycemia are up to 6-fold greater in those affected. Intensive management of T1D is necessary in preventing long-term complications, but can be complicated by recurrent episodes of hypoglycemia which lead to and sustain the CRR deficits of IAH. Technologies such as continuous glucose monitoring (CGM) and hybrid closed-loop (HCL) systems can reduce severe hypoglycemia (and also may reduce IAH) but the ability of technology to reverse impaired CRR (as assessed with experimental hypoglycemia clamp) remains unclear. Behavioral and psycho-educational interventions targeting knowledge/skills gaps, as well as particular cognitions and behaviors driving recurrent hypoglycemia, can also reduce severe hypoglycemia and improve awareness. No studies have compared technology with such behavioral interventions in terms of assessing their impact on IAH or the CRR (as a primary outcome). Unanswered questions include the degree of reduction in hypoglycemia required to restore awareness. Furthermore, participants may respond to different interventions according to their characteristics. For example, it remains unclear whether older individuals benefit from such interventions since they usually are excluded from studies. Therefore, there is an urgent need to determine effective interventions that can reverse IAH in a large representative population of adults with T1D and IAH. The investigators propose to study the effect of specific interventions aimed at restoring

* the CRR (tested via an experimental hypoglycemia clamp procedure) * hypoglycemia awareness (self-reported via the Towler Questionnaire during the experimental hypoglycemia clamp procedure)

The study will use a Sequential Multiple Assignment Randomized Trial (SMART) design. At baseline, all participants who are HCL naïve will be randomized to HCL or Usual Care (UC) plus brief education (My HypoCOMPaSS) with a follow-up of two years. UC will consist of real-time continuous glucose monitoring (CGM) and insulin delivery via pump or multiple daily injections. Participants who fail to increase their CRR at 12 months will be randomized, or assigned, to a second intervention consisting of a small-group educational program focusing on motivations and unhelpful cognitions acting as barriers to hypoglycemia avoidance (HARPdoc). At baseline, all participants who are HCL non-naïve will be randomized to optimized HCL or HCL plus My HypoCOMPaSS; those with non-responsive CRR at 12 months will be randomized to either continue HCL (on the basis they need a longer period to reverse impaired CRR and total symptomatic responses) or to the HARPdoc intervention. Participants randomized to an HCL device are expected to wear the device continually, as well as a CGM. The My HypoCOMPaSS education requires 4-5 hours of training, whereas, the HARPdoc education requires four training sessions of seven hours each during weeks 1,2,3, and 6.

The specific aims and hypotheses are as follows:

Aim 1: To determine the effect on CRR (epinephrine increase ≥ 125 pg/ml over baseline) and total symptom responses (Towler Questionnaire increase ≥ 20% over baseline) during a hyperinsulinemic-hypoglycemic clamp procedure (glucose \< 50 mg/dl) after 12 months of HCL versus Usual Care plus My HypoCOMPaSS Educational Intervention among adults with T1D and IAH who have never used HCL therapy previously.

Hypothesis 1: At 12 months, those allocated to Usual Care plus My HypoCOMPaSS will be more likely to have improved CRR and total symptomatic responses than those allocated to HCL.

Aim 2: To determine the effect on CRR and total symptom responses at 12 months of HCL plus My HypoCOMPaSS versus HCL alone among adults with T1D and IAH who are currently using HCL therapy prior to entering the study.

Hypothesis 2: At 12 months, those allocated to HCL plus My HypoCOMPaSS will be more likely to have improved hypoglycemic awareness and improved CRR than those using HCL alone.

Aim 3: To determine the durability of effect over 24 months of the intervention that improves CRR at 12 months among adults with type 1 diabetes and IAH at baseline.

Hypothesis 3: At 24 months, CRR will improve further among those who had restored CRR at 12 months.

Aim 4. To determine the effect on hypoglycemic awareness (Towler Questionnaire increase ≥ 20% over baseline) and CRR (epinephrine increase ≥ 125 pg/ml over baseline) during a hyperinsulinemic hypoglycemic clamp procedure at 24 months of an in-depth educational program (HARPdoc), initiated throughout months 12-24, among adults with T1D and IAH at baseline, for whom the intervention allocated at baseline did not restore CRR at 12 months.

Hypothesis 4: At 24 months, those allocated to HARPdoc for months 12-24 months will be more likely to have improved hypoglycemic awareness and CRR than those who continue with the therapy allocated at baseline.

• geometric mean of plasma glucagon [Time frame: measured during the clamp studies at 0 (baseline), 12, and 24 months]
• geometric mean of plasma pancreatic polypeptide [Time frame: measured during the clamp studies at 0 (baseline), 12, and 24 months]
• geometric mean of plasma free fatty acids [Time frame: measured during the clamp studies at 0 (baseline), 12, and 24 months]
• glucose infusion rate [Time frame: measured during the clamp studies at 0 (baseline), 12, and 24 months]
• HbA1c [Time frame: measured during the clamp studies at 0 (baseline), 12, and 24 months]
• % of time with sensor hypoglycemia <70 mg/dL [Time frame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months]
• % of time with sensor hypoglycemia <54 mg/dL [Time frame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months]
• number of hypoglycemia events [Time frame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months]
• % time with sensor glucose in range [Time frame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months]
• sensor glucose coefficient of variation [Time frame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months]
• sensor use as the average numbers of days per week [Time frame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months]
• glycemia risk index [Time frame: measured during the four weeks prior to each clamp study at 0 (baseline), 12, and 24 months]