effect of basal-bolus closed-loop co-administration of insulin and pramlintide on improving the glycemic control in type 1 diabetes

Conditions: Diabetes Mellitus, Type 1

Summary: the closed-loop delivery system is composed of an insulin pump, a continuous glucose sensor and a dosing algorithm that calculates the insulin dose to infuse based on sensor readings. pramlintide is a drug and an analog of amylin, a hormone that is co-secreted with insulin in healthy individuals, and is deficient in people with type 1 diabetes. co-injection of pramlintide with insulin at meal times improves glucose control in type 1 diabetes. literature data suggests that regular insulin may better match the effect of pramlintide compared to rapid insulin in regulating post-prandial glucose levels. the purpose of this study is to compare the effectiveness of 3 strategies to control your day-and-night glucose levels: 1. rapid insulin-alone closed-loop delivery; 2. rapid insulin-plus-pramlintide closed-loop delivery; 3. regular insulin-plus-pramlintide closed-loop delivery. the primary hypotheses are: 1. during closed-loop control, the simultaneous basal-bolus infusion of pramlintide and fast-acting insulin improves glucose control compared to fast-acting insulin-alone infusion. 2. during closed-loop control, the simultaneous basal-bolus infusion of pramlintide and regular insulin improves glucose control compared to fast-acting insulin-alone infusion.

the closed-loop delivery system is composed of an insulin pump, a continuous glucose sensor and a dosing algorithm that calculates the insulin dose to infuse based on sensor readings. pramlintide is a drug and an analog of amylin, a hormone that is co-secreted with insulin in healthy individuals, and is deficient in people with type 1 diabetes. co-injection of pramlintide with insulin at meal times improves glucose control in type 1 diabetes. literature data suggests that the pharmacodynamics of regular insulin may better match the effect of pramlintide compared to the pharmacodynamics of fast-acting insulin. moreover, the cost of regular insulin is significantly lower than fast-acting insulin. therefore, if a similar (or better) glucose profile can be achieved with regular insulin-plus-pramlintide compared to fast-acting insulin-plus-pramlintide, then a co-formulation employing regular insulin should be prioritized. therefore, in this protocol, we aim to assess the effect of the simultaneous, closed-loop, basal-bolus infusion of pramlintide with insulin at a fixed ratio in controlling glucose levels. in the first experimental arm, we propose to infuse pramlintide with fast-acting insulin. in the second experimental arm, pramlintide will be infused with regular insulin. the control arm will be fast-acting insulin-alone closed-loop system. the aim of the study is to assess the efficacy of the simultaneous, closed-loop, basal-bolus infusion of pramlintide with fast-acting insulin at a fixed ratio and pramlintide with regular insulin at a fixed ratio in controlling glucose levels compared to fast-acting insulin-alone closed-loop infusion. the investigators aim to conduct a randomized, three-way, crossover trial to compare the efficacy of 1) fast-acting insulin-plus-pramlintide closed-loop delivery, 2) regular insulin-plus-pramlintide closed-loop delivery, and 3) fast-acting insulin-alone closed-loop delivery in regulating glucose levels over a period of 24 hours in a study on adults in inpatient settings. insulin (fast-acting and regular) and pramlintide are given with fixed ratio (6 µg of pramlintide for each unit of insulin). before each 24-hour intervention visit, the participant's insulin therapy (basal rates and insulin-to-carbohydrate ratios) will be optimized for a minimum of 10 days, with a target of 14 days. there will be a wash-out period of 0 to 42 days between the three intervention arms (termination of 24-hr intervention and start of next optimization period). the primary hypotheses are: 1. during closed-loop control, the simultaneous basal-bolus infusion of pramlintide and fast-acting insulin improves glucose control compared to fast-acting insulin-alone infusion. 2. during closed-loop control, the simultaneous basal-bolus infusion of pramlintide and regular insulin improves glucose control compared to fast-acting insulin-alone infusion.

Eligibility criteria:
inclusion criteria: * males and females ≥ 18 years of age. * clinical diagnosis of type 1 diabetes for at least 12 months. (the diagnosis of type 1 diabetes is based on the investigator's judgment; c peptide level and antibody determinations are not needed.) * the subject will have been on insulin pump therapy for at least 6 months. * hba1c ≤ 10%. exclusion criteria: * current or ≤ 1 month use of other antihyperglycemic agents (sglt2, glp-1, metformin, acarbose, etc....). * severe hypoglycemic episode within one month of screening. * severe diabetes keto-acidosis episode within one month of screening. * planned or ongoing pregnancy. * known or suspected allergy to the study drugs. * gastroparesis. * use of prokinetic drugs that stimulate gastric emptying (domperidone, cisapride, metoclopramide). * clinically significant nephropathy, neuropathy or retinopathy as judged by the investigator. * recent (\< 6 months) acute macrovascular event e.g. acute coronary syndrome or cardiac surgery. * current use of glucocorticoid medication. * other serious medical illness likely to interfere with study participation or with the ability to complete the trial by the judgment of the investigator. * failure to comply with team's recommendations (e.g. not willing to eat meals/snacks, not willing to change pump parameters, etc.).

Keywords: diabetes mellitus, type 1 pramlintide artificial pancreas closed-loop system insulin