Clinical trial NCT02814123: Effect of Basal-Bolus Closed-Loop Co-Administration of Insulin and Pramlintide on Improving the Glycemic Control in Type 1 Diabetes
Official title: A Randomized, Three-way, Crossover Study to Assess the Efficacy of Fast-acting Insulin-plus-pramlintide Closed-loop Co-administration, Regular Insulin-plus-pramlintide Closed-loop Co-administration, and Fast-acting Insulin-alone Closed-loop Infusion in Regulating Glucose Levels Over a 24-hour Period in Adults With Type 1 Diabetes in Inpatient Settings.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: Diabetes Mellitus, Type 1
Pramlintide
Artificial Pancreas
Closed-Loop System
Insulin
Lead sponsor: McGill University
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
First posted: 2016-06-27
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.).

Primary outcomes:
measure: Percentage of time of plasma glucose levels spent in target range. Target range is defined to be between 3.9 and 10.0 mmol/L of fast-acting insulin-plus-pramlintide closed-loop delivery vs. fast-acting insulin-alone closed-loop delivery.
timeFrame: Up to 24 hours
measure: Percentage of time of plasma glucose levels spent in target range. Target range is defined to be between 3.9 and 10.0 mmol/L of regular insulin-plus-pramlintide closed-loop delivery vs. fast-acting insulin-alone closed-loop delivery.
timeFrame: Up to 24 hours
Secondary outcomes:
measure: Percentage of time of plasma glucose levels spent in target range, comparing fast-acting insulin-plus-pramlintide closed-loop delivery vs. regular insulin-plus-pramlintide closed-loop delivery.
timeFrame: Up to 24 hours
measure: Percentage of time (8:00-8:00) of plasma glucose levels spent: a. 3.9-7.8 mmol/L; b. 3.9-10 mmol/L; c. <3.9 mmol/L; d. <3.3 mmol/L; e. <2.8 mmol/L; f. >7.8 mmol/L; g. >10 mmol/L; h. >13.9 mmol/L; i. >16.7 mmol/L
timeFrame: Up to 24 hours
measure: Percentage of overnight time (23:00-8:00) of plasma glucose levels: a. 3.9-7.8 mmol/L; b. 3.9-10 mmol/L; c. <3.9 mmol/L; d. <3.3 mmol/L; e. <2.8 mmol/L; f. >7.8 mmol/L; g. >10 mmol/L; h. >13.9 mmol/L; i. >16.7 mmol/L
timeFrame: Up to 24 hours
measure: Standard deviation of glucose levels as a measure of glucose variability.
timeFrame: Up to 24 hours
measure: Total insulin delivery.
timeFrame: Up to 24 hours
measure: Total pramlintide delivery.
timeFrame: Up to 24 hours
measure: Mean plasma glucose level during: a. the overall study period; b. overnight period.
timeFrame: Up to 24 hours
measure: Mean plasma insulin concentration.
timeFrame: Up to 24 hours
measure: Mean plasma glucagon concentration.
timeFrame: Up to 24 hours
measure: Mean plasma amylin concentration.
timeFrame: Up to 24 hours
measure: Number of subjects experiencing hypoglycemia requiring oral treatment during: a. the overall study period; b. the night.
timeFrame: Up to 24 hours
measure: Gastrointestinal symptoms during the treatment optimization (i.e., the minimum 10 days prior to the 24-hour closed-loop visits) and during the 24-hour closed-loop visits.
timeFrame: Up to 24 hours
Other outcomes:
Locations:
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
Study officials:
affiliation: McGill University
name: Ahmad Haidar
role: PRINCIPAL_INVESTIGATOR
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Laurent Legault
role: PRINCIPAL_INVESTIGATOR
References:
citation: Haidar A, Tsoukas MA, Bernier-Twardy S, Yale JF, Rutkowski J, Bossy A, Pytka E, El Fathi A, Strauss N, Legault L. A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial. Diabetes Care. 2020 Mar;43(3):597-606. doi: 10.2337/dc19-1922. Epub 2020 Jan 23.
citation: Tsoukas M, Rutkowski J, El-Fathi A, Yale JF, Bernier-Twardy S, Bossy A, Pytka E, Legault L, Haidar A. Accuracy of FreeStyle Libre in Adults with Type 1 Diabetes: The Effect of Sensor Age. Diabetes Technol Ther. 2020 Mar;22(3):203-207. doi: 10.1089/dia.2019.0262. Epub 2020 Jan 23.