Diluted Insulin in Young Children: Bigger Volumes for Smaller Patients

The aim of this study is to compare the pharmacokinetic (PK) profile of diluted insulin aspart (U25) with undiluted insulin aspart (U100) in school-aged children and adolescents with type 1 diabetes (T1D) utilizing the euglycemic clamp technique and a standardized meal in a controlled research environment.

The investigators hypothesize that dilution of insulin aspart (U25) will alter the PK properties as compared to undiluted aspart.

Study Overview

• Status: Completed
• Conditions: Type1diabetes
• Intervention / Treatment: Drug: Aspart insulin

Detailed Description

Study Design: participants age 9-15 y/o will be enrolled in a randomized cross-over trial, in which each participant will undergo two 24-hour admissions. Each admission will include a meal-study on the evening of admission followed by a euglycemic clamp study performed the following morning. During one of the admissions, participants will use undiluted insulin aspart (U100) while on the other the participants will receive diluted insulin aspart (U25).

(Figure 1)

Participants. 12 participants will be recruited between the ages of 9-15 years, who have had diabetes for at least 6 months' duration, on continuous subcutaneous insulin therapy for at least 1 month and have an HbA1c ≤ 10%. Those with a history of diabetes ketoacidosis (DKA) or severe hypoglycemia in the month prior to enrollment and those with other conditions/medications affecting insulin sensitivity (e.g. metformin) will be excluded from the study.

Study drugs: Diluted insulin U25 will be formulated by adding diluent, which will be obtained from Novo Nordisk, with insulin aspart. The diluted insulin will be formulated by the investigational pharmacy.

Study procedures:

1. Enrollment Visit: The study will be explained to potential participants who meet eligibility criteria and informed consent will be obtained. Demographic data will be recorded and history and physical exam will be performed. HbA1c, hematocrit and urine pregnancy tests in female participants who could become pregnant will be measured to confirm eligibility. Participants will be randomized for the first admission to either diluted insulin studies followed by a second admission for undiluted insulin studies or vice versa.

2. 1st Inpatient Standard Meal Study and Euglycemic Clamp Study: Participants will be admitted to the research unit in the afternoon on the day before the clamp procedure. The participants will be asked to change their infusion set and use the insulin provided for the study procedures- either the diluted or standard concentration insulin, based on randomization at enrollment. On the admission with diluted insulin, pump settings will be adjusted to account for the dilution (increased by a factor of 4 for basal rates, correction factors, and carbohydrate ratios). An intravenous catheter will be inserted into antecubital vein for blood sampling. Once the IV is placed, Yellow Springs Instrument (YSI) glucose values and insulin levels will be obtained at least every half hour.

   At dinner (~6p.m.), participants will receive a meal prepared in the metabolic kitchen to allow for accurate determination of carbohydrate, fat and protein content. Participants will be asked to estimate the carbohydrate content of the meal prepared by the metabolic kitchen. The participant will bolus just prior to the start of the meal based on the carbohydrates estimated and the pre-meal glucose levels.

   Glucose will be measured by YSI and aspart levels will be measured using the Mercodia iso-insulin enzyme-linked immunosorbent assay. Samples will be taken before the meal and every 10 minutes after the start of the meal for the first hour, every 15 minutes for the second hour, and then every 30 minutes for up to 4 hours after the bolus; namely, at 0, 10, 20, 30, 40, 50, 60, 75, 90, 105, 120, 150, 180, 210, and 240 minutes.

   Participants will then have YSI glucose levels obtained at least every hour overnight with titration of insulin doses as needed to achieve targeted control (goal 80-140mg/dL) by 8a.m. A second IV line will be placed for glucose infusion. Once IV access is established and glucose is in the target range, the euglycemic clamp study will be initiated.

   Prior to the start of the clamp, -15 and 0 minute samples will be obtained for baseline plasma glucose and insulin levels.

   At time zero, a bolus of 0.1 U/kg will be administered via the pump. After administration of the bolus, the insulin pump will be disconnected. Plasma aspart insulin will be measured every 10 minutes for the first 120 minutes and then every 15 minutes for up to 240 minutes using the Mercodia iso-insulin enzyme-linked immunosorbent assay. Plasma glucose will be measured at least every 5 minutes for the duration of the clamp study, which will allow for titration of the glucose infusion rate to maintain euglycemia (target 90 +/- 10mg/dL).

   Following completion of the clamp, the participant will be offered a meal and discharged home with standard concentration insulin and their usual pump settings.

3. 2nd Inpatient Standard Meal Study and Euglycemic Clamp Study: Participants will return for a second admission after a minimum of 7 days since the first study.

The participant will receive whichever concentration of insulin not received during their first admission (ie. If first admission is diluted, then second admission will be standard concentration and vice versa).

The remainder of the study procedures are as indicated above. Following completion of the second clamp study, participants will have completed all study related procedures.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Lori Carria, MS; Phone Number: 203-737-3595; Email: lori.carria@yale.edu
• Study Contact Backup: Name: Jennifer Sherr, MD; Phone Number: 203-785-2483; Email: jennifer.sherr@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 9 years to 15 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• T1D of at least 6 months' duration
• Aged 9-15 years
• Continuous subcutaneous insulin therapy for at least 1 month;
• HbA1c ≤ 10%
• Normal hematocrit
• Able to give consent

Exclusion Criteria:

• Admission for DKA during the past 4 weeks
• Severe hypoglycemia during the past 4 weeks
• Other conditions/medications affecting insulin sensitivity (e.g. metformin)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Aspart-U100 Insulin; Standard Concentration Rapid Acting Insulin	Drug: Aspart insulin; Standard insulin; Other Names: Standard Concentration insulin
Experimental: Aspart-U25 Insulin; Diluted Concentration of Rapid Acting Insulin	Drug: Aspart insulin; Standard insulin; Other Names: Standard Concentration insulin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
maximum insulin concentration	maximum insulin concentration	240 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to peak insulin concentration	Time to peak insulin concentration	240 minutes
Mean Glucose Infusion Rate (GIR)	Mean Glucose Infusion Rate	240 minutes
GIR Max	Glucose Infusion Rate Maximum	240 minutes
Time to GIR Max	Time to Glucose Infusion Rate Maximum	240 minutes

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Juvenile Diabetes Research Foundation
• Investigators: Principal Investigator: Jennifer Sherr, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Actual): June 30, 2023
• Study Completion (Actual): June 30, 2023

Study Registration Dates

• First Submitted: September 7, 2018
• First Submitted That Met QC Criteria: September 7, 2018
• First Posted (Actual): September 11, 2018

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin Aspart
• Other Study ID Numbers: 2000023577; 5-ECR-2014-112-A-N (Other Grant/Funding Number: Juvenile Diabetes Research Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No