Clinical trial NCT00105352: Improving Metabolic Assessments in Type 1 Diabetes Mellitus Clinical Trials
Official title: Improving Metabolic Assessments in Type 1 Diabetes Mellitus Clinical Trials
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Keywords: Type 1 Diabetes Study Group
TrialNet
type 1 diabetes
juvenile onset diabetes
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Juvenile Diabetes Research Foundation
name: National Center for Research Resources (NCRR)
First posted: 2005-03-14
Enrollment: 120
Sex: ALL
Minimum age (years): 8
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: DIAGNOSTIC

Brief summary: OBJECTIVE:

This study is being conducted by the Type 1 Diabetes TrialNet Study Group, funded by the National Institutes of Health, in collaboration with the European C-Peptide Group. The goal is to evaluate comparability and reproducibility of measures of beta cell function in type 1 diabetes comparing the mixed meal tolerance tests (MMTT) and glucagon stimulation test (GST). These two tests will be compared to assess the relationship between the MMTT and IV (intravenous) Glucagon stimulated C-peptide responses as measured by time to peak C-peptide and AUC (area under the curve) values.

Based on the understanding that type 1 diabetes results from an immune mediated loss of pancreatic beta cells, therapeutic trials and newer measures of beta cell function can be evaluated as endpoints for clinical trials. Direct assessment of residual beta cell function is an appropriate endpoint, as retention of beta cell function in patients with T1D is known to result in improved glycemic control and reduced hypoglycemia, retinopathy and nephropathy. Endogenous beta cell function or insulin secretion is best measured by determination of C-peptide (which is co-secreted with insulin in a 1:1 molar ratio). Intervention studies over the past few decades have usually used measurement of C-peptide. However, the relationship between these or other measures of beta cell function has not been well studied. The relative advantages of one measure over another in terms of variability, sensitivity and burden to the subject is unknown. In addition, the optimal conditions for the conduct of the test need to be determined.

An important goal is to develop an international consensus about the conduct of metabolic tests in the context of large, multicenter trials involving type 1 diabetes (T1D) by balancing the scientific data with the burden on the subject.

Detailed description: Overview:

The study is a multi-center, two-arm, randomized clinical trial. Each participant will undergo four tests within a limited period according to the test sequence assignment. The tests will randomly start with either MMTT or GST.

Specific Aims

* To compare the reliability of the MMTT and Glucagon stimulated C-peptide responses as measured by time to peak C-peptide on MMTT, and the peak and AUC values on both tests.
* To determine the relationship between MMTT and Glucagon stimulated C-peptide responses as measured by time to peak C-peptide on MMTT and peak and AUC values on both tests.
* To determine the impact of basal glucose, peak glucose, age of participant, time from diagnosis, and basal C-peptide with respect to the reliability of measures and relationship between MMTT and Glucagon results.
* Describe the palatability of, patient compliance with, and adverse effects of each test (MMTT vs. GST) and to compare the participant and investigator burden to conduct the MMTT and Glucagon tests.

TEST INFORMATION:

* Mixed Meal Tolerance Test (MMTT):

BOOST is a liquid meal (like a milkshake) containing a standard amount of fat, protein, and carbohydrate. BOOST raises blood sugar and causes the pancreas to produce insulin. After drinking BOOST, about one-half teaspoon of blood will be drawn through an IV line in the arm after 15, 30, 60, 90, and 120 minutes. (Using an IV line avoids multiple needle sticks). The test takes about 2 hours.

* Glucagon Stimulation Test (GST):

Glucagon is a hormone that circulates in the blood and stimulates insulin secretion. Glucagon will be injected into the bloodstream through an IV line, and about one-half teaspoon of blood will be drawn five times during ten minutes. The test takes about 30 minutes.

OTHER TEST INFORMATION:

* Participants will have tests on four different days over a six week period. Participants will have either a) two MMTTs and then two GSTs OR b) two GSTs and then two MMTTs. Each test will be done 3-10 days apart.
* Participants will follow a special high carbohydrate diet (150 grams) for at least three days prior to each study visit. Dietary information will be provided.
* Participants will fast overnight (at least 8 hours) and arrive at the clinic between 7 AM - 10 AM.
* It is essential that participants have a blood glucose level of 70-200 mg/dl in the morning before starting the test. If blood glucose is too high or too low the morning of the test, the test will be re-scheduled on another day.
* Tests will be re-scheduled if, on the morning of the test, your blood sugar or ketones are not within acceptable ranges. Testing could take up to eight visits if tests need to be re-scheduled.
* Participants will learn whether their pancreas is still secreting insulin and, if so, how much insulin is being secreted. This information may help their diabetes health care team design for them a better insulin regimen and diabetes management program to improve their longterm blood sugar control.
* This study will help researchers learn which test (MMTT or GST) is best to use in other research studies looking at treatments that may stop or delay type 1 diabetes.

Eligibility criteria: * Informed consent obtained from participants (over 12 years of age) and parents (for participants below 18 years of age). Assent is obtained from younger children.
* Age 8 - 35 years at the time of inclusion
* Body weight \> 30 kg
* Type 1 diabetes defined by: ADA (American Diabetes Association) criteria or judgment of physician
* Duration of diabetes: 1 month to 3\* years (\*The TrialNet Coordinating Center will monitor fasting C-peptide levels as they are reported to ensure that a wide range of values is included. This review may result in widening the duration of diabetes window to allow for subjects with low C-peptide).
* Must maintain good glycemic control
* Be willing to travel to a TrialNet Clinical Center for a minimum of four separate visits that are spaced 3-10 days apart, and be willing to complete the study within a six week period.

Exclusion Criteria:

* Actual treatment with drugs influencing beta cell function (e.g. oral hypoglycaemic agents, beta-2-receptor agonists)
* Actual treatment with drugs influencing insulin sensitivity (e.g. steroids)
* Significant concomitant disease likely to interfere with glucose metabolism (e.g. febrile illness within the prior 3 days)
* Expected poor compliance
* If a female of child-bearing age, currently pregnant or not using a form of birth control
* Any other condition that by the judgement of the investigator may be potentially harmful to the patients

Primary outcomes:
measure: Stimulated C-peptide response derived from the 2-hour MMTT and the glucagon stimulation test (GST)
measure: Time to peak C-peptide on MMTT, and the peak and AUC values from each test
measure: Co-efficient of reproducibility of the MMTT, and the GST, provided from the duplicate tests within the same individuals
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: Barbara Davis Center for Childhood Diabetes, University of Colorado
state: Colorado
city: Gainesville,
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Indianapolis
country: United States
facility: Riley Hospital for Children, Indiana University
state: Indiana
city: Boston
country: United States
facility: Joslin Diabetes Center/ Children's Hospital Boston
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Naomi Berrie Diabetes Center, Columbia University
state: New York
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Medical Center at Dallas
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
city: Parkville
country: Australia
facility: Walter and Eliza Hall Institute of Medical Research
state: Victoria
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Turku
country: Finland
facility: University of Turku
city: Milan
country: Italy
facility: Vita-Salute San Raffaele University
city: Bristol
country: United Kingdom
facility: University of Bristol
Study officials:
affiliation: University of Miami
name: Jay S Skyler, M.D.
role: STUDY_CHAIR
References:
citation: Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004 Jan;53(1):250-64. doi: 10.2337/diabetes.53.1.250.
citation: Greenbaum CJ, Harrison LC; Immunology of Diabetes Society. Guidelines for intervention trials in subjects with newly diagnosed type 1 diabetes. Diabetes. 2003 May;52(5):1059-65. doi: 10.2337/diabetes.52.5.1059. No abstract available.
citation: Greenbaum CJ, Mandrup-Poulsen T, McGee PF, Battelino T, Haastert B, Ludvigsson J, Pozzilli P, Lachin JM, Kolb H; Type 1 Diabetes Trial Net Research Group; European C-Peptide Trial Study Group. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care. 2008 Oct;31(10):1966-71. doi: 10.2337/dc07-2451. Epub 2008 Jul 15.