Current DirecNet Studies

A Randomized Clinical Trial to Assess the Efficacy and Safety of Real-Time Continuous Glucose Monitoring in the Management of Type 1 Diabetes in Young Children (4 to <10 Year Olds)

Click Here to View Protocol

Tight glycemic control in young children with diabetes is limited by hypoglycemia and the associated risk of impaired cognitive development. There are a number of factors that contribute to the risk of hypoglycemia in this age group; including irregular patterns of eating, inability to recognize and report hypoglycemia, inability to self manage a low blood glucose, and unpredictable peaks and valleys in long acting basal insulins. Young children are also very sensitive to small changes in insulin doses and the inability to deliver insulin by very small increments can only be possible via pump therapy. Night time is the most vulnerable period for hypoglycemia in youth with T1DM, since sleep blunts the counter-regulatory responses to hypoglycemia even in non-diabetic children. A large, multicenter study funded by JDRF explored the use of CGM technology further in a cohort of T1DM patients age 8 - ≥25 years for an entire year; however, young children (<8y/o) were not included. Hence, it remains to be seen whether CGM technology can be used safely, whether it is tolerable and useful in very young children with T1DM, and whether it can improve glycemic control without increasing hypoglycemia. The purpose of this study is to determine the efficacy, tolerability, safety, and effect on quality of life of CGM in children 4 to less than 10 years of age with type 1 diabetes.

Subjects with T1D who are 4.0 to <10.0 years old will be enrolled into the multi-center protocol which consists of two phases:

(1) A 6-month randomized trial comparing a CGM group with a control group that will use home glucose meter (HGM) monitoring and have the same number of scheduled phone contacts and visits as the CGM group, followed by:

(2) A 6-month period during which the CGM Group continues to use CGM and CGM is initiated in the control group. This 2^nd phase of the study will evaluate whether any beneficial effect seen in the first 6 months can be sustained with longer-term use and less intensive contact. As the control group will initiate CGM use with less intensive contact after the first month than was provided at initiation of CGM use in the CGM group in phase 1, this will also allow us to assess if beneficial effects of CGM use can be obtained with more practical personnel intervention.

To take part in the study, subjects will need to have:

1) Clinical diagnosis of type 1 diabetes and using daily insulin therapy for at least twelve months

2) Age >4.0 to <10.0 years

3) HbA1c >7.0% (measured with DCA2000 or other local point-of-care device)

4) Current insulin regimen involves either use of an insulin pump or multiple daily injections of insulin (at least 3 shots per day) for the last three months, with no plans to switch the modality of insulin administration during the next 6 months.

5) Not been diagnosed prior to 6 months of age

6) Not be taking a medication or have another disease that the investigator feels would prevent him or her from completing any aspect of the study.

7) Not used a CGM at home in the last 6 months

8) Not participating in an intervention study in the last 6 weeks

9) No expectation that subject will be moving out of the area of the clinical center during the next 12 months, unless the move will be to an area served by another study center.

Study Procedures

On the day of enrollment, a hemoglobin A1c level will be obtained, and potential subjects will be evaluated for study eligibility through the elicitation of a medical history and performance of a physical examination by a study investigator.

The subject will return for a second visit about 6 weeks after the enrollment visit. At this visit, quality of life questionnaires will be completed and a CGM sensor will be inserted. The monitor will be blinded so that the glucose values cannot be seen. The parent will be instructed on insertion, calibration, and care of the CGM.

The subject will return for a randomization visit 14 to 28 days after the blinded CGM was initiated.

· Subjects who have been compliant with use of the CGM and HGM will be randomized to one of two treatment groups: CGM Group or Control Group

· For the CGM Group, the CGM, HGM, and pump data (if applicable) will be reviewed and changes will be made to diabetes management as needed. Parents will be taught to use the protocol-developed instructions for changes to diabetes management to be used in real time based on CGM and HGM data. Instructions for downloading the CGM and HGM will be provided to subjects with a home computer.

· For the Control Group, a HGM and test strips will be provided. The HGM and pump data (if applicable) will be reviewed and changes will be made in diabetes management as needed. The blinded CGM data will be downloaded but will not be reviewed by study personnel until the end of the first 6 months of the study. Parents will be taught to use the protocol-developed instructions for how to make changes to diabetes management based on HGM data.

Both groups will have follow-up visits at 1,4,8,13,19, and 26 weeks (+/- 1 week) plus one contact between each visit (including one phone contact between the second visit and the one week visit) to review their diabetes management.

· Both groups will download device data on a weekly basis (if the subject has a computer). Subjects with email access will be instructed to email the downloaded data to the clinical center prior to each phone contact.

· For both groups, at each visit, the HGM and pump (if applicable) will be downloaded and for the CGM group, the CGM will be downloaded.

In the 13th and 26th weeks, the Control Group will use a blinded CGM for one week. The CGM Group will continue to use the blinded CGM. The Control Group will return the blinded CGM to the clinic after a week. The data will be reviewed by personnel who are not involved in the care of the subject to determine if additional blinded sensor data are needed. The blinded data will not be reviewed by the study personnel for management decisions until the end of the first 6 months of the study.

Following the 26-week visit:

· Subjects in the RT-CGM Group will continue to use the CGM.

· Subjects in the Control Group will be provided with a CGM and sensors after the week of blinded use and will have visits after 1 week and 4 weeks, with a phone contact during the first and second weeks.

· Both groups will have visits after 13 weeks and 26 weeks

A Pilot Study to Assess the Feasibility of Real-Time Continuous Glucose Monitoring in the Management of Infants and Toddlers with Type 1 Diabetes

Click Here to View Protocol

Because of the unique challenges involved in the use of CGM technology in very small children, including unpredictability of meals, extraordinary sensitivity to very small insulin doses, and very limited body surface area where to place the sensors, to name a few, this study will be extended to children less than age 4 yr (i.e., infants and toddlers) as a pilot assessment of the feasibility of the use of these devices in this young age group.

Following a run-in period with a blinded CGM, CGM use will be initiated in each enrolled subject. Subjects will remain in the study for up to six months as long as the CGM is still being used. If CGM use is discontinued prior to six months, with no intention to restart it, then a close-out visit will be performed at which the testing listed for the 26 week visit will be performed.

To take part in the study, subjects will need:

1) Clinical diagnosis of type 1 diabetes

2) Age <4.0 years

3) Current insulin regimen involves either use of an insulin pump or multiple daily injections of insulin (at least 2 shots per day) for at least one month

4) No expectation that subject will be moving out of the area of the clinical center during the next 6 months, unless the move will be to an area served by another study center

Study Procedures

On the day of enrollment, a hemoglobin A1c level will be obtained, and potential subjects will be evaluated for study eligibility through the elicitation of a medical history and performance of a physical examination by a study investigator. The parent will be asked to complete a series of quality of life questionnaires. At this visit, a CGM sensor will be inserted. The monitor will be blinded so that the glucose values cannot be seen. The parent will be instructed on insertion, calibration, and care of the CGM.

The subject will return for a second visit about 7-14 days after the enrollment visit. At this visit, compliance with use of the CGM and HGM will be assessed in addition to a skin reaction assessment. If the subject is compliant, the CGM, HGM, and pump data (if applicable) will be reviewed and changes will be made to diabetes management as needed. Parents will be taught to use the protocol-developed instructions for changes to diabetes management to be used in real time based on CGM and HGM data. Instructions for downloading the CGM and HGM will be provided to subjects with a home computer. A hemoglobin A1c level will also be obtained during the visit.

Follow-up visits are scheduled at 1,4,8,13,19, and 26 weeks (+/- 1 week) plus one contact between each visit to review their diabetes management. Compliance with use of the CGM and HGM will be assessed at each visit in addition to a skin reaction assessment. A hemoglobin A1c will be obtained at each visit with the exception of the 1 week visit and the parent will be asked to complete a series of quality of life questionnaires during the 26 week visit.

Relationship Between Loss of β‑Cell Function and Loss of the α‑Cell Response to Hypoglycemia Early in Type 1 Diabetes

Click Here to View Protocol

The Diabetes Research in Children Network (DirecNet) is conducting a study to find out more information about the cells in the pancreas that produce a substance called glucagon in children with type 1 diabetes. Glucagon is released when the blood sugar is becoming low and helps to keep the blood sugar level from falling too far. The purpose of the study is to find out more about the relationship of the cells in the pancreas that produce insulin and the cells that produce glucagon.

The study will include individuals 8 to 18 years old who were diagnosed with type 1 diabetes between 6 week and 12 months ago and non-diabetic individuals 8 to 18 years of age who will serve as controls. The study will include 2 tests within 2 weeks of each other: the Mixed Meal Tolerance Test (or MMTT) and Clamp Test (only completed by T1DM subjects.

To take part in the study, T1DM subjects will need to have:

1) Clinical diagnosis of type 1 diabetes between 6 weeks and 12 months prior to enrollment in the study.

2) Subjects must have positive antibody determinations.

· For subjects who have not had a prior positive antibody determination, blood will be drawn for antibody measurement (GAD65 and ICA512) and enrollment into the study will be deferred until the results are available.

3) Age >8.0 to <19.0 years

4) Not be taking any oral antidiabetic medication

5) Not be taking a medication or have another disease that the investigator feels would prevent him or her from completing any aspect of the study.

6) No expectation that subject will be moving out of the area of the clinical center during the next 18 months, unless the move will be to an area served by another study center.

To take part in the study, control subjects will need to have:

1) Age >8.0 to <19.0 years

2) Not be clinically diagnosed with type 1 diabetes

Study Procedures

On the day of enrollment, a hemoglobin A1c level will be obtained, and potential subjects will be evaluated for study eligibility through the elicitation of a medical history and performance of a physical examination by a study investigator. T1DM subjects will be scheduled for both the Mixed Meal Tolerance Test and Clamp Test. Non-diabetic subjects will only be scheduled for the Mixed Meal Tolerance Test.

· In preparation for the Mixed Meal Tolerance Test (or MMTT), subjects will be asked to consume a drink called “Boost”. Blood samples will be collected and blood sugar levels checked at regular intervals for 4 hours

o The target glucose level at the start of the test should be between 70 and 200 mg/dL for subjects with T1DM.

o Control subjects with a fasting blood glucose >110 mg/dL will not be eligible for continuation with the MMTT.

o Blood will be obtained for measurement of plasma glucose, c-peptide and glucagon at -10, 0, 15, 30, 60, 90, 120, 150, 180, 210 and 240 minutes. A split-duplicate sample for quality control will also be collected.

· For the Clamp Test in T1DM subjects:

o The subject will be asked to wear a blinded continuous glucose monitor for 6-7 days before returning to the clinic for this test

o Subjects will be asked not to eat or drink anything after midnight except water the night prior to the Clamp Test. Liquids that contain only simple sugars can be used to treat or prevent hypoglycemia during the night and morning prior to study.

o IV lines will be inserted in each arm: one for blood sampling and one for infusion of 10-20% dextrose solution.

o If possible, the subject will wear a calibrated CGM sensor that had been inserted 2-3 days prior to study.

o The target glucose level at the start must be at least 90 mg/dL. After resting for 15 min after IV insertions, three baseline plasma glucose levels (-30, -15 and 0 min) will be obtained prior to starting a continuous infusion of regular insulin.

o A dextrose infusion will be used to clamp the plasma glucose level between 90-100 mg/dl for 60 minutes.

o Plasma glucose levels will be measured every 5 minutes at the bedside throughout the clamp procedure.

o At the end of 60 min of euglycemic–hyperinsulinemia, the glucose infusion will be temporarily suspended and the plasma glucose levels will be allowed to fall to ~ 55 mg/dl, where it will be clamped for another 75 min.

o The insulin infusion will be stopped and euglycemia restored by increasing the intravenous glucose infusion at the end of the study.

o Blood samples for glucose, glucagon, epinephrine and norepinephrine measurements will be obtained just prior to the start of the clamp between 90-100 mg/dL (0 min), 30, 45 and 60 minutes after starting the euglycemic hyperinsulinemic phase of the study and after 15, 30, 45, 60, and 75 minutes of hypoglycemia. A split-duplicate sample for quality control will also be collected.

For T1DM subjects the tests will be repeated 1 year later and may be done again 6 months after that.

Effect of Metabolic Control at Onset of Diabetes on Progression of Type 1 Diabetes

Click Here to View Protocol

The purpose of this study is to test the impact of intensive metabolic control from the onset of diabetes on preservation of C-peptide secretion. This study will also test the feasibility and acceptance of this therapy so that it could be considered in future immune intervention studies. The therapy consists of a short course of sub-cutaneous closed-loop diabetic control at the onset of diabetes followed by real-time continuous glucose monitoring (CGM) with use of an insulin pump.

Following completion of the baseline procedures, participants are randomized to either the Intensive Treatment Group which includes a hospital admission for up to 4-6 days for inpatient closed loop therapy followed by outpatient use of an insulin pump and CGM or the Standard Treatment Group.

To take part in the study, T1DM subjects will need to have:

1) Age 10.0 to <46.0 years.

2) Diagnosis of type 1 diabetes with initiation of insulin therapy within past 7 days (day 1 being the first day of insulin therapy)

3) If participant is female with reproductive potential, willing to avoid pregnancy and pregnancy test negative.

4) Willing to accept randomization to either the intensive diabetes management group or the standard care group.

5) Willing to complete the planned 2 years of follow-up.

6) Able to electronically transmit data monthly.

7) Investigator believes that the participant (and parent/guardian for children) understands and agrees to comply with the study protocol and is capable of undertaking all necessary testing.

8) Not be currently pregnant or lactating, or anticipate getting pregnant in the next one year.

9) Not be currently anemic.

7) Not be taking a medication or have another disease that the investigator feels would prevent him or her from completing any aspect of the study.

10) Not have received inpatient psychiatric treatment in the past 6 months.

11) Not currently participating in another type 1 diabetes treatment study, including an intervention trial for treatment of diabetic ketoacidosis.

Study Procedures

On the day of enrollment, a hemoglobin A1c and autoantibodies samples will be obtained. An abbreviated Mixed Meal Tolerance Test will be administered and potential subjects will be evaluated for study eligibility through the elicitation of a medical history and performance of a physical examination by a study investigator.

Study subjects will be consented and randomized at the clinical sites as soon as possible after diagnosis of diabetes. The goal is to have randomization occur within 48 hours of diagnosis of diabetes; however, enrollment up to seven days after initiation of insulin therapy will be acceptable. Subjects admitted for treatment of DKA with IV insulin and fluids will be asked to consent to the study and will be randomized before their first meal. Subjects who were diagnosed as an outpatient and did not necessarily require hospital admission will come to the CRC for a morning admission for a mixed meal tolerance test, and will be randomized at the time of that admission.

Subjects will be randomly assigned to one of two treatment groups:

If assigned to Standard Treatment, the subject will:

· Start insulin therapy (this may take place at the clinical site or hospital, depending on the physician's recommendation)

· At home, check blood sugars 4 or more times a day using a blood glucose meter.

· Wear a blinded CGM for 3 days following visits every 3 months for the first 2 years and every 6 months during the last 2 years if they are continuing to produce insulin.

If assigned to Intensive Treatment, which is not usually prescribed to patients who have been recently diagnosed with type 1 diabetes because it is not certain whether this much effort will be helpful, the patient will:

· Stay in the hospital for 4 to 6 days, during which an insulin pump, continuous glucose monitor, and computer to control glucose levels will be used.

· Keep using an insulin pump and continuous glucose monitor at home for two years.

· At home, check blood sugars 4 or more times a day using a blood glucose meter.

All participants will be seen for follow-up visits at 2 weeks, 6 weeks, 3 months and then every 3 months for 2 years. If at the end of two years the participant is continuing to produce insulin, he or she will be asked to return for additional visits every 6 months for an additional 2 years.

The following procedures will be completed at each follow-up visit:

· History, including recording of medications and adverse events

· Physical exam (full exam at annual visits and limited/directed exam at other visits)

· Urine pregnancy test (for females with reproductive potential) at the 12-month visit and anytime a period is missed

· Blood sample for local HbA1c assessment at all visits except 2 weeks

· Blood sample for central laboratory HbA1c assessment at all visits beginning with the 3-month visit (except the visits at 15 and 21 months)

· Blood samples for autoantibodies, PBMC, RNA and extra plasma and serum to be stored for possible future analyses

· Mixed Meal Tolerance Test (except the visits at 15 and 21 months)

· Download study devices

Main Menu