Randomized Study of Real-Time Continuous Glucose Monitors (RT-CGM) in the Management of Type 1 Diabetes

Study Overview
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Brief Summary
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Subjects with intensively-treated type 1 diabetes and glycated hemoglobin (HbA1c) 7.0%-10.0% in 3 age groups (>25, 15-24, 8-14) will be randomized to a continuous glucose monitoring (CGM) group or control group. The primary outcome is change in HbA1c after 26 weeks. A parallel randomized trial is being conducted for a second cohort with HbA1c <7.0% that will follow an identical protocol to that of the first cohort with HbA1c >=7.0%. The >=7.0% trial was specifically designed and statistically powered to compare separately the impact of continuous versus standard intensive glucose monitoring in the three age groups. Both trials used standardized treatment algorithms and equivalent frequent contacts with subjects in both the CGM and control group. After completion of the 26-week trial, the CGM group continues to use CGM for another 26 weeks to evaluate whether any beneficial effect seen in the first 6 months is sustained with longer-term use and less intensive contact and the control group initiates CGM use with less intensive contact after the first month than was provided at initiation of CGM use in the CGM group in the randomized trial.

Detailed Description
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On the day of enrollment, a glycated hemoglobin (HbA1c) level will be obtained, psychosocial questionnaires will be completed, and instructions will be given for use of the real time continuous glucose monitoring device (RT-CGM). The study personnel will supervise the subject or parent inserting the RT-CGM sensor in the clinic and will instruct the subject or parent to insert a second sensor at home as needed. To obtain a baseline assessment of glycemic control and variability, the RT-CGM used during the first week will be blinded so subjects will not be able to view the data from the sensor. The subject will be instructed to complete at least four glucose measurements a day using the study home glucose meter (HGM) and as needed to calibrate the RT-CGM. The subject will return for a second visit about 10 days after the enrollment visit. Subjects who have been compliant with use of the RT-CGM and HGM will be randomized to one of two treatment groups: RT-CGM Group or Control Group. Compliance will be defined as use of the RT-CGM for at least 6 out of the 7 days prior to the second visit, at least 96 hours of RT-CGM glucose values obtained with at least 24 hours between the hours of 10 p.m. and 6 a.m., and use of the HGM for testing at least 3 times each day prior to the second visit. Subjects who are not compliant will be given another opportunity to complete the baseline requirements at the discretion of the investigator. For the RT-CGM Group, the RT-CGM, HGM, and pump data (if subject uses an insulin pump) will be reviewed and changes will be made to diabetes management as needed. Subjects/parents will be taught to use the protocol-developed instructions for changes to diabetes management to be used in real time based on RT-CGM and HGM data. Instructions for downloading the RT-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 subject uses an insulin pump) will be reviewed and changes made in diabetes management as needed. The blinded RT-CGM data will be downloaded but will not be reviewed by study personnel until the end of the first 6 months of the study. Subjects and 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 phone 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 subject uses an insulin pump) will be downloaded and for the RT-CGM Group, the RT-CGM will be downloaded. In the 13th and 26th weeks, the Control Group will use a blinded RT-CGM for one week. The RT-CGM Group will continue to use the unblinded RT-CGM. The Control Group will return the blinded RT-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 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 RT-CGM. Subjects in the Control Group will be provided with a RT-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 third weeks. Both groups will have visits after 13 weeks and 26 weeks (study time 9 and 12 months).

Official Title
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A Randomized Clinical Trial to Assess the Efficacy of Real-Time Continuous Glucose Monitoring (RT-CGM) in the Management of Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Device: Continuous glucose monitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of type 1 diabetes and using daily insulin therapy for at least one year The diagnosis of type 1 diabetes is based on the investigator's judgment; C peptide level and antibody determinations are not needed. Age >8 years Glycated hemoglobin(HbA1c) 7.0%-10.0% for the primary cohort and <7.0% for the secondary cohort The DCA2000 or comparable point of care device will be used to assess eligibility. Insulin regimen involves either use of an insulin pump or multiple daily injections of insulin (at least 3 shots per day) and has been stable for the last two months, with no plans to switch the modality of insulin administration during the next 6 months (e.g., injection user switching to a pump, pump user switching to injections, or the addition of Lantus (Glargine) insulin) Subjects using premixed fixed doses of insulin at the time of enrollment will not be eligible Subject (and parent/guardian for children) understands the study protocol and agrees to comply with it Subjects >9 years old and primary care giver (i.e., parent or guardian if subject is a minor) comprehend written English or Spanish This requirement is due to the fact that the questionnaires to be used as outcome measures do not have validated versions in other languages. Spanish-speaking subjects will be enrolled only if a RT-CGM device that functions in Spanish and has a User Guide in Spanish is available. No expectation that subject will be moving out of the area of the clinical center during the next year, unless the move will be to an area served by another study center. Informed Consent Form signed by the subject (or parent/guardian if subject is a minor, with subject signing the Child Assent Form) Exclusion Criteria: The presence of a significant medical disorder or use of a medication such as oral/inhaled glucocorticoids that in the judgment of the investigator will affect the wearing of the sensors or the completion of any aspect of the protocol. The presence of any of the following diseases: Asthma if treated with systemic or inhaled corticosteroids in the last 6 months Cystic fibrosis Adequately treated thyroid disease and celiac disease do not exclude subjects from enrollment Inpatient psychiatric treatment in the past 6 months (if the subject is a minor, for either the subject or the subject's primary care giver). Home use of RT-CGM in past 6 months Use of a CGMS or GlucoWatch does not exclude subjects from enrollment Participation in an intervention study (including psychological studies) in past 6 weeks. Another member of the same household is participating in this study. For females, pregnant or intending to become pregnant during the next year Pregnancy is an exclusion because of uncertainty about the lag between interstitial fluid glucose and blood glucose during pregnancy, which might affect the accuracy of the sensor. Subjects who become pregnant during the study will be discontinued from the study.

Ages Eligible for Study
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Minimum Age: 8 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard intensive glucose monitoring<br>Patients in the control group were given blood glucose meters and test strips and asked to perform home blood glucose monitoring at least four times daily. | |
| Active Comparator: Continuous Glucose Monitoring (CGM)<br>Patients in the CGM group were instructed to use the CGM device on a daily basis and to verify the accuracy of the glucose measurement with a home blood glucose meter (provided by the study) before making management decisions (as per the regulatory labeling of the devices). | Device: Continuous glucose monitor<br>* Daily use of a continuous glucose monitor<br>* Other names: Medtronic Paradigm REAL-Time;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Glycated Hemoglobin (HbA1c) From Baseline to 26 Weeks in the Continuous Glucose Monitoring (CGM) and Control Groups (for the Cohort With Baseline HbA1c >=7.0% Cohort) | The primary outcome was the Change in glycated hemoglobin (HbA1c) from baseline to 26 weeks, as determined by a central laboratory (for the cohort with baseline HbA1c >=7.0% cohort). | Baseline and 26 weeks | 
| Time With Glucose Level <=70 mg/dL (for the Cohort With Baseline HbA1c <7.0%) | The primary outcome was the change in the time per day with glucose values <=70mg/dL comparing baseline sensor values with those obtained following the 26-week visit. | Baseline and 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severe Hypoglycemia (for the Cohort With Baseline HbA1c >=7.0% Cohort) | Measure of the number of severe hypoglycemic events in the cohort with baseline HbA1c >=7.0% cohort | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values 71-180 mg/dL (for the Cohort With Baseline HbA1c >=7.0% Cohort) | Data regarding CGM were obtained after completion of the 26-week visit with the use of an unblinded device in the RT-CGM group and a blinded device in the Control group. Measure consists of minutes/day in range. | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values >180 mg/dL (for the Cohort With Baseline HbA1c >=7.0% Cohort) | Data regarding CGM were obtained after completion of the 26-week visit with the use of an unblinded device in the RT-CGM group and a blinded device in the Control group. Measure consists of minutes/day in range. | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values >250 mg/dL (for the Cohort With Baseline HbA1c >=7.0% Cohort | Data regarding continuous glucose monitoring were obtained after completion of the 26-week visit with the use of an unblinded device in the RT-CGM group and a blinded device in the Control group. Measure consists of minutes/day in range. | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values <=70 mg/dL (for Cohort With Baseline HbA1c >=7.0%) | Data regarding continuous glucose monitoring in both groups after the 26-week visit were used to estimate the amount of time per day the glucose level was hypoglycemic (<=70 mg/dL) | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values <=50 mg/dL (for Cohort With Baseline HbA1c >=7.0%) | Data regarding continuous glucose monitoring in both groups after the 26-week visit were used to estimate the amount of time per day the glucose level was hypoglycemic (<=50 mg/dL) | Baseline and 26 weeks | 
| Glucose (mg/dl) at Baseline and 26 Weeks (for Cohort With Baseline HbA1c >=7.0%) | Glucose variability was assessed by computing the absolute rate of change. | Baseline and 26 weeks | 
| Change in Glycated Hemoglobin (HbA1c) From Baseline to 26 Weeks in the Continuous Glucose Monitoring (CGM) and Control Groups (for the Cohort With Baseline HbA1c <7.0% Cohort) | The secondary outcome was the change in glycated hemoglobin (HbA1c) from baseline to 26 weeks in the Continuous Glucose Monitoring (CGM) and Control groups (for the cohort with baseline HbA1c <7.0% cohort), as determined by a central laboratory. | Baseline and 26 weeks | 
| Minutes Per Day of Continuous Glucose Monitoring (CGM) Glucose Values 71-180 mg/dL (for Cohort With Baseline HbA1c <7.0%) | Data regarding CGM were obtained after completion of the 26-week visit with the use of an unblinded device in the RT-CGM group and a blinded device in the Control group. Measure consists of minutes/day in range. | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values >180 mg/dL (for Cohort With Baseline HbA1c <7.0%) | Data regarding CGM were obtained after completion of the 26-week visit with the use of an unblinded device in the RT-CGM group and a blinded device in the Control group. Measure consists of minutes/day in range. | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values >250 mg/dL (for the Cohort With Baseline HbA1c <7.0% Cohort | Data regarding continuous glucose monitoring were obtained after completion of the 26-week visit with the use of an unblinded device in the RT-CGM group and a blinded device in the Control group. Measure consists of minutes/day in range. | Baseline and 26 weeks | 
| Minutes Per Day Continuous Glucose Monitoring (CGM) Glucose Values <=50 mg/dL (for Cohort With Baseline HbA1c <7.0%) | Data regarding continuous glucose monitoring in both groups after the 26-week visit were used to estimate the amount of time per day the glucose level was hypoglycemic (<=50 mg/dL) | Baseline and 26 weeks | 
| Absolute Rate of Change (mg/dl/Min) at 26 Weeks (for Cohort With Baseline HbA1c <7.0%) | Glucose variability was assessed by computing the absolute rate of change. | Baseline and 26 weeks | 
| Quality of Life | Hypoglycemia Fear Survey Total Score Average score of all items giving equal weight to each item. Scale 0-100 with higher score denoting more fear or more likely to avoid low blood glucose. | 26 weeks | 
| Cost-effectiveness of CGM. | Estimated total costs divided by estimated Quality-Adjusted Life Weeks (QALW) calculated per group | 26 weeks | 
| QALW | Quality Adjusted Life Weeks: We collected experienced utility data by eliciting time tradeoff (TTO) utilities for overall experience. Patients were asked to consider their current state of health in comparison to life in perfect health. Experienced utilities were elicited at baseline, 13 weeks, and 26 weeks. For children aged <18 years, parents served as surrogates. The total quality-adjusted life weeks (QALWs) were calculated as the area under the quality-of-life time trends under each arm. | 26 weeks | 
| Total Costs: Direct and Indirect Costs | Investigators reported time spent with patients on CGM training and diabetes management excluding research time. Adult patients (or caregivers of children) self-reported health service utilization including routine office visits, after-hours clinic visits, emergency room visits, 911 calls, and hospitalizations. The daily cost of CGM technology was calculated based on FDA recommended frequency of sensor replacement and the expected frequency of receiver and transmitter replacement. The costs of the three devices used during the trial were averaged to arrive at a daily cost of CGM of $13.85. This daily cost was multiplied by the reported weekly use of CGM to arrive at an overall cost of CGM technology. Indirect costs: self-reported number of hours devoted to diabetes care per day, number of days missed from work or school due to diabetes, and number of days of work underperformance. Unit costs available at: http://care.diabetesjournals.org/cgi/content/full/dc09-2042/DC1 (Table 1). | 26 weeks |