Use of Continuous Glucose Sensors by Adolescents With Inadequate Diabetic Control
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Sponsor: Nemours Children's Clinic

Document Cover Page 
Official Title of the Study: 
Use of Continuous Glucose Sensors by Adolescents with Inadequate Glycemic Control 
NCT Number: NCT00945659 
Date of Document: March 22, 2018 

 
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1. INTRODUCTION TO THE RESUBMISSION 
 
This is a resubmission of R01-DK080831 in response to PA-07-097 "Chronic Illness Self Management in 
Children and Adolescents". Below, we have outlined responses to each issue raised in the study section's 
insightful and thorough critique. We have italicized the most substantive changes in the revised text. 
 
The safety of giving continuous glucose sensors (CGS) to adolescents with poor adherence and poor 
glycemic control was questioned. Adolescents may stop doing finger-stick blood glucose monitoring, 
they may not calibrate the devices properly and they may make treatment changes based on CGS only 
rather than finger-stick glucose checks. These human subjects concerns suggest that the proposed study 
is potentially unsafe and thus unethical. We have addressed these points in multiple ways. The GuardControl 
trial results 1 show that youths with baseline HbA1C > 8.1% randomized to daily CGS use were treated safely 
and effectively. Patients who were randomized to the Guardian-RT had mean decrease in HbA1C of 1.0% at 3 
months and HbA1C did not increase for controls during the study. Frequency of conventional self monitoring of 
blood glucose (SMBG) did not decline significantly in either control or CGS patients and remained at 4.6 
checks per day at the end of the study, which is above the commonly recommended 4 checks per day. 
Correspondence from the PI indicates that safety concerns expressed by the study section were not observed 
in the GuardControl trial. Youths in the two CGS groups had a total of two episodes of severe hypoglycemia, 
one not during CGS use and one detected by the CGS that did not respond to corrective carbohydrate intake. 
Diabetic ketoacidosis occurred once in each group. Thus, in a randomized trial enrolling an adolescent sample 
similar to that proposed here, CGS use decreased HbA1C safely without increasing severe hypoglycemia and it 
was not associated with significant decreases in the frequency of SMBG. Also, we have summarized the 
DirecNet studies of the Freestyle Navigator CGS with youths on insulin pump therapy 2 and multiple daily 
injections. 3-4 These data show that 13 weeks' use of the Navigator decreased mean HbA1C by 0.3% from 
baseline for insulin pump patients and 0.6% for multiple daily injection patients. When data from only patients 
with baseline HbA1C > 7.5% were analyzed, decreases in HbA1C were more pronounced (0.5% and 0.8%, 
respectively). Reportable adverse events were negligible and did not differ among those with baseline HbA1C > 
7.5% versus <7.5%. Although SMBG frequency declined somewhat more in the DirecNet studies than in the 
GuardControl trial, the frequency of conventional SMBG in the DirecNet studies was not correlated with HbA1C 
or severe hypoglycemia; hence, a decrease in SMBG frequency can occur safely in the context of CGS-
augmented therapy. Finally, the Juvenile Diabetes Research Foundation's Artificial Pancreas Project, in which 
Dr. Wysocki is an investigator, has an external Data Safety Monitoring Board that reviews study performance 
and adverse events every 6 months. The DSMB met recently now that recruitment has ended (n = 451 
patients) and, after more than 1,600 patient-months of CGS use, has recommended the continuation of the 
trial without any required changes in the study protocol or safety monitoring procedures. The GuardControl 
and DirecNet studies suggest that CGS use as an adjunct to intensive diabetes management can be both 
therapeutic and safe when used in patients with previously inadequate glycemic control. Also, an external, 
independent DSMB for the very large JDRF trial has concluded that use of CGS with youths with T1DM is safe 
and has sufficient therapeutic promise to warrant continuation of the trial.  
 
In addition to these published data and clinical experience supporting the safety and efficacy of CGS use in 
teens with suboptimal glycemic control, there are several safeguards that were part of the initial application 
and others that have been added. First, the study was to be offered only to patients who were already on 
stable, intensified insulin regimens or who were interested in transitioning to such a regimen from a 
conventional regimen. In the revision, eligibility is limited to patients already on intensified regimens. Thus, all 
patients entering the study will have an established intent to achieve excellent glycemic control and enhanced 
lifestyle flexibility. Second, diabetes education about CGS use will emphasize that CGS is to be used as an 
adjunct to conventional SMBG and that SMBG checks should be used to verify CGS results before any 
regimen adjustments are made in response to CGS results. Also, all three of the currently available CGS 
devices will simply stop operating if the required calibration SMBG checks are not entered during the windows 
of time required for each device. Hence, youths who do not perform calibrations as required will not be making 
treatment adjustments or decisions based on CGS data that is flawed due to that type of noncompliance. 
Third, we have changed the entry criteria to further ensure patient safety. We lowered the minimum HbA1C 
required for enrollment from 8.0% to 7.5% and imposed a maximum allowable baseline HbA1C of 10.0%. 
Adolescents will be eligible to enroll only if they have completed an average of 3 or more SMBG tests daily 
during the preceding 3 months. Fourth, we have planned a "rescue" procedure for any participant whose 
HbA1C remains above 9% for 2 consecutive visits or whose HbA1C increases by more than 1.0% over 

 
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baseline. As would typify clinical practices at the participating sites, this will consist of offering monthly clinic 
visits with a diabetes nurse, weekly telephone consultation with the nurse and referral to a dietitian, social 
worker, psychologist or psychiatrist at the discretion of the treating endocrinologist. Fifth, an external Data 
Safety Committee will carefully monitor the safety of study participants, particularly with respect to the 
concerns about youths' decreasing the frequency of conventional SMBG to unsafe levels. Finally, CGS 
sensors will be distributed once each 2 weeks to patients and, if a youth fails to demonstrate an average of at 
least 3 SMBG checks per day in the intervals between these distributions, no further sensors will be supplied 
until adequate SMBG frequency has been restored. Together with the promising data on therapeutic efficacy 
and safety of CGS use discussed above, and these numerous procedural safeguards, we are confident that 
participants in the proposed trial will enjoy levels of glycemic control and freedom from foreseeable adverse 
events that are at least as favorable as those experienced by comparable patients who do not enroll in this 
study. 
 
There is no manual for the Behavior Therapy intervention and no preliminary data supporting its 
efficacy. This was an important oversight; the initial application did not include adequate detail about the 
CGS+BT intervention. We have developed and appended a detailed intervention manual that provides an 
organized conceptual and practical guide to how, within a motivational interviewing framework, we will assess 
participants' behavioral strengths and weaknesses that may affect therapeutic benefit from the CGS device 
and how we will select, implement, evaluate and refine an individualized behavior therapy intervention to 
enable participants to derive the greatest possible benefit from CGS use and to enhance maintenance and 
generalization of those changes. Our intent was to reflect the best clinical practice of behavior therapy as 
applied to adolescents' CGS-specific behavioral problems. 5-10 Hence, the approach is intentionally flexible 
since it will be applied to varied target behaviors in diverse family contexts. At the same time, the intervention 
is conceptually driven by Behavioral-Family Systems Theory and carefully manualized for dissemination and 
portability. In fact, all empirically validated behavioral interventions with this population were highly flexible, 
manualized, theoretically driven interventions. This includes our own Behavioral Family Systems Therapy for 
Diabetes, 11-16 Ellis, et al.'s Multi-systemic Therapy, 17-18 Gray's Coping Skills intervention, 19 Delamater's 
Diabetes Self Management Training, 20 Anderson and Laffel's Diabetes Teamwork intervention, 21-22, Nansel et 
al.'s Diabetes Personal Trainer model 23 and Channon's applications of motivational interviewing to this 
population. 24-25 Also, Dr. Wysocki is a PI in the multicenter Family Management of Childhood Diabetes trial, 
which is testing a flexible, individualized family intervention targeting diabetes adherence and problem solving 
among early teens with T1DM. In all of these trials, intervention targets and methods were negotiated with 
patients and families to produce an individualized, problem-focused strategy with the patient/family at the 
center of the treatment team. We have expanded our rationale for the design of the behavioral intervention 
and the extensive empirical data from multiple research groups that supports the hypothesized efficacy of our 
approach. Each element of the planned intervention has empirical support with this specific clinical population, 
either from our own studies or from others' research, except that the targeted behaviors relate specifically to 
utilization of CGS technology in diabetes management. We are more explicit about this in Sections 3 and 4 of 
the application and in the intervention manual (See Appendix). We have added Linda C. Sobell Ph.D. as an 
expert consultant in behavior therapy interventions conducted in a Motivational Interviewing context.   
 
The conceptual basis of the study needs to be articulated more clearly, especially regarding Specific 
Aims 2 and 3. In Section 3, we added a detailed conceptual framework for the study, placing it in the context 
of Robin and Foster's integration of Behavioral and Family Systems Theories and devoted substantial space to 
articulating how the model constructs may affect the optimal use of CGS in diabetes therapy.  
 
Patients currently on conventional regimens would be changed to intensive regimens at enrollment. It 
is unclear how intervention effects will be disentangled from effects of this change. This is an excellent 
point. We will enroll only adolescents who have been intensively treated for at least 6 months on either insulin 
pump or multiple daily injection regimens based on carbohydrate counting and use of insulin dose correction 
factors. This characterizes about 80-85% of all patients at the three sites and so this change will not 
appreciably affect the feasibility of the sampling plan. 
 
Skills of the team and family in selection of the CGS device may impact study outcomes. While this 
concern is legitimate, we believe our planned approach reflects evolving clinical practice in the incorporation of 
technological advances in diabetes management and is consistent with our objective of evaluating CGS 
addition to care as it is likely to be practiced clinically. It is unclear how one would measure the proficiency of a 
team's skills in CGS device selection. Variability in families’ pertinent skills will further cloud this picture. 

 
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Regardless, there are no pertinent empirical data and no validated measures that would enable us to explore 
this rigorously. Involvement in the selection of the device with advice and consultation from the medical team 
tailors CGS use to individual needs, preferences and circumstances and therefore may generate initial and 
lasting enthusiasm among study participants. Limiting participants’ input in CGS device selection would 
possibly lead to loss of interest and motivation and would depart from what is likely to be standard clinical 
practice. This aspect of the protocol is consistent with current emphases in chronic disease management such 
as patient empowerment, 26 autonomy support 27 and motivational interviewing. 28-30 We will train clinical staff 
involved in this process to encourage a consistent approach. Materials developed in the JDRF Artificial 
Pancreas Project will be used to assist adolescents, parents and clinicians in the CGS selection process. 
Stratified randomization should also minimize effects of this potential concern.  
 
Overlapping clinical and research duties may create sources of bias. We have clarified in Section 5 that 
recruitment of families will be done by diabetes nurses and research assistants who will not deliver the 
behavioral intervention. The behavioral interventionists will not be involved in data collection. We have added a 
30% FTE Research Assistant at each clinical site so that administration of questionnaires and interviews can 
be segregated effectively from diabetes clinical management and the behavioral intervention. 
 
The design requires a control group for the extra attention to the CGS and CGS+BT groups. We would 
argue that the "extra attention" given to the CGS and CGS+BT groups is the independent variable in the study 
and so it is scientifically sound that the control and experimental groups differ on this dimension. The Diabetes 
Control and Complications Trial, perhaps the most influential diabetes study ever done, did not control for the 
added attention given to the Intensive Therapy group. 
 
The method of stratified randomization was not specified. We have described in more detail in Section 5 
exactly how randomization will be stratified. Patients will be grouped into high and low HbA1C strata (> or < 
8.8%). Separate randomization lists will be developed and utilized for each center so that patients within each 
HbA1C stratum will be randomized with equal probabilities to the SMBG, CGS or CGS+BT groups at each 
center. These features will enhance the likelihood that the three groups will have similar baseline HbA1C and 
ensure that about one third of participants will be randomized to each group at each center.  
 
The statistical analysis plan lacks detail about the model variables. Possible "site effects" need to be 
anticipated. The analysis plan has been completely rewritten to correct these deficiencies and our new 
statistical consultant, Rusan Chen, Ph.D. of Georgetown University has substantial experience in behavioral 
diabetes research. Neither the DirecNet Navigator, GlucoWatch nor the GuardControl studies revealed 
significant site effects on primary outcomes and so this concern may be inconsequential. Nonetheless, the 
revised analysis plan addresses this issue and randomization will be stratified within centers. 
 
Several budgetary and overlap concerns were mentioned. Concerns about the budget being excessive are 
addressed in the Budget Justification section. The budget is driven largely by costs for personnel, CGS 
devices and replaceable sensors and these have been justified carefully. We obtained four estimates for 
central HbA1C lab functions and selected the most economical alternative, Baptist Medical Center in 
Jacksonville. Other budget reductions have been incorporated, most notably limiting provision of SMBG test 
strips to participants who lack insurance coverage for them. There is no overlap with the DirecNet studies 
(which will not focus on continuous glucose sensors as of September, 2007) or the JDRF Artificial Pancreas 
Trial (which does not include a behavior therapy intervention). Dr. Wysocki is no longer supported by the 
DirecNet grant and the JDRF trial will conclude before the earliest start date for the research proposed here.  
 
More detail is needed regarding the analysis of cost effectiveness data. We have described exactly how 
the cost effectiveness data for this secondary objective will be analyzed. We will complete descriptive analyses 
to estimate and report the incremental costs associated with the CGS and CGS+BT interventions relative to 
SC and, if there are group differences in the frequencies of emergency room visits or hospitalizations, we will 
calculate the incremental cost for each such event prevented by the CGS and CGS+BT regimens. 
 
SUMMARY 
We believe that we have carefully and thoroughly addressed each concern expressed in the prior critique and 
that we have submitted a substantially stronger application as a result. We hope that the reviewers concur with 
this assessment. Substantive changes appear in italics throughout the research plan. 
 
 

 
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2.   SPECIFIC AIMS This revised application responds to NIH Announcement #PA-07-097 "Chronic Illness 
Self-Management in Children and Adolescents". It addresses the priorities stated in that announcement 
related to testing interventions targeting improved self-management of pediatric chronic diseases.  
 
Treatment of type 1 diabetes mellitus (T1DM) requires daily insulin injections or use of an insulin pump, self-
monitoring of blood glucose (SMBG) several times daily, regulation of carbohydrate intake, regular exercise 
and correction of hyperglycemia and hypoglycemia. 31 The outcomes of family management of pediatric T1DM 
reflect many psychosocial influences. 32-35 Some youths and families negotiate these challenges effectively, but 
others endure poorer glycemic control, treatment adherence, family relations and quality of life during this 
period. 32-35 Poor adaptation to T1DM in youth may persist into early adulthood, increasing the risks of long-
term complications. 36-37 Practical methods are needed to enhance the capacity of youths and parents to 
manage T1DM effectively. Continuous glucose sensors (CGS) have now been developed that provide 
continuous real-time data on glucose levels and trends. The CGS could benefit many adolescents with T1DM 
by providing more useful feedback on glycemic levels, direction and variability than is feasible with 
conventional SMBG. 38-43 But, these benefits may depend on how well families can collaborate in using CGS 
data for therapeutic decision-making. 44-45 While youths in sub-optimal glycemic control could benefit from 
CGS, the benefits could be enhanced if they received a specific, targeted behavioral intervention. Drawing on 
our prior studies, the proposed research will explore whether glucose regulation by youths with T1DM using 
CGS can be enhanced by a behavioral intervention targeting diabetes management behaviors of adolescents 
and parents/caregivers that are critical to effective CGS use. This application addresses these specific aims: 
 
SPECIFIC AIM 1. In a 3-center sample of 150 adolescents with T1DM and HbA1C of 7.5% to 10.0%, we will 
compare the effects of Standard Care (SC) alone or augmented by either CGS alone (CGS) or CGS plus a 
behavior therapy intervention designed to optimize CGS benefits (CGS+BT). Primary outcome measures will 
be HbA1C, 7-day continuous glucose profiles, and indices of blood glucose variability and risks for severe 
hypoglycemia. Frequency of severe and moderately severe hypoglycemia will be secondary outcomes. 
SPECIFIC AIM 2. The study will determine if and how adding the behavioral intervention to accepted clinical 
and educational practices related to CGS use affects diabetes treatment adherence, parent-adolescent 
teamwork, satisfaction with CGS use, quality of life, and family communication about diabetes management. 
SPECIFIC AIM 3. The proposed work will evaluate mediating and moderating effects of certain demographic 
variables and diabetes-specific behaviors of adolescents and parents that are suggested by theory or related 
empirical research as likely to affect benefits realized from CGS use. 
 
3.   BACKGROUND AND SIGNIFICANCE 
3.1. Evolution of diabetes management since the Diabetes Control and Complications Trial.  The 
Diabetes Control and Complications Trial (DCCT) proved that maintenance of near-normoglycemia reduced 
the onset and progression of long-term complications. 46-48 DCCT adults had lower HbA1C than did 
participating youths, but the form of treatment effects and associations between HbA1C and complication rates 
were similar. Our NIH-funded trial of Intensive Therapy versus Usual Care for youths with T1DM explored 
prediction of benefit from these regimens. Our study 49-51 and another 52 suggest that intensive therapy is safe 
and effective with adolescents with T1DM and that it can improve glycemic control without appreciable adverse 
effects. Unfortunately, a minority of adolescents today maintain HbA1C < 7.5%, the American Diabetes 
Association's recommended target 53 (< 7.0% if considered safe by the physician). Although there has been 
substantial improvement in the management of T1DM in adolescence in the past few decades, much room for 
improvement remains. Continuous glucose sensors could enable additional therapeutic benefits. 
 
3.2. Continuous Glucose Sensors: Medical, Educational and Psychological Context. So-called 
“continuous glucose sensors” (CGS) yield near-continuous glucose feedback automatically and with minimal 
discomfort. Various devices have been tested 54-58 and several are FDA-approved as adjuncts to SMBG in 
T1DM regimens. The accuracy of these devices is adequate compared to laboratory assays 59-62 and their 
provision of 24-hour glucose profiles and detection of glycemic trends are not feasible with conventional 
SMBG. Existing CGS devices will be refined and new ones will emerge. 63-67 CGS use could change T1DM 
care greatly, with major increases in the breadth and amount of glucose data, and timely feedback about the 
glycemic effects of treatment events and thus yield many benefits. 1-4, 38-43, 68 CGS use could enable reduced 
HbA1C, glycemic variability, and severe hypoglycemia. Improved detection of previously unrecognized 
glycemic patterns could guide treatment adjustments. CGS feedback could reinforce educational concepts 
and possibly reduce health care costs. By revealing more saliently the effects of non-adherence, some 

 
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patients may be motivated to comply more consistently. CGS could enhance clinicians’ refinement of youths’ 
diabetes problem solving, helping them to develop more self-confidence in their self-care skills. Parents and 
teens could develop a proactive, rather than reactive, approach to managing diabetes, achieving more lifestyle 
flexibility.  Based on experience in the CGS studies described below, CGS became an integral part of T1DM 
care for about 75-80% of youths who tried it. But this estimate is based on samples of highly selected, well-
motivated and younger children and it may not pertain to adolescents with suboptimal glycemic control.  
 
But some youths and families may not benefit from CGS use since it increases the care burden and introduces 
new self-care demands. 42, 44-45 Some youths and parents may have unrealistic expectations about what CGS 
can achieve and be easily discouraged by slow improvement. Many youths might view CGS as a threat to their 
privacy and autonomy. The amount of CGS data may be overwhelming and highly anxious individuals may 
over-react to CGS feedback by over-correcting momentary glucose fluctuations. Wearing the CGS increases 
the salience of diabetes to peers, possibly increasing social stigma and unwanted intrusions of diabetes into 
one’s social life. Access to CGS data may aggravate teen-parent conflict over unwanted glucose excursions or 
cause guilt when preventable problems are not recognized. Research on the adoption of this technology 
should include plans to analyze possible unwanted effects of CGS use.  
  
Outcomes from medical advances such as use of CGS may depend on psychological variables. 42, 44-45 
Previous research identified many psychosocial variables that influence T1DM outcomes and we will measure 
those that have yielded the most robust associations. 32-35 Key demographic factors are: child age, pubertal 
stage, parents’ marital status, socioeconomic status, race/ethnicity and family composition. 69-72 Psychological 
characteristics of individuals associated with T1DM outcomes are: child or parent psychological adjustment, 73-
74, diabetes knowledge and problem-solving, 75-80 treatment adherence, 81-83 fear of hypoglycemia, 84-85 attitudes 
toward SMBG, 79-80 and stress and coping. 86-87 Family variables that influence T1DM outcomes are family 
function, 88-89 family sharing of T1DM responsibilities, 90-96 and diabetes-related conflict. 97-98 These variables 
will be measured throughout this study to clarify their effects on glycemic outcomes. We will evaluate both 
moderation and mediation of therapeutic benefit from CGS use with appropriate analyses of the contributions 
of such variables to treatment effects on the primary outcomes.  
 
3.3. Available CGS devices. Dr. Wysocki has been involved since 2001 in studies of the accuracy and clinical 
use of CGS. 2-4, 45, 56-57, 59, 61-62 Three CGS devices either have FDA-approval for use in adults or approval is 
expected soon. These are the Guardian RT/Paradigm (Medtronic-Minimed, Inc.), the Freestyle Navigator 
(Abbott Laboratories) and DexCom 7 (DexCom, Inc.). Features of these devices are shown here, and links to 
current product information websites are in the appendix. 
 
Table 1. Comparison of features of currently available continuous glucose sensors. 
 
Navigator 
DexCom 7 
Paradigm/Guardian 
Range of glucose values 
20 to 500 mg/dL 
40 to 400 mg/dL 
40 to 400 mg/dL 
Frequency of glucose values 
Every minute (saved every 10 
minutes) 
Every 5 minutes 
Every 5 minutes 
Lifespan of sensor 
120 hours 
168 hours 
72 hours 
Warm up period 
10 hours 
2 hours 
2 hours 
Calibration frequency 
4 times at ~10, 12, 24 and 72 hours  
after sensor insertion 
2 times a day (every 12hrs) 
2 times a day (every 12hrs) 
SMBG Meter for Calibration 
FreeStyle (built in) 
One Touch Ultra (connected 
via a cable) 
BD Logic (connected via radiofrequency); can 
also enter manual calibrations from any HGM 
Alarms 
Hypo, hyper (adjustable) 
Predicted alarms based on rate of 
change 
Hypo, hyper (adjustable) 
No predicted alarms 
Hypo, hyper (adjustable) 
No predicted alarms 
Trend Arrows  Displayed 
Yes 
No 
Yes 
Memory capacity 
Max. 60 days of glucose readings 
Max. 30 days of glucose 
readings 
Max. 90 days of glucose readings 
Entering of events 
Insulin, meals, exercise, health, other 
Not available 
Insulin, meals, exercise 
Other features 
Sensor is waterproof 
Sensor is waterproof 
Can be combined with a Medtronic pump in a 
single device (functioning separately) 
FDA approval status 
Pending for adults 
Approved for >=18 year olds as 
adjunct to SMBG 
Approved for children and adults as adjunct 
to SMBG 
 
Other CGS's will emerge and the proposed study will use the most advanced devices at the time this work 
begins. If any device selected for this study does not have FDA approval by the start date, an IDE will be 
sought for its use. The current devices all measure glucose in interstitial fluid using indwelling electro-chemical 
sensors to yield time-averaged estimates derived from the electronic "signature" of glucose molecules. The 
various sensors are designed for 3 to 7 days' use. All yield nearly continuous glucose profiles, but there is a 

 
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physiological lag of 10-15 minutes between glucose levels in blood versus the interstitium. Each device gives 
feedback on estimated interstitial glucose levels over brief (e.g. 5-min) intervals and alarms notify the user of 
out of range glucose values or of rapid glycemic changes. All require entry of SMBG tests for calibration at 
varied intervals. All of the devices can be downloaded to a computer, although the analytic options vary. The 
Medtronic-Minimed Paradigm CGMS is integrated within an insulin pump housing, but the infusion of insulin is 
not directly regulated by the CGS glucose data. The Medtronic-Minimed Guardian-RT is the same CGS device 
but it is not incorporated into an insulin pump. Insulin infusion via pumps may some day be driven by CGS 
glucose data, but that development is probably several years in the future. 68, 99, 100  We will offer to participants 
the CGS devices that offer the greatest accuracy, convenience, safety and reliability when the study begins.  
 
It is difficult to compare the accuracy of CGS devices to methods yielding point-in-time glucose estimates. 101-
102 CGS accuracy has improved steadily and now rivals the accuracy of SMBG meters, while enabling 
detection of glycemic trends that is not feasible with SMBG. Current CGS devices tend to blunt rapid or 
extreme glycemic changes, 56-57 but they may still detect fluctuations that are missed by SMBG. The current 
CGS devices, while imperfect, may be accurate enough to enable more timely decision-making and glycemic 
benefits. Consultant mathematician Boris Kovatchev, Ph.D. is a leading expert on quantifying the accuracy of 
CGS devices and analyzing glucose dynamics using SMBG and CGS data. Dr. Kovatchev will bring his 
expertise to this study, continuing his work on prediction and quantification of glycemic variability. 102-113  
 
Comparing available CGS devices is not an aim of this application. The protocol is intended to reflect best 
clinical practice in adding CGS to T1DM care. This includes evaluating the patient's needs and characteristics, 
considering the pros and cons of the CGS options for that youth and, with the family, selecting the "best-fitting" 
CGS device. The proposed study will evaluate benefit from CGS use that is initiated in this way. Each enrolled 
youth will consult with his or her parent(s) and diabetes team to select the best CGS device for that patient. 
 
3.4. Cost effectiveness analysis. Cost-effectiveness analysis (CEA) quantifies the added value of medical 
advances. After ascertaining all costs of each intervention, optimal CEA methods yield an Incremental Cost 
Effectiveness Ratio (ICER). 114-116 This requires calculation of Quality-Adjusted Life Years based on health 
utilities measures (e.g. treatment utilities, experienced utilities, complications utilities, willingness to pay). 114 
Utilities measures often employ "time-tradeoff" questions asking respondents to indicate how many years in 
their current health state they would be willing to trade for a given health outcome. 114 Many youths may 
struggle with these abstractions, the methods have not been studied with pediatric diseases and parental 
proxy for youths' responses has not been validated. A simpler, more affordable approach to cost effectiveness 
analysis is proposed here. During four selected 2-week periods, all clinicians treating adolescents in this study 
will record their time devoted to delivery of each adolescent's care, not including time specifically for research 
tasks. Methods used successfully in Dr. Wysocki's prior trial of intensive therapy 45-46 will be used in this study. 
Key drivers of health care costs will be recorded systematically, including hospitalizations, emergency room 
visits and clinic visits. The collection of these data will permit a basic assessment of the relative costs and 
therapeutic benefits from CGS use with and without a behavioral intervention relative to standard care and of 
possible cost savings due to CGS use through reduced health care utilization compared with standard care. 
 
3.5. Conceptual model. From the perspective of behavior theory and applied behavior analysis, CGS use 
could yield both therapeutic and contratherapeutic behavioral effects in youths with suboptimal HbA1C. Family 
systems theory implies that adding CGS to T1DM care could affect, and be affected by, all elements of the 
family system. CGS could yield benefits that SMBG cannot provide, permitting more informed decisions about 
insulin dosing, eating and exercise, allowing patients to anticipate and prevent glycemic excursions, reduce 
glycemic variability and achieve normoglycemia more often. Also, CGS can illustrate the glycemic effects of 
events such as overeating, over-exertion, and missed or delayed insulin injections. If CGS data are used 
carefully to guide T1DM care, youths may enjoy better short-term outcomes, more flexible lifestyle, and more 
meticulous adherence. If these changes reduce the burdens of living with diabetes, youths may also enjoy 
improved quality of life and family relations. To the extent that behaviors entailed in optimal CGS use yield 
positive consequences rather than aversive consequences (direct effects on glycemic control or indirect social 
effects), these optimal behaviors may be strengthened and maintained.  
 
But, adding CGS may entail complications that could counteract these benefits. CGS may compound the 
burden of T1DM self-care since it must be checked, cleaned, stored, calibrated, safeguarded and explained to 
others. Use of the CGS in school and some recreational activities may be difficult or impossible. The CGS 
compounds the complexity of blood glucose data, increasing the frequency of events requiring remediation. 

 
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Youths may be confused when CGS values differ from SMBG results or from "expected" values. Alarms 
signaling unwanted glucose fluctuations may intrude into activities that teens are unwilling to interrupt. False 
alarms, especially if repetitive, may induce adolescents to disregard the alarms. For teens whose self-care 
behaviors are inconsistent, their CGS results may also seem capricious, making it difficult to adjust the 
regimen effectively. CGS feedback could aggravate conflict between youths and parents about glycemic 
control. Hence, these potential "response costs" from CGS use may undermine its potential benefits. While 
CGS carries potential benefits, the above concerns suggest that incorporation of CGS into T1DM care may 
place a premium on family characteristics that influence the effectiveness of diabetes management. 
 
In our prior studies of the GlucoWatch and Navigator, frequency of use of both devices declined steadily over 
time. The best estimates of frequency of use are from our Navigator pilot studies (See Section 4). Insulin 
pump patients used the Navigator for about 149 hours per week (88% of maximal) in the first 4 weeks, but this 
declined to 134 hours per week during the last 4 weeks of the 13 week study (80% of maximal). Children on 
MDI therapy used the Navigator slightly more often initially (153 hours/week) but declined more rapidly to 109 
hours per week (65% of maximal) by the last 4 weeks. Given that MDI patients have actively decided against 
the use of one T1DM device (insulin pump) it is not surprising that they would be somewhat less enthusiastic 
than pump patients about use of CGS. Since we plan to enroll youths with suboptimal glycemic control and 
follow them longer, frequency of CGS use may decline more rapidly and to lower levels in this study. Thus, 
there are many behavioral variables that may impact effective use of CGS technology. Teens who are already 
struggling with T1DM management may be at the highest risk of counterproductive behavioral reactions to 
CGS use. Yet, these same youths could also derive the most therapeutic benefits from CGS if these 
impediments can be anticipated and prevented and if more positive and constructive behaviors can be 
encouraged. The behavioral intervention proposed for this study is designed to achieve these effects. 
 
Various counter-productive behaviors of adolescents or parents could impede benefit from CGS use. Also, 
there are certain behaviors that could promote benefit from CGS use. Targets of intervention in the proposed 
study will include these "negative" behaviors: Inadequate frequency of CGS use, Resistance to completing 
calibration SMBG checks, Ignoring alarms warning of impending hypoglycemia or hyperglycemia, Resistance 
to completing finger-stick BG checks when CGS readings seem inaccurate, Adolescent concern about 
parental "snooping" or inordinate family attention to glucose levels, and arguments about BG levels. The 
intervention will also seek to promote "positive" behaviors such as: Problem solving to prevent unwanted BG 
fluctuations, Parent-youth teamwork and brainstorming around CGS results, Goal setting for improved BG 
control, Conducting "experiments" to measure effects of exercise changes, etc. on BG levels and trends, 
Improving family communication about out of range BG levels, Parent-youth negotiation about diabetes goals, 
responsibilities, etc. Other positive and negative target behaviors will likely emerge as the study proceeds. 
  
The proposed intervention is based on a conceptual model adapted from Robin & Foster's Behavioral Family 
Systems theory that Dr. Wysocki has explored in his prior NIH-funded trials. 117 While Robin and Foster 
developed their model for the prediction of the frequency and intensity of parent-adolescent conflict, we have 
adapted it for the prediction of therapeutic benefit from clinical use of CGS technology in the management of 
T1DM in adolescents. We contend that the same processes that mediate and moderate parent-adolescent 
conflict will influence the family's capacity to work together cooperatively to derive benefit from CGS use. 
Specifically, the model asserts that the degree of CGS benefit achieved by families of adolescents with T1DM 
is a function of several interactive behavioral characteristics of the family: 
 
• 
Characteristics of the family system that provides the social context for T1DM care. 22, 32,69-74,87, 90-91, 94- 96 
• 
Family problem solving and communication skills related to diabetes management. 75-80, 92, 95, 98  
• 
Cognitive distortions held by parents and adolescents about T1DM and its management 11-13, 84, 85, 88, 89, 130 
(Citations inserted above are T1DM studies that offer empirical support for these relationships) 
 
A diagram of this conceptual model appears below, followed by discussion of how these constructs are 
thought to operate in the context of CGS-augmented diabetes management. The fundamental tenet of the 
model is that families are interconnected systems such that perturbations affecting one element of the system 
are likely to influence other elements of the system. Family members exert reciprocal influences on the 
contingencies of reinforcement and punishment that prevail upon one another's behaviors. Adolescence is a 
period that challenges these prevailing contingencies of reinforcement and punishment and that stresses the 
family's organization of power, influence and decision-making. 
 

 
8 
Robin and Foster integrated the molar perspective of Family Systems Theory with several principles derived 
from Behavioral and Social Learning Theories that offer a more molecular perspective of the processes and 
mechanisms that may govern how families adapt, successfully or not, to the demands of adolescence. They 
argue that three 'molecular" characteristics determine the degree to which families adapt successfully to the 
challenges of adolescence, and this application asserts that these characteristics will affect families' capacity 
to benefit from use of CGS in diabetes care. These characteristics are effectiveness of family communication 
skills, effectiveness of family problem solving skills and the degree to which family members have distorted 
cognitions or beliefs about each other's behavior. Robin and Foster summarized an extensive literature on the 
developmental psychology and family psychology of adolescence and identified variables that differentiate 
distressed from non-distressed families. Non-distressed families are better able to communicate openly and 
directly with their adolescents to negotiate disagreements, resolve conflicts and solve problems. Non-
distressed families of adolescents are less likely to demonstrate distorted cognitions regarding the behaviors, 
attitudes and motives of other family members. These distorted cognitions are logical errors that tend to 
inflame, divert, obfuscate or stop conversation such as overgeneralization, exaggeration, selective abstraction, 
arbitrary inference, dichotomous reasoning, perfectionism, ruination, insistence on fairness, insistence on 
autonomy, and inference of malicious intent. In this model, families who have deficient communication and 
problem solving skills and whose thoughts about each other and about diabetes management are heavily 
laden with cognitive distortions such as these, are unlikely to exhibit the kinds of family interactions that are 
conducive to optimal therapeutic benefit from CGS use in diabetes management. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Robin and Foster's Behavioral Family Systems Theory 117 asserts that the interactive behaviors of family 
members exert reinforcing or punishing consequences upon one another's behaviors and that the 
development and maintenance of cooperative family problem solving depend on the occurrence of interactions 
that specifically set the occasion for and reinforce those behaviors. A molecular perspective of CGS-related 
family interactions suggests that specification, analysis and remediation of the family's implicit contingencies of 
reinforcement and punishment could enable behavior change specialists to promote family environments that 
enhance benefit from adding CGS to T1DM care. Use of CGS to improve glycemic control among youths with 
T1DM requires a family environment that is rich in parental supportive involvement, exhibits healthy and open 
communication about diabetes and that encourages parent-adolescent cooperative problem solving without 
exacerbating developmentally typical conflict between teens and adults. Family systems that have anomalous 
distributions of decision making and influence (e.g. weak parental coalitions, cross-generational coalitions, or 
triangulation) 117 often demonstrate major difficulties in the domains of family communication, cooperative 
problem solving and conflict resolution. For example, adolescents whose parents have widely discordant 
attitudes about the benefits of tight glycemic control may "seek protection" from the more lenient parent when 
glycemic control is poor. Frequent expressions of distorted cognitions such as those above, often inflame 
emotions and "de-rail" conversations, and so impede family communication and problem solving. For example, 
adolescents whose parents over-react to transient glucose fluctuations with angst and foreboding may be 
                       Family Systemic Characteristics 
                                          Family structure and composition 
                                  Distribution of decision-making and authority 
Communication 
       Problem Solving 
Distorted Cognitions 
CGS-related family interactions 
Change in Diabetes Outcomes 
HbA1C 
Glycemic variability 
Treatment adherence 
Diabetes conflict 
Quality of life 

 
9 
disinclined to further CGS use. Families who lack effective communication and problem solving skills may 
have difficulty cooperating to respond appropriately to CGS use and the resulting data. For example, families 
who frequently interrupt one another, change topics of conversation, bring up past failures, or engage in 
frequent blaming may find it difficult to reach consensus about responding to CGS results and thus miss 
opportunities to improve the adolescent's glycemic control. To further illustrate the behavioral mechanisms and 
processes that could be targeted for intervention in the proposed study, the table below lists key interactive 
behaviors of families of adolescents with T1DM that the model predicts will be important determinants of 
benefits from CGS use. Therapists who will implement the planned intervention will be trained to identify these 
characteristics clinically and to target encouragement of these positive behaviors in their treatment plans. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.6. Pertinent behavioral interventions. Many studies affirm the merits of brief behavioral interventions 
targeting family management of T1DM. 11-25, 118-131 These include trials of behavior modification and behavioral 
contracting, 121-125 coping skills training, 19, 126-128 peer group and multifamily group interventions, 11-18, 118-119, 129-
130 family teamwork interventions, 21-22 and other family approaches. 131 Motivational Interviewing has shown 
promise with youths with T1DM 23-26 and other adolescent issues. 132-135 Key components of the latter approach 
are expressions of empathy, development of a discrepancy between the patient's present behavior and 
important goals or values, and support for self-efficacy and patient autonomy. Motivational Interviewing, rather 
than being an intervention itself, offers a fertile context for the negotiated development of a patient-centered 
intervention that is particularly useful with individuals who are resistant to change. We have designed our 
intervention to include the key ingredients of effective, brief behavioral interventions and to reflect best clinical 
practices in the application of these tools to enhance family management of T1DM in adolescence. 
 
3.7. Safety and efficacy of CGS use by adolescents with T1DM. Three recent studies affirm the safety and 
efficacy of CGS use in teens with T1DM. All three showed that augmenting conventional SMBG with CGS use 
yielded modest, but lasting reductions in HbA1C and glycemic variability. The GuardControl trial 1 randomized 
81 youths and 81 adults with HbA1C > 8.0% to SMBG, 3 days' bi-weekly CGS use or continuous CGS use. At 
3 months, the continuous CGS group achieved a mean 1.0% reduction in HbA1C compared with 0.6% for the 
bi-weekly CGS group and 0.3% for the SMBG group. More evidence of the safety and efficacy of CGS in this 
population was obtained in the Diabetes Research in Children Network's 13-week pilot studies of the Abbott 
Freestyle Navigator CGS in youths with T1DM on insulin pump (CSII) and multiple daily injection (MDI) 
regimens described in Section 4.2. 2-4 None of these studies yielded increased frequencies of severe 
hypoglycemia or diabetic ketoacidosis during CGS use. In all of the studies, frequency of SMBG declined 
during CGS use, but this was not associated with adverse events. These studies show that CGS use in 
pediatrics is safe and may yield modest glycemic benefits, even if SMBG frequency declines while it is used. 
Coupled with the extensive safeguards that are described in Section 5, participation in this clinical trial is likely 
to result in fewer adverse events among participants than among similar patients who do not enter the study.   
 
4.  PRELIMINARY STUDIES AND PROGRESS REPORT  
 
Family behavioral characteristics that may enhance benefit from adding CGS to diabetes management: 
 
• There is greater emphasis on praise and positive reinforcement than on punishment and criticism. 
• Family members display positive reciprocity and absence of coercive family processes. 
• Blood glucose fluctuations serve as a cue for problem solving discussions rather than arguments. 
• Parental withdrawal from diabetes management is gradual, stepwise, and experimental. 
• Increased adolescent responsibility precedes parental withdrawal from diabetes management.  
• Parents are willing and able to resume more involvement in diabetes management if necessary. 
• Parental withdrawal from T1DM care is goal-directed rather than due to burnout, avoidance of conflict, etc. 
• Parents monitor and are aware of youths' T1DM management behaviors when away from home.  
• Parents engage in diabetes problem solving with, rather than for, the adolescent. 
• There is frequent, effective family communication about T1DM and clear accountability for management tasks.  
• Parents maintain involvement as a resource or advisor with minimal parent-adolescent conflict 
• Adolescent often displays self-disclosure about coping with T1DM. 
• Parental concern about T1DM self-management is expressed lovingly rather than in anger or frustration. 
• Constructive social supports for T1DM self-care are available from other family members, siblings, and peers. 
• Recurring problems mobilize more intensive or diverse family problem solving efforts.  
• Parents advocate for effective diabetes management in school and other such settings. 

 
10
4.1. Qualifications of the study team.  Dr. Wysocki has 1.) Served as the only non-MD PI in the NIH-funded 
Diabetes Research in Children Network and the Juvenile Diabetes Research Foundation Artificial Pancreas 
Project. Both networks have conducted CGS studies as described below; 2.) Served as PI on 4 NIH-funded 
multi-center studies of youths with T1DM, including trials of behavioral interventions and an analysis of 
prediction of benefit from intensive therapy; and 3.) Published extensively on SMBG and CGS (See Section 7).  
 
Dr. Wysocki has enlisted as co-investigators the Division Chiefs for Pediatric Endocrinology at the Nemours 
Children's Clinics in Orlando, (Jorge Daaboul, M.D.) Pensacola, (Mark Kummer, M.D.) and Wilmington, 
Delaware (Grafton Reeves, M.D.). Kimberley Englert, R.N, who has been the Nemours coordinator for several 
CGS studies, will train nurses at the other sites on the CGS devices and consult regarding education and 
counseling methods that were effective in those trials. Nemours Children's Clinic-Jacksonville will be the 
Coordinating Center. Dr. Wysocki has extensive experience with multi-center studies structured in this way, 
including four NIH grants and service as a PI in the JDRF Artificial Pancreas Project. Coordinating centers for 
these studies managed enrollment, randomization, data management and statistical analysis while clinical 
sites recruited participants, obtained informed consent, implemented study protocols, collected data and sent it 
to the coordinating center. Dr. Wysocki's team has been the coordinating center for several major grants and 
he has learned other coordinating centers' practices through the multi-site studies described below. These 
experiences have equipped him to manage the proposed study using a similar organizational structure. Boris 
Kovatchev, Ph.D. of the University of Virginia brings an international reputation as a quantitative researcher on 
glucose dynamics, quantification of accuracy of continuous glucose sensors, mathematical models of glycemic 
variability and prediction of extreme glycemic excursions. His contributions will capitalize on the extensive CGS 
and SMBG data that will be collected. Rusan Chen, Ph.D. of Georgetown University will be the statistician. He 
has substantial experience in this role in behavioral research in pediatric diabetes and has special expertise in 
the use of the Individual Growth Modeling methods that are central to the proposed analysis plan. Linda C. 
Sobell, Ph.D. will provide expert consultation on integrating motivational interviewing with behavior therapy. 
 
4.2 Diabetes Research in Children Network (DirecNet; 1-U10-HD/DK-41918). A 2001 RFA sought 
applications for studies of the pediatric use of CGS's. Dr. Wysocki's application, "Continuous Glucose Sensors 
in Youth: Biobehavioral Study", sought to identify predictors of benefit from CGS use. His application was 
funded and he became a member of the DirecNet Steering Committee along with 4 physician PI's and this 
group has since conducted multiple CGS studies. Dr. Wysocki has published on psychological aspects of CGS 
use, 45 measurement of satisfaction with CGS 57 and methods of quantifying CGS measurement error. 101 Initial 
DirecNet studies tested the accuracy of two early CGS devices, the GlucoWatch Biographer (GWB) and 
Medtronic-Minimed CGMS during stable, rapidly decreasing and rapidly increasing glucose levels in youths 
during 24-hour hospital stays. 59, 62 Point estimates of glycemia by both devices were adequate during the 
 
 
 
 
 
 
 
 
  ACCURACY AT DIFFERENT GLUCOSE CONCENTRATIONS 
 
MEDIAN 
RELATIVE 
ABSOLUTE 
DEVIATION 

 
11
steady-state but both devices underestimated rapidly changing glycemia. Both devices detected glycemic 
trends accurately, implying that adding them to T1DM therapy could be beneficial. The figure above shows the 
improvements in accuracy of these devices, but both remain less accurate than SMBG meters in terms of 
point estimates of glucose. All tested CGS devices overestimate very low glucose levels. Manufacturing 
changes for the CGMS sensors improved accuracy compared with the original CGMS. The figure above 
portrays the Median Relative Absolute Deviation between CGS devices and SMBG meters compared to 
readings with the Beckman Glucose Analyzer.  This figure compares three CGS devices, the GlucoWatch 
Biographer (GWB), the first and second generation Minimed CGMS, and the Freestyle Navigator and the Ultra 
and the Freestyle SMBG meters. The results show that the successive iterations of CGS devices have shown 
steadily improved accuracy. While CGS accuracy for point estimates of glucose levels lags behind that of 
SMBG meters, its detection of trends and potential for prevention of extreme fluctuations warrants optimism 
for its clinical utility. 
 
DirecNet completed a randomized, controlled trial of the GlucoWatch Biographer (GWB), with HbA1C and 
"blinded" use of the Medtronic CGMS as primary outcomes. 56 A sample of 200 highly motivated, compliant 
T1DM patients with mean baseline HbA1C of 7.9% was randomized to SMBG alone or augmented with GWB 
use for 6 months. The study showed that the GWB did not affect glycemic control, hypoglycemia, quality of 
life, or adherence. GWB use declined steadily and 26% of patients stopped using it. Skin problems, gaps in 
data, inaccuracy, and calibration failures limited benefit from the device.  
 
DirecNet also evaluated the accuracy of the Freestyle Navigator 62 and completed pilot studies of its clinical 
utility among 30 youths with T1DM on insulin pumps 2 and 27 youths on multiple daily injections. 3-4 Complete 
data are available for 13 weeks' use of the Navigator for 51 of the 57 children who enrolled. A total of 9 
patients stopped using the Navigator within 13 weeks, 2 on insulin pumps and 7 on MDI regimens. Mean 
HbA1C declined significantly for pump patients (p < .01) and for MDI patients (p < .04) over 13 weeks, with 
larger decreases among patients with higher baseline HbA1C on either regimen. Further slight decreases in 
HbA1C have been observed among the patients who have continued using the Navigator for up to 18 months. 
There was no change in the frequency of severe hypoglycemia relative to the 6 months prior to enrollment for 
either sub-sample, showing that reduction in HbA1C was not accompanied by increased risk of severe 
hypoglycemia. Scores on the Continuous Glucose Monitor Satisfaction Scale were uniformly positive for both 
pump and MDI participants. Among pump patients, the added Navigator burden did not adversely affect 
quality of life for parents or children. Youths on MDI regimens, but not their parents, reported significantly 
improved scores on the PedsQL Diabetes Module 136 after 13 weeks of CGS use. All of these results should 
be interpreted in context, since the enrolled children and parents were carefully selected and highly motivated 
and may not be representative of the broader clinical population. 
 
A 2006 RFA to renew this network sought applications focusing on hypoglycemia rather than CGS. Dr. 
Wysocki transferred his role as a DirecNet PI to his colleague, Nelly Mauras, M.D. to maintain his interests in 
CGS use by pursuing the study proposed here. Dr. Wysocki's service as a DirecNet PI over the past 6 years 
provided him with extensive multidisciplinary experience, detailed knowledge regarding available and 
emerging CGS devices, thorough understanding of the measurement and analytic issues that are unique to 
CGS evaluations and healthy skepticism and curiosity about the clinical adoption of this technology. He has 
also developed and validated several measures proposed for collection in this study.  
 
4.3. Juvenile Diabetes Research Foundation (JDRF) Artificial Pancreas Project 
The 5 DirecNet centers are among the 9 clinical sites for this JDRF-funded trial comparing CGS and SMBG 
regimens in T1DM. Dr. Wysocki is the Nemours' PI. Recruitment occurred from January to December, 2007 
and a diverse sample of 451 patients has been randomized to SMBG or to CGS for 6 months; all patients will 
be offered CGS for the succeeding 6 months. Glycemic control, severe hypoglycemia, health care use, 
satisfaction with CGS, fear of hypoglycemia, quality of life, and health utilities will be measured periodically. 
Many aspects of this protocol were integrated into the present application, including: Patient/family selection of 
preferred CGS device; Clinical use of one of three CGS devices proposed for this study; Continuation Phase 
with CGS offered as an enrollment incentive; Collection of several of the same measures for evaluating impact 
of CGS on diabetes care and family life; and Incorporation of periodic 7-day use of a "blinded" CGS device by 
the SMBG group for comparisons of their glucose profiles to those of the two CGS groups. While working on 
the JDRF Artificial Pancreas Project, Dr. Wysocki has gained further experience within a large scale, 
multidisciplinary trial of CGS use in pediatric diabetes. This project also provided psychometric validation data 
for the Glucose Monitoring System Rating Survey that will be used in the proposed study. 
 

 
12
 
4.3. Family Management of Childhood Diabetes (NICHD Research Contract # N01-HD-4-3361). Dr. 
Wysocki is one of four PI’s for this NICHD research contract. Applications were sought to design and conduct 
this randomized trial of a low-intensity, family-focused, clinic-integrated behavioral intervention. The 
intervention seeks to prevent deterioration in glycemic control, treatment adherence, family relations and 
quality of life in early adolescence. The conceptual framework is that modest behavior change in most families 
could yield substantial public health benefits. To enhance clinical translation, the interventionists are B.A. and 
M.A.-prepared persons and the intervention has been manualized. Numerous behavior change handouts have 
been prepared and refined to address common diabetes-specific behavioral problems. A 9-month pilot and 
feasibility study of 122 families affirmed the feasibility of the recruitment, retention, measurement and 
intervention protocols for the study and enabled refinement of the intervention. Subsequently, 410 families 
enrolled in the main trial, with 94% retention to date over 9 months. Data collection will end in the fall of 2008. 
Many aspects of this protocol have been incorporated into the present application, particularly an intervention 
manual, educational materials, behavior management handouts, behavioral homework assignments, and 
attention to practicality for clinical translation. The primary implication of the FMOD trial for this application is 
that the PI has gained substantial experience developing, implementing and evaluating a family-focused, 
clinic-integrated behavioral intervention targeting more effective family management of T1DM in early 
adolescence. These experiences directly informed the structure and process of the proposed intervention. 
 
4.4. Behavior Therapy for Families of Diabetic Adolescents (1-R01-DK-43802). Dr. Wysocki was also PI 
on this NIH-funded multi-center trial that has completed its second funding cycle. During the first funding cycle, 
BFST yielded improved parent-adolescent relationships and reduced family conflict about diabetes, but these 
changes did not yield corresponding improvements in treatment adherence or glycemic control. 11-13 In the 
second funding cycle, the BFST intervention was revised to enhance its impact on diabetes outcomes. A 
sample of 104 adolescents with HbA1C > 8.0% enrolled at Nemours Children's Clinic and at Washington 
University School of Medicine. Families were randomized to Standard Care alone or augmented by 6 months' 
treatment either in a multifamily educational support group or in Behavioral Family Systems Therapy.  The 
revised intervention exerted substantially greater effects on adherence and glycemic control, particularly 
among youths with HbA1C above 9.0%. The revised BFST-D yielded durable improvements in adherence and 
glycemic control clearly relative to the Standard Care group and more equivocally relative to the Educational 
Support group, and similar effects occurred on measures of directly observed family communication. 14-16 This 
confirms Dr. Wysocki's capacity to coordinate a multi-site intervention trial and the studies provided substantial 
experience with family problem solving and communication training interventions in T1DM. Many of the 
intervention educational materials and handouts developed for this work will be used in the planned trial.  
 
4.5. Intensive Therapy for IDDM in Youths: Outcome Prediction (1-RO1-DK-50860-05). Dr. Wysocki was 
PI of this NIH-funded randomized, controlled trial of Intensive Therapy versus Usual Care that enrolled 147 
children and adolescents with T1DM. The objective of this 5-year, 2-center project was to identify psychosocial 
predictors of treatment outcomes. Data collection was completed for 129 of the 147 families. Average HbA1C 
was 8.2% for both groups at baseline and after 9 months of treatment was 8.3% for Usual Care and 7.7% for 
Intensive Therapy. 49 Incidence of severe hypoglycemia was 56/100 patient-years for Intensive Therapy and 
45/100 patient-years for Usual Care, for a relative risk of 1.24. This study demonstrated the PI's capacity to 
conduct and disseminate a multi-center trial with this population, and to coordinate a complex clinical 
intervention and investigative protocol requiring close collaboration with medical colleagues.   
 
The trial results showed greater absolute and relative glycemic benefit from Intensive Therapy for patients who 
were lower in self-management competence 50 and parental supportive involvement 51 at enrollment than those 
with more favorable status. Thus, youths who might be considered poor candidates for intensive therapy 
enjoyed more glycemic benefit from it. These findings suggest that adolescents with suboptimal diabetic 
control might also derive benefits from adding CGS to T1DM care. The pertinence of this intensive therapy trial 
for the present application is that patients with initially poor glycemic control, self-management competence 
and parental support ultimately realized greater benefit from intensive therapy. The findings underscore the 
present emphasis on evaluating the impact of CGS use by adolescents with sub-optimal glycemic control.   
 
4.6. Publications on Self-Monitoring of Blood Glucose.  Dr. Wysocki has published on the therapeutic  
impact of SMBG and CGS. 45, 57, 101, 140-142 He was an invited speaker at the ADA 1994 Consensus Conference 
on Self Monitoring of Blood Glucose. His interest in optimizing the benefits of CGS is a logical extension of 
these interests. Relevant publications are listed in Section 7. These papers emphasize Dr. Wysocki's lasting 

 
13
interests in the psychological context of evolving glucose monitoring technology. These papers also argue that 
such variables will affect therapeutic outcomes as these technologies are disseminated into clinical practice. 
 
4.7. Summary. Dr. Wysocki has many qualifications for conducting the planned study, including previous CGS 
research, directing and contributing to multi-center clinical trials with this population, studies of psychological 
aspects of T1DM management and evaluation of behavioral interventions to enhance family management of 
T1DM. The proposed study is a logical extension and integration of this prior work that would evaluate a 
specialized behavioral intervention targeted to optimize therapeutic benefits of CGS technology. 
 
5.  RESEARCH DESIGN AND METHODS 
5.1 Experimental Design.  We propose a randomized controlled trial in which 150 adolescents with T1DM 
and their primary diabetes caregivers will be randomized to 9 months in one of three experimental conditions. 
 
                                                              DIAGRAM OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 Standard Care (SC): Intensified T1DM therapy based on conventional finger-stick SMBG and either   
       insulin pump or multiple daily injection regimens and the use of carbohydrate counting and insulin  
       dose correction factors. The incorporation of a CGS device into diabetes management presumes  
       the intent to strive for optimal glycemic control. Hence, patients on conventional, fixed dose insulin  
       regimens would not represent an appropriate comparison group for the two groups described below. 
• 
 Continuous Glucose Sensor (CGS): The SC regimen above augmented by use of a CGS for glucose  
monitoring, managed by a physician, diabetes educator and dietitian as in typical clinical practice. Parents  
and youths will receive very detailed training in all aspects of CGS use and interpretation. 
• 
Continuous Glucose Sensor Plus Behavior Therapy (CGS+BT): The CGS regimen above 
supplemented with a psychological intervention targeting family diabetes management behaviors that are 
hypothesized to mediate benefit from CGS use. 
 
After the 9-month Randomized Phase, all three groups will be offered a 3-month Continuation Phase during 
which youths would receive the CGS regimen as above. The goal of all three regimens will be to achieve 
HbA1C < 7.0% while minimizing risks for severe hypoglycemia.  A 9-month duration for the Randomized Phase 
was selected because: 1.) DirecNet data suggests that frequency of CGS use declines among youths and this 
continues beyond 6 months; 2.) Prolonged CGS use may change T1DM self-care behaviors and we hope to 
observe this over a sufficient interval. 3.) We hope to achieve adequate statistical power for evaluation of 
Eligibility of adolescent and family confirmed 
Parental permission and adolescent assent obtained (n=150)  
Baseline evaluation and  
7-day period of blinded CGS use  
Randomization stratified by HbA1C and center 
Standard Care Group  (SC) 
Continuous Glucose Sensor Group 
(CGS) 
Continuous Glucose Sensor Plus 
Behavior Therapy Group (CGS+BT) 
Continuation Phase, consisting of 3 months' use of a 
Continuous Glucose Sensor for all groups 
Quarterly data collection 
9 months treatment with assigned regimen 

 
14
effects on severe hypoglycemia; 4.) Multiple data collection points for the primary outcomes capitalize on the 
strengths of individual growth modeling; 5.) A longer duration would delay availability of these important data. 
The 3-month duration for the Continuation Phase of the study was chosen because it is sufficient time for 
those randomized to the SC group to benefit from CGS use and it was a sufficient incentive in past DirecNet 
studies to achieve recruitment and retention goals and to be fair to study volunteers. The Continuation Phase 
will provide an incentive for SC participants to enroll and remain active in the study during the 9-month 
randomization phase. In the DirecNet and JDRF studies, access to CGS use was a key reason many families 
chose to enroll. It will also enable evaluation of the maintenance of intervention effects among CGS+BT 
youths. Deterioration of CGS+BT gains during the Continuation Phase would provide further evidence of the 
intervention's effectiveness. It will also permit evaluation of the longer-term CGS use by the CGS group, by 
tracking the degree to which those youths maintain CGS use over 12 months. Finally, it will enable replication 
of CGS benefits among SC youths who elect to use CGS during the Continuation Phase. 
 
5.2. Participants.  A sample of 150 youths with T1DM will be recruited from Nemours Children's Clinics 
(~50/center) in Wilmington, Delaware and in Orlando and Pensacola, Florida. Participants will not be recruited 
in Jacksonville because ongoing studies there would impede recruitment for this study. Nemours registrations 
show 914 current T1DM patients at the three sites who will be in the targeted age range (11 to <17 years old) 
at the start of enrollment. Of these, 518 patients (57%) have HbA1C > 7.5%, and this will probably increase as 
these patients age. The combined clinical populations at the three sites have been growing by about 300 
T1DM patients annually, and so there should be over 550 eligible patients by the start date. The proposed 
sample size is justified in Section 5.13. With 35-45% recruitment rates in prior similar studies, and the 
likelihood that 15-20% of prospective youths are likely to be excluded based on the enrollment criteria, 
achievement of the recruitment goal requires that the study draw upon three clinics. Based on similar studies, 
we expect <10% attrition over the 12-months, yielding complete data on at least 135 youths. The parent or 
other caregiver who is most involved in each child's diabetes care will be required to participate, and other 
caregivers will be allowed to participate. Eligibility criteria were designed to enroll appropriate candidates for 
use of a CGS device who have recently achieved suboptimal HbA1C. These criteria include: 
• 
Age of child > 11 years and < 17 years. This age range was chosen because families of adolescents often 
struggle with diabetes management. Youths > 18 years old may be likely to leave home during the study. 
• 
Duration of diabetes > 2 years or > 1 year with negligible stimulated c-peptide level, to exclude those with 
significant residual pancreatic insulin production. 
• 
Most recent HbA1C > 7.5% and < 10.0% or mean HbA1C over the prior 12 months within that same range. 
• 
Youth has never used a CGS device for clinical management of diabetes.  
• 
Absence of any other medical conditions that, in the opinion of the attending endocrinologist, would 
impede completion of the study protocol. 
• 
Youths may not be on daily glucocorticoid medications due to hyperglycemic effects of these agents. 
• 
Intention to remain in the same region and to maintain diabetes care at the enrolling center for 12 months. 
• 
Not enrolled in special education for mental retardation, autism or severe behavior disorders. 
• 
Primary diabetes caregiver not diagnosed or in treatment for major depression, psychosis, bipolar disorder 
or substance use disorder within the 6 months prior to enrollment; Child not in an inpatient psychiatric unit 
or day treatment program during the 6 months prior to enrollment. 
• 
Family has working telephone service. 
 
The objective is to enroll 150 youths with T1DM with HbA1C above target despite treatment with intensified 
T1DM regimens. We limited enrollment to youths with HbA1C > 7.5% and < 10.0% since they have much to 
gain in terms of improved glycemic control, reduction of health care costs and deferral of complications. 
Youths with HbA1C < 7.5% have different goals for adding CGS to diabetes care, such as decreased severe 
hypoglycemia and glycemic variability rather than reduction in HbA1C., while those with HbA1C > 10.0% may 
be unable to use CGS safely. Inclusion of two sub-samples with differing primary outcomes would create 
analytic problems that are avoided with a more homogeneous sample. The JDRF Artificial Pancreas Project 
will enroll a sub-sample of patients with HbA1C < 7.0%, while our study will make a unique contribution by 
focusing on adolescents with suboptimal glycemic control. 
 
5.3. Stratified randomization Youths entering the study must have been on a T1DM regimen for >6 months 
comprising either a "basal-bolus" multiple daily injection (MDI) or continuous subcutaneous insulin infusion 
(CSII; insulin pump) regimens using carbohydrate counting and insulin correction factors. To promote equality 
of the groups in HbA1C, randomization will be stratified by two HbA1C levels: <8.8% and >8.8%. Separate 

 
15
randomization lists will be used for each center and HbA1C stratum. After the baseline evaluation, adolescents 
within each stratum will be randomized with equal probability to the three groups (SC, CGS or CGS+BT) so 
that each center randomizes similar numbers into each group and so that the groups are similar in HbA1C. 
 
5.4. Representation of Genders, Minorities and Children. We will ensure a diverse sample via taxi fare, 
meal vouchers, and payment for child care to enable low-SES families to enroll. We will provide 15 personal 
computers for families who do not have one for CGS and SMBG downloads. Test strips for SMBG will be 
provided to those lacking insurance coverage. Written materials will be translated into Spanish and back-
translated into English. Sampling goals will be: Gender: 50% boys, 50% girls; Children: All enrolled patients 
are <18; Race: 80% Caucasian; 20% African-American; Ethnicity: 90% Non-Hispanic; 10% Hispanic.  
 
5.5. Measures. We will measure biomedical, behavioral and psychological outcomes and potential mediators 
or moderators of those outcomes. Questionnaires will be scored automatically with an optical scanner.  
 
Measures Collected at Baseline Only 
 
General Information Form (GIF) This form used in our prior studies records the child's age, sex, date of birth, 
date of diagnosis of diabetes, treatment regimen, family composition, parents' marital status, and each 
parent’s occupation and highest level of educational attainment. We will calculate the Hollingshead Four 
Factor Index of Social Status, an index of socioeconomic status (SES). 144 
 
Diabetes Problem Solving Interview (DPSI) This is a structured interview validated in the FMOD trial that 
assesses parents' and youths' skills in the correction and prevention of unwanted blood glucose fluctuations. 75 
Respondents are given 2 of 12 available diabetes scenarios and asked these questions about each: 1.) What 
is the diabetes problem here? 2.) Why is this a problem? 3.) What would happen if he/she did nothing? 4.) Tell 
me all the ways this problem could be fixed; 5.) How would you fix this problem? 6.) How would that solution 
work? and 7.) How would you know if you really fixed the problem? Responses are audio-recorded and then 
coded with scenario-specific scoring rules. An in-press paper verified the psychometric properties of the 
instrument and showed that baseline DPSI scores predicted youths' HbA1C over 9 months. 75 
 
Measures Collected Quarterly The following measures will be obtained at each quarterly diabetes clinic visit: 
 
One-Week "Blinded" CGS Use As in the JDRF Artificial Pancreas Project, prior to randomization, each family 
will be given a "blinded" CGS device (glucose feedback disabled) to use for 7 days and to return to the clinic 
for downloading. A minimum prerequisite for randomization will be at least 96 hours of analyzable CGS data. 
In addition to providing valuable data, this will serve as a "run-in" period to screen out participants who cannot 
comply with basic requirements and enable them to withdraw if they find CGS use to be intolerable (6 of 451 
JDRF participants did so). Blinded CGS use will recur at 3, 6 and 9 months. CGS data obtained from SC 
participants in this manner will be compared to comparable data obtained during CGS use by those in the 
CGS and CGS+BT groups. Periodic 7-day samples of CGS data will be randomly selected from these 
participants' downloaded CGS data from within the month prior to each quarterly clinic visit. 
 
Hemoglobin A1C and other medical variables  Finger-stick blood samples will be obtained for central 
laboratory HbA1C assays at Baseline and each 3 months. For eligibility verification and clinical use, HbA1C will 
be measured on DCA-2000 analyzers (Bayer Diagnostics Inc.) at each site as usual. 146 Blood samples will be 
obtained at each quarterly visit and sent to the Baptist Medical Center lab in Jacksonville using the sample 
collection and shipping protocol that is currently used in the FMOD trial. Assays will be run on a Tosoh 
Analyzer using cation-exchange HPLC to separate hemoglobin fractions, including stable A1C, by a buffer 
gradient of increasing ionic strength. Coefficients of variation range from 2-3%. Several studies have shown 
high correlations between HbA1C measured by DCA-2000 versus central labs using such HPLC, but there is 
consistent bias in DCA-2000 results so that central lab measurement is needed. 132 Other medical variables 
that will be obtained quarterly include Tanner Stage (breasts for females; genitalia for males; pubic hair for 
both), height, weight, Body Mass Index, linear growth velocity, and details of T1DM regimens. 
 
Glucose meter with memory All patients with T1DM at these clinics use glucose meters with memory, 
enabling storage of SMBG results by date and time. Downloading stored data provides a complete record of 
the patient's SMBG results. Patients will bring their meters to all clinic visits for downloading and discussion of 
treatment changes. Adolescents will receive a $10 gift card at each clinic visit if they bring their blood glucose 
meters with them for downloading, a procedure that has yielded 94% adherence in the FMOD trial. 

 
16
Downloaded data will yield descriptive statistics and measures of glycemic variability described below. The 
project will provide SMBG test strips to those without insurance coverage for them. 
 
Continuous Glucose Sensor Diabetes Nurses will be trained by representatives of each CGS company, and 
with an on-line curriculum that will soon be on the JDRF website. 149 Kim Englert, R.N, a Diabetes Nurse in the 
JDRF Artificial Pancreas Project, will coordinate bi-weekly video-conferences for study nurses before 
enrollment and monthly case discussions in the first 2 years. Patients in the CGS and CGS+BT groups will 
select, with the help of diabetes nurses and physicians, the available CGS device that best matches their 
preferences for use during the study. The devices and supplies will be provided without charge. The same will 
apply to SC participants during the 3-month Continuation Phase. For the CGS and CGS+BT groups, a 7-day 
continuous sample of CGS data will be selected randomly from the months prior to the 3-month, 6-month and 
9-month study visits to provide profiles for direct comparison to blinded CGS data for the SC group. 
Adolescents will be paid $10 for downloading the CGS device and sending the data to the coordinating center 
monthly. In the DirecNet and JDRF studies, virtually all families have been able to arrange this using either 
their own computers or one owned by a relative, neighbor or employer. The study will provide a home 
computer, internet access and training for up to 15 low-SES families. 
 
Glycemic Variability Kovatchev's Low Blood Glucose Index (LBGI) and High Blood Glucose Index (HBGI) are 
derived from SMBG values 104-108 and they reflect cumulative deviations of low and high glucose values from 
the logarithmic midpoint of the normal range. The LBGI and HBGI were validated as predictors of severe 
hypoglycemia and HbA1C, respectively. The LBGI integrates the weighted values of each BG value that is 
below 112.5 mg/dl, the logarithmic midpoint of the normal range. The LBGI can be calculated over any interval 
ranging from a single SMBG result to multiple tests. The HBGI is calculated similarly from BG readings above 
112.5 mg/dl. Kovatchev et al. have developed another metric derived from SMBG data, the Average Daily Risk 
Range (ADRR) and compared prediction of hypoglycemic and hyperglycemic events based on the ADRR with 
predictions from other indices of variability. 109 The ADRR was the best predictor of both hypoglycemic and 
hyperglycemic events. The proposed study will permit validation of the ADRR with children, which has not 
been done. Kovatchev et al. have also validated methods of quantifying glycemic variability for CGS data 
(Poincare Plots; blood glucose rate of change; Markov Chain interpretations) and these methods also warrant 
study in children. 110-113 We will calculate all of these measures of glycemic variability quarterly from SMBG 
data (all groups) or CGS data (patients using CGS). For patients randomized to SC, we will calculate these 
indices based on the 7-day periods of blinded use of a CGS device at Baseline, 3-months, 6-months and 9-
months. Comparisons of these measures as predictors of severe hypoglycemia will enable a direct 
comparison of the utility of SMBG and CGS for predicting those events. Kovatchev and colleagues have also 
shown that these indices are sensitive to changes in diabetes regimens such as initiation of pramlinitide 111 
and islet cell transplantation. 112 Kovatchev and Clarke 112-113 have recently reported that the initial effect seen 
after adding CGS to T1DM therapy is reduced glycemic variability followed by decreased HbA1C. The 
proposed study will examine whether similar effects occur in our sample during CGS use. Dr. Kovatchev's 
consultation provides added assurance that the substantial CGS data to be collected in this study will yield 
important contributions in the analysis of blood glucose dynamics and the validation of measures of glycemic 
variability. 
 
Hypoglycemia Diary As in our intensive therapy trial and DirecNet studies, parents will record youths' 
hypoglycemic episodes detailing the child’s symptoms, date and time of the episode, results of SMBG tests, 
possible contributing factors, and the type of treatment. Hypoglycemia will be categorized by the Diabetes 
Nurse as Moderately Severe (requiring assistance from another person), or Severe (including seizures or loss 
of consciousness). Parents will report these events by phone, fax or e-mail to the clinic promptly after the 
episode. The nurse will interview the parent and patient to verify that the reported episode meets the criteria 
for severe hypoglycemia, to attempt to specify the cause of the event and to educate the family in an effort to 
prevent recurrence. The low frequency of severe or moderately severe hypoglycemia may impede treatment 
of these variables as primary outcomes in the statistical analyses. If so, we will analyze Kovatchev's measures 
of glycemic variability that are empirically validated indices of risk for severe hypoglycemia that confer the 
added analytic advantage of being continuous measures rather than discrete events. 102-113 
 
Diabetes Self Management Profile This 24-item structured interview yields subscale scores for five domains 
of diabetes adherence (Exercise, Diet, Hypoglycemia, Glucose Testing and Insulin) and a total adherence 
score. 83,147 Cronbach's alpha coefficient was .76 for the total score and inter-rater agreement was .94. The 
correlation between total scores of parents and adolescents was .72. Correlations with HbA1C reported by 

 
17
several research groups were consistently significant (range -.25 to -.60). 14, 51, 147 Youths and parents will be 
interviewed separately by telephone by trained staff at Nemours-Jacksonville who are not associated with the 
diabetes clinical teams. Some interviewers will be native Spanish speakers. Interviews will be audio-recorded 
for later scoring and reliability checks. We will also record the frequency of SMBG testing and the extent of 
CGS use from computer downloads as additional indices of treatment adherence. 
 
Glucose Monitoring System Rating Questionnaire This instrument was developed for the JDRF Artificial 
Pancreas Project to permit direct comparison of conventional SMBG using a home glucose meter to 
conventional SMBG augmented by use of a CGS device. By contrast, the CGM Satisfaction Scale 56-57 was 
constructed by DirecNet to obtain participants' ratings of satisfaction with and impact of CGS devices that they 
had used for 3 months. The 25 items were drawn from the earlier 44-item CGM Satisfaction Scale and re-
worded such that participants rate the glucose monitoring system they are using (SMBG with or without CGS). 
Preliminary data from the JDRF trial show that the revised instrument has equally sound psychometric 
properties as the CGM Satisfaction scale, with the added advantage of enabling direct comparisons of SMBG 
and CGS within and between patients. Alpha coefficients were .93 for parents and .89 for youths. Parent-
Youth agreement was r = .61. Test-retest reliability was .71 for parents and .59 for youths at 3 months.  
 
Blood Glucose Monitoring Communication Questionnaire This is an 8-item scale on which respondents 
describe their communication and affect about SMBG data. 79 It is a three-choice Likert scale, with higher 
scores indicating more frequent negative affect around SMBG. Internal consistency was .77 for 153 youths 
and .82 for parents, parent and adolescent scores correlated significantly, and 1-year test-retest reliability was 
.70. Scores correlated significantly with HbA1C, diabetes-related conflict and quality of life. This measure will 
enable assessment of the extent to which provision of CGS data impacts emotional reactions to glucose levels 
and evaluation of the moderation of CGS treatment benefits as a function of scores on this measure. 
 
Hypoglycemia Fear Survey This scale 84-85 measures worry and behavior related to hypoglycemia. Separate 
parent and youth versions have been validated. 84-85 This measure will clarify if CGS use affects anxiety related 
to hypoglycemia. Since the content of this measure emphasizes aversion to experienced hypoglycemia rather 
than apprehension about its occurrence, we have added four items to evaluate this latter construct. 
 
Diabetes Family Responsibility Questionnaire Anderson et al 93 validated this measure of the degree to 
which 17 diabetes-related tasks is a parent, child or shared responsibility. This scale has been used in multiple 
T1DM studies 11-16, 21-23 and its psychometric properties have been strong consistently. This measure will 
enable assessment of the degree of parental involvement in diabetes management as a moderator/mediator 
of benefit from CGS use and whether CGS use, in turn, yields changes in this aspect of family function. 
 
Parental Support Interview Wiebe's 95-96 semi-structured interview assesses youths ratings of parents' 
emotionally supportive involvement in T1DM care. Children who reported low levels of parental support had 
worse treatment adherence and higher HbA1C. 95 The measure focuses on emotionally supportive involvement 
of parents, rather than instrumental involvement as in the Diabetes Family Responsibility Questionnaire. 93  
 
Diabetes Responsibility and Conflict Scale This scale 97 assesses parent-child conflict over 15 diabetes 
tasks. A recently validated revised scale has made it more applicable to modern T1DM regimens. 148 We have 
used this scale in several studies and have found excellent internal consistency (alpha .86 to .92). Only the 
conflict items will be used, and these should be sensitive to effects of CGS use on parent-child conflict. 
 
PedsQL Diabetes Module This is a 28-item questionnaire with separate forms for parents and youths. 136 The 
DirecNet Navigator studies showed positive effects of CGS use on this index among adolescents but not 
parents. Participants in those studies were highly compliant and enthusiastic patients with very favorable 
quality of life at baseline. Quality of life improvement due to CGS use could be more readily detectable in the 
proposed study since less favorable baseline scores are expected due to the enrollment criteria. 
 
Readiness to Change Questionnaire This brief scale, utilized previously by Sobell and colleagues 137-139 in 
other brief intervention studies, yields a convenient measure of motivation for change. It will be obtained 
quarterly from CGS+BT participants with regard to their selected target behaviors. 
 
5.6. Cost-Effectiveness During 4 selected 2-week periods during months 18 through 36, all clinicians will 
record the time spent in clinical interactions with participants. These "time-sampled" recordings will include all 
activities related to clinical diabetes care, including clinic appointments, telephone contacts, e-mail exchanges, 
downloading of glucose meter or CGS devices, interpretation of downloaded data, etc. Activities that are done 

 
18
for research purposes only (recruiting, informed consent, questionnaire administration, data transmission) will 
be excluded. Clinicians will record the duration, nature and purpose of each clinical contact (clinic, phone, e-
mail) or other clinical activity (downloading, CGS or meter maintenance, provision of supplies) with each 
patient using methods employed successfully in Dr. Wysocki's intensive therapy trial. The ratio of time 
dedicated to Intensive Therapy patients to that for Standard Care patients during that study was about 4.5:1 
for Diabetes Nurses, 3:1 for Dietitians and Psychologists and 1.3:1 for Physicians. The similarity of these 
estimates to those reported in the DCCT supports this method as a valid estimate of the degree of health 
professional time devoted to patients receiving varied interventions, permitting a reasonable derivation of the 
per-patient incremental costs for the CGS and CGS+BT regimens relative to the SC regimen. We anticipate 
that the personnel time for the CGS groups will decline as the study proceeds, but distributing the observation 
periods throughout the study will yield a valid estimate of the relative personnel requirements for each 
condition. From these "time-sampled" cost estimates we will extrapolate the per-patient personnel costs of 
each of three conditions for the entire 9-month Randomized Phase.  At quarterly clinic visits, parents will report 
the occurrence of hospitalizations, emergency room visits, and clinic visits. These reports will be verified by the 
Diabetes Nurse by medical records checks whenever possible. The costs for hospitalizations, ER visits and 
clinic visits will be obtained from the involved medical facilities. The retail costs of CGS devices and supplies 
will be included. Cost effectiveness of the CGS and CGS+BT will be evaluated descriptively both by direct 
comparison of the estimated costs of SC, CGS and CGS+BT and by reporting the cost per 0.5% improvement 
in HbA1C during the study for each group. These descriptive analyses will also focus on whether the added 
costs associated with the CGS regimens are offset by reductions in health care utilization (clinic visits, 
emergency room visits, hospitalizations) for those groups relative to Standard Care.  
5.7. Measurement schedule. In the measurement schedule below, “P” indicates collection of the measure 
from parent, "A" = from adolescents and “B” = from both parents and youths. All measures will be translated 
into Spanish and back-translated into English by native Spanish speakers. Participants may choose whether to 
complete the English or Spanish versions. Internal consistency and test-retest reliability will be calculated for 
each measure based upon data collected in the proposed study. 
MEASUREMENT SCHEDULE 
         Study Visits (Months) 
Measure 
 
0 
3 
6 
9 
12 
General Information Form (P)
•
Glucose Meter memory downloads (A) 
 
•
•
•
•
•
CGS Device downloads (A) 
 
 
•
•
•
•
•
Measures of glycemic variability (A) 
 
•
•
•
•
•
Hypoglycemia Diary (B) 
 
•
•
•
•
•
HbA1C  
(A) 
 
•
•
•
•
•
7-Day Blinded CGS use (SC only) 
 
•
•
•
•
•
Diabetes Self Management Profile (B) 
 
•
•
•
 
•
Glucose Monitoring System Rating Scale (B) 
 
•
•
•
•
•
BG Monitoring Communication Questionnaire 
 
•
•
•
•
•
Hypoglycemia Fear Survey (B) 
 
•
•
•
•
•
Diabetes Family Responsibility Questionnaire (B) 
 
•
•
•
•
•
Wiebe Parental Involvement Interview (A) 
 
•
•
•
•
•
Diabetes Responsibility & Conflict Scale (B) 
 
•
•
•
•
•
PedsQL Diabetes Module (B )  
 
•
•
•
•
•
Readiness to Change Questionnaire (B) (CGS+BT only) 
 
•
•
•
•
•
Diabetes Problem Solving Interview (B) 
      
•
 
 
 
 
 
The only copyrighted instrument being administered is the PedsQL quality of life questionnaire, but Nemours 
owns a site license that permits free use and distribution for research purposes at all Nemours entities. 
Consequently, it will be possible to enable administration of the various measures via a secure internet 
connection using the Opinio software platform. This functionality will enable participants to complete 
questionnaires from anywhere that provides internet access at any time within the 2 week period immediately 
preceding each quarterly diabetes clinic visit.  If participants are unable to accomplish this, the questionnaires 
will be available for hard-copy administration at clinic visits and they will be encouraged to do so during waiting 
times before and during their visits. This flexibility should enable participants to control the amount of time 
dedicated to study participation on clinic visit days. 
 
5.8. Procedures.  Prior to randomization, all participants will complete the 7-day period of blinded CGS use. 
Data from the blinded CGS use will not be used for clinical management for the SC group. Participants who 
complete this run-in period will then complete the Baseline evaluation. Randomization will be stratified on 
Baseline HbA1c (<8.8% and >8.8%) and center. After the Baseline evaluation, the Diabetes Nurse will call the 
Project Coordinator at NCC-JAX to report the adolescent's HbA1C. A randomization list will dictate the 

 
19
adolescent's group assignment. The nurse will inform the family of their group assignment and then schedule 
an appointment with them for CGS training and with an endocrinologist to initiate intensive therapy.   
 
 
The Standard Care regimen will have these features: 
• 
Targets consisting of pre-prandial blood glucose of 70-120 mg/dl, 90 minute postprandial blood glucose 
below 180 mg/dl and 3AM blood glucose >65 mg/dl, unless the attending endocrinologist determines that a 
particular patient's risk of severe hypoglycemia requires revised targets. 
• 
Targeted HbA1c  < 7.0% unless the attending endocrinologist determines that a particular patient's risk of 
severe hypoglycemia requires revised targets.  
• 
Targeted absence of severe hypoglycemic episodes and minimization of symptomatic hypoglycemia. 
• 
Multiple daily subcutaneous insulin injections of a long acting (e.g. glargine) and short acting (e.g. Novalog 
or Humalog) insulin or continuous subcutaneous insulin infusion with an insulin pump. There will be 
enough patients using each type of insulin regimen to permit statistical comparisons between them. 
• 
Completion of 4-6 blood glucose tests daily using a meter with memory function. Patients in all 3 groups 
will be instructed to use SMBG data to guide treatment decisions and insulin adjustments. 
• 
Completion of a 3AM blood glucose test monthly using a meter (SC group only). 
• 
Quarterly clinic visits with a Pediatric Endocrinologist.  
• 
Monthly telephone consultation with a Diabetes Nurse. 
• 
Advanced diabetes education regarding real-time and retrospective use of blood glucose data to minimize 
glycemic variability and optimize proportion of time spent in normoglycemia. 
• 
Dietary management using carbohydrate counting with appropriate nutritional education and counseling. 
• 
Referral for psychological services as needed based upon the opinion of the attending endocrinologist. 
• 
Incorporation of therapy advances that emerge before or during the study. The SC group may not use a 
CGS device during the 9-month randomization phase except in the blinded 7-day CGS use periods. 
• 
A "rescue procedure" will be employed for any youth whose HbA1C remains above 9% for 2 consecutive 
visits or whose HbA1C increases by more than 1.0% over baseline or who has more than one episode of 
severe hypoglycemia. As would typify clinical practices with similar patients, this will consist of offering 
monthly clinic visits with a diabetes nurse, weekly telephone consultation with the nurse and referral to a 
dietitian, social worker, psychologist or psychiatrist at the discretion of the treating endocrinologist. 
 
Patients randomized to SC will be treated as above but they will not use a CGS during the 9-month 
Randomized Phase. Given the enrollment criteria for this study, a baseline mean HbA1C for this group can be 
expected to be about 8.8% and we anticipate a 0.2% increase (~0.15 SD) to about 9.0% during the 9-month 
randomization phase of the study.  
 
All study participants will receive the above SC regimen. CGS and CGS+BT regimens will differ as below.  
 
Continuous Glucose Sensor (CGS) With consultation from the diabetes team, patients randomized to CGS 
will select a CGS device for use during the study from among those that can be made available for use in this 
study. Appropriate training and counseling will be provided by the diabetes nurse to include:  
• 
Parents and youths will be carefully trained in the safe and proper use of the selected CGS device and 
associated analytic software. Substantial emphasis will be placed on making treatment decisions 
suggested by CGS results only after a confirmatory SMBG check is done. CGS use will be portrayed as a 
supplement to SMBG, not a replacement. 149 Training will cover real-time and retrospective analysis of 
CGS data and appropriate responses to alarms, using a book by H. Peter Chase, M.D. 150 and the JDRF 
website "Continuous Glucose Monitoring Classroom" that will soon be available for public access.  
• 
Weekly phone contact initiated by the diabetes nurse during the first month of CGS use. 
• 
24-hour telephone access to an on-call pediatric endocrinologist. 
• 
Week-day telephone access to the diabetes nurse to report device-related problems. 
• 
A 2-week follow-up visit with the diabetes nurse to download the CGS device and further education about 
responding to CGS data prospectively and retrospectively. Clinical insulin dose adjustment algorithms 
previously developed and validated in DirecNet studies will be taught to adolescents and parents. A JDRF 
website will soon be available that will offer additional teaching materials and supports designed for 
patients using CGS as a component of diabetes management. 
• 
A 1-month follow-up visit with the diabetes nurse to review the family's use of the insulin adjustment 
algorithms and to evaluate the need for individual refinement of the algorithms. 

 
20
• 
The diabetes nurse will be permitted to bring selected adolescents and parents in for interim clinic visits 
as needed for remedial education to ensure that the adolescent and parent have the requisite knowledge 
and skills required for deriving optimal benefit from use of the CGS. 
 
Based on the DirecNet Navigator pilot study, we expect HbA1C to decline by approximately 0.3 SD over 9 
months to a mean value of about 8.4% for this group.  
 
Continuous Glucose Sensor Plus Behavior Therapy (CGS+BT) Patients randomized to CGS+BT will 
receive the same education and care as the CGS group. Also, a mental health professional (MHP; e.g. a 
licensed counselor, post-doctoral fellow, licensed clinical social worker, or psychologist) will deliver a 
behavioral intervention within a motivational interviewing context that is designed to identify each family's 
unique behavioral, cognitive or affective barriers and resources pertaining to optimal CGS use, negotiate with 
the youth and parent a plan addressing the identified targets, and assist the family in implementing, evaluating 
and possibly refining the selected intervention over the ensuing months. The MHP's role in this study will be 
very similar to that of the Health Advisor interventionists in the FMOD trial and we will make extensive use of a 
manual, intervention handouts, telephone contact protocols, intervention plan outlines and other such 
materials that were developed in that study. A preliminary draft of the intervention manual appears in the 
Appendix, to be further refined prior to initiation of the study. Each MHP will receive extensive training in 
Motivational Interviewing coordinated by our expert consultant, Linda C. Sobell, Ph.D. The MHP will guide the 
family in preparing an action plan that will include responsibilities of each family member in implementing it, 
methods of measuring the plan's effectiveness, and a timeframe for evaluation and refinement of the plan. At 
a minimum, the MHP will telephone the teen and parent 2 weeks before and 2 weeks after diabetes clinic visits 
to review the family's success with their plan, and trouble-shoot with them any problems they report in 
implementation of the plan. Like the diabetes educators, the MHP's will be permitted to make appointments 
with CGS+BT families for more phone contacts and supplemental face-to-face clinic visits as needed to 
provide the assistance they need to benefit from CGS. MHP's will see each CGS+BT family at every diabetes 
clinic visit, including with the Diabetes Nurse or Dietitian as needed. MHP's may target for intervention any 
problem that a family may report that may be impeding the adolescent from using the CGS optimally. MHP's 
will document the date, time, duration and content of all telephone and face-to-face encounters with CGS+BT 
families. MHP's will be trained to identify certain negative behaviors related to CGS use that could be 
intervention targets and to recognize instances in which families could benefit from targeting the promotion of 
positive behaviors rather than on remediation. Below are some CGS-specific target behaviors that MHP's may 
select with CGS+BT families. Additional target behaviors are likely to be identified during the study. 
 
The overall intent of this intervention trial is to maximize the therapeutic benefits obtained through 
augmentation of T1DM management with the use of CGS technology. This will be achieved through the 
application of best clinical practice of behavior therapy with adolescents when applied to the specific 
behavioral processes that modulate their benefits from CGS use. Components of this intervention, as 
described in greater detail in the appendix, were selected based on these key criteria: 
• 
  Reliance on motivational interviewing techniques to encourage patients and parents to play a central role   
        in the specification of behavioral goals, target behaviors and intervention methods. 
• 
 Emphasis on parent-adolescent interaction around CGS use as an intervention target. 
• 
 Extensive empirical support for all intervention components, ideally obtained from pediatric T1DM studies.  
• 
 Flexibility to enable application to unique CGS-related behavioral problems. 
• 
 Extent to which M.A.-trained therapists can learn to implement the intervention component proficiently. 
• 
Ease of dissemination of intervention materials and methods to other clinical sites. 
 
The structure of the planned intervention rests on three components, the first two of which will be delivered in 
the same manner to all participants and the last of which will be tailored to each family's unique targeted 
behaviors and contextual circumstances: 
 
1.) Reliance on Motivational Interviewing techniques to establish the patient-centered and family-centered 
focus of the intervention, and to assist participants in identifying and prioritizing goals that will be targeted by 
the behavior therapy intervention components. Motivational Interviewing is viewed here not as an intervention 
in and of itself, but rather as an entre' to enhance engagement with other intervention components. 
2.) All participants will receive training in Problem Solving and Communication Skills using materials and 
methods developed and validated in Dr. Wysocki's trials of Behavioral Family Systems Therapy for Diabetes. 
In addition, evidence of common Cognitive Distortions pertinent to family management of T1DM will be 

 
21
monitored and treated as communication errors using the above model, as has been done in our prior BFST 
trials. This approach includes extensive reliance on the common behavior therapy practices of instructions, 
feedback, modeling, rehearsal and individualized behavioral homework assignments. 
3.) Mental Health Professionals (MHP's) who will deliver the intervention will use a systematic method for the 
selection and implementation of behavior therapeutic intervention components to achieve improvements in the 
identified target behavior(s). For each of the anticipated target behaviors, the MHP will strive to select the 
intervention approach that has the strongest empirical support as the "first choice" approach to utilize with the 
family. This determination will be guided by a thorough compendium of empirical studies supporting various 
behavioral interventions in pediatric T1DM that appears in the appended intervention manual. Consistent with 
the Motivational Interviewing framework, parents and youths will play a central role in selecting from among 
recommended intervention components and tailoring the details to their preferences and circumstances.  
Failure of the selected strategy to achieve the therapeutic goal can result in the MHP modifying the 
intervention approach after proposing and defending the alternative approach to the satisfaction of Dr. 
Wysocki. A similar approach will be employed in selecting intervention strategies for families who identify 
intervention goals or target behaviors other than those that have been anticipated based on prior experience. 
 
Target Behaviors: Expected targets of intervention will include these "negative" behaviors: Inadequate 
frequency of CGS use; Resistance to completing calibration SMBG checks; "Ignoring" of alarms warning of 
impending hypo or hyper-glycemia; Resistance to doing finger-stick SMBG when CGS readings seem 
inaccurate; Adolescent concern about parental "snooping"; Inordinate family attention devoted to BG levels; 
Arguments about BG levels; etc. Targets of intervention will also include efforts to promote "positive" 
behaviors such as: Problem solving to prevent unwanted BG fluctuations; Parent-youth teamwork and 
brainstorming around CGS results; Goal setting for improved BG control; Conducting "experiments" to 
measure effects of dietary intake, exercise, etc. on subsequent BG levels and changes; Improving family 
communication about out of range BG levels; Parent-youth negotiation about diabetes management goals, 
responsibilities, etc. Other target behaviors are likely to be identified as the study proceeds. 
 
Intervention Intensity: Given the planned five sessions, the planned intervention is conceived as a brief, 
relatively low intensity intervention with quite specific treatment foci. Although each of the primary constructs of 
the Behavioral Family Systems model will be measured, 117, 145 we do not expect to observe profound treatment 
effects on complex, deeply ingrained systemic anomalies that may characterize some families. Instead, these 
theoretical constructs will be evaluated as moderators of CGS+BT treatment effects. 
 
Qualifications and skills of the Mental Health Professionals (MHP): MHP's will have prior experience in the 
delivery of brief behavioral interventions, ideally from among existing staff or associates of the respective 
diabetes clinics. Those who do not have substantial clinical experience with T1DM will receive extensive 
training, including directed readings, observation of diabetes education with newly diagnosed families, 
accompanying physicians or nurse practitioners in clinic visits with T1DM patients, and training in the use of all 
glucose meters, insulin pumps and CGS devices that might be used by study participants. MHP's will utilize 
behavioral intervention tactics that have been empirically validated with this population. MHP's will not be 
involved in recruitment of participants or with collection of study data to minimize possible reactivity and bias. 
 
In addition to relying on empirically validated behavior therapy techniques, the intervention for each 
patient/family will rely heavily upon motivational interviewing techniques. These methods have been validated 
with adolescent substance abuse, truancy, obesity and dietary habits 132-135 and have shown promise with 
adolescents with T1DM. 23-25 All MHP's will receive training in Motivational Interviewing 28-30, 132-135 as an adjunct 
to adolescent behavior therapy in two 2-day workshops conducted by Linda C. Sobell, Ph.D., a pre-eminent 
behavior therapist who has extensive experience integrating these two approaches. A draft of the workshop 
curriculum and plan is included in the appended intervention manual. After negotiated selection of target 
behaviors and intervention goals, the MHP will guide each parent-adolescent dyad/triad in the selection and 
design of an appropriate behavior therapy intervention that may draw upon one or more validated approaches. 
Problem solving training and family communication training materials and methods used in the BFST studies 
will be employed. 11-16 Behavior modification and behavioral contracting methods 121-125 have been validated in 
studies targeting increased frequency of SMBG in adolescents and these techniques are readily adaptable to 
similar behaviors in the CGS context. Self-monitoring and goal-setting 151-152 are commonly used behavior 
therapy methods that are effective in promoting behavior change. Behavioral homework assignments are a 
staple of behavior therapy interventions. Pertinent materials from the FMOD study and BFST studies will be 
utilized in the proposed study, for example, to explore glycemic effects of dietary behaviors or to measure the 

 
22
frequency of targeted parent-adolescent communication problems. Cognitive behavior therapy 153-154 and 
cognitive restructuring methods validated in the BFST studies 11-16 will be applicable to situations in which 
either parents or adolescents exhibit cognitions that are impediments to initiating or maintaining behavior 
change or in which anxiety is a key element of the target problem. Drawing upon treatment manuals 
developed and used in the BFST and FMOD studies, a CGS-specific intervention manual has been developed 
for this study. The further refinement of this manual will facilitate cross-site consistency in the intervention and 
enhance dissemination of the methods to other clinical settings once the research has been completed.  
 
Intervention visits will be scheduled to coincide with other study visits. The MHP will see each CGS+BT family 
at the Baseline visit, the 2-week and 1-month follow-up nursing visits and each quarterly clinic visit during the 
9-month Randomized Phase of the study, for a total of 5 scheduled clinical encounters. Telephone follow-ups 
will be scheduled at 2-weeks before and 2-weeks after each clinic visit, with more frequent contacts or e-mail 
communication if deemed necessary by the MHP. MHP's will be allowed to see CGS+BT families for separate 
face-to-face appointments if needed. The Baseline, 2-week and 1-month visits will be dedicated to delivery of 
a common psychoeducational curriculum to each CGS+BT family and to initial assessment of each family's 
current adaptation to T1DM and its management. The content of this curriculum will include basic principles of 
behavior change, positive reinforcement, problem solving skills, healthy communication, and conflict 
resolution. Examples of specific behavior change goals related to optimal CGS use will be employed to 
illustrate each of these principles in that context. The conclusion of the 1-month visit will be dedicated to 
assisting each family in identifying one or more targeted behaviors related to CGS use, ideally focusing on 
both positive and negative behavior change goals. CGS+BT visits beginning with the 3-month visit will be 
dedicated to evaluating and refining the behavior change plan(s) developed at prior visits.  
 
All face-to-face contacts between MHP's and CGS+BT families will be audio-recorded and sent to Dr. Wysocki 
for evaluation and coding for treatment integrity, using previously developed coding systems used in prior 
trials. This will include recording of the target behaviors and the type of behavior therapy methods used. 
Deviations from the intervention manual will result in re-training of the MHP involved as well as possible 
revision of the intervention manual to clarify sources of ambiguity. 
 
Based upon effect sizes achieved in our studies with similar samples, we anticipate that the CGS+BT group 
will achieve and maintain a mean HbA1C of about 7.4% for effect sizes of 1.2 SD relative to the SC group and 
0.8 SD relative to the CGS group. The sampling plan is designed to achieve adequate statistical power to 
detect effects of this magnitude. A 0.8 SD treatment effect is clinically significant. In terms of glucose 
variability and risk for hypoglycemia (measured by the LBGI), a recent study of 40 days CGS use (Navigator), 
20 days blinded followed by 20 days un-blinded, showed that the LBGI was reduced by ~0.35 SD during the 
period of un-blinded use of CGS compared to the blinded use period. 109 We anticipate larger effects in our 
trial due to its longer duration and enrollment of a sample with more pronounced baseline glycemic variability. 
 
5.9. Data Management and Statistical Analysis Plans. Prior to excusing a parent or youth after completion 
of any type of data collection, the researcher will ensure that missing items are completed and that errors are 
corrected.  Measures will be recorded on scannable forms for scoring using the Opscan 4.0 optical scanner 
(NCS-Pearson, Inc., Minneapolis, MN). Data will be double-entered and cross-checked before final computer 
entry. Data files will be backed up nightly, password-protected and stored on a local area network.  
Participants will be assigned study ID numbers that will be used rather than names to label completed 
questionnaires, paper records, etc. All raw data obtained during the project will be stored in locked file 
cabinets without names recorded on these items. The researchers will maintain a list of ID numbers paired 
with participants’ names and will keep this list in a password-protected computer file separately from other 
data. Signed informed consent forms, which will contain participants’ names, will also be stored separately in 
locked cabinets. Error checking routines will be created as part of the database application.  Weekly reports 
will be generated for the purpose of monitoring the accrual patterns and for the completeness of data. 
 
Statistical analysis will begin with treatment of missing data, preliminary descriptive analysis and visual 
inspection of distributions. 155-156 Appropriate transformations of variables will be used to restore normality if 
needed. Baseline values of the primary outcome and predictor variables will be compared to determine if there 
are significant pretreatment differences between the groups that require adjustments. Visual examination of 
scatter plots, histograms and other graphical summaries will be used to identify possible associations or 
treatment effects of interest. Where multiple statistical comparisons are planned, we will make appropriate 
multiplicity adjustments. 155-158 Internal consistency will be calculated for each psychometric measure based on 

 
23
data from this study and only those with alpha > .70 will enter data analyses. Upon completion of these 
preparatory activities, we will apply Individual Growth Modeling 160-161 to test the hypotheses listed below (see 
Section 5.12 for details).  
 
5.10. Hypotheses. The following hypotheses, corresponding to the three specific aims, will be tested: 
Hypothesis 1: Adolescents in CGS+BT will show more improvement in glycemic control (HbA1C, Kovatchev's 
measures of glycemic variability derived from SMBG and CGS data, and proportion of CGS values in the 
normal range) compared with those in SC and CGS over the 9-month Randomized Phase. 
 
Hypothesis 2: Adolescents in CGS+BT will realize more improvement in diabetes-related behavioral 
outcomes (Diabetes Self-Management Profile; PedsQL Diabetes Module; Diabetes Responsibility and Conflict 
Scale; Hypoglycemia Fear Survey; Blood Glucose Monitoring Communication Questionnaire: Blood Glucose 
Monitoring System Rating Questionnaire) compared with those in SC and CGS and in scores on the CGM 
Satisfaction Scale (CGS vs CGS+BT only) over the 9-month randomization phase of the study. 
 
Hypothesis 3a: Improvements in HbA1C during the 9-month Randomized Phase will be moderated by 
adolescents' and parents’ baseline status on the following measures: Socioeconomic status; Family 
composition; Adolescent age; Diabetes Problem Solving Interview, Parent-Adolescent Relationship 
Questionnaire; Diabetes Family Responsibility Questionnaire; Wiebe Parental Supportive Involvement 
Interview; and Diabetes Responsibility and Conflict Scale).  
 
Hypothesis 3b: Improvements in HbA1C during the 9-month Randomized Phase will be mediated by improved 
scores on the Diabetes Self-Management Profile, Diabetes Problem Solving Interview, Diabetes Responsibility 
and Conflict Scale, Wiebe Parental Supportive Involvement Interview, and Blood Glucose Monitoring 
Communication Questionnaire. 
 
5.11. Other planned analyses. The proposed study will yield a rich data set, permitting many interesting 
analytic directions.  Of special interest will be analyses of 1.) Maintenance (CGS and CGS+BT) and replication 
(SC) of treatment effects during the 3-month Continuation Phase; 2.) Determination of the frequency of CGS 
use that is associated with improvement in the various indices of glycemic control; 3.) Validation of 
mathematical models of CGS dynamics as predictors of the occurrence of severe hypoglycemia and HbA1C; 
4.) Evaluation of the temporal course of changes in glycemic variability and changes in HbA1C during CGS 
use; 5.) Descriptive analyses of cost effectiveness as described in section 5.6; 6.) Between-group comparison 
using survival analysis of the time to first occurrence of severe or moderately severe hypoglycemia; and 7.) 
Prediction of changes in frequency of CGS use over time based on demographic and behavioral variables. 
 
5.12. Analytic procedures. The randomized experimental design in this study will collect longitudinal data in a 
sequence of 5 time points at about 3-month intervals (Baseline, 3, 6, 9 and 12 months) from 3 treatment 
groups (SC, CGS, CGS+BT).  Individual Growth Modeling 160-164 will be applied to evaluate the treatment 
effects specified in the above hypotheses. The IGM approach, which also has been termed multilevel 
modeling, hierarchical linear modeling, or mixed effects modeling, is a particularly powerful and flexible 
approach for evaluating treatment effects within longitudinal data sets. The IGM approach has numerous 
advantages over traditional methods including 1) It compares the change of the outcome variable, such as 
HbA1C, over time instead of comparing mean differences at specific time points; 2) It does not require that time 
points be equally spaced or data be collected at the same time at each time point for all participants. In fact, 
participants may have individually varying data collection over time during the study; 3) The covariates, such 
as site differences in this study, can be easily included in the model to adjust for these possible nuisance 
effects. 4) The covariance structure of the repeated outcome measures can be modeled and statistically 
compared to obtain more accurate estimates; and 5). It handles missing values flexibly—all available 
measurements of the outcome variable can be included in the analysis, thus increasing the power of the study.  
 
The basic individual growth model consists of two levels. The level-1 model is the estimation of the shape of 
individual change curves over time. The level-1 model for linear change is: 
 
 
 
 
  
Y it =  π 0i   + π 1i * Time + ε it  
 
where Y it is the outcome variable for subject i assessed at time t, π 0i  is the expected intercept for subject i,    
π 1i  is the expected change rate (the slope) in the outcome for subject i, and ε it is the within random error for 
subject i conditional on that subject's change parameters. In this study, the outcome variables will be the 

 
24
youth’s glycemic control, Kovatchev measures of glycemic variability derived from SMBG and CGS data, 
Diabetes Self-Management Profile, Diabetes Responsibility, and Conflict Scale, etc., that will be repeatedly 
measured over time. The variable Time in the level-1 model will be measured in months, starting from the 
baseline of the study to the time of data collection.   
 
The level-2 models are used to test whether time-invariant predictors are related to the initial status and the 
change of the outcome over time. The treatment effect in this study will be coded as a dummy variable, a time-
invariant predictor of change to be evaluated in the level-2 models. Other examples of time-invariant predictors 
include socioeconomic status, parent marital status, and gender that are thought to be stable over time, and 
will be tested as the moderators of the treatment effect. Specifically, the level-2 models are  
 
 
 
 
 
π 0i    = β 00 + β 01 * X i  +  µ 0 i 
 
 
 
 
π 1i    = β 10 + β 11 * X i    + µ 1i 
 
where β 00  and β 10  are the grand means for the intercepts and the slopes estimated in the level-1 model, 
respectively. β 01 and β 11 are regression coefficients for X i which is a time-invariant variable for subject i, with 
µ 0 i and µ 1i the random errors in the models. When X i is the treatment effect coded as a dummy variable, a 
significant β 01 indicates that the outcome variable is different for the treatment groups at the baseline. Our 
major research interest is to evaluate coefficient β 11 ------ a significant β 11 shows that the change in the 
outcome variable is different for treatment groups due to the intervention program.  
 
Both the basic level-1 and level-2 models in IGM can be extended by including more variables in the models. 
In general, variables measured repeatedly over time, also referred to as time-varying or within-subject 
variables, are included in level-1 models.  The between-subject variables, also referred to as time-invariant 
variables and usually only measured at baseline, are included in level-2 models. The shape of the curves for 
the outcome variables will be determined first. Time-invariant and time-varying predictors will then be 
examined for their relationship with the outcome using the estimated growth factors of the trajectories. The 3 
primary hypotheses proposed in this study will be evaluated within the IGM framework. SAS Proc Mixed and 
Proc Glimmix will be used for the IGM analysis for the 3 primary hypotheses.  
 
Hypothesis 1: Adolescents in CGS+BT will show more improvement in glycemic control (HbA1C; 
Kovatchev's measures of glycemic variability derived from SMBG and CGS data; Proportion of CGS 
values in the normal range) compared with those in SC and CGS over the 9-month Randomized Phase. 
 
To evaluate the treatment effects on the change of glycemic control over time, HbA1C measured from baseline 
to end of study will be the outcome variable in the level-1 model.  A participant without missing values will 
have a total of 5 measures of HbA1C. The time interval between baseline and the measure of each HbA1C in 
the unit of months will be the Time variable in the level-1 model.  The shape of the HbA1C trajectory will be 
determined statistically by comparing a linear model and a quadratic model using the AIC and BIC indices 
produced by SAS Proc Mixed. In level-2 models, X i will be a dummy variable indicating treatment groups. For 
example, to evaluate the treatment effects between CGS+BT and CGS groups, the dummy variable will be 
coded 1 for CGS+BT and 0 for CGS.  A significant coefficient of the dummy variable will indicate that the 
change rate of HbA1C over time is different for the two groups due to the treatment effect. A similar strategy 
will be applied to evaluate the difference in the change of HbA1C between CGS+BT and SC, and CGS and SC 
groups. Since Kovatchev's measures of glycemic variability and the proportion of CGS values in the normal 
range are on continuous scales that are comparable across repeated measures, these variables are also 
appropriate to use as outcome variables with IGM estimated using SAS Proc Mixed.  
 
If the treatment groups are significantly different in the outcome measures, it is of interest to examine whether 
the difference in treatment groups persists after adjusting the covariates that are known to be associated with 
the outcome.  This process will be conducted by including covariates in the IGM framework. For example, 
demographic variables (SES, parent marital status, etc.) and disease variables (diabetes onset age, duration, 
etc.) can be included in the models as covariates to improve the precision of estimation when evaluating the 
treatment effect.  If the dummy variable is still significant with the covariates in the model, the interpretation is 
that the treatment accounts for some unique variance in the change of the outcome over time above and 
beyond the effects of the covariates. The effect of site difference will be included as a between-subject 
covariate with a random effect. Specific programming to include the site difference as a random effect using 
SAS Proc Mixed will follow Dmitrienko et al for clinical trial data collected from multiple sites. 162 
 

 
25
The IGM approach allows for comparison and selection of the appropriate covariance structure of the outcome 
measured over time. Candidate structures include compound symmetry (CS), autoregressive order-1 AR(1), 
unstructured, and AR(1) with random effect which will be specified in SAS Proc Mixed. The AIC and BIC 
indices will be used for model selection, with smaller AIC or BIC values indicating relatively better models 
fitting the data. The selection of an appropriate covariance structure may further reduce the bias of model 
estimation.  
 
Hypothesis 2: Youths in CGS+BT will realize more improvement in diabetes-related behavioral 
outcomes (Diabetes Self-Management Profile; PedsQL Diabetes Module; Diabetes Responsibility and 
Conflict Scale; Hypoglycemia Fear Survey; Blood Glucose Monitoring Communication Questionnaire: 
Blood Glucose Monitoring System Rating Questionnaire) compared with those in SC and CGS over the 
9-month randomization phase of the study. 
 
The data analysis strategy to evaluate Hypothesis 2 will be similar to that applied to Hypothesis 1 within the 
IGM framework.  Specifically, in the level-1 model the outcome variables will be the Diabetes Self-
Management Profile, the PedsQL Diabetes Module, the Diabetes Responsibility and Conflict Scale, the 
Hypoglycemia Fear Survey, the Blood Glucose Monitoring Communication Questionnaire, and the Blood 
Glucose Monitoring System Rating Questionnaire. The Time variable in the level-1 model will be the time 
interval from baseline to the time of measurement in month. In level-2 models, a dummy variable indicating 
treatment groups will indicate the treatment effect. A significant coefficient of the dummy variable will show 
that the change rate of the outcome is different for the treatment groups due to the treatment program.  
 
To adjust for the effects of important covariates in examining the treatment effect, the covariates will be 
included in level-1 and level-2 models. The time-varying covariates will be included in the level-1 model and 
the time-invariant covariates will be in level-2 models. There are two advantages of adjusting the covariates 
when evaluating the treatment effect.  First, the adjusted analysis will improve the power of evaluating the 
treatment effect because of increased precision of estimation. 163-165 By adjusting a covariate in a linear model, 
the precision gained is proportional to the correlation between the covariate and the outcome variable. 
Second, omitting important covariates in the model may lead to bias of the results. Therefore, important 
covariates will be included in the models to evaluate the group difference in all the outcomes. Similar to the 
strategies in Primary Hypotheses 1, the effect of site difference will be treated as an additional between-
subject variable as a random effect in the models.  
 
Hypothesis 3a: Improvements in HbA1C during the 9-month Randomized Phase will be moderated by 
adolescents' baseline status on the following measures: Socioeconomic status; Family composition; 
Adolescent age; Parent-Adolescent Relationship Questionnaire; Diabetes Family Responsibility 
Questionnaire; Wiebe Parental Supportive Involvement Interview; and Diabetes Responsibility and 
Conflict Scale).  
 
Analysis of moderator effects can identify variables that are predictive of intervention outcomes. . For example, 
in Hypothesis 3a, if the treatment effect on HbA1C differs as a function of the family's socioeconomic status, 
then socioeconomic status is a moderator variable.  It is important to evaluate the heterogeneity of the 
treatment effect to identify the subgroups that derive lesser or greater benefit from the intervention.  
 
The testing of moderators will be conducted within the IGM framework outlined above.  Specifically, HbA1C will 
be the outcome and Time will be measured in months in the level-1 model.  A dummy variable indicating 
treatment groups will be the predictor in level-2 models. A product term of the proposed moderator and the 
dummy variable, together with the main effect of the moderator candidate, will be entered into the level-2 
models.  A significant coefficient of the product term indicates that the candidate is a significant moderator.  
The analysis process will be carried out using Socioeconomic Status, Family composition, adolescent age at 
baseline, and scores on the Diabetes Problem Solving Interview, Parent-Adolescent Relationship 
Questionnaire, Diabetes Family Responsibility Questionnaire, Wiebe Parental Supportive Involvement 
Interview, and Diabetes Responsibility and Conflict Scale separately to determine significant moderators.  
 
To interpret the effects of any significant moderators, estimated individual growth factors (e.g., the slope in 
linear trajectory) will be compared among subgroups of the moderator. The analysis will reveal subgroup 
differences in the change of outcome due to the treatment effects.  For moderators measured on continuous 
scales, such as adolescent age at baseline, appropriate categorization will be applied for meaningful 
interpretation of the findings. Important covariates will be included in the models to adjust the possible effects 

 
26
of the covariates.  Within this model, site differences will be treated as a between-subject covariate to adjust 
for its possible effects on the outcome.  
 
Hypothesis 3b: Improvements in HbA1C during the 9-month Randomized Phase will be mediated by 
improved scores on the Diabetes Self-Management Profile, Diabetes Responsibility and Conflict Scale, 
Wiebe Parental Supportive Involvement Interview, Diabetes Problem Solving Interview, and Blood 
Glucose Monitoring Communication Questionnaire. 
 
Mediators are process variables that are affected by the treatment effect and are believed to have effects on 
the outcome. Mediator analysis will help us to understand the mechanisms why the treatment is effective. In 
mediator analysis we will determine whether the treatment effect is wholly or partial due to the mediators.  
Following Baron and Kenny, 166 traditional mediator analysis using cross-sectional data involves three 
regression equations, the outcome regressed on the treatment effect, the outcome regressed on both the 
treatment and the mediator, and the mediator regressed on the treatment.  In the multi-level modeling 
framework, Krull & MacKinnon 163 introduced a detailed process of mediator analysis that has advantages over 
the methods used in the context of cross-sectional data. We will closely follow the approach recommended by 
Krull & MacKinnon 163 to examine the possible mediators proposed in Hypothesis 3b.  
 
Specifically, in the IGM framework described above, HbA1C will be the outcome in level-1 models and the 
treatment effect will be a dummy variable indicating treatment groups in level-2 models. Since all mediating 
variables in this study (the Diabetes Self-Management Profile, Diabetes Responsibility and Conflict Scale, 
Wiebe Parental Supportive Involvement Interview, and Blood Glucose Monitoring Communication 
Questionnaire) are within-subject variables measured repeatedly during the study, these mediators will be 
included in the level-1 model.  Following Krull & MacKinnon, 163 the mediator analysis involves three stages of 
IGM: HbA1C predicted by treatment alone, HbA1C predicted by both treatment and the mediator, and the 
mediator predicted by the treatment alone. Combining the results from the three stages of IGM, we can 
determine if a candidate is a whole, partial, or non-mediator of the treatment effect in improving HbA1C. 
 
5.13. Sample size and statistical power. Power analysis and sample size estimation were based on 
projected treatment effects on HbA1C, the primary outcome measure, as shown in the figure below To 
estimate sample sizes needed in the three groups for sufficient statistical power, a Monte Carlo simulation 
study was conducted using MPlus (Version 5). 164 The Monte Carlo procedure is the most common and the 
preferred methodology to estimate sample size in Individual Growth Modeling. 167-168 In a Monte Carlo study, 
random samples are generated repeatedly using the known population parameters with a specified sample 
size. The percentage of simulated samples that have reached significance on the parameters is the estimated 
power of the study. Thus, the required sample size can be determined accurately by varying sample sizes in a 
series of simulations. MPlus provides extensive facilities for conducting Monte Carlo studies on IGM. Our 
simulation study followed the procedures recommended by Muthen & Muthen, 164, 168 including generating 
missing values to reflect expected attrition and the pattern of missing data in the proposed study. The primary 
contrast of interest in this study is change in HbA1C relative to baseline values among adolescents in the SC, 
CGS, and CGS+BT groups. Based on the mean HbA1C obtained in several prior trials at Nemours Children's 
Clinic in Jacksonville and the stated enrollment criteria, we expect that the baseline mean and standard 
Projected Effects on HbA1C
6
7
8
9
10
0
3
6
9
12
SC
CGS
CGS+BT
Mean HbA1c (%)
Months

 
27
deviation values will be approximately 8.8% + 1.2%. The standard deviation of HbA1C will increase gradually 
with each measure spaced about 3 months.  At the end of 12 months, we expect a 0.8% difference in HbA1C 
between the CGS and CGS+BT groups. Assuming a standard deviation of approximately 1.5% at the end of 
the study, the effect size will be 0.533, a moderate effect size as defined by Cohen 169 that is clearly clinically 
significant. Based on the retention rates in our NIH-funded randomized trials, we anticipate an attrition rate 
<10% during the 1-year study. Therefore, enrollment of 150 patients (50 per group) should result in at least 
135 (45 per group) at the end of the 9-month randomization phase of the study. We anticipate that about 120 
participants (40 per group) will complete the 3-month Continuation Phase of the study. 
 
Based on these parameters with 5 equally spaced measures of HbA1C (Baseline, 3, 6, 9, and 12 months) and 
random missing values, the Monte Carlo study with 3000 simulated samples showed that the power of the 
design is 94.5%. Muthen and Muthen 164, 168 also recommend that the parameter bias should not exceed 10% 
and standard error bias should not exceed 5%.  All of these criteria were satisfied in the Monte Carlo study. A 
similar Monte Carlo study was conducted for estimating the statistical power contrasting the SC and CGS 
groups.  We expect a mean difference of approximately 0.6% in HbA1C between the two groups at the end of 
the study. The Monte Carlo study showed with 50 participants in each group and approximately10% missing 
values, the statistical power remains above 80%.Fan 167 compared the statistical power between IGM and the 
traditional Repeated Measures ANOVA with longitudinal data under different situations.  Fan’s conclusion was 
that IGM consistently showed higher power than Repeated Measures ANOVA to compare group differences in 
change over time. Since we will apply IGM to the evaluation of all three primary hypotheses, we are confident 
that the planned sample size offers sufficient statistical power in this study. 
 
5.14. Data and Safety Monitoring. An external panel not otherwise involved in this study will serve on a Data 
and Safety Committee (DSC). The DSC membership will include a Pediatric Endocrinologist, a Certified 
Diabetes Educator and a Pediatric Psychologist who are not Nemours employees. The DSC will receive 
quarterly reports of recruitment statistics, gender and minority distributions of the samples enrolled at each 
center, frequency of SMBG and CGS use, summaries of minor adverse events, and a detailed description of 
any serious or unexpected adverse events on a standardized reporting form. Serious Adverse Events are 
those that result in death, a life threatening situation, hospitalization, disfigurement, disability or a congenital 
anomaly/birth defect, whether or not that event appears to be attributable to the study procedures. Unexpected 
adverse events will be events that were not described in the study protocol or informed consent documents. 
Events of either type will be reported as soon as possible after they occur to the PI, the DSC and the IRB. 
Special attention will be given to episodes of severe hypoglycemia, since this occurs more frequently among 
intensively treated patients. Treatment regimens will be "de-intensified" and glycemic targets raised for any 
patient experiencing an episode of severe hypoglycemia. Additional special attention will be given to the 
patients randomized to Standard Care to minimize the chance that any of these patients would endure 
significant deterioration in glycemic control. Adolescents with increases in HbA1C of more than 1.0%, who have 
HbA1C > 9.0% for two consecutive clinic visits, or who experience more than one episode of severe 
hypoglycemia during the study will be seen more frequently in clinic, or referred for additional diabetes 
education, nutritional counseling, or psychological/psychiatric services at the discretion of the treating 
endocrinologist, consistent with routines for patients not participating in this study at each clinic. 
 
5.15. Project Time Frame. In the DirecNet and JDRF studies, preparation for trials such as that proposed 
here was very time-consuming and complex. The nursing and educational time required for training 
adolescents and parents to use and download the CGS device proficiently and to follow them clinically 
thereafter was also extremely labor-intensive. We have planned the time frame and personnel needs of the 
project accordingly to enable a realistic and careful evaluation of the treatment regimens being compared.  
 
Months 
 
 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
51 
54 
57 
60 
Form steering committee & DSC 
 
■ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refine protocol 
 
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Negotiate CGS purchase 
 
■ 
■ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Write procedure manual 
 
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Refine intervention manual 
 
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Hire and train staff 
 
 
■ 
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Consultant activities 
 
■ 
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■ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
28
IRB and DSC reviews 
 
 
■ 
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■ 
 
 
 
■ 
 
 
 
■ 
 
 
 
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■ 
Procurement & purchasing 
 
 
■ 
■ 
■ 
 
■ 
 
■ 
 
■ 
 
■ 
 
■ 
 
■ 
 
■ 
 
 
Submit progress reports 
 
 
 
 
■ 
 
 
 
■ 
 
 
 
■ 
 
 
 
■ 
 
 
 
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Recruit participants 
 
 
 
 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
■ 
 
 
 
 
 
 
 
 
Data collection and entry 
 
 
 
 
■ 
■ 
■ 
■ 
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■ 
 
 
 
Data cleaning & verification 
 
 
 
 
■ 
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Statistical analyses 
 
 
 
 
 
 
 
 
 
 
 
 
■ 
 
 
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Write journal articles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
■ 
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Submit renewal application 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
■ 
 
 
The first 12 months will consist of preparatory activities including hiring and training project staff, training study 
nurses for certification on the CGS devices, insulin pumps and glucose meters to be used during the study, 
obtaining IRB approval, establishing procedures for data collection, transmission and storage, developing the 
study procedure manual, curriculum for CGS education and refining the intervention manual for use with the 
CGS+BT group. Recruitment of participants will begin at about month 12 and will continue until about month 
36. Each of the three clinics will be expected to enroll approximately 2-3 patients per month, until the full 
sample of 150 adolescents has been enrolled at the combined sites. Based on experience with similar trials 
(JDRF, DirecNet and our Intensive Therapy trial), this pace of recruitment enables efficient completion of the 
research plan without rapidly overloading the clinical staff with patient encounters, phone contacts and follow-
up visits as can easily happen with more rapid recruitment. As has been the case in similar trials, we expect 
the recruitment rate to taper off gradually. The clinical and educational demands associated with starting 
patients on CGS devices may exceed that associated with initiation of insulin pump therapy. While there are 
enough eligible patients, more rapid recruitment could overload the clinical staff and result in sub-optimal 
delivery of CGS-related education and management supports and compromise the internal validity of the 
study. The proposed recruitment rate ensures that each clinic will have no more than 30 active study patients 
concurrently, or about 20 patients in the two CGS groups. We judge the extra demands entailed in CGS-
based regimens to be manageable by a 50% FTE Diabetes Nurse and a 10% FTE physician. Data collection 
will continue through approximately Month 48-51.  DSC conference calls will occur once prior to the initiation of 
recruitment of participants, and then at 6-month intervals beginning 6 months after recruitment commences. A 
competing renewal application will be prepared and submitted at approximately Month 51. Data cleaning and 
verification, statistical analysis and dissemination of project results will occur during the final 9-12 months. 
 
5.16. Limitations of the study. The most important limitation derives from the fact that CGS technology is 
changing rapidly and it is being incorporated rapidly into clinical care. We will utilize the most advanced CGS 
technology that is available to us when we begin recruitment. While the various manufacturers protect their 
research and development plans due to the highly competitive business environment, it is clear that each  
company has a new iteration of its device in development. Our prior interactions with the manufacturers in the 
DirecNet and JDRF work have cultivated a climate of collaborative trust with these companies. The proposed 
research could be seen by the companies as useful to them in seeking FDA approval for pediatric indications 
for their devices and for expanding the marketability of CGS to adolescents with suboptimal glycemic control. 
Thus, there is a strong likelihood that the proposed study can utilize the most advanced CGS technology at 
the time enrollment would begin. Regardless of the specific CGS devices used, the study will still yield 
valuable information about enhancement of the capacity to derive glycemic benefits from this technology 
through the provision of a targeted behavior therapy intervention. The study could also inform other studies of 
the prediction and facilitation of benefit from technological advances in other medical contexts. Also, we will 
permit study participants to change to CGS devices that may emerge during the study, consistent with our 
intention of evaluating variables affecting the achievement of glycemic benefits from CGS use in a generic 
sense rather than a focus on evaluating or comparing specific CGS devices. 
 
Another conceivable limitation is that the study design was driven in part by the desire to keep the direct costs 
for the project below $500K in each year. This strategy was recommended by the NIDDK Program Officer 
responsible for behavioral science research. Completing the study in less than 5 years is not possible without 
exceeding that limit substantially or without major design changes. 

 
29
6. INCLUSION ENROLLMENT REPORT 
This report is not applicable since this is a new application. 
 
7. PRELIMINARY STUDIES AND PROGRESS REPORT PUBLICATION LIST 
Wysocki, T. (1988).  SMBG: Has the promise been fulfilled? Diabetes Spectrum, 1, 83-87. 
Wysocki, T., Green, L.B. & Huxtable, K. (1989).  Blood glucose monitoring by diabetic adolescents:  
 
Compliance and metabolic control. Health Psychology, 8: 267-84. 
Wysocki, T. (1989).  Impact of blood glucose monitoring on diabetic control: Obstacles and interventions.   
 
Journal of Behavioral Medicine, 12: 183-205. 
Green, L.B., Wysocki, T. & Reineck, B.M. (1990).  Fear of hypoglycemia in children and adolescents with 
diabetes mellitus. Journal of Pediatric Psychology,15, 5:  633-641. 
Wysocki, T., Hough, B., Ward, K.M., Allen, A. & Murgai, N. (1992). Use of blood  glucose data by families of  
 
children and adolescents with IDDM. Diabetes Care, 15 (8): 1041-1044. 
Wysocki, T. (1994).  The psychological context of SMBG. Diabetes Spectrum, 7, 4: 266-270. 
Wysocki, T. (2000).  Effective utilization of self-monitored blood glucose data: Cognitive and behavioral  
prerequisites. In Bercu, B. and Stabler, B.T. (Eds.)  Symposium on Therapeutic Outcome of Endocrine 
Disorders: Efficacy, Innovation and Quality of Life. New York: Springer-Verlag, pp151-160. 
Wysocki, T., Harris, M.A., Wilkinson, K., Sadler, M., Mauras, N., & White, N.H. (2003). Self management 
competence as a predictor of outcomes of  intensive therapy or usual care for children with type 1 
diabetes mellitus. Diabetes Care, 26, (7), 2043-2047. 
Fox L.A., Buckloh, L.M., Smith, S., Wysocki, T., & Mauras, N. (2005). A randomized trial of insulin pump  
 
therapy in toddlers and preschool age children with type 1 diabetes (DM1).  Diabetes Care, 28 (6),  
 
1177-1181. 
Wysocki, T., Buckloh, L.M., Lochrie, A. & Antal, H. (2005).  The psychologic context of pediatric diabetes.  
Pediatric Clinics of North America, 52, (6): 1755-1778. 
Wysocki, T. (2006). Behavioral assessment and intervention in pediatric diabetes.  Behavior Modification, 30  
(1), 72-92. 
Wysocki, T., Harris, M.A.,Buckloh, L.M., Mertlich, D., Lochrie, A.S., Taylor, A., Sadler, M., Mauras, N., &  
White, N.H. (2006). Effects of behavioral family systems therapy for diabetes on adolescents' family  
relationships, treatment adherence and metabolic control. Journal of Pediatric Psychology, 31 (9), 928-
938. 
Wysocki, T., Harris, M.A., Buckloh, L., Wilkinson, K., Sadler, M., Mauras, N., & White, N.H. (2006). Self care  
autonomy and outcomes of intensive therapy or usual care in youth with type 1 diabetes. Journal of 
Pediatric Psychology, 31, (10), 1036-1045. 
Wysocki, T., Harris, M.A., Buckloh, L.M., Mertlich, D., Lochrie, A.S., Muaras, N. & White, N.H. (2007).  
Randomized controlled trial of Behavioral Family Systems Therapy for Diabetes: Maintenance of 
effects on diabetes outcomes in adolescents. Diabetes Care, 30, (3), 555-560. 
Wysocki, T., Harris, M.A., Buckloh, L.M., Mertlich, D., Lochrie, A.S., Taylor, A., Sadler, M. & White, N.H. (in  
press). Randomized controlled trial of Behavioral Family Systems Therapy for Diabetes: Maintenance 
and generalization of effects on parent-adolescent communication. Behavior Therapy. 
Wysocki, T., Iannotti, R., Weissberg-Benchell, J., Laffel, L., Hood, K., Anderson, B.J., & Chen, R. (in press).  
Diabetes Problem Solving by youths with type 1 diabetes and their caregivers: Measurement, validation  
and longitudinal associations with glycemic control. Journal of Pediatric Psychology. 
Tamborlane, W.V., Ruedy, K.J., Wysocki, T., O'Grady, M., Kollman, C., Block, J., Chase, H.P., Hirsch, I.,  
Huang, E., Beck, R.W., Wilson, D., Lawrence, J., & Laffel, L. (in press). JDRF randomized clinical trial 
to assess the efficacy of real-time continuous glucose monitoring in the management of type 1 
diabetes: Research design and methods. Diabetes, Technology and Therapeutics. 
 
Diabetes Research in Children Network (DirecNet) Peer-Reviewed Journal Articles:  These papers 
resulted from activities of the Diabetes Research in Children Network. Dr. Wysocki is PI (#U10-HD41918) for 
the Nemours Children's Clinic site and a member of the DirecNet Steering Committee that designs and 
conducts studies of CGS technology. The Steering Committee appoints members and chairs of writing 
committees for each paper, and Steering Committee members are co-authors on all of these papers. 
 
*:    Member of Writing Committee 
**:  Chair of Writing Committee 

 
30
 
*Diabetes Research in Children Network (DirecNet) Study Group. (2003). The Accuracy of the CGMS™ in  
Children with Type 1 Diabetes: Results of the Diabetes Research in Children Network (DirecNet) 
Accuracy Study. Diabetes Technology and Therapeutics,5, (5)  781-790. 
*Diabetes Research in Children Network (DirecNet) Study Group. (2003) The Accuracy of the GlucoWatch®  
G2TM Biographer in Children with Type 1 Diabetes: Results of the Diabetes Research in Children 
Network (DirecNet) Accuracy Study. Diabetes Technology and Therapeutics, 5, (5)  791-800. 
*Diabetes Research in Children Network (DirecNet) Study Group. (2003). A multicenter study of the accuracy  
of the One Touch Ultra home glucose meter in children with type 1 diabetes. Diabetes Technology and 
Therapeutics, 5, (6)  933-941. 
Diabetes Research in Children Network (DirecNet) Study Group. (2004). Accuracy of The GlucoWatch G2  
Biographer and the Continuous Glucose Monitoring System  During Hypoglycemia.  Experience of the  
Diabetes Research in Children Network (DirecNet). Diabetes Care, 27, (3) 722-726. 
Diabetes Research in Children Network (DirecNet) Study Group. (2004).  Lack of Accuracy of Continuous  
Glucose Sensors in Healthy, Nondiabetic Children. Results of the Diabetes Research in Children 
Network (DirecNet) Accuracy Study. Journal of Pediatrics, 144 (6), 770-775. 
Diabetes Research in Children Network (DirecNet) Study Group. (2004). GlucoWatch G2 Biographer Alarm  
 
Reliability During Hypoglycemia in Children. Diabetes Technology and Therapeutics, 6, (5)  559-566. 
*Diabetes Research in Children Network (DirecNet) Study Group. (2005). Performance of the DCA-2000 for  
measurement of HbA1c levels in children with T1DM in a DirecNet outpatient clinical trial.  Pediatric 
Diabetes, 6 (1), 13-16. 
*Diabetes Research in Children Network (DirecNet) Study Group (2005). A Randomized Multicenter Trial  
Comparing the GlucoWatch Biographer with Standard Glucose Monitoring in Children with Type 1 
Diabetes. Diabetes Care, 28, (5), 1101-1106. 
Diabetes Research in Children Network (DirecNet) Study Group. (2005). Accuracy of the modified Continuous  
Glucose Monitoring System (CGMS) sensor in an outpatient setting: Results from a Diabetes Research 
in Children Network  (DirecNet) study. Diabetes Technology and Therapeutics, 7, (1): 109-114. 
**Diabetes Research in Children Network (DirecNet) Study Group. (2005). Youth and Parent Satisfaction with  
Clinical Use of the Glucowatch G2 Biographer in the Management of Pediatric Type 1 Diabetes. 
Diabetes Care, 28 (8), 1929-1935. 
Diabetes Research in Children Network (DirecNet) Study Group. (2005). Impact of exercise on overnight  
glycemic control in children with type 1 diabetes. Journal of Pediatrics, 174, (4): 528-534. 
**Diabetes Research in Children Network (DirecNet) Study Group. (2005). Diabetes Self Management Profile  
for Flexible Insulin Regimens: Cross-Sectional and Longitudinal Analysis of Psychometric Properties in 
a Pediatric Sample. Diabetes Care, 28 (8), 2034-2035.  (Brief Report).            
 Diabetes Research in Children Network (DirecNet) Study Group (2005). Eight-point Glucose Testing versus  
the Continuous Glucose Monitoring System (CGMS) in Evaluation of Glycemic Control in Type 1 
Diabetes. Journal of Clinical Endocrinology and Metabolism, 90, (6): 3387-3391. 
*Diabetes Research in Children Network (DirecNet) Study Group. (2005). Limitations of statistical measures of  
error in assessing the accuracy of continuous glucose sensors. Diabetes Technology and 
Therapeutics, 7 (5), 665-672.      
Diabetes Research in Children Network (DirecNet) Study Group. (2005). Accuracy of newer-generation home  
blood glucose meters in a Diabetes Research in Children Network  (DirecNet) inpatient exercise study. 
Diabetes Technology and Therapeutics, 7 (5), 675-680.      
Diabetes Research in Children Network (DirecNet) Study Group. (2006). The effects of aerobic exercise on  
glucose and counter-regulatory hormone concentrations in children with type 1 diabetes. Diabetes 
Care, 29, (1): 20-25.     
**Diabetes Research in Children Network (DirecNet) Study Group. (2006). Psychological aspects of  
 
continuous glucose monitoring in pediatric type 1 diabetes. Pediatric Diabetes, 7: 32-38. 
Diabetes Research in Children Network (DirecNet) Study Group. (2006). Prevention of hypoglycemia during  
exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care, 29, (10), 2200-
2204. 
Diabetes Research in Children Network (DirecNet) Study Group. (2007). The accuracy of the Freestyle  
Navigator continuous glucose monitoring system in children with type 1 diabetes.  Diabetes Care, 30, 
(1), 59-64. 
Diabetes Research in Children Network (DirecNet) Study Group. (2007). Relative inaccuracy of the A1cNow in  

 
31
 
children with type 1 diabetes. Diabetes Care, 30, (1), 135-137 (Brief Report). 
*Diabetes Research in Children Network (DirecNet) Study Group. (2007). Relative accuracy of the BD Logic  
 
and Freestyle blood glucose meters.  Diabetes Technology and Therapeutics, 9, (2), 165-168. 
Diabetes Research in Children Network (DirecNet) Study Group. (2007). Impaired overnight counter-regulatory  
hormone responses to spontaneous hypoglycemia in children with type 1 diabetes. Pediatric Diabetes, 
8, 199-205. 
*Diabetes Research in Children Network (DirecNet) Study Group. (2007). Continuous glucose monitoring in  
 
children with type 1 diabetes. Journal of Pediatrics, 151, 388-393. 
*Diabetes Research in Children Network (DirecNet) Study Group. (in press). FreeStyle Navigator TM   
 
Continuous Glucose Monitoring System Use in Children with Type 1 Diabetes using glargine-based  
 
multiple daily dose regimens: Results of a Pilot Trial. Diabetes Care (Brief Report). 
Diabetes Research in Children Network (DirecNet) Study Group. (in press). Educating families on real-time  
 
continuous glucose monitoring: The DirecNet Navigator pilot study experience. The Diabetes Educator. 
*Diabetes Research in Children Network (DirecNet) Study Group. (under review). Use of continuous glucose  
monitors in children with type 1 diabetes on subcutaneous insulin infusion versus multiple daily 
injections. Diabetes Care. 
 
8. PROTECTION OF HUMAN SUBJECTS 
The Nemours Foundation has registered its three IRB’s with the NIH Office of Human Research Protections 
and has an approved Federal-Wide Assurance (#00000293). The proposed studies and the associated 
procedures for parental permission (informed consent), adolescent assent and protection of research 
volunteers will be reviewed by the Nemours-Florida IRB. As chairperson of that IRB, Dr. Wysocki will recuse 
himself from the IRB's review of this study. Policies and Procedures for the Nemours Office of Human 
Subjects Protection are available at this URL: http://www.nemours.org/internet?url=no/nohsp/policies.html. 
The Nemours Foundation has recently applied for accreditation of its human subjects protection program by 
the Accreditation Agency for Human Research Protection Programs. Procedures for the protection of study 
participants in the proposed investigation are summarized below. 
 
8.1. Description of participants and eligibility criteria: A sample of 150 adolescents with T1DM and at least 
one parent of each will be recruited from the three participating clinics (~50 per center). For each child, the 
parent or other legal caregiver who is most involved in the child's daily diabetes management will be required 
to participate, while the other parent will be encouraged, but not required, to participate. Eligibility criteria were 
designed to target for enrollment patients who might be considered clinically appropriate candidates for 
intensive therapy and for use of a CGS device. These criteria include: 
 
• 
Age of child > 11 years and < 17 years. This age range was chosen to maximize the yield of clinically 
useful information from this study regarding the appropriate selection of candidates for use of CGS 
devices. Most recent HbA1C > 7.5% and < 10.0% or mean HbA1C > 7.5% and < 10.0% over the past three 
measurements prior to enrollment.  
• 
Duration of diabetes > 2 years or > 1 year with a negligible stimulated c-peptide level. 
• 
Adolescent treated on an intensified T1DM regimen for at least 6 months prior to enrollment, consisting of 
either continuous subcutaneous insulin infusion or a multiple daily injection regimen using carbohydrate 
counting and insulin dose correction factors to calculate pre-meal insulin dosing. 
• 
Youth cannot have used a CGS device for clinical diabetes management in the past. 
• 
Absence of other systemic chronic diseases except well-controlled asthma and Hashimoto's thyroiditis. 
• 
Intention to remain in the same geographic area and to maintain diabetes treatment at the enrolling center 
for the duration of the study. 
• 
Willingness to accept random assignment to the experimental conditions. 
• 
Not in special education for mental retardation, autism or severe behavior disorders. 
• 
Parent not diagnosed or in treatment for major depression, psychosis, bipolar disorder or substance use 
disorder within the 6 months prior to enrollment. 
• 
Child not hospitalized in a psychiatric unit or enrolled in a psychiatric day treatment program during the 6 
      months prior to enrollment. 
 
Each of the three clinics will seek to enroll families of 50 children meeting the above eligibility criteria. 
Procedures will be established to ensure enrollment of children and families representing low-income racial 
and ethnic minorities. To minimize these impediments, we will offer evening and weekend appointments for 

 
32
data collection, taxi fare, meal vouchers, reimbursement for child care and other such inducements to enable 
participation of members of racial/ethnic minorities who may be of lower socioeconomic status. Before 
beginning recruitment of patients, the Steering Committee will compile a report of the racial/ethnic composition 
of potentially eligible patients at each clinic. Then, each clinic will be given a sampling objective to ensure that 
the enrolled sample for the entire study achieves the following targets: Gender: 50% male, 50% female 
adolescents with diabetes; Children: All enrolled patients will be children; Race/Ethnicity: 70% Caucasian; 20% 
African-American; 10% Hispanic. 
 
8.2. Sources of research material: Adolescents (11-<17 years old) with T1DM mellitus and their parents will 
complete a variety of questionnaires and structured interviews related to their experiences with intensive 
therapy for diabetes with conventional self-monitoring of blood glucose or the same therapy regimen 
augmented by use of a CGS. Patients will download data stored in memory by their blood glucose meters and 
by the CGS approximately monthly using personal computers as well as at periodic clinic visits. 
Questionnaires and interviews were selected to capture information on the typical range of reactions to these 
various diabetes regimens and to identify possible predictors of outcomes of these differing approaches. 
Finally, audio recordings will be made of intervention visits with the Mental Health Professionals for families in 
the CGS+BT group for the purpose of evaluation of treatment integrity and for recording details of the 
intervention process experienced by each family.   
 
8.3. Methods of recruitment: The Diabetes Nurse or Research Assistant at each participating Nemours site 
will review upcoming appointments for diabetes visits in the Division of Endocrinology and Metabolism to 
identify potential participants. A brief study summary, signed by the PI and the patient’s attending 
endocrinologist, and a copy of the informed consent form will be mailed to the parents about 10-14 days prior 
to the scheduled clinic appointment. In the letter, the parents will be told to expect a call from the project staff 
to answer their questions about the study and it will also give the parents the name and telephone number of 
the Diabetes Nurse or Research Assistant if they would prefer to call for this information. The Diabetes Nurse 
will offer to meet with the family just before or after the clinic visit to confirm their eligibility and to discuss their 
possible participation in the study. Those who are eligible and agree to participate will sign the Parental 
Permission and/or Adolescent Assent forms as appropriate and then be scheduled for a Baseline evaluation.  
 
8.4. Assessment of research-related risks: Risks of participation include those associated with using a 
CGS, those associated with management of diabetes mellitus with an intensive therapy approach, those 
associated with remaining in standard care for diabetes and those associated with threats to privacy and 
confidentiality. We believe that these represent minimal risks as defined by the DHHS Office of Human 
Research Protection and by the Policies and Procedures of the Nemours Office of Human Subjects 
Protection. 
 
Risks associated with the various CGS's that will be evaluated consist primarily of irritation of the skin in the 
area on which the device is worn. This can manifest as an edematous rash that was rated as more than mild 
in about 10% of children who have worn these devices in previous DirecNet studies. This complication can be 
reduced or prevented by proper hygiene and skin care before and after wearing the device and by rotating the 
site on which it is worn from one period to the next. 
 
A further risk associated with CGS's is the possibility that they will provide inaccurate data on prevailing 
glucose levels, potentially leading to inappropriate decisions with respect to insulin, eating or exercise. CGS 
education for adolescents and parents will instruct them to make no adjustments to insulin, food intake or 
exercise based on CGS data alone and to always confirm the CGS readings by performing a conventional 
SMBG test.  Patient education on use of these devices will emphasize the necessity for healthy skepticism 
regarding the sensor data and the necessity of completing finger-stick blood glucose checks whenever the 
sensor readings do not appear congruent with recent trends or with treatment events such as insulin 
administration, eating or physical activity. These potential risks have not materialized in the European 
GuardControl Trial or in any of the DirecNet or JDRF studies of CGS devices that Dr. Wysocki has 
participated in. Most patients and parents have quickly learned that CGS results must be confirmed by 
conventional SMBG before treatment actions are taken. 
 
Finally, adolescents who are non-compliant with their diabetes regimens may also be noncompliant with 
responsibilities and precautions associated with CGS use. Adolescents who do not calibrate the CGS properly, 
who ignore alarms, or who do not complete confirmatory SMBG checks when necessary may face risks of 

 
33
worsened glycemic control, rather than improvement, during CGS use. The planned education, monitoring of 
anticipated variants of noncompliance with CGS use, limited provision of replaceable sensors and rescue 
procedures all provide protections against these sources of risk. 
 
Intensive therapy for T1DM provides extensive professional resources and involvement to provide the medical, 
educational, nutritional or psychological services and/or support that are necessary to achieve the closest 
approximation to maintenance of normoglycemia that can be achieved without unacceptable or clinically 
dangerous risks of severe hypoglycemia or unwanted weight gain. Since the DCCT, intensified therapy for 
youths with T1DM mellitus has become increasingly common, such that the mean HbA1C for patients entering 
our intensive therapy trial (8.2%) did not differ appreciably from the mean HbA1C levels reported for intensively 
treated adolescents in the DCCT. The achievement of near-normoglycemia in the DCCT was accompanied by 
a threefold increase in the occurrence of severe hypoglycemia among adolescent participants, as well as by 
unwanted weight gain.  While these are legitimate risks as revealed by the DCCT, our experiences in our 
intensive therapy trial and recent continuous glucose sensor studies with children showed that both the 
absolute levels of these risks and the levels of these risks relative to patients treated with what has since 
become standard care for T1DM are both lower than those reported previously for DCCT adolescents. In the 
DCCT, intensively treated adolescents had about 86 episodes of severe hypoglycemia per 100 patient-years, 
compared with conventionally treated adolescents who had about 29 episodes per year, for a Relative Risk of 
2.9. In our intensive therapy trial, patients in the Intensive Therapy (IT) group experienced 56 episodes of 
severe hypoglycemia per 100 patients per year compared with 45 episodes per 100 patient-years for the Usual 
Care (UC) group, for a Relative Risk of 1.24. Within the narrow range of HbA1C in which we were operating 
(means of ~7.7 for IT and 8.3% for UC), the correlation between HbA1C and frequency of severe hypoglycemia 
was -0.07 (ns) and the mean HbA1C levels of patients who had one or more episodes of severe hypoglycemia 
did not differ significantly from those who had no episodes.  In fact, SH frequency in the IT group declined 
steadily during the study, to approximately 35 episodes per 100 patients per year during the last 6 months of 
the trial and this has been similar to the frequency of severe hypoglycemia observed in the various DirecNet 
CGS trials and pilot studies. Thus, treatment with intensive therapy yields only a modest increase in the risk of 
severe hypoglycemia compared with the current standard care for type 1 diabetes at Nemours Children's 
Clinics. A recent, larger study of intensive therapy in pediatric T1DM also showed that the anticipated risks of 
intensive therapy in this age group simply did not materialize in that study either. If, as expected, patients in 
the CGS and CGS+BT groups in this study realize a lower risk of severe hypoglycemia compared with patients 
in the SC group, then the former two groups of patients may experience a lower risk than do comparable 
patients receiving routine care for T1DM at these clinics. 
 
Weight gain was also less of a problem for our IT patients compared with the DCCT adolescents. Mean BMI 
increased slightly for both groups, with a slightly higher mean BMI for the UC group throughout.  The 
percentage of patients with BMI > 25, a commonly used clinical cutoff for overweight, increased slightly during 
the study for both groups. BMI > 30, suggestive of obesity, was evident in about 4-6% of enrolled patients at 
each data point. Changes in BMI and HbA1C were not correlated significantly in our study. Thus, unwanted 
weight gain was a minimal problem in our intensive therapy trial, although we will monitor its occurrence . 
 
 
The SC group participants may not achieve substantial improvements in glycemic control during the initial 9-
month Randomized Phase of the study since they will not be allowed to use CGS devices as part of their 
T1DM  care. Nonetheless, these adolescents will be managed with intensive therapy regimens and they will be 
offered clinical and educational resources to permit improved glycemic control. Many adolescents achieve 
HbA1C < 7.0% with such a regimen without using a CGS device. All SC patients will be offered 3 months' use 
of a CGS device during the Continuation Phase of the study. 
 
Although the measures do not include norm-referenced scales to detect possible psychopathology, it is likely 
that some study participants will experience the onset or exacerbation of serious psychological or behavioral 
problems during the study. When any such instance is detected, the adolescent and family will be referred for 
evaluation and treatment through established referral sources in the various clinic communities. The draft 
intervention manual in the appendix includes explicit criteria for such referrals. 
 
Completion of questionnaires, interviews and other data collection for the study carries risks associated with 
threats to privacy and confidentiality. All paper study forms and questionnaires will be labeled with a unique 
study ID code number rather than participant's names or other identifiers before being sent to the coordinating 

 
34
center at Nemours-Jacksonville. Should any of these materials be lost, it will not be possible for others to 
identify the participant. Digital audio recordings of CGS+BT intervention visits will contain the participants' 
voices and are therefore potentially identifiable. All of the measures planned for collection in the proposed 
study have been used in the principal investigator's prior research without significant concerns being 
expressed by any participants.  None of these measures seek participants' responses about potentially 
stigmatizing, embarrassing or illegal behaviors, thoughts or attitudes. 
 
8.5. Assessment of research-related benefits: All patients who enroll in the study will receive intensive 
therapy for T1DM and may therefore achieve better glycemic control. Our Intensive Therapy patients achieved 
mean HbA1C levels of 7.6%-7.7% that emerged after 3 months of treatment and remained near that level. 
Patients who are randomized to either CGS or CGS+BT may achieve lower HbA1C levels than those in the SC 
condition and/or they may experience fewer episodes of severe hypoglycemia. SC participants will be allowed 
to use a CGS device during the 3-month continuation phase of the study. Assuming that all CGS's used in the 
study will have FDA approval for such therapeutic indications by the end of the study, all participants in the 
study will be allowed to keep their CGS's after the study. In order to continue using the device after the study, 
participants would then assume responsibility for the costs of purchasing additional sensors.  
 
8.6. Safeguards to protect against risks: The most important risks faced by patients in the proposed study 
are possible deterioration in glycemic control and possible increased occurrence of severe hypoglycemia.  
 
With respect to the risks of possible deterioration in glycemic control, patients in all three groups will be seen 
approximately quarterly by pediatric endocrinologists as well as by other members of the diabetes team as 
needed. Immediate telephone access to a pediatric endocrinologist on call will be available on a 24-hour basis. 
Diabetes educators, dietitians and other members of the diabetes teams are available by telephone during 
weekday business hours. All treatment regimens and targets will be in accord with the guidelines promulgated 
by the American Diabetes Association for this clinical population throughout the study. A "rescue procedure" 
will be employed for any youth whose HbA1C remains above 9% for 2 consecutive visits or whose HbA1C 
increases by more than 1.0% over baseline or who has more than one episode of severe hypoglycemia. As 
would typify clinical practices with similar patients, this will consist of offering monthly clinic visits with a 
diabetes nurse, weekly telephone consultation with the nurse and referral to a dietitian, social worker, 
psychologist or psychiatrist at the discretion of the treating endocrinologist. 
 
The study design includes several protections against the risks of severe hypoglycemia: 
• 
All patients will receive thorough, frequent assessments of severe hypoglycemia risks through repeated 
calculation of the Low Blood Glucose Index. These data are not routinely obtained for diabetes clinic 
patients and its availability permits counseling of patients and parents to reduce their individual risks. 
• 
Targets for HbA1C and daily blood glucose will be raised for any child who experiences an episode of 
severe hypoglycemia in an effort to reduce its recurrence. Also, following such events, the Diabetes Nurse 
will make a special effort to have the family keep the child’s glucose levels on the high end of normal for 
the subsequent 2 weeks. 
• 
Patients randomized to CGS and CGS+BT may have some protection against severe hypoglycemia if the 
clinical use of these devices achieves the expected outcomes.  
 
8.7. Informed consent process: Parental permission (Informed consent) and adolescent assent will be 
obtained by the Diabetes Nurse. Parents will sign an IRB-approved parental permission and informed consent 
form. Adolescents  will sign an IRB-approved adolescent assent form. All participating parents will receive a 
copy of the signed consent/assent forms for their records. The original signed consent/assent forms will be 
stored in a locked file cabinet accessible only by the Principal Investigator and project staff. 
 
8.8. Protection of confidentiality: Confidentiality of information obtained from participants in this project will 
be protected to the full extent permitted by law. In accord with Nemours Policies and Procedures, all study 
staff will be required to show documentation of completion of required on-line curricula in human subjects 
protection and HIPAA research regulations. Each participant will be assigned a unique code number and the 
names and identities of participants associated with each code number will be known only to the research 
staff. All raw data and computerized data files will refer to participants only by code number and not by names, 
initials or other identifiers. No individually identifiable health information will be disclosed to any organization or 
individual that is external to Nemours. Digital audio recordings of CGS+BT intervention visits will contain 
images of participants' voices and will therefore be potentially identifiable. These recordings will be made 

 
35
using digital voice recorders and will be stored in password-protected electronic files before transmission to 
the coordinating center. They will be labeled with participant ID numbers rather than names or other identifiers. 
Youths, parents and mental health professionals will be instructed to avoid using full names when referring to 
one another during these visits. The recordings will be deleted once they have been rated. All data will be 
stored in locked file cabinets and in password-protected computer files and no names will appear in any of 
these files. Signed parental permission and adolescent assent forms will be stored separately in locked file 
cabinets. Access to these files will be limited to the Principal Investigator and research staff as well as to those 
agencies and individuals who have legitimate legal rights and authority to inspect such records. 
 
9. INCLUSION OF WOMEN AND MINORITIES 
 
Each clinic will enroll families of about 50 eligible adolescents. The sampling plan ensures equitable 
representation of racial and ethnic minorities so that comparisons of minorities and non-Hispanic Caucasians 
are feasible. To encourage participation of minorities, we will offer evening and weekend appointments for 
data collection, taxi fare, meal vouchers, and reimbursement for child care to enable participation of members 
of minorities who are of lower socioeconomic status. Sampling objectives will ensure that the study achieves 
these targets: Gender: 50% male, 50% female adolescents; Children: All enrolled patients will be children; 
Race: 80% Caucasian; 20% African-American; Ethnicity: 90% Non-Hispanic and 10% Hispanic. The Florida 
and Delaware populations have become increasingly Hispanic over the past decade. The study 
questionnaires, informed consent and assent forms, and educational materials will be translated into Spanish 
by native Spanish-speaking persons and back-translated into English to ensure accurate translation. The three 
clinics will provide access to about 550 eligible patients, ensuring the enrollment of a diverse sample meeting 
these targets. 
 

 
36
 
10. Targeted/Planned Enrollment Table 
This report format should NOT be used for data collection from study participants. 
Study Title: 
Clinical Use of Continuous Glucose Sensors in Adolescents with Inadequate Diabetic Control 
Total Planned Enrollment: 
150 parents (P) (90% of parents are expected to be female) and 150 youths (Y) 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects (Adolescents) 
Ethnic Category 
Sex/Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
8 
7       
15 
Not Hispanic or Latino 
67    
68 
135 
Ethnic Category: Total of All Subjects * 
           75 
    75 
          150 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander  
0 
0 
0 
Black or African American  
15 
15 
30 
White 
60 
60 
120 
Racial Categories: Total of All Subjects * 
75 
75 
150 
• 
The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All Subjects.” 
• 
 
 
PHS 398/2590 (Rev. 09/04, Reissued 4/2006) 
Page     
Targeted/Planned Enrollment Format Page 
 
 

 
37
11. INCLUSION OF CHILDREN 
All enrolled patients will be children and adolescents between 11 and 17 years old at enrollment. 
 
12. VERTEBRATE ANIMALS 
Not applicable 
 
13. SELECT AGENTS 
Not applicable 
 
14. MULTIPLE PI LEADERSHIP PLAN 
Not applicable as there is one Principal Investigator 
 
15. CONSORTIUM & CONTRACTUAL ARRANGEMENTS 
Not applicable. All participating sites are operating entities of the Nemours Foundation and they share one Tax 
ID and DUNS number. 
 
16. LETTERS OF SUPPORT 
• 
Grafton Reeves, M.D. 
• 
Mark Kummer, M.D. 
• 
Jorge Daaboul, M.D.  
• 
Boris Kovatchev, Ph.D. 
• 
Rusan Chen, Ph.D. 
• 
Linda C. Sobell, Ph.D. 
 
17. RESOURCE SHARING PLAN 
Data Sharing Plan 
The proposed study will be registered on www.clinicaltrials.gov as soon as an award statement is received, 
ensuring that information about the study will be available to interested parties and so that they will understand 
when archived data will be made available. Publications resulting from this study will also be shared on the 
pertinent NIH website in accord with the NIH policies and procedures regarding internet sharing of publications 
resulting from NIH-supported investigations. The intervention manual will be made available to appropriately 
qualified psychologists, child and adolescent psychiatrists and other licensed mental health professionals with 
appropriate training and experience. 
 
The proposed research will include data from 150 adolescents with type 1 diabetes and their parents recruited 
through 3 diabetes clinics. Data gathering will include audiotapes of telephone interviews; however, access to 
these tapes will not be permitted as it will be impossible to assure anonymity of participants.  The final dataset 
will include: self-reported demographic and behavioral data from the participants obtained periodically during 
the study; laboratory data from quarterly clinic visits including, but not limited to, data on pubertal 
development, hemoglobin A1c, patterns of health care utilization, and psychological adjustment; self-report 
data collected at the quarterly clinic visits including information about health status and diabetes management; 
coded interactions from the audiotapes mentioned above.  Identifying information will include, but not be 
limited to, age, age of diagnosis, gender, clinic identifier, height, weight, race/ethnicity, and socioeconomic 
status. Even though the final dataset will be stripped of identifiers prior to release for sharing, we believe that 
there remains the possibility of deductive disclosure of subjects with unusual characteristics. Thus, we will 
make the data and associated documentation available to users only under a data-sharing agreement that 
provides for: (1) a commitment to using the data only for research purposes and not to identify any individual 
participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a 
commitment to destroying or returning the data after analyses are completed.  
 
The dataset will be redacted to protect subjects’ identities. This project has specified research questions that 
address both the long-term effects of the intervention and longitudinal changes in specific variables. Datasets 
will be made available through a data enclave immediately following acceptance for publication of papers 
addressing all research questions specified in the protocol only when those data are not to be used to address 
subsequent specified research questions. The data will be kept for at least 3 years after the publication of the 
last article based on the proposed research questions.  
 
 

 
38
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