Adjusting Insulin Delivery to Activity (AIDA)
Phase: NA
Conditions: Diabetes, Nocturnal Hypoglycemia
Sponsor: Boston Children's Hospital

 
 
 
Adjusting Insulin Delivery to Activity 
(AIDA): 
 
Use of Activity Data to Adjust Insulin Pump 
Therapy for Children with Type 1 Diabetes 
 
AIDA Investigation Protocol 
 
Investigators: 
                                   Paulina Ortiz-Rubio, MD 
                                  Carmen Soto-Rivera, MD 
                                         Garry Steil, PhD 
                                       Michael Agus, MD 
 
 
 
 
 
NCT: 022994479 
Version Date: September 21, 2016 
 

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Summary/Abstract 
Being diagnosed with type 1 diabetes at a young age places a lifelong 
burden on the child together with new challenges and responsibilities for the 
parents of that child.  New technologies such as continuous glucose monitors 
(CGM) and high resolution insulin pumps with the ability to deliver the low basal 
rates required for very young children have reduced the burden, but the pumps 
need to be carefully configured with some of the setting needing to be subtly 
adjusted following exercise, which if performed later in the day has been shown 
to reduce the nighttime basal requirements.  Many adults with type 1 diabetes 
(T1D) are able to intuitively make adjustments based on prior activity; however, 
parents of younger children may not even be aware of their child’s activity levels 
while at day-care or school.  Moreover, the amount and timing of the adjustments 
are not well defined and may be highly variable between subjects.  The present 
study looks to assess the feasibility of combining new generation activity 
monitors (FitBit or similar), with data obtained from CGM and insulin pump 
records to improve insulin dose adjustments and prevent hypoglycemia in the 
pediatric population.  
 
Abbreviations: SAP – sensor augmented pump therapy; CGM – continuous 
glucose monitor; T1D – type 1 diabetes; TDD – total daily dose;  
 
1. Specific Aim: 
To determine the feasibility of using activity monitor data to predict the need 
to make temporary insulin pump dose adjustments to prevent nighttime 
hypoglycemia. 
2. Background and significance 
The 1993 landmark Diabetes Control and Complications Trial (DCCT) 
showed intensive insulin therapy reduced the rate of long-term micro vascular 
complications from T1D (1).  Since the trial, new insulin formulations with more 
rapid absorption kinetics have been developed, pumps delivering the insulin have 
been improved, and continuous glucose monitors (CGM) providing glucose 
values every 1 to 5 minutes have become available. These advances have 
provided renewed hope that a fully automated artificial pancreas (AP) will soon 
be available; however, a substantial number of hurdles still need to be overcome.  
CGM devices first available in 1999 are not as yet approved by the FDA for 
calculating insulin doses, reflecting ongoing concerns that the devices are still not 
sufficiently accurate or reliable. In addition, many researchers believe insulin 
absorption from the most likely delivery site (subcutaneous) is still too slow.  At 
best, the timeline for the first commercially available AP is unclear.   What is clear 
however, is that the level of control now achieved with the best available 
technology – widely considered as insulin pump therapy combined with CGM - is 
less than optimal. 
 

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Insulin pump therapy requires the managing physician or patient to set basal 
insulin rates, which may vary throughout the day.  Bolus estimators included with 
the pumps require a subject specific carbohydrate-to-insulin ratio (CIR) to 
estimate the insulin needed to cover a meal, and an insulin sensitivity factor (ISF) 
to calculate correction boluses in the event of an error in estimating the 
carbohydrate content of meal.  An insulin-on-board (IOB) time is also required to 
prevent the patient from taking a second correction bolus before the first bolus 
has had time act.  While guidelines exist to aid the physician in initially 
configuring the pump settings, changes in the configuration are often made with 
the final values often arrived at simply by trial and error.  Complicating the trial-
and-error approach is that some settings may need to be acutely adjusted in 
response to stress, illness, or exercise, with the latter often having what could 
potentially be a prolonged effect to lower the insulin requirement (2; 3).  
 
CGM, when first introduced, was widely thought to be a transformative 
technology.  Hypo- and hyper-glycemic alarms were anticipated to provide an 
added level of safety.  Information on the trend, or rate-of-change, of glucose 
was anticipated to improve boluses estimates which could be increased if the 
levels were increasing or lowered if decreasing.  And, having a retrospective 
continuous trace of the patient’s glucose profile was thought to be a mechanism 
by which pump settings could logically be set.  Unfortunately, false alarms limited 
the effectiveness in preventing hypoglycemia, no clear guidelines emerged on 
how to incorporate rate information into the bolus estimate, and the sheer volume 
of data obtained over multiple days or weeks, and the need to merge that data 
with meal information, insulin dosing, and patient logbook records, made it 
virtually impossible for a physician to go through the tracings in sufficient detail to 
make an informed decision on how to adjust pump settings.  Moreover, the 
reliance on logbook records to identify instances of nighttime hypoglycemia that 
might have been related to an elevation in daytime activity is unrealistic.  Most 
individuals with T1D simply do not maintain records with this level of detail and 
parents of younger children may not even be aware of all the activities their child 
participates in during school hours. 
 
The effect of physical activity on glycemic control in diabetic patients can 
often be complex. However, there is significant evidence linking increased 
physical activity with risk of overnight hypoglycemia. The DirectNet study group, 
for example, found that children 11 to 17 years old made to exercise under a 
controlled setting were more likely to develop hypoglycemia the night following 
the exercise intervention compared to sedentary days (2).  A more recent study 
reported overnight and next-day hypoglycemia was most likely in adolescents 
with type 1 diabetes who had > 30 min/day of moderate-to-vigorous physical 
activity (MVPA); measured using data from accelerometers (3). 
 
The present study looks to assess the feasibility of combining information 
from an activity monitor, with CGM and pump data, and determine if the 
combined data can be used to guide adjustments in insulin-pump settings.  We 

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seek to determine whether the activity data can identify instances when those 
settings may need to be adjusted in response to activity, as well as help 
determine the extent of the dosing change required.  Our long-term goal is to 
create a cloud-based software tool that will alert the patient when the settings 
may need to be lowered in response to high activity.  This is a pilot study to 
gather data regarding feasibility of using activity monitors to adjust insulin pump 
therapy and obtain preliminary data to power a larger outcome study.  We 
include children from 1 to 17 years, in order to observe energy expenditure in 
children of different ages. 
 
3. Preliminary studies 
Our prior studies controlling blood glucose have been in fully automated 
glucose control in individuals with T1D (aka the artificial pancreas), and in 
physician supervised control of critically ill patients (aka tight glycemic control; 
TGC).  The studies were performed by at Boston Children’s Hospital (BCH), and 
combined CGM with different Proportional-Integral-Derivative (PID) control 
algorithms to guide insulin dose adjustments in the subcutaneous insulin infusion 
pumps used by individuals with T1D, and in the intravenous insulin infusion 
pumps used to manage critically ill patients in the ICU (4-10).   
 
In the current study we plan to use a version of the same algorithm to 
guide changes in the basal insulin rates used in today’s open-loop pump therapy.  
Specifically, we look to identify more appropriate rates for use during nights 
following high daytime activity level.  It is on these nights that many subjects find 
it necessary to lower their basal rates.  To assess the ability of the PID algorithm 
to identify and adjust these rates, we performed a preliminary computer 
simulation study of the algorithm (Figure 1).  Such simulations are increasingly 
being used to assess algorithms used to adjust insulin delivery (11; 12) in 
advance of performing a clinical studies.  In our simulation study, the P and I 
components of the PID algorithm were used to make a sequence of 
recommendations on the midnight to 3 am basal rate in order to achieve target 
glucose values in the range 110-130 mg/dL.  Adjustments were made following 
an equation in the form of: 
 
In the equation, the basal rate from midnight to 3 am on a future day, is denoted 
with a superscript N+1, is calculated from the value used on the current day, 
denoted by superscript N.  Recommendations to increase or decrease the basal 
rate are based not just on whether the CGM glucose value is below target, but 
also on what the rate of change of glucose is at that time.  Thus, a 3 AM CGM 
value that is consistently at target but decreasing may result in a 
recommendation to decrease the midnight to 3 AM basal rate, and a value is 
above target but approaching target at a desired rate may leave the basal rate 
un-changed, the desired rate being set by parameter TI.  Changes are not made 
from day-to-day; rather, the value is updated each day but needs to pass a 
threshold set by the user (0.05 U/hr in this simulation).  Thus, a value slightly 
above target range on one day, and slightly below target on a subsequent day, 

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has no net effect, with a change only occurring following an interval where the 
values are consistently above or below target.  In the simulation study, the pump 
basal rates were initially set to be higher than needed, leading to a 3 AM glucose 
value of 50 mg/dL on the first observation (simulating a night following a high 
level of activity during the day).   For the values of KP and TI chosen, the first 
recommended change requires a repeat occurrence at 50 mg/dL, and a total 6 
changes are required to decrease the basal rate from the initial 0.5 U/hr to 0.2 
U/hr.  Different values of KP and TI lead to more rapid or slower adaptation.  As 
well, the target range can be decreased, but will require additional pump 
adjustments that the physician or patients may find unnecessary. 
 
Figure 2.  
𝐵𝐴𝑆𝐴𝐿0−3
𝑁+1 = 𝐵𝐴𝑆𝐴𝐿0−3
𝑁
+ 𝐾𝑃(𝐺3𝑎𝑚−𝑡𝑎𝑟𝑔𝑒𝑡)/𝑇𝐼+ 𝐾𝑃
𝑑𝐺3𝑎𝑚
𝑑𝑡
 
 
To identify high activity days, subjects will be provided with activity 
monitors (FitBit or similar). These monitors have become popular but are not 
medical devices per se; thus, we will be taking care not to rely solely on the 
device for identifying high activity days.  While not approved as a medical device, 
our evaluation of one device (FitBit) indicated it could provide a reasonable 
estimate of the number of calories burned and steps taken and that the data was 
easily accessed through the cloud (Figure 2). Other research groups have used 
similar devises to show days that include 30 min of moderate to vigorous 
physical activity are flowed by a 31% increase in hypoglycemia (95% CI 1.05–
1.63; P = 0.017)(3). 
 
 
Figure 1. Simulated pump adaptation 
showing changes in 3 am glucose over 
28 days of adaptive pump therapy. 

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Figure 3.  FitBit activity data obtained from cloud. 
 
The devices are small (about the size of a quarter) and rely on accelerometers to 
estimate activity.  They are, however, subject to errors whenever the activity 
does not involve acceleration of the device per se (e.g. riding a stationary bike).  
Software provided with the devices allows these events to be separately tracked.  
Still, published studies have validated that these devices provide objective, 
reliable assessments of activity completed and calories expended per day (14-
17). Therefore, we believe that they will provide a more reliable estimate of 
activity than can be inferred from log-book records, and allow us to assess the 
validity of using daytime activity to effect changes in nighttime insulin basal rates.  
However, changes in the rates will not be recommended to the patient without 
physician approval.  Rather, if we determine a relationship between high daytime 
activity and low overnight basal requirements, the physician will discuss with the 
patient how best to identify days involving high activity without relying solely on 
FitBit device. 
 
 
4. Design and Methods 
 
a. 
Study design 
This study is a pilot trial investigating the feasibility of using activity 
monitoring data to adjust insulin pump therapy and prevent hypoglycemia.  The 
study will enroll 20 patients 1-17 years old with type 1 diabetes mellitus on insulin 
pump therapy. Subjects will be provided with continuous glucose monitors 
(DexCom G4) and FitBit activity monitors. Study duration will be 3 to 4 months. 
During the course of the study patients will continue to receive routine care by 
their primary endocrinologist and DNE. Insulin dose adjustments unrelated to 
activity monitor data will continue to be at the discretion of the patient’s primary 
diabetes team.  
Activity level (steps and calories burned) will be uploaded over the web in a 
secure fashion to our central firewall-protected database on a daily basis while 

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CGM glucose values and insulin pump data will be collected once a week. Data 
from the activity monitor is automatically sent to a secure study team RedCap 
database once a day. This occurs by automatic, wireless syncing of the activity 
monitor with the patient/family’s computer or smartphone. The activity monitor 
and activity monitor data is not associated with any personal health information. 
The activity monitor is only set up with a study identification number. Only study 
team members have access to the list of study identification numbers and 
associated patient information and this is stored in a secure computer a locked 
office. CGM and insulin pump data will be downloaded onto a patient or study 
team computer and then emailed to the study team once a week. Families will 
also have the option of coming to clinic once a week and having a study team 
member download the CGM and insulin pump data for them.  
The initial 2 weeks of a subject’s enrollment in the study will be used to 
establish his or her baseline activity level and no changes to the insulin regimen 
will be made based on the activity monitor data. During weeks 3-6 to 12-16, 
activity data will be reviewed daily and an alternate basal insulin rate will be 
recommended on days considered to be increased activity days. We will use an 
adaptive algorithm to help guide suggested nighttime insulin basal rate changes. 
All recommendations will be reviewed and approved by a study physician prior to 
implementation. The alternate rate will be derived using the subject’s usual care 
pump settings as an initial starting point from which to make incremental changes 
in the 3 hour interval leading up to the hypoglycemic event.  Target will be the 
overnight nadir obtained with usual care settings.  Residual error (CGM-target) 
will be used to assess the validity of using the 3 hour window prior to the event to 
effect lower basal. The patient’s primary diabetes team will be informed about the 
recommended nighttime basal insulin dose change and this will be documented 
in the patient’s medical record in powerchart. The primary diabetes team will not 
give recommendations regarding nighttime insulin rate dose changes based on 
activity monitor data; however, they will continue to guide all other aspects of the 
patient’s diabetes management. 
 
 
b. 
Patient Selection and Inclusion/Exclusion Criteria 
Subjects will be recruited from the outpatient endocrinology clinic based 
on physician recommendation and approval to approach at Boston Children’s 
Hospital (BCH) as well as through public notice. 20 subjects will be recruited in 
two different age designations. 
 
 Inclusion Criteria: 
 
 Age: 1 to 17 years old  
 Type 1 diabetes (as clinically diagnosed by outpatient endocrinologist).   
 Treated with insulin pump therapy for greater than or equal 3 months 

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 Families will need to have access to Wi-Fi and a compatible smartphone 
in order for the data from the activity monitor and other devices to be 
transmitted to the research team 
Exclusion Criteria: 
 
 Current glucocorticoid use or other medication known to affect insulin 
action at investigator’s discretion. 
 Hospitalization within the last month 
 
c. 
Description of Study Treatments and Procedures  
RECRUITMENT, SCREENING AND CONSENT:  
 
Subject 
will 
be 
recruited 
from 
the 
Boston 
Children’s Hospital 
Endocrinology Clinic. We will screen the clinic schedule for eligible candidates. 
Eligibility will be assessed.. Primary providers will be approached regarding 
eligible patients and asked to introduce the research team at the time of the clinic 
visit. Consent, and assent for patients older than 7 years old, will be obtained 
during the patient’s clinic visit. Additionally, we will contact by email all diabetes 
providers to inform them of our study and ask them to give interested families the 
approved study information sheet, which has study team contact information 
(email and phone number is given on the sheet). For interested subjects who 
contact us but do not have an upcoming clinic visit, consent will be obtained at 
the Training and Education visit.  
   
 
TRAINING AND EDUCATION:  
 
After initial recruitment discussions, subjects will be requested to come to 
the Endocrine outpatient clinic located at 333 Longwood. A trained research 
team member will teach during a 1-2 hour session use of the continuous glucose 
monitor and the activity monitor. Families will also be instructed how and when to 
upload data from the insulin pump, CGM and activity monitor. Families will have 
the choice to use their own computers, use a study team-provided computer or 
come to clinic in order to upload data once a week. Activity monitor data will be 
uploaded automatically on a daily basis when subjects are near a Wi-Fi 
connection. 
 
CGM Education:  A trained research team member (nurse or physician) 
will provide education surrounding the use of the CGM, including technical 
aspects related to insertion and removal of the device, alarms, and calibration.  
Subjects will be informed that sensor values are not to be used to dose insulin 
and that prior to administering insulin they should obtain a blood glucose value 
from their standard meter (i.e., follow normal routines).  Subjects will be 

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instructed to calibrate the CGM a minimum of twice daily, before breakfast and 
before going to bed. Additional calibrations may be performed at the subject’s 
discretion as in clinical practice.  Sensors will be provided for replacement as 
needed (e.g. sensor falls off or fails internal quality checks included in the 
manufacture’s product).  Sensors may also be replaced at the subject’s 
discretion should they observe the sensor is consistently not tracking blood 
glucose values as is standard practice.  Subjects’ CGM will be programmed with 
a low glucose alarm at 60 mg/dl. Subjects will also be requested to confirm 
episodes in which the sensor reports hypoglycemia with a capillary blood glucose 
meter measurement, and to treat hypoglycemia as per their home routine.  At the 
completion of the study, CGMs devices will be collected.  
 
Use of the FitBit Device.  Combined with the initial training on CGM will be 
a short description of how the FitBit device works, and how the data obtained 
from the device will be used.  Subjects will be encouraged not to make 
adjustments in insulin delivery based on the device readings, unless instructed 
by a research team member. At the completion of the study each subject will be 
allowed to keep FitBit monitors (valued at $49.95 - $99.95).       
 
STUDY PROCEDURES: 
 
Insulin Pump Therapy:  Participants will continue to use their own insulin 
pump and home blood glucose meter. All subjects will continue to receive routine 
care from their primary diabetes team. We propose to enact insulin dosing 
changes if we discover significant hyperglycemia and informing the diabetes 
providers of these changes.” All other insulin dose changes unrelated to activity 
monitor data and energy expenditure estimates will be at the discretion of the 
primary team. We recognize that initial use of CGM may reveal previously 
undetected hypo- or hyperglycemia. Subjects and their families should discuss 
these findings with their primary diabetes team as they would for any other 
concerning blood glucose levels. If significant nocturnal hyperglycemia is 
detected, an increase in nighttime insulin basal rate will be recommended by the 
study team after being reviewed by the study endocrinologist. The dosing 
changes to address the hyperglycemia will be made by the study team directly in 
order to prevent delays in correction of the hyperglycemia as can occur if forced 
to wait for a response from the primary provider. Nevertheless, Tte 
recommended changes will also be sent as a powerchart message to the 
subject’s primary diabetes care team and they will be given the option to opt out 
of the recommendation and contact the patient directly to address the discovered 
hyperglycemia. If the provider responds after the changes have been enacted 
then we will simply contact the family and ask them to resume their prior settings 
and discuss with their provider an alternative plan to treat the hyperglycemia.  
 
Changes in Pump Therapy Based on Activity: During the first two to six 
weeks of the study, a baseline activity level will be established for each subject 
(average and standard deviation of first 14 days of available data). High activity 

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days will be initially defined as any day where the activity is greater than one 
standard deviation above the mean. This definition, however, may need to be 
adjusted on a subject specific basis as it may vary due to physical fitness. Nadir 
glucose on increased activity days will be inputted into an adaptive basal 
algorithm. The algorithm is initialized with the subject’s baseline insulin rate 
settings. Once the algorithm detects a need to modify the basal rate based on 
activity level, then an alternate basal profile will be recommended by the study 
physicians if deemed appropriate. The change will be made by the parent during 
one of the scheduled weekly phone calls or any other time of the week if needed.  
A study team member will walk the parent through the required steps to change 
insulin pump settings and confirm by verbal read back, screenshot or download 
that the pump settings are correct. Any changes to insulin pump therapy will be 
communicated to the subject’s primary diabetes team via a note entered into the 
patient’s BCH medical record.  
 
Subject-Study Team communication: All subjects/families will be asked to 
contact the study team and perform a data download on a weekly basis. Families 
will be asked if they were compliant with CGM and activity monitor, it they had 
issues with blood glucose levels and if there were any intercurrent illnesses. 
Additionally, participants should contact a study team member if they experience 
any technical difficulties with their CGM or activity monitor, if they experience any 
nocturnal hypoglycemia (confirmed by home glucometer) or if they have 
concerns regarding a high activity day. Study team members will review daily 
activity data and call subject’s families if an insulin dose change is 
recommended. A study team member will be available on page 24 hours a day.  
 
Safety Monitoring: If CGM review reveals significant and recurrent 
hyperglycemia or activity-unrelated hypoglycemia, the subject’s diabetes team 
will be alerted so that they may decide if changes to the subject’s baseline insulin 
regimen are required. The study team may enact nighttime basal insulin dosing 
changes 
if 
significant 
nocturnal 
hyperglycemia 
is 
encountered 
while 
simultaneously alerting the patient’s primary diabetes providers of these changes 
and giving them the option to change or refuse the recommendation.  
  
d. 
Definition of Primary and Secondary Outcomes/Endpoints 
This is a pilot study to determine the feasibility of combining activity 
monitor data with CGM and pump data to make prospective recommendations to 
reduce basal insulin delivery following high activity days.  There is no planned 
hypothesis for the pilot phase; however, planed comparisons for a larger study 
will be powered from the data obtained.  The primary endpoint for the larger 
study will be a reduction in the incidence of nighttime hypoglycemia.  Secondary 
outcomes will include the ability of activity data to predict nighttime nadir glucose. 
Hypoglycemia will be defined as home meter glucose < 70 mg/dl for all 
subjects, CGM values below threshold for >30 minutes with no concomitant 
blood sugar reading (i.e. subject is sleeping at home and ignores the low glucose 

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alarm but the CGM is <70 for more than 30 minutes). Hypoglycemia episodes 
within one hour of each other will be considered as one event. Two hypoglycemic 
events with an intermittent blood glucose value above 70 mg/dL will be treated as 
a single event. Hypoglycemia and “use-of-supplemental- carbohydrate-to-
prevent-hypoglycemia” will be treated identically.   
 
5. Data Management and Statistical Analysis 
One study folder, with IRB approved consent forms and case report forms 
(CRF), will be maintained for each subject recruited into the study.  Sensor 
information, as provided by the manufacturer, will also be recorded on CRFs 
(identification numbers such as lot or serial together with expiration).  Electronic 
data downloads for the insulin pump, containing a history of insulin delivery 
commands; glucose meter and glucose sensor, containing a record of all glucose 
values received and any alarms will be obtained weekly and the downloaded files 
copied to a password protected study computer in subdirectory labeled with the 
patient identification number.  A copy of the spreadsheet used to screen blood 
glucose and activity data will also be placed in this directory.   
a. Data Analysis Plan 
Data analysis will begin by calculating the baseline (average and standard 
deviation) activity level for each subject during the first two to six weeks. High 
activity days will be defined as any day where the activity is greater than one 
standard deviation above the mean. Correlations will be performed to assess if 
there is relationship between daytime activity (8- am to 9 pm) and nighttime nadir 
blood glucose level (continuous).  Nadir glucose will also be categorized as hypo- 
or no-hypo (binary), with a binary logistic regression model used to assess the 
significance of daytime activity, insulin dosing, and carbohydrate intake, as 
independent factors increasing the risk of hypoglycemia.  Analysis will proceed 
with generalized estimating equations (not powered but in preparation of the 
larger study to be conducted).  Characteristics of the nighttime glucose profile 
(nadir glucose, time in target, time below target) will be calculated weekly, with 
mean and 95% confidence plotted by week.  In the event usual-care pump 
settings are adjusted during the course of the study, the average nighttime 
glucose values observed for the week following the most recent adjustment will 
be compared to average values obtained during the final week (assures 
improvements are due to the availability of the FitBit data rather than the CGM 
data). Chi2 analysis will be used to assess differences in the incidence of 
hypoglycemia. Statistical analyses will be performed both as intention to treat 
and per protocol. The intention to treat analysis will include all data; per protocol 
analysis will exclude cases in which the subject does not comply with 
recommendations of the study team or does not complete all 12 weeks of the 
study.  The algorithm will be considered feasible if all data can be assembled, 
and recommendations deemed reasonable (accepted) in a majority of cases.   
 
 

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Statistical Power and Sample Considerations 
 
This is a feasibility study and therefore is not powered; however, the 
choice of 10 subjects with any one group is generally considered acceptable for 
feasibility/pilot-studies and should provide sufficient data to power a larger study. 
 
Study Organization 
This is a single center study with limited enrollment.  There are three 
participating physicians (medical team: Drs. Paulina Ortiz-Rubio, Carmen Soto-
Rivera, and Michael Agus).  This team will be responsible for guiding subjects on 
the use of CGM and for approving pump therapy changes.  Dr. Steil will be 
responsible for incorporating input from the medical team into the adaptive pump 
therapy (APT) algorithm, overseeing data analysis, and publication of results.  
Recruitment at BCH will be primarily performed by Dr. Steil’s research assistant. 
 
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Children Network Direcnet Study G: Impact of exercise on overnight glycemic control in 
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