subjects were recruited from the diabetes clinic at boston children s hospital between september 2011 and april 2012 .
eligibility criteria included type 1 diabetes diagnosed by a pediatric endocrinologist , age < 7 years , duration of diabetes > 6 months , and insulin pump use > 6 weeks . subjects were excluded for any significant comorbid illnesses except for treated celiac disease .
each subject was admitted to the inpatient clinical research center for a single 45-h admission .
this study was a crossover controlled trial comparing standard open - loop therapy with closed - loop therapy from 10:00 p.m. to 12:00 p.m. on each day of the hospitalization ( fig .
the order of administration of the two modes of therapy was randomized from a computer - generated list .
the individual assignments were sealed in sequentially numbered envelopes , which were opened after enrollment and consent . on the morning of admission , two cgms ( abbott freestyle navigator ; abbott diabetes care , alameda , ca )
an initial blood glucose calibration was performed at 1 h. subjects then returned for admission at 3:00 p.m. , when a repeat calibration was performed .
calibrations were then performed at 10 and 24 h postinsertion as per the manufacturer s recommendation .
additional calibrations for discrepancy between the sensor and venous glucose were not done . by convention ,
the sensor in the right leg was used for running the closed - loop algorithm except in one case when sensor data from the right sensor were unavailable at 10:00 p.m. , in which case the left - leg sensor was used . the sensor used for control
all subjects were switched to the study onetouch ping insulin pump ( animas corporation , west chester , pa ) , which was preprogrammed with their home settings .
meals and snacks were served on the following schedule : dinner , 5:00 p.m. ; bedtime snack , 8:00 p.m. ; breakfast , 8:00 a.m. ; morning snack , 10:00 a.m. ; lunch , 12:00 p.m. ; and afternoon snack , 3:00 p.m. this represents a typical meal schedule for children with diabetes in this age - group . parents chose the subjects meals off a standard menu , and identical meals and snacks were served on both days of the study . all meals and snacks were pre- and postweighed to assess intake . at 5:00 p.m. and 8:00 p.m. on both days ,
an insulin bolus was given for dinner and bedtime snack based on the subject s blood glucose level and planned carbohydrate intake , using the subject s home carbohydrate ratios , correction factors , and blood glucose targets .
the insulin - on - board feature was activated on the onetouch ping insulin pump as per the subject s home insulin pump settings .
the study period commenced at 10:00 p.m. from 10:00 p.m. to 7:40 a.m. , venous blood glucose values were obtained every 20 min . from 7:40 a.m. to 8:40 a.m. , venous samples were obtained every 10 min for glucose and insulin levels , followed by every 20 min until 10:00 a.m. , and then samples were obtained at 10:30 a.m. , 11:00 a.m. , and 12:00 p.m. fasting serum c - peptide levels were drawn at 8:00 a.m. on the open - loop day . during open - loop therapy , insulin boluses were given at 8:00 a.m. and 10:00 a.m. per the subject s home insulin routine .
for the 10:00 a.m. snack , carbohydrate coverage was given but a correction dose of insulin for hyperglycemia was not given , as the subject had received a bolus of insulin for breakfast 2 h prior .
basal rates were not adjusted overnight during open - loop therapy , but an additional correction dose of insulin could be given for hyperglycemia at the parents discretion to mimic their standard home therapy . during closed - loop therapy , insulin basal rates were adjusted every 20 min overnight from 10:00 p.m. to 8:00 a.m. , and mini - boluses of insulin ( 0.050.1 units ) were given up to every minute from 8:00 a.m. to 12:00 p.m .. delivery rates were calculated using closed - loop algorithms ( described below ) but with the dose approved by a physician and administered via manual entry by the physician into the pump .
all episodes of hypoglycemia defined as plasma glucose < 70 mg / dl were treated with oral carbohydrates ( juice or glucose tabs ) .
one subject ( subject 4 ) did not receive the dinner insulin bolus on the open - loop therapy night as the result of an error .
a correction dose of insulin was given with the bedtime snack at 8:00 p.m. ( see supplementary fig .
different algorithms were used to effect control during the nighttime ( 10:00 p.m. to 8:00 a.m. ) and daytime ( 8:00 a.m. to 12:00 p.m. ) closed - loop periods . during the nighttime ,
control was effected with a proportional - integral component in series with a proportional - derivative component .
the proportional - integral component recommended stepwise increases in the basal rate whenever sensor glucose was above target ( 150 mg / dl , 10:00 p.m.6:00 a.m. ; 120 mg / dl , 6:00 a.m.8:00 a.m. ) and not returning to target at a desired rate : [ ( sensor glucose  target)/ti ] , where ti is 120 min .
this was modified by the proportional - derivative component to be accompanied by a bolus ( bolus = basal change in units per minutes  td , where td is 30 min ) .
recommendations were made every 20 min with the aid of a spreadsheet ( microsoft excel ) . at 8:00 a.m.
, control was transferred to an algorithm using a proportional - integral component in parallel with a proportional - derivative component .
the proportional - integral component increased the anticipated basal rate whenever sensor glucose was above target ( 120 mg / dl ) and not returning to target at a desired rate : [ ( sensor glucose  target)/ti ] , where ti = 60 min .
the anticipated basal rate was then summed with the proportional - derivative component , which recommended insulin delivery be adjusted in proportion to the sensor glucose value expected at a future time point ( sensor glucose + td  rate of change of sensor glucose , where td = 120 min ) .
the sum of the two components was then modified by insulin feedback as previously described ( 5,16 ) but with pharmacokinetic / pharmacodynamic profiles obtained in children ( 17,18 ) . the modified rate ( units / hour ) was then converted to a series of 0.05-unit boluses and delivered to the subject on a minute - to - minute interval as needed , with blood glucose assessed every 1020 min . during the study ( subject 6 and forward ) , the nighttime control configuration was modified to reduce the desired rate for glucose to return to target ( ti increased from 60 to 120 min ) , reduce the bolus accompanying each change in basal rate ( td reduced from 60 to 30 min ) , and add insulin feedback .
venous glucose was measured on the hemocue glucose 201 dm analyzer ( hemocue , cypress , ca ) and is reported as plasma equivalents .
plasma insulin was measured using a chemiluminescent immunoassay ( beckman coulter , fullerton , ca ) .
c - peptide was measured by radioimmunoassay ( siemens , los angeles , ca ) .
primary outcome was defined as plasma glucose time in range ( 110200 mg / dl ; hemocue ) during the night ( 10:00 p.m.8:00 a.m. ) .
incidence of hypoglycemia ( blood glucose < 70 mg / dl as measured by the hemocue meter ) was combined with supplemental carbohydrate given to prevent hypoglycemia with paired difference in open- versus closed - loop control made using mcnemar test with continuity correction .
continuous outcome measures ( time in range , mean glucose , etc . ) were compared using paired t tests as indicated .
statistical analysis was performed using graphpad prism version 6.0 for windows ( graphpad software , san diego , ca ) .
statistical significance was taken as p < 0.05 ; correction for multiple comparisons was not performed .
on the morning of admission , two cgms ( abbott freestyle navigator ; abbott diabetes care , alameda , ca ) were placed in the thighs of each subject .
an initial blood glucose calibration was performed at 1 h. subjects then returned for admission at 3:00 p.m. , when a repeat calibration was performed .
calibrations were then performed at 10 and 24 h postinsertion as per the manufacturer s recommendation .
additional calibrations for discrepancy between the sensor and venous glucose were not done . by convention
, the sensor in the right leg was used for running the closed - loop algorithm except in one case when sensor data from the right sensor were unavailable at 10:00 p.m. , in which case the left - leg sensor was used . the sensor used for control
all subjects were switched to the study onetouch ping insulin pump ( animas corporation , west chester , pa ) , which was preprogrammed with their home settings .
meals and snacks were served on the following schedule : dinner , 5:00 p.m. ; bedtime snack , 8:00 p.m. ; breakfast , 8:00 a.m. ; morning snack , 10:00 a.m. ; lunch , 12:00 p.m. ; and afternoon snack , 3:00 p.m. this represents a typical meal schedule for children with diabetes in this age - group .
parents chose the subjects meals off a standard menu , and identical meals and snacks were served on both days of the study . all meals and snacks were pre- and postweighed to assess intake . at 5:00 p.m. and 8:00 p.m. on both days ,
an insulin bolus was given for dinner and bedtime snack based on the subject s blood glucose level and planned carbohydrate intake , using the subject s home carbohydrate ratios , correction factors , and blood glucose targets .
the insulin - on - board feature was activated on the onetouch ping insulin pump as per the subject s home insulin pump settings .
the study period commenced at 10:00 p.m. from 10:00 p.m. to 7:40 a.m. , venous blood glucose values were obtained every 20 min . from 7:40 a.m. to 8:40 a.m. , venous samples were obtained every 10 min for glucose and insulin levels , followed by every 20 min until 10:00 a.m. , and then samples were obtained at 10:30 a.m. , 11:00 a.m. , and 12:00 p.m. fasting serum c - peptide levels were drawn at 8:00 a.m. on the open - loop day . during open - loop therapy , insulin boluses
were given at 8:00 a.m. and 10:00 a.m. per the subject s home insulin routine .
for the 10:00 a.m. snack , carbohydrate coverage was given but a correction dose of insulin for hyperglycemia was not given , as the subject had received a bolus of insulin for breakfast 2 h prior .
basal rates were not adjusted overnight during open - loop therapy , but an additional correction dose of insulin could be given for hyperglycemia at the parents discretion to mimic their standard home therapy . during closed - loop therapy
, insulin basal rates were adjusted every 20 min overnight from 10:00 p.m. to 8:00 a.m. , and mini - boluses of insulin ( 0.050.1 units ) were given up to every minute from 8:00 a.m. to 12:00 p.m .. delivery rates were calculated using closed - loop algorithms ( described below ) but with the dose approved by a physician and administered via manual entry by the physician into the pump .
all episodes of hypoglycemia defined as plasma glucose < 70 mg / dl were treated with oral carbohydrates ( juice or glucose tabs ) .
one subject ( subject 4 ) did not receive the dinner insulin bolus on the open - loop therapy night as the result of an error .
a correction dose of insulin was given with the bedtime snack at 8:00 p.m. ( see supplementary fig .
different algorithms were used to effect control during the nighttime ( 10:00 p.m. to 8:00 a.m. ) and daytime ( 8:00 a.m. to 12:00 p.m. ) closed - loop periods . during the nighttime ,
control was effected with a proportional - integral component in series with a proportional - derivative component .
the proportional - integral component recommended stepwise increases in the basal rate whenever sensor glucose was above target ( 150 mg / dl , 10:00 p.m.6:00 a.m. ; 120 mg / dl , 6:00 a.m.8:00 a.m. ) and not returning to target at a desired rate : [ ( sensor glucose  target)/ti ] , where ti is 120 min .
this was modified by the proportional - derivative component to be accompanied by a bolus ( bolus = basal change in units per minutes  td , where td is 30 min ) .
recommendations were made every 20 min with the aid of a spreadsheet ( microsoft excel ) . at 8:00 a.m. ,
control was transferred to an algorithm using a proportional - integral component in parallel with a proportional - derivative component .
the proportional - integral component increased the anticipated basal rate whenever sensor glucose was above target ( 120 mg / dl ) and not returning to target at a desired rate : [ ( sensor glucose  target)/ti ] , where ti = 60 min .
the anticipated basal rate was then summed with the proportional - derivative component , which recommended insulin delivery be adjusted in proportion to the sensor glucose value expected at a future time point ( sensor glucose + td  rate of change of sensor glucose , where td = 120 min ) .
the sum of the two components was then modified by insulin feedback as previously described ( 5,16 ) but with pharmacokinetic / pharmacodynamic profiles obtained in children ( 17,18 )
. the modified rate ( units / hour ) was then converted to a series of 0.05-unit boluses and delivered to the subject on a minute - to - minute interval as needed , with blood glucose assessed every 1020 min . during the study ( subject 6 and forward ) , the nighttime control configuration was modified to reduce the desired rate for glucose to return to target ( ti increased from 60 to 120 min ) , reduce the bolus accompanying each change in basal rate ( td reduced from 60 to 30 min ) , and add insulin feedback .
venous glucose was measured on the hemocue glucose 201 dm analyzer ( hemocue , cypress , ca ) and is reported as plasma equivalents .
plasma insulin was measured using a chemiluminescent immunoassay ( beckman coulter , fullerton , ca ) .
c - peptide was measured by radioimmunoassay ( siemens , los angeles , ca ) .
primary outcome was defined as plasma glucose time in range ( 110200 mg / dl ; hemocue ) during the night ( 10:00 p.m.8:00 a.m. ) .
incidence of hypoglycemia ( blood glucose < 70 mg / dl as measured by the hemocue meter ) was combined with supplemental carbohydrate given to prevent hypoglycemia with paired difference in open- versus closed - loop control made using mcnemar test with continuity correction .
incidences separated by < 30 min were treated as a single event . continuous outcome measures ( time in range ,
statistical analysis was performed using graphpad prism version 6.0 for windows ( graphpad software , san diego , ca ) .
statistical significance was taken as p < 0.05 ; correction for multiple comparisons was not performed .
one subject withdrew after randomization but before any study procedures because of scheduling conflicts and is excluded from all analysis
. baseline demographics and clinical characteristics of the remaining 10 subjects are presented in table 1 .
subjects ages ranged from 2 to 6 years ( mean 5.1 ) with a mean duration of diabetes of 2.1 years .
seven subjects had a1c values < 8.5% ( american diabetes association target for this age range ) , and all had a1c values < 9% .
baseline demographic information six subjects were randomized to receive closed - loop therapy on the first night of the admission , with the remaining four receiving closed - loop therapy on the second night . during closed - loop therapy
total daytime insulin delivery was greater during closed - loop therapy ( mean 5.9 vs. 4.6 units during open loop ; p = 0.03 ) .
five episodes of hypoglycemia occurred between 12:00 p.m. and 5:00 p.m. while the subjects were on their standard open - loop therapy but outside of the study outcome period .
110 . comparison of average ( n = 10 ) open- and closed - loop glucose ( a ) and insulin delivery ( b , left axis ) and concentration ( b , right axis ) curves .
a trend toward a higher mean time for plasma glucose within target range ( 110200 mg / dl ) was noted for closed- versus open - loop therapy ( 5.3 vs. 3.2 h , respectively ) , although this difference did not achieve statistical significance ( p = 0.12 ) ( table 2 ) .
closed - loop therapy significantly reduced time spent > 300 mg / dl ( 0.18 vs. 1.3 h , p = 0.035 ) and the total area under the curve of glucose > 200 mg / dl ( p = 0.049 ) . during open - loop therapy
, five subjects received an additional correction dose of insulin overnight due to persistent hyperglycemia ( fig .
there was no significant difference in the number of episodes of hypoglycemia / supplemental carbohydrate ( p = 1.0 ) .
there were no significant differences in time spent below the target range or frankly hypoglycemic ( table 2 ) .
there were no instances of hypoglycemia between 8:00 a.m. and 12:00 p.m. in either group and no differences in the peak postprandial glucose concentration ( table 2 ) .
there was significant improvement in the prelunch blood glucose on closed - loop therapy ( 189 vs. 273 mg / dl on open - loop , p = 0.009 ) .
we performed the first study of closed - loop insulin therapy in children aged < 7 years . in our study ,
closed - loop insulin delivery decreased the severity of overnight hyperglycemia without increasing time spent below the glucose target range .
closed - loop therapy was also able to return glucose levels closer to target in advance of consuming a subsequent meal .
having subjects in this age - group ( aged < 7 years ) achieve near - target glucose levels in a timely manner is particularly challenging , as it is not always possible to predict in advance how much the child will eat .
although our study did not show an improvement in nighttime time in target , 50% of the subjects received additional insulin boluses during the open - loop nighttime . generally , our protocol sought to mimic the subjects home therapy during the open - loop study period ; however , we worked closely with the parents in trying to achieve the best possible open - loop control and allowed additional correction insulin boluses to be given overnight in response to the frequent blood glucose measurements .
this should have biased our results to the null ; yet , a significant decrease in hyperglycemia was still obtained with the closed - loop system .
our study subjects likely represent a highly motivated subgroup of families with type 1 diabetes who are more likely to closely monitor their children s blood glucose and give additional correction doses as needed .
thus , it is likely that widespread implementation of a similar closed - loop algorithm would yield an even greater benefit to overnight glycemic control , as many patients do not receive supplemental correction doses overnight .
parents of young children with type 1 diabetes have a significant fear of hypoglycemia , especially at night ( 20 ) . in a recent randomized controlled trial , use of a cgm did not decrease episodes of hypoglycemia in young children or fear of hypoglycemia in their caregivers ( 15 ) .
additional longer - term studies are needed to assess the ability of a closed - loop system to prevent hypoglycemia in young children and to alleviate hypoglycemia fear in their caregivers .
first , our closed - loop system was implemented every 20 min overnight , which significantly hampers the algorithm s ability to rapidly adjust to changes in glucose values .
implementation on a fully automated minute - to - minute system will improve performance significantly .
second , as this is the first study of closed - loop therapy in this age - group , the initial algorithm parameters were set based on estimates from adult studies .
computer modeling ( 2123 ) of the profiles obtained here may allow for optimization of algorithm performance and should lead to improved outcomes in subsequent clinical studies .
closed - loop therapy was able to provide similar peak postprandial glucose concentrations and then return the glucose concentration closer to target prior to the next meal .
typically , open - loop therapy has a better meal response than closed - loop therapy , as the insulin is given prior to the subject eating . in closed - loop therapy ,
insulin is not delivered until the blood glucose begins to rise after eating , leading to a delay in insulin action .
it is for this reason that some have suggested using a hybrid approach where a portion of the meal bolus is given prior to eating and the remaining insulin is determined by the closed - loop system .
however , in the case of young children it is very difficult to predict how much food they are going to eat at an individual meal and thus how much insulin to deliver .
parents often divide the meal bolus , giving a small portion in advance and the remainder postprandially . however , even this approach can prove difficult to implement safely and can result in hypoglycemia when the child eats significantly less than anticipated .
a reactive closed - loop insulin algorithm can prevent these episodes from occurring and could serve a great clinical need in these young children . another possible hybrid closed - loop approach is to give a noncommittal insulin bolus prior to the meal .
this bolus could improve the postprandial hyperglycemia , but if the subject decides not to eat at all the controller could still prevent hypoglycemia by reducing future basal delivery . alternatively , a partial meal bolus could be given postprandially after the parents witness how much the child eats  similar to current practice in young children .
either of these approaches will speed up insulin delivery , allowing for improvement in the meal response and then allowing the hybrid closed - loop system to deliver the remainder of the necessary insulin .
of course , these approaches require input from the patient or parent and thus increase the burden of the system .
finally , other groups have experimented with including glucagon in a closed - loop system to prevent hypoglycemia .
the inclusion of glucagon can potentially allow for more aggressive up - front insulin delivery , as the glucagon can counteract the effects of overdelivery of insulin and prevent postprandial hypoglycemia ( 3,24 ) .
while this approach is quite appealing at some level , there are a number of technical challenges to a dual hormonal system such as a substantial increase in the complexity of the system , manufacturing of a dual - chamber pump , and a stable formulation of glucagon , all of which have yet to be resolved .
it was performed in an inpatient setting on a limited number of individuals , and the subjects activity levels were much lower than their typical daily routine . yet to be determined is how a closed - loop system will deal with the day - to - day variability in young children s activity levels and eating patterns .
additionally , our closed - loop arm was implemented manually as opposed to on a fully automated system .
this allowed for physician oversight of every dose but limited the frequency of adjustments overnight .
however , it is quite difficult to optimize insulin basal rates in young children , and 70% of subjects had a1c levels within the american diabetes association target range , indicating that they were relatively well controlled .
finally , our study included a midmorning snack , as is routine for children in this age - group .
this snack may have played a role in preventing postbreakfast hypoglycemia due to aggressive insulin delivery .
additional studies will be needed to validate the improved prelunch blood sugars with closed - loop therapy without hypoglycemia in the absence of a midmorning snack . in conclusion
, we performed the first study of closed - loop insulin therapy in children aged < 7 years .
the development of a fully closed - loop system is critical for improving the well - being of patients with type 1 diabetes .
we believe that young children are especially difficult to manage with standard diabetes therapy because of high risk of nocturnal hypoglycemia , erratic activity , and unpredictable eating patterns and will benefit significantly from closed - loop therapy . additional research is needed in this underrepresented patient population .
 objectiveto assess the possibility of improving nocturnal glycemic control as well as meal glycemic response using closed - loop therapy in children aged < 7 years.research design and methodsthis was a randomized controlled crossover trial comparing closed - loop with standard open - loop insulin pump therapy performed in an inpatient clinical research center . 
 ten subjects aged < 7 years with type 1 diabetes for > 6 months treated with insulin pump therapy were studied . 
 closed - loop therapy and standard open - loop therapy were compared from 10:00 p.m. to 12:00 p.m. on 2 consecutive days . 
 the primary outcome was plasma glucose time in range ( 110200 mg / dl ) during the night ( 10:00 p.m.8:00 a.m. ) . 
 secondary outcomes included peak postprandial glucose levels , incidence of hypoglycemia , degree of hyperglycemia , and prelunch glucose levels.resultsa trend toward a higher mean nocturnal time within target range was noted for closed- versus open - loop therapy , although not reaching statistical significance ( 5.3 vs. 3.2 h , p = 0.12 ) . 
 there was no difference in peak postprandial glucose or number of episodes of hypoglycemia . 
 there was significant improvement in time spent > 300 mg / dl overnight with closed - loop therapy ( 0.18 vs. 1.3 h , p = 0.035 ) and the total area under the curve of glucose > 200 mg / dl ( p = 0.049 ) . 
 closed - loop therapy returned prelunch blood glucose closer to target ( 189 vs. 273 mg / dl on open loop , p = 0.009).conclusionsclosed - loop insulin delivery decreases the severity of overnight hyperglycemia without increasing the incidence of hypoglycemia . 
 the therapy is better able to reestablish target glucose levels in advance of a subsequent meal . 
 younger children with type 1 diabetes may reap significant benefits from closed - loop therapy . 
RESEARCH DESIGN AND METHODS
Procedures
Closed-loop control system
Statistics
RESULTS
CONCLUSIONS
Supplementary Material