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Trial record 57 of 750 for:    Area Under Curve AND meal

Effect of Gain on Closed-Loop Insulin

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ClinicalTrials.gov Identifier: NCT02065895
Recruitment Status : Completed
First Posted : February 19, 2014
Results First Posted : April 6, 2018
Last Update Posted : May 17, 2018
Sponsor:
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Joslin Diabetes Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Type 1 Diabetes
Interventions Device: HIGH error
Device: NO error
Device: LOW error
Enrollment 8
Recruitment Details Written informed consent was obtained from all 8 participants at the Joslin Diabetes Center. All study related activities were conducted at the Center for Clinical Investigations at the Beth Israel deaconess Medical Center.
Pre-assignment Details  
Arm/Group Title HIGH Error First, LOW Error Second, Then NO Error Third HIGH Error First, NO Error Second, Then LOW Error Third NO Error First, LOW Error Second, HIGH Error Third NO Error First, HIGH Error Second, LOW Error Third LOW Error First, NO Error Second, HIGH Error Third LOW Error First, HIGH Error Second, NO Error Third
Hide Arm/Group Description In this arm, subjects were randomized to undergo in-clinic closed-loop control of nighttime and breakfast glucose on three occasions: first with the glucose value used for control calculated to be 33% higher than the true glucose value (HIGH error), then second with the value calculated to be 20% lower than the true value (LOW error), then third with the value equal to the true value (NO error). These conditions reflect real-life conditions that would be expected if closed-loop artificial pancreas control is effected with different sensor calibration error. No meal announcement was provided (simulates condition where patient forgets to announce meal), and all subjects were controlled with the same closed-loop gain (simulates conditions where an individual's insulin sensitivity changes). Intervention period: 17 hours; minimum washout period was 7 hours, maximum was 62 days (varied among subjects, allowed up to 3 months to complete all 3 interventions). In this arm, subjects were were randomized to undergo in-clinic closed-loop control of nighttime and breakfast glucose on three occasions: first with the glucose value used for control calculated to be 33% higher than the true glucose value (HIGH error), then second with the value calculated to equal the true value (NO error), and then third with the value calculated to be 20% lower than the true value (LOW error). These conditions reflect real-life conditions that would be expected if closed-loop artificial pancreas control is effected with different sensor calibration error. No meal announcement was provided (simulates condition where patient forgets to announce meal), and all subjects were controlled with the same closed-loop gain (simulates conditions where an individual's insulin sensitivity changes). Intervention period: 17 hours; minimum washout period was 7 hours, maximum was 62 days (varied among subjects, allowed up to 3 months to complete all 3 interventions). In this arm, subjects were were randomized to undergo in-clinic closed-loop control of nighttime and breakfast glucose on three occasions: first with the glucose value used for control equal the true value (NO error), then second with the value calculated to be 20% lower than the true value (LOW error), and then third with the value calculated to be 33% higher than the true glucose value (HIGH error). These conditions reflect real-life conditions that would be expected if closed-loop artificial pancreas control is effected with different sensor calibration error. No meal announcement was provided (simulates condition where patient forgets to announce meal), and all subjects were controlled with the same closed-loop gain (simulates conditions where an individual's insulin sensitivity changes). Intervention period: 17 hours; minimum washout period was 7 hours, maximum was 62 days (varied among subjects, allowed up to 3 months to complete all 3 interventions). In this arm, subjects were were randomized to undergo in-clinic closed-loop control of nighttime and breakfast glucose on three occasions: first with the glucose value used for control calculated equal the true value (NO error), and then second with the value calculated as 33% higher than the true glucose value (HIGH error), and then third with the value calculated to to be 20% lower than the true glucose value (LOW error). These conditions reflect real-life conditions that would be expected if closed-loop artificial pancreas control is effected with different sensor calibration error. No meal announcement was provided (simulates condition where patient forgets to announce meal), and all subjects were controlled with the same closed-loop gain (simulates conditions where an individual's insulin sensitivity changes).Intervention period: 17 hours; minimum washout period was 7 hours, maximum was 62 days (varied among subjects, allowed up to 3 months to complete all 3 interventions). In this arm, subjects were were randomized to undergo in-clinic closed-loop control of nighttime and breakfast glucose on three occasions: first with the glucose value used for control calculated to be 20% lower than the true glucose value (LOW error), then second with the value calculated to equal the true value (NO error), and then third with the value calculated to be 33% higher than the true value. These conditions reflect real-life conditions that would be expected if closed-loop artificial pancreas control is effected with different sensor calibration error. No meal announcement was provided (simulates condition where patient forgets to announce meal), and all subjects were controlled with the same closed-loop gain (simulates conditions where an individual's insulin sensitivity changes). Intervention period: 17 hours; minimum washout period was 7 hours,maximum was 62 days (varied among subjects, allowed up to 3 months to complete all 3 interventions). In this arm, subjects were were randomized to undergo in-clinic closed-loop control of nighttime and breakfast glucose on three occasions: first with the glucose value used for control calculated to be 20% lower than the true glucose value (LOW error), then second with the value calculated to be 33% higher than the true value (HIGH error), and then third with the value calculated to be equal the true value (NO error). These conditions reflect real-life conditions that would be expected if closed-loop artificial pancreas control is effected with different sensor calibration error. No meal announcement was provided (simulates condition where patient forgets to announce meal), and all subjects were controlled with the same closed-loop gain (simulates conditions where an individual's insulin sensitivity changes). Intervention period: 17 hours; minimum washout period was 7 hours, maximum was 62 days (varied among subjects, allowed up to 3 months to complete all 3 interventions).
Period Title: Overall Study
Started 1 3 1 1 1 1
Completed 0 2 1 0 1 1
Not Completed 1 1 0 1 0 0
Reason Not Completed
Protocol Violation             1             0             0             1             0             0
Scheduling conflicts             0             1             0             0             0             0
Arm/Group Title Closed-loop Control
Hide Arm/Group Description Closed-loop control was performed from 9:00 PM to 2:00 the day following admission on three occasions: once with a glucose-value-used-for control calculated to be higher than the true blood glucose (analogous to a sensor glucose signal that is miss-calibrated); once with the value equal to blood glucose (analogous to a sensor signal with no calibration), and once with the value calculated to be lower than blood glucose. Six different arms were utilized, defined by the differing sequences of each of the three values used for control (no error, high error and low error previously defined). On each occasion control was separated into the nighttime period (midnight to 08:00 AM) and breakfast period (8:00 AM to 2:00 PM).
Overall Number of Baseline Participants 8
Hide Baseline Analysis Population Description
One subject withdrew prior to visit 1; of the seven subjects admitted on 3 occasions, two had protocol violations on one occasion (one subject experienced technical problems; one subject completed the nighttime period but was called away on an emergency prior to breakfast); 5 subjects completed the study per protocol.
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 8 participants
57
(40 to 71)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 8 participants
Female 0
Male 8
Region of Enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 8 participants
8
[1]
Measure Analysis Population Description: One subject withdrew
Median duration of diabetes  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 8 participants
47
(11 to 62)
Daily insulin use  
Mean (Full Range)
Unit of measure:  Units/day
Number Analyzed 8 participants
35.4
(27 to 45.2)
HbA1c  
Mean (Full Range)
Unit of measure:  %
Number Analyzed 8 participants
7.7
(6.8 to 8.4)
1.Primary Outcome
Title Glucose Area Under the Curve (AUC) Breakfast
Hide Description Glucose Area Under the Curve (AUC) Breakfast defines the total exposure to glucose during breakfast. Breakfast is typically considered the most difficult meal to control; low AUC is desirable.This outcome measure was analyzed for each of the three calibration error values (high error, no error and low error).
Time Frame On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 8:00 AM to 2:00 PM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title HIGH Error NO Error LOW Error
Hide Arm/Group Description:
Glucose sensor errors leading to sensor glucose reading higher than that true blood glucose result in closed-loop control systems (artificial pancreas) behaving as if the control gain is increased and the target is lowered. In this arm we study closed-loop control with a sensor signal reading 33% higher than blood glucose.
Glucose sensor errors leading to sensor glucose reading higher than that true blood glucose result in closed-loop control systems (artificial pancreas) behaving as if the control gain is increased and the target is lowered. In this arm we study closed-loop control with a sensor signal reading equal to blood glucose.
Glucose sensor errors leading to sensor glucose reading higher than that true blood glucose result in closed-loop control systems (artificial pancreas) behaving as if the control gain is increased and the target is lowered. In this arm we study closed-loop control with a sensor signal reading 20% lower than blood glucose.
Overall Number of Participants Analyzed 5 5 5
Mean (95% Confidence Interval)
Unit of Measure: mmol/l/min
66.8
(53.3 to 80.3)
48.8
(41.1 to 56.4)
37.4
(33.4 to 41.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection HIGH Error, NO Error, LOW Error
Comments Differences among the 3 groups were assessed by repeated measures ANOVA using Sidak’s correction for multiple comparisons. All subjects were analyzed as a single group, no comparison group.
Type of Statistical Test Other
Comments ANOVA was used to first tests the hypothesis that there is a difference among the three groups.
Statistical Test of Hypothesis P-Value 0.0011
Comments The p value was adjusted for multiple comparisons using Sidak’s correction. A priori the pimary outcome was defined as blood glucose AUC from 8 am - 12pm; however we used blood glucose AUC from 8am - 2pm to capture the entire meal response.
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 66.8
Confidence Interval (2-Sided) 95%
33.4 to 80.3
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Peak and Nadir Postprandial Glucose Concentration
Hide Description Highest and lowest glucose concentrations obtained during breakfast meal.
Time Frame On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 8:00 AM to 12:00 PM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was limited to the 5 subjects completed all aspects of the study per protocol (i.e. 5 subjects who completed all three scheduled breakfast meals).
Arm/Group Title Gain Increased and Target Decreased Nadir Mean Gain Decreased and Target Increased
Hide Arm/Group Description:
Closed-loop control performed with a sensor reading higher than blood glucose behave as if the control gain has been increased and the target set lowered
Closed-loop control performed with a sensor reading higher than blood glucose behave as if the control gain has been increased and the target set lowered
Closed-loop control performed with a sensor reading lower than blood glucose behave as if the control gain has been lowered and the target increased
Overall Number of Participants Analyzed 5 5 5
Mean (95% Confidence Interval)
Unit of Measure: mmol/l
Peak glucose concentration
13.3
(11.3 to 15.4)
11.8
(9.8 to 14.0)
11.3
(10.2 to 12.4)
Nadir glucose concentration
4.5
(3.8 to 5.2)
4.8
(3.7 to 6.5)
6.6
(5.6 to 7.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Gain Increased and Target Decreased
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0059
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
3.Other Pre-specified Outcome
Title Nighttime Time-in-target 5.0-8.33mmol/l (Controller Set-point Plus and Minus 15 mg/dL)
Hide Description Night-time in target range 5.0-8.33, following the 3 hour controller initialization period blood glucose remained at or near target.
Time Frame On day #1, day #2 and day #3 (each day could be 24 hours to 7 days apart from prior one, and completed within 6 week period) 12:00 AM to 6:00 AM on day following admission, with samples obtained every 10-15 minutes, for each sequence of calibration errors
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was limited to the 6 subjects completing all 3 nighttime periods per protocol
Arm/Group Title HIGH Error NO Errror LOW Error
Hide Arm/Group Description:
Closed-loop control performed with sensor glucose reading higher than blood glucose behaves as if the controller gain has been increased and the target lowered
Reference nighttime response for comparison with closed-loop control with sensor glucose reading higher than blood glucose and lower than blood glucose.
Closed-loop control performed with sensor glucose reading lower than blood glucose behaves as if the controller gain has been lowered and the target increased
Overall Number of Participants Analyzed 6 6 6
Median (Inter-Quartile Range)
Unit of Measure: percentage of time in target range
88
(87 to 100)
100
(100 to 100)
80
(54 to 86)
Time Frame Study data was collected over a 6 month period, in the Center for Clinical Investigations at the Beth Israel Deaconess Medical Center
Adverse Event Reporting Description Adverse events were to be reported to the CCI in accordance with CCI policy (Section XII, G of the CCI Policy and Procedure manual) on reporting such events
 
Arm/Group Title HIGH Error First, NO Error Second, LOW Error Third HIGH Error First, LOW Error Second, NO Error Third NO Error First, HIGH Error Second, LOW Error Third NO Error First, LOW Error Second, HIGH Error Third LOW Error First, NO Error Second, HIGH Error Third LOW Error First, HIGH Error Second, NO Error Third
Hide Arm/Group Description Nighttime and Breakfast closed-loop glucose control was performed on 3 occasions: first with the glucose value used for control calculated to be 33% higher than the true glucose (HIGH error), then with the value equal to the true glucose (NO error), and then with the value calculated to be 80% of the true value (LOW error). Nighttime and Breakfast closed-loop glucose control was performed on 3 occasions: first with the glucose value used for control calculated to be 33% higher than the true glucose (HIGH error), then with the value calculated to be 80% of the true value (LOW error), and then with the value equal to the true glucose (NO error). Nighttime and Breakfast closed-loop glucose control was performed on 3 occasions: first with the glucose value used for control equal to the true glucose (NO error), then with the value calculated to be 33% higher than the true glucose (HIGH error), and then with the value calculated to be 80% of the true value (LOW error). Nighttime and Breakfast closed-loop glucose control was performed on 3 occasions: first with the glucose value used for control equal to the true glucose (NO error), then with the value calculated to be 80% of the true value (LOW error) and then with the value calculated to be 33% higher than the true glucose (HIGH error) Nighttime and Breakfast closed-loop glucose control was performed on 3 occasions: first with the glucose value used for control equal 80% of the true value (LOW error), then with value equal to the true glucose (NO error), and then with the value calculated to be calculated to be 33% higher than the true glucose (HIGH error). Nighttime and Breakfast closed-loop glucose control was performed on 3 occasions: first with the glucose value used for control calculated to be 20% lower than the true glucose (LOW error), then with the value calculated to be 30% higher than the true value (HIGH error) and then with the value equal to the true glucose (NO error)
All-Cause Mortality
HIGH Error First, NO Error Second, LOW Error Third HIGH Error First, LOW Error Second, NO Error Third NO Error First, HIGH Error Second, LOW Error Third NO Error First, LOW Error Second, HIGH Error Third LOW Error First, NO Error Second, HIGH Error Third LOW Error First, HIGH Error Second, NO Error Third
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/2 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
HIGH Error First, NO Error Second, LOW Error Third HIGH Error First, LOW Error Second, NO Error Third NO Error First, HIGH Error Second, LOW Error Third NO Error First, LOW Error Second, HIGH Error Third LOW Error First, NO Error Second, HIGH Error Third LOW Error First, HIGH Error Second, NO Error Third
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/2 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
HIGH Error First, NO Error Second, LOW Error Third HIGH Error First, LOW Error Second, NO Error Third NO Error First, HIGH Error Second, LOW Error Third NO Error First, LOW Error Second, HIGH Error Third LOW Error First, NO Error Second, HIGH Error Third LOW Error First, HIGH Error Second, NO Error Third
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/2 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%)   0/1 (0.00%) 
In this study sensor calibration errors were simulated using a YSI reference glucose values; however, this may not fully capture errors that are due to delays between plasma and the interstitial fluid glucose value measured by a glucose sensor.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Garry M. Steil, PhD
Organization: Boston Children's Hospital
Phone: 617-355-7504
EMail: garry.steil@childrens.harvard.edu
Publications:
Layout table for additonal information
Responsible Party: Joslin Diabetes Center
ClinicalTrials.gov Identifier: NCT02065895     History of Changes
Other Study ID Numbers: 2012P-000401
First Submitted: February 7, 2014
First Posted: February 19, 2014
Results First Submitted: August 23, 2017
Results First Posted: April 6, 2018
Last Update Posted: May 17, 2018