The protocol was finalized with guidance from the Food and Drug Administration and from the study’s principal investigators. Five clinical centers experienced in CGM and insulin pump therapy were involved in the study. The study was approved by the Institutional Review Boards (IRBs) of the participating investigational centers. California subjects reviewed the California Experimental Subject’s Bill of Rights, and all subjects signed the informed consent approved by their institution’s IRB. Subjects aged 16–17 years provided informed assents and a parent or guardian provided informed consent.
This study design is a multicenter, randomized, controlled, crossover with a run-in period. Subjects 16–60 years of age with type 1 diabetes for at least 1 year and at least 3 months of experience with a Medtronic insulin pump were recruited. Subjects were selected based on the investigator’s assessment that they would be able to tolerate the exercise experiments, but there was no formal assessment of physical fitness. The inclusion and exclusion criteria are listed in , and the overall visit schedule is presented in . Enrollment proceeded in stages, with adults aged 22–60 years studied first. The study’s Clinical Events Committee (CEC) reviewed the hypoglycemic induction data on the first 10 enrolled adults, which included all adverse events and symptoms associated with exercise or exercise-induced hypoglycemia during the experiment. Upon determining that the protocol did not pose an unacceptable safety risk, the CEC allowed 4 young adults aged 18–21 years to enroll; a similar safety review then occurred before 4 pediatric subjects aged 16–17 years were enrolled. The remaining 32 enrolled subjects were adults.
ASPIRE study inclusion and exclusion criteria at time of enrollmenta
ASPIRE study design and visit plan.
After enrollment, all subjects were required to perform a 2-week run-in period that included three phone visits from the investigational center staff to verify and optimize each subject’s basal rates. The run-in period included an exercise visit wherein each subject’s glycemic response to exercise was quantified via finger stick or venous glucose readings (visit 6); the exercise regimen was reproduced in the exercise-induced hypoglycemia visits (visits 8 and 11). During the run-in period, subjects used the Paradigm Veo pump with the LGS feature off, and the OneTouch® UltraLink™ blood glucose (BG) meter for periodic CGM sensor calibration.
Following the run-in period, subjects were randomized into two groups. The first hypoglycemia induction visit for group A was conducted with the LGS feature set to suspend insulin delivery at CGM sensor readings of ≤70 mg/dl (LGS on); the first hypoglycemia induction visit for group B was with the LGS feature off. After a washout period lasting from 3–10 days, a subsequent hypoglycemia induction visit was conducted with the LGS feature off for group A and on for group B ().
Conduct of the hypoglycemia induction visits is outlined in . Visits were to start between 7:00 a.m. and 9:00 a.m. after an overnight fast. During the in-clinic procedure, the UltraLink meter was used to calibrate the CGM sensor. The reference instrument (YSI 2300 STAT Plus, YSI Life Sciences, Yellow Springs, OH) was also set up. Venous access was established for frequent blood sample collection. Plasma glucose values were collected at 5–30 min intervals; the time between each blood sample was determined by the YSI values. Once subjects reached a YSI glucose level 100–140 mg/dl, the experiment was initiated. The exercise session consisted of up to six cycles of mild- to moderate-intensity exercise on a stationary bicycle or treadmill lasting 15–30 min each.
Exercise-induced hypoglycemia visits. If a stopping condition was met, the visit was repeated. SG, interstitial fluid glucose concentration as measured by the glucose sensor.
Each cycle was followed by a rest period of 5–15 min. There was no attempt to standardize the duration or intensity of exercise. Subjects exercised until they reached a YSI value of ≤85 mg/dl. If the subject did not reach this YSI value with exercise, the experiment was repeated. In addition, subjects who were prematurely terminated from the experiment because of low or high BG values or who did not reach target range (<70 mg/dl by YSI) could repeat the experiment up to three times following a washout period of 3–10 days.
The observation period started once a YSI level <70 mg/dl was observed. All hypoglycemic induction visits were supervised by a registered nurse and a physician trained in diabetes management. If, during the experiment a subject’s BG concentration remained >250 mg/dl, then a recheck (finger stick or YSI) was required. If the BG concentration was repeatedly >250 mg/dl, a check of ketones was required. Additional insulin was to be given for BG concentrations >250 mg/dl in the presence of large urine ketones, a blood ketone level of >1.5 mM, or BG concentration >300 mg/dl. If insulin was needed at any time for the critically elevated glucose levels mentioned above, the experiment was to be terminated.
Upon completion of the experiment, the investigational center uploaded the YSI values and pump and sensor data into Medtronic CareLink Clinical. After a washout period of 3–10 days following the first hypoglycemia induction visit, the subject then repeated the experiment. At the end of the second hypoglycemia induction visit, all study device data were uploaded and returned. Staff at the investigational center performed final follow-up and an end-of-study phone call visit.
The primary end point of this study is a comparison of the duration and severity of hypoglycemia (as measured in venous plasma with the YSI reference instrument) with LGS feature turned on versus LGS feature turned off. The study will be considered successful if use of the LGS feature results in significant reductions in either the duration or severity of exercise-induced hypoglycemia. Secondary end points include area under the curve of time spent with YSI glucose values <60 mg/dl, <70 mg/dl, and >180 mg/dl. Continuous glucose monitoring sensor values will be compared to YSI glucose values <90 mg/dl to estimate sensor accuracy. The YSI value 4 h after reaching <70 mg/dl and the number of times the experiment was terminated for YSI glucose values <50 mg/dl or >300 mg/dl were recorded. Device- and procedure-related adverse events were recorded. Unanticipated device effects were also to be collected for this study.
Sample size estimation
Fifty subjects were projected to provide 80% power to detect a treatment group difference as small as 15% using a paired t-test with a one-sided 2.5% criterion significance level and a standard deviation (SD) of 49.5 min (a 102 min duration for LGS-on experiments and a 120 min duration for LGS-off experiments). The target sample size provided a 99% power to detect a treatment group difference as small as 15% or 3 mg/dl in severity of hypoglycemia, using a paired t-test with a one-sided 2.5% criterion significance level and a SD of 5 mg/dl (20 mg/dl severity for LGS-off experiments and a 17 mg/dl severity for LGS-on experiments).
The analysis will include the intent-to-treat and per-protocol populations. The treatment difference will be calculated and tested for statistical significance using a linear model and will provide a 95% confidence interval for treatment effect contrast. The linear model will include carryover and treatment effects. The test for carryover effect will be set at a = 0.1. If the carryover effect is significant, then only period 1 data will be used to estimate treatment effect. Parameters in the model will include hypoglycemia duration and severity, group assignment, inter-subject variance, carryover effect, effect of the treatment, and random residual variation. An interim analysis will be performed on the first 30 subjects (15 in each arm) using the O’Brien-Fleming approach and used to provide direction for continuing enrollment. For this two-stage design, hypothesis testing will be conducted at p1 = 0.005 for the first stage or interim analysis, and p2= 0.048 for the second stage or final analysis. Descriptions of adverse events (ketonemia, diabetic keto-acidosis, and rebound hyperglycemia) will be presented for all randomized subjects. Secondary efficacy end point comparisons will be descriptive.