Pregnancy Intervention With a Closed-Loop System (PICLS) Study

Study Overview
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Brief Summary
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In pregnancies associated with diabetes, lowering glucose to the recommended targets to prevent adverse health outcomes often leads to significant hypoglycemia. Hybrid closed-loop (HCL) therapy, automated insulin delivery using an insulin pump getting feedback from a continuous glucose monitor (CGM), may improve outcomes. This exploratory, novel pilot feasibility randomized clinical trial will evaluate pregnant women with type 1 diabetes (T1D) on HCL therapy or Sensor-Augmented Pump Therapy (SAPT, non-communicating pump and CGM) from the 2nd trimester, throughout pregnancy, and 4-6 weeks post-partum. Comparisons will be made on safety (Specific Aim [SA] 1), indices of glycemic variability and fear of hypoglycemia (SA 2), and quality of life and device satisfaction (SA 3) between groups. Exploratory SA 4 will compare maternal and fetal outcomes between groups. Safety data will include episodes of severe hypoglycemia requiring 3rd party assistance, diabetic ketoacidosis, and skin reactions. Glycemic control will be measured by CGM time spent in glucose ranges (<63, 63-140, >140 mg/dL) and other measures of glycemic variability. Subjects will fill out surveys (Fear of Hypoglycemia, a quality of life survey, and 2 questionnaires about device satisfaction) at baseline, throughout gestation, and early post-partum. Data on maternal and fetal outcomes will be collected. Findings will reveal the safety profile and glucose control with a novel therapy for pregnant women with type 1 diabetes.

Detailed Description
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This is a two-center, prospective, 'open-label', single-blind, investigator-initiated randomized controlled pilot study evaluating hybrid closed-loop (HCL) insulin delivery among pregnant women with T1D compared with sensor-augmented pump therapy (SAPT) throughout most of gestation and the first 6 weeks of the post-partum period at the Barbara Davis Center for Diabetes and Ohio State University. Up to 37 women will be enrolled at ≤11 weeks gestation, sign informed consent, and begin a run-in phase. At baseline, the investigators will obtain data about demographics, health history, pregnancy history, and medication use. The investigators will conduct a physical exam, download diabetes devices already in use by subjects, obtain blood and urine tests, and administer validated questionnaires (Hypoglycemia Fear Survey, MOS Short-Form 36 [SF-26], INSPIRE Questionnaire, Insulin Delivery Satisfaction Survey [IDSS], and Glucose Monitoring Satisfaction Survey [GMSS]). During run-in, women will wear a CGM, fill out log sheets (glucose levels, insulin doses, carbohydrate intake, exercise), upload the CGM, and be in contact with research staff. Eligible subjects will then be trained on study devices for SAPT therapy. At the start of the 2nd trimester, women will be randomized to SAPT or HCL therapy. During pregnancy, women will be seen at each institution monthly for vital signs, HbA1c measurements, device downloads, pump adjustments, medication use, reporting of adverse events and device-related deficiencies, and once a trimester the investigators will additionally obtain serum and urine measurements, specimens for the repository of biological specimens, and ask subjects to fill out questionnaires (Hypoglycemia Fear Survey, SF-35, IDSS, GMSS). Weekly remote contact will be obtained for pump adjustments and reporting of adverse events and device-related deficiencies. Women on HCL therapy will use SAPT during labor and delivery until 3-7 days post-partum, when a study clinician will put them back into auto mode (HCL therapy), if it is safe to do so. The final study visit will take place 4-6 weeks post-partum where the physical exam will be done, HbA1c obtained, device downloads obtained, and final questionnaires submitted (as above plus a post-partum survey). Medical records of the labor and delivery admission will be obtained.

Official Title
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Pregnancy Intervention With a Closed-Loop System (PICLS) Study

Conditions
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Type 1 Diabetes Mellitus, Pregnancy in Diabetes

Intervention / Treatment
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* Device: Hybrid closed-loop therapy
* Device: Sensor-augmented pump therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: women with T1D, pregnant within the first 11 weeks of gestation, 18 years of age or older, diabetes duration >1 year, using MDI (multiple daily injections) or CSII (continuous subcutaneous insulin infusion) therapy, willingness to routinely check at least 3-7 blood glucose measurements per day, ability and willingness to receive routine and specialty obstetric care throughout the course of the study, ability and willingness to adhere to the protocol including scheduled study visits for the duration of the pregnancy and early post-partum period, A1C 5.5 - 9%, willing to participate in the run-in phase and full study (if eligible), and able to speak, read, and write English Exclusion Criteria: women with T2D, gestational diabetes, or other type of diabetes (e.g., MODY), - - pregnancy beyond gestational week 11 or higher, age <18 years, T1D duration <1 year, screening A1C <5.5% or >9%, use of basal insulin alone, use of bolus insulin alone, extensive skin changes/diseases that inhibit wearing an infusion set, insulin pod, or sensor on normal skin, known severe allergic reaction to device adhesives within the last 3 months, unwillingness to use an insulin pump with tubing, unwillingness to be randomized to study group, unwillingness to switch from MDI to CSII and CGM (continuous glucose monitor) use (if applicable), unwillingness to switch from MDI or to change from current insulin pump to HCL system (if applicable), severe hypoglycemic episode requiring the assistance of a 3rd party within the last 6 months, non-compliance with run-in phase, inadequate access to a phone and computer (for downloading devices and web-based communications), intention to move out of state within the next year, and any other condition determined by the PI which could make the subject unsuitable for the trial or impairs the validity of the informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized clinical trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sensor-augmented pump therapy (SAPT)<br>Pregnant women with T1D with use an insulin pump and a continuous glucose monitor but there will be no automated insulin adjustments made by the system. | Device: Sensor-augmented pump therapy<br>* Insulin pump + non-communicating CGM<br>* Other names: SAPT;|
| Experimental: Hybrid closed-loop therapy (HCL)<br>Pregnant women with T1D with use an insulin pump and a continuous glucose monitor with automated insulin adjustments made by the system, but continued meal boluses from the women. | Device: Hybrid closed-loop therapy<br>* Hybrid closed-loop therapy with a proportional integral derivative (PID) algorithm<br>* Other names: artificial pancreas therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Episodes of Severe Hypoglycemia | Safety of HCL therapy compared to SAPT in women with T1D throughout gestation and the early post-partum period assessed through the number of episodes of severe hypoglycemia requiring 3rd party assistance | through study completion, an average of 9 months | 
| Time Spent With Glucose <54 mg/dL | Safety of HCL therapy compared to SAPT in women with T1D throughout gestation and the early post-partum period assessed through continuous glucose monitor time spent with glucose <54 mg/dL | Through study completion, an average of 9 months | 
| Indices of Glucose Control: Time Spent in Glucose Ranges by Continuous Glucose Monitoring | Indices of glucose control are time spent in the glucose target ranges <54 mg/dL and <63 mg/dL (hypoglycemia), 63-140 mg/dL (time in range), and >140 mg/dL and >180 mg/dL (hyperglycemia) of HCL compared to SAPT in women with T1D throughout gestation and the first 4-6 weeks post-partum | Through study completion, an average of 9 months | 
| Fear of Hypoglycemia Score | Fear of hypoglycemia is assessed as behavior, worry, and total scores of fear of hypoglycemia determined by the Hypoglycemia Fear Survey of HCL compared to SAPT in women with T1D throughout gestation and the first 4-6 weeks post-partum. Score Explanation: Change(s) in behavior and/or concerns of diabetics as detected by the hypoglycemia fear questionnaire. Behavior sub-scale score ranges from 10-50, with higher scores indicating more behavioral changes in the participant's daily routine to avoid low blood sugar. Worry sub-scale score ranges from 17-85, with higher scores indicating more worry or concerns because of low blood sugar. Total score ranges from 27-135, with higher scores for both sub-scales indicating more fear and a worse outcome. Subscales are added for the total scale score. Time Points: Baseline: 9 weeks gestation or earlier Visit 7: 18-20 weeks gestation Visit 10: 30-32 weeks gestation Visit 16: 4-6 weeks after delivery | Through study completion, an average of 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Episodes of Diabetic Ketoacidosis | Secondary safety assessed through the number of episodes of diabetic ketoacidosis of HCL therapy compared to SAPT in women with T1D throughout gestation and the early post-partum period. | Through study completion, an average of 9 months | 
| Number of Adverse Skin Reactions | Secondary safety assessed through the number of adverse skin reactions of HCL therapy compared to SAPT in women with T1D throughout gestation and the early post-partum period | through study completion, an average of 9 months | 
| Secondary Indices of Glucose Control: Mean Glucose ± Standard Deviation | Secondary outcomes of indices of glycemic variability by continuous glucose monitoring as mean glucose ± standard deviation in pregnant women with T1D using HCL or SAPT therapy throughout pregnancy and early post-partum | through study completion, an average of 9 months | 
| Secondary Indices of Glucose Control: J-index | Secondary outcomes of indices of glycemic variability by continuous glucose monitoring as J index in pregnant women with T1D using HCL or SAPT therapy throughout pregnancy and early post-partum. J index is a measure of the quality of glycemic control. Lower values represent more glycemic control and higher values represent less glycemic control. Formula: J-Index= 0.001 x (mean blood glucose level + SD)^2 The J-Index has not been validated in this population of Type 1 Diabetes pregnancies. | through study completion, an average of 9 months | 
| Secondary Indices of Glucose Control: High Blood Glucose Index (HBGI) | Secondary outcomes of indices of glycemic variability by continuous glucose monitoring as High Blood Glucose Index (HBGI) in pregnant women with T1D using HCL or SAPT therapy throughout pregnancy and early post-partum. HBGI is a Glucose-variability-based metric of the risk for hyperglycemia that can be calculated from CGM readings. HBGI increases with the frequency and extent of hyperglycemic excursions and has been used as a predictor of severe events. The range of values is 0-100 with 0 indicating no risk of high blood sugar and 100 indicating maximum possible risk of high blood sugar. | through study completion, an average of 9 months | 
| Secondary Indices of Glucose Control: Low Blood Glucose Index (LBGI) | Secondary outcomes of indices of glycemic variability by continuous glucose monitoring as Low Blood Glucose Index (LBGI) in pregnant women with T1D using HCL or SAPT therapy throughout pregnancy and early post-partum. LBGI is a Glucose-variability-based metric of the risk for hypoglycemia. LBGI increases with the frequency and extent of hypoglycemic excursions and has been used as a predictor of severe events. The range is from 0-100 with 0 indicating no risk of low blood sugar and 100 indicating maximum possible risk of low blood sugar. | through study completion, an average of 9 months | 
| Secondary Indices of Glucose Control: Mean Amplitude of Glycemic Excursions (MAGE) | Secondary outcomes of indices of glycemic variability by continuous glucose monitoring as Mean Amplitude of Glycemic Excursions (MAGE) in pregnant women with T1D using HCL or SAPT therapy throughout pregnancy and early post-partum. MAGE is the average difference between consecutive glucose peaks and nadirs greater than 1 standard deviation (SD) of the average value of glucose in a given day. Lower values represent less glycemic variability on average. Higher values represent more glycemic variability on average. | through study completion, an average of 9 months | 
| Secondary Indices of Glucose Control: Continuous Overall Net Glycemic Action (CONGAn) | Secondary outcomes of indices of glycemic variability by continuous glucose monitoring as Continuous Overall Net Glycemic Action (CONGAn) in pregnant women with T1D using HCL or SAPT therapy throughout pregnancy and early post-partum. CONGAn assesses glycemic variability by calculating the difference between the glucose values taken at different timeframes. Lower values represent less glycemic differences between the timepoints. Higher values represent more glycemic differences between timepoints. | through study completion, an average of 9 months | 
| Medical Outcomes Study (MOS) Short-Form 36 Score | Quality of life as measured by scores from the MOS Short-Form 36 (quality of life) of HCL and SAPT arms in pregnant women with T1D. The SF-36 has eight scaled scores; the scores are weighted sums of the questions in each section. Scores range from 0 - 100 Lower scores = more disability, higher scores = less disability Sections: Vitality, Physical functioning, Bodily pain, General health perceptions, Physical role functioning, Emotional role functioning, Social role functioning, Mental health | through study completion, an average of 9 months | 
| INSPIRE Questionnaire Score | Quality of life as measured by scores from the INSPIRE questionnaire of HCL in pregnant women with T1D. The INsulin Dosing Systems: Perceptions, Ideas, Reflections, and Expectations (INSPIRE) is a survey consisting of 22 questions that assess user expectations and experiences with automated insulin delivery systems. Scores are calculated by determining the mean of the sum of all questions then multiplying the mean by 25 for a range of 0 to 100. Higher scores indicate more positive perceptions of the system. Each survey question uses a 5 point Likert scale ranging from 0 (strongly disagree) to 4 (strongly agree). | through study completion, an average of 9 months | 
| Insulin Delivery Satisfaction Survey (IDSS) Score | Device acceptability as measured by scores from the Insulin Delivery Satisfaction Survey of HCL and SAPT arms in pregnant women with T1D. The IDSS scale has a total score and 3 subscales: effective, burdensome, and inconvenient. Possible scores range from 1-5, with higher scores indicating higher satisfaction with insulin delivery system. Scores are reflective of the mean of the Total or subscale questions. | through study completion, an average of 9 months | 
| Glucose Monitoring Satisfaction Survey (GMSS) Score | Device acceptability as measured by scores from the Glucose Monitoring Satisfaction Survey questionnaires of HCL compared to SAPT in pregnancy women with T1D. The GMSS has a total score and 4 subscales: openness, emotional burden, behavioral burden, and trust. Possible scores range from 1-5, with higher total scores indicating greater satisfaction. Scores are reflective of the mean of the Total or subscale questions. | through study completion, an average of 9 months | 
| Maternal Outcomes: Number of Participants With Preeclampsia/Eclampsia | Maternal outcomes includes preeclampsia/eclampsia in pregnant women with T1D using HCL therapy compared to those using SAPT throughout gestation and in the early post-partum period | through study completion, an average of 9 months | 
| Maternal Outcomes: Number of Participants With Cesarean Delivery | Maternal outcomes includes cesarean delivery in pregnant women with T1D using HCL therapy compared to those using SAPT throughout gestation and in the early post-partum period | through study completion, an average of 9 months | 
| Maternal Outcomes: Average Gestational Weight Gain | Maternal outcomes includes gestational weight gain in pregnant women with T1D using HCL therapy compared to those using SAPT throughout gestation and in the early post-partum period | through study completion, an average of 9 months | 
| Fetal Outcomes: Number of Participants With a Fetal Loss (Miscarriage or Stillbirth) | Fetal outcomes includes fetal loss (miscarriage or stillbirth) in pregnant women with T1D using HCL therapy compared to those using SAPT throughout gestation and in the early post-partum period | through study completion, an average of 9 months | 
| Fetal Outcomes: Number of Infants With Large-for-gestational Age Outcome | Fetal outcomes includes large-for-gestational age in pregnant women with T1D using HCL therapy compared to those using SAPT throughout gestation and in the early post-partum period | through study completion, an average of 9 months | 
| Fetal Outcomes: Number of Participants With Neonatal Hypoglycemia Infants | Fetal outcomes includes neonatal hypoglycemia in pregnant women with T1D using HCL therapy compared to those using SAPT throughout gestation and in the early post-partum period | through study completion, an average of 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 1 diabetes mellitus, pregnancy, hybrid closed-loop therapy, artificial pancreas therapy, sensor-augmented pump therapy