Unified Safety System (USS) Virginia Closed-Loop Versus Sensor Augmented Pump Therapy for Hypoglycemia Reduction in Type 1 Diabetes
Phase: NA
Conditions: Type 1 Diabetes Mellitus
Sponsor: University of Virginia

SCHOOL OF MEDICINE 
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Department of Psychiatry & Neurobehavioral Sciences 
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Center for Diabetes Technology 
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CLINICAL PROTOCOL 
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UNIFIED SAFETY SYSTEM (USS) VIRGINIA
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CLOSED-LOOP
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VERSUS 
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SENSOR AUGMENTED PUMP (SAP) THERAPY
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FOR HYPOGLYCEMIA REDUCTION IN TYPE 1
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DIABETES 
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NCT02302963
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A. Purpose/Objectives
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The purpose of this study is to evaluate the effectiveness of the control system in reducing 
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hypoglycemia by comparing, in a randomized study, 24 hour control with USS Virginia 
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versus sensor augmented pump (SAP) therapy in subjects with type 1 diabetes and 
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hypoglycemia unawareness and/or risk for hypoglycemia. We will also evaluate the 
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effectiveness of the control system to improve hypoglycemia counterregulation, 
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hypoglycemia awareness, and overall glycemic control. To achieve this goal, we will 
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conduct pre- and post-intervention inpatient assessments of hypoglycemia 
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counterregulation and symptom awareness. Subjects randomized to USS Virginia will 
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participate in two training visits at a monitored outpatient setting for the step-wise 
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deployment of the cell phone based on the Artificial Pancreas (AP) system at home. The 
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first training visit includes training on the study pump and AP system followed by 1 week 
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use of AP system at home in Pump mode. The second training visit includes additional 
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training on USS Virginia+AP system and confirmation of independent use by the subject 
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followed by 4 week use of AP system at home in Closed Loop mode. Subjects 
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randomized to sensor-augmented pump therapy will complete 5 weeks of CGM with the 
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home pump. 
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This protocol will complement our recently completed protocol (IDE G130143) in which 
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results demonstrate significantly improved glucose control overnight. Additionally, this 
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protocol represents a culmination of prior clinical trials in the development of this USS 
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Virginia system and benefits from the synthesis of those components.  
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The DiAs platform is now licensed to a local startup company, TypeZero Technologies LLC, 
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which has further locked down its design features and re-implemented the system under the 
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name inControl, for increased reliability and clear requirements traceability. 
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B. Study Design Overview
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This is a randomized, controlled trial of Unified Safety System (USS) Virginia closed-loop 
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versus sensor-augmented pump (SAP) therapy for hypoglycemia prevention in subjects with 
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type 1 diabetes and hypoglycemia unawareness and/or risk for hypoglycemia.  
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Subjects: We will recruit up to 85 subjects aged 12-70 years old with type 1 diabetes 
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for at least the past 1 year, on insulin for at least the past 1 year, and on insulin pump 
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therapy for at least the past 6 months to achieve a goal of 44 completed subjects. 
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Subjects will be recruited at two clinical sites: University of Virginia and Stanford 
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University.  
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Procedure:  Figure 1 below presents the overall flow of the study. 
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Figure 1:  Study flow diagram 
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Visit 1: Screening 1 Visit. A meter ± CGM download will be performed to evaluate subject 
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eligibility (i.e. Average Daily Risk Range [ADRR] >40 or LBGI >2.5 from SMBG data or 
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LBGI >1.1 from 1 week of CGM data within the prior 3 weeks) and to determine pre-study 
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CGM use in the prior 4 weeks (active [CGM use ≥5 days/week] or no CGM use). Baseline 
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HbA1c, hypoglycemia symptom awareness (presence of adrenergic symptoms at BG 60 
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mg/dL) and hypoglycemia questionnaires (Clarke Hypoglycemia Perception Awareness and 
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Fear of Hypoglycemia – APPENDIX A-5) will be assessed. Those subjects that qualify will 
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be trained to use the study glucometer and CGM in blinded mode and complete 1 week of 
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baseline blinded CGM and SMBG at least 4 times daily. 
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Visit 2: Screening 2 Visit. The blinded CGM will be downloaded and if review of the data 
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shows that the CGM was functional >80% of the time and the subject has confirmed risk of 
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hypoglycemia with LBGI >1.1 (#2) (per 1 week of blinded CGM), the subject will be 
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randomized to USS Virginia AP system experimental treatment or Sensor-Augmented Pump 
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Therapy control treatment and proceed to Visit 3. The experimental and control groups will 
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be matched for LBGI and pre-study CGM use. The study glucometer will be downloaded 
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and assessed for average SMBG/day and randomness of data. Subjects with average SMBG 
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<3.5/day and/or poor randomness of SMBG testing will be reminded of SMBG requirements 
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4-6 times daily (pre-meal, bedtime, before driving, before exercise, and as indicated). CGM 
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data collection period may be repeated.  
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Visit 3: 8 hr Inpatient Assessment of Hypoglycemia Counterregulation and Symptom 
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Awareness. The subjects will undergo hypoglycemia induction via a previously validated 
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method (1) using subcutaneous insulin pump therapy with frequently sampled YSI glucose 
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levels. Hypoglycemia counterregulation and symptoms will be assessed by epinephrine 
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levels and hypoglycemia symptom scoring as the BG is decreased from 100-150 mg/dL to 
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<60 mg/dL. Subjects will be trained on the Dexcom Share AP CGM and either proceed to 
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Visit 4 if randomized to the experimental group or 5 weeks of CGM and home pump use if 
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randomized to the control group. 
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Visit 4: Study Pump & AP System Training. Subjects in the USS Virginia group will 
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present to the monitored outpatient setting to complete a training session including study 
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pump training and AP system training. Subjects will be provide a copy of the AP system 
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manual. Subjects will then use AP system at home in Pump mode, connected to the study 
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CGM and study pump. During this week, study staff will contact the subject daily to answer 
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any questions and enquire about any device complaints, adverse events, and whether the 
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adverse event was related to AP system use. Study staff will also check the number of 
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SMBG tests entered on the AP system and will remind the subject to perform 4-6 SMBG 
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daily. The ability of AP system to be remotely monitored in the subject’s daily environment 
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will also be assessed with daily checks of the remote monitoring site. After completion of 1 
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week of AP Pump mode home use, study staff will determine whether additional training 
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and practice with the AP system is needed and whether the subject will repeat all or portions 
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of Visit 4 and 1 week of home use (up to 1 time if needed) or proceed to Visit 5. Subject’s 
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that cannot be adequately monitored at least 75% of the time in their local environment will 
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not be allowed to proceed. 
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Visit 5: USS Virginia Training. Visit 5 may occur remotely via GoToMeeting or similar 
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HIPAA compliant web conferencing.  This visit may also occur with visit 4 as determined 
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by the study team. Subjects in the USS Virginia group will present to the monitored 
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outpatient setting to complete a training session including an initial AP system closed-loop 
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training followed by independent use of the system and completion of the AP Training 
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Checklist. The study team will be immediately available as needed. Subjects will then use 
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the AP system at home in Closed Loop mode, connected to the study CGM and study pump.  
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There will be an initial 3-5 day trial of the system at home in Closed Loop mode during 
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which, the subject will receive daily contact from study staff and remote monitoring 
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automated alerts will be in place. Study staff will also check the number of SMBG tests 
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entered on the AP system and will remind the subject to perform 4-6 SMBG daily. Study 
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staff will then determine whether additional training and practice is needed and whether the 
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subject will repeat all or portions of Visit 5 and 3-5 days of the AP system home use (up to 1 
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time) or proceed with the remainder of the 4 weeks of the system Closed Loop home use. 
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During the 4 weeks of home use, study staff will continue to contact the subject (daily for 
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the first 5 days, then weekly) to answer any questions and enquire about any device 
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complaints, adverse events, and whether the adverse event was related to the AP system use. 
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Study staff will check the number of SMBG entered on the AP system daily and contact the 
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subject if <4 SMBG are observed on any day. The subject’s CGM data and meter data will 
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be collected at week 2 and week 4. Subjects will be required to have average SMBG 
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>4.5/day and random SMBG data to continue. 
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Visit 6: 8 hr Inpatient Assessment of Hypoglycemia Counterregulation and Symptom 
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Awareness. Within approximately one week of completing either USS Virginia or sensor-
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augmented pump therapy at home, the subjects will undergo a final hypoglycemia induction 
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using the home pump therapy with frequently sampled YSI glucose levels. Hypoglycemia 
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counterregulation and symptoms will be assessed by epinephrine levels and hypoglycemia 
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symptom scoring as the BG is decreased from 100-150 mg/dL to <60 mg/dL. Post-
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intervention HbA1c, and hypoglycemia questionnaires, and a DiAs Usability questionnaire 
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(DiAs users only) will be completed. If a subject completes more than 1 week of either USS 
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Virginia or sensor-augmented pump therapy and subsequently withdraws from the study 
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intervention, they will be asked to complete Visit 6 within one week of discontinuing the 
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intervention. 
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C. Pilot subjects 
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Each site will study two initial Pilot subjects: one aged 21-65 years old and one aged 15-20 
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years old. The Pilot subjects and their respective diabetes care partners will be used to test 
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the adequacy of the AP system training period and the system performance (in Pump mode) 
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in the subject’s local environment. If significant changes are made to the system or to the 
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protocol after the Pilot subjects or the AP system did not meet success criteria in the local 
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environment, an additional two Pilot subjects (one aged 21-70 years old and one aged 12-20 
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years old) will be studied at each site. Pilot subjects may be repeated as necessary until no 
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further changes are needed. Those sites that have already used the identical closed-loop 
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system (phone, pump, sensor, MAF version of AP system) in two subjects at home for at 
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least 1 week (336 hours) each do not need to complete the Pilot subjects as the system has 
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already been tested in the home environment.  
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Pilot subjects will participate in Visit 1 (Consent and Screening). The study inclusion and 
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exclusion criteria will apply to the Pilot subjects with the following exceptions: 1) the Pilot 
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subjects will not have a significant risk of hypoglycemia (as assessed by LBGI <1.1 and 
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ADRR <20 from the prior 30 days of meter data), and 2) the Pilot subjects will not have 
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hypoglycemia unawareness (as assessed by a Clarke Hypoglycemia Perception Awareness 
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score of 2 or less). If the Pilot subject is CGM-naïve, s/he may be trained on the study 
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glucometer and study CGM and wear an unblinded CGM for up to a week at home at the 
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discretion of the investigator. Prior CGM wearers may skip the home CGM use if they have 
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previously been trained on the study CGM. Within 4 weeks of Visit 1, the Pilot subjects will 
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proceed directly to Visit 4 (Study Pump and AP Training) with a subsequent 5 days of the 
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AP system use in Pump mode in the subject’s local environment and with remote 
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monitoring and automated notifications in place. The Pilot subjects will receive daily contact 
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by the study team and the remote monitoring site will be checked daily. Success of the Pilot 
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subjects will be determined by >80% time of functional system components including: 
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CGM, pump, AP system, connectivity with the CGM, and AP system connectivity with the 
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pump. There will also need to be remote monitoring capability at least 75% of the time. 
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After the Pilot subjects at each site have successfully completed Visit 4 and 5 days of use at 
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home in Pump mode, study enrollment and randomization may proceed at each site. The 
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data from the Pilot subjects will not be used in the final analysis. Pilot subjects will not be 
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counted in the enrollment tally. 
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D. Sample Size and Investigational Sites 
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The studies will be conducted at University of Virginia and Stanford and will require IRB 
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approval at each site prior to the initiation of the trial.  
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At the University of Virginia, all inpatient studies (Visit 3 and Visit 6) will be performed at 
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the Clinical Research Unit (CRU) of the University of Virginia Health System with website 
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at: (http://research.med.virginia.edu/clinicalresearch/research-resources/offices-supporting-
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clinical-research/clinical-research-unit/). The street address is:  
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UVA Medical Center 
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1215 Lee St, Barringer Wing 
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Charlottesville, VA 22903 
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The monitored outpatient studies (Visit 4 and Visit 5) will occur at a UVa CRU. 
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At Stanford, all inpatient studies (Visit 3 and Visit 6) will be performed at The Stanford 
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Center for Clinical and Translational Research and Education (CTRU) with website at: 
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http://spectrum.stanford.edu/accordions/clinical-and-translational-research-unit.  
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The monitored outpatient studies (Visit 4 and Visit 5) will in 3 rooms available for 
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outpatient research studies through “ACCESS”, a clinical research resource available at 
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Stanford. These rooms are available in the same building as the Endocrine Division and are 
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adjacent to the CTRU. 
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Forty-four subjects (N=44) with type 1 diabetes mellitus will be needed to complete the 
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protocol.  
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Based on our experience with similar studies and the additional requirement of 
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hypoglycemia unawareness or risk for hypoglycemia, we estimate an expected ~40% screen 
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failures, dropouts, or withdrawals, thus we intend to set a recruiting target of 70 subjects.  
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Hypothesis:  
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We hypothesize that in patients with hypoglycemia unawareness and a risk for 
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hypoglycemia, the AP system equipped with USS Virginia compared with CGM-augmented 
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pump therapy will result in: 
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1. Reduced risk for hypoglycemia and exposure to hypoglycemia (measured by the 
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Low Blood Glucose Index and by CGM time in hypoglycemia).  
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2. Restoration of hypoglycemia counterregulation (as assessed by epinephrine 
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response measured in a hospital setting), restoration of hypoglycemia awareness, 
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and reduced fear of hypoglycemia. 
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Primary Specific Aim:  
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Reduction in hypoglycemia during the study on USS Virginia versus SAP as assessed by: 
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 LBGI from CGM during 1 week of baseline blinded use versus during the last week 
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of intervention. 
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Secondary Specific Aims: 
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Reduction in hypoglycemia during the study on USS Virginia versus SAP as assessed by: 
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 CGM time <70 mg/dL and <50 mg/dL by retrofitted CGM and SMBG trace during a 
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24 hour period and the overnight period (11PM – 7AM) from 1 week of baseline 
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blinded use versus the last week of intervention. 
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Improvement in counterregulatory response to hypoglycemia at baseline versus follow-up as 
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assessed by: 
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 Peak epinephrine 
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 Epinephrine area under the curve (AUC) 
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 Epinephrine increase over baseline 
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Improvement in hypoglycemia awareness at baseline versus follow-up as assessed by: 
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 Hypoglycemia symptom ratings  
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 Clarke Hypoglycemia Perception Awareness and Fear of Hypoglycemia scores  
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Improvement in glycemic control at baseline versus the last week of intervention as assessed 
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by: 
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 Time within target (70-180 mg/dL) over a 24 hour period. 
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 Time within target (80-140 mg/dL) in the overnight period (11PM – 7AM) 
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 Distribution of wake-up glucose levels at 7AM 
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Sample size determination is based on literature data (#3) and on results from our previous 
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studies of hypoglycemia unawareness (#4)Error! Reference source not found.. We 
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estimate, conservatively, that the effect size of using the AP system+USS Virginia vs. CGM 
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in terms of restoration of epinephrine response will be moderate ~0.35. Power calculations 
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assuming =0.05, and power of 80% yield a required sample size of N=36 (using G*Power 
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3 software [#5]). With this sample size, the power for finding significant effects on 
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frequency and extent of hypoglycemia (Low BG Index [#6]) exceeds 0.9. Assuming a 
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proportion of noncompliance R=20% for Intention-to-Treat (ITT) analysis (#7), 44 
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completed subjects will adequately address the specific aims of this study. Per-protocol 
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analysis will also be performed. In order to achieve 44 completed subjects, up to 70 subjects 
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may sign consent given an expected screen failure, withdrawal and drop-out rate of ~40% 
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due to the rigorous exclusion criteria and requirements imposed for the AP system use in the 
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subject’s local environment. 
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E. Study Duration 
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Subject participation will last roughly 7-14 weeks depending on whether Visit 4 and/or Visit 
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5 and the subsequent home use portions of the study need to be repeated as per Figure 1 
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above. This includes: 1 day screening visit, 1 week baseline blinded CGM use, 1 day 
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eligibility assessment and randomization visit, 1 day inpatient assessment of hypoglycemia 
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counterregulation and symptom awareness, then either 5 weeks of sensor augmented pump 
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therapy at home or the AP system+USS Virginia training and use at home. The AP system 
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+USS Virginia training and use includes: 1 day outpatient study pump and the AP system 
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training, 1 week use of the system at home in Pump mode, 1 day outpatient AP system 
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+USS Virginia training and 4 weeks use of the AP system +USS Virginia at home. Each 
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group will additionally complete a final 1 day inpatient assessment of hypoglycemia 
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counterregulation and symptom awareness. Up to 14 days are able to be repeated in the 
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scheme above, up to 4 weeks may elapse between Visit 1 and Visit 3, and up to 1 week may 
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elapse between completion of the study intervention and Visit 6. 
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Participation for the Pilot subjects will last up to 6 weeks including: 1 day screening visit, 0-
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1 week use of study CGM at home,1 day outpatient study pump and AP training, and 5 day 
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use of the AP system at home in Pump mode. Up to 4 weeks may elapse between the 
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screening and the AP training visit.  
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F. Inclusion and Exclusion Criteria 
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Inclusion Criteria: To be eligible for the study, a subject must meet the following criteria: 
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 Clinical diagnosis of type 1 diabetes for at least 1 year. For an individual to be enrolled 
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at least one criterion from each list must be met. 
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o Criteria for documented hyperglycemia (at least 1 must be met): 
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 Fasting glucose ≥126 mg/dL – confirmed 
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 Two-hour OGTT glucose ≥200 mg/dL – confirmed 
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 HbA1c ≥6.5%  – confirmed 
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 Random glucose ≥200 mg/dL with symptoms 
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 No data at diagnosis is available but the participant has a convincing 
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history of hyperglycemia consistent with diabetes or in the opinion of the 
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investigator participant has history consistent with type 1 diabetes.  
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o Criteria for requiring insulin at diagnosis (at least 1 must be met): 
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 Participant required insulin at diagnosis and continually thereafter 
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 Participant did not start insulin at diagnosis but upon investigator review 
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likely needed insulin (significant hyperglycemia that did not respond to 
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oral agents) and did require insulin eventually and used continually 
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 Participant required insulin at diagnosis but continued to be 
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hyperglycemic, had positive islet cell antibodies – consistent with latent 
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autoimmune diabetes in adults (LADA) and did require insulin eventually 
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and used continually thereafter 
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 Use of insulin for the last 12 months or more 
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 Use of an insulin infusion pump for the last 6 months or longer 
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 Age 12-70 years old 
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 HbA1c <10.0% as measured with DCA2000 or equivalent device; if HbA1c <6.0% then 
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total daily insulin must be ≥0.5 U/kg 
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 Risk of hypoglycemia or hypoglycemia unawareness as defined by any of the following: 
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o Clarke Hypoglycemia Perception Awareness questionnaire score of ≥4 (#8). 
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o Average Daily Risk Range (ADRR) >40 as assessed from SMBG readings from 
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the prior month (#9). Subject must have a glucometer that can be downloaded for 
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this assessment. The subjects may alternatively provide a spreadsheet of their 
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past 30 days of blood glucose values. 
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o Low Blood Glucose Index (LBGI) >2.5 as assessed from SMBG from the prior 
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month or LBGI >1.1 as assessed from 1 week of CGM readings from the prior 
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three weeks. Subject must have a glucometer or CGM that can be downloaded 
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for this assessment. For the glucometer data, the subjects may alternatively 
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provide a spreadsheet of their past 30 days of blood glucose values. 
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o Subject reports no recognition of hypoglycemia until the glucose is <60 mg/dL 
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and no adrenergic symptoms at glucose of 60 mg/dL (shakiness, palpitations, 
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diaphoresis). 
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 Able to speak and read English and use basic technology such as a cell phone.  
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 Currently using an insulin-to-carbohydrate ratio to calculate meal bolus sizes. 
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 Access to Internet or cell phone service in the subject’s local environment. 
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 Willingness to maintain uninterrupted availability via personal cell phone at all times 
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during the study. 
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 Willingness to perform SMBG testing 4-6 times daily (before meals, bedtime, before 
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driving, before exercise, and as indicated) during the interventional phases of the study. 
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 Living with a diabetes care partner ≥18 years old who meets the following inclusion 
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criteria: 
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o Committed to potentially (if randomized to the AP system) participating in all 
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training activities involving components and emergency procedures,  
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o Knowledgeable at all times of the participant’s location during the day when 
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closed loop is in use,  
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o Committed to maintaining uninterrupted availability via personal cell phone,  
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o Being present and available to provide assistance when the closed loop system is 
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being used at night, 
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o Able to speak and read English and use basic technology such as a cell phone, 
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and 
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o Absence of known medical condition that in the judgment of the investigator 
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might interfere with the completion of the protocol such as the following 
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examples: 
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 Inpatient psychiatric treatment in the past 6 months, 
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 Current or recent abuse of alcohol or recreational drugs by history 
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 A recent injury to body or limb, muscular disorder, use of any 
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medication, any carcinogenic disease, or other significant medical 
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disorder if that injury, medication, or disease in the judgment of the 
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investigator will affect the completion of the protocol. 
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Exclusion Criteria: The presence of any of the following is an exclusion for the study: 
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 Admission for diabetic ketoacidosis in the 12 months prior to enrollment. 
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 Severe hypoglycemia resulting in seizure or loss of consciousness in the 3 months prior 
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to enrollment. 
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 Hematocrit less that the lower limit of normal for the assay. 
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 Pregnancy, breast-feeding, or intention of becoming pregnant over time of study 
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procedures  
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o If female and sexually active, must agree to use a form of contraception to 
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prevent pregnancy while a participant in the study.  A negative urine pregnancy 
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test will be required for all premenopausal women who are not surgically sterile.  
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Subjects who become pregnant will be discontinued from the study. 
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 Conditions which may increase the risk of induced hypoglycemia such as: known 
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coronary artery disease, congestive heart failure, history of any cardiac arrhythmia 
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(benign premature atrial contractions and premature ventricular contractions allowed), 
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history of seizure disorder, history of cerebrovascular event or transient ischemic attack, 
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hypoglycemia-induced migraine within the last 6 months, or neurological disease. 
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 Cystic fibrosis 
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 A known medical condition that in the judgment of the investigator might interfere with 
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the completion of the protocol such as the following examples: 
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o Inpatient psychiatric treatment in the past 6 months for either the subject or the 
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subject’s diabetes care partner 
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o Presence of a known adrenal disorder 
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o Abnormal liver function tests (transaminase >3 times the upper limit of normal); 
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testing required for subjects taking medications known to affect liver function or 
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with diseases known to affect liver function 
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o Abnormal renal function test results (estimated GFR <60 mL/min/1.73m2); 
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testing required for subjects with diabetes duration of greater than 5 years post 
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onset of puberty 
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o Active gastroparesis 
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o If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack 
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of stability on the medication for the past 2 months prior to enrollment in the 
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study 
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o Uncontrolled thyroid disease (TSH undetectable or >10 mIU/L); testing required 
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within 3 months prior to admission for subjects with a goiter, positive antibodies, 
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or who are on thyroid hormone replacement, and within one year otherwise 
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o Current or recent abuse of alcohol or recreational drugs by patient history 
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o Infectious process not anticipated to resolve prior to study procedures (e.g. 
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meningitis, pneumonia, osteomyelitis) 
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o Any skin condition in the area of insertion that prevents safe sensor or pump 
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placement (e.g. bad sunburn, pre-existing dermatitis, intertrigo, psoriasis, 
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extensive scarring, cellulitis) 
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o Diagnosed with celiac disease and not currently following a gluten free diet 
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 A recent injury to body or limb, muscular disorder, use of any medication, any 
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carcinogenic disease, or other significant medical disorder if that injury, medication, or 
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disease in the judgment of the investigator will affect the completion of the protocol 
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 Current use of any of the following drugs and supplements: 
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o Any medication being taken to lower blood glucose, such as Pramlintide, 
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Metformin, GLP-1 Analogs such as Liraglutide, and nutraceuticals intended to 
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lower blood glucose 
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o Beta blockers 
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o Oral glucocorticoids 
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o Pseudoephedrine 
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o Any other medication that the investigator believes is a contraindications to the 
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subject’s participation 
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Restrictions on use of other drugs or treatments: 
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 Acetaminophen will be restricted starting 24 hours prior to CGM use and continuing 
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through the entire study. 
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 Caffeinated products will be restricted on the day of Visit 3 and Visit 6 until sampling of 
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blood for epinephrine is completed. 
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 Study procedures will be put on hold if acetaminophen use is medically necessary. A 
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need for repeated doses may result in stopping study participation at the discretion of the 
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investigator. 
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 The CGM sensor will be removed if MRI is needed. Study procedures will be put on 
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hold and continued subject participation will be at the discretion of the investigator.  
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 The subject should not donate blood for other purposes while enrolled in this study. 
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 A medical need for oral or injected glucocorticoids will result in stopping study 
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participation. 
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G. STUDY TIMELINE 
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1. Visit 1: Screening 1 Visit 
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At the Screening Visit, the following procedures will be performed / criteria will be 
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checked and documented: 
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 Signed and dated informed consent +/- assent if applicable 
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 Inclusion and exclusion criteria 
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 Meter and CGM (if CGM user) download from prior 30 days to assess LBGI 
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and ADRR 
419 
 CGM download from prior 4 weeks (if CGM user) to assign subject to one of 
420 
two pre-study CGM groups: 
421 
o Active user: CGM use ≥5 days/week  
422 
o Non-user: No CGM use  
423 
 Clarke Hypoglycemia Perception Awareness survey  
424 
 Fear of Hypoglycemia questionnaire  
425 
 Demographics (date of birth, gender, race and ethnicity) 
426 
 Medical history 
427 
 Details of the diabetic history: duration of disease (number of years), diagnosis 
428 
details, current treatment (including basal rates, carbohydrate ratios, insulin 
429 
sensitivity factors, target glucose, average total daily insulin over 7 days, 
430 
hypoglycemia awareness and adrenergic symptom assessment, history of DKA, 
431 
history of severe hypoglycemia, and SMBG values) 
432 
 Past and current medical conditions 
433 
 Surgical history 
434 
 Menstrual history (females), sexual activity and contraceptive use agreement 
435 
 Allergies 
436 
 Medications and supplements 
437 
 Social history including drinking, smoking, and drug habits 
438 
 Review of systems 
439 
 Physical examination 
440 
 Weight and height 
441 
 Vital signs  
442 
 Blood draw for screening labs: 
443 
o HbA1c (results from DCA 2000 or equivalent device within 2 weeks of 
444 
screening may be accepted) 
445 
o Basic metabolic panel (testing required for subjects with diabetes 
446 
duration of greater than 5 years post onset of puberty) 
447 
o Liver function tests (testing required for subjects taking medications 
448 
known to affect liver function or with diseases known to affect liver 
449 
function) 
450 
o Qualitative serum HCG in women with childbearing potential. If not 
451 
performed, document reason (i.e. hysterectomy, postmenopausal) 
452 
o Hematocrit 
453 

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o TSH (testing required within 3 months prior to screening for subjects 
454 
with a goiter, positive antibodies, or who are on thyroid hormone 
455 
replacement, and within one year otherwise) 
456 
 Preferred foods for the subject’s self-treatment of hypoglycemia will be 
457 
documented to have available in the monitored research setting. 
458 
 
459 
Subjects travelling from a distance or subjects wishing to be pre-screened for 
460 
eligibility (e.g. review of meter download, assessment for presence of 
461 
hypoglycemia unawareness, labs performed locally, etc.) may elect to have 
462 
the consent +/- assent (50.53) read and explained by study staff by phone. 
463 
Once all questions have been answered, the signed consent +/- assent will be 
464 
faxed or mailed to study personnel and the subject may then have pre-
465 
screening with labs performed locally (e.g. LabCorp) prior to Visit 1. The 
466 
consent +/- assent form will be reviewed again with the subject +/- parents at 
467 
Visit 1. 
468 
 
469 
Once all results of the screening evaluations are available, a decision will be made to 
470 
determine the subject eligibility for the study.  The study physician will have the 
471 
discretion to repeat screening tests. The repeat screening tests may be conducted 
472 
locally (e.g. LabCorp). The subject may request a copy of any of the results from the 
473 
screening evaluation to review with their primary care provider. 
474 
 If an exclusionary condition is identified, the study subject will be 
475 
excluded from participation with follow up and referral to their 
476 
primary care physician as needed.  
477 
 If the study subject is pregnant, the study physician will discuss the 
478 
results of the blood test with the subject and the subject will be asked 
479 
to seek confirmation of the test and the appropriate medical care.  
480 
 If an abnormal hematocrit is detected, the patient may have the 
481 
hematocrit re-tested to exclude the possibility of lab error or 
482 
hydration effects. If anemia is confirmed on repeat testing, the study 
483 
subject will be excluded. A copy of the result will be provided and 
484 
the subject will be advised to discuss the result with the personal 
485 
physician for further evaluation and treatment.  
486 
 Subjects may be re-screened at a later date if their clinical situation 
487 
changes as determined by the study physician. Subjects that stopped 
488 
study participation due to need for oral glucocorticoids (e.g. bout of 
489 
poison ivy) may be re-screened and re-enrolled after there is no 
490 
further anticipated need for oral glucocorticoids. 
491 
 
492 
The total amount of blood to be withdrawn during the screening visit is up to 
493 

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25 cc. If a subject meets all the study criteria, s/he will be enrolled in the trial 
494 
and trained on the study glucometer and Dexcom CGM.  
495 
 
496 
Study Glucometer and Dexcom CGM Training: 
497 
 The subject will be trained on the use of the study glucometer and will 
498 
demonstrate proficiency with a fingerstick test.  
499 
 Subjects will be reminded to use the same study glucometer for all 
500 
finger sticks and calibrations.   
501 
 The subject will be trained on Dexcom CGM use and will be supervised 
502 
during the initial CGM sensor placement.  
503 
 If the participant is a Pilot subject, s/he will use the CGM for up to 1 
504 
week (unblinded) at home and will be reminded to base all treatment 
505 
decisions on glucometer results, not CGM data. 
506 
 For non-Pilot subjects, once the initial calibration BG is entered and 
507 
the Dexcom is confirmed to be functional, the CGM will be placed in 
508 
blinded mode for 1 week use of blinded CGM at home. 
509 
 If the participant experiences a sensor failure or issue with the CGM 
510 
device while at home, the subject will contact the study team. The 
511 
subject will replace the sensor at home with guidance from the study 
512 
team if appropriate or return to the office and the study team will 
513 
replace the sensor or device. 
514 
 Subjects will be required to perform 4-6 SMBG measurements daily 
515 
(recommended before meals, about 2 hours after meals and at 
516 
bedtime), and as needed to calibrate the CGM.  Additional 
517 
fingersticks may be obtained, if desired.  
518 
 If a subject is a CGM-wearer at screening, the subject may continue to 
519 
use the home CGM during blinded study CGM use. 
520 
 
521 
The screening visit and training session will last approximately 3 hours. This 
522 
may be shorter depending on the amount of pre-screening that was performed 
523 
and the subject’s prior knowledge of study devices.  
524 
 
525 
If the subject cannot schedule Visit 3 within 4 weeks of screening, the 
526 
inclusion and exclusion criteria will be re-evaluated. The study physician will 
527 
have the discretion to repeat any test as needed. 
528 
 
529 
2. Visit 2: Screening 2 Visit  
530 
After completion of 1 week of baseline blinded CGM use, the subject will return to have the 
531 
Dexcom CGM and study glucometer downloaded to assess the subject’s baseline risk for 
532 
hypoglycemia and evaluate the reliability of CGM data collection. The meter data will be 
533 

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assessed for average SMBG/day and randomness of data. Subjects with average SMBG 
534 
<3.5/day and/or poor randomness of SMBG testing will be reminded of SMBG requirements 
535 
4-6 times daily (pre-meal, bedtime, before driving, before exercise, and as indicated). 
536 
 
537 
In order to continue with the trial, the subject must have all of the following: 
538 
 Baseline LBGI >1.1 as assessed by the prior 1 week of blinded CGM data  
539 
 CGM must have been functional >80% of the time (i.e. >1600 CGM data 
540 
points/week).  
541 
 
542 
CGM data collection period may be repeated. Eligible subjects will be scheduled for 
543 
Visit 3 within 3 weeks of Visit 2. Subjects will be randomized to experimental 
544 
treatment with the AP system+USS Virginia or control treatment with sensor-
545 
augmented pump therapy. Groups will be matched for LBGI and pre-study CGM 
546 
use.   
547 
 
548 
Preparation for Visit 3: 
549 
 All subjects will be given written instructions to bring their pump supplies, 
550 
glucometer supplies, CGM supplies, insulin and all of their current 
551 
medications (including aspirin or regular analgesics) with them for use during 
552 
the admission.  
553 
 These instructions will also advise the subject to contact the study team in the 
554 
event of a febrile or vomiting illness within 24 hours of the admission, so that 
555 
the admission can be rescheduled.  
556 
 The subject will be asked to avoid the need for a pump site change during Visit 
557 
3. 
558 
 The subjects will be asked to arrive at the unit fasting and to not consume 
559 
caffeine on the morning of admission.  
560 
 Subjects will be asked to check a fingerstick BG at 03:00 and 06:00 on the 
561 
morning of admission for Visit 3 and to aim for a steady BG between 100-150 
562 
mg/dL upon arrival to the research unit at 07:00.  
563 
 The subject may administer a correction bolus of insulin to stabilize BG or treat 
564 
hyperglycemia. 
565 
 The subject may consume fast acting glucose (glucose tablets, gel or liquid) to 
566 
stabilize BG or treat BG <100 mg/dL. 
567 
 
568 
Visit 2 is anticipated to last approximately 30 minutes.  
569 
 
570 
3. Visit 3: 8 hr Inpatient Assessment of Hypoglycemia Counterregulation and 
571 
Symptom Awareness  
572 
 
573 

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Visit 3 will occur within 4 weeks of the Screening Visit (Visit 1). 
574 
 
575 
Admission Overview: 
576 
The subject will be admitted to the research unit by 07:00 for a blinded assessment of 
577 
hypoglycemia counterregulation and symptom awareness. After a Run-in Period for 
578 
stabilization of the subject’s BG in the ~100-150 mg/dL range, the subject will 
579 
participate in a previously validated Hypoglycemia Induction (#1) where the home 
580 
insulin pump therapy will be used to induce an episode of hypoglycemia with goal 
581 
glucose of <60 mg/dL. After carbohydrate rescue to BG ≥80 mg/dL, the subject will 
582 
receive a meal and will be monitored for at least an additional hour in the Recovery 
583 
Period. The subject may then be discharged once the glucose is stable (i.e. at least 
584 
the prior 2 values) between 100-300 mg/dL and fingerstick ketone level <0.6 
585 
mmol/L. The subject will additionally receive training on the Dexcom CGM as 
586 
needed and will receive supplies and instructions to complete the next portion of the 
587 
study. The specific details of the ~8 hour inpatient admission are provided below. 
588 
 
589 
Clinical Research Unit (CRU) Procedures: 
590 
 A nurse will be at the bedside or on the unit throughout the study. 
591 
 Study staff (MD or NP who has experience in diabetes management) will 
592 
also be immediately available at the bedside or on the unit throughout the 
593 
entire study. 
594 
 
595 
Blood Sampling and Hypoglycemia Symptom Questionnaires 
596 
 The clinical centers will either use reinfusion of blood or will discard blood 
597 
with each blood draw depending on the standard practice at each center’s 
598 
Clinical Research Unit.  
599 
 Subjects and parents (or diabetes care partners) will be blinded to the results 
600 
of the glucose testing until the Recovery Period in an attempt to eliminate 
601 
bias when answering questions regarding symptoms of hypoglycemia. 
602 
 Once IV access has been established, blood will be sampled for YSI glucose 
603 
every 5-30 minutes. The frequency of blood draws for YSI sampling is 
604 
dependent on the value of the previous sample, according to the following 
605 
ranges: 
606 
o BG >200: every 30 minutes 
607 
o BG >100-200: every 15 minutes 
608 
o BG ≤100 mg/dL:  every 5 minutes 
609 
 Blood may be sampled for YSI glucose as needed for patient safety or to 
610 
recheck a suspected erroneous value (e.g. dilute sample). 
611 
 Blood will be sampled for epinephrine and glucagon and Hypoglycemia 
612 
Symptom Questionnaires will be performed during the admission as follows: 
613 

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o Run-in Period:  
614 
 Blood will be sampled for epinephrine at the initial sampling 
615 
time for YSI glucose after the IV access is established. 
616 
 Once BG is between 100 to 150 mg/dL, baseline 
617 
Hypoglycemia Symptom Questionnaires will be completed 
618 
and blood will be sampled for epinephrine and glucagon at the 
619 
next scheduled sampling time for YSI glucose.  
620 
o Hypoglycemia Induction Period:  
621 
 Blood will be sampled for epinephrine approximately every 15 
622 
minutes once the blood glucose has decreased to ≤90 mg/dL 
623 
with goal of epinephrine sampling at BGs of 90, 75, 60 and 
624 
<60 mg/dL. 
625 
 Blood will be sampled for glucagon when the blood glucose is 
626 
<60 mg/dL, just prior to the administration of hypoglycemia 
627 
rescue therapy. 
628 
 A Hypoglycemia Symptom Questionnaire will be completed 
629 
approximately every 15 minutes once the blood glucose has 
630 
decreased to ≤90 mg/dL (any time blood is sampled for 
631 
epinephrine) until hypoglycemia BG <60 mg/dL and recovery 
632 
BG ≥80 mg/dL has been achieved. 
633 
o Recovery Period:  
634 
 Blood will be sampled for epinephrine every 15 minutes for a 
635 
total of 4 samples after the nadir blood glucose. 
636 
 The actual time (rounded to the nearest minute) of all blood draws and 
637 
questionnaires per the study clock set to an atomic clock will be documented 
638 
on the nursing flow sheet. 
639 
 There will be about 31 blood draws for glucose sampling during the 
640 
admission. Approximately 1 cc discard (at discard centers) and 1 cc sample 
641 
will be taken for each blood draw for glucose. There will additionally be 
642 
about 11 blood draws for epinephrine in duplicate (2 cc total per epinephrine 
643 
draw) and 2 blood draws for glucagon in duplicate (2 cc total per glucagon 
644 
draw). Therefore, the anticipated blood drawn for the entire admission will be 
645 
about 88 cc at centers using a discard technique and 57 cc at centers using 
646 
blood-sparing procedures. 
647 
 For subjects ≥18 years old, the total blood drawn in the entire study will not 
648 
exceed 400 cc. 
649 
 For subjects <18 years old, the maximum allowed volume will be determined 
650 
by subject’s weight. A maximum of 4 ml/kg may be drawn within 30 days 
651 
and a maximum of 7 ml/kg may be drawn in an 8 week period. 
652 
 
653 

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YSI Instructions  
654 
 Once IV access has been established, blood will be sampled for YSI glucose 
655 
every 5-30 minutes. The frequency of blood draws for YSI sampling is 
656 
dependent on the value of the previous sample, according to the following 
657 
ranges: 
658 
o BG >200: every 30 minutes 
659 
o BG >100-200: every 15 minutes 
660 
o BG ≤100 mg/dL:  every 5 minutes 
661 
 Blood may be sampled for YSI glucose as needed for patient safety or to 
662 
recheck a suspected erroneous value (e.g. dilute sample). 
663 
 In the event of loss of IV access or loss of a functional YSI and need for 
664 
continued subject monitoring, glucose measurements will be made on 
665 
capillary whole blood using the study glucometer.  
666 
 
667 
IV Access  
668 
 During the CRC portion of the study, intravenous access will be maintained 
669 
for blood sampling and for the treatment of severe hypoglycemia or 
670 
hyperglycemia during the study. If an IV fails, a new IV will be inserted.  
671 
 If there is failure of intravenous access, the study physician will be available 
672 
at the bedside to make decisions about appropriate insulin and glucose 
673 
adjustments. Fingerstick glucose measurements on the study glucometer may 
674 
be used during times of inadequate IV access and need for glucose 
675 
monitoring.  
676 
 
677 
Heating Device  
678 
 To facilitate IV insertion and blood drawing, and to obtain arterialized blood 
679 
samples, heat may be applied to the subject’s arm using a hospital-approved 
680 
Gaymar T/pump (Gaymar Industries, Inc., Orchard Park, NY).  
681 
 
682 
β-Hydroxybutyrate Testing  
683 
 Subject blood ketones should be evaluated from capillary blood using the 
684 
ketone meter at the following times: 
685 
o On arrival to and at discharge from the clinic 
686 
o Glucose ≥250 mg/dL every 60 minutes 
687 
o Ketones  ≥0.6 mmol/L every 60 minutes 
688 
o Nausea, vomiting or abdominal pain regardless of glucose level 
689 
o A subject will be observed in the clinic until the ketone level is <0.6 
690 
mmol/L 
691 
 
692 
Capillary Glucose Testing  
693 

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 In the event of loss of IV access or loss of functional YSI, glucose 
694 
measurements may be taken from fingersticks using the study glucometer. 
695 
Fingersticks will be performed approximately every 30 minutes when the 
696 
glucose level is >80 mg/dL and approximately every 15 minutes when the 
697 
glucose level is ≤80 mg/dL. Additional fingersticks may be taken as needed 
698 
for patient safety. 
699 
 
700 
Inpatient Hypoglycemia Treatment 
701 
 Glucose <60 mg/dL will be treated orally with fast acting carbohydrate as 
702 
needed until a glucose level of ≥80 mg/dL is achieved.  
703 
 In the event that there is intravenous access and the subject is at risk for 
704 
severe hypoglycemia, the subject will be treated with a ~2-3 mL/kg D10 
705 
intravenous glucose bolus. Risk for severe hypoglycemia is defined as any of 
706 
the following situations: 
707 
o Glucose <50 mg/dL 
708 
o The subject is unable to cooperate with oral treatment of 
709 
hypoglycemia 
710 
o The glucose is dropping at a rate that may not respond adequately to 
711 
oral treatment 
712 
o The subject experiences symptoms of neuroglycopenia (e.g. lethargy, 
713 
disorientation, confusion [disordered processing of information or 
714 
communication], or inappropriate behavior)  
715 
o The subject experiences symptoms of severe hypoglycemia (i.e. 
716 
hypoglycemic seizure or loss of consciousness)  
717 
 In the event that there is NO intravenous access and the subject is at risk for 
718 
severe hypoglycemia (as defined above), the subject will be treated with 1 mg 
719 
of glucagon subcutaneously or intramuscularly.  
720 
o The drug will be reconstituted and administered per package 
721 
insert/instructions.  
722 
o Glucagon may be repeated as needed every 20 minutes to achieve 
723 
glucose level ≥80 mg/dL. Once the subject is able to consume oral 
724 
treatment, the subject will be treated orally with fast acting 
725 
carbohydrate as needed until a glucose level of ≥80 mg/dL is 
726 
achieved. Orange juice and milk will be avoided after glucagon 
727 
administration.  
728 
o Attempts will be made to reestablish intravenous access.  
729 
 The Hypoglycemia Induction Admission will be stopped if the subject 
730 
experiences a hypoglycemic seizure or loss of consciousness and only safety 
731 
procedures will be continued. The study physician or nurse practitioner will 
732 
take control over glucose sampling decisions in order to stabilize the 
733 

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subject’s glucose between 100-300 mg/dL and determine the appropriate 
734 
subject disposition (i.e. home or medical facility).  
735 
 
736 
Inpatient Hyperglycemia and Ketone Treatment 
737 
 If the subject’s glucose is >300 mg/dL or β–hydroxybutyrate level is ≥0.6 
738 
mmol/L on admission, the subject will be stabilized per the procedures 
739 
below. The subject will continue to be monitored until a glucose level 
740 
between 100-300 mg/dL and β–hydroxybutyrate measurement <0.6 mmol/L 
741 
has been achieved (or the subject is discharged to an appropriate medical 
742 
team).  
743 
 Subsequently, glucose >300 mg/dL for >2 hours or glucose ≥400 mg/dL at 
744 
any time will prompt discontinuation of the Hypoglycemia Induction 
745 
Admission. 
746 
 β–hydroxybutyrate will be assessed hourly while the glucose is ≥250 mg/dl 
747 
or the β–hydroxybutyrate level is ≥0.6 mmol/L.  
748 
 If the glucose is >300 mg/dL and β–hydroxybutyrate level is <0.6 mmol/L, 
749 
corrective action will be taken only after it has been at least 90 minutes from 
750 
the last subcutaneous insulin dose. Specifically, the subject will be asked to 
751 
bolus with his/her pump an amount of corrective insulin that will bring 
752 
him/her to a target glucose of 120 mg/dL. 
753 
 If the β–hydroxybutyrate level is ≥0.6 mmol/L, the cause of the elevated 
754 
ketone level will be investigated (e.g. pump or pump site malfunction). 
755 
Additional insulin may be administered either via insulin syringe or via a new 
756 
pump site. The amount of insulin administered will be calculated using the 
757 
subject’s insulin sensitivity factor and a target glucose of 120 mg/dL.   
758 
 If the β–hydroxybutyrate level is ≥1.5 mmol/L, the Hypoglycemia Induction 
759 
Admission will be stopped and the study MD or NP will take control of the 
760 
subject's insulin dosing. The cause of the elevated ketone level will be 
761 
investigated (e.g. pump or pump site malfunction). If the subject's home 
762 
parameters are not felt to be working adequately due to hyperglycemia, 
763 
ketonemia, or other factors (e.g. intercurrent illness), the study MD or NP 
764 
will administer corrective insulin either via insulin syringe or via a new pump 
765 
site using an ISF determined to be appropriate for the setting and a goal 
766 
glucose of 120 mg/dL. The subject will continue to be monitored until a 
767 
glucose level between 100-300 mg/dL and β–hydroxybutyrate measurement 
768 
<0.6 mmol/L has been achieved (or the subject is discharged to an 
769 
appropriate medical team).  
770 
 
771 
Acceptable Medications 
772 
 The subject may continue any home medications including his/her home 
773 

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over-the-counter or prescribed analgesics as long as the medication is not on 
774 
the list of restricted drugs and the subject brought his/her own supply. The 
775 
patient may use his/her own ibuprofen or aspirin per package labeling. 
776 
 
777 
Inpatient Admission Detail (~6.5-9.5 hours) 
778 
1. Admission at approximately 07:00 
779 
2. Run-in Period for glucose stabilization at approximately 07:30-08:00 
780 
3. (Optional extension of the Run-in Period for glucose stabilization until 11:00) 
781 
4. Hypoglycemia Induction Period to achieve hypoglycemia to goal glucose <60 
782 
mg/dL from ~08:00 – 12:00) 
783 
5. Recovery Period with meal and glucose stabilization from ~12:00-13:00 
784 
6. Discharge Preparation Period ~13:00-13:30 
785 
7. Discharge at ~13:30. Discharge may be as late as 16:30 if the Run-in Period 
786 
is extended.  
787 
 
788 
Admission Day: 
789 
 Pre-Admission Set-up: 
790 
o At approximately 06:30 the CRU study equipment (YSI, Precision 
791 
Xtra Blood Glucose and Ketone Monitoring System, and study 
792 
glucometer) will be calibrated and the appropriate Quality Controls 
793 
will be run per the manufacturer’s guidelines.  
794 
o The times on all study devices (i.e. study clocks, YSI(s), glucometers, 
795 
and Precision Xtra β-ketone monitor) will be synchronized to the 
796 
Official US Time using www.time.gov or to an equivalent atomic 
797 
clock. 
798 
o All of the medications required for the treatment of hypoglycemia, 
799 
hyperglycemia or hypotension including glucose tablets, glucose 
800 
gel/liquid, D10W, glucagon 1 mg emergency kit, and 1 L normal 
801 
saline bags will be placed at the subject’s bedside. 
802 
o The CRC code cart will be in close proximity to the subject’s room. 
803 
 
804 
 Subject Admission Readiness Assessment: 
805 
o The subject will meet the study team at the Clinical Research Unit by 
806 
approximately 07:00 and the subject will be assessed for admission 
807 
readiness. 
808 
o The subject will be asked about any adverse events since the last 
809 
study visit. 
810 
o The subject will continue to use his/her individual insulin pump for 
811 
insulin dosing throughout the admission. 
812 
o The study team will confirm that the subject brought his/her personal 
813 

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insulin and insulin pump supplies and regular medications.  
814 
o The study team will confirm the absence of a febrile or vomiting 
815 
illness within 24 hours of the admission. 
816 
o Female subjects of childbearing capacity will perform a urine 
817 
pregnancy test. If positive, the subject will discontinue study 
818 
participation. The subject will be asked to seek confirmation of the 
819 
test and the appropriate medical care.  
820 
o Vital signs (blood pressure, pulse, temperature) will be performed and 
821 
documented. The subject must have T <99.5ºF (<37.5ºC) for 
822 
admission. 
823 
o The study nurse will perform a fingerstick glucose with the study 
824 
glucometer and fingerstick β-hydroxybutyrate with the study 
825 
Precision Xtra meter. The subject must have an admission glucose 
826 
≤300 mg/dL and β-hydroxybutyrate <0.6 mmol/L to continue with the 
827 
inpatient admission. 
828 
 If glucose is >300 mg/dl or β-hydroxybutyrate is ≥0.6 
829 
mmol/L, the subject will be rescheduled and stabilized per the 
830 
procedures above (Inpatient Hyperglycemia and Ketone 
831 
Treatment).  
832 
 The subject will continue to be monitored until a glucose level 
833 
between 100-300 mg/dL and β–hydroxybutyrate measurement 
834 
<0.6 mmol/L has been achieved (or the subject is discharged 
835 
to an appropriate medical team).  
836 
o If all admission readiness criteria are not met, the subject will be 
837 
rescheduled. If all of the admission readiness conditions are met, the 
838 
subject will be admitted to the Clinical Research Unit. 
839 
 
840 
 Procedures Upon Admission: 
841 
o Heat may be applied to the sites of IV insertion with a hospital-
842 
approved Gaymar T/pump heating pad. 
843 
o Intravenous access appropriate for blood drawing and potential 
844 
intravenous DW10 rescue will be established.  
845 
o The subject’s current pump parameters will be reviewed by the study 
846 
physician and documented. Any insulin boluses administered on the 
847 
day of admission will be recorded. 
848 
o Aside from administered meals and carbohydrate rescue, the subject 
849 
will remain fasting on the unit except for ad lib water and glucose-
850 
free beverages. Caffeine will be restricted until blood sampling for 
851 
epinephrine is completed. 
852 
o Strenuous activity is restricted until blood sampling for epinephrine is 
853 

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completed. 
854 
o Subjects and parents (or diabetes care partners) will be blinded to the 
855 
results of the glucose testing until the Recovery Period in an attempt 
856 
to eliminate bias when answering questions regarding symptoms of 
857 
hypoglycemia. 
858 
 
859 
 Procedures Related to the Run-in Period: 
860 
o The Run-in Period will nominally occur from 07:30-08:00. 
861 
o The goal of the Run-in Period is to reach a target glucose of 100-150 
862 
mg/dL.  
863 
o Once IV access has been established, blood will be sampled for YSI 
864 
glucose every 5-30 minutes per the Blood Sampling guidelines above.  
865 
o Blood will be sampled for epinephrine at the initial sampling time for 
866 
YSI glucose. 
867 
o Fast acting carbohydrates may be used to stabilize the glucose or treat 
868 
BG <100 mg/dL at any time during the Run-in Period.  
869 
o For glucose >150 mg/dL, correction boluses may be administered 
870 
with the home pump up to every 90 minutes for a maximum of 2 
871 
correction boluses. The amount of insulin administered will be 
872 
calculated using the subject’s insulin sensitivity factor and a target 
873 
glucose of 120 mg/dL.   
874 
o Once BG is between 100 to 150 mg/dL, baseline Hypoglycemia 
875 
Symptom Questionnaires will be completed and blood will be 
876 
sampled for epinephrine and glucagon at the next scheduled sampling 
877 
time for YSI glucose.  
878 
o The Run-in Period may be extended until 11:00 to ensure that it has 
879 
been at least 90 minutes since the last correction bolus, at least 60 
880 
minutes since the last glucose <70 mg/dL, and at least 30 minutes 
881 
since the last carbohydrate treatment. The subject may enter the 
882 
Hypoglycemia Induction Period once these criteria are met and 
883 
glucose is 100-150 mg/dL. If these criteria are not attained by 11:00, 
884 
the subject will be rescheduled. The subject MD or NP will take 
885 
control of the glucose sampling and insulin management and the 
886 
subject will continue to be monitored until a glucose level of 100-300 
887 
mg/dL is attained prior to discharge. 
888 
 
889 
 Procedures Related to Hypoglycemia Induction Period: 
890 
o The Hypoglycemia Induction Period is anticipated to last 
891 
approximately 2-4 hours (~08:00-12:00). If the subject has not 
892 
reached the endpoint (<60 mg/dL) within ~4 hours, the subject will 
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proceed to the Preparation for Discharge Period at the discretion of 
894 
the investigator.  
895 
o At the start of the hypoglycemia induction, the basal insulin rate will 
896 
be increased by approximately 25-50% to provide a gradual decline in 
897 
blood glucose (~1 mg/dL/min). A small priming bolus dose of insulin 
898 
equal to approximately one hour of the subject’s usual basal dose +/- 
899 
correction dose with goal 120 mg/dL may also be given at the 
900 
discretion of the investigator (e.g. trend upward) in addition to the 25-
901 
50% increase in the basal insulin. 
902 
o The basal insulin rate may be increased approximately hourly and 
903 
additional bolus insulin doses may be given as described above at the 
904 
discretion of the investigator in order to get a gradual decline in the 
905 
glucose concentration (decline rate of ~1 mg/dL/min). 
906 
o Blood will be sampled for YSI glucose every 5-30 minutes per the 
907 
Blood Sampling guidelines above. 
908 
o Blood will be sampled for epinephrine approximately every 15 
909 
minutes once the blood glucose has decreased to ≤90 mg/dL with goal 
910 
of epinephrine sampling at BGs of 90, 75, 60 and <60 mg/dL. 
911 
o Blood will be sampled for glucagon when BG <60 mg/dL, just prior 
912 
to hypoglycemia rescue therapy. 
913 
o A Hypoglycemia Symptom Questionnaire will be completed 
914 
approximately every 15 minutes once the blood glucose has decreased 
915 
to ≤90 mg/dL (any time blood is sampled for epinephrine) and until 
916 
hypoglycemia BG <60 mg/dL and recovery BG ≥80 mg/dL has been 
917 
achieved. 
918 
o Once the study endpoint is reached (the first time YSI glucose is <60 
919 
mg/dL), the pump will be stopped and the subject will be treated with 
920 
oral fast acting carbohydrates (preferred), a 2-3 mL/kg D10 
921 
intravenous glucose bolus (for BG <50 or risk of severe 
922 
hypoglycemia with IV access), or a glucagon emergency kit (for 
923 
severe hypoglycemia with NO IV access) per the Inpatient 
924 
Hypoglycemia Treatment guidelines above to achieve a recovery 
925 
glucose ≥80 mg/dL.  
926 
o Once a recovery glucose of ≥80 mg/dL is achieved, the subject will 
927 
resume pump therapy with the normal basal rate and will proceed to 
928 
the Recovery Period.  
929 
 
930 
 Procedures Related to the Recovery Period: 
931 
o Once the procedures related to the Hypoglycemia Induction Period 
932 
are complete and the subject’s glucose is ≥80 mg/dl, the subject will 
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be served a regular meal and will be monitored for a 1 hour Recovery 
934 
Period.  
935 
o The meal carbohydrates will be estimated by the subject and the meal 
936 
will be covered with insulin via the subject’s pump based on the 
937 
subject’s individual carbohydrate ratio and insulin sensitivity factor 
938 
parameters and a glucose goal of 120 mg/dL or the subject’s home 
939 
glucose goal, whichever is higher. The subject may use the YSI 
940 
glucose information and the insulin dosing chosen will be discussed 
941 
with the study physician prior to administration. The amount of 
942 
insulin given and time of administration will be documented.  
943 
o During the 1-hour Recovery Period, blood will be sampled for YSI 
944 
glucose every 5-30 minutes per the Blood Sampling guidelines above. 
945 
o Blood will also be sampled for epinephrine every 15 minutes x 4 
946 
samples after the nadir blood glucose.  
947 
o Subjects will then enter the Discharge Preparation Period. 
948 
 
949 
 Procedures Related to the Discharge Preparation Period: 
950 
o A fingerstick β-hydroxybutyrate test will be performed.  
951 
o Blood will be sampled for YSI glucose every 5-30 minutes per the 
952 
Blood Sampling guidelines above. 
953 
o Once plasma glucose is 100-300 mg/dL, and β–hydroxybutyrate is 
954 
≤0.6 mmol/L, blood sampling will be discontinued and the subject 
955 
will be prepared for discharge.  
956 
o If plasma glucose is <100 mg/dL, carbohydrates will be given to raise 
957 
the glucose to ≥100 mg/dL.  
958 
o If plasma glucose is >300 mg/dL, or fingerstick β–hydroxybutyrate is 
959 
>0.6 mmol/L, the Inpatient Hyperglycemia and Ketone Treatment 
960 
guidelines will be followed. 
961 
o Additional inpatient time for BG stabilization will not be considered 
962 
an adverse event.  
963 
o A final set of vital signs (temperature, blood pressure and pulse) will 
964 
be performed and documented. 
965 
o The subject will be provided with a Precision Xtra ketone meter (if 
966 
the subject does not have one) and blood ketone test strips and 
967 
instructed on their use to monitor for ketones. Patients will be 
968 
instructed to check ketones as follows: 
969 
  Hourly if the glucose is >300 mg/dL for >2 hours until 
970 
glucose is <300 mg/dL and ketones <0.6 mmol/L  
971 
 If symptoms of nausea, vomiting, or abdominal pain occur.  
972 
o The subject will be given instructions on how to contact study staff 24 
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hours a day to report any study-related problems.  
974 
o The subject will be instructed to contact the study staff for prolonged 
975 
hyperglycemia >300 mg/dL, ketones ≥1.5 mmol/L, or if s/he 
976 
experiences nausea, vomiting, or abdominal pain within 48 hours after 
977 
discharge. 
978 
o The IVs will be removed and the IV sites will be observed and the 
979 
condition will be documented along with any AEs.  
980 
o The subject will be instructed to contact the study staff for any 
981 
problems related to IV insertion sites, including fever, pain, redness, 
982 
itching, discharge or swelling at the IV insertion sites. 
983 
o Any existing protocol-related problems will be followed-up after 
984 
discharge until resolution.  
985 
o The subject will be informed of possible fluctuations in their glucose 
986 
control during the next 72 hours. 
987 
o The study subject will be contacted within 48-72 hours after 
988 
discharge. 
989 
 
990 
Study Glucometer and Dexcom CGM Training (1 hour): 
991 
CGM training may occur at any time that the subject is not hypoglycemic during 
992 
Visit 3. 
993 
 Subjects will be provided with a study blood glucose meter, test strips, 
994 
and standard control solution to perform quality control (QC) testing at 
995 
home per manufacturer guidelines.   
996 
 Study staff will answer any questions the subject has about the study 
997 
glucometer and the subject will demonstrate proficiency with a fingerstick test.  
998 
 Subjects will be reminded to use the same study glucometer for all 
999 
finger sticks and calibrations and to only use SMBG values (not CGM 
1000 
values) to guide treatment decisions.    
1001 
 Subjects will be required to perform 4-6 SMBG measurements daily 
1002 
(recommended before meals, about 2 hours after meals and at bedtime), 
1003 
and as needed to calibrate the CGM.  Additional fingersticks may be 
1004 
obtained, if desired.  
1005 
 Subjects will be given additional training on the Dexcom Share AP CGM to 
1006 
be proficient with its use during the experimental or control treatment. 
1007 
 The subject will be taught how to calibrate the CGM per manufacturer’s 
1008 
guidelines with the study glucometer. For this study, the subject will be asked 
1009 
to perform calibrations before meals and at bedtime, and as prompted by the 
1010 
CGM receiver. Only BG values taken within 5 minutes of the intended 
1011 
calibration should be used for calibration. The antenna symbol needs to be 
1012 
present on the Dexcom receiver before a blood glucose value is entered for 
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calibration.  
1014 
 If the subject is in the control group, s/he will be given appropriate 
1015 
supplies to complete 5 weeks of sensor augmented pump therapy at 
1016 
home.  
1017 
o The low glucose alert will be set per patient preference, but may 
1018 
not be lower than 70 mg/dL.  
1019 
o The subject may determine the settings for any of the other 
1020 
alerts. 
1021 
o The subject will be contacted daily by study staff for the first 5 
1022 
days, then weekly. CGM downloads will occur at week 2 and 
1023 
week 5. 
1024 
o An appointment will be made for Visit 6 to be scheduled within 
1025 
8 weeks of Visit 3 and within 1 week of completing the 
1026 
intervention. 
1027 
 If the subject is in the experimental group, s/he will be given appropriate 
1028 
supplies for CGM use until Visit 4.  
1029 
o The low glucose alert will be set per patient preference, but may 
1030 
not be lower than 70 mg/dL.  
1031 
o The subject may determine the settings for any of the other 
1032 
alerts. 
1033 
 
1034 
4. Visit 4: Study Pump and AP system Training 
1035 
Subjects in the experimental group will participate in a training session in a 
1036 
monitored outpatient setting during which the subject and diabetes care companion 
1037 
will be trained to use the study pump, the AP system controlling the study pump, and 
1038 
the Dexcom receiver to display CGM values on the system. Visit 4 may start on the 
1039 
same day as Visit 3.  
1040 
 
1041 
Monitored Outpatient Setting Procedures: 
1042 
 More than one subject and diabetes care partner may be admitted at a time.  
1043 
 The subject and diabetes care partner will meet the study team and check into 
1044 
the monitored outpatient setting at the agreed upon time. 
1045 
 The subject will be asked to perform a fingerstick glucose using the study 
1046 
glucometer shortly after arrival. 
1047 
 The study team will confirm that the subject brought his/her insulin, insulin 
1048 
pump supplies, and regular medications including the home glucagon 
1049 
emergency kit (if available).  
1050 
 The study team will also confirm the absence of a febrile or vomiting illness 
1051 
and absence of acetaminophen use. The subject may be rescheduled if these 
1052 
criteria are not met. 
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 Female subjects of childbearing potential will perform a urine pregnancy test. 
1054 
If positive, the subject will discontinue study participation. The subject will 
1055 
be asked to seek confirmation of the test and the appropriate medical care. 
1056 
 The subject and care partner will be trained as needed on the Outpatient 
1057 
Hypoglycemia, Hyperglycemia and Ketone Treatment Instructions that will 
1058 
be followed during the visit and any time a study pump is in use (APPENDIX 
1059 
A-12). 
1060 
 If the subject requires glucagon while at the research facility, it will be 
1061 
administered by qualified study staff. The diabetes care partner will be 
1062 
educated as needed on the use of glucagon per the package instructions in the 
1063 
event the subject requires glucagon for severe hypoglycemia outside of the 
1064 
research facility. 
1065 
 The subject and care partner will be trained as needed on the use of the study 
1066 
ketone meter and the subject will be asked to check fingerstick ketone levels 
1067 
per the Outpatient Hypoglycemia, Hyperglycemia and Ketone Treatment 
1068 
Instructions. 
1069 
 The subject will continue to perform 4-6 SMBG measurements daily 
1070 
(recommended before meals, about 2 hours after meals and at bedtime), and 
1071 
as needed to calibrate the CGM or follow the Outpatient Hypoglycemia, 
1072 
Hyperglycemia and Ketone Treatment Instructions.  Additional fingersticks 
1073 
may be obtained, if desired.   
1074 
 The subject will be instructed to enter each SMBG result in The AP system . 
1075 
 The subject will continue to use the study CGM.  
1076 
 The research facility will be stocked with the subject’s preferred 
1077 
hypoglycemia treatment foods (e.g. juice, glucose tablets, milk, etc.).  
1078 
 Study medical personnel will additionally have glucose tablets, glucose 
1079 
gel/liquid, and a glucagon emergency kit available for treatment at all sites. 
1080 
 The research facility at all sites will be located within 4 miles of an 
1081 
emergency department and will have an automated external defibrillator 
1082 
(AED) and Ambu bag for ventilation. 
1083 
 Hypoglycemic treatments can occur at any time per the subject’s request.   
1084 
 The subject will have access to ad lib beverages. 
1085 
 All meals will be provided by the study and the study staff will try to 
1086 
accommodate patient preferences. 
1087 
 The subject may also administer snacks or correction boluses per their usual 
1088 
regimen. 
1089 
 The subjects will be encouraged to follow a regular sleep pattern between 
1090 
11PM and 7AM. 
1091 
 
1092 
Visit 4 Study Pump Training Procedures: 
1093 

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 The subject and the care partner will be fully instructed on the study insulin 
1094 
pump. A qualified staff member will conduct the training and in particular 
1095 
discuss differences from their home pump in important aspects such as 
1096 
calculation of insulin on board and correction boluses. Additional topics not 
1097 
limited to but may include: site initiation, cartridge/priming procedures, 
1098 
setting up the pump, changing batteries, navigation through menus, bolus 
1099 
procedures including stopping a bolus, pairing procedures with the meter 
1100 
remote, etc. 
1101 
 The study team will assist the subject in study pump infusion site initiation 
1102 
and will start the subject on the study pump. The study pump will be 
1103 
programmed with the subject’s usual basal rates and pump parameters. The 
1104 
subject’s personal pump will be removed. 
1105 
 The subject will be supervised with the study pump during at least one meal 
1106 
bolus to ensure subject understanding of the pump features. 
1107 
 The subject may eat meals and snacks and bolus for the meals and snacks 
1108 
using the study pump per the home routine.  
1109 
 The subject and diabetes care partner will be encouraged to review the 
1110 
literature provided with the pump, infusion sets, and meter remote after the 
1111 
training is completed. 
1112 
 Once the subject is adequately trained on the study pump, study staff will 
1113 
meet with the subject and diabetes care partner for training on the use of the 
1114 
AP system with the study pump and study CGM. 
1115 
 
1116 
Visit 4 AP System Training Procedures: 
1117 
 Prior to initial use, the AP system will be initialized by a study team member 
1118 
with the subject’s individual parameters, including carbohydrate ratio, 
1119 
correction factor, and basal rate pattern. The settings will be confirmed by the 
1120 
study physician or NP. 
1121 
 The subject and care partner may be taught how to unpair the study pump 
1122 
from the meter remote and how to turn off the meter Bluetooth. The meter 
1123 
remote will continue to be used as a glucometer for the remainder of the 
1124 
study. (When there is no Bluetooth connection to the meter remote, the 
1125 
subject’s basal rate pattern is still administered according to the 
1126 
preprogrammed basal rates on the study pump.)  
1127 
 All study equipment including the AP system cell phone, insulin pump, and 
1128 
CGM receiver will be set using an atomic clock as a reference.  
1129 
 The subject will be taught how to initiate Pump mode. Once Pump mode is 
1130 
activated, the system will take control of the insulin pump and will direct the 
1131 
administration of insulin according to the subject’s usual basal rate pattern. 
1132 
 The meal screen on the system will be introduced and the subject will be 
1133 

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supervised during at least one meal bolus. 
1134 
 The subject and care partner will be trained to use the AP interface and the 
1135 
pertinent portions of the User Manual will be reviewed; the training will 
1136 
continue until all questions are answered. The User Manual is included in 
1137 
APPENDIX A-13. 
1138 
 Study team members will train the subject and diabetes care companion in 
1139 
performing specific tasks including the following: 
1140 
o How to switch the system between Pump mode (with the AP system 
1141 
in control of delivering preprogrammed basal insulin) and Stopped 
1142 
mode (with the study insulin pump in control of delivering 
1143 
preprogrammed basal insulin) depending on circumstances. Stopped 
1144 
mode is used when a cartridge/infusion set needs to be changed or 
1145 
when disconnecting from the pump as for showering. Stopped mode 
1146 
is also used when switching from the study pump to an alternative 
1147 
form of insulin administration. 
1148 
o How to start a new sensor and connect the AP system with the CGM 
1149 
receiver. 
1150 
o How to calibrate the CGM unit as usual via the CGM receiver unit. 
1151 
o How to access the CGM trace and insulin delivery plot on the AP user 
1152 
interface. 
1153 
o How to perform a pump site change when using the system. 
1154 
o How to activate the meal screen of the system any time insulin will be 
1155 
given with a meal or snack or any time additional correction insulin is 
1156 
desired. 
1157 
o How the Hypoglycemia and Hyperglycemia color coding functions in 
1158 
Pump mode. The coding will activate per the safety system, and 
1159 
audible alerts will be sounded.  
1160 
o How to inform the system of hypoglycemia treatment via the 
1161 
hypoglycemia treatment button on the AP user interface. 
1162 
o How to assess whether remote monitoring is working. 
1163 
o The subject and diabetes care partner will be assessed for 
1164 
understanding of the system interface and how the to react to any 
1165 
messages on the AP system. 
1166 
o The subject and diabetes care partner will be given a printed User 
1167 
Manual as a reference. 
1168 
 Once all questions are answered, the subject will then be primarily 
1169 
responsible for using the system, with the study team serving as back-up 
1170 
when needed.  
1171 
 The subject and diabetes care partner will be re-educated as needed until they 
1172 
are able to complete all system-related tasks on the AP Training (APPENDIX 
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A-15). 
1174 
 
1175 
The subject may be discharged after all training and monitoring is successfully 
1176 
completed. The subject must be able to complete system-related tasks 
1177 
independently to be eligible to continue in the study.   
1178 
 
1179 
Eligible subjects will be provided with the following: 
1180 
 Subjects will receive sufficient device supplies to use the AP system at home 
1181 
for one week with the study pump and study CGM.  
1182 
 Subjects will also receive a study emergency kit for the treatment of low or 
1183 
high blood glucose (contents described in APPENDIX A-19).  
1184 
 Subjects will also be provided with a study blood ketone meter and test strips.  
1185 
All study blood ketone meters will be QC tested with at least two different 
1186 
concentrations of control solution prior to use.  A tested meter will not be 
1187 
used in a study if it does not read within the target range at each 
1188 
concentration per manufacturer labeling.   
1189 
 The subject will continue to perform 4-6 SMBG measurements daily 
1190 
(recommended before meals, about 2 hours after meals and at bedtime), and 
1191 
as needed to calibrate the CGM or follow the Outpatient Hypoglycemia, 
1192 
Hyperglycemia and Ketone Treatment Instructions.  Additional fingersticks 
1193 
may be obtained, if desired.   
1194 
 The subject will be asked to check fingerstick ketone levels per the 
1195 
Outpatient Hypoglycemia, Hyperglycemia and Ketone Treatment 
1196 
Instructions. 
1197 
 
1198 
5. Home Use with the AP system in Pump Mode 
1199 
Eligible subjects will then use the AP system at home in Pump mode, connected to 
1200 
the study CGM and study pump.  
1201 
 Remote monitoring will be available during this period for the purposes of 
1202 
data collection and assessment of system performance by study clinicians or 
1203 
engineers.  
1204 
 Study staff will contact the subject daily to answer any questions and enquire 
1205 
about any device complaints, adverse events, and whether the adverse event 
1206 
was related to system use.  
1207 
 Study staff will also check the number of SMBG tests entered on the AP 
1208 
system via remote monitoring and will remind the subject to perform 4-6 
1209 
SMBG daily. 
1210 
 If a study device malfunctions, it may be replaced. 
1211 
 CGM will be downloaded after one week at home.  
1212 
 The ability of the AP system to be remotely monitored in the subject’s daily 
1213 

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environment will also be assessed with daily checks of the remote monitoring 
1214 
site.  
1215 
 After completion of 1 week of AP use Pump mode at home, study staff will 
1216 
determine whether additional training and practice is needed and whether the 
1217 
subject will repeat all or portions of Visit 4 and 1 week of home use (up to 1 
1218 
time if needed) or proceed to Visit 5.  
1219 
 Subjects who failed to use the system for more than 80% of the time during 
1220 
this phase will be ineligible to continue in the study. 
1221 
 Subject’s that cannot be adequately monitored at least 75% of the time in 
1222 
their local environment by the final day of home use will be ineligible to 
1223 
continue in the study. 
1224 
 
1225 
 
1226 
6. Visit 5: USS Virginia Training 
1227 
Eligible subjects in the experimental group will participate in a training session in a 
1228 
monitored outpatient setting during which the subject and diabetes care partner will 
1229 
be trained to use the AP system +USS Virginia. The training will include an initial 
1230 
the AP system Closed Loop mode training followed by independent use. The study 
1231 
team will be in a different room during the independent use time, but immediately 
1232 
available as needed. 
1233 
 
1234 
Monitored Outpatient Setting Procedures: Identical to Visit 4. 
1235 
 
1236 
Visit 5 AP System Training Procedures: 
1237 
 Any questions regarding the study equipment will be answered. 
1238 
 The subject may eat meals and snacks and bolus for the meals and snack 
1239 
using the AP system and study pump per the home routine.  
1240 
 Study staff will meet with the subject and diabetes care partner for training on 
1241 
the use of the AP system +USS Virginia with the study pump and study 
1242 
CGM. 
1243 
The system will be reconfigured to allow Closed Loop operation.  
1244 
 The study MD or NP will confirm that the subject’s home pump parameters 
1245 
including carbohydrate ratios, correction factors, and basal rate pattern are 
1246 
reproduced in the AP settings.   
1247 
 The subject and care partner will be trained to use the AP system interface in 
1248 
Closed Loop mode and the pertinent portions of the User Manual will be 
1249 
reviewed; the training will continue until all questions are answered.  
1250 
 Study team members will train the subject and diabetes care companion in 
1251 
performing specific tasks including the following: 
1252 
o How to switch the system between Pump mode and Closed Loop 
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mode  
1254 
o How to start a new sensor when connected to the AP system in Closed 
1255 
Loop mode. 
1256 
o How to calibrate the CGM unit as usual via the CGM receiver unit. 
1257 
o How to perform a pump site change when using the AP system in 
1258 
Closed Loop mode. 
1259 
o How to activate the meal screen with the AP system in Closed Loop 
1260 
mode any time insulin will be given with a meal or snack or any time 
1261 
additional correction insulin is desired. 
1262 
o How the Hypoglycemia and Hyperglycemia color code functions in 
1263 
Closed Loop mode and how to respond to Red alerts.  
1264 
o How to inform the system of hypoglycemia treatment via the 
1265 
hypoglycemia treatment button on the AP system user interface. 
1266 
o How to switch to Exercise mode for activities such as exercise, 
1267 
driving, or operating heavy machinery. 
1268 
o The subject and diabetes care partner will be assessed for 
1269 
understanding of the system interface and how the to react to any 
1270 
messages on the system. 
1271 
o The subject and diabetes care partner will be given a printed User 
1272 
Guide as a reference. 
1273 
 Once all questions are answered, the subject will then be primarily 
1274 
responsible for using the system, with the study team serving as back-up 
1275 
when needed.  
1276 
 During the first part of the training session, the subject and diabetes care 
1277 
partner will be re-educated as needed until they are able to complete all 
1278 
system-related tasks on the AP Training (APPENDIX A-15) and study staff 
1279 
will be immediately present for training and to respond to system issues.   
1280 
 During the second part of the admission, study staff will be nearby and 
1281 
available, but will not immediately assist the subject in completing the 
1282 
described training tasks or responding to system issues (unless the study is 
1283 
stopped due to a problem that is unable to be resolved by the subject). 
1284 
Nursing staff will monitor the subjects during the entire admission, report 
1285 
fingerstick BG values to the medical team, and ensure that Outpatient 
1286 
Hypoglycemia, Hyperglycemia and Ketone Treatment Instructions are 
1287 
followed by the subject.  
1288 
 
1289 
The subject may be discharged after all of the of training and monitoring is 
1290 
successfully completed. The subject must be able to complete system-related tasks 
1291 
independently to be eligible to continue in the study.   
1292 
 
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Eligible subjects will be provided with the following: 
1294 
 Subjects will receive sufficient device supplies to use the AP system at home 
1295 
for four weeks with the study pump and study CGM.  
1296 
 Subjects will also have any supplies replenished as needed for the Study 
1297 
Emergency Kit for the treatment of low or high blood glucose. 
1298 
 The subject will continue to perform 4-6 SMBG measurements daily 
1299 
(recommended before meals, about 2 hours after meals and at bedtime), and 
1300 
as needed to calibrate the CGM or follow the Outpatient Hypoglycemia, 
1301 
Hyperglycemia and Ketone Treatment Instructions.  Additional fingersticks 
1302 
may be obtained, if desired.   
1303 
 The subject will be instructed to enter each SMBG in the AP system.  
1304 
 The subject will be asked to check fingerstick ketone levels per the 
1305 
Outpatient Hypoglycemia, Hyperglycemia and Ketone Treatment 
1306 
Instructions. 
1307 
 
1308 
7. Closed Loop Mode Home Use Trial Period 
1309 
After a successful training of Closed Loop mode in Visit 5, eligible subjects will 
1310 
then initiate a 3-5 day trial period of the AP system at home in Closed Loop mode, 
1311 
connected to the study CGM and study pump. Remote monitoring will be in place 
1312 
and designated study medical and technical staff will receive automated 
1313 
notifications when alert conditions are met. 
1314 
 The subject will be instructed to use the system in a Closed Loop mode 
1315 
except when no calibrated CGM sensor is available. Pump mode may be used 
1316 
during times of no active CGM.   
1317 
 The subject will be instructed to perform a fingerstick and switch the system 
1318 
to Exercise Mode prior to exercising or engaging in potentially dangerous 
1319 
activities such as driving or operating heavy machinery.  
1320 
 When exercising, the subject will be instructed to limit activity to no more 
1321 
than one hour at no more than a moderate level of intensity. 
1322 
 While using the AP system +USS Virginia system, the subject will be 
1323 
instructed to avoid deviating from his/her regular daily routine in regards to 
1324 
diet and exercise, aside from potentially limiting exercise duration and 
1325 
intensity as described above.   
1326 
 The subject will specifically be asked to avoid consuming more than 3 
1327 
alcoholic drinks in any one day. 
1328 
 The subject will also be instructed to avoid use of Closed-Loop mode during 
1329 
periods of illness with an elevated temperature >101.5 degrees Fahrenheit, 
1330 
periods of significant illness, or during periods of use of medications such as 
1331 
epinephrine (e.g. for the emergency treatment of a severe allergic reactions or 
1332 
asthma attack) and oral or injectable glucocorticoids.   
1333 

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1334 
After each day of system use, clinical staff will contact the subject and assess the 
1335 
subject’s system use via a review of the subject’s data from the previous day.  Study 
1336 
staff will also check the number of SMBG tests entered on The AP system and will 
1337 
remind the subject to perform 4-6 SMBG daily. The study team will determine 
1338 
whether the subject used the system in the appropriate mode at least 80% of the time 
1339 
during the day and night and whether remote monitoring was functional at least 75% 
1340 
of the time. Subjects who meet the success criteria on three days in a period of up to 
1341 
five days are eligible, at the discretion of the investigator, to continue to the next 
1342 
phase of the study. 
1343 
 
1344 
Subjects who do not meet the success criteria on three nights in a period of up to 
1345 
five days may, at the discretion of the investigator, repeat part or all of the Visit 5 
1346 
USS Virginia Training and then repeat the 3-5 day Closed Loop Mode Home Use 
1347 
Trial Period one time.        
1348 
 
1349 
8. Four-Week USS Virginia Closed Loop Home Use Period 
1350 
Eligible subjects will continue to use the AP system at home in Closed Loop 
1351 
configuration for a total of four weeks.  
1352 
 Study staff will continue to contact the subject daily for the first 5 days, then 
1353 
weekly to answer any questions and enquire about any device complaints, 
1354 
adverse events, and whether the adverse event was related to the AP system 
1355 
use. Study staff will also check the number of SMBG tests entered on the AP 
1356 
system and will remind the subject to perform 4-6 SMBG daily. 
1357 
 Study staff will check the number of SMBG entered on the AP system daily 
1358 
via remote monitoring and contact the subject is <4 SMBG are observed on 
1359 
any day.  
1360 
 CGM downloads will occur at week 2 and week 4.  
1361 
 If an alert is triggered, the staff that received the alert will log onto the remote 
1362 
monitoring system to evaluate the problem and follow it until a reasonable 
1363 
resolution has occurred. In some instances, this may require a call to the 
1364 
subject to resolve the condition. For example, if no data was received from 
1365 
the AP system and a technical alert was issued, the technical staff on call may 
1366 
determine that a call is needed to find out why the system was not 
1367 
communicating with remote monitoring. Attempts to contact the subject 
1368 
would be made multiple times for up to 30 minutes. If the subject is not able 
1369 
to be contacted within 30 minutes, the care partner would be contacted in a 
1370 
similar manner. We would have additional contact information provided by 
1371 
the subject at enrollment (e.g. home number, work number, other family 
1372 
members, etc.) that would also be tried. If a subject is unreachable for more 
1373 

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than 2 hours with these attempts on more than 2 occasions, s/he may be 
1374 
dropped from the study per investigator discretion. Other alerts may be 
1375 
triggered that resolve without the need for subject contact. For example, a 
1376 
hypoglycemia red light occurs and the medical staff gets a notification. If the 
1377 
medical staff observes on remote monitoring that the subject has 
1378 
acknowledge the alert, checked a BG and administered appropriate treatment, 
1379 
the medical staff may decide to observe that event via remote monitoring 
1380 
until the event is resolved.  
1381 
 
1382 
 
1383 
9. Visit 6: 8 hr Inpatient Assessment of Hypoglycemia Counterregulation and 
1384 
Symptom Awareness 
1385 
Within one week of completing either USS Virginia or sensor-augmented pump 
1386 
therapy at home, the subjects will undergo a final hypoglycemia induction using 
1387 
the home pump therapy with frequently sampled YSI glucose levels. Additionally, 
1388 
if a subject completes more than 1 week of either USS Virginia or sensor-
1389 
augmented pump therapy and subsequently withdraws from the study intervention, 
1390 
they will be asked to complete Visit 6 within one week of discontinuing the 
1391 
intervention. 
1392 
 
1393 
Procedures for this visit are identical to the Visit 3 inpatient procedures with the 
1394 
exception of no additional study glucometer and CGM training. 
1395 
 
1396 
The subject will have a post-intervention HbA1c assessed at the time of one of the 
1397 
scheduled blood sampling times and will complete the hypoglycemia 
1398 
questionnaires (Clarke Hypoglycemia Perception Awareness, Fear of 
1399 
Hypoglycemia II and a DiAs Usability questionnaire (DiAs users only) 
1400 
(APPENDIX A-5)). 
1401 
 
1402 
The subject will return all study equipment and unused supplies. 
1403 
 
1404 
If during the trial it becomes evident that the pump parameters of a subject may 
1405 
benefit from adjustment, the study physician will discuss this with the subject. 
1406 
This is possible because the USS is initialized with each subject’s established 
1407 
pump parameters and then works as add-on to normal pump therapy manipulating 
1408 
insulin delivery around the subject’s normal insulin rate. For example, overnight 
1409 
the basal rate module can attenuate basal rate smoothly to prevent hypoglycemia. 
1410 
If this happens systematically, this would suggest that the normal basal rate of the 
1411 
subject may be too high during certain periods. The study physician would 
1412 
therefore discuss such an observation with the subject upon discharge. 
1413 

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H. SAFETY MONITORING / RISK ANALYSIS 
1414 
 Glucose Monitoring Risk:  
1415 
 
1416 
The YSI method for glucose monitoring will be employed during the inpatient 
1417 
Visits 3 and 6 in order to have the most accurate method available during the 
1418 
Hypoglycemia Induction procedures. 
1419 
 
1420 
During outpatient procedures the Accu-Chek Aviva glucometer will be used. It is 
1421 
an FDA approved 510K Class II Medical Device (510K number K101299). 
1422 
Subjects and diabetes care partners will be trained on the use of the glucometer. 
1423 
 
1424 
 Hypoglycemic/Hyperglycemic and Ketone Risk:  
1425 
 
1426 
To decrease the risk of severe hypoglycemia or hyperglycemia, the following 
1427 
schedule for monitoring blood glucose concentrations during the inpatient 
1428 
procedures will be adhered to  
1429 
 Once IV access has been established, blood will be sampled for YSI glucose 
1430 
every 5-30 minutes. The frequency of blood draws for YSI sampling is 
1431 
dependent on the value of the previous sample, according to the following 
1432 
ranges: 
1433 
o BG >200: every 30 minutes 
1434 
o BG >100-200: every 15 minutes 
1435 
o BG ≤100 mg/dL:  every 5 minutes 
1436 
 Blood may be sampled for YSI glucose as needed for patient safety or to 
1437 
recheck a suspected erroneous value (e.g. dilute sample). 
1438 
 In the event of loss of IV access or loss of a functional YSI and need for 
1439 
continued subject monitoring, glucose measurements will be made on 
1440 
capillary whole blood using the study glucometer.  
1441 
 
1442 
The Inpatient Hypoglycemia Treatment and Inpatient Hyperglycemia and Ketone 
1443 
Treatment instructions (below) will be followed during the inpatient portions of 
1444 
the study at Visit 3 and Visit 6. 
1445 
 
1446 
Inpatient Hypoglycemia Treatment 
1447 
 Glucose <60 mg/dL will be treated orally with fast acting carbohydrate as 
1448 
needed until a glucose level of ≥80 mg/dL is achieved.  
1449 
 In the event that there is intravenous access and the subject is at risk for 
1450 
severe hypoglycemia, the subject will be treated with a ~2-3 mL/kg D10 
1451 
intravenous glucose bolus. Risk for severe hypoglycemia is defined as any of 
1452 
the following situations: 
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o Glucose <50 mg/dL 
1454 
o The subject is unable to cooperate with oral treatment of 
1455 
hypoglycemia 
1456 
o The glucose is dropping at a rate that may not respond adequately to 
1457 
oral treatment 
1458 
o The subject experiences symptoms of neuroglycopenia (e.g. lethargy, 
1459 
disorientation, confusion [disordered processing of information or 
1460 
communication], or inappropriate behavior)  
1461 
o The subject experiences symptoms of severe hypoglycemia (i.e. 
1462 
hypoglycemic seizure or loss of consciousness)  
1463 
 In the event that there is NO intravenous access and the subject is at risk for 
1464 
severe hypoglycemia (as defined above), the subject will be treated with 1 mg 
1465 
of glucagon subcutaneously or intramuscularly.  
1466 
o The drug will be reconstituted and administered per package 
1467 
insert/instructions.  
1468 
o Glucagon may be repeated as needed every 20 minutes to achieve 
1469 
glucose level ≥80 mg/dL. Once the subject is able to consume oral 
1470 
treatment, the subject will be treated orally with fast acting 
1471 
carbohydrate as needed until a glucose level of ≥80 mg/dL is 
1472 
achieved. Orange juice and milk will be avoided after glucagon 
1473 
administration.  
1474 
o Attempts will be made to reestablish intravenous access.  
1475 
 The Hypoglycemia Induction Admission will be stopped if the subject 
1476 
experiences a hypoglycemic seizure or loss of consciousness and only safety 
1477 
procedures will be continued. The study physician or nurse practitioner will 
1478 
take control over glucose sampling decisions in order to stabilize the 
1479 
subject’s glucose between 100-300 mg/dL and determine the appropriate 
1480 
subject disposition (i.e. home or medical facility).  
1481 
 
1482 
Inpatient Hyperglycemia and Ketone Treatment 
1483 
 If the subject’s glucose is >300 mg/dL or β–hydroxybutyrate level is ≥0.6 
1484 
mmol/L on admission, the subject will be stabilized per the procedures 
1485 
below. The subject will continue to be monitored until a glucose level 
1486 
between 100-300 mg/dL and β–hydroxybutyrate measurement <0.6 mmol/L 
1487 
has been achieved (or the subject is discharged to an appropriate medical 
1488 
team).  
1489 
 Subsequently, glucose >300 mg/dL for >2 hours or glucose ≥400 mg/dL at 
1490 
any time will prompt discontinuation of the Hypoglycemia Induction 
1491 
Admission. 
1492 
 β–hydroxybutyrate will be assessed hourly while the glucose is ≥250 mg/dl 
1493 

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or the β–hydroxybutyrate level is ≥0.6 mmol/L.  
1494 
 If the glucose is >300 mg/dL and β–hydroxybutyrate level is <0.6 mmol/L, 
1495 
corrective action will be taken only after it has been at least 90 minutes from 
1496 
the last subcutaneous insulin dose. Specifically, the subject will be asked to 
1497 
bolus with his/her pump an amount of corrective insulin that will bring 
1498 
him/her to a target glucose of 120 mg/dL. 
1499 
 If the β–hydroxybutyrate level is ≥0.6 mmol/L, the cause of the elevated 
1500 
ketone level will be investigated (e.g. pump or pump site malfunction). 
1501 
Additional insulin may be administered either via insulin syringe or via a new 
1502 
pump site. The amount of insulin administered will be calculated using the 
1503 
subject’s insulin sensitivity factor and a target glucose of 120 mg/dL.   
1504 
 If the β–hydroxybutyrate level is ≥1.5 mmol/L, the Hypoglycemia Induction 
1505 
Admission will be stopped and the study MD or NP will take control of the 
1506 
subject's insulin dosing. The cause of the elevated ketone level will be 
1507 
investigated (e.g. pump or pump site malfunction). If the subject's home 
1508 
parameters are not felt to be working adequately due to hyperglycemia, 
1509 
ketonemia, or other factors (e.g. intercurrent illness), the study MD or NP 
1510 
will administer corrective insulin either via insulin syringe or via a new pump 
1511 
site using an ISF determined to be appropriate for the setting and a goal 
1512 
glucose of 120 mg/dL. The subject will continue to be monitored until a 
1513 
glucose level between 100-300 mg/dL and β–hydroxybutyrate measurement 
1514 
<0.6 mmol/L has been achieved (or the subject is discharged to an 
1515 
appropriate medical team).  
1516 
 
1517 
The Outpatient Hypoglycemia, Hyperglycemia and Ketone Treatment instructions 
1518 
will be followed during Visit 4 and 5 and at any time that the study pump is in use. 
1519 
The treatment guidelines are attached in APPENDIX A-12. 
1520 
 
1521 
 Calibration of CGM Risk:  
1522 
 
1523 
During the portions of the study when CGM is used, subjects should calibrate the 
1524 
CGM with fingerstick values before meals and at bedtime and no less than every 
1525 
12 hours.  
1526 
 
1527 
 Sterilization Risk:  
1528 
 
1529 
Study equipment cannot be sterilized in an autoclave. Cleaning instructions 
1530 
for study equipment provided to study the subject are provided below. 
1531 
 
1532 
 Device Reuse Risk 
1533 

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1534 
The Dexcom Gen 4 is labeled for single use only. The sensor (the component of 
1535 
the system that enters the skin) will be single use only. The transmitter and 
1536 
receiver will be reused after cleaning as described below. The transmitter is 
1537 
attached to the sensor but does not enter the skin and the receiver is a hand held 
1538 
device. The transmitter and receiver will be cleaned adhering to Dexcom 
1539 
Professional Cleaning Instructions described below. Subjects will be informed 
1540 
that the FDA has approved these devices for single use and that by using them 
1541 
among multiple patients, bloodborne pathogens (i.e. Hepatitis B) may be spread 
1542 
through the use of multiple users.  
1543 
 
1544 
Dexcom CGM Cleaning Procedure: Healthcare professionals must clean and 
1545 
disinfect the transmitter before providing to each user. Use caution when handling 
1546 
products worn or handled by another person. Wear personal protective equipment 
1547 
as appropriate (gloves, protective goggles, lab coat, etc.). Clean the transmitter 
1548 
before disinfecting. Cleaning the transmitter removes dirt from the surface of 
1549 
the transmitter, but it does not kill bacteria or viruses.  
1550 
 
1551 
Products: 
1552 
1. Clorox Healthcare Bleach Germicidal Cleaner (EPA registration number 
1553 
56392-7) – spray bottle and pourable gallon size. 
1554 
2. Dispatch Hospital Cleaner Disinfectant Towels with Bleach (EPA 
1555 
registration number 56392-8). 
1556 
3. Nylon bristled brush 
1557 
4. Low-lint wipes 
1558 
 
1559 
Cleaning Instructions: 
1560 
1. Prepare a soaking container by adding enough Clorox Healthcare Bleach 
1561 
Germicidal Cleaner solution to submerge a transmitter.  
1562 
2. Place the transmitter with the contact (metal circles) side down on an 
1563 
absorbent wipe or clean surface.  
1564 
3. Hold the Clorox Healthcare Bleach Germicidal Cleaner spray bottle 6-8 
1565 
inches from unit and dispense two sprays on surface. 
1566 
4. Flip the transmitter to expose the contacts (metal circles). 
1567 
5. Hold Clorox cleaner spray bottle 6-8 inches from unit and dispense two 
1568 
sprays on surface. 
1569 
6. Using nylon brush, scrub the transmitter on all sides for 30 seconds. 
1570 
7. Submerge transmitter into prepared Clorox Healthcare Bleach Germicidal 
1571 
Cleaner for one minute. 
1572 
8. Remove transmitter and rinse under flowing tap water for ten seconds. 
1573 
9. Wipe transmitter with a cloth until completely dry. 
1574 

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1575 
Disinfecting Instructions: 
1576 
1. Prepare a soaking container by adding enough Clorox Healthcare Bleach 
1577 
Germicidal Cleaner solution to submerge a transmitter.  
1578 
(DO NOT USE SOLUTION USED IN CLEANING PROCEDURE.) 
1579 
2. Place the transmitter with the contact (metal circles) side down on an 
1580 
absorbent wipe or clean surface.  
1581 
3. Remove a pre-saturated Dispatch Hospital Cleaner Disinfectant Towel 
1582 
with Bleach from its packaging. 
1583 
4. Fold the Dispatch Towel into 2x2 inch square. 
1584 
5. Wipe all surfaces of the transmitter by passing over the transmitter by 
1585 
passing over the transmitter surface in one direction and then back in the 
1586 
opposite direction (back and forth means two passes). 
1587 
6. Turn over the Dispatch Towel to use a clean side for a second back and 
1588 
forth wipe. 
1589 
7. Refold the Dispatch Towel to use a clean side for a third back and forth 
1590 
wipe 
1591 
8. Turn over the Dispatch Towel to use a clean side for a fourth back and 
1592 
forth wipe. 
1593 
9. Keep track to be sure you wiped four times back and forth for a total of 
1594 
eight passes and that the transmitter surfaces are covered with disinfectant. 
1595 
10. Place the transmitter on a clean non-porous surface and allow the 
1596 
disinfectant to contact it for one minute. 
1597 
11. Place the transmitter into prepared Clorox Healthcare Bleach Germicidal 
1598 
Cleaner for one minute. 
1599 
12. Remove transmitter and rinse under flowing tap water for ten seconds. 
1600 
13. Wipe transmitter with a low lint, absorbent cloth until completely dry. 
1601 
 
1602 
 
1603 
 
1604 
The Accu-Chek Combo System is labeled for single-patient use. The Accu-Chek 
1605 
Combo system is comprised of the Accu-Chek Spirit Insulin Pump and the Aviva 
1606 
Combo Device. The Aviva Combo device when used as a glucometer will be 
1607 
single patient use at all times.  The Accu-Chek Spirit Insulin Pump itself is 
1608 
handheld and is not a glucometer. The subject interactions are primarily with the 
1609 
AP system interface and the Aviva Combo device, not with the Accu-Chek Spirit 
1610 
Insulin Pump menu interface itself. The Accu-Chek Spirit Insulin Pump handheld 
1611 
device will be reused after cleaning with Super Sani-Cloth (EPA registration 
1612 
number 9480-4). Do not clean/disinfect the pump when the reservoir and infusion 
1613 
set are connected to the insulin pump. All infusion set equipment will be single 
1614 
patient use only (infusion set insertion kits, tubing, cartridges etc.) Equipment will 
1615 

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be stored in a clean zipped bag. 
1616 
 
1617 
 
1618 
Hb1Ac Risk: The University of Virginia central labs have College of American 
1619 
Pathologist (CAP) and the Clinical Laboratory Improvement Amendments 
1620 
(CLIA) certifications. While the central lab is not NGSP certified, the calibrators 
1621 
for the HbA1c assay are traceable to NGSP. The equipment (Tosoh G7) is NGSP 
1622 
certified.  
1623 
 
1624 
 Misuse Risk: 
1625 
 
1626 
CGM training: 
1627 
Subjects will be introduced to the CGM by a qualified member of the study team. 
1628 
The subject will be instructed how the device is inserted, calibrated and removed. 
1629 
Subject will be trained how to upload the CGM. The subject will verbalize 
1630 
understanding of how the device is used, how to insert the device, how to calibrate 
1631 
the device and how to remove the device to the study team. The subject, with the 
1632 
guidance of the study team, will then insert the sensor and begin wearing the 
1633 
CGM. The study team will confirm that all questions have been answered and that 
1634 
the subject has understood the training. The subject will be given a contact sheet 
1635 
containing phone numbers for the study team to call with any questions 24 hours 
1636 
per day. 
1637 
Study Glucometer training: 
1638 
The Accu-Chek Aviva Combo will be used throughout the study as the study 
1639 
glucometer. Subjects will be trained on that device.  At the training session, study 
1640 
staff will demonstrate proper use of the meter as described in the user manual. The 
1641 
subject will then be required to demonstrate proficiency on the use of the device. 
1642 
The subject will be instructed to wash their skin with warm water and a clean 
1643 
towel or with an alcohol swap and allowed to dry prior to obtaining fingerstick 
1644 
values. The subject will be instructed to obtain a fingerstick, avoiding alternative 
1645 
sites, when obtaining blood values. The first drop will be discarded. The second 
1646 
hanging drop will be used to measure the glucose level. QC will be completed 
1647 
prior to subject receiving the study glucometer and when study glucometer results 
1648 
are suspect. The study team will confirm that all questions have been answered 
1649 
and that the subject has understood the training. 
1650 
Insulin Pump training: 
1651 
The training with the Accu-Chek Spirit Insulin Pump is part of the Visit 4 training 
1652 
visit and will occur with a qualified clinical member of the study team.  
1653 
 
1654 
Visit 4 Study Pump Training Procedures: 
1655 

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 The subject and the care partner will be fully instructed on the study 
1656 
insulin pump. A qualified staff member will conduct the training and in 
1657 
particular discuss differences from their home pump in important aspects 
1658 
such as calculation of insulin on board and correction boluses. Additional 
1659 
topics not limited to but may include: site initiation, cartridge/priming 
1660 
procedures, setting up the pump, changing batteries, navigation through 
1661 
menus, bolus procedures including stopping a bolus, pairing procedures 
1662 
with the meter remote, etc. 
1663 
 The study team will assist the subject in study pump infusion site initiation 
1664 
and will start the subject on the study pump. The study pump will be 
1665 
programmed with the subject’s usual basal rates and pump parameters. 
1666 
The subject’s personal pump will be removed. 
1667 
 The subject will be supervised with the study pump during at least one 
1668 
meal bolus to ensure subject understanding of the pump features. 
1669 
 The subject may eat meals and bolus for the meals using the study pump 
1670 
per the home routine.  
1671 
 The subject and diabetes care partner will be encouraged to review the 
1672 
literature provided with the pump, infusion sets, and meter remote after the 
1673 
training is completed. 
1674 
 Once the subject is adequately trained on the study pump, study staff will 
1675 
meet with the subject and diabetes care partner for training on the use of 
1676 
the AP system with the study pump and study CGM. 
1677 
 
1678 
AP system training: 
1679 
The AP system training occurs during both the Visit 4 and Visit 5 training 
1680 
sessions with a qualified clinical member of the study team and with the User 
1681 
Manual in hand (APPENDIX A-13).  
1682 
 
1683 
Visit 4 AP System Training Procedures: 
1684 
 Prior to initial use, the system will be initialized by a study team member 
1685 
with the subject’s individual parameters, including carbohydrate ratio, 
1686 
correction factor, and basal rate pattern. The settings will be confirmed by the 
1687 
study physician or NP. 
1688 
 The subject and care partner will be taught how to unpair the study pump 
1689 
from the meter remote and how to turn off the meter Bluetooth. The meter 
1690 
remote will continue to be used as a glucometer for the remainder of the 
1691 
study. (When there is no Bluetooth connection to the meter remote, the 
1692 
subject’s basal rate pattern is still administered according to the 
1693 
preprogrammed basal rates on the study pump.)  
1694 
 All study equipment including the AP system cell phone, insulin pump, and 
1695 

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CGM receiver will be set using an atomic clock as a reference.  
1696 
 The subject will be taught how to initiate Pump mode on the AP. Once Pump 
1697 
mode is activated, the system will take control of the insulin pump and will 
1698 
direct the administration of insulin according to the subject’s usual basal rate 
1699 
pattern. 
1700 
 The meal screen on the AP will be introduced and the subject will be 
1701 
supervised during at least one meal bolus. 
1702 
 The subject and care partner will be trained to use the AP interface and the 
1703 
pertinent portions of the User Manual will be reviewed; the training will 
1704 
continue until all questions are answered.  
1705 
 Study team members will train the subject and diabetes care companion in 
1706 
performing specific tasks including the following: 
1707 
o How to switch the system between Pump mode (with the AP system 
1708 
in control of delivering preprogrammed basal insulin) and Stopped 
1709 
mode (with the study insulin pump in control of delivering 
1710 
preprogrammed basal insulin) depending on circumstances. Stopped 
1711 
mode is used when a cartridge/infusion set needs to be changed or 
1712 
when disconnecting from the pump as for showering. Stopped mode 
1713 
is also used when switching from the study pump to an alternative 
1714 
form of insulin administration. 
1715 
o How to start a new sensor and connect the AP system with the CGM 
1716 
receiver. 
1717 
o How to calibrate the CGM unit as usual via the CGM receiver unit. 
1718 
o How to access the CGM trace and insulin delivery plot via the Plots 
1719 
button on the AP user interface. 
1720 
o How to perform a pump site change when using the AP system. 
1721 
o How to activate the meal screen of the system any time insulin will be 
1722 
given with a meal or snack or any time additional correction insulin is 
1723 
desired. 
1724 
o How the Hypoglycemia and Hyperglycemia color code functions in 
1725 
Pump mode. The colors will activate per the safety system, and 
1726 
audible alerts will be sounded.  
1727 
o How to inform the system of hypoglycemia treatment via the 
1728 
hypoglycemia treatment button on the AP user interface. 
1729 
o How to assess whether remote monitoring is working. 
1730 
o The subject and diabetes care partner will be assessed for 
1731 
understanding of the system interface and how the to react to any 
1732 
messages on the AP system. 
1733 
o The subject and diabetes care partner will be given a printed User 
1734 
Manual as a reference. 
1735 

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 Once all questions are answered, the subject will then be primarily 
1736 
responsible for using the system, with the study team serving as back-up 
1737 
when needed.  
1738 
 Subjects will be provide a copy of the AP system manual.  
1739 
 The subject and diabetes care partner will be re-educated as needed until they 
1740 
are able to complete all system-related tasks on the AP Training (APPENDIX 
1741 
A-15). 
1742 
 
1743 
Visit 5 AP system Training Procedures: 
1744 
 Any questions regarding the study equipment will be answered. 
1745 
 The subject may eat meals and snacks and bolus for the meals and snack 
1746 
using the AP system and study pump per the home routine.  
1747 
 Study staff will meet with the subject and diabetes care partner for training on 
1748 
the use of the AP system+USS Virginia with the study pump and study 
1749 
CGM. 
1750 
The system will be reconfigured to allow Closed Loop operation.  
1751 
 The study MD or NP will confirm that the subject’s home pump parameters 
1752 
including carbohydrate ratios, correction factors, and basal rate pattern are 
1753 
reproduced in the settings.   
1754 
 The subject and care partner will be trained to use the AP interface in Closed 
1755 
Loop mode and the pertinent portions of the User Manual will be reviewed; 
1756 
the training will continue until all questions are answered.  
1757 
 Study team members will train the subject and diabetes care companion in 
1758 
performing specific tasks including the following: 
1759 
o How to switch the system between Pump mode and Closed Loop 
1760 
mode depending on circumstances.  
1761 
o How to start a new sensor when connected to the AP system in Closed 
1762 
Loop mode. 
1763 
o How to calibrate the CGM unit as usual via the CGM receiver unit. 
1764 
o How to perform a pump site change when using the AP system in 
1765 
Closed Loop mode. 
1766 
o How to activate the meal screen with the AP system in Closed Loop 
1767 
mode any time insulin will be given with a meal or snack or any time 
1768 
additional correction insulin is desired. 
1769 
o How the Hypoglycemia and Hyperglycemia color code functions in 
1770 
Closed Loop mode and how to respond to Red alerts.  
1771 
o How to inform the system of hypoglycemia treatment via the 
1772 
hypoglycemia treatment button on the AP user interface. 
1773 
o How to switch to Exercise mode for activities such as exercise, 
1774 
driving, or operating heavy machinery. 
1775 

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o The subject and diabetes care partner will be assessed for 
1776 
understanding of the system interface and how the to react to any 
1777 
messages on the system. 
1778 
o The subject and diabetes care partner will be given a printed User 
1779 
Guide as a reference. 
1780 
 Once all questions are answered, the subject will then be primarily 
1781 
responsible for using the system, with the study team serving as back-up 
1782 
when needed.  
1783 
 During the first half of the training session, the subject and diabetes care 
1784 
partner will be re-educated as needed until they are able to complete all 
1785 
system-related tasks on the AP Training Checklist and study staff will be 
1786 
immediately present for training and to respond to system issues.   
1787 
 During the last half of the admission, study staff will be nearby and available, 
1788 
but will not immediately assist the subject in completing the described 
1789 
training tasks or responding to system issues (unless the study is stopped due 
1790 
to a problem that is unable to be resolved by the subject). Nursing staff will 
1791 
monitor the subjects during the entire admission, report fingerstick BG values 
1792 
to the medical team, and ensure that Outpatient Hypoglycemia, 
1793 
Hyperglycemia and Ketone Treatment Instructions are followed by the 
1794 
subject. 
1795 
 
1796 
The subject may be discharged after all of training and monitoring is 
1797 
successfully completed. The subject must be able to complete system-related 
1798 
tasks independently to be eligible to continue in the study. 
1799 
 
1800 
 Risks of blood sampling collection, contamination from sampling techniques 
1801 
 Hand washing with either soap & water or waterless hand sanitizer will 
1802 
be used prior to caring for the study subject. Gloves will be worn during 
1803 
blood sample collection and processing. Medical personnel will 
1804 
continue to practice hygiene for the patient's protection (i.e. hand 
1805 
washing, changing gloves frequently, disposing needles properly). 
1806 
Gloves will be removed and hands washed prior to leaving and upon 
1807 
return to the subject’s room. Soiled linen will be changed to minimize 
1808 
the transfer of pathogenic organisms. 
1809 
 Study personnel with direct subject contact are required to complete 
1810 
Blood borne Pathogens and Infection Control training annually. 
1811 
 
1812 
Medical Personnel Training at All Study Sites 
1813 
All study nurses will be currently licensed RNs or Nurse Practitioners. All RNs that are 
1814 

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employed by the study are oriented to the care of the T1D research subject. Certification 
1815 
of their skill level is supervised by the study team. Other medical personnel may be 
1816 
licensed Emergency Medical Technicians. All medical personnel who will have direct 
1817 
contact with the study subject have current certification in Basic Life Support including 
1818 
CPR and AED. Study physicians will be available during the inpatient procedures and 
1819 
outpatient training sessions during the trial. A designated MD or NP will be on call to 
1820 
receive automated alerts when remote monitoring is in place. 
1821 
I. STOPPING RULES 
1822 
Stopping Rules for Subjects during the Visit 3 and Visit 6 Inpatient Assessment of 
1823 
Hypoglycemia Counterregulation and Symptom Awareness (that may result in 
1824 
stopping the entire study): 
1825 
 Hypoglycemic seizure 
1826 
 Loss of consciousness 
1827 
 Diabetic ketoacidosis (DKA) 
1828 
Subjects who were not able to complete the study for reasons other than a serious adverse 
1829 
event (i.e. hypoglycemic seizure, etc.) will be permitted to repeat the inpatient session. 
1830 
 
1831 
Stopping Rules for Subjects during the Visit 3 and Visit 6 Inpatient Assessment of 
1832 
Hypoglycemia Counterregulation and Symptom Awareness (that will not result in 
1833 
stopping the entire study): 
1834 
 Presence of a febrile or vomiting illness within 24 hours of the admission 
1835 
 Positive urine pregnancy test 
1836 
 Temperature ≥99.5ºF (≥37.5ºC) 
1837 
 Fingerstick glucose >300 mg/dL or fingerstick ketone level ≥0.6 mmol/L during 
1838 
Admission Readiness Assessment 
1839 
 Glucose >300 mg/dL for >2 hours 
1840 
 Glucose ≥400 mg/dL at any time  
1841 
 Fingerstick β–hydroxybutyrate level ≥1.5 mmol/L 
1842 
 
1843 
 
1844 
Reason Inpatient Study Stopped 
Repeat Session? 
Equipment Failure or similarly related 
issues that invalidate study data 
Can repeat session 
Hyperglycemic Events that did not result in 
Serious Adverse Event 
Can repeat session 
Hypoglycemic Events that did not result in 
Serious Adverse Event 
Can repeat session 
PI initiated discontinuation of study due to 
patient or equipment concerns 
Can repeat session 
Serious or unanticipated adverse event 
deemed related to the study 
Unable to repeat session 

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1845 
Table 1:  Repeat Session Table 
1846 
Stopping Rules for Subjects during the outpatient portions of the study (that may 
1847 
result in stopping of the entire study): 
1848 
 Hypoglycemic seizure 
1849 
 Loss of consciousness due to hypoglycemia 
1850 
 Glucagon is required to treat hypoglycemia 
1851 
 Confirmed diabetic ketoacidosis per review of the medical record 
1852 
 Subject had a serious adverse event deemed related to the study. 
1853 
 
1854 
Stopping Rules for Subjects during the outpatient portions of the study (that will not 
1855 
result in stopping of the entire study): 
1856 
 Medical need for repeated doses of Tylenol / acetaminophen 
1857 
 Medical need for oral or injected glucocorticoids 
1858 
 Positive pregnancy test 
1859 
 At Visit 2 review of the blinded CGM shows that the CGM was functional 
1860 
≤80% of the time or LBGI ≤1.1  
1861 
 If after completion of 1 week of the AP system Pump mode home use, the 
1862 
investigator determines that the subject cannot be adequately monitored at least 
1863 
75% of the time in their local environment. 
1864 
 If after the Visit 4 Study Pump and the AP system Training, the subject is 
1865 
unable to complete system-related tasks independently.   
1866 
 If during Home Use with the AP system in Pump Mode the subject failed to use 
1867 
the system for more than 80% of the time during this phase or the subject could 
1868 
not be adequately monitored at least 75% of the time in their local environment 
1869 
by the final day of home use. 
1870 
 If after the Visit 5 USS Virginia Training, the subject is unable to complete 
1871 
system-related tasks independently.   
1872 
 If during a second Closed Loop Mode Home Use Trial Period the subject used 
1873 
the system in the appropriate mode <80% of the time during the day and night 
1874 
or the remote monitoring was functional <75% of the time.  
1875 
 If study staff are persistently unable to contact the subject or the care partner in 
1876 
a timely manner during the course of the study. 
1877 
 
1878 
Study Procedures will be put on hold during the outpatient portions of the study if: 
1879 
 Fingerstick β–hydroxybutyrate level ≥3.0 mmol/L 
1880 
 Abdominal pain 
1881 
 Vomiting illness 
1882 
 Unable to eat or drink 
1883 

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 Fever ≥101.5 ºF 
1884 
 Clinical need for Tylenol / acetaminophen 
1885 
 Significant illness 
1886 
 Use of epinephrine to treat a severe allergic reaction or asthma 
1887 
 
1888 
Stopping Rules for the Entire study: 
1889 
The study will be stopped if three similar AE’s occur that result in individual subjects 
1890 
stopping the study (except those identified above that will not stop the entire study) or if 
1891 
there are system communication failures, which may trigger revision of the system 
1892 
software.  Additionally, the Principal Investigator, IRB-HSR, the Data Safety Monitoring 
1893 
Board (DSMB), or sponsor may decide to stop the trial or part of the trial at any time. In 
1894 
this case, the Principal Investigator will promptly inform the subjects and assure 
1895 
appropriate therapy and follow-up. Additionally the Principal Investigator will notify the 
1896 
IRB and DSMB if the study is temporarily stopped. The pertinent regulatory authorities 
1897 
will be informed according to national regulations. The DSMB will meet to determine if 
1898 
changes to the protocol or system are needed prior to restarting the study and whether the 
1899 
study may be restarted. 
1900 
 
1901 
Early study stop will be documented and following information will be collected: 
1902 
 Date and cause of the ending 
1903 
 Description of any serious adverse event leading to the study ending 
1904 
 
1905 
A subject who does not complete the at least 1 week of the study intervention may 
1906 
be replaced. Available data will be exploited. 
1907 
 
1908 
In the case of an unanticipated adverse device effects (UADE), the overall study may be 
1909 
suspended while the problem is diagnosed and the PI investigates the UADE. If the PI 
1910 
determines that the UADE poses an unreasonable risk to subjects, the study should be 
1911 
suspended until this UADE can be resolved. If it cannot be resolved, the study should be 
1912 
terminated. Termination should occur no later than 5 working days after PI makes the 
1913 
decision. The result of the investigation and the PI’s decision to terminate the study shall 
1914 
be reported the site IRB, and the FDA per 21CFR 812.46(b) (2). The DSMB must 
1915 
determine if the UADE presents an unreasonable risk to subjects. If so, the DSMB must 
1916 
ensure that all investigations, or parts of investigations presenting that risk, are terminated 
1917 
as soon as possible but no later than 5 working days after the DSMB makes this 
1918 
determination and no later than 15 working days after first receipt notice of the UADE. 
1919 
 
1920 
The study may resume if the underlying problem can be corrected by a protocol or 
1921 
system modification that will not invalidate the results obtained prior to suspension. The 
1922 
IRB and DSMB will be notified if the study is stopped, and permission to resume will be 
1923 
obtained from the FDA, DSMB and IRB prior to restarting. 
1924 
 
1925 

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CATASTROPHIC EVENT PLAN 
1926 
The Outpatient Emergency Plan will go into effect should a catastrophic event occur 
1927 
during any monitored outpatient setting (Visit 4 or Visit 5). A catastrophic event is 
1928 
defined as any event that requires emergency treatment by medical professionals that 
1929 
exceed the expected parameters of the protocol. A copy of this plan will be located at the 
1930 
monitoring desk. Staff will be aware of its location at all times. 
1931 
 
1932 
Event 
RN Response 
Tech Response 
Respiratory Arrest 
1) Tell Tech to call 911 
2) Begin Basic Life Support 
Refer to Study Physician 
Cardiac Arrest 
1) Tell Tech to call 911 
2) Begin Basic Life Support 
Refer to Study Physician  
Severe Hypoglycemic Event as 
defined by hypoglycemia 
accompanied by 
unconsciousness or seizure 
1) Tell Tech to call 911 
2) Administer glucagon IM 
(described in Outpatient 
Hypoglycemia, 
Hyperglycemia and 
Ketone Treatment 
Instructions APPENDIX 
A-12) 
3) Remove study pump 
Refer to Study Physician  
Severe Hyperglycemic Event as 
defined by β-ketone level ≥3.0 
mmol/L 
 
1) Discuss correction dose of 
Refer to Study Physician  
insulin to administer s.c. via 
syringe with study M.D. 
2) Encourage p.o. water intake 
3) Remove study pump and 
start home insulin pump 
4) Go to nearest medical 
facility for evaluation and 
treatment. 
Table 2:  Outpatient Emergency Plan  
1933 
In the unlikely event of a disruption in 911 phone service, the sites will contact their local 
1934 
non-emergency number (e.g. Charlottesville-UVA-Albemarle Emergency 
1935 
Communications Center can be reached via their non-emergency number 434-977-9041). 
1936 
This number feeds into their main call area where 911 dispatchers are available 24/7. 
1937 
 
1938 
DATA AND SAFETY MONITORING PLAN 
1939 
Adverse Events, Unanticipated Problems, Protocol Violations and Data Breaches 
1940 
Reporting Table 
1941 

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Type of Event 
To whom will it 
be reported: 
Time Frame 
for 
Reporting 
How reported? 
Any internal event resulting in 
death that is deemed 
DEFINITELY related to (caused 
by) study participation 
(Note:  An internal event is one 
that occurs in a subject enrolled in 
a UVa protocol.) 
IRB-HSR, 
DSMB 
Within 24 
hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected 
adverse event.  
 
IRB-HSR, 
DSMB 
Within 7 
calendar days 
from the time 
the study 
team received 
knowledge of 
the event. 
 
Timeline 
includes 
submission of 
signed 
hardcopy of 
AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
For Device Studies:  Unanticipated 
adverse device effects (internal) 
IRB-HSR, 
DSMB 
Within 10 
day calendar 
days of the 
study team 
receiving 
knowledge of 
the event 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that are 
not adverse events or protocol 
violations  
This would include a Data Breach.   
IRB-HSR 
 
 
Within 7 
calendar days 
from the time 
the study 
team received 
knowledge of 
the event.  
Unanticipated Problem report 
form.  
 
http://www.virginia.edu/vprgs/i
rb/HSR_docs/Forms/Reporting_
Requirements-
Unanticipated_Problems.doc ) 
Protocol Violations  
The IRB-HSR only requires that 
MAJOR violation be reported, 
unless otherwise required by the 
sponsor 
 
 
IRB-HSR 
 
 
Within 7 
calendar days 
from the time 
the study 
team received 
knowledge of 
the event.  
 
Protocol Violation and 
Enrollment Exception 
Reporting Form 
 
 
http://www.virginia.edu/vprgs/i
rb/hsr_forms.html 
Go to 3rd bullet from the bottom 

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Data Breach  
The UVa 
Corporate 
Compliance and 
Privacy Office, a 
 
ITC:  if breach 
involves  
electronic data-  
 
UVa Police if 
breach includes 
such things as 
stolen 
computers.  
As soon as 
possible and 
no later than 
24 hours from 
the time the 
incident is 
identified. 
 
As soon as 
possible and 
no later than 
24 hours from 
the time the 
incident is 
identified. 
 
IMMEDIAT
ELY.  
 
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-
9741 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/secu
rity/reporting.html 
 
 
Phone- (434) 924-7166 
UVA PI- IDE 
Life-threatening and/or fatal 
unexpected events related or 
possibly related to the use of the 
investigational agent. 
FDA, DSMB 
Within 7 
calendar days 
of the study 
team learning 
of the event 
Form FDA 3500A (MedWatch) 
or narrative 
Serious, unexpected and related 
or possibly related adverse 
events 
FDA, DSMB 
Within 15 
calendar days 
after the 
study team 
receives 
knowledge of 
the event 
Form FDA 3500A (MedWatch) 
or narrative 
For Device Studies:  
Unanticipated adverse device 
effects (internal or external) 
FDA, DSMB 
Within 10 
working days 
of the study 
team 
receiving 
knowledge of 
the event 
Form FDA 3500A (MedWatch) 
or narrative 
All adverse events 
 
FDA, DSMB 
Annually 
IDE annual report 
UVA PI of MULTI-SITE TRIAL 
Serious, unexpected and related 
or possibly related adverse 
events 
All Research 
Sites 
Within 15 
days after 
the Overall 
PI receives 
knowledge 
IND/IDE Safety Report 
(Cover letter, copy of 
MedWatch/narrative) 

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of the event.   
 
 
For Device Studies:   
Unanticipated adverse device 
effects (internal or external) 
All Research 
Sites 
Within 15 
calendar 
days from 
the time the 
Overall PI 
receives 
knowledge 
of the event. 
Letter to Participating PIs, 
Copy of MedWatch or 
narrative 
Unanticipated Problem 
All Research 
Sites 
Within 15 
calendar 
days from 
the time the 
Overall PI 
receives 
knowledge 
of the event. 
Letter to Participating PIs, 
Copy of MedWatch or 
narrative 
 
1942 
 
1943 
J. ENDPOINTS 
1944 
This study is a randomized, controlled trial involving subjects with type 1 diabetes to test the 
1945 
effectiveness of the Unified Safety System (USS) Virginia closed-loop in preventing 
1946 
hypoglycemia compared with sensor-augmented pump (SAP) therapy. We will also evaluate 
1947 
the effectiveness of the control system (USS Virginia) at improving hypoglycemia 
1948 
counterregulation, hypoglycemia awareness, and overall glycemic control compared with 
1949 
versus SAP. To achieve this goal, we will conduct pre- and post-intervention inpatient 
1950 
assessments of hypoglycemia counterregulation and symptom awareness. For the 
1951 
interventions, subjects randomized to USS Virginia will participate in two training visits at a 
1952 
monitored outpatient setting for the step-wise deployment of the AP system at home in Pump 
1953 
mode followed by 4 weeks using AP at home in Closed Loop mode running USS Virginia. 
1954 
Subjects randomized to sensor-augmented pump therapy will complete 5 weeks of CGM 
1955 
with the home pump. 
1956 
 
1957 
The basic unit for analyses of hypoglycemia risk and occurrence is the glucose trace of 
1958 
an individual, i.e. a time-stamped series of CGM data recorded for each person. Summary 
1959 
characteristics and group-level analyses are derived after the individual traces are 
1960 
processed to produce meaningful individual markers of average glycemia and glucose 
1961 
variation.  
1962 
 
1963 
The following primary endpoint of reduction in hypoglycemia will be assessed by: 
1964 
1. LBGI from CGM during 1 week of blinded use versus during the last week of 
1965 

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intervention 
1966 
 
1967 
The secondary endpoints of improvement in counterregulatory response to hypoglycemia and 
1968 
hypoglycemia awareness at baseline versus follow-up will be assessed by: 
1969 
1. Peak epinephrine 
1970 
2. Epinephrine AUC 
1971 
3. Epinephrine increase over baseline 
1972 
4. Hypoglycemia symptom ratings  
1973 
5. Clarke Hypoglycemia Perception Awareness score  
1974 
6. Fear of hypoglycemia scores 
1975 
  
1976 
Additional secondary endpoints of reduction in hypoglycemia will be assessed by: 
1977 
1. CGM time <70 mg/dL and <50 mg/dL by retrofitted CGM and SMBG trace from 1 
1978 
week of blinded use versus the last week of intervention  
1979 
a. During 24 hours, and  
1980 
b. Overnight (11PM – 7AM)  
1981 
 
1982 
Additional secondary endpoints of improvement in glycemic control at baseline versus the 
1983 
last week of intervention will be assessed by: 
1984 
1. Time within target (70-180 mg/dL) over a 24 hour period 
1985 
2. Time within target range of 80-140 mg/dL overnight (11PM – 7AM), and 
1986 
3. Distribution of wake-up glucose levels at 7AM 
1987 
 
1988 
K. SUCCESS CRITERIA / GOAL 
1989 
As a general rule, a subject’s data will be considered useful for data analysis if the 
1990 
subject completes at least 1 week of study intervention with USS Virginia+AP system or 
1991 
SAP.   
1992 
L. STATISTICAL ANALYSIS PLAN 
1993 
Sample size determination is based on literature data (#3) and on results from our 
1994 
previous studies of hypoglycemia unawareness (#4)(#5). We estimate, conservatively, 
1995 
that the effect size of using the AP system+USS Virginia vs. CGM in terms of 
1996 
restoration of epinephrine response will be moderate ~0.35. Power calculations assuming 
1997 
=0.05, and power of 80% yield a required sample size of N=36 (using G*Power 3 
1998 
software [#5]). With this sample size, the power for finding significant effects on 
1999 
frequency and extent of hypoglycemia (Low BG Index [#6]) exceeds 0.9. Assuming a 
2000 
proportion of noncompliance R=20% for Intention-to-Treat (ITT) analysis (#7), 44 
2001 
completed subjects will adequately address the specific aims of this study. Per-protocol 
2002 
analysis will also be performed. In order to achieve 44 completed subjects, up to 70 
2003 

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subjects may sign consent given an expected screen failure, withdrawal and drop-out rate 
2004 
of ~40% due to the rigorous exclusion criteria and requirements imposed for the AP 
2005 
system use in the subject’s local environment. 
2006 
 
2007 
 
2008 
REFERENCES 
2009 
#1 Diabetes Research in Children Network (DirecNet) Study Group, Tsalikian E, 
2010 
Tamborlane W, Xing D, Becker DM, Mauras N, Fiallo-Scharer R, Buckingham B, 
2011 
Weinzimer S, Steffes M, Singh R, Beck R, Ruedy K, Kollman C. Blunted counterregulatory 
2012 
hormone responses to hypoglycemia in young children and adolescents with well-controlled 
2013 
type 1 diabetes. Diabetes Care, 32 (11):1954-1959, 2009. 
2014 
 
2015 
#2 Kovatchev BP, Cox DJ, Kumar A, Gonder-Frederick LA and WL Clarke. Algorithmic 
2016 
evaluation of metabolic control and risk of severe hypoglycemia in type 1 and type 2 
2017 
diabetes using self-monitoring blood glucose (SMBG) data. Diabetes Technol Ther, 5: 817-
2018 
828, 2003. 
2019 
 
2020 
#3 Ly TT, Hewitt J, Davey RJ, Lim EM, Davis EA, Jones TW. Improving epinephrine 
2021 
responses in hypoglycemia unawareness with real-time continuous glucose monitoring in 
2022 
adolescents with type 1 diabetes. Diabetes Care, 34:50-2, 2011 
2023 
 
2024 
#4 Cox DJ, Gonder-Frederick LA, Polonsky W, Schlundt D, Julian D, Kovatchev BP, Clarke 
2025 
WL. Blood Glucose Awareness Training (BGAT-II): Long term benefits.  Diabetes Care, 24: 
2026 
637-642, 2001. 
2027 
 
2028 
#5 Faul F, Erdfelder E, Lang A-G, & Buchner A. G*Power 3: A flexible statistical power analysis 
2029 
program for the social, behavioral, and biomedical sciences. Behavior Research Methods, 39, 
2030 
175-191, 2007. 
2031 
 
2032 
#6 Kovatchev BP, Cox DJ, Gonder-Frederick LA Young-Hyman D, Schlundt D, Clarke WL. 
2033 
Assessment of risk for severe hypoglycemia among adults with IDDM: Validation of the Low 
2034 
Blood Glucose Index. Diabetes Care 21: 1870-1875, 1998. 
2035 
 
2036 
#7 Lachin JM. Statistical considerations in the intent-to-treat principle. Control Clin 
2037 
Trials, 21:167-89, 2000. 
2038 
 
2039 
#8 Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
2040 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
2041 
frequency and associated symptoms. Diabetes Care, 18:517-22, 1995 
2042 
 
2043 
#9 Kovatchev BP, Otto E, Cox DJ, Gonder-Frederick LA, Clarke WL. Evaluation of a New 
2044 
Measure of Blood Glucose Variability in Diabetes. Diabetes Care, 29: 2433-2438, 2006. 
2045 
 
2046 
 
2047