Project Nightlight: Efficacy and System Acceptance of Dinner/Night vs. 24hr Closed Loop Control
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Sponsor: University of Virginia

 
 
ClinicalTrials.gov Cover Page 
 
NCT 02679287 
 
Title: Project Nightlight: Efficacy and System Acceptance of Dinner/Night vs. 24hr Closed 
Loop Control  
 
 
 
Date of Documents: 
Clinical Protocol 29 March 2018 
Informed Consent 06 August 2018 
 
Upload Date: 06 April 2020 
 

 
 
 
 
 
 
 
 
 
 
 
Project Nightlight: 
Efficacy and System Acceptance of Dinner/Night vs. 
24hr Closed Loop Control 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
School of Medicine 
Center for Diabetes Technology 
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Table of Contents 
CHAPTER 1 
INTRODUCTION ............................................................................................................. 3 
 
Background and Rationale .............................................................................................................. 3 
 
Preliminary Studies ......................................................................................................................... 4 
 
Study Objective ............................................................................................................................... 6 
 
Closed-Loop Control System ........................................................................................................... 6 
 
Protocol Overview ........................................................................................................................... 7 
CHAPTER 2 
SUBJECT ENROLLMENT AND STUDY INITIATION ............................................................ 10 
 
Study Population ........................................................................................................................... 10 
 
Eligibility and Exclusion Criteria .................................................................................................... 10 
 
Informed Consent, Eligibility Assessment and Baseline Data Collection ...................................... 12 
CHAPTER 3 
STUDY PROTOCOL ........................................................................................................ 13 
 
Visit 1 – Screening ......................................................................................................................... 13 
 
Randomization .............................................................................................................................. 14 
 
Visit 2 – CGM Training and Run-In ................................................................................................ 15 
 
Visit 3 - Study Pump Training and Run-In Period .......................................................................... 15 
 
Visit 4 – Closed Loop Training Visit ............................................................................................... 16 
 
Visit 5 - AP System Run-In phase: Home Use in Pump Only (Open Loop) Configuration ............. 17 
 
Visit 6 + Visit 7 + Visit 8 Washout Following Completion of the Each Study Phase ...................... 17 
 
Visit 9 - End of Study Visit ............................................................................................................. 18 
 
Study Procedures during SAP ........................................................................................................ 18 
 Study Procedures during USS + SAP(d) and USS + CLC(d) ............................................................. 18 
 Monitoring when the AP system is in Use during Visit 5, USS + SAP(d) and USS + CLC(d) ........... 19 
 Duration of Study .......................................................................................................................... 20 
CHAPTER 4 
CLOSED-LOOP CONTROL SYSTEM OPERATION AND SAFETY ........................................... 21 
 
Algorithm Details ........................................................................................................................... 21 
 
System Details ............................................................................................................................... 21 
 
Setup and Operation of the Closed-loop Control System ............................................................. 22 
 
Safety Measures ............................................................................................................................ 23 
CHAPTER 5 
ADVERSE EVENT REPORTING AND PROTOCOL MONITORING ........................................ 26 
 
Definition ....................................................................................................................................... 26 
 
Recording of Adverse Events ........................................................................................................ 26 
 
Reportable Device Issues .............................................................................................................. 27 
 
Definition of a Protocol Enrollment Exception ............................................................................. 27 
 
Definition of a Data Breach ........................................................................................................... 27 
 
Data Collection .............................................................................................................................. 27 
 
Reporting Serious or Unexpected Adverse Events ....................................................................... 31 
 
Data and Safety Monitoring Board ............................................................................................... 31 
 
Potential Risks and Side Effects..................................................................................................... 33 
 Study Stopping Criteria ................................................................................................................. 35 
CHAPTER 6 
STATISTICAL CONSIDERATIONS .................................................................................... 36 
 
Analysis Plan .................................................................................................................................. 36 
 
Sample Size.................................................................................................................................... 37 
 
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Chapter 1 INTRODUCTION 
 
 Background and Rationale 
As advancements in technology continue, we propose the use of the inControl Diabetes 
Management Platform for this protocol. It remains a smartphone-based, artificial pancreas 
platform that automatically controls insulin delivery with an advisory system that generates real-
time recommendations for meals, basal rates, bolus calculations and exercise decisions. This 
cloud based system provides real-time monitoring as well as retrospective analysis on data. The 
data generated are stored at an inControl Cloud permitting the research team and support 
networks to observe blood glucose values in real-time if needed. The insulin dosing strategies 
used in this device are the same strategies currently used in DiAs. This system is identical to the 
system approved by the FDA in IDE G150221/S002. 
 
In 2009 we initiated one of the first NIH studies dedicated to engineering and clinical testing of 
closed-loop control (CLC) of type 1 diabetes. Since then, we have achieved key milestones and 
derived conclusions which enabled further research in this rapidly growing field. Notably, we 
proposed the idea that the artificial pancreas is not a single all-in-one device but a network 
encompassing the patient in a digital treatment ecosystem that can offer and alter different 
treatment modalities in real time depending on the patient’s clinical state.  
This new notion was reflected in: (1) Our modular engineering design of CLC algorithms, which 
now allows various treatment modalities to be initiated and swapped without interruption; (2) 
The Diabetes Assistant (DiAs) – the first portable CLC hub using a smart phone to run control 
algorithms and specifically designed to be operated by the patient, which is now used in a 
number of outpatient studies in the U.S. and in Europe, and (3) The Unified Safety System (USS 
Virginia) – the first CLC algorithm engineered to adapt its mode of operation during the course of 
every night, first mitigating after-dinner hyperglycemia and then sliding the patient to a target 
morning glucose of 120mg/dl, thereby resetting his/her metabolic state for a new day. 
 
Using these technologies, we now propose to compare in a randomized cross-over trial the long-
term efficacy of three treatment modalities –  
 
SAP=sensor-augmented pump only  
 
USS+SAP (d)=SAP during day and CLC starting at dinner and continuing overnight 
 
USS+CLC (d)=24-hour Day and Night Closed Loop Control 
 
We plan to randomize up to 110 patients with type 1 diabetes into two different treatment 
sequences: 
Group A following the sequence SAPUSS+SAP(d)USS+CLC(d)USS+SAP(d), and  
Group B following the sequence USS+SAP(d)USS+CLC(d)USS+SAP(d)SAP.  
These treatment modality sequences are presented in the figure below, and are color coded to 
match the color-coding of active control modules relevant to each treatment modality presented 
in Figure 1:   
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Figure 1: Design of One 11-month Study Session 
 
Each treatment modality will continue for 8 weeks – sufficient time to address the following 
specific aims:   
SA1: Dinner/Night CLC achieved by USS+SAP(d) will be superior to SAP alone in terms of: 
(1) Improved HbA1c without increasing the risk for hypoglycemia; (2) Reduced incidence 
and risk for hypoglycemia overnight, and (3) Reduced fear of hypoglycemia and improved 
diabetes quality of life scores. 
SA2: CLC during the day achieved by USS+CLC(d) will preserve the benefits of USS+SAP(d) 
and will be superior to USS+SAP(d) in terms of: (1) Increased time within target range of 
70-180mg/dl during the day; (2) Reduced risk for hypoglycemia, particularly during and 
after exercise, and (3) Reduced postprandial glucose variability. 
SA3: CLC system acceptance evaluated by individual structured interviews and technology 
acceptance scores will be: (1) Superior, for USS+SAP(d) compared to SAP alone, i.e. adding 
USS in the evening and overnight will increase patients’ acceptance of CLC, and (2) 
Marginally inferior, for USS+CLC(d) compared to USS+SAP(d); i.e. some patients would 
prefer SAP alone during the day due to perceived increased system complexity. 
 
 Preliminary Studies 
This protocol benefits from extensive study of the Artificial Pancreas system with over 184,000 
hours of clinical use with various component structures. 
Two recent trials present examples particularly relevant to the proposed clinical studies:  
Efficacy and Safety of Overnight CLC in Children and Adolescents with Type 1 Diabetes (UVA and 
Stanford): In 2013, we tested USS Virginia to determine its overnight safety and efficacy in a 
summer-camp setting: 20 subjects were randomized to CLC using DiAs or SAP (sensor-augmented 
pump), completing 54 CLC and 52 SAP nights. On nights when DiAs was active for at least 6h, the 
median time spent in range was 73% for CLC vs. 55% for SAP, p=0.012. Less time was spent below 
70mg/dl on CLC vs. SAP, p<0.001; there were no hypoglycemic episodes below 60mg/dl on CLC.  
Figure 2 presents the data distributions on CLC vs. SAP across several BG ranges. The study 
concluded that USS Virginia is effective in improving time spent in range, as well as reducing 
nocturnal hypoglycemia in children and adolescents with type 1 diabetes in a summer camp 
setting.   
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Figure 2: % time within several glucose ranges during overnight closed-loop vs. sensor augmented pump in 
summer camps for children with type 1 diabetes 
 
Overnight Control in Adults with Type 1 Diabetes (UVA and Univ. of Padova): In this study, 10 
subjects spent 5 nights on USS Virginia vs. 5 nights on SAP, in random order. CLC resulted in over 
30mg/dl lower average BG and over 25% higher time within target range. The mean morning BG 
on CLC was 119.3mg/dl; thus the USS performed exactly to its design specification–reset BG to 
120mg/dl by 7AM (Figure 3).  
 
Figure 3: Glucose distribution during overnight closed-loop (blue) vs. sensor augmented pump (red) 
0
10
20
30
40
50
60
70
80
90
100
< 50
< 60
< 70
70 - 150
> 150
≥ 180
≥ 250
Percentage
Glucose range (mg/dl)
Sensor-augmented pump
Closed-loop control
Closed-loop
(mean; quartiles)
Sensor-augmented
pump (mean; quartiles)
Time of Night
22:00
00:00
02:00
04:00
06:00
70
110
150
180
250
300
07:00
Blood Glucose Level (mg/dl)
23:00
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Overnight glucose correlated with glucose control on the next day, r=0.52, p<0.01; peak BG and 
BG variability during the day (USS inactive) were improved after CLC nights as well. Details are 
given in the table below.  
 
Main Outcomes of this Study 
Sensor-Augmented Pump 
Closed-Loop Control 
P-value 
Average Blood Glucose at 7AM 
152.9 
119.3 
<0.001 
Average Blood Glucose (mg/dl) 
170.3 
139.0 
<0.001 
Percent time within 70-180mg/dl 
59.1% 
85.4% 
<0.001 
Percent time below 70mg/dl 
1.56% 
0.55% 
0.06 
These results support the significant glycemic benefits of using USS Virginia overnight and indicate strongly 
that control during days following well-controlled nights is correspondingly improved. Thus, evaluation of 
this system is warranted in long-term clinical trials with outcomes gauged by accepted metrics of glucose 
control. 
 
 Study Objective 
Overall, we expect to establish that a distinct overnight CLC modality (USS Virginia) combined 
with SAP therapy during the day is a viable precursor to future adaptable therapeutic schemes, 
achieving glycemic control that is superior to SAP alone and optimal balance between system 
complexity and perceived benefits.  
 
 Closed-Loop Control System 
A general description of the Artificial Pancreas Platform devices identified below will be used in 
the Closed-Loop Control System.  New generations of CGMs and insulin pumps with embedded 
inControl-AP could become available for inclusion in this trial and could be used providing these 
new developments do not change the core functionality of the system.  
 
For the inControl Platform, (see Figure 4-Panel A): 
• inControl Diabetes Management Platform – a smart-phone Artificial Pancreas medical 
platform; 
• CGM – study CGM connected to the AP using low power Bluetooth communication 
protocols;   
• Insulin Pump – insulin pump connected to AP system via wireless Bluetooth.   
• Remote Monitoring Server connected to inControl Cloud via 3G or local Wi-Fi network, 
and 
• Modular Closed-Loop Control Algorithm Running on the AP system, which is of Control-
to-Range (CTR) class  
 
We have successfully completed a pilot study of the Tandem t:slim X2 with Control-IQ 
Technology. This pilot study included 5 adults (mean HbA1c 6.5%) using the system between 36-
48 hours, and was successfully completed with 86% mean time in target range of 70-180 mg/dL 
and 2.8% median time below 70 mg/dL. The system maintained connectivity 98% of the intended 
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time in closed-loop. Given the positive results from this pilot study, we now plan to incorporate 
t:slim X2 with Control-IQ Technology in this protocol as well. 
 
For the Tandem-G6 configuration, (see Figure 4-Panel B): 
The Closed-Loop Control System contained in t-slim X2 with Control-IQ Technology is described in 
Master File MAF-2032/A003 and has been approved in G170255 and G170267. Control-IQ 
Technology is derived from inControl previously described in IDE# G160097, G160181, G150240 
and G140169/S010. The CLC is an “artificial pancreas” (AP) application that uses advanced closed 
loop control algorithms to automatically manage blood glucose levels for people with Type 1 
Diabetes. The system modulates insulin to keep blood glucose in a targeted range. The system 
components include the t:slim X2 with Control-IQ Technology and the Dexcom CGM G6 (Fig. 4-B). 
 
Figure 4. AP System Components: Panel A – G4+Roche pump configuration; Panel B – G6+Tandem Control IQ 
 
 Protocol Overview 
 Sample Size 
Up to 110 adult subjects age ≥18 to <70 years old will be enrolled so that approximately 76 
subjects complete the entire study at University of Virginia, allowing for up to 31% attrition rate 
due to the duration of the study protocol).  
 
 Protocol Summary  
For the proposed studies, the AP system will be deployed with different functionalities at 
different stages of the trial, resulting in variation in what the subject will be responsible for and 
what the system will drive. A trial outline is contained in Figure 1 and visits detailed in Figure 5. 
Study Phases without the AP system 
A 
B 
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CGM Run-in Phase:  Study participants will begin with a maximum 2 week run-in period during 
which they will have a CGM (i.e. sensor-augmented pump therapy or CGM+CSII) but otherwise be 
on their usual diabetes management with respect to BG monitoring, pump basal rates, insulin-to-
carbohydrate ratios and correction factors. This is necessary because some of the study 
participants will not have had experience with CGMs in the past.  
Study Pump Run-in Phase: All subjects will have a run-in period on the study pump of up to two 
week duration. Subjects who have had prior experience with the study pump may either skip this 
run-in phase or may require a shorter run-in period depending on their proficiency with the study 
pump. 
Sensor-Augmented Pump (SAP) Therapy: During this phase, the subject is on the study CGM and 
their personal insulin pump. There are no predictive or control algorithms. The subjects will 
administer basal and bolus insulin using their usual home insulin parameters. 
 
Study Phases with the AP System 
AP system Run-In Phase: Subjects who have not had recent use of the system (more than 
approximately 2 weeks of use in the past 6 months or more than 2 months of use in the past 
year) will complete an up to 2-week home use period with the full system in pump only (open 
loop) configuration where no closed loop algorithms are activated. Subjects who have had prior 
experience with the system as defined above will not be required to do Visit 5.  
 
USS+SAP (d): USS Virginia plus SAP during the day (d). Subjects will be using the study pump and 
CGM with the AP system in Pump mode (open loop only, no closed loop algorithms running). The 
subject will activate the USS Virginia Closed-Loop Control as early as pre-dinner but is expected to 
activate CLC by bedtime.  The subject will continue in Closed-Loop Control until the time of 
awakening in the morning. The USS will monitor CGM and insulin-on-board data and predicts the 
patient’s risk of hypoglycemia and adjust insulin delivery accordingly.  
 
USS+CLC (d): USS Virginia and Closed Loop Control over 24 hours. This arm will test fully-
integrated closed-loop control (CLC) system.  When hypoglycemia is predicted, the USS reduces 
basal rate insulin to prevent hypoglycemia, or issues an alert that signals that carbohydrates are 
required to treat hypoglycemia. The USS also generates alerts about correction bolus requests 
that are considered potentially dangerous, or meal bolus requests that require user approval 
prior to delivery.  
 
 
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Figure 5: Visit flow diagram 
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Chapter 2 SUBJECT ENROLLMENT AND STUDY INITIATION 
 Study Population 
We anticipate recruiting up to 110 subjects, ages ≥18 and <70 years. An equal number of males 
and females will be recruited, and all racial/ethnic groups will be eligible for participation. Based 
on our experience, we expect that approximately 76% in each arm will complete the study (N=64) 
and has been increased to account for inclusion of new devices. The randomization will aim to 
balance the age/gender distributions of the participants in the two groups and to match the 
groups by baseline HbA1c. 
 
 Eligibility and Exclusion Criteria 
 Eligibility 
To be eligible for the study, a subject must meet the following criteria at time of screening: 
• Clinical diagnosis, based on investigator assessment, of type 1 diabetes for at least one 
year and using insulin for at least 1 year and an insulin pump for at least 6 months 
• Criteria for documented hyperglycemia (at least 1 must be met): 
i. 
Fasting glucose ≥126 mg/dL  
ii. 
Two-hour OGTT glucose ≥200 mg/dL 
iii. 
HbA1c ≥6.5% documented  
iv. 
Random glucose ≥200 mg/dL with symptoms 
v. 
No data at diagnosis is available but the participant has a convincing history of 
hyperglycemia consistent with diabetes 
• Criteria for requiring insulin at diagnosis (1 must be met): 
i. 
Participant required insulin at diagnosis and continually thereafter 
ii. 
Participant did not start insulin at diagnosis but upon investigator review likely 
needed insulin (significant hyperglycemia that did not respond to oral agents) and 
did require insulin eventually and used continually 
iii. 
Participant did not start insulin at diagnosis but continued to be hyperglycemic, had 
positive islet cell antibodies – consistent with latent autoimmune diabetes in adults 
(LADA) and did require insulin eventually and used continually 
• Age ≥18 and <70 
• For females, not currently known to be pregnant; If female and sexually active, must 
agree to use a form of contraception to prevent pregnancy while a participant in the 
study.  A negative pregnancy test will be required for all premenopausal women who are 
not surgically sterile.  Subjects who become pregnant will be discontinued from the 
study. 
• Demonstration of proper mental status and cognition for the study 
• Currently using an insulin-to-carbohydrate ratio to calculate meal bolus sizes 
• Access to internet and/or cell phone service at home and work 
• Ability to access the Internet and upload study data. 
• An understanding of and willingness to follow the protocol and sign the informed consent 
 
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• Willingness to switch to lispro (Humalog) or aspart (Novolog) if using glulisine (Apidra). 
   
 Exclusion 
The presence of any of the following is an exclusion for the study: 
• Admission for diabetic ketoacidosis in the 12 months prior to enrollment 
• Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 months prior 
to enrollment  
• History of a seizure disorder (except hypoglycemic seizure), unless written clearance is 
received from a neurologist and not currently on a seizure medication  
• Cystic fibrosis  
• Coronary artery disease or heart failure, unless written clearance is received from a 
cardiologist or primary care provider 
• Pregnancy, breast-feeding, or intention of becoming pregnant over time of study 
procedures  
• A known medical condition that in the judgment of the investigator might interfere with 
the completion of the protocol such as the following examples: 
o Inpatient psychiatric treatment in the past 6 months  
o Presence of a known adrenal disorder 
o Abnormal liver function test results (Transaminase >2 times the upper limit of normal); 
testing required for subjects taking medications known to affect liver function or with 
diseases known to affect liver function 
o Abnormal renal function test results (calculated GFR <60 mL/min/1.73m2); testing 
required for subjects with diabetes duration of greater than 5 years post onset of 
puberty  
o Active gastroparesis 
o If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, lack of 
stability on the medication for the past month (except thyroid medication requires 2 
months) prior to enrollment in the study 
o Uncontrolled thyroid disease (TSH undetectable or >10 mlU/L); testing required within 
6 months prior to admission for subjects with a goiter, positive antibodies, or who are 
on thyroid hormone replacement, and within one year otherwise 
o Abuse of alcohol or recreational drugs 
o Infectious process not anticipated to resolve prior to study procedures (e.g. meningitis, 
pneumonia, osteomyelitis).  
o Uncontrolled arterial hypertension (Resting diastolic blood pressure >90 mmHg and/or 
systolic blood pressure >160 mmHg). 
o Oral steroids 
o Uncontrolled microvascular complications such as current active proliferative diabetic 
retinopathy defined as proliferative retinopathy requiring treatment (e.g. laser 
therapy) in the past 12 months. 
o A recent injury to body or limb, muscular disorder, use of any medication, any 
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  
• Basal Rates <0.1 units/hour or minimal total daily basal rates <2.40 units/day. 
• Use of the following drugs and supplements during the study:   
o Acetaminophen 
o Medications being taken to lower blood glucose, such as Pramlintide, Metformin, GLP-
1 Analogs such as Liraglutide, and SGLT-2 inhibitors intended to lower blood glucose. 
Subjects who are on these agents either intermittently or continuously prior to the 
trial or at the time of screening will be asked to consult with their personal care 
provider prior to determining whether they can discontinue these agents. 
o Beta-blockers or nutraceuticals intended to lower blood glucose may not be initiated 
during the trial. Subjects who are on beta-blockers or nutraceuticals intended to lower 
blood glucose at the time of enrollment may continue on those 
medications/supplements if the doses have been stable for ≥ 6 months.  
o Any other medication that the investigator believes is a contraindication to the 
subject’s participation 
 
 Informed Consent, Eligibility Assessment and Baseline Data Collection 
The study will be discussed with the subject. The subject will be provided with the Informed 
Consent Form to read and will be given the opportunity to ask questions.  If the subject agrees to 
participate, the Informed Consent Form will be signed. A copy of the consent form will be 
provided to the subject and another copy will be added to the subject’s chart. 
Written informed consent must be obtained from the subject prior to performing any study-
specific procedures that are not part of the subject’s routine care. 
Subjects will be evaluated for study eligibility through the elicitation of a medical history, 
documentation of a physical examination (by study personnel or local MD) and local laboratory 
testing if needed to screen for exclusionary medical conditions.  Subject exclusion will be at the 
discretion of the investigator based on study inclusion/exclusion criteria and lab results.     
 
 Historical Information and Physical Exam 
A history will be elicited from the subject and extracted from available medical records with 
regard to the subject’s diabetes history, current diabetes management, other past and current 
medical problems, past and current medications, and drug allergies.  A standard physical exam 
(including vital signs and height and weight measurements) will be either performed by the study 
investigator/ designee (study staff) or a physical exam from the subject’s personal physician 
within 6 months will be reviewed.   
 
 HbA1c 
HbA1c level will be measured at baseline using the method utilized by the clinic as part of patient 
care: DCA2000 or equivalent NGSP-certified point-of-care method or local laboratory.  HbA1c 
measurements performed within 4 weeks of randomization may be used.  
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Chapter 3 STUDY PROTOCOL 
 
 Visit 1 – Screening 
At the Screening Visit, the following procedures will be performed / criteria will be checked and 
documented:  
 
Eligibility Screening Events (to be completed prior to randomization): 
• Signed and dated informed consent 
• HbA1c assessment via blood draw or fingerstick and DCA2000 or equivalent NGSP-certified 
point-of-care method (value -4 weeks prior to randomization acceptable) 
• Inclusion and exclusion criteria 
• Demographics (date of birth, gender, race and ethnicity) 
• Diabetic history  
• Medical history  
• Substance use history (drinking, smoking, and drug habits) 
• Concomitant medications 
• Physical examination (by study staff or subject’s personal MD within 6 mos.)Urine or serum 
pregnancy test for all premenopausal women who are not surgically sterile                                                
• Blood draw for:  
o Chemistry panel for subjects with diabetes duration of greater than 5 years post onset of 
puberty (values within 6 months prior to enrollment acceptable). 
o Liver function tests in subjects taking medications known to affect liver function or diseases 
known to affect liver function (values within 6 months prior to enrollment acceptable). 
o TSH within 6 months for subject with a goiter, positive antibodies, or who are on thyroid 
hormone replacement. A normal TSH within the past year is otherwise acceptable. 
o Hematocrit  
 
Non-Eligibility Screening  Events: 
• Weight, height (by study staff or subject’s personal MD within 3 mos.) 
• Blood pressure and heart rate (by study staff or subject’s personal MD within 1 mo.) 
• Questionnaires (may be completed electronically): 
o inControl Technology Expectations Questionnaire (administered prior to starting inControl) 
o inControl Technology Acceptance Questionnaire (administered at subsequent time points 
after starting inControl) 
o DSPQ_Diabetes Specific Personality Questionnaire (administered at onset of trial only) 
o Clarke Hypoglycemia Awareness Questionnaire 
o DDS_Diabetes Distress Scale 
o High Blood Sugar Survey 
o HFS-II (Part 1 and 2) (Adult Low Blood Sugar Survey) 
• All blood glucose meters used in the study (either personal or study provided glucometers) 
will be QC tested with at least two different concentrations of control solution if available at 
the start of the study. A tested meter will not be used in a study if it does not read within the 
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target range at each concentration per manufacturer labeling.  The subject will be instructed 
to perform quality control testing of the BG meter at home per manufacturing guidelines, and 
to contact study staff for a replacement of the meter, test strips, and control solution if a 
meter fails the testing.   
• Subjects will be asked to perform SMBG measurements at least 4 times daily (before meals, 
and at bedtime) throughout the study.  Subjects will be reminded to use the same glucometer 
for all finger sticks and calibrations and to only use SMBG values (not CGM values) to guide 
treatment decisions.  Subjects will use their personal glucometer throughout the study but 
will be provided with a study glucometer if needed. 
• Subjects will be provided with a study blood ketone meter and test strips. All study blood 
ketone meters will be QC tested at the start of the study with at least two different 
concentrations of control solution if available.  A tested meter will not be used in a study if it 
does not read within the target range at each concentration per manufacturer labeling.   
• Subjects will be asked to obtain a glucagon kit per usual care guidelines from their personal 
physician. If subject is unable to obtain, study physicians may provide a prescription for the 
subject to obtain at their local pharmacy. 
 
The total amount of blood to be withdrawn during this screening visit is ~9 cc. The visit will last 
approximately 2-4 hours. 
 
3.1.1 Pilot Study 
Prior to implementation of inControl use at home, we will conduct a pilot study of up to 4 subjects 
using inControl under supervision. This may occur within this protocol or another protocol/IDE 
(G150221). These subjects will have an approximately 48 hour visit to a research house/hotel. These 
subjects will be under closed loop control with continuous remote monitoring. We will  have a 
technician and medical personnel (e.g. nurse, EMT) with the subjects at all time. The data will be 
reviewed by the DSMB and, if no serious adverse events and approved by the DSMB, subjects will 
continue to be enrolled as described in this protocol.  
 
 Randomization 
A subject who meets all the inclusion and exclusion criteria will be enrolled in the study. After 
completion of the eligibility criteria, the participant will be randomized to one of the two arms: Group 
A and Group B as described and illustrated in Figure 1.   
 
Subjects who are randomized to Group A will start SAP within four weeks of completing Visit 2; Visit 3 
and Visit 4 will occur following completion of SAP. 
 
Subjects who are randomized to Group B will proceed directly to Visit 2, Visit 3 and 4.  
 
All training and run-in visits were structured to accommodate subjects who are experienced with the 
system or system components as well as subjects who have little to no experience with the system or 
system components. As a result, training/run-in visits may be combined as described in the protocol 
depending on the skill level of the individual subject. 
 
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 Visit 2 – CGM Training and Run-In 
Visit 2 may occur concurrently with Visit 1. 
• A urine pregnancy tests may need to be repeated in premenopausal women who are not 
surgically sterile if Visit 2 occurs more than 6 weeks after their Visit 1. 
• Current CGM use will be evaluated, data may be downloaded for any CGM currently in use. 
• Eligible subjects will receive study CGM training including proper insertion, calibration and 
maintenance of the CGM sensor. Training will be tailored to their individual experiences. 
• Subjects will take one of three paths forward in the study based on prior CGM experience: 
o Dexcom CGM users with use in the past 12 weeks 
These subjects will not require any further CGM run-in. 
o Non-Dexcom CGM users (current or past users) or Dexcom CGM users with last use more 
than 12 weeks prior 
These subjects will be given study CGM supplies and move into an up to 1-week home use 
period with the study CGM to confirm the ability to use the CGM successfully. Subjects may 
skip this CGM run-in period if subject demonstrates adequate CGM skills. 
o CGM non-users  
These subjects will be given study CGM supplies and move into an up to 2-week home use 
period with the study CGM to confirm the ability to use the CGM successfully and to help 
establish baseline glycemic control during frequent CGM use.  Subjects will be contacted 
weekly by study staff to review CGM use. 
• If the subject has not demonstrated adherence to use of CGM after any applicable run-in 
period, study staff may discontinue that subject at their discretion. 
• Subjects will be required to set the CGM hypoglycemia threshold alarm to a value no less than 
60 mg/dl and the CGM hyperglycemia threshold alarm to a value no greater than 300 mg/dl. 
 
 Visit 3 - Study Pump Training and Run-In Period 
Visit 3 may occur concurrently with Visit 1 and 2. 
Subjects will have supervised training on the study pump as described below. 
Study staff will review subject’s pump parameters by manual review and/or download of personal 
insulin pump.  
 
All subjects will have a run-in period on the study pump of up to two weeks duration. Subjects who 
have had prior experience with the study pump may skip or require a shorter run-in period. 
The pump run-in period may overlap with any required CGM run-in period. 
Pump training will include: 
• The subject will be fully instructed on the study insulin pump. A qualified  staff member or 
pump trainer will conduct the training and in particular discuss differences from their home 
pump in important aspects such as calculation of insulin on board and correction boluses. 
Additional topics not be limited to but may include: infusion site initiation, cartridge/priming 
procedures, setting up the pump, changing batteries, navigation through menus, bolus 
procedures including stopping a bolus, etc. 
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• The study team will assist the subject in study pump infusion site initiation and will start the 
subject on the study pump. The study pump will be programmed with the subject’s usual basal 
rates and pump parameters. The subject’s personal pump will be removed. 
• The subject will be supervised with the study pump during at least one meal or snack bolus to 
ensure subject understanding of the pump features. 
• The subject will be encouraged to review the literature provided with the pump, infusion sets, 
and other pump related supplies after the training is completed. 
 
 Visit 4 – Closed Loop Training Visit 
Visit 4 will occur just prior to starting the first session of Closed-Loop Control to ensure that the 
training is in close proximity to the initiation of the system in closed loop control (for Group B this will 
occur earlier than Group A). 
 
Visit 3 and 4 may occur concurrently for inControl users. For subjects starting on the Tandem-G6 
system, Visit 3 and 4 will be concurrent.  
 
Visit 4 will consist of a ~5-10 hour training session in a transitional setting at a research house, hotel or 
clinic during which the subject will be trained to use the system to control the study pump, including 
meal announcement, meal bolusing, exercise, and switching back and forth between Pump (open-
loop) mode and Stopped mode.   Subjects may be asked to view study materials at home (e.g. User 
Guides and/or study videos on the Use of the AP System) prior to coming to Visit 4. This visit may 
shorter than 5-10 hours depending on the subject’s proficiency with the system as well as prior 
experience. 
 
A serum or urine pregnancy test will be collected for all premenopausal women who are not surgically 
sterile. 
 
Prior to initial use, the system will be initialized with each subject’s individual parameters, including 
carbohydrate ratio, correction factor, and basal rate pattern.   
 
Study team members will train the subject in performing specific tasks including the following: 
• The study team will confirm the pump parameters entered in the system with the subject. 
• How to switch the system between Pump mode (open-loop, preprogrammed basal insulin 
delivery) and Stopped mode depending on circumstances.  For the Tandem-G6 system, this 
will consist of turning Control-IQ off. 
• How to calibrate the CGM unit during the study. 
• How to access the CGM trace on the user interface. 
• How to activate the meal screen of the system any time insulin will be given with a meal or 
any time additional correction insulin is desired. 
• How to inform the system of hypoglycemia treatment on the user interface. 
• What to do in when engaging in strenuous exertion  
• How to perform blood ketone testing and perform rescue therapy actions with the glucagon 
kit 
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• The subject will be assessed for understanding of the system interface and how to react to 
safety/alert messages. 
• The subject will be given a AP system User Guide relevant to their system (Appendix A-10) as a 
reference. 
 
The subject must be able to complete system-related tasks independently to be eligible to continue in 
the study.   
 
 Visit 5 - AP System Run-In phase: Home Use in Pump Only (Open Loop) Configuration 
Eligible subjects who have not had recent use of the system (more than ~2 weeks of use in the past 6 
months or more than ~2 months of use in the past year) will complete up to 2-week home use period 
with the full system in pump only (open loop) configuration where no closed loop algorithms are 
activated. Subject will be instructed not to start closed loop during this run-in phase.  Subjects who 
have had prior experience with the AP system as defined above will not be required to do Visit 5. 
Subjects who are demonstrating proficiency, as determined by the study physician, may have a shorter 
open loop run-in phase with a minimum of 5 days duration Criteria for proficiency is listed in section 
3.11. 
 
For the inControl system, remote monitoring will be available during this period for the purposes of 
data collection and ad hoc assessment of system performance by study team.  The study team will be 
available for the subject to contact during this phase. Study staff will contact the subject and review 
data on the Remote Monitoring once daily. The subject may contact the study staff at any time. 
 
For the Tandem-G6 system, remote monitoring will not be available. Study staff will contact the 
subject daily to assess difficulties with the use of the system. The subject may contact the study staff 
at any time. If the study team requires additional information, the subject may be asked to upload the 
pump at home so that the study can review data on the t:connect website. 
 
 Visit 6 + Visit 7 + Visit 8 Washout Following Completion of the Each Study Phase 
At the completion of the each phase of the study, subjects will have up to a two week washout prior to 
proceeding to the next phase.  
First Phase: Group A 8 weeks of SAP; Group B 8 weeks of USS +SAP(d) 
Second Phase: Group A 8 weeks of USS +SAP(d); Group B 8 weeks of USS + CLC(d) 
Third Phase: Group A 8 weeks of USS + CLC(d); Group B 8 weeks of USS +SAP (d) 
Fourth Phase: Group A 8 weeks of USS + SAP(d); Group B 8 weeks of SAP 
 
Visit 6 may occur concurrently with Visits 3, 4 and 5.  During this time, subjects may continue on the 
study pump if Visit 4 has been completed or switch to their own personal pump. Subjects will either 
come to the study site or complete the following locally: HgbA1c, and psychometric questionnaires 
(Appendix A-11) 
 
Individual Structured Interviews [Optional]:  Subjects will be asked to participate in an individual 
structured interview after using the AP system (Group A= after visit 7, 8, 9; Group B=after visit 6, 7, 8). 
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These structured interviews will be audiotaped to assist staff in recording subjects’ responses. These 
interviews may be conducted in person or over the phone. The audio recordings will be labeled with 
the study subject ID number and will be stored with other study documentation.  
 
Data will be downloaded from study devices, glucometer and personal pump (during SAP) by one of 
several methods: locally by the subject and sent to study staff, by study staff at time of a visit or 
devices not in use being mailed to the study staff for downloading. 
 
 Visit 9 - End of Study Visit 
At the completion of the final phase of the study, subjects will complete their final visit. Subjects will 
resume their personal pump. Subjects will either come to the study site or complete the following 
locally: HgbA1c, questionnaires, and may participate in an individual structured interview.  
 
Data will be downloaded from study equipment, glucometer and personal pump (during SAP) by one 
of several methods: locally by the subject and sent to study staff, by study staff at time of a visit or 
equipment mailed to the study staff for downloading.   
 
 Study Procedures during SAP 
• Study subjects will be using the study CGM (Dexcom G4) and either their home pump or study 
pump for 8 weeks. Subjects using the Tandem-G6 system during AP phases will use their home 
pump during SAP. 
• Subjects will be following their usual home insulin parameters. There are no predictive 
algorithms running for insulin administration.  
• Subjects will be requested to use their personal glucometer or study glucometer for all 
fingersticks including CGM calibrations.  
• Subjects will perform their usual activities and manage their diabetic regimen per their usual 
routine.  
• Study staff will be available at any time for the study subject to contact.  
• Staff will contact the subject once a month after the first month.  
 
 Study Procedures during USS + SAP(d) and USS + CLC(d) 
The subject will be wearing the study CGM, the study pump and utilizing the AP system for 8 weeks. 
Subject will be doing fingerstick testing using their personal glucometer or study provided glucometer. 
 
For USS + SAP(d): The subject will be instructed to activate closed-loop operation each evening any 
time between just before eating dinner and prior to bedtime.  The subject will be instructed to switch 
back to open-loop mode upon waking up in the morning. 
 
For USS +CLC(d): The subject will be instructed to remain in closed-loop operation for 24 hours. 
 
While using the closed loop system, the subject will be instructed to avoid deviating from his/her 
regular daily routine in regards to diet and exercise and to maintain his or her usual sleep schedule 
during the course of the study.  The subject will specifically be asked to avoid consuming more than 3 
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alcoholic drinks in any one day.  The subject will also be instructed to avoid use of closed-loop mode 
during periods of illness with an elevated temperature >101.5 degrees Fahrenheit, periods of 
significant illness, or during periods of use of medications such as epinephrine for the emergency 
treatment of a severe allergic reactions or asthma attack in addition to use of oral or injectable 
glucocorticoids. The subject will be asked to put the system in exercise mode when engaging in 
strenuous exertion. 
 
The total duration during each of these phases will be 8 weeks of AP system use regardless of whether 
CLC was activated or not. If a subject was off the system entirely and unable to use the system (e.g. in 
Stopped Mode) on one or more days due to illness or other factors such as extended travel, the use 
period may be extended at investigator discretion to obtain 8 weeks of use. 
        
 Monitoring when the AP system is in Use during Visit 5, USS + SAP(d) and USS + CLC(d) 
Throughout the study, the study subject will be given contact information for study team members 
and can contact the study team at any time. 
 
During the first use of the system at visit 5 and following completion of Visit 5 (second phase for Group 
A and first phase for Group B), the following procedures will be in place: 
• The study team will contact the subject daily for the first week. 
• The study team will review the Remote Monitoring System once daily for the first week (if 
using inControl). 
• A subject will be assessed by the study team at the end of the first week on the following 
criteria: 
o The subject used the system appropriately including the following: 
 Responded to system alerts and treated hypo- and hyperglycemia appropriately 
 Avoided deviating from his/her regular daily routine in regard to diet and exercise and 
maintained his or her usual sleep schedule   
 Avoided consuming more than 3 alcoholic drinks in any one day   
 Performed a fingerstick BG at least 4 times daily (inControl subjects using Dexcom G5 
only) and/or appropriate fingerstick BG testing by investigator discretion  
 Avoided use of closed-loop mode during periods of illness with an elevated 
temperature >101.5 degrees Fahrenheit, periods of significant illness, or during periods 
of use of medications such as epinephrine for the emergency treatment of a severe 
allergic reaction or asthma attack in addition to use of oral or injectable glucocorticoids 
o Did not experience severe hypoglycemia or severe hyperglycemia/DKA (not associated with 
infusion set failure) as defined in Section 5.1 
o Did not develop >1.0 mmol/L ketones on 3 or more study days due to prolonged periods of 
inadequate insulin delivery  
o Study staff were able to contact the subject without difficulty and in a timely manner when 
the system was in use  
o Subject was able to communicate with the remote monitoring server without more than 3 
prolonged periods of loss of connection during the time that the system use was active for 
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inControl. Subjects using Tandem-G6 will be asked to upload their pump to the t:connect 
website at least one time during this timeframe for the study team to ensure adequate 
data capture. 
 
If the study subject did not meet these criteria, then an additional week of daily contact (all subjects) 
and daily remote monitoring (inControl subjects only) will be performed provided that the subject did 
not trigger any of the study stopping rules for individual subjects (as defined in Section 5.9). 
 
Subject will be reeducated as appropriate and reassessed again at the end of the second week. Study 
staff will continue this weekly assessment per the staff’s discretion in those subjects that are not 
meeting criteria.  
 
When the subject meets all the criteria, then study staff will be contacting them (all subjects) and 
reviewing the remote monitoring data (inControl subjects only) once a week until the subjects 
complete their first 8 week time period using the AP system. 
 
During the subsequent 8 week time periods of using the system, subjects will be contacted (all 
subjects) and remote monitoring data (inControl subjects only) reviewed every other week by the 
study staff. 
 
Subjects using Tandem-G6 system will upload the study pump a minimum of once every 4 weeks and 
anytime the staff requests review of the data. 
 
 Duration of Study 
Each study subject is expected to participate in the study for 44-50 weeks. The completion of the study 
(up to N=110 recruited) is expected to last approximately 42 months.  
 
 
Figure 7. Timeline for recruitment 
Session 1: Recruit and 
study N=28 subjects 
randomized into two 
treatment groups
6
12
24
42
36
30
48
18
Technology
refinement;
IDE writing 
and FDA 
approval
Month
Reporting of 
Results and 
Clinical 
Translation
Session 2: Recruit and 
study N=28 subjects 
randomized into two 
treatment groups
Session 3: Recruit and 
study N=28 subjects 
randomized into two 
treatment groups
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Chapter 4 CLOSED-LOOP CONTROL SYSTEM OPERATION AND SAFETY 
 
 Algorithm Details 
The control system consists of several modes with different functions adapted to different activities:  
• Module 1 –Safety Supervision (SSM) responsible for prevention of hypoglycemia. This is a passive 
safety module that can only attenuate insulin delivery.  
• Module 2 -- Basal Rate (BRM) responsible for augmentation of basal rate up to a total of 3X basal, 
to compensate for changes in insulin sensitivity (e.g. dawn phenomenon).   
• Module 3 – Range Control (RCM) is responsible for postprandial correction insulin administered as 
needed. 
 
In addition, the system includes a sophisticated meal bolus calculator that takes into account the 
current glucose state of the subject and available insulin to make a recommendation for a pre-meal 
bolus. The recommendation must be confirmed before delivery; if not confirmed, pre-meal insulin is 
not delivered automatically. The bolus calculator is activated on demand by the user, prior to meals. 
 
 System Details  
The study system will function in different operational modes in the proposed study:  Stopped, Pump, 
and Closed-Loop. Pump mode will be referred to throughout this protocol and consistently means the 
delivery of preprogrammed basal rates (Open-Loop) regardless of the system being used. In Closed-
Loop mode, basal delivery can be attenuated or increased by the control algorithms.   
 
For inControl system only: If the system malfunctions but the system can still communicate with the 
pump, the system will fail safe to Pump mode so that the user will continue to receive basal insulin 
under the direction of the system.  If there is a malfunction in which the system cannot communicate 
with the pump, the system will fail safe to Stopped mode.  If the system is in Stopped mode and the 
Roche pump is being used, the user will begin receiving basal insulin from the pump without any 
direction from the AP system within a short period of time. 
 
The table below summarizes the system modes for inControl and some of the functionality available in 
each mode: 
 
 
 
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Mode 
Overview 
CGM 
data? 
Basal Insulin 
delivered via AP? 
Bolus 
Insulin 
delivered 
via AP? 
Hypo-/Hyper 
Glycemia 
Alerts? 
Data 
Transfer to 
Remote 
Server to 
allow 
monitoring? 
“Stopped” System comes 
online in 
Stopped mode 
and awaits user 
action.  User 
may switch the 
system into 
Stopped mode 
at any time. 
No 
No 
No 
No 
No 
“Pump” 
Emulates 
traditional 
insulin pump 
behavior of 
open-loop basal 
insulin delivery 
according to 
preprogrammed 
pattern; used 
instead of 
Closed-Loop 
mode when 
replacing CGM 
sensor 
Yes, if 
available 
Yes, identical to 
preprogrammed 
pattern 
Yes, but 
only user-
requested 
manual 
boluses; no 
automated 
boluses 
Yes 
Yes 
“Closed 
Loop” 
Control 
algorithm 
determines 
appropriate 
automated 
insulin delivery.  
Can only 
activate if CGM 
data is 
available. 
Yes 
Yes, according to 
algorithm based on 
preprogrammed 
pattern attenuated 
or increased when 
needed 
Yes, 
automated 
boluses if 
algorithms 
are active, 
and user-
requested 
manual 
boluses at 
any time 
Yes 
Yes 
Table 1: Basic functionality of system in each operational mode 
 
 Setup and Operation of the Closed-loop Control System 
Prior to closed-loop use, the AP system is initialized with each subject’s individual parameters, 
including carbohydrate ratio, correction factor, and basal rate pattern.   
 
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 Safety Measures 
 Safety Measures of Insulin Dosing 
In Closed-Loop mode, all dosing is supervised by a dedicated safety supervision system module and 
insulin correction for meal boluses must be manually confirmed.  In Pump and Closed-Loop mode: 
• Bolus size is checked by the algorithm to ensure it is smaller than the maximum bolus that the 
pump can handle; 
• For inControl, switching to “Stopped” mode includes a ‘cancel all’ delivery message to the 
pump so that any active but incomplete bolus is cancelled with the Roche Accu-Chek pump. 
• All insulin requests are made in the form of boluses or temporary basal rate changes; this 
ensures that in case of a system crash or pump disconnection, no request has permanence; 
• Users will be able to monitor delivered insulin in the plots menu on the phone which is 
available from the main screen in any operating mode. The remote monitoring displays the 
delivered insulin and total insulin delivered during the past 4 hours via the web interface; 
• It is important to note that IOB constraint is an internal safety feature of the closed-loop 
system. It is not read from the pump or any other external source. The IOB in the system is 
computed by the system using a model of the transport and clearance of insulin from the 
subcutaneous infusion site to the circulation, and is intended to prevent insulin overdose. 
  
 Hypoglycemia Safety Guidelines 
If the subject receives a hypoglycemia alert from the study system, the subject will be instructed to 
perform a fingerstick test with the blood glucose meter.  The hypoglycemia alerts will be active in 
Pump and Closed-loop modes. If the subject’s BG result is ≤80 mg/dL, the subject will be instructed to 
treat with ~8-16 grams of oral glucose and for inControl users indicate treatment was given on the 
system by activating the hypoglycemia treatment button.  Further details will be included in a Subject 
User Guide regarding retesting, retreatment, and criteria for glucagon treatment, stopping the system, 
contacting the study physician, and contacting emergency responders. 
 
 CGM Calibration 
Throughout the study, the subject will be instructed to calibrate the CGM at least twice a day (Dexcom 
G4) and any time there is a calibration request from the CGM itself, provided that the fingerstick 
glucose is between 40-400 mg/dL and the CGM arrow is flat (horizontal), indicating that the sensor 
glucose value is not changing rapidly. 
 
 Hyperglycemia Safety Guidelines 
If the subject receives a hyperglycemia alert from the study system, the subject will be instructed to 
perform a fingerstick test with the blood glucose meter.  The hyperglycemia alerts will be active in 
Pump and Closed-loop modes. If the subject’s BG result is ≥300 mg/dL for over 1 hour, or over ≥400 
mg/dL at any point, the subject will be instructed to perform a blood ketone measurement with the 
study ketone meter.  Further details will be included in a Subject User Guide regarding criteria for 
stopping the system, administering correction boluses, retesting, retreatment, infusion set 
replacement, contacting the study physician, and contacting emergency responders. 
 
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 CGM Sensor Failure 
If the CGM signal becomes unavailable for an extended period of time during Closed-Loop mode, the 
system will revert to Pump mode.   
 
 Pump Failure 
For inControl, If the insulin pump stops communicating for >10 minutes, the system will generate an 
alert on the phone and will eventually switch to Stopped mode if the communication problem persists.  
If loss of pump communication persists, the Roche pump will automatically revert to preprogrammed 
basal insulin delivery without any need for instruction from the controller (within 15-45 minutes from 
time of failure of communication based on estimated glucose at the time of loss of communication).   
 
 Study System Failure 
For inControl, If the study system stops working, the Roche pump will automatically revert to 
preprogrammed basal insulin delivery without any need for instruction from the controller (within 15-
45 minutes from time of failure of communication based on estimated glucose at the time of loss of 
communication).   
 
For Tandem-G6 system, if the t:slim X2 detects a system error that does not allow the pump to 
operate, the Malfunction Alarm will display and the subject will be instructed to contact the study 
team.  
  
 
 Remote Monitoring for inControl 
REMOTE MONITORING SERVER – The TypeZero Technologies inControl-Cloud data collection and 
monitoring application is a cloud-based system that stores de-identified user data received from the 
inControl-AP artificial pancreas smartphone application over a secure SSL link.  Access to inControl-
Cloud is password protected and access is restricted by account to members of the study team and to 
TypeZero authorized personnel.  inControl Cloud may run on systems from one of a number of 
vendors such as Amazon Web Services. The system offers the possibility to track many patients at the 
same time, with automated alarms and alerts (Figure 6).   
 
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Figure 6: Remote Monitoring Interface 
 
During the Closed-Loop Training visit, the subject will be supervised using the monitoring system in 
order to verify that the system cell phone, data link and server are all functioning properly.  The 
subject will be shown how to verify that the data link to the server is working and what to do if the 
system indicates link failure.  The subject will also have a chance to ask questions and discuss with 
study staff where they may travel during the trial such that continuous monitoring of the system is 
possible. Subjects will be provided a Subject User Manual containing glycemic guidelines and the AP 
system manual.  
 
 
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Chapter 5 ADVERSE EVENT REPORTING AND PROTOCOL MONITORING 
 
 Definition 
A reportable adverse event is any untoward medical occurrence or any unexpected medical 
occurrence in a study subject.     
 
Hypoglycemic events are recorded as Adverse Events if the event required assistance of another 
person due to altered consciousness to actively administer carbohydrate, glucagon, or other 
resuscitative actions.  This means that the subject was impaired cognitively to the point that 
he/she was unable to treat him or herself, was unable to verbalize his or her needs, was 
incoherent, disoriented, and/or combative, or experienced seizure or coma.  These episodes may 
be associated with sufficient neuroglycopenia to induce seizure or coma.  If plasma glucose 
measurements are not available during such an event, neurological recovery attributable to the 
restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.   
 
Hyperglycemic events are recorded as Adverse Events if evaluation or treatment was obtained 
from a health care provider or if the event involved diabetic ketoacidosis (DKA), as defined by the 
Diabetes Control and Complications Trial (DCCT), and had all of the following:  
• Symptoms such as polyuria, polydipsia, nausea, or vomiting;  
• Serum ketones or large/moderate urine ketones;  
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
• Treatment provided in a health care facility 
 
 Recording of Adverse Events 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
events or untoward findings.  The first concern will be the safety of the subject, and appropriate 
medical intervention will be made. 
 
The investigator will elicit reports of adverse events from the subject at each visit and complete all 
adverse event forms online.   
 
The investigator will assess the relationship of any adverse event to be related or unrelated by 
determining if there is a reasonable possibility that the adverse event may have been caused by 
the study device or study procedures.    
 
The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 
severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse 
event is not necessarily serious.  For example, itching for several days may be rated as severe, but 
may not be clinically serious.   
 
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Adverse events that continue after the participant’s discontinuation or completion of the study 
will be followed until their medical outcome is determined or until no further change in the 
condition is expected.   
 
Definitions of relationship and intensity are listed on the website data entry form.   
 
Documentation of adverse events will discontinue at the completion of Visit 9 Washout Period.   
 
 Reportable Device Issues  
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
whether an adverse event occurred, except in the following circumstances.  
 
The following device issues are anticipated and will not be recorded on a CRF but will reported as 
an Adverse Event if the criteria for AE reporting described above are met:  
• Component disconnections  
• CGM sensors lasting fewer than manufacturer recommended use 
• CGM tape adherence issues  
• Pump infusion set occlusion not leading to ketosis  
• Battery lifespan deficiency due to inadequate charging or extensive wireless 
communication  
• Intermittent device component disconnections/communication failures not leading to 
system replacement  
• Device issues clearly addressed in the user guide manual that do not require additional 
troubleshooting  
• Skin reactions from CGM sensor placement or pump infusion set placement that do not 
meet criteria for AE reporting 
 
 Definition of a Protocol Enrollment Exception 
No enrollment exceptions will be permitted in this trial. 
 
 Definition of a Data Breach 
A data breach is defined in the HITECH Act (43 USC 17932) as an unauthorized acquisition, access, 
or use of protected health information (PHI) that compromises the security or privacy of such 
information. 
 
 Data Collection 
Endpoint data be collected/recorded in the form of source documents and will be stored on a 
database on a Health Systems Computing Services (HS/CS) managed server that is configured to 
store data regulated by HIPAA.  
 
At UVa, safety data oversight will be completed by a member the UVa Clinical Trials Office. An 
example of the Monitoring Form is presented in Appendix A-13. 
 
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The PI will conduct an aggregate review of the following data: 
• All adverse events 
• Unanticipated Problems 
• Protocol violations 
• Audit results 
• Early withdrawals 
• Data processing review 
 
IRB-HSR will be updated annually on the IRB-HSR continuation status form. This annual report will 
address: 
• Brief summary of research progress 
• Whether adverse event rates are consistent with pre-study assumptions 
• Enrollment status 
• Reason for dropouts from the study 
• Whether continuation of the study is justified 
• Conditions whereby the study might be terminated prematurely 
 
The relevant device regulation for reporting adverse events to the FDA will also be followed. 
Data from each subject will be reviewed by the PI after completion of participation to determine 
whether the system was working properly and whether there were safety concerns. 
 
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 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected 
adverse event  
 
 
IRB-HSR 
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/ 
 
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For Device Studies:  
Unanticipated adverse device 
effects (internal) 
IRB-HSR 
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 10 day 
calendar days of 
the study team 
receiving 
knowledge of the 
event 
IRB Online 
 
www.irb.virginia.edu/ 
 
Protocol 
Violations/Noncompliance  
The IRB-HSR only requires 
that MAJOR violation be 
reported, unless otherwise 
required by the sponsor 
 
OR  
Enrollment Exceptions 
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 ) 
Data Breach  
IRB-HSR 
 
 
Within 7 calendar 
days from the 
time, the study 
team received 
knowledge of the 
event.  
 
Protocol Violation, 
Noncompliance and 
Enrollment Exception 
Reporting Form 
 
 
http://www.virginia.edu/vprgs/i
rb/hsr_forms.html 
Go to 3rd bullet from the 
bottom 
Data Breach 
The UVa 
Corporate 
Compliance 
and Privacy 
Office, a 
 
 
ITC:  if breach 
involves  
electronic 
data-  
 
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 
UVa Corporate Compliance 
and Privacy Office- Phone 
924-9741 
 
 
 
 
ITC:  Information Security 
Incident Reporting procedure,  
http://www.itc.virginia.edu/sec
urity/reporting.html 
 
 
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Police if 
breach 
includes items 
that are 
stolen: 
 
Stolen on 
UVA Grounds 
 
OR  
 
Stolen off 
UVa Grounds- 
contact police 
department 
of jurisdiction 
of last known 
location of 
PHI 
time, the incident 
is identified. 
 
IMMEDIATELY.  
 
 
 
 
 
 
UVa Police- Phone-  
(434) 924-7166 
UVa PI HELD IDE 
Life-threatening and/or fatal 
unexpected events related or 
possibly related to the use of 
the investigational agent. 
FDA 
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 
Within 15 
calendar days 
after the study 
team receives 
knowledge of the 
event 
Form FDA 3500A 
(MedWatch) or narrative 
Unanticipated adverse device 
effects (internal or external) 
FDA 
Within 10 
working days of 
the study team 
receiving 
knowledge of the 
event 
 
Form FDA 3500A 
(MedWatch) or narrative 
All adverse events 
FDA 
Annually 
IDE annual report 
 
Table 2:  Reporting Table 
 
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 Reporting Serious or Unexpected Adverse Events 
A serious adverse event is any untoward occurrence that: 
• Results in death 
• Is life-threatening (a non-life-threatening event which, had it been more severe, might 
have become life-threatening, is not necessarily considered a serious adverse event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in significant disability/incapacity  
• Is a congenital anomaly/birth defect 
 
An unanticipated problem is any event, experience that meets ALL 3 criteria below: 
• 
Is unexpected in terms of the nature, severity or frequency given the research procedures 
that are described in the protocol –related documents AND in the characteristics of the 
population under study. 
• 
Is related or possibly related to participation in research.  This means that there is a 
reasonable possibility that the incident may have been caused by the procedures involved 
in the research study. 
• 
The incident suggests that the research places the subject or others at greater risk of harm 
(physical, psychological, economic or social) than was previously known or recognized OR 
results in actual harm of the subject or others.  An unanticipated problem generally 
required a change in policy or procedure, warrants consideration of substantive changes to 
the protocol/consent or other immediate corrective actions in order to reduce the risk or 
eliminate immediate hazard. 
 
As noted in the table above, the study team will notify the FDA of any adverse event that is 
serious, unexpected, and related or possibly related.  Notification will be made within 15 days 
after the study team becomes aware of the event.   
 
The principal investigator is responsible for informing his/her IRB of serious study-related adverse 
events and abiding by any other reporting requirements specific to their IRB.  
 
 Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be informed of all serious adverse 
events and any unanticipated adverse device events that occur during the study and will review 
compiled safety data at periodic intervals.  
 
We will implement a system to oversee and monitor our randomized clinical trial to ensure the 
safety of participants, as well as the validity and integrity of the data. We will establish a data 
safety monitoring board, ensuring that the DSMB’s responsibilities are commensurate with the 
risks, complexity, and nature of our studies.  We will define the role of the DSMB prior to initiating 
the clinical trial and clearly delineate the operating procedures and policies of the board, including 
“stopping rules” for the study.  
 
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Membership: Our DSMB will be comprised of experts in diverse scientific disciplines to ensure 
participant safety and help interpret the data in our studies.   
 
Meetings: Prior to implementation of the study, the DSMB will meet to review the consent and 
protocol, making recommendations for any needed changes.  For this meeting, study investigators 
will be on hand to answer any specific questions.  After the initial meeting, the DSMB will plan to 
meet in-person or by conference call once yearly.  DSMB members will have the ability to request 
more frequent reviews or meetings at any time during the study if they determine such reviews 
could help ensure patient safety or data integrity.  The DSMB may meet in "closed session," and 
they may periodically ask study investigators to attend a meeting to provide additional details on 
the implementation or conduct of the trial or other pertinent information.  After its initial meeting, 
the DSMB will review the implementation and progress of the study, evaluating study data in both 
individual and aggregate form to detect evidence of significant benefit or harm for participant 
while the trial is in progress.  This latter review, beyond that provided by the IRB, serves as a 
means of additional human subject protection.  It does not supplant the regulatory requirement 
for the principal investigator to report serious and unanticipated adverse events to the local IRB or 
relevant regulatory bodies. 
 
Summary of DSMB duties: The DSMB will perform the following activities: 1) Review of the 
research protocol and plans for data and safety monitoring; 2) Evaluate the progress of the 
intervention trial, including periodic assessments of data quality and timeliness, participant 
recruitment, accrual and retention, participant risk versus benefit, and other factors that could 
potentially affect study outcome; 3) Protect the confidentiality of the trial data and the results of 
monitoring; and 4) Make recommendations to the investigators concerning continuation, 
modification, or termination of the trials.  The DSMB also has the right to make independent 
representation to the regulatory bodies (NIH, IRB) if there has been any failure in reporting by the 
principal investigator. The DSMB can also instruct the principal investigator to pause or terminate 
pursuance of research if there is a breach in regulatory guidelines or good clinical practices.  If the 
DSMB notes serious and unexpected adverse events, or unanticipated problems involving risks to 
participants or others, which are related to the study, the PI will be notified immediately in 
writing.  
 
To assist the DSMB in their duties, the investigators will prepare a report prior to each DSMB 
meeting, including issues related to participant recruitment (consent, enrollment, dropout), data 
collection (e.g., quality, timeliness, completeness, security), outcome analyses, and all serious and 
unexpected adverse experiences. The investigators will also notify the DSMB of any significant 
study modifications, emphasizing any changes made in response to adverse events (see definition 
below) 
 
After the DSMB meeting, the DSMB will issue a report summarizing their findings.  More 
specifically, they will provide commentary on participant recruitment, consent, and drop out; the 
quality, timeliness, and completeness of data collection; outcome analyses that help determine 
whether a study should continue; and all serious and unexpected adverse experiences.  In each 
area (e.g., participants consent), they will recommend any necessary changes in study policies or 
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protocol and explain how the changes will help ensure participant safety or data integrity.  These 
reports will be kept by the PI, who will file them with the local IRB.  
 
This application includes a trial that requires registration in ClinicalTrials.gov. 
 
 Potential Risks and Side Effects 
 Venipuncture Risks 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws can 
cause some common reactions like pain, bruising, or redness at the sampling site.  Less common 
reactions include bleeding from the sampling site, formation of a small blood clot or swelling of 
the vein and surrounding tissues, and fainting. 
 
 Fingerstick Risks 
About 1 drop of blood will be removed by finger stick for measuring blood sugars and sometimes 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital 
laboratory tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount of 
bleeding under the skin will produce a bruise.  A small scar may persist for several weeks.  The risk 
of local infection is less than 1 in 1000.  This should not be a significant contributor to risks in this 
study as finger pokes are part of the usual care for people with diabetes. 
 
 Subcutaneous Catheter Risks (Continuous Glucose Sensor) 
Subjects using the continuous glucose sensor will be at low risk for developing a local skin infection 
at the site of the sensor needle placement.  There may be bleeding where the catheter is put in 
and bleeding under the skin causing a bruise (1 in 10 risk).   
 
Study staff should verbally alert the subject that on rare occasions, the continuous glucose sensor 
may break and leave a small portion of the sensor under the skin that may cause redness, swelling 
or pain at the insertion site.  The subject should be further instructed to notify the study 
coordinator immediately if this occurs. 
 
 Risk of Hypoglycemia 
As with any person having insulin-dependent diabetes, there is always a risk of having a low blood 
sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and possibly less than it 
would be as part of daily living.  Symptoms of hypoglycemia can include sweating, jitteriness, and 
not feeling well.  Just as at home, there is the possibility of fainting or seizures (convulsions) and 
that for a few days patients may not be as aware of symptoms of low blood sugar.   
 
 Risk of Hyperglycemia 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
extended period or if the pump or infusion set is not working properly.  A sensor which was 
functioning poorly and significantly under-reading glucose values could lead to inappropriate 
suspension of insulin delivery.     
 
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 Risk of Device Reuse 
The Dexcom CGM is labeled for single use only. The sensor (the component of the system that 
enters the skin) will be single use only. The transmitter and receiver will be reused after cleaning 
as described below. The transmitter is attached to the sensor but does not enter the skin and the 
receiver is a hand held device. The transmitter and receiver will be cleaned adhering to hospital 
protocol as described below. Subjects will be informed that the FDA has approved these devices 
for single use and that by using them among multiple patients, bloodborne pathogens (i.e. 
Hepatitis B) may be spread through the use of multiple users.  
 
The Accu-Chek Combo System and Tandem t:slim X2 insulin pump are labeled for single-patient 
use. The Accu-Chek Combo system is comprised of the Accu-Chek Spirit Insulin Pump and the 
Aviva Combo Device. The Aviva Combo device when used as a glucometer will be single patient 
use at all times.  The Accu-Chek Spirit Insulin Pump itself is handheld and is not a glucometer. The 
subject interactions are primarily with the AP system interface and the Aviva Combo device, not 
with the Accu-Chek Spirit Insulin Pump menu interface itself. The Accu-Chek Spirit Insulin Pump 
handheld device and the Tandem t:slim X2 insulin pump will be reused after cleaning adhering to 
hospital protocol as described below. All infusion set equipment will be single patient use only 
(infusion set insertion kits, tubing, cartridges etc.) 
 
Cleaning Procedure: Equipment that touches intact skin will be cleaned with ethyl or isopropyl 
alcohol (70-90%), quaternary ammonium germicidal detergent (i.e. CaviCide) or household bleach. 
The contact time on the surface depends on the method used to clean the equipment. CaviCide 
requires three minutes on the surface. Clorox Germicidal Bleach Wipes require two minutes on the 
equipment. The surface should remain wet (i.e. slightly damp) with the disinfectant to be 
considered effective though not wet enough to leave drops of liquid. Equipment will be stored in a 
clean zipped bag. 
 
Hb1Ac Risk: The University of Virginia central labs have College of American Pathologist (CAP) and 
the Clinical Laboratory Improvement Amendments (CLIA) certifications. While the central lab is not 
NGSP certified, the calibrators for the HbA1c assay are traceable to NGSP. The equipment (Tosoh 
G7) is NGSP certified. An NGSP Point of Care analyzer (i.e. DCA Vantage Analyzer) may also be 
utilized at the research site to obtain the subject’s HbA1c level. 
 
 Other Risks 
Some subjects may develop skin irritation or allergic reactions to the adhesives used to secure the 
CGM, or to secure the insulin infusion sets for the CSII.  If these reactions occur, different 
adhesives or “under-taping” (such as with IV 3000, Tegaderm, etc.) will be tried, sites will be 
rotated frequently, and a mild topical steroid cream or other medication may be required. 
 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump infusion 
sites are inserted under the skin.  It is possible that any part that is inserted under the skin may 
cause an infection.  These occur very infrequently, but, if an infection was to occur, oral and/or 
topical antibiotics can be used.  The risk of skin problems could be greater if a sensor is used for 
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longer than manufacturer recommendations.  Therefore, participants will be carefully instructed 
about proper use of the sensor. 
 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be collected 
for the study as measures of diabetes self-management behaviors.  Some people may be 
uncomfortable with the researchers' having such detailed information about their daily diabetes 
habits. 
 
Loss of confidentiality is a potential risk; however, data are handled to minimize this risk.   
 
 Study Stopping Criteria 
 Criteria for Individual Subjects 
Rules for stopping the study for an individual subject are as follows: 
1. System or controller malfunctions that impose on the safety of the subject, unless the 
problem can be clearly identified and the system definitively repaired 
2. Two distinct episodes of severe hypoglycemia or hyperglycemia/DKA (not associated with 
infusion set failure) as defined in section 5.1 related to automated insulin delivery during 
closed loop use 
3. The subject requests the study be stopped 
4. Subject pregnancy 
5. Use of oral or injectable glucocorticoids during closed-loop system operation (subject may 
resume study procedures once effects of glucocorticoids are no longer present) 
6. Study staff are persistently unable to contact the subject in a timely manner during the 
course of the study 
7. Persistent subject non-adherence to safety-related procedures such as frequency of 
fingersticks or hypoglycemia, hyperglycemia and ketone treatment instructions 
8. Ketones ≥ 3 mmol/L or with symptoms requiring action regardless of blood sugar or 
ketones (i.e. abdominal pain, vomiting illness, unable to eat or drink , fever ≥ 101.5, clinical 
need for Tylenol/acetaminophen, significant illness, use of epinephrine). Subject may 
resume study procedures once conditions or symptoms are no longer present. 
 
 Criteria for Suspending/Stopping Overall Study 
In case of a recurring system malfunction or a severe hypoglycemia event or severe hyperglycemia 
event during closed loop control (as defined in Section 5.1) that is thought to be device-related 
(either due to excess insulin administration or suspension due to system malfunction) that occurs 
in more than two (2) subjects, the overall study will be suspended while the problem is diagnosed.  
The study may resume if the underlying problem can be corrected by a protocol or system 
modification that will not invalidate the results obtained prior to suspension. 
 
An instance of severe hypoglycemia or hyperglycemia as defined in section 5.1 will result in DSMB 
review of the data to determine whether the event was triggered by the system or not and 
whether it is safe to proceed.  The currently-enrolled subjects will continue use of the system 
during this time unless the DSMB determines it is unsafe for them to do so.  
 
 
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Chapter 6  STATISTICAL CONSIDERATIONS 
 
  Analysis Plan 
 
Statistical Analysis: The overall analysis will follow Intention-to-treat approach and will use 
Generalized Linear Mixed Models (e.g. those available in IBM SPSS) including fixed factors 
following the factorial designs presented in study figure for the specific aims listed below, and 
random effects reflecting patients’ attrition rate.   
Metrics:  
(i) 
Five HbA1c determinations approximately 10 weeks apart;  
(ii) 
Eight-week sequences of CGM data accompanied by BG self-monitoring readings and 
recording of the timing of events such as meals and exercise through the GUI  
(iii) 
Psychometric questionnaires administered concurrently with HbA1c, and  
(iv) 
Individual structured interview and qualitative/quantitative technology acceptance 
assessments. CGM data will be used to compute established metrics of risk for 
hypoglycemia, e.g. the Low BG Index (LBGI), glucose variability, and BG dynamics, as 
presented in our review of statistical tools for CGM data analysis.  
 
Primary Hypothesis by Specific Aims of the Study 
Specific Aim 1: Overnight CLC achieved by USS+SAP(d) will be superior to SAP alone in terms 
of: (1) Improved HbA1c without increasing the risk for hypoglycemia; (2) Reduced incidence 
and risk for hypoglycemia overnight, and (3) Reduced fear of hypoglycemia and improved 
diabetes quality of life scores. 
Specific Aim 2: CLC during the day achieved by USS+CLC(d) will preserve the benefits of 
USS+SAP(d) and will be superior to USS+SAP(d) in terms of: (1) Increased time within target 
range of 70-180mg/dl during the day; (2) Reduced risk for hypoglycemia during and after 
exercise, and (3) Reduced postprandial glucose variability. 
Specific Aim 3: CLC system acceptance evaluated by an individual structured and technology 
acceptance scores will be: (1) Superior, for USS+SAP(d) compared to SAP alone, i.e. adding 
USS overnight will increase patients’ acceptance of CLC, and (2) Marginally inferior, for 
USS+CLC(d) compared to USS+SAP(d); i.e. some patients would prefer SAP alone during the 
day due to perceived increased system complexity. 
 
Primary Outcomes 
Specific Aim 1: The primary outcome is improvement in diabetes control on USS+SAP(d) vs. 
SAP alone as defined by reduced risk for hypoglycemia (Time <70 mg/dL by CGM) without 
increase in HbA1c. Repeated Measures ANOVA with covariate will assess this effect. 
Inversely, comparing HbA1c with covariate overnight Time <70 mg/dL by CGM will address 
SA1-2, while comparing the psychometric questionnaire scores pre-post treatment will 
address SA1-3.  
Specific Aim 2: The primary outcome is improved time within the target range of 70-
180mg/dl during the day on USS+ CLC(d) vs. USS+SAP(d). Repeated Measures ANOVA 
following the study design outlined will assess this effect. SA2-2 will be addressed 
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comparing frequency of hypoglycemia within the post-exercise periods recorded by the 
system; SA2-3 will be addressed using Variability-Grid Analysis, and SA-4 will be addressed 
by a sub-analysis limited to those who did not achieve HBA1c≤7.5% during the first 3 
months of the study.  
Specific Aim 3: will be addressed by comparing structured interviews and technology 
acceptance scores along the two sequences of treatment modalities specified in the study 
design: treatment escalation for Group A and de-escalation for Group B. Analyzing the 
random effect of patient attrition will shed additional light on system acceptance. 
 
 Sample Size 
Sample Size Determination is based on our pilot studies of overnight CLC. We conservatively 
estimate that the effect size of USS+SAP(d) vs. SAP will be f≥0.2. Power calculations (G*Power 3) 
assuming α=0.01, 90% power, correlation of 0.4 between the repeated measures, and attrition of 
up to 31% yield a sample size of N=110 subjects to be randomized at baseline, with N=76 subjects 
completing the study. For SA2 using USS+CLC(d), our pilot data with this same system during the 
day indicate a larger effect size f=0.3. For SA-3, the expected effect size is f=0.35-0.4 based on our 
previous interviews. Thus, a sample size that is adequate for SA-1 will have adequate power to 
address SA-2 and SA-3 as well. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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