CGM for the Early Detection and Management of Hyperglycemia in Pregnancy
Phase: NA
Conditions: Gestational Diabetes Mellitus in Pregnancy
Sponsor: Jaeb Center for Health Research

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Signature PageAE 
CGM FOR THE EARLY DETECTION AND MANAGEMENT OF 
HYPERGLYCEMIA IN PREGNANCY 
Protocol Identifying Number: IMAGINE 
Version Number: 1.2 
January 21, 2025 
 
JCHR Protocol Director  
 
Name, degree 
Judy Sibayan, MPH 
Signature/Date 
 
 
Protocol 
Chair/Coordinating 
Investigator 
 
Name, degree 
Celeste Durnwald, MD 
Signature/Date 
 
 
Medical Monitor 
 
Name, degree 
Roy W. Beck, MD, PhD 
Signature/Date 
 
 

 
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KEY ROLES 
 
 
Protocol 
Chair/Coordinating 
Investigator 
 
Name, degree 
Celeste Durnwald, MD 
Title 
Director, Penn Perinatal Diabetes Program 
Institution Name 
Penn Medicine 
 
JCHR Protocol Director 
 
Name, degree 
Judy Sibayan, MPH 
Title 
Epidemiologist III 
Institution Name 
Jaeb Center for Health Research 
 
Medical Monitor 
 
Name, degree 
Roy W. Beck, MD, PhD 
Title 
Medical Director 
Institution Name 
Jaeb Center for Health Research 
 

 
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VERSION HISTORY 
VERSI
ON 
NUMB
ER 
AUTHOR 
APPROVER 
EFFECTI
VE DATE 
REVISION DESCRIPTION 
 1.0 
Judy Sibayan 
Celeste 
Durnwald 
Roy Beck 
 
Original 
1.1* 
Judy Sibayan 
Sarah Frey 
Shannon 
Peleg 
Celeste 
Durnwald 
Roy Beck 
Judy Sibayan 
 
1. Updated HbA1c eligibility 
criteria for RCT. 
2. Updated the target glucose 
time in range. 
3. Added nonparticipation in a 
separate intervention trial as 
eligibility criteria for RCT. 
4. Clarified risk of glycemic 
management. 
5. Added DSMB safety 
management information 
6. Clarified statistical 
considerations 
 
 
 
 
 
 
 
 
 
 
 
   *Version in effect at study initiation 

 
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TABLE OF CONTENTS 
CHAPTER 1: BACKGROUND INFORMATION ............................................................................................. 20 
1.1 Background and Rationale ................................................................................................................. 20 
1.2 Potential Risks and Benefits .............................................................................................................. 21 
1.2.1 Known Potential Risks ................................................................................................................ 21 
1.2.1.1 Risks of Glycemic Management ......................................................................................... 21 
1.2.2 Known Potential Benefits ............................................................................................................ 22 
1.2.3 Risk Assessment .......................................................................................................................... 22 
1.3 General Considerations...................................................................................................................... 22 
CHAPTER 2: STUDY ENROLLMENT AND SCREENING .............................................................................. 23 
2.1 Participant Recruitment and Enrollment ........................................................................................... 23 
2.1.1 Informed Consent and Authorization Procedures ....................................................................... 24 
2.2 Participant Inclusion Criteria ............................................................................................................. 24 
2.3 Participant Exclusion Criteria ............................................................................................................ 24 
2.4 Screening Procedures ........................................................................................................................ 25 
2.4.1 Determination of Eligibility for RCT .......................................................................................... 25 
2.5 Randomization ................................................................................................................................... 26 
2.6 Screen Failures .................................................................................................................................. 26 
2.7 Observational Cohort ......................................................................................................................... 26 
CHAPTER 3: RANDOMIZED TRIAL PROCEDURES .................................................................................... 27 
3.1 Office Visits ....................................................................................................................................... 27 
3.2 Glucose Lowering Group .................................................................................................................. 27 
3.2.1 Glycemic Management Guidelines ............................................................................................. 27 
3.2.2 Oral Glucose Tolerance Test ....................................................... Error! Bookmark not defined. 
3.2.3 Usual Care Group ........................................................................................................................ 27 
3.2.4 Oral Glucose Tolerance Test ....................................................................................................... 27 
3.3 Data Collected at End of Pregnancy .................................................................................................. 28 
CHAPTER 4: STUDY DEVICES .................................................................................................................... 29 
4.1 CGM .................................................................................................................................................. 29 
4.2 Blood Glucose Meter and Strips ........................................................................................................ 29 
4.3 Study Device Accountability Procedures .......................................................................................... 29 
CHAPTER 5: ADVERSE EVENT AND DEVICE ISSUE REPORTING ............................................................. 30 
5.1 Adverse Events .................................................................................................................................. 30 
5.1.1 Definitions ................................................................................................................................... 30 
5.2 Reportable Adverse Events ............................................................................................................... 31 

 
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5.3 Relationship of Adverse Event to Study Intervention ....................................................................... 32 
5.4 Severity (Intensity) of Adverse Events .............................................................................................. 33 
5.5 Expectedness ..................................................................................................................................... 33 
5.6 Coding of Adverse Events ................................................................................................................. 33 
5.7 Outcome of Adverse Events .............................................................................................................. 34 
5.8 Reportable Study Device Issues ........................................................................................................ 34 
5.9 Timing of Event Reporting ................................................................................................................ 35 
5.10 Safety Oversight .............................................................................................................................. 35 
5.11 Stopping Criteria.............................................................................................................................. 36 
5.11.1 Participant Discontinuation of Study Intervention .................................................................... 36 
5.11.2 Criteria for Suspending or Stopping Overall Study ................................................................... 36 
CHAPTER 6: MISCELLANEOUS CONSIDERATIONS ................................................................................... 37 
6.1 Collection of Medical Conditions and Medications in Randomized Study Participants ................... 37 
6.2 Participant Compensation .................................................................................................................. 37 
6.3 Participant Withdrawal ...................................................................................................................... 37 
6.5 Confidentiality ................................................................................................................................... 37 
CHAPTER 7: STATISTICAL CONSIDERATIONS .......................................................................................... 38 
7.1 Statistical and Analytical Plans ......................................................................................................... 38 
7.2 Statistical Hypotheses ........................................................................................................................ 38 
7.3 Sample Size ....................................................................................................................................... 38 
7.4 Outcome Measures ............................................................................................................................ 38 
7.4.1 Primary Efficacy Endpoint .......................................................................................................... 38 
7.4.2 Secondary Efficacy Endpoints .................................................................................................... 39 
7.4.3 Safety Endpoints .......................................................................................................................... 39 
7.5 Analysis Datasets and Per-Protocol Analyses ................................................................................... 39 
7.6 Analysis of the Primary Efficacy Endpoint ....................................................................................... 39 
7.7 Sensitivity Analyses .......................................................................................................................... 40 
7.8 Analysis of Secondary Efficacy Endpoints ....................................................................................... 40 
7.8.1 Binary Outcomes ......................................................................................................................... 40 
7.8.2 Additional Exploratory Analyses ................................................................................................ 40 
7.9 Safety Analyses ................................................................................................................................. 41 
7.10 Planned Interim Analyses ................................................................................................................ 41 
7.11 Subgroup Analyses .......................................................................................................................... 41 
7.12 Glucose Exposure Assessment ........................................................................................................ 42 
7.13 Multiple Comparison/Multiplicity ................................................................................................... 43 
7.14 Additional Tabulations and Analyses .............................................................................................. 43 

 
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7.15 Observational Study ........................................................................................................................ 43 
CHAPTER 8: DATA COLLECTION AND MONITORING .............................................................................. 44 
8.1 Case Report Forms and Other Data Collection ................................................................................. 44 
8.2 Study Records Retention ................................................................................................................... 44 
8.3 Quality Assurance and Monitoring .................................................................................................... 44 
8.4 Protocol Deviations ........................................................................................................................... 45 
CHAPTER 9: ETHICS/PROTECTION OF HUMAN PARTICIPANTS .............................................................. 46 
9.1 Ethical Standards ............................................................................................................................... 46 
9.2 Institutional Review Boards .............................................................................................................. 46 
9.3 Participant and Data Confidentiality ................................................................................................. 46 
9.4 Future Use of Stored Data ................................................................................................................. 46 
CHAPTER 10: REFERENCES ....................................................................................................................... 47 
 
 
 

 
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LIST OF ABBREVIATIONS 
Add any abbreviations used in the protocol document. The use of abbreviations should be 
minimized to only those that are commonly known. 
 

 
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SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: CGM FOR THE EARLY DETECTION AND MANAGEMENT OF 
HYPERGLYCEMIA IN PREGNANCY 
Protocol Version/Date: 1.0/21OCT2024 
I have read the protocol specified above and agree to personally conduct or supervise the study in 
accordance with the current protocol. In my formal capacity as a Site Principal Investigator, my 
duties include ensuring the safety of the study participants enrolled under my supervision and 
providing the Jaeb Center for Health Research, which serves as the Coordinating Center for the 
protocol, with complete and timely information, as outlined in the protocol. It is understood that 
all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. I agree to maintain accurate and 
current records and to make those records available for inspection in accordance with 21 CFR 
812.40. 
This trial will be carried out in accordance with ICH E6 (R2) Good Clinical Practice (GCP) and 
United States (US) Code of Federal Regulations (CFR) 45 CFR 46, 21 CFR 50, 21 CFR 56, and 
21 CFR 812. 
[For participating sites outside of the United States, the trial will be carried out in accordance 
with ICH E6 (R2) Good Clinical Practice (GCP), the Declaration of Helsinki, and specific 
regulations applicable to the countries in which the trial will be conducted.] 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol will 
take place without prior agreement from the Coordinating Center and documented approval from 
the Institutional Review Board (IRB), or other approved Ethics Committee, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. I will ensure that an IRB 
will be responsible for the initial and continuing review and approval of the investigation. I also 
agree to promptly report to the IRB all unanticipated problems involving risks to human subjects 
or others. 
I agree to inform all participants that the investigational product is being used for investigational 
purposes. I agree to report to the Coordinating Center adverse experiences that occur in the 
course of the investigation in accordance with 21 CFR 812 and the current protocol. I understand 
the potential risks and side effects of the investigational product. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Good Clinical Practice Training. Further, I agree to ensure that all staff members 
involved in the conduct of this study are informed about their obligations in meeting the above 
commitments. 
Investigator’s Signature __________________________________ Date: _____ / _____ / _____ 
 
dd 
mmm  yyyy 
Investigator’s Name: ____________________________________ 
Site Name/Number: _____________________________________ 
 

 
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PROTOCOL SUMMARY 
 
Title 
CGM FOR THE EARLY DETECTION AND MANAGEMENT OF 
HYPERGLYCEMIA IN PREGNANCY: “IMAGINE” 
Rationale 
Recent findings suggest that maternal hyperglycemia and its 
correlated increased risk with adverse pregnancy outcomes (APOs) 
is best mitigated with early detection and intervention prior to the 
24th week of gestation, particularly in the first trimester or the 
beginning of the second trimester.1 This underscores a potential 
limitation in the current standard of care in which the OGTT is 
administered in the late second/early third trimester  (24-28 weeks) 
when, as an increasing body of clinical research suggests, it may be 
too late to counteract the perinatal consequences of maternal 
hyperglycemia. There may be benefit in identification and initiating 
treatment of maternal hyperglycemia earlier in pregnancy (prior to 
16 weeks 6 days of gestation). 
1. Management of Diabetes in Pregnancy: Standards of Medical 
Care in Diabetes—2019. Diabetes Care. 2019;42(Supplement 
1):S165-S172. doi:10.2337/dc19-S014 
Précis 
• Pregnant individuals without diabetes and a singleton, 
uncomplicated (low-risk) pregnancy will be enrolled by 14 
weeks 6 days of gestation. Initially, a blinded CGM sensor will 
be worn to screen for hyperglycemia.   
• Participants with HbA1c (<6.5% [48 mmol/mol]) and 
exceeding the study-defined continuous glucose monitoring 
(CGM) threshold for hyperglycemia (≥5.0% of values >140 
mg/dL [7.8 mmol/L]) will be randomly assigned to initiation of 
glucose management (unblinded CGM and medical therapy as 
indicated to minimize glucose levels >140 mg/dL [7.8 
mmol/L]) or to usual care with collection of blinded CGM data 
at intervals.  
• Participants will be followed through the end of pregnancy and 
pregnancy outcomes will be assessed, including select APOs.   
• Participants not meeting CGM hyperglycemia criteria on initial 
screen or who do not enter the randomized controlled trial 
(RCT) for another reason and who have HbA1c <6.5% (48 
mmol/mol), will form an observational cohort and have results 
of their OGTT and pregnancy outcomes recorded. 
Objectives 
• To determine whether the identification of maternal 
hyperglycemia using CGM early in pregnancy with initiation of 

 
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dietary management and intensive glucose management, 
including medications if needed, at this early timepoint 
(intervention group) results in fewer APOs in the infant and 
mother compared with usual care (control group). 
• To compare CGM-measured glycemic metrics during the 
second and third trimesters of pregnancy in the Glucose 
Lowering group versus the Usual Care group. 
• To identify factors that modify the effect of early glucose-
lowering intervention compared with usual care on a reduction 
in the risk of APOs.  
• To determine the frequency of normal and abnormal OGTTs at 
24-28 weeks and APOs in pregnant individuals with no or little 
hyperglycemia at the time of study screening (i.e., screening 
CGM had hyperglycemia below the amount required for RCT 
eligibility) 
Study Design 
1. RCT of pregnant individuals with HbA1c (<6.5% [48 
mmol/mol]) and CGM-measured hyperglycemia (5% to <25% 
of values >140 mg/dL [(7.8 mmol/L)]) on initial CGM 
screening 
2. Observational study of pregnant individuals who undergo CGM 
screening but do not enter the RCT (provided that HbA1c is 
<6.5% [48 mmol/mol]) 
Number of Sites 
~10-12 sites in the United States or United Kingdom 
RCT Endpoints 
Primary Efficacy Outcome 
• Composite endpoint of (1) neonatal complications of large 
for gestational age (LGA), shoulder dystocia (including 
humeral or clavicular fracture), elevated bilirubin requiring 
phototherapy, or neonatal intensive care unit (NICU) 
admission; or (2) maternal hypertensive disorder of 
pregnancy (HDP)  
Key Secondary Efficacy Outcomes 
• Composite of neonatal complications  
• Individual maternal and neonatal complications 
• Neonatal death 
Key Safety Outcomes for Treatment Group Comparison: 
• Small for gestational age (<10th percentile) 
• CGM-measured time <54 mg/dL [3.0 mmol/L] (during 
comparative periods where Usual Care group has blinded 
CGM) 

 
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• Severe hypoglycemia events 
• Other serious adverse events 
Glycemia Exposure 
Assessment 
• CGM data obtained in the Glucose Lowering group will be 
compared with data obtained using blinded sensors in the 
Usual Care group. 
• CGM data will be assessed longitudinally within the 
Glucose Lowering group 
Population 
Inclusion Criteria 
1) Maternal age of 18 years and older 
2) Singleton pregnancy 
3) Gestational age up to 14w 6d of pregnancy, determined on 
ultrasound, for initiation of screening 
• Although it is preferable that ultrasound results be 
available prior to enrollment, if ultrasound results are not 
available at the time of enrollment, participant can have 
CGM initiated but will be dropped if not eligible after 
results are available 
4) HbA1c <6.5% (48 mmol/mol) since onset of pregnancy 
• If HbA1c result not available at time of enrollment, 
participant can have blinded screening CGM initiated, but 
results will be needed prior to randomization to verify 
eligibility. 
5) No prior history of gestational diabetes mellitus (GDM) 
6) Able to read English or Spanish 
Exclusion Criteria 
1) Signs of abnormal fetal or placental development (suspected 
fetal anomaly or placenta accreta spectrum, low PAPPA) at first 
routine prenatal visit/ultrasound 
2) Planned termination of pregnancy or any indications of 
miscarriage 
3) Prior gastric bypass surgery 
4) Pregravid diabetes (type 1 or type 2) 
5) Unwillingness/inability to wear CGM sensor  
6) Unwillingness to attend routine antenatal obstetric 
appointments 
7) Use of corticosteroids by a route that can produce 
hyperglycemia (e.g., oral, intravenous, intramuscular, intra-
articular) during the 7 days prior to initiating CGM screening or 

 
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during the CGM screening 
• Topical and inhaled corticosteroids are acceptable 
8) Use of insulin during the pregnancy prior to enrollment 
9) Use of metformin within one week of the initiation of the 
blinded CGM sensor for screening or use of a GLP-1 or other 
weight-reduction medication that can affect glucose levels 
within 4 weeks of the initiation of the blinded CGM sensor for 
screening 
10) Deemed unable to participate for medical reasons identified by 
their physician 
Additional Criteria for RCT Eligibility 
1) Screening CGM meeting study criteria for hyperglycemia: 5% 
to <25% time >140 mg/dL  
2) Randomization by 16 week 6 days of pregnancy 
3) No participation in a separate intervention trial. 
Sample Size 
Screening sample size: ~6,000 
RCT sample size: ~1,500 
Treatment Groups 
Random assignment (1:1) to  
• Glucose Lowering Group 
• Usual Care Group (with periodic blinded CGM) 
Participant Duration 
~26-30 weeks 
Study Duration 
(planned) 
~30 months from first enrollment until last participant delivery 
Protocol 
Overview/Synopsis 
Clinics 
Clinics will be selected to provide a broad representation of 
pregnant individuals, including a substantial number of underserved 
individuals. 
CGM 
Both the Dexcom G7 and Abbott FreeStyle Libre 3 sensors will be 
used in the study in both blinded and unblinded modes.   
Clinical sites will be randomly assigned to be either a Dexcom site 
or an Abbott site.  All participants at a site will use the site-assigned 
type of sensor in both blinded and unblinded modes.  
• In analyses comparing treatment groups, type of sensor will 
be a covariate 
Screening for Eligibility 
After consent is signed and eligibility determined, participants will 
wear a blinded CGM sensor for up to 10-14 days to assess for the 

 
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presence of hyperglycemia. 
• As part of usual obstetric care, HbA1c will be measured and 
an ultrasound performed if not already done. 
Determination of Eligibility for the RCT 
The blinded CGM sensor data will be evaluated to determine if the 
following criterion is met: 5% to <25% of values >140 mg/dL 
• An initial assessment will be made after 5 days and for 
those not meeting the criterion, again after 10 days 
Participants meeting the CGM hyperglycemia criteria and the other 
study eligibility criteria will proceed to randomization, which must 
be performed by 16 weeks 6 days of gestation. 
Participants who do not meet the CGM hyperglycemia criteria will 
form an observational cohort, provided that HbA1c is <6.5% (48 
mmol/mol) (see below) 
Randomized Trial 
Eligibility for the RCT will be reassessed in participants meeting 
the blinded CGM hyperglycemia criteria, including a determination 
that the participant is willing and able to follow the study protocol 
and will accept assignment to either treatment group. 
The Randomization Visit will be in clinic. All visits after 
randomization will be standard care visits. 
Eligible participants will be randomly assigned (1:1) to  
• Glucose Lowering Group: unblinded CGM plus glucose 
lowering management  
• Usual Care Group: usual care plus blinded CGM at intervals 
Glucose Lowering Group 
Management will include: 
• An unblinded CGM sensor worn 24/7 
• GDM specific nutrition information 
• Training on using CGM in daily glucose management to 
achieve euglycemia (maximizing time 63-140 mg/dL [3.5-
7.8 mmol/L]) 
• Guidelines for the clinician investigator on when and how 
to intervene pharmacologically with insulin or metformin 
o Insulin may be any commercially-available insulin 
by subcutaneous injection or inhalation in the U.S. 
or subcutaneous injection in the U.K., based on 
investigator and participant preference 
• Visits (which could be telehealth) per usual obstetrical care 
for glycemia management (expected to be about every 4 

 
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weeks for most participants)  
• Weekly glycemic management with review of CGM data by 
site and by central CGM Resource Center for flagged cases 
• Participants not receiving glucose lowering medication by 
24-28 weeks will undergo OGTT per usual obstetrical 
management 
o Participants with positive OGTT will be treated for 
GDM per usual clinic routine and continue to wear 
an unblinded CGM.  
Usual Care Group 
The control group will receive usual obstetrical care at the clinical 
center.  
• General pregnancy nutrition information handout will be 
provided to each participant. 
• A blinded CGM sensor will be placed at routine obstetrical  
care visits (no more often than once approximately every 4 
weeks) and worn for 10-14 days each time throughout the 
pregnancy beginning between 18-22 weeks gestation 
(ideally to include 20, 28, 32 and 36 weeks if available).  
o If a routine visit is performed by telemedicine, then 
the participant may place the sensor at home 
• At 18-22 weeks, blinded CGM data will be reviewed to 
assess if participant has ≥25% time >140 mg/dL to 
determine if an early OGTT or glycemic management is 
required. Site clinicians will be unblinded to the masked 
CGM data for participants with CGM data ≥25% time >140 
mg/dL and those participants may be treated as those with a 
positive OGTT. 
• An OGTT will be performed at ~24-28 weeks per the 
clinic’s usual routine 
o Participants with positive OGTT will be treated for 
GDM per usual clinic routine  
▪ Insulin, if prescribed, can be any 
commercially-available insulin by 
subcutaneous injection or inhalation in the 
U.S. or subcutaneous injection in the UK, 
based on investigator and participant 
preference 
▪ If real-time CGM is to be used, then 
unblinded study CGM sensors can be used 
instead of blinded sensors for the duration of 
the study. 

 
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▪ The usual target range will be standard of 
care targets and left to the discretion of the 
investigator. 
Both Groups 
• Serious adverse events will be reported during the 
pregnancy. Other reportable adverse events will be captured 
as part of the review of the Electronic Health Record (EHR) 
after completion of the pregnancy. 
• After completion of the pregnancy, data collected from the 
EHR will include: gestational week at time of delivery/end 
of pregnancy, maternal outcomes, fetal/neonatal outcomes, 
infant birth weight, adverse events, OGTT results, glycemic 
treatment 
Observational Cohort 
Participants who undergo CGM screening but do not enter the RCT 
(provided that HbA1c is <6.5% [48 mmol/mol]) will form an 
observational cohort. (There may be some with ≥5% time >140 
mg/dL (7.8 mmol/L) who are not randomized.) 
• There will be no study-specific visits, procedures, or data 
collection.   
• At the end of the pregnancy, information collected as part of 
usual care will be obtained from the EHR: OGTT results, 
diagnosis of GDM, and maternal and infant outcomes. 
 

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SCHEMATIC OF STUDY DESIGN 
Figure 1. Study Flow Diagram 
 
 
 
 

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SCHEDULE OF STUDY VISITS AND PROCEDURES 
Table 1. Schedule of Enrollment/Screening 
 
SCREENING 
VISIT 
PRIOR TO 
16W 6D 
GESTATION 
 
RANDOMIZATION 
VISIT 
Informed Consent 
X 
 
 
Eligibility 
Assessment* 
X 
 
X 
Blinded CGM sensor 
insertion  
X 
 
 
Review of CGM data 
centrally** 
 
X  
 
Randomization of 
eligible participants 
 
 
X 
*Although it is preferable that ultrasound and HbA1c results be available prior to enrollment, if results are not 
available at the time of enrollment, participant can be enrolled and have CGM initiated but will be dropped if not 
eligible after results are available 
**CGM data will be assessed centrally after 5 days (and again at 10 days for those not meeting the initial criterion 
at 5 days) for eligibility. Site will be informed whether participant is eligible for randomization. 
 
 

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Table 2. RCT Schedule of Procedures for Glucose-Lowering Group 
 
RANDOMIZ
ATION 
VISIT 
STANDARD 
CARE 
FOLLOW-
UP  
RESEARCH 
PROCEDURES 
END OF 
PREGNANCY 
Eligibility Assessment 
X 
 
 
 
GDM Nutrition CGM 
Education, and Glucose 
Lowering Management 
X 
 
X 
 
Clinical review of 
unblinded CGM data 
reports* 
 
 
X 
 
OGTT** 
 
X 
 
 
Chart review at end of 
pregnancy 
 
 
 
X 
Follow-up visits per standard care. 
*Weekly review of CGM data; feedback/treatment recommendations to participants as indicated. 
**May not be performed for participants receiving glucose lowering medications. 
 
 
 

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Table 3. RCT Schedule of Procedures for Usual Care Group 
 
RANDOMIZATION 
VISIT 
STANDARD 
CARE 
FOLLOW-
UP  
RESEARCH 
PROCEDURES 
END OF 
PREGNANCY 
Eligibility 
Assessment 
X 
 
 
 
General Pregnancy 
Nutrition 
Education 
X 
 
 
 
Blinded CGM use* 
 
 
X 
 
OGTT 
 
X 
 
 
Chart review at 
end of pregnancy 
 
 
 
X 
Follow-up visits per standard care 
*Blinded CGM sensor inserted at standard care visits ~every 4 weeks beginning at 18-22 weeks. 
At about 20 week CGM data will be assessed to identify participants with ≥25% CGM time >140 
mg/dL and the site will be unmasked to those identified participants CGM data.  
 

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Chapter 1: Background Information 
1 
1.1 Background and Rationale 
2 
Recent findings suggest that maternal hyperglycemia and its correlated increased risk with many 
3 
adverse pregnancy outcomes (APOs) is best mitigated with early detection and intervention prior 
4 
to the 24th week of gestation, particularly in the first trimester or the beginning of the second 
5 
trimester.1 This underscores a potential weakness in the current standard of care in which the 
6 
OGTT is administered towards the end of the second trimester when- as an increasing body of 
7 
clinical research suggests- it may be too late to counteract the adverse effects of maternal 
8 
hyperglycemia. There may be benefit in assessing and treating maternal hyperglycemia prior to 
9 
the 16th week of pregnancy. 
10 
The GLAM observational study showed overall, CGM-derived mean glucose was slightly higher 
11 
and percent time 63-120 mg/dL (3.5-6.7 mmol/L) was slightly lower in the first trimester, but 
12 
both mean glucose and percent time 63-120 mg/dL (3.5-6.7 mmol/L) remained steady in the 
13 
second and third trimesters for participants with uncomplicated pregnancies.2 The median 
14 
percent time 63-120 mg/dL (3.5-6.7 mmol/L) was 86% (interquartile range 82%-89%) 
15 
suggesting this range is seen in a large percentage of uncomplicated pregnancies and may be an 
16 
important metric to use when comparing CGM-derived metrics to perinatal outcomes in 
17 
pregnancies complicated by gestational diabetes mellitus (GDM). The median percent time >140 
18 
mg/dL (>7.8 mmol/L) was 2.5% (IQR: 1.3% to 4.1%) indicating most uncomplicated 
19 
pregnancies had approximately 30 minutes per day with glucose above 140 mg/dL (7.8 mmol/L) 
20 
often occurring after lunch or dinner. 
21 
There is no standard CGM-based glucose range for euglycemic pregnancies; recommendations 
22 
for glucose levels using CGM are mainly based off studies of participants with type 1 diabetes.3 
23 
In one study of 58 normoglycemic pregnant individuals between gestational age 8-20 weeks, 
24 
CGM data for up to 72 hours showed a percent time 63-140 mg/dL (3.5-7.8 mmol/L) of 98.2%.4 
25 
In another study of individuals with gastric bypass that used a matched control group based on 
26 
age, parity and BMI (no GDM), and found a percent time 63-140 mg/dL (3.5-7.8 mmol/L) of 
27 
96.1%, 95.9% and 93.5% in trimesters one, two and three, respectively among those without 
28 
GDM.5 The CGM-based glucose ranges observed in this study may be representative of glucose 
29 
levels in all trimesters of uncomplicated pregnancies. 
30 
The post-prandial GLAM CGM data showed the peak glucose remained relatively stable 
31 
throughout pregnancy. While there is no CGM-based consensus on a post-prandial glucose target 
32 
in non-pregnant individuals, the post-prandial levels measured by CGM in this pregnant 
33 
population are in the range of 100 to 120 mg/dL, which is similar to previously published post-
34 
prandial capillary glucose levels in participants with normoglycemic pregnancies.6, 7 Additional 
35 
analyses to confirm the observed time to peak glucose of approximately 60 minutes is similar in 
36 
the GDM population of this cohort will help assess the optimal timing for basing postprandial 
37 
glycemic targets in pregnancy, particularly when it comes to treatment with insulin. 
38 
In the current study, we propose use of blinded continuous glucose monitoring (CGM) as a tool 
39 
to detect maternal hyperglycemia in early pregnancy prior to 16 weeks 6 days gestation and then 
40 
randomly assign participants who meet a pre-specified threshold of hyperglycemia either to 
41 
begin use of unblinded CGM and glucose lowering treatment or to standard care with interval 
42 

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blinded CGM sensor wear and have a routine OGTT administered between the 24th and 28th 
43 
week of gestation (and initiate GDM treatment thereafter if so diagnosed).  
44 
Towards the goal of assessing these hypotheses, we aim:  
45 
1) To determine whether the identification of hyperglycemia using continuous glucose 
46 
monitoring (CGM) early in pregnancy with initiation of dietary and glucose management at 
47 
this timepoint (intervention group) results in fewer adverse pregnancy outcomes (APOs) 
48 
associated with hyperglycemia in the mother and infant compared with usual care (control 
49 
group). 
50 
2) To compare CGM-measured glycemic metrics during the second and third trimesters of 
51 
pregnancy in the intervention group versus the control group. 
52 
3) To identify factors that modify the effect of intensive intervention compared with usual care 
53 
on a reduction in the risk of APOs. 
54 
4) To determine the frequency of normal and abnormal OGTTs at 24-28 weeks and APOs in 
55 
pregnant individuals with no or little hyperglycemia at the time of study screening (i.e., 
56 
screening blinded CGM had hyperglycemia below the amount required for RCT eligibility) 
57 
1.2 Potential Risks and Benefits 
58 
1.2.1 Known Potential Risks 
59 
The CGM sensor may briefly produce pain when it is inserted just underneath the skin. There is a 
60 
low risk for developing a local skin infection at the site of the sensor placement.  Itchiness, 
61 
redness, bleeding, and bruising at the insertion site may occur as well as local tape reactions.  On 
62 
rare occasions, the sensor may break and leave a small portion of the sensor under the skin that 
63 
may cause redness, swelling or pain at the insertion site.  
64 
In any study with transmission of data, there is always a risk of breach of confidentiality.  
65 
However, all electronic data transfers will be encrypted, and data will be stored securely to 
66 
prevent breaches. 
67 
1.2.1.1 Risks of Glycemic Management 
68 
The goal of treatment of GDM is to achieve glucose levels as close to normal as possible to 
69 
reduce the risk of APOs.  In the study, the treatment prescribed to participants will be at 
70 
investigator discretion and may include the use of metformin and any commercially-available 
71 
insulin administered in the U.S. by subcutaneous injection or inhalation and in the UK by 
72 
subcutaneous injection.  The risks associated with metformin and insulin are described in each 
73 
drug’s Prescribing Information (product label).  The main risk of intensive glucose management 
74 
is that it may lead to an increased risk of hypoglycemia.  
75 
GDM is a known risk factor for the birth of large for gestational age (LGA) newborns. Glucose 
76 
management has been effective in reducing the incidence of LGA. However, these interventions may also 
77 
increase the risk of small for gestational age (SGA) infants. 
78 
Glucose-lowering medications that are being prescribed are considered usual care for treatment 
79 
of GDM.  Although there is no study drug or protocol specifying what drug or dose should be 
80 

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prescribed, the informed consent form nevertheless will describe the risks of insulin and 
81 
metformin. 
82 
All insulins have similar information regarding use in pregnancy, indicating that an association 
83 
with fetal abnormalities has not been demonstrated but data are lacking, and that it is clear that 
84 
treatment to limit hyperglycemia is important to minimize risks to the fetus. 
85 
1.2.2 Known Potential Benefits 
86 
Participants in the intensive group may have a reduced risk of pregnancy complications and 
87 
adverse pregnancy outcomes in their infant. 
88 
The individual participant may not benefit from study participation. 
89 
1.2.3 Risk Assessment 
90 
The study is considered greater than minimal risk with prospect of benefit as defined in 
91 
45CFR46.102. 
92 
1.3 General Considerations 
93 
The study is being conducted in compliance with ethical principles that have their origin in the 
94 
Declaration of Helsinki, with the protocol described herein, and with the standards of Good 
95 
Clinical Practice (GCP). 
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Chapter 2: Study Enrollment and Screening 
97 
2.1 Participant Recruitment and Enrollment 
98 
Enrollment will proceed with the goal of screening at least 6,000 participants (maximum 9,000) 
99 
to identify approximately 1,500 who meet the study defined threshold of CGM hyperglycemia to 
100 
be included in the randomized trial.  Screening will continue until the target for the randomized 
101 
trial is reached (unless changed as part of interim sample size reestimation as described in 
102 
section 7.10). 
103 
• Participants who have signed consent and don’t meet the CGM screening minimum 
104 
hyperglycemia criteria for eligibility for the RCT, or who meet the criteria but do not 
105 
enter the RCT, will have OGTT and maternal and neonatal outcome data collected from 
106 
medical record at the end of the pregnancy. 
107 
Study participants will be recruited from ~10 clinical centers in the United States and ~2 clinical 
108 
centers in the United Kingdom. Participants will be included without regard to gender/sex, race, 
109 
or ethnicity. There is no restriction on the number of participants to be enrolled by each site 
110 
toward the overall recruitment goal. Clinics will be selected to provide a broad representation of 
111 
pregnant individuals, including a substantial number of underserved individuals. A recruitment 
112 
target will be to have at least 25% of the cohort be from a minoritized race or ethnicity. 
113 
Individuals generally will be recruited from each site’s existing patient population or from a list 
114 
of individuals who contact the site.  Study recruitment methods may consist of one or more of 
115 
the following: 
116 
• Culling of pre-existing databases at the clinical sites to identify patients who may be 
117 
eligible. Those identified will be contacted via IRB-approved mailing sent through post, 
118 
email, or via phone and will be provided information about the study and how to proceed 
119 
if potentially interested; 
120 
• IRB-approved press release announcing study and study fact sheet; 
121 
• IRB-approved information about the study distributed through support groups, other 
122 
internet groups, patient education classes, not-for-profit organizations; 
123 
• IRB-approved paper and digital advertisements; 
124 
• IRB-approved digital advertisements posted on social media sites like LinkedIn, Twitter, 
125 
YouTube, Instagram, Facebook, and other public forums;  
126 
• In-person recruitment of patients seen in the clinic; and 
127 
• An IRB-approved website dedicated to clinical trial recruitment. 
128 
All recruitment methods and specific advertising materials will be approved by the Central 
129 
and/or local IRB prior to their implementation. 
130 
Individuals from all methods of recruitment who express an interest in participation will be 
131 
contacted by members of the research team by phone or in-person to discuss the study details and 
132 
responsibilities and evaluate whether they are likely to be eligible if they are formally screened 
133 
for the study. No study data will be recorded prior to consent being signed. 
134 
 
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2.1.1 Informed Consent and Authorization Procedures 
136 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
137 
the study and continues throughout the individual’s study participation. Informed consent will be 
138 
obtained by a method approved by the IRB (either written or electronic). 
139 
The study protocol will be discussed with the potential study participant by study staff. The 
140 
potential study participant will be given the Informed Consent Form to read. Potential study 
141 
participants will be encouraged to discuss the study with family members and their personal 
142 
physicians(s) before deciding whether to participate in the study. 
143 
If a potential participant is unable to read and understand English, then the consent form(s) must 
144 
be translated to that person’s primary language before consent occurs and a qualified interpreter 
145 
must be available for the consent process and all subsequent study interactions.  
146 
As part of the informed consent process, each participant will be asked to sign an authorization 
147 
for release of personal information. The investigator, or his or her designee, will review the 
148 
study-specific information that will be collected and to whom that information will be disclosed. 
149 
After speaking with the participant, questions will be answered about the details regarding 
150 
authorization. 
151 
A participant is considered enrolled when the informed consent form has been signed. 
152 
2.2 Participant Inclusion Criteria 
153 
Individuals must meet all of the following inclusion criteria in order to be eligible to participate 
154 
in the study. 
155 
1) Maternal age of 18 years and older 
156 
2) Singleton pregnancy 
157 
3) Gestational age up to 14w 6d of pregnancy, determined on ultrasound, for initiating of 
158 
screening 
159 
• Although it is preferable that ultrasound results be available prior to enrollment, if 
160 
ultrasound results are not available at the time of enrollment, participant can be enrolled 
161 
and have CGM initiated but will be dropped if not eligible after results are available 
162 
4) HbA1c <6.5% (48 mmol/mol) since onset of pregnancy 
163 
• If HbA1c is not available at time of consent, blinded screening CGM sensor wear can 
164 
proceed but HbA1c value must be available prior to randomization 
165 
5) No prior history of GDM 
166 
6) Able to read English or Spanish.   
167 
2.3 Participant Exclusion Criteria 
168 
1) Signs of abnormal fetal or placental development (suspected fetal anomaly or placenta 
169 
accreta spectrum, low Pregnancy Associated Plasma Protein-A (PAPPA)) at first routine 
170 
prenatal visit/ultrasound 
171 
2) Planned termination of pregnancy or any indications of miscarriage 
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3) Prior gastric bypass surgery 
173 
4) Pregravid diabetes (type 1 or type 2) 
174 
5) Unwillingness/inability to wear CGM sensor  
175 
6) Unwillingness to attend routine antenatal obstetric appointments 
176 
7)  Use of corticosteroids by a route that can produce hyperglycemia (e.g., oral, intravenous, 
177 
intramuscular, intra-articular) during the 7 days prior to initiating CGM screening or during 
178 
the CGM screening 
179 
• Topical and inhaled corticosteroids are acceptable 
180 
8) Use of insulin during the pregnancy prior to enrollment 
181 
9) Use of metformin within one week of the initiation of the blinded CGM sensor for screening 
182 
or use of a GLP-1 or other weight-reduction medication that can affect glucose levels within 
183 
4 weeks of the initiation of the blinded CGM sensor for screening 
184 
10) Deemed unable to participate for medical reasons identified by their physician 
185 
Additional Criteria for RCT Eligibility 
186 
1. Screening CGM meeting study criteria for hyperglycemia: 5% to <25% time >140 mg/dL  
187 
2. Randomization by 16 weeks 6 days of pregnancy 
188 
3. No participation in a separate interventional trial. 
189 
2.4 Screening Procedures 
190 
After informed consent has been signed, a potential participant will be evaluated for study 
191 
eligibility. Except for the 10-14 days of blinded CGM data collection, no procedures will be 
192 
performed that are not part of usual care and generally data to assess eligibility will be available 
193 
in the electronic medical record. 
194 
These data may include patient health history, prior pregnancies, demographics, height/weight, 
195 
HbA1c, and relevant ultrasound abnormalities.  
196 
A blinded CGM sensor will be placed, and replaced as needed, no later than 15 weeks 2 days of 
197 
gestation (so that there will be 10 days of sensor wear prior to the maximum time to 
198 
randomization). Participants will be instructed on care of the sensor. 
199 
2.4.1 Determination of Eligibility for RCT 
200 
The blinded CGM sensor data will be evaluated at ~5 days of blinded CGM wear to determine if 
201 
the following criteria are met:   
202 
• 5% to <25% of values >140 mg/dL 
203 
If eligibility is not met after ~5 days of blinded CGM wear, then the CGM data may be re-
204 
evaluated at ~10 days or at the end of the CGM wear. If the participant has ≥ 25% of CGM 
205 
readings >140 mg/dL, then the participant will be placed into the observational cohort.  Eligible 
206 
participants meeting the CGM hyperglycemia criteria will proceed to randomization, which must 
207 
be performed by 16 weeks 6 days of gestation. 
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2.5 Randomization 
209 
Eligibility for the RCT will be reassessed in participants meeting the screening blinded CGM 
210 
hyperglycemia criteria, including a determination that the participant is willing and able to 
211 
follow the study protocol and will accept assignment to either treatment group. 
212 
Eligible participants will be randomly assigned (1:1) to one of the following: 
213 
• Glucose Lowering Group: unblinded CGM plus glucose-lowering management  
214 
• Usual Care Group: usual care plus blinded CGM at intervals 
215 
Randomization will be stratified by site and use a permuted block design within each site. 
216 
Once a study participant is randomized, that participant will be counted regardless of whether the 
217 
assigned treatment is received. Thus, the investigator must not proceed to randomize an 
218 
individual until he/she is convinced that the individual is eligible and will accept whichever 
219 
treatment group is assigned through randomization. 
220 
Participants who are eligible but don’t proceed into the RCT will become part of the 
221 
observational cohort as described in section 2.7. 
222 
2.6 Screen Failures 
223 
Individuals who do not initially meet study eligibility requirements will not be randomized and 
224 
will not be eligible to be rescreened. 
225 
2.7 Observational Cohort 
226 
Participants screened with CGM who do not meet the CGM hyperglycemia criteria or who meet 
227 
the criteria but do not enter the RCT will form an observational cohort. There will be no study-
228 
specific visits, procedures, or data collection.  At the end of the pregnancy, information collected 
229 
as part of usual care will be obtained from the EHR, including results of the usual care OGTT 
230 
(generally at 24-28 weeks), diagnosis and treatment of GDM, and maternal and infant outcomes.
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Chapter 3: Randomized Trial Procedures 
232 
3.1 Office Visits 
233 
All visits after randomization will follow a standard care schedule, which for most participants 
234 
will be about every 4 weeks per usual care. (Some of these visits may be done via telemedicine.)  
235 
3.2 Glucose Lowering Group 
236 
Glycemic management will include the following: 
237 
• GDM-specific nutrition information handout will be provided to each participant in 
238 
addition to counseling by the clinical care team. 
239 
• An unblinded CGM sensor will be worn continuously 24/7 if possible 
240 
• Training will be provided on using CGM in daily glucose management to achieve 
241 
normoglycemia 
242 
o Participants may be trained to use the CGM app to indicate meals and exercise 
243 
when possible to aid glucose management. 
244 
The clinician investigator will perform the following: 
245 
• Weekly review of CGM data  
246 
• Intervene pharmacologically with insulin and/or metformin as determined by the 
247 
investigator 
248 
3.2.1 Glycemic Management Guidelines 
249 
Investigators will prescribe treatment in accordance with their standard care. Glycemic 
250 
management, including the type and dose of insulin to prescribe, will be at investigator 
251 
discretion. Guidelines will be provided for utilizing CGM data in the determination of optimal 
252 
therapy.  Metformin may be used based on usual prescribing practices of the clinical site. 
253 
3.3 Usual Care Group 
254 
The Usual Care group will receive usual pregnancy care at the site.  
255 
• At each routine clinic visit (expected to be about every 4 weeks through pregnancy), a 
256 
blinded CGM sensor will be placed and worn for 10-14 days.  
257 
• Blinded CGM data collection will begin around the 18-22 week routine clinic visit. 
258 
• At ~20-weeks, blinded CGM data will be reviewed to assess if participant has ≥25% time 
259 
>140 mg/dL and if an OGTT should be performed earlier or glycemic management 
260 
needed. 
261 
• Participants with positive usual care OGTT will be treated for GDM per usual clinic 
262 
routine.  
263 
3.4 Oral Glucose Tolerance Test 
264 
3.4.1 Glucose Lowering Group 
265 
An OGTT is not part of the study protocol. Per usual care, it is not expected that an OGTT will 
266 
be performed for Glucose Lowering group participants who are receiving insulin or other 
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glucose-lowering medications. An OGTT may be performed according to institutional guidelines 
268 
for participants not receiving glucose-lowering medications.  
269 
3.4.2 Usual Care Group 
270 
An OGTT, which may involve more than one test, is expected to be performed as part of usual 
271 
care for the Usual Care group, according to the sites’ institutional guidelines, generally between 
272 
24 and 28 weeks.  Results will be recorded in the study database.  
273 
• A blinded CGM sensor may be worn during the OGTT unless this is not feasible (e.g., 
274 
timing related to new sensor placement). 
275 
Participants with positive OGTT will be treated for GDM per usual clinic routine. Insulin, if 
276 
prescribed, can be any commercially-available insulin by subcutaneous injection or inhalation in 
277 
the U.S. or by subcutaneous injection in the UK, based on investigator and participant 
278 
preference. If real-time CGM is to be used, then unblinded study CGM sensors can be used 
279 
instead of blinded sensors for the duration of the study. The participant may use an unblinded 
280 
sensor or can opt to use a personal CGM that is not provided by the site; however, in the instance 
281 
of utilizing a personal CGM, that participant must continue to use the study blinded CGM sensor 
282 
per protocol for their Randomization group (see section 3.3). The usual target range will be 
283 
standard of care targets and left to the discretion of the investigator. 
284 
3.5 Data Collected at End of Pregnancy 
285 
After completion of the pregnancy, data to be entered into the study database will include 
286 
glucose-lowering treatments, maternal weight, reportable adverse events during the study, 
287 
gestation week at time of delivery/end of pregnancy, maternal outcomes, OGTT results, 
288 
fetal/neonatal outcomes, infant birth weight and height. 
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Chapter 4: Study Devices 
290 
4.1 CGM 
291 
Commercially-available Dexcom and Abbott CGM sensors will be used in the study in both 
292 
blinded and unblinded modes.   
293 
Clinical sites will be assigned to the brand of CGM used.  All participants at a site will use the 
294 
site-assigned type of sensor in both blinded and unblinded modes.  
295 
At the enrollment visit, a CGM sensor will be inserted, and the participant will be instructed on 
296 
its use and care. The device will be blinded so that the participant is not able to see the sensor 
297 
readings. A study mobile phone may be provided if necessary for running the app used for CGM 
298 
blinding.   
299 
Participants randomly assigned to the Glucose Lowering group will be supplied with sensors for 
300 
the duration of pregnancy and be instructed on sensor placement and use of CGM data in 
301 
managing glycemia.  
302 
Participants in the Usual Care group will have blinded sensors inserted during routine prenatal 
303 
care visits about every 4 weeks (or could be inserted remotely). Sensors may be replaced if 
304 
necessary. Usual Care participants diagnosed with GDM may be given an unblinded study sensor 
305 
as part of GDM management per investigator discretion.  
306 
CGM may continue through labor and delivery for the Glucose Lowering group.   
307 
4.2 Blood Glucose Meter and Strips 
308 
The Glucose Lowering group will be provided with a commercially-available blood glucose 
309 
meter that may be used to calibrate the sensor and to check the blood glucose level as 
310 
recommended by CGM manufacturers’ labeling. 
311 
4.3 Study Device Accountability Procedures 
312 
Device accountability procedures will be detailed in the site procedures manual. 
313 

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Chapter 5: Adverse Event and 
314 
Device Issue Reporting 
315 
5.1 Adverse Events 
316 
5.1.1 Definitions 
317 
Adverse Event (AE): Any untoward medical occurrence (including laboratory findings) 
318 
associated with study procedures, the use of a device, biologic, or drug in humans, including any 
319 
comparator used, whether or not the event is considered related (i.e., irrespective of the 
320 
relationship between the adverse event and the device(s) under investigation). 
321 
• To further clarify, an adverse event is any unintended disease or injury, or untoward 
322 
clinically significant clinical sign (including abnormal laboratory findings) in a 
323 
research participant that manifests while in the study if it was not present before 
324 
enrolling in the study, or if it was present before enrolling, it has increased in severity, 
325 
frequency or type since enrolling in the study. For this purpose, a participant is 
326 
considered enrolled once the participant has signed the consent form. Reportable AEs 
327 
for this protocol are defined in section 5.2. 
328 
• Medical interventions such as surgeries, diagnostic procedures, and therapeutic 
329 
procedures are not AEs but the action taken to treat a particular medical condition. If 
330 
the medical intervention relates to a pre-existing medical condition that has not 
331 
worsened since enrollment, the intervention does not need to be reported unless an 
332 
AE occurs as a result of the procedure or study drug/device needs to be temporarily 
333 
discontinued due to the procedure. Also, if the intervention is done in the absence of a 
334 
condition meeting the definition of an AE, such as for prevention (e.g. colonoscopy) 
335 
or cosmetic surgery, the intervention should not need to be reported as an AE.  If a 
336 
pre-existing medical condition worsens after enrollment, this will be reported as an 
337 
AE and the medical intervention will be recorded on the AE form as treatment of the 
338 
AE.  
339 
Serious Adverse Event (SAE): Any untoward medical occurrence that results in any of the 
340 
following outcomes: 
341 
• Maternal death 
342 
• A life-threatening adverse event; (a non-life-threatening event which, had it been 
343 
more severe, might have become life-threatening, is not necessarily considered a 
344 
serious adverse event). 
345 
• Inpatient hospitalization or prolongation of existing hospitalization. 
346 
• A persistent or significant disability/incapacity or substantial disruption of the ability 
347 
to conduct normal life functions. 
348 
• A congenital anomaly or birth defect. 
349 
An important medical event that may not result in death, be life-threatening, or require 
350 
hospitalization may be considered serious when, based upon appropriate medical 
351 
judgment, they may jeopardize the patient or subject and may require medical and 
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surgical intervention to prevent one of the outcomes listed in this definition. Note: If 
353 
either the Medical Monitor or investigator believes that the event is serious, the event 
354 
must be considered serious and evaluated by the Coordinating Center for expedited 
355 
reporting. See 21 CFR 312 for more information. 
356 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
357 
any life-threatening problem or death caused by, or associated with a study device, if that effect, 
358 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
359 
investigational plan or application (including a supplementary plan or application), or any other 
360 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
361 
welfare of participants (21 CFR 812.3(s)). 
362 
Adverse Device Effect (ADE): An adverse event related to the use of a study investigational 
363 
medical device. This definition includes adverse events resulting from insufficient or inadequate 
364 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
365 
the investigational medical device. This definition includes any event resulting from use error or 
366 
from intentional misuse of the investigational medical device. This includes comparator if the 
367 
comparator is a medical device. (Note that an Adverse Event CRF is to be completed in addition 
368 
to a Device Deficiency or Issue CRF, unless excluded from reporting as defined in section 5.8). 
369 
Comparator: Medical device, therapy (e.g., active treatment, normal clinical practice), placebo or 
370 
no treatment, used in the control group in a clinical investigation. (ISO 14155:2020) 
371 
Device Complaints and Malfunctions: A device complication or complaint is something that 
372 
happens to a study device or related to study device performance, whereas an adverse event 
373 
happens to a participant. A device complaint may occur independently from an AE, or along 
374 
with an AE. An AE may occur without a device complaint or there may be an AE related to a 
375 
device complaint. A device malfunction is any failure of a device to meet its performance 
376 
specifications or otherwise perform as intended. Performance specifications include all claims 
377 
made in the labeling for the device. For cleared devices, the intended performance of a device 
378 
refers to the intended use for which the device is labeled or marketed (21 CFR 803.3). Note: for 
379 
reporting purposes, sites will not be asked to distinguish between device complaints and 
380 
malfunctions. 
381 
User Error: User action or lack of user action while using the medical device that leads to a 
382 
different result than that intended by the manufacturer or expected by the user. Includes the 
383 
inability of the user to complete a task. Use errors can result from a mismatch between the 
384 
characteristics of the user, user interface, task or use environment. Users might be aware or 
385 
unaware that a use error has occurred. An unexpected physiological response of the patient is not 
386 
by itself considered a use error. A malfunction of a medical device that causes an unexpected 
387 
result is not considered a use error. (ISO 14155:2020) 
388 
5.2 Reportable Adverse Events 
389 
For this protocol, a reportable adverse event includes treatment related events that meets one of 
390 
the following criteria: 
391 
1. An SAE as defined in section 5.1.1, that is considered related to the study intervention in 
392 
the Glucose Lowering Group or a maternal death in both groups 
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2. 
Severe hypoglycemia meeting the following criteria: Hypoglycemia producing altered 
394 
consciousness, which required the assistance of another person to actively administer 
395 
carbohydrate, glucagon, or other resuscitative actions. This means that the participant 
396 
was impaired cognitively to the point that he/she was unable to treat himself/herself, 
397 
was unable to verbalize his/her needs, was incoherent, disoriented, and/or combative, 
398 
or experienced seizure or loss of consciousness. These episodes may be associated 
399 
with sufficient neuroglycopenia to induce seizure or loss of consciousness. If glucose 
400 
measurements are not available during such an event, neurological recovery 
401 
attributable to the restoration of glucose to normal is considered sufficient evidence 
402 
that the event was induced by a low glucose concentration. 
403 
3. Diabetic ketoacidosis (DKA) meeting the following criteria: 
404 
• Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
405 
• Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
406 
• Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate (or CO2) 
407 
<15; and 
408 
• Treatment provided in a health care facility 
409 
4. Severe skin reaction from CGM sensor that requires medical treatment 
410 
All reportable AEs in the Glucose Lowering Group will be reported on an AE CRF online. Each 
411 
AE CRF is reviewed by the Medical Monitor to assess safety and to verify the coding and the 
412 
reporting that is required. Reportable skin reactions in the Usual Care Group will be captured on 
413 
an AE CRF; other reportable AEs in the Usual Care Group will be recorded at the time of EMR 
414 
review at the end of pregnancy.  
415 
Hospitalizations, emergency room visits, and intercurrent events or treatments that could affect 
416 
glucose levels will be captured from the medical record review at the end of the pregnancy for 
417 
both groups.  
418 
5.3 Relationship of Adverse Event to Study Intervention 
419 
The site investigator will assess the relationship of any reportable adverse event to be related or 
420 
unrelated by determining if there is a reasonable possibility that the adverse event may have been 
421 
caused by the study device or intervention. The Medical Monitor also will make this assessment, 
422 
which may or may not agree with that of the site investigator. Reporting requirements will be 
423 
based on the Medical Monitor’s assessment. 
424 
To ensure consistency of adverse event causality assessments, investigators should apply the 
425 
following general guideline when determining whether an adverse event is related: 
426 
• Unrelated: The AE is clearly not related to a study drug/device/procedure and a likely 
427 
alternative etiology exists such as an underlying disease, environmental or toxic factors or 
428 
other therapy. 
429 
• Unlikely Related: The AE does not follow a reasonable temporal sequence during or after 
430 
use of study drug/device/procedure and a more likely alternative etiology exists such as an 
431 
underlying disease, environmental or toxic factors, or other therapy.  
432 

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• Possibly Related: The AE occurred in a reasonable time during or after use of study 
433 
drug/device or a study procedure; but could be related to another factor such as an underlying 
434 
disease, environmental or toxic factors, or other therapy; and there is a possible, though 
435 
weak, scientific basis for establishing a causal association between the AE and the study 
436 
drug/device. 
437 
• Probably Related: The AE occurred in a reasonable time during or after use of study 
438 
drug/device or a study procedure; is unlikely to be related to another factor such as an 
439 
underlying disease, environmental or toxic factors, or other therapy; and there is a plausible, 
440 
though not strong, scientific basis for establishing a causal association between the AE and 
441 
the study drug/device.  
442 
• Definitely Related: The AE occurred in a reasonable time during or after use of study 
443 
drug/device or a study procedure; cannot be explained by another factor such as an 
444 
underlying disease, environmental or toxic factors, or therapy; and there is a strong scientific 
445 
basis for establishing a causal association between the AE and the study drug/device. 
446 
Events determined to be Possibly Related, Probably Related, or Definitely Related will be 
447 
considered to meet the reasonable possibility causality standard for relatedness and necessitate 
448 
reporting as required (see 21 CFR 312.32 for more information).  
449 
5.4 Severity (Intensity) of Adverse Events 
450 
The severity (intensity) of a reportable adverse event will be rated on a three-point scale by the 
451 
site investigator and the Medical Monitor: (1) mild, (2) moderate, or (3) severe. A severity 
452 
assessment is a clinical determination of the intensity of an event. Thus, a severe adverse event is 
453 
not necessarily serious. For example, itching for several days may be rated as severe, but may 
454 
not be clinically serious. 
455 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
456 
participant’s daily activities. 
457 
• MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
458 
participant and may interfere with daily activities, but is usually ameliorated by simple 
459 
therapeutic measures and participant is able to continue in study. 
460 
• SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
461 
cause discontinuation of study device, and generally requires systemic drug therapy or other 
462 
treatment. 
463 
5.5 Expectedness 
464 
For a serious adverse event that is considered possibly related to study device/procedure, the 
465 
Medical Monitor will classify the event as unexpected if the nature, severity, or frequency of the 
466 
event is not consistent with the risk information previously described CGM device labeling. 
467 
5.6 Coding of Adverse Events 
468 
To facilitate coding, the site will enter a preliminary event code which the Medical Monitor may 
469 
accept or change (the Medical Monitor’s event description code will be used for all reporting and 
470 
site’s preliminary coding will not be updated or used in reporting). The Medical Monitor will 
471 
review the investigator’s assessment of causality and severity and may agree or disagree. Both 
472 

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the investigator’s and Medical Monitor’s assessments will be recorded for causality and severity. 
473 
The Medical Monitor will make the final determination with respect to causality as well as 
474 
whether an event is classified as a serious adverse event and/or an unanticipated adverse device 
475 
effect. 
476 
5.7 Outcome of Adverse Events 
477 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
478 
• RECOVERED/RESOLVED (COMPLETE RECOVERY) – The participant recovered from 
479 
the AE/SAE without sequelae. Record the AE/SAE stop date. 
480 
• RECOVERED/RESOLVED WITH SEQUELAE – AE/SAE where the subject recuperated 
481 
but retained pathological conditions resulting from the prior disease or injury.. Record the 
482 
AE/SAE stop date. 
483 
• FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that 
484 
was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time 
485 
of death; however, were not the cause of death, will be recorded as “resolved” at the time of 
486 
death. 
487 
• ONGOING (NOT RECOVERED/NOT RESOLVED) – An ongoing AE/SAE is defined as 
488 
an ongoing event with an undetermined outcome. 
489 
 
An ongoing outcome will require follow-up by the site in order to determine the final 
490 
outcome of the AE/SAE. 
491 
 
The outcome of an ongoing event at the time of death that was not the cause of death, 
492 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
493 
date. 
494 
• ONGOING (MEDICALLY STABLE) – AE/SAE is ongoing, but medically stable. For 
495 
example, a chronic condition where no further change is expected. 
496 
If any reported adverse events are ongoing when a participant completes the study (or 
497 
withdraws), adverse events classified as [SUSARs or] UADEs or related SAEs will be followed 
498 
until they are either resolved, or have no prospect of improvement or change, even after the 
499 
participant has completed all applicable study visits/contacts. For all other adverse events, data 
500 
collection will end at the time the participant completes the study unless further follow up is 
501 
requested by the Medical Monitor. Note: participants should continue to receive appropriate 
502 
medical care for an adverse event after their participation in the study ends. 
503 
If a participant is lost to follow up and participant outcome cannot be determined, outcome 
504 
classification will be the last known outcome. 
505 
5.8 Reportable Study Device Issues 
506 
CGM is the only study device. Device issues associated with a reportable AE will be reported in 
507 
a Device Issue CRF in addition to the AE CRF. 
508 
Study device complaints and device malfunctions related to CGM will only be reported if the 
509 
issue affected the CGM glucose measurements or data capture.  
510 
The following occurrences will not be reported:  
511 

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• CGM sensor or transmitter needing replacement prior to labelled maximum use duration 
512 
CGM tape adherence issues 
513 
• Battery lifespan deficiency  
514 
• Intermittent communication failures 
515 
• Device issues addressed in the user guide manual that do not require additional 
516 
troubleshooting 
517 
• Skin reaction that is not severe or does not require treatment 
518 
5.9 Timing of Event Reporting 
519 
Reportable SAEs possibly related to a study intervention and UADEs must be reported by the 
520 
investigator to the Coordinating Center within twenty-four (24) hours of the site becoming aware 
521 
of the event. This can occur via phone or email, or by completion of the AE CRF and Device 
522 
Issue CRF if applicable. If the AE CRF is not initially completed, it should be completed as soon 
523 
as possible after there is sufficient information to evaluate the event. All other reportable ADEs 
524 
and other reportable AEs should be submitted by completion on the respective CRF within seven 
525 
(7) days of the site becoming aware of the event.  
526 
The Coordinating Center will notify all participating investigators of any adverse event that is 
527 
serious, related, and unexpected. Notification will be made within ten (10) working days after the 
528 
Coordinating Center becomes aware of the event. 
529 
Each site principal investigator is responsible for reporting serious study-related adverse events 
530 
and abiding by any other reporting requirements specific to his/her Institutional Review Board or 
531 
Ethics Committee.  
532 
Upon receipt of a qualifying event, the Coordinating Center will investigate the event to 
533 
determine if a UADE has occurred, and if indicated, report the results of the investigation to all 
534 
overseeing IRBs, and the FDA within ten (10) working days of the Coordinating Center 
535 
becoming aware of the UADE per 21CFR 812.46(b) (2). The Coordinating Center in conjunction 
536 
with the Medical Monitor must determine if the UADE presents an unreasonable risk to 
537 
participants. If so, the Coordinating Center must ensure that all investigations, or parts of 
538 
investigations presenting that risk, are terminated as soon as possible but no later than five (5) 
539 
working days after the Coordinating Center makes this determination and no later than fifteen 
540 
(15) working days after first receipt notice of the UADE. The investigator(s) may then be 
541 
required to provide approval or acknowledgment of receipt of that notification and must submit 
542 
to their overseeing IRB as required.  
543 
The investigators are also required to report, without unjustified delay, all reportable device 
544 
deficiencies that could have led to a UADE, including device deficiencies, irrespective of 
545 
whether an adverse event occurred. 
546 
5.10 Safety Oversight 
547 
The study Medical Monitor will review all reported adverse events and device issues that are 
548 
reported during the study. SAEs typically will be reviewed within twenty-four (24) hours of 
549 
reporting. Other AEs typically will be reviewed on a weekly basis. Additionally, the Medical 
550 
Monitor will review compiled safety data at periodic intervals. 
551 

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The Clinical Study Director will be informed of all cases of severe hypoglycemia and DKA and 
552 
the Medical Monitor’s assessment of relationship to the study intervention. 
553 
A Data and Safety Monitoring Board (DSMB) will be informed of all cases of severe 
554 
hypoglycemia, diabetic ketoacidosis, and intervention-related SAEs that occur in the Glucose 
555 
Lowering Group at the time that they occur during the study and will review compiled safety 
556 
data annually. The DSMB can request modifications to the study protocol or suspension or 
557 
outright stoppage of the study if deemed necessary based on the totality of safety data available. 
558 
Details regarding DSMB review will be documented in a separate DSMB document. 
559 
5.11 Stopping Criteria 
560 
5.11.1 Participant Discontinuation of Study Intervention 
561 
The study intervention will be discontinued if any of the following occur:  
562 
• The investigator believes it is unsafe for the participant to continue on the intervention. 
563 
This could be due to the development of a new medical condition or worsening of an 
564 
existing condition; or participant behavior contrary to the indications for use of the 
565 
device that imposes on the participant’s safety 
566 
• The participant requests that the treatment be stopped 
567 
Even if the study intervention is discontinued, the participant will be encouraged to remain in the 
568 
study through the end of pregnancy, unless the participant formally withdraws. Medical record 
569 
information collected up to the time of formal withdrawal will still be captured. 
570 
5.11.2 Criteria for Suspending or Stopping Overall Study 
571 
Study activities could be suspended if the Medical Monitor deems suspension of study activities 
572 
or stoppage of the study necessary based on the totality of safety data available or if the CGM 
573 
manufacturer requires stoppage of device use for safety reasons (e.g., product recall). The 
574 
affected study activities may resume if the underlying problem can be corrected by a protocol or 
575 
system modification that will not invalidate the results obtained prior to suspension. 
576 

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Chapter 6: Miscellaneous Considerations 
577 
6.1 Collection of Medical Conditions and Medications in Randomized Study Participants 
578 
At the end of the pregnancy, information will be retrieved from the medical record for relevant 
579 
medical conditions that developed during the study and the use of medications that could affect 
580 
glucose levels or maternal or fetal health. 
581 
6.2 Participant Compensation 
582 
Participant compensation will be specified in the informed consent form. 
583 
6.3 Participant Withdrawal 
584 
Participation in the study is voluntary, and a participant may withdraw at any time. The reason 
585 
for withdrawal will be recorded. For participants who discontinue the study but don’t formally 
586 
withdraw consent for further data collection, data will be extracted from the EMR after the end 
587 
of pregnancy similar to the Observational cohort. For participants who withdraw consent for 
588 
further data collection, their data collected for the study and available in the EMR will be used 
589 
up until the time of withdrawal. 
590 
6.4 Unanticipated Problems 
591 
Site investigators will promptly report all suspected unanticipated problems meeting the criteria 
592 
below to the Coordinating Center. Sites must also report Unanticipated Problems to the IRB of 
593 
record within the timeline specified by the IRB. For this protocol, an unanticipated problem is 
594 
any incident, experience, or outcome that meets all of the following criteria: 
595 
• Unexpected (in terms of nature, severity, or frequency) given the information provided in 
596 
research-related documents and the characteristics of the subject population being studied 
597 
• Related or possibly related to participation in the research  
598 
• Suggests that the research places participants or others at a greater risk of harm than was 
599 
previously known or recognized 
600 
6.5 Confidentiality 
601 
For security and confidentiality purposes, participants will be assigned an identifier that will be 
602 
used instead of their name. Protected health information gathered for this study will be shared 
603 
with the coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified 
604 
participant information may also be provided to research sites involved in the study. 
605 

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Chapter 7: Statistical Considerations 
606 
7.1 Statistical and Analytical Plans 
607 
The approach to sample size and statistical analyses are summarized below. 
608 
A detailed statistical analysis plan (SAP) will be finalized before the first database lock. Any 
609 
deviations from the analyses described below will be described in the SAP. 
610 
The statistical plan below refers to the RCT.  The statistical plan for the observational study is 
611 
described in section 7.15. 
612 
7.2 Statistical Hypotheses 
613 
The primary endpoint is a test for superiority in the incidence of the primary composite endpoint 
614 
comparing the two treatment groups (the Glucose Lowering group and the Usual Care group). 
615 
The statistical hypotheses for the primary endpoint is as follows: 
616 
Null Hypothesis: There is no difference in the incidence of the composite endpoint between the 
617 
Glucose Lowering and Usual Care groups. 
618 
Alternative Hypothesis: There is a nonzero difference in the incidence of the composite endpoint 
619 
between the Glucose Lowering and Usual Care groups. 
620 
7.3 Sample Size 
621 
Sample size has been computed for the primary composite endpoint. We expect ~25% of 
622 
screened participants to meet the eligibility requirement of 5 to <25% time >140 mg/dL at prior 
623 
to 17 weeks’ gestation.  To achieve 90% power in detecting a difference in composite endpoint 
624 
prevalence between the Glucose Lowering and Usual Care groups, assuming an estimated 41% 
625 
of participants with the composite endpoint in the Usual Care group, an expected relative risk 
626 
reduction of the composite endpoint of 25% in the Glucose Lowering group, a two-sided test, 
627 
and a type I error rate of 5%, the calculated sample size is 900 participants randomized. The 
628 
sample size has been increased to 1,500 randomized (~6,000 screened) to account for dropouts 
629 
and additional exposure time. Screening will continue until 1,500 have been randomized (or 
630 
expected to be randomized), unless this number is changed following an interim sample size re-
631 
estimation. 
632 
7.4 Outcome Measures 
633 
7.4.1 Primary Efficacy Endpoint 
634 
The primary endpoint is: 
635 
• A composite that includes the following: 
636 
o Large for gestational age (LGA) 
637 
o Shoulder dystocia (including humeral or clavicular fracture) 
638 
o Elevated bilirubin requiring phototherapy 
639 
o Neonatal intensive care unit (NICU) admission 
640 
o Maternal hypertensive disorder of pregnancy (HDP) 
641 

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642 
7.4.2 Secondary Efficacy Endpoints 
643 
• Composite consisting of neonatal complications of LGA, shoulder dystocia (including 
644 
humoral or clavicular fracture), elevated bilirubin requiring phototherapy, NICU 
645 
admission 
646 
• Maternal HDP 
647 
• LGA  
648 
• Shoulder dystocia 
649 
• Elevated bilirubin requiring phototherapy 
650 
• Neonatal death 
651 
• NICU admission 
652 
7.4.3 Safety Endpoints 
653 
• Small for gestational age (SGA, <10th percentile) 
654 
• CGM-measured time <54 mg/dL (during comparative periods where Usual Care group 
655 
has blinded CGM) 
656 
• Severe hypoglycemia events 
657 
• Other serious adverse events 
658 
7.5 Analysis Datasets and Per-Protocol Analyses 
659 
All efficacy and safety analyses comparing the treatment groups will follow the intention-to-treat 
660 
approach, which means participants will be analyzed in the treatment arm assigned by 
661 
randomization regardless of actual treatment received. All randomized participants will be 
662 
included in the efficacy and safety analyses unless otherwise specified. 
663 
A per-protocol analyses will be performed for the primary endpoint only if >5% of participants 
664 
will be excluded due to not adhering to the protocol as defined in the SAP. 
665 
7.6 Analysis of the Primary Efficacy Endpoint 
666 
The primary composite endpoint at delivery will be compared between the Glucose Lowering 
667 
and Usual Care groups using a logistic regression model with a compound symmetry covariance 
668 
structure to handle the correlation within site. In the event that the primary composite endpoint at 
669 
delivery is missing, multiple imputation with treatment group in the model will be used to handle 
670 
missing values. Imbalances between groups in important covariates are not expected to be of 
671 
sufficient magnitude to produce confounding. However, the presence of confounding will be 
672 
evaluated in the sensitivity analyses by including factors potentially associated with the outcome 
673 
for which there is an imbalance between groups (section 7.7). 
674 
A 95% confidence interval (CI) will be constructed on the treatment group risk difference 
675 
(Glucose Lowering minus Usual Care). 
676 

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7.7 Sensitivity Analyses 
677 
Confounding 
678 
A sensitivity analysis will be conducted if potential confounding factors collected at baseline are 
679 
imbalanced between treatment groups. The imbalance will be assessed based on clinical 
680 
judgment reviewing the distributions in the two treatment arms, not on a p-value. The person 
681 
making this judgement will be unaware of whether there is an association between baseline 
682 
variables and study outcome. All variables obtained on a continuous scale will be entered into 
683 
the models as continuous variables, unless it is determined that a variable does not have a linear 
684 
relationship with the log odds of the outcome. In such a case, categorization and/or 
685 
transformation will be explored. 
686 
Missing Data 
687 
Missing data will be handled using multiple imputation using treatment group in the imputation 
688 
model assuming the outcome is missing at random. It is worth noting that all statistical methods 
689 
for handling missing data rely on untestable assumptions and there is no one correct way to 
690 
handle missing data. The goal is to minimize the amount of missing data so that the results will 
691 
not be sensitive to which statistical method is used.  
692 
To that end, sensitivity analyses will be performed to explore whether results are similar for the 
693 
primary analysis when using different methods. Sensitivity analyses will only be performed if 
694 
>5% of the primary composite outcome is missing. The following methods will be applied: 
695 
• Multiple imputation with a pattern mixture model assuming the dropout trajectory of the 
696 
Glucose Lowering group is that of the Usual Care group 
697 
• Available cases only  
698 
• Two-way tipping point analysis 
699 
7.8  Analysis of Secondary Efficacy Endpoints 
700 
7.8.1  Binary Outcomes 
701 
Binary outcomes will be compared between the Glucose Lowering and Usual Care groups using 
702 
models similar to that of the primary composite endpoint (section 7.6). Endpoints are only tested 
703 
if there are enough events (at least 5 events combined between the two treatment groups).  
704 
7.8.2 Additional Exploratory Analyses 
705 
Weight gain from randomization to end of pregnancy will be compared between groups.  
706 
Within each group, the association of hyperglycemia and other CGM metrics with maternal and 
707 
fetal/neonatal outcomes will be explored. 
708 
Additional exploratory analyses will be detailed in the SAP. 
709 

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7.9  Safety Analyses 
710 
All randomized participants will be included in the safety analyses. All reportable adverse events 
711 
will be tabulated by treatment group. Safety analyses for the RCT will include events occurring 
712 
on or after randomization until hospital discharge following the delivery. 
713 
For the following outcomes, the number of participants with ≥1 event and number of events will 
714 
be tabulated by treatment group:  
715 
• SGA (<10th percentile) 
716 
• Severe hypoglycemia events 
717 
• Other serious adverse events 
718 
If enough events occur (at least 5 events combined between the two treatment groups), the 
719 
prevalence of SGA will be summarized and a formal statistical comparison between treatment 
720 
groups will be performed using a model similar to that used for the primary composite endpoint 
721 
(section 7.6).  
722 
CGM-measured time <54 mg/dL will be calculated and compared between treatment groups 
723 
using a linear mixed effects regression model adjusting for the baseline time <54 mg/dL, sensor 
724 
type, and site (random effect).  A separate variance will be modelled for each treatment group.  
725 
Residual values will be examined for an approximate normal distribution.  If residuals are highly 
726 
skewed, then a generalized linear mixed effects regression model with the t-distribution for the 
727 
error terms will be used instead. Missing data will be handled using direct likelihood. 
728 
7.10  Planned Interim Analyses 
729 
Re-estimation of the sample size will be undertaken as specified in the Statistical Analysis Plan 
730 
or a separate Sample Size Re-estimation Plan. The analysis will determine if the eligibility 
731 
criterion based on the blinded CGM screening and the planned RCT sample size meets the 
732 
desired power.  The sample size may be modified or eligibility criteria revised based on the 
733 
analysis. 
734 
7.11 Subgroup Analyses 
735 
In exploratory analyses, the primary composite endpoint, LGA, and HDP will be compared in 
736 
baseline subgroups. Treatment group by subgroup factor interaction terms will be added to the 
737 
models described in sections 7.6 and 7.8.1. 
738 
• Formal statistical testing for interaction will be done only if the overall result is 
739 
statistically significant. Results will be tabulated by subgroups regardless of statistical 
740 
significance.  For continuous variables, results will be displayed in subgroups based on 
741 
the distribution of the data although the analysis will utilize the variable as continuous. 
742 
Cut point selection for display purposes will be made masked to the outcome data. 
743 
• Subgroups will be analyzed according to the following baseline factors: 
744 
o Baseline HbA1c 
745 

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o Baseline % time >140 mg/dL 
746 
o Age  
747 
o Race/Ethnicity  
748 
o BMI 
749 
o Additional subgroups to be defined in the SAP 
750 
7.12 Glucose Exposure Assessment 
751 
Glucose exposure will be assessed using CGM which will be unblinded in the Glucose Lowering 
752 
group and blinded in the Usual Care group. CGM data collected during screening will be used to 
753 
calculate the baseline values for each CGM metric. CGM data collected after randomization up 
754 
until the day before the delivery date will be used to calculate the CGM metrics for the follow-up 
755 
period. During the follow-up period, time periods of CGM data in the Glucose Lowering group 
756 
will be matched to the blinded CGM wear periods in the Usual Care group (the matching process 
757 
will be described in the SAP). 
758 
CGM Metrics  
759 
• Mean glucose 
760 
• Glucose standard deviation 
761 
• Glucose coefficient of variation 
762 
• % Time 63-120 mg/dL 
763 
• % Time 63-140 mg/dL 
764 
• % Time <63 mg/dL 
765 
• % Time >120 mg/dL 
766 
• % Time >140 mg/dL 
767 
• Glucose level at 5 AM 
768 
Summary statistics (mean ± SD or median [interquartile range]) will be reported for the CGM 
769 
metrics at baseline and follow-up for each treatment group. CGM metrics will also be 
770 
summarized by daytime and nighttime, by trimester, and by 4-week time periods. Daytime is 
771 
defined as 6:00am to 11:59pm and nighttime from 12:00mn to 5:59am. 
772 
CGM metric differences between treatment groups will be compared using a linear mixed effects 
773 
regression model adjusting for the baseline value of the metric, type of sensor, and site (random 
774 
effect).  A separate variance will be modelled for each treatment group.  Residual values will be 
775 
examined for an approximate normal distribution.  If residuals are highly skewed, then a 
776 
generalized linear mixed effects regression model with the t-distribution for the error terms will 
777 
be used instead. Missing data will be handled using direct likelihood.   
778 
Within the Glucose Lowering group, additional tabulations of CGM metrics will be done by 
779 
gestational week. 
780 

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7.13 Multiple Comparison/Multiplicity 
781 
The primary statistical analysis will be conducted using a p value threshold for significance of 
782 
0.05. For the secondary and exploratory efficacy analyses, the false discovery rate will be 
783 
controlled using the adaptive Benjamini-Hochberg procedure. 
784 
P-values from the safety analyses, sensitivity analyses, and per-protocol analyses will not be 
785 
adjusted for multiple comparisons. 
786 
7.14 Additional Tabulations and Analyses 
787 
The following tabulations will be performed according to treatment group: 
788 
• Baseline demographic and clinical characteristics, including maternal weight, gestational 
789 
week at time of delivery/end of pregnancy, infant birth weight and height 
790 
• Flow chart accounting for all participants 
791 
• Protocol deviations 
792 
• Usual Care group: diagnosis of GDM 
793 
• Glucose Lowering group: glucose-lowering treatment received 
794 
7.15 Observational Study 
795 
All participants who complete the screening blinded CGM data collection, except for participants 
796 
with HbA1c ≥6.5%, are enrolled into the Observational cohort. 
797 
Data will be extracted from the EHR after the end of pregnancy. Tabulations will include 
798 
• Baseline demographic and clinical characteristics 
799 
• OGTT results/GDM diagnosis 
800 
• Fetal and maternal outcomes as described in sections 7.4.1 and 7.4.2. 
801 
Exploratory analyses will compare the screening CGM metrics to the OGTT and fetal/maternal 
802 
outcomes. 
803 

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Chapter 8: Data Collection and Monitoring 
804 
8.1 Case Report Forms and Other Data Collection 
805 
The main study data are collected on electronic case report forms (CRFs) from EHR review and 
806 
from CGM data downloads. When data are directly collected in electronic case report forms, this 
807 
will be considered the source data. For any data points for which the eCRF is not considered 
808 
source (e.g., lab results that are transcribed from a printed report into the eCRF), the original 
809 
source documentation must be maintained in the participant’s study chart or medical record and 
810 
be able for verification as needed per the monitoring plan. This source must be readily verifiable 
811 
against the values entered into eCRF. Even where all study data are directly entered into the 
812 
eCRFs at office visits, evidence of interaction with a live subject must be recorded (e.g., office 
813 
note, visit record, etc.). 
814 
Electronic device data files are obtained from the study software and individual hardware 
815 
components. These electronic device files are considered the primary source documentation. 
816 
8.2 Study Records Retention 
817 
Each participating site will maintain appropriate medical and research records for this trial, in 
818 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
819 
confidentiality of participants. 
820 
Study documents should be retained for a minimum of 2 years after the date that the 
821 
investigation is terminated or completed. These documents should be retained for a longer 
822 
period, however, if required by local regulations. No records will be destroyed without the 
823 
written consent of the Coordinating Center. It is the responsibility of the Coordinating Center to 
824 
inform the investigator when these documents no longer need to be retained. 
825 
8.3 Quality Assurance and Monitoring 
826 
Designated JCHR personnel will be responsible for maintaining quality assurance (QA) and 
827 
quality control (QC) systems to ensure that the clinical portion of the trial is conducted and data 
828 
are generated, documented and reported in compliance with the protocol, Good Clinical Practice 
829 
(GCP) and the applicable regulatory requirements, as well as to ensure that the rights and 
830 
wellbeing of trial participants are protected and that the reported trial data are accurate, complete, 
831 
and verifiable. Adverse events will be prioritized for monitoring. 
832 
A risk-based monitoring plan will be developed and revised as needed during the study, 
833 
consistent with FDA’s risk-based monitoring guidance, “Guidance for Industry Oversight of 
834 
Clinical Investigations — A Risk-Based Approach to Monitoring” (August 2013). Study conduct 
835 
and monitoring will conform with 21 Code of Federal Regulations (CFR) 812. The monitoring 
836 
plan details who will conduct the monitoring, at what frequency monitoring will be done, at what 
837 
level of detail monitoring will be performed, and the distribution of monitoring reports. 
838 
The data of most importance for monitoring at the site are participant eligibility and adverse 
839 
events. Therefore, the monitoring plan will focus on these areas. As much as possible, remote 
840 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
841 
verity and completeness of critical data and processes. Elements of the monitoring plan may 
842 
include: 
843 

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• Qualification assessment, training, and certification for sites and site personnel 
844 
• Oversight of Institutional Review Board (IRB) coverage and informed consent 
845 
procedures 
846 
• Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
847 
review of entered data and edits, statistical monitoring, study closeout 
848 
• On-site monitoring (site visits): source data verification, site visit report 
849 
• Investigational Product accountability 
850 
• Communications with site staff 
851 
• Patient retention and visit completion 
852 
• Quality control reports 
853 
• Management of noncompliance 
854 
• Documenting monitoring activities 
855 
• Adverse event reporting and monitoring 
856 
JCHR representatives or their designees may visit the study facilities at any time to maintain 
857 
current and personal knowledge of the study through review of the records, comparison with 
858 
source documents, observation and discussion of the conduct and progress of the study. Clinical 
859 
sites will provide direct access to all trial-related facilities/equipment, source data/documents, 
860 
and reports for the purpose of monitoring and auditing by the Coordinating Center, and 
861 
inspection by local and regulatory authorities. 
862 
8.4 Protocol Deviations 
863 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
864 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
865 
the study site staff. A significant (or major) deviation is any deviation that departs from the 
866 
established materials in such a way that it poses an increase in the risk to subjects, adversely 
867 
affects the welfare, rights, or safety of the research subjects, or negatively influences the 
868 
scientific study integrity. As a result of a significant deviation, a corrective and preventive action 
869 
plan shall be developed by the site and implemented promptly. 
870 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements. 
871 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
872 

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Chapter 9: Ethics/Protection of Human Participants 
873 
9.1 Ethical Standards 
874 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
875 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
876 
21 CFR Part 56, and/or the ICH E6. 
877 
9.2 Institutional Review Boards 
878 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
879 
be submitted to the JCHR IRB for review and approval as the IRB of Record for the US sites. 
880 
Approval of both the protocol and the consent form must be obtained before any participant is 
881 
enrolled. Any amendment to the protocol will require review and approval by the IRB before the 
882 
changes are implemented to the study. All changes to the consent form will be approved by the 
883 
IRB, which will determine whether previously consented participants need to be re-consented. 
884 
9.3 Participant and Data Confidentiality 
885 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
886 
and the Coordinating Center and their agents. This confidentiality is extended to cover testing of 
887 
biological samples and genetic tests in addition to the clinical information relating to 
888 
participants. Therefore, the study protocol, documentation, data, and all other information 
889 
generated will be held in strict confidence. No information concerning the study or the data will 
890 
be released to any unauthorized third party without prior written approval of the Coordinating 
891 
Center. 
892 
The study monitor, other authorized representatives of the Coordinating Center, representatives 
893 
of the IRB, regulatory agencies or company supplying study product may inspect all documents 
894 
and records required to be maintained by the investigator, including but not limited to, medical 
895 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
896 
clinical study site will permit access to such records. 
897 
The study participant’s contact information will be securely stored at each clinical site for 
898 
internal use during the study. At the end of the study, all records will continue to be kept in a 
899 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
900 
Coordinating Center requirements. 
901 
Study participant research data, which is for purposes of statistical analysis and scientific 
902 
reporting, will be transmitted to and stored at the Jaeb Center for Health Research. This will not 
903 
include the participant’s contact or identifying information, unless otherwise specified in the 
904 
informed consent form. Rather, individual participants and their research data will be identified 
905 
by a unique study identification number. The study data entry and study management systems 
906 
used by clinical sites and by the Jaeb Center for Health Research staff will be secured and 
907 
password protected. At the end of the study, all study databases will be de-identified and 
908 
archived at the Jaeb Center for Health Research. 
909 
9.4 Future Use of Stored Data 
910 
Data collected for this study will be analyzed and stored at the Jaeb Center for Health Research. 
911 
No specimens will be stored from the study.
912 

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Chapter 10: References 
913 
1. Management of Diabetes in Pregnancy: Standards of Medical Care in Diabetes—2019. 
914 
Diabetes Care. 2019;42(Supplement 1):S165-S172. doi:10.2337/dc19-S014 
915 
2. Carlson, A.L., Beck, R.W., Li, Z., et al. Glucose levels measured with continuous glucose 
916 
monitoring in uncomplicated pregnancies. BMJ Open Diabetes Res Care 2024; 12:(3). 
917 
doi:10.1136/bmjdrc-2023-003989.PMID:38729771. PMC11097821. 
918 
3. Feig DS, Donovan LE, Corcoy R, et al. Continuous glucose monitoring in pregnant women 
919 
with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial. 
920 
Lancet 2017;390:2347-2359 
921 
4. Gupta Y, Singh C, Goyal A, et al. Continuous glucose monitoring system profile of women 
922 
diagnosed as gestational diabetes mellitus by International Association of Diabetes and 
923 
Pregnancy Study Groups criteria and labeled as normoglycemic by alternate criteria in early 
924 
pregnancy. J Diabetes Investig 2022;13:1753-1760 
925 
5. Stentebjerg LL, Madsen LR, Støving RK, et al. Roux-en-Y Gastric Bypass Increases 
926 
Glycemic Excursions During Pregnancy and Postpartum: A Prospective Cohort Study. 
927 
Diabetes Care 2023;46:502-510 
928 
6. Harmon KA, Gerard L, Jensen DR, et al. Continuous glucose profiles in obese and normal-
929 
weight pregnant women on a controlled diet: metabolic determinants of fetal growth. 
930 
Diabetes Care 2011;34:2198-2204 
931 
7. Hernandez TL, Friedman JE, Van Pelt RE, et al. Patterns of glycemia in normal pregnancy: 
932 
should the current therapeutic targets be challenged? Diabetes Care 2011;34:1660-1668 
933 
 
934