Human Versus Analogue Insulin for Youth With Type 1 Diabetes in Low-Resource Settings: A Randomized Controlled Trial
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 1, Type 1 Diabetes
Sponsor: Jing Luo

Human versus Analogue Insulin for Youth with Type 1 
Diabetes in Low-Resource Settings: A Randomized 
Controlled Trial (HumAn-1 trial) 
 
Protocol Number: 1 
National Clinical Trial (NCT) Identified Number:  NCT05614089 
Principal Investigator: Jing Luo, MD, MPH 
Sponsor: University of Pittsburgh 
Funded by: The Leona M. and Harry B. Helmsley Charitable Trust 
 
Version Number:  6.1 
9 July 2025 
 
 
Summary of Changes from Previous Version (6.0): 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
9.4.2 
 
Updated info about replacement sensors and 
how they will be analyzed. 
 
Included example that replacement sensors 
should be replaced when no data is present 
due to “sensor error/download error”. 
Added how replacement errors applied 
belatedly will be analyzed in an exploratory 
analysis. 
 
 
 
 
 
 

  
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 2 
1.3 
Schedule of Activities (SoA) / Evaluations Calendar ...................................................................... 3 
2 
INTRODUCTION ............................................................................................................................................ 4 
2.1 
Study Rationale .................................................................................................................................... 4 
2.2 
Background........................................................................................................................................... 4 
2.3 
Risk/Benefit Assessment .................................................................................................................... 5 
2.3.1 
Known Potential Risks ..................................................................................................... 5 
2.3.2 
Known Potential Benefits ................................................................................................ 5 
2.3.3 
Assessment of Potential Risks and Benefits ................................................................ 5 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 6 
4 
STUDY DESIGN ............................................................................................................................................. 7 
4.1 
Overall Design ...................................................................................................................................... 7 
4.2 
Scientific Rationale for Study Design................................................................................................ 8 
4.3 
Justification for Dose ........................................................................................................................... 8 
4.4 
End of Study Definition ....................................................................................................................... 8 
5 
STUDY POPULATION .................................................................................................................................. 8 
5.1 
Inclusion Criteria .................................................................................................................................. 8 
5.2 
Exclusion Criteria ................................................................................................................................. 8 
5.3 
Lifestyle Considerations ...................................................................................................................... 9 
5.4 
Screen Failures .................................................................................................................................... 9 
5.5 
Strategies for Recruitment and Retention ........................................................................................ 9 
6 
STUDY INTERVENTION ............................................................................................................................ 10 
6.1 
Study Intervention(s) Administration ............................................................................................... 10 
6.1.1 
Study Intervention Description ..................................................................................... 10 
6.1.2 
Dosing and Administration ............................................................................................ 10 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 11 
6.2.1 
Acquisition and accountability ...................................................................................... 11 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 12 
6.2.3 
Product Storage and Stability ....................................................................................... 12 
6.2.4 
Preparation ...................................................................................................................... 12 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 12 
6.4 
Study Intervention Compliance ........................................................................................................ 12 
6.5 
Concomitant Therapy ........................................................................................................................ 13 
6.5.1 
Rescue Medicine ............................................................................................................ 13 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 13 
7.1 
Discontinuation of Study Intervention ............................................................................................. 13 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 13 
7.3 
Lost to Follow-Up ............................................................................................................................... 14 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 14 
8.1 
Efficacy Assessments ....................................................................................................................... 14 
8.2 
Safety and Other Assessments ....................................................................................................... 14 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 16 

  
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 16 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 16 
8.3.3 
Classification of an Adverse Event .............................................................................. 16 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 17 
8.3.5 
Adverse Event Reporting .............................................................................................. 18 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 18 
8.3.7 
Reporting Events to Participants ................................................................................. 18 
8.3.8 
Events of Special Interest ............................................................................................. 18 
8.3.9 
Reporting of Pregnancy ................................................................................................ 18 
8.4 
Unanticipated Problems .................................................................................................................... 18 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 18 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 19 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 19 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 19 
9.1 
Statistical Hypotheses ....................................................................................................................... 19 
9.2 
Sample Size Determination .............................................................................................................. 20 
9.3 
Populations for Analyses .................................................................................................................. 21 
9.4 
Statistical Analyses............................................................................................................................ 21 
9.4.1 
General Approach .......................................................................................................... 21 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 21 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 23 
9.4.4 
Safety Analyses .............................................................................................................. 23 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 23 
9.4.6 
Planned Interim Analyses ............................................................................................. 24 
9.4.7 
Sub-Group Analyses ..................................................................................................... 24 
9.4.8 
Tabulation of Individual participant Data .................................................................... 24 
9.4.9 
Exploratory Analyses ..................................................................................................... 24 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 24 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 24 
10.1.1 
Informed Consent Process ........................................................................................... 24 
10.1.2 
Study Discontinuation and Closure ............................................................................. 25 
10.1.3 
Confidentiality and Privacy ........................................................................................... 26 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 26 
10.1.5 
Key Roles and Study Governance .............................................................................. 26 
10.1.6 
Safety Oversight ............................................................................................................. 27 
10.1.7 
Clinical Monitoring .......................................................................................................... 27 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 27 
10.1.9 
Data Handling and Record Keeping ............................................................................ 28 
10.1.10 
Protocol Deviations ........................................................................................................ 28 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 29 
10.1.12 
Conflict of Interest Policy .............................................................................................. 29 
10.2 
Additional Considerations ................................................................................................................. 30 
10.3 
Abbreviations ...................................................................................................................................... 31 
10.4 
Protocol Amendment History ........................................................................................................... 33 
11 
REFERENCES ............................................................................................................................................. 36 
 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the University of Pittsburgh Institutional Review Board (IRB) for review and approval.  
Approval of both the protocol and the consent form must be obtained before any participant is enrolled.  
Any amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from participants 
who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Analogue vs Human Insulin for Youth with Type 1 Diabetes in Low-
Resource Settings: A Randomized Controlled Trial (HumAn-1 trial) 
Study Description: 
The HumAn-1 trial is 1:1 randomized, parallel-group, open-label trial 
comparing insulin glargine, a basal insulin analogue, against human insulin 
(NPH or premixed 70/30) in youth living with type 1 diabetes (T1D) in low 
resource settings. 
Objectives 
Primary Objective: To determine whether insulin glargine reduces the risk 
of serious hypoglycemia or improves Time in Range over 3-6 months when 
compared against standard of care human insulin (e.g. NPH or premixed 
70/30) among youth living with type 1 diabetes (T1D) in low resource 
settings. 
Endpoints: 
Co-Primary Endpoints: Time in serious hypoglycemia and Time in range 
Study Population: 
Youth living with type 1 diabetes (T1D) in low resource settings. 
Phase: 
N/A 
Description of 
Sites/Facilities Enrolling 
Participants: 
Bangladesh (Dhaka), Tanzania (Mwanza)  
Description of Study 
Intervention: 
Insulin glargine (a long-acting insulin analogue) 
Study Duration: 
3 Years 
Participant Duration: 
1 Year (12 months) 
 
 

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1.2 
SCHEMA 
 
 
 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) / EVALUATIONS CALENDAR 
 
Procedures 
Screening/Baseline 
Visits 
Day -8 weeks to -1 Day 
Clinic Visit #0 (Run-in) 
Day 0 
 Phone Visits #1-4 
Day +3 to +14 
Clinic Visit 1 
+3 months 
Home Visit* #1 
+3.5 months 
Clinic Visit 2 
+6 months 
Home Visit* #2 
+6.5 months 
Home Visit # 3 
+7 months 
Clinic Visit 3 
+9 months 
Home Visit* #4 (2 
weeks before final 
Final clinic visit (4) 
+12 months 
Confirm Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics + Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
Quality of Life Survey  (e.g. 
PedsQL, ITSQ) 
X 
 
 
 
 
X 
 
 
 
 
X 
Baseline labs are drawn 
X 
 
 
 
 
 
 
 
 
 
 
Baseline CGM placed (sensor 
#0) 
X 
 
 
 
 
 
 
 
 
 
 
Scan and upload baseline 
CGM sensor data 
 
X 
 
 
 
 
 
 
 
 
 
CGM Device Acceptability 
Questionnaire 
 
X 
 
 
 
 
 
X 
 
 
X 
Baseline lab results and vitals 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Dispense glargine if 
randomized to intervention 
arm 
 
X 
 
 
 
 
 
 
 
 
 
Dispense glucagon 
 
X 
 
 
 
 
 
 
 
 
 
Provide in depth education 
and counseling 
 
X 
 
 
 
 
 
 
 
 
 
Titrate insulin glargine or 
continue to adjust human 
insulin at home, based on 
fasting glucose 
 
 
X 
 
 
 
 
 
 
 
 
Draw HbA1c 
X 
 
 
X 
 
X 
 
 
X 
 
X 
CGM sensor #1 placed 
 
 
 
X 
 
 
 
 
 
 
 
Scan/upload CGM sensor data 
 
 
 
 
X 
 
X 
X 
 
 
X 
CGM sensor #2 placed 
 
 
 
 
 
X 
 
 
 
 
 
CGM sensor #3 placed 
 
 
 
 
 
 
X 
 
 
 
 
CGM sensor #4 placed 
 
 
 
 
 
 
 
 
 
X 
 
*In some cases, scheduled “home visits” will actually be done in the clinic (i.e. another clinic visit), if requested by the participant. In the 
Bangladesh site only: Due to unexpected circumstances (e.g. public transport blockade), for select home visits only (i.e. Home Visit #1 and 
Home Visit #3), participants or their caregiver may be asked to remove a CGM sensor on their own. In such cases, plans will be made for reliable 
courier service that will pick up and deliver that sensor to appropriate study staff at predetermined study site location(s). 
 
 

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2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Long-acting insulin analogues have become a de-facto standard of care for patients with T1D living in 
high-income countries. Unfortunately, insulin analogues remain unavailable or unaffordable for much of 
the global population. In both 2017 and 2019, applications to add long-acting insulin analogues to the 
WHO’s Model List of Essential Medicines (EML) were rejected due to insufficient evidence of superiority 
and an unfavorable cost-effectiveness profile when compared against older, less expensive, human 
insulins (e.g., NPH insulin and premixed 70/30 insulin). In 2021, long-acting insulin analogues were 
added to the EML but the decision remains controversial since the WHO concluded that “magnitude of 
clinical benefit of long-acting insulin analogues over human insulin for most clinical outcomes was 
small.” Moreover, studies that compare long-acting insulin analogues versus human insulins conducted 
in high-income settings may not generalize to children and young adults living with T1D in very low-
resource settings. 
 
To address this unmet need, Pitt has partnered with BWH and Life for a Child to conduct a randomized 
controlled trial comparing insulin glargine, a long-acting analogue insulin, against human insulin among 
400 children and young adults living with T1D in a lower resource setting (initial clinical sites planned in 
Bangladesh and Tanzania; potential to add sites in other LMICs as trial progresses). 
 
2.2 
BACKGROUND  
This proposal addresses an important unmet clinical need by generating rigorous evidence on the 
comparative clinical benefits, risks, quality of life and cost-effectiveness of a long-acting insulin analogue 
vs. intermediate-acting human insulin in low-resource settings. Prior studies conducted in higher income 
settings are not sufficient because they do not address this specific population(s) of interest and have 
also not used continuous glucose monitoring (CGM) to capture important glycemic outcomes. 
 
In low-resource or humanitarian settings where glycemic control is typically poor and food insecurity is 
common, long-acting insulin analogues may offer tangible clinical benefits for patients with T1D. NPH 
insulin must be dosed at least twice daily in individuals with T1D to ensure 24-hour basal insulin 
coverage and peaks 4-6 hours after injection, which can lead to hypoglycemia if not eating or overnight. 
Premixed 70/30 human insulin contains a mix of 70% NPH insulin and 30% short-acting regular insulin, 
which has been associated with a significant hypoglycemia risk. Glargine has a duration of 24 hours, can 
be injected once a day, and has a smoother time-action profile. In settings of food insecurity, the 
pharmacokinetic profile of glargine may reduce the risk of severe hypoglycemic events overnight, which 
can be fatal. Moreover, it may reduce potential long-term sequalae of recurrent hypoglycemia, such as 
hypoglycemia unawareness, and may allow for improved glycemic control thereby reducing the risk of 
long-term complications (e.g., microvascular disease) from diabetes. 
 
Existing efforts to overcome a two-tiered system of global diabetes care (i.e. access to modern, designer 
insulin analogues in high-income settings, but only human insulins for much of the world’s poor) are 
currently hampered by a lack of hard evidence. Although conclusive evidence for the clinical superiority 
of insulin analogues in these settings is lacking, many patients and global advocates strongly prefer 
newer insulins. This is due in part to their added convenience and reduced risk of hypoglycemic events 

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(especially overnight) when compared against human insulins (Pedersen-Bjergaard et al., The Lancet 
Diabetes & Endocrinology 2014). In fact, existing WHO treatment guidelines recommend considering 
long-acting insulin analogues in cases where patients experience recurrent episodes of hypoglycemia on 
human insulin (Roglic & Norris, Annals of Internal Medicine 2018).  
 
The landscape of global access to medicine for patients living with insulin-dependent diabetes is 
undergoing a dramatic transformation. Clinics in low-resource settings supported by Life for a Child will 
soon begin transitioning some children and young adults with T1D from usual care with human NPH 
insulin to insulin glargine (Basaglar; Lilly/Boehringer Ingelheim). Given these changes, and existing gaps 
in the evidence, this is an opportune time to conduct a rigorous study that directly compares long-acting 
insulin analogues vs. human insulins (e.g., NPH or premixed 70/30 insulin) in low-resource settings. 
The overall goal of this project is to generate high-quality evidence on the potential clinical benefits and 
comparative cost-effectiveness of long-acting insulin analogues versus standard-of-care human insulin 
for patients living with T1D in these settings.  
 
We will achieve this by conducting a randomized trial comparing glargine, a long-acting insulin analogue, 
against human NPH insulin or premixed 70/30 human insulin among 400 children and young adults living 
with T1D in lower resourced settings. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Discomfort, skin rash/infection, inconvenience, or stigma of wearing a CGM sensor 
Low blood sugar, high blood sugar, diabetic ketoacidosis, all due to change in insulin regimen 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Subjects may increase knowledge of diabetes management and experience improvements in blood 
glucose control (although this cannot be guaranteed). They may find out what type of insulin is better 
for management of their blood sugars and reduce the risk of having low blood sugar events. Participants 
will receive compensation (and/or transportation reimbursement) for their time participating in the 
study and in addition, will be provided with no-cost laboratory studies and a nasal spray or auto-injector 
medication called glucagon to help manage severe hypoglycemic events, should they occur. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
CGM sensors: subjects will be advised to clean the area of the skin prior to placement. Study staff will 
use typical hygiene procedures to clean the area prior to sensor replacement. The devices are small (size 
of two stacked quarters) and can be covered up by a shirt sleeve. The sensors are silent - they do not 
beep, make noise, or emit light. The sensors can be worn while bathing, swimming or while the 
participant is engaged in physical activities. We will advise participants to take extra care while removing 
clothing or while drying off. During especially intense physical activity, we will also advise participants to 
cover the sensor with an additional layer of protection (e.g. transparent dressing or elastic wrap). 
 
Low blood sugar (hypoglycemia), high blood sugar, diabetic ketoacidosis (DKA): Use of any insulin 
(including the standard of care human insulins) confers the risk of experiencing hypoglycemia. Underuse 
(or underdosing) of insulin may also result in hyperglycemia or DKA. This risk already exists for all study 

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participants. Most mild cases of hypoglycemia can be managed by taking in food or beverages that 
contain sugar (e.g. having some candies or juice available). Mild cases of hyperglycemia can be managed 
by using additional insulin. DKA is typically managed in an inpatient setting. Insulin glargine has been 
shown to reduce the risk of hypoglycemia in some settings and patient populations. In addition, the 
protocol specifies that the insulin titration will be conservative - namely that subjects will start with a 
lower dose of insulin glargine than their previous total basal insulin dose. Study personnel will be 
available via a dedicated study phone number (or via SMS) should hypoglycemia occur. Further, all 
participants will be provided with an medication called glucagon (administered via intranasal spray or 
auto-injector) that can be used as a rescue medication in cases of severe and life-threatening 
hypoglycemic events. These events are expected to be rare. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To determine whether insulin 
glargine reduces the risk of serious 
hypoglycemia or improves glycemic 
Time in Range (TIR) at 6 months 
when compared against standard 
of care human insulin (e.g. NPH or 
premixed 70/30) 
 
 
The coprimary outcomes for this trial 
are 1) percent time-in-serious-
hypoglycemia (<54 mg/dl) and 2) 
percent time-in-range (70-180mg/dl). 
We selected these 
coprimary outcomes 
after consulting 
international experts 
and reviewing 
international 
consensus guidelines. 
Even though level 2 
hypoglycemic events 
(i.e. <54mg/dl) are less 
common than milder, 
level 1 events (i.e. 
<70mg/dl), they are far 
more likely to be 
clinically significant. 
Experts also provided 
feedback that it was 
important to assess 
efficacy on both 
hypoglycemia and 
time-in-range 
(increasingly accepted 
among clinicians as a 
valid surrogate 
endpoint by itself since 
durable increases in TIR  
are likely strongly 
associated with good 
glycemic control and 
therefore a reduction 
in the risk of 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
microvascular 
complications of type 1 
diabetes), since a 
benefit on either of 
these two outcomes 
will be useful clinical 
knowledge. 
Secondary 
 
 
To determine whether insulin 
glargine improves glycemic control 
when compared against standard 
of care human insulin (e.g. NPH or 
premixed 70/30) 
 
HbA1c (%) 
 
HbA1c is a widely 
accepted surrogate for 
glycemic control and 
currently serve as 
treatment targets 
recommended by 
several professional 
societies, including the 
ADA/EASD, ACP and 
others.  
 
Ascertainment of the Study Outcomes: Patients will be followed from the start of randomization (day 0) 
up through +12 months. At every 3 months, study participants will return to clinic for routine follow-up 
(including insulin refills) and HbA1c testing, as is currently the standard of care.  
 
Blinded CGM sensors (duration=14 days each) will be placed on every study participant according to 
following schedule: (1) One baseline sensor during the run-in phase (i.e. before randomization), (2) one 
follow-up sensor starting 3 months after randomization, (3) two back-to-back sensors at 6 months after 
randomization and (4) one sensor at the final 2 weeks of the study (during month 12), to assess 
durability of CGM results. 
 
Secondary outcomes will include: Time-in-hypoglycemia (<70mg/dl), time-above-range (either >180mg/dl 
or >250mg/dl), and number nocturnal hypoglycemic events (1200-0600h). We will also measure and 
compare overall glycemic control (HbA1c), the rate of severe hypoglycemic events (requiring the external 
assistance of another party), and the rate of symptomatic hypoglycemic events reported by clinical 
history, rate of diabetic ketoacidosis (measured by self-report and confirmed through review of hospital 
records) and overall mortality (all cause death).  We will also explore durability of treatment effects by 
comparing % time <54mg/dl during the final 2 weeks of the 1-year follow-up. 
 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
 
HumAn-1 is a randomized, placebo-controlled, parallel group (1:1 allocation ratio), open-label, multi-site 
RCT that compares insulin glargine against NPH or premixed 70/30 among youth with type 1 diabetes in 
low resource settings. 
 

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Justification for open-label nature of trial: it is not practical and would be very challenging in a low 
resource setting to administer the appropriate matching placebos. For example, NPH may be dosed 
twice a day whereas insulin glargine is typically dosed only once daily. NPH is a cloudy liquid where 
glargine is clear (transparent). Furthermore, the formulations that will be employed in this study differ. 
Specifically, regular insulin is available in glass vials for use with syringe and needle (in Bangladesh), or as 
a prefilled, disposable pen (in Tanzania). NPH or premixed 70/30 are supplied in glass cartridges (in 
Bangladesh) or as prefilled, disposable pens (Tanzania). The insulin glargine will be supplied as a 
cartridge to be used in reusable pens. 
 
We do not expect the lack of blinding to impact the primary outcome(s) because of two reasons: 1) 
percent time-in-range and time-in-hypoglycemia are not patient-reported outcomes, and 2) they will be 
obtained from professional (blinded) CGM sensors. As stated before, participants will not be able to 
view their own daily glucose readings since the CGM sensors used in this study (Abbott Freestyle Libre 
Pro) can only be read by dedicated Reader devices which are in the sole possession of study staff. If 
study participants would like, they may view their CGM sensor data at the conclusion of the study (i.e. 
when she or he has completed the final study visit and all study related procedures). 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
NPH or premixed 70/30 is an appropriate control given that this is the current standard of care for the 
vast majority (over 90%) of youth living with T1D in low resource settings. 
 
4.3 
JUSTIFICATION FOR DOSE 
There is no fixed or target insulin dose for either the intervention or usual care treatment arms. Rather, 
insulin will be titrated by each participants’ treating clinician according to local standard of care and 
treatment practices. 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Children and young adults (age 7-25)  
2. Have a clinical diagnosis of type 1 diabetes (T1D) 
 
5.2 
EXCLUSION CRITERIA 
 An individual who meets any of the following criteria will be excluded from participation in this study: 

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1. Prior use of any insulin analogue 
2. Patients (or parents for children <18 years old) who refuse to or cannot provide informed 
consent 
3. Who are currently pregnant or plan to become pregnant over the next year 
4. Who have previously used a continuous glucose monitor (CGM) for glucose monitoring 
5. Who were first diagnosed with T1D less than 12 months ago 
6. Who is diagnosed with severe malnutrition 
 
The rationale for selecting this patient population is threefold: (1) they comprise most of the individuals 
living with T1D in the settings that Life for a Child (LFAC) supports and where we hope to conduct the 
trial, (2) it will be difficult to ensure that CGM sensors are not accidentally removed prior to the end of 
each 14-day measurement period for children under 7 years of age, and (3) this patient population is 
likely the group that will be treated first with analogue insulins if/when such products are more widely 
procured globally. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable 
 
5.4 
SCREEN FAILURES 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
modifiable factor (e.g. were recently diagnosed with type 1 diabetes) may be rescreened. Rescreened 
participants will be assigned a new study participant number. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Patients with T1D and their parents or guardians (if under 18 years old) will be approached by local 
study staff or will be referred by their physicians as they present for routine clinical care at diabetes 
centers within each trial site. We will use a convenience sampling approach, akin to first-come first-
served. The rationale for this sampling approach is twofold: 1) this approach best mimics real world 
clinical practice and 2) may be easiest to operationalize. 
 
For example, at the large urban diabetes hospital in Dhaka, Bangladesh (BIRDEM), potential participants 
will be approached as they present for diabetes follow-up at the large outpatient pediatric diabetes 
clinic. They will then be presented with information, in their local language, about the study. Those who 
meet all inclusion or exclusion criteria and who provide consent (or in some cases, assent) will be 
enrolled in the study. See Figure below. 
 

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6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Insulin glargine (intervention) 
Human insulin (control) 
6.1.2 DOSING AND ADMINISTRATION 
Intervention (glargine) 
Formulation: Available as a clear liquid in a glass cartridge (1 cartridge =3ml=300 units) for use with 
reusable pen.  
Route: Injected subcutaneously using a reusable pen (i.e. cartridges are replaced when empty). 
Amount of each dose: varies depending on baseline basal insulin needs 
Dose escalation scheme: Participants randomly assigned to glargine will start with a dose that is 
generally equal to 80% of their total basal human insulin dose prior to the switch (per ISPAD guidelines 
and the switching guide developed by Life for a Child with the guidance of Dr. Ragnar Hanas and two 
other ISPAD members familiar with less-resourced settings).  
Frequency and Timing of dose: once per day (usually administered before bedtime). In some cases, 
glargine may be administered twice a day, at the discretion of the treating clinician. 
Duration of therapy: 12 months 
 
 

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Control (human insulin) 
Drug: NPH or Premixed 70/30 
Formulation: In Bangladesh, NPH and premixed 70/30 are available as a glass cartridge (3ml=300IU). In 
Tanzanian sites, NPH and premixed 70/30 are available only as prefilled, disposable pens (3mls=300IU). 
Route: In Bangladesh, these insulins are administered via subcutaneous injection via reusable pens. In 
Tanzania, all human insulins are administered via prefilled, disposable pens. 
Amount of each dose: varies depending on baseline basal insulin needs (per usual care or treating 
clinician) 
Frequency and Timing of dose: once or twice per day (per usual care or treating clinician). NPH 
administered at night should occur prior to bedtime. 
Duration of therapy: 12 months 
 
Drug: Regular 
Formulation: In Bangladesh, regular was available as a liquid in glass vials (10ml=1000ml), intended for 
use with syringes and needles. Starting January 28, 2024, regular insulin was transitioned from glass vials 
to cartridges (3ml=300ml) intended for use with reusable pens. In Tanzanian sites, regular human insulin 
is only available in prefilled, disposable pens. 
Route: Subcutaneous injection using either insulin syringe and needle (in Bangladesh prior to 
1/28/2024), reusable pens (Bangladesh starting after 1/28/2024) or prefilled, disposable pens 
(Tanzania). 
Amount of each dose: varies depending on mealtime needs (per usual care or treating clinician) 
Frequency and Timing of dose: usually corresponds to the number of meals per day (e.g. with breakfast, 
lunch and dinner). Regular should be administered 30 mins prior to each meal. 
Duration of therapy: 12 months 
 
 
After random treatment assignment, all participants will enter a 4 week titration phase. During this 
phase, participants randomly assigned to human insulin will continue their usual care, however they will 
receive the same frequency of blood glucose testing and the same intensity of education and counseling 
as those randomized to glargine (e.g. titration advice according to fasting glucose targets and strategies 
to avoid hypoglycemia). Specifically, participants in both groups will have equal access to test strips 
(sufficient to test up to 5 times per day during the active titration phase and thereafter 3 times per day). 
During the first 2 weeks of this insulin titration phase, all participants (regardless of random assignment) 
will receive 4 phone based encounters from study staff. Each phone visit will occur every 3 days (see 
Schedule of Activities above). 
 
Both treatment arms will subsequently titrate their assigned basal insulin dosage according to a fasting 
glucose target set according to local practice patterns (as recommended by LFAC). We will not 
recommend aggressive lowering of fasting glucose levels or HbA1c, because prior studies show that the 
rate of severe hypoglycemia is common in these settings. 
 
Participant compliance will be measured at each clinic and/or home visit using case report forms. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 

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All insulins, test strips, glucometers will be supplied to the investigator as a donation from the Australian 
based non-profit humanitarian organization Life for a Child.  
 
Medications and CGMs will be securely stored at the clinical or medical supply distribution facilities of 
the BIRDEM hospital located in Dhaka Bangladesh, or the Tanzanian Diabetes Association in Dar Es 
Salaam, Tanzania. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
See 6.1.2 above 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
For longer term storage, insulin should be kept below 25 degrees C, or per package insert instructions. 
 
 
6.2.4 PREPARATION 
 
Not applicable. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Randomization: We will use a stratified blocked randomization approach with variable block sizes. Since 
we aim to conduct a multi-center trial, we will stratify randomization by center, since there will likely be 
differences in the patient population or clinical practice patterns at each center that may affect the 
outcome. For example, stratifying randomization by center may also help to protect against imbalances 
in the distribution of participants who use NPH or 70/30 at baseline, as these choices may reflect local 
(i.e. center-specific) practice patterns. 
 
The randomization sequence will be prepared in advance by the lead statistician, Dr. Joyce Chang, and 
integrated into an online, secure, data management system that will be developed specifically for this 
trial. Dr. Chang will use the ”blockrand” package in R statistical software to generate the randomization 
sequence.  
 
Allocation concealment: Local trial staff will use the online data management system developed for this 
trial to obtain the next randomization sequence. Neither the PI nor the local trial staff will have access to 
the randomization sequence. Treatment assignment will only occur after a study participant has been 
determined to meet all inclusion and exclusion criteria (i.e. screening) and completed the baseline study 
procedures in the run-in phase. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Adherence to both study interventions and use of CGMs will be assessed at each home and clinic visit 
using electronic case report forms.  
 
We will measure adherence to the study interventions by asking each participant during all clinic and 
home visits what type(s) of insulin they are currently using. To monitor adherence, staff will also ask 
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the participant takes per day during all clinic and home visits. To confirm adherence, staff will ask to see 
the participant’s insulin vials or cartridges. 
 
Use of CGMs and any potential sensor malfunctions will be directly assessed in person (or by telephone) 
by local trial staff. 
 
6.5 
CONCOMITANT THERAPY 
 
We will also assess whether any non-study insulin analogues have been introduced or used by any 
participant during follow-up. 
 
6.5.1 RESCUE MEDICINE 
 
The study site will supply glucagon as a rescue medication that will be provided by the sponsor to all 
participants. The use of rescue medications is allowable at any time during the study. Training on use of 
the nasal or injectable glucagon will also be provided at the time of dispensing. The date and time of 
rescue medication administration as well as the name and dosage regimen of the rescue medication will 
be recorded. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from the study intervention does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. For example, a 
participant may decide that they would like to go back to their previously used human insulin regimen. 
During the study, participants will be encouraged to stay on their randomly assigned treatment group, 
unless there is a clinical reason to switch (i.e. cross-over).  
 
At the end of this study, participants will be given the opportunity to switch to the contralateral 
treatment group if they would like to (and the treating provider agrees). 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon written request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Subjects who sign the informed consent form and are randomized but do not receive 

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the study intervention (e.g. did not receive their randomly assigned medication) may be replaced. 
Subjects who sign the informed consent form, and are randomized and receive the study intervention, 
and subsequently withdraw, or are withdrawn or discontinued from the study, will not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled clinic visits 
and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 weeks 
and counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
See primary outcome. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Study Measurements 
 
Baseline demographics/comorbidities 
Description 
  Age 
At time of randomization, in years 
  Duration of type 1 diabetes 
Based on self-report or extraction 
from medical record, in years 
  Type of insulin regimen 
Generally, as two categories, NPH + 
regular (basal/bolus regimen) or 
premixed 70/30 
  Number of units of insulin per day 
Total number of international units of 
insulin used per day, including all 
basal and bolus insulins. 
  Mean HbA1c (%) [SD] 
HbA1c laboratory result (units=%), 
most recent 
  Complications of Type 1 Diabetes 
Clinical presence or absence of 
diabetic retinopathy, neuropathy, or 
nephropathy (extracted from medical 
record)  

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  Hypoglycemic events 
Number of episodes of symptomatic 
hypoglycemic events in the past 12 
months 
Co-Primary Outcomes:  
  Time-in-serious hypoglycemia 
% spent less than 54mg/dl, averaged 
across all daily measures averaged 
across two CGM sensors starting 6 
months after randomization 
  Time-in-range (TIR) 
% between 70 and 180mg/dl 
inclusive, averaged across two CGM 
sensors 6 months after 
randomization 
Secondary Outcomes: 
  Time-in-hypoglycemia 
% spent less than 70mg/dl 
  Time-above-range 
% spent greater than 180mg/dl 
  Nocturnal hypoglycemic events 
Number of events (defined as 
>=15mins in duration < 70mg/dl) 
between 1200 and 0600 
  Glycemic control (HbA1c) 
Mean HbA1c lab result at baseline, 3, 
6, 9 and 12 months after 
randomization 
  Rate of severe hypoglycemic events 
Events requiring the assistance of an 
external third party person 
  Rate of diabetic ketoacidosis (DKA) 
Measured by self-report and 
confirmed through review of hospital 
records 
  Quality of Life (e.g. Fear of Hypoglycemia 
Survey) 
As assessed using validated 
instruments (PedsQL and Insulin 
Treatment Satisfaction Questionaire 
(ITSQ)). 
Adverse Events 
  Hypoglycemic events (clinically significant 
events) 
See primary and secondary outcomes 
above. Insulin in any form is known to 
be associated with low blood sugars. 
Therefore, we are measuring this as a 
primary/secondary outcome…but it 
also may be considered an adverse 
event/safety event. 
  Severe hypoglycemic events (<54mg/dl by 
CGM) > 10% 
In the case severe hypoglycemia 
exceeds 10% on any CGM sensor, the 
treating clinician will be notified. 
  Skin discomfort/irritation 
Self-report 
  Skin infection 
Self-report 
  Mortality 
All-cause mortality, assessed by 3rd-
party voluntary report to study staff 
and/or during failed attempts to 
follow-up with a trial participant 

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  All other adverse events 
Will be assessed periodically and 
categorized according to established 
procedures and taxonomy. 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 

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• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.] 
 
8.3.3.3 EXPECTEDNESS  
The local site PI will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s baseline condition deteriorates 
at any time during the study, it may be recorded as an AE.  

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Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The local trial coordinator or research assistant will record all reportable events with start dates 
occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) 
after the last day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information until 
resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
Non-serious AE will be recorded in the study database and will be summarized (by treatment arm) in 
safety reports for the DSMB to discuss at regular meetings.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The study clinician will immediately report to the sponsor (University of Pittsburgh) any serious adverse 
event, whether or not considered study intervention related, including those listed in the protocol or 
investigator brochure and must include an assessment of whether there is a reasonable possibility that 
the study intervention caused the event. Study endpoints that are serious adverse events (e.g., all-cause 
mortality) must be reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study intervention and the event (e.g., death from anaphylaxis). In that case, 
the investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the Data Coordinating Center (DCC)/study sponsor and should be 
provided as soon as possible. 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Not applicable. 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not Applicable. 
 
8.3.9 REPORTING OF PREGNANCY  
If a participant becomes pregnant or decides to try and get pregnant during the study (i.e. changes their 
mind or has an unplanned pregnancy), the participant should inform the local trial staff and local site PI 
immediately. Since this is one of the main exclusion criteria, these participants would then drop out of 
the study. 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 

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The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP report will 
include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study 
sponsor within 7 business days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 10 days of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 10 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Not Applicable. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 

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Null hypothesis: % Time-in-serious hypoglycemia and % Time in Range (TIR) in the insulin glargine group 
is the same as % Time-in-serious hypoglycemia and % TIR in the control group (usual care with human 
insulin). 
 
Alternative hypothesis: % Time-in-serious hypoglycemia or % TIR in the insulin glargine group is different 
than in the control group (usual care with human insulin). 
 
Since this trial has 2 coprimary outcomes, a win on either outcome will be considered to be a positive 
trial. For example, if insulin glargine “wins” (p<0.025 for benefit) on either the Time-in-serious 
hypoglycemia OR TIR outcome, it’s considered a positive trial for analogue insulin. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
We estimated power using a bootstrap-resampling approach due to the expected non-standard 
distribution of the outcome variables (i.e. %time in serious hypoglycemia and %time-in-range). Using 
individual patient level CGM data collected from a pilot study involving more than 80 children with T1D 
in Uganda and Kenya (personal communication Professor Antoinette Moran, University of Minnesota), 
we calculated a mean percent time<54 mg/dl of 5.8, standard deviation of 6.6, a maximum of 24. We 
next assumed a clinically meaningful 33% relative reduction in percent time-in-serious-hypoglycemia 
(e.g., from a median of 6% to 4%) since clinical guidelines3 recommend that patients and providers aim 
for <15 minutes per day (~1%) in hypoglycemia spent at <54 mg/dl. Therefore, in each simulated trial, 
the simulated patients in the usual-care arm had an outcome drawn from the “control” distribution; the 
simulated patients in the glargine arm had an outcome drawn from the control distribution multiplied 
by 0.67 (e.g. corresponding to a 33% relative reduction in time-in-serious-hypoglycemia). 
 
To estimate the study power, we simulated outcomes for control-group (human insulin) and treatment-
group (analogue insulin) at sample sizes ranging from 100 up to 400 patients and performed the planned 
primary analyses described above on the simulated datasets. The power to detect a treatment benefit 
of glargine insulin is thereby computed as the percentage of simulated trials with a p-value less than 
0.025 favoring glargine on each of the respective coprimary outcomes. Since we have 2 coprimary 
outcomes, an alpha threshold of 0.025 is used for each analysis to control the overall trial-wide type 1 
error probability at 0.05. Using this approach, an analytic sample size of 300 patients (150 per arm) 
would have 77.7% power to detect a treatment benefit corresponding to approximately a 33% relative 
reduction in time-in-serious-hypoglycemia. If the benefit is larger (e.g. 50% relative reduction) we will 
have over 99% power to detect a treatment benefit on the hypoglycemia endpoint. 
 
For the time-in-range endpoint, we used an absolute increase rather than a relative decrease; this is 
because of the different distribution of time-in-range as opposed to time-in-serious-hypoglycemia 
(which has a large clustering of values in single digits). The pilot data showed a mean time-in-range of 27 
with a standard deviation of 17; most values ranged between about 10 and 70; we felt that a 10% 
absolute increase in time-in-range would be a clinically meaningful improvement. Using a similar 
resampling-based approach described above, for this endpoint simulated patients in the usual care arm 
had an outcome drawn from the “control” distribution; simulated patients in the analogue arm had an 
outcome drawn from the control distribution plus 10 (corresponding to a 10% absolute increase in the 
time-in-range endpoint). The planned sample size of N=300 retains excellent power (>99%) for a 10% 
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Table. Power For “%Time<54mg/dl” and “%Time-In-Range” Outcomes At Various Sample Sizes 
(alpha=0.025) 
Sample Size 
%Time<54mg/dl 
%Time-In-Range 
33% Relative 
Decrease 
50% Relative 
Decrease 
10% Absolute 
Increase 
N=200  
56.2% 
96.6% 
97.5% 
N=250  
64.3% 
99.0% 
99.5% 
N=300  
77.7% 
99.8% 
>99.9% 
 
Therefore, we believe that a sample size of N=300 patients (150 per group) with analyzable outcome 
data will be sufficient to have sufficient power for clinically relevant effects on the co-primary outcomes 
of time-in-serious-hypoglycemia (77.7% power to detect a 33% relative decrease at alpha=0.025) and 
time-in-range (>99% power to detect a 10% absolute increase at alpha=0.025). This analytic strategy 
allows the trial to conclude as a positive trial if glargine demonstrates a benefit on either the time-in-
serious-hypoglycemia endpoint or the time-in-range endpoint. Splitting the alpha to use 0.025 for each 
coprimary endpoint controls the overall trial-wide error at 0.05; this gives the opportunity to test both 
endpoints, which is important as knowledge of a benefit on either aspect of glycemic control is useful to 
inform clinical practice. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Intention-to-treat (ITT) Analysis Dataset (i.e. all randomized participants) 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
Not Applicable 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The trial will have coprimary outcomes.  The first of these will be percent time-in-serious-hypoglycemia 
(<54 mg/dl) as described above, which will be recorded as a continuous variable theoretically ranging 
from 0 (no time spent in serious hypoglycemia) to 100 (all time spent in serious hypoglycemia); the 
realistic range for this outcome is ~0 to 25, as described below. Data on percent time in hypoglycemia 
will be downloaded from individual CGM sensors and then pooled across both sensors collected during 
the intensive CGM phase (month +6 to +7) to compute a single value for “time in serious hypoglycemia” 
for each patient. The primary analysis will be performed using a multivariable linear regression model 
where treatment assignment is the primary fixed effect of interest, with age, study site, and time-in-
serious-hypoglycemia and time-in-range from the baseline CGM (run-in phase, prior to initiation of 
study treatment) included as covariates. This approach will be used because adjustment for covariates 
known to be strongly associated with the outcome increases statistical power; including the baseline 
measurement as a covariate also provides a safeguard against random imbalances in individual level 
baseline risk of hypoglycemia (e.g. one arm having patients with more hypoglycemic tendencies than 
the other arm) introducing a bias in the estimated treatment effect.   
 
The second coprimary outcome will be percent time-in-range (70-180 mg/dl).  Likewise, this also will be 
recorded as a continuous variable theoretically ranging from 0 (no time spent in range) to 100 (all time 
spent in range).  The realistic range for this outcome variable is about 10 to 70, based on pilot data also 

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described below.  Again, data from all CGM sensors collected during the intensive CGM phase (month +6 
to +7) will be pooled to compute a single value for “time in range” for each patient.  The analytic 
approach used for this endpoint will mirror the approach used for the time-in-serious-hypoglycemia 
endpoint: a multivariable linear regression model where treatment assignment is the primary fixed 
effect of interest, with age, study site, and time-in-range from the baseline CGM (run-in phase, prior to 
initiation of study treatment) included as covariates. 
 
Incomplete or missing CGM Sensor Data: Even though returning a baseline CGM sensor (i.e. the one 
placed during the run-in phase) is one of the trial eligibility criteria, it is expected that some participants 
may have incomplete or missing CGM sensor data. For example, a CGM sensor could fall off accidentally 
before the end of each 14 day sensor wear period. Such sensors may also be lost before study staff have 
an opportunity to download the glucose data.  
 
If a CGM sensor falls off early, or presents with no data due to a sensor download error, or is 
accidentally removed less than 9.8 days (70% of 14 days; consistent with international consensus 
recommendations on the use of CGMs in clinical trials), they may receive a replacement sensor. If a 
participant is able to successfully wear a sensor for 14 days, but a sensor shuts-off early (e.g. only 6 days 
of glucose measurement data is captured), they will not have a replacement sensor. Rationale: 
randomization should balance incomplete sensor data across the two study arms. 
 
In the primary analysis, we will include all available sensor data (regardless of the duration of sensor 
wear or the number of days of glucose measurements) collected while enrolled in the study. In a 
sensitivity analysis, we will include only sensors with at least 70% of data availability during each 14 day 
wear period (i.e. >=9.8 days). In another sensitivity analysis, we will impute for missing data.  
In an exploratory analysis, we will include data from 12-month follow-up replacement sensors that were 
collected after a participant completed study.  
 
Lost to follow-up: If a participant discontinues before any of the follow-up CGM data are recorded (e.g. 
participant has no recorded CGM data at all during follow-up) they will not contribute data to the 
primary efficacy analysis. As described above, we are planning the study to have sufficient power with a 
usable analytic sample of n=300 participants. We propose to recruit n=400 participants, which allows for 
up to 25% attrition (participants that are lost shortly after randomization, before any CGM data have 
been collected) while retaining sufficient power to test our primary hypothesis. 
 
In recognition of the fact that in some cases a participant’s discontinuation could represent a negative 
clinical outcome, we will perform several sensitivity analyses to ensure that we are thorough and 
transparent in reporting the possible effects that the missingness would have on our primary analysis. 
The first sensitivity analysis will be multiple imputation analysis, imputing the missing outcome data 
based on observed baseline data; this approach is preferred to single-imputation (e.g. last observation 
carried forward or assign-the-worst) as it takes into account residual uncertainty in the missing values. 
The second sensitivity analysis will be a win-ratio analysis where participants that died during the study 
are ranked as having the worst possible outcome; participants that discontinued study participation due 
to an adverse event are ranked as having the second worst outcome value; participants that 
discontinued with no known adverse event are ranked as having the third worst outcome value; and 
participants that return complete CGM data during the intensive follow-up period are ranked according 
to their % time-in-serious-hypoglycemia (<54 mg/dl), with higher scores representing worse outcomes. 
This approach provides an estimate of which treatment arm led to better overall outcomes while 
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not be the primary analysis due in part to difficulty interpreting the results and the emphasis on 
glycemic control as the most important outcome in this therapeutic trial, but it will provide an important 
check that any observed benefits on a time-in-serious-hypoglycemia outcome or the time-in-range 
outcome are not offset or explained by greater death or discontinuation in the other treatment arm. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary outcomes are: Time-in-hypoglycemia (<70mg/dl), time-above-range (either >180mg/dl or 
>250mg/dl), and number nocturnal hypoglycemic events (1200-0600h). We will also measure and 
compare overall glycemic control (HbA1c), the rate of severe hypoglycemic events (requiring the 
external assistance of another party), and the rate of symptomatic hypoglycemic events reported by 
clinical history, rate of diabetic ketoacidosis (measured by self-report and confirmed through review of 
hospital records) and overall mortality (all cause death). 
 
We will also measure and compare quality of life using validated tools (PedsQL v3 and Insulin Treatment 
Satisfaction Questionnaire) at baseline and at 6 and 12 months after randomization. A minimum 
clinically important difference in QoL scores will be determined a priori. The primary treatment 
comparison for QoL will be made between the two treatment arms at 6 months after randomization. 
 
9.4.4 SAFETY ANALYSES 
See primary outcome and statistical analysis plan (9.4.2). We anticipate that hypoglycemia will be one of 
the most frequently occurring safety endpoints. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline Characteristic 
Glargine 
Usual care Human Insulin 
Age 
 
 
  7-10 
 
 
  10-14 
 
 
  15-25 
 
 
Male sex 
 
 
Race 
 
 
  Asian 
 
 
  African 
 
 
  Other 
 
 
Country 
 
 
  Bangladesh 
 
 
  Tanzania 
 
 
   
 
 
  Other 
 
 
Duration of type 1 diabetes, 
years, mean [SD] 
 
 
Comorbidities 
 
 
  Retinopathy 
 
 
  Nephropathy 
 
 
  Diabetic foot disease 
 
 
HbA1c (%), mean [SD] 
 
 
Insulin Regimen 
 
 

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  NPH + regular 
 
 
  Premixed 70/30 
 
 
  Premixed 70/30 + regular 
 
 
  Other 
 
 
Baseline insulin dose, IU per kg, 
mean [SD] 
 
 
  Total 
 
 
  Basal 
 
 
# of hypoglycemic events in past 
month, mean [SD] 
 
 
Hypoglycemic unawareness 
 
 
c-peptide level, ng/ml, 
mean[SD] 
 
 
 
9.4.6 PLANNED INTERIM ANALYSES  
There will be no planned interim analyses testing for efficacy or futility; by the time a sufficient amount 
of patients have completed follow-up to perform such analyses the trial should be almost fully enrolled.  
Data on enrollment, progress during the trial, and safety will be reported to the DSMB every 6 months 
during the study so they may monitor for any safety concerns.  There are no pre-specified stopping 
triggers, but the DSMB has leeway to recommend a pause in enrollment if they judge a preponderance 
of safety events in one arm to warrant closer examination. 
 
9.4.7 SUB-GROUP ANALYSES 
In recognition of the possibility that treatment effect may vary according to select baseline factors that 
may influence our clinical outcomes, we will include several planned subgroup analyses.  The most 
important of these will be the patient’s insulin prior to randomization (NPH versus 70/30), which allows 
an unbiased comparison of the glargine versus NPH and the glargine versus 70/30, though admittedly 
these comparisons will be underpowered. In addition, we will examine whether the treatment effect 
differs by clinical site (Bangladesh or Tanzania) and when comparing the route of insulin delivery (pens 
versus syringe and vial). The principal goal of these subgroup analyses will be to check for apparent 
consistency in the treatment effect of analogue against both potential options within the usual care 
group.  We will also perform subgroup analyses by age groups (e.g. younger vs older children/youth), 
and baseline hypoglycemia risk.   
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Not Applicable. 
 
9.4.9 EXPLORATORY ANALYSES 
 
Not Applicable. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 

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10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent and assent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. The following consent materials are submitted with this 
protocol (see approved consent from from Pitt IRB). 
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document electronically prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. Upon request, a copy of the informed consent document will be 
given to participants. 
 
Since this study uses a fully electronic data management system, consent will be collected using an 
electronic signature. The electronic signature will include a typed name, the subjects place of birth and 
date of birth. Signatures will be documented in the electronic data management system (including the 
date) before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigators, funder, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
 

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Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB. 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
To protect the identity of the participant, unique identifiers (e.g. name, address) will be removed prior 
to any data being transmitted to the investigators at the University of Pittsburgh. Study participants will 
be assigned a unique Study ID number. The key or crosswalk file that converts a scrambled Study ID 
number to a patient medical record number (i.e. re-identification) will only be available to local study 
staff. The University of Pittsburgh study staff will not have access to these key(s). 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Not Applicable. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator:  
Jing Luo, MD, MPH 
 
 
 
  
 
 
 
 
Assistant Professor of Medicine 
 
 
 
  
 
 
 
 
Division of General Internal Medicine  
 
 
 
  
 
 
 
 
University of Pittsburgh School of Medicine 
 
 
 
  
 
 
 
 
3609 Forbes Avenue, 2nd Floor 
 
 
 
  
 
 
 
 
Pittsburgh, PA 15213 
 
 
 
  
 
 
 
 
+1(412) 383-0627 
 
Co-Investigators:  
 
Joyce Chang, PhD 
 
 
 
  
 
 
 
 
Professor of Medicine, Biostatistics, and Clinical and Translational Science 
 
 
 
  
 
 
 
 
Division of General Internal Medicine  
 
 
 
  
 
 
 
 
University of Pittsburgh School of Medicine 
 
 
 
  
 
 
 
 
200 Meyran Avenue, Suite 200 
 
 
 
  
 
 
 
 
Pittsburgh, PA 15213 
 
 
 
 
  
 
 
 
 
Bruce Rollman, MD, MPH 
 
 
 
  
 
 
 
 
Professor of Medicine 
 
 
 
  
 
 
 
 
Division of General Internal Medicine  
 
 
 
  
 
 
 
 
University of Pittsburgh School of Medicine 
 
 
 
  
 
 
 
 
230 McKee Place, Suite 600 
 
 
 
  
 
 
 
 
Pittsburgh, PA 15213 
 
 
 
 
  
 
 
 
 
Sylvia Kehlenbrink, MD 
 
 
 
  
 
 
 
 
Instructor of Medicine 
 
 
 
  
 
 
 
 
Division of Endocrinology, Diabetes and Hypertension 
 
 
 
  
 
 
 
 
Brigham and Women’s Hospital 
 
 
 
  
 
 
 
 
221 Longwood Avenue, RFB-2 
 
 
 
  
 
 
 
 
Boston, MA  02115 
 
 
 
 
  
 
 
 
 
Bedowra Zabeen, MBBS FCPS(Paediatrics) 
 
 
 
 
 
 
 
 
Consultant Paediatrician and Paediatric Endocrinologist 

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Department of Paediatrics 
 
 
 
 
 
 
 
 
Diabetic association of Bangladesh 
Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and 
Metabolic Disorders (BIRDEM) 
 
 
 
 
 
 
 
 
Room 309 
 
 
 
 
 
 
 
 
1/A Segunbagicha 
 
 
 
 
 
 
 
 
Dhaka 1000 
 
 
 
 
 
 
 
 
 
Professor Kaushik Ramaiya 
 
 
 
 
 
 
 
 
Honorable General Secretary  
 
 
 
 
 
 
 
 
Tanzania Diabetes Association (TDA) 
 
 
 
 
 
 
 
 
P O Box 65201 
 
 
 
 
 
 
 
 
Dar es Salaam 
 
 
 
 
 
 
 
 
Tanzania 
 
10.1.6 SAFETY OVERSIGHT 
The Pitt PI (Dr. Luo) will interact with the local study team through virtual meetings (Zoom calls) 
occurring at least once per month. During these meetings, the study team will monitor participant 
enrollment, baseline characteristics, insulin titration, completion of follow-up visits and CGM sensor 
data collection, withdrawals, and adverse events. 
 
We will establish an independent data safety monitoring committee that will meet once every 6 months 
to go over interim study findings and reports. The committee will be comprised of experts from outside 
of the study team and sponsor and will ideally include someone living with type 1 diabetes. For example, 
it may include a pediatric endocrinologist from UPMC or an academic pediatric endocrinologist or 
diabetes researcher from outside of Pitt/UPMC. It will also include an outside statistician. They will be 
tasked with assessing the risks and benefits to study subjects and the chair will be empowered to 
contact the IRB and sponsor independently if it is determined that the trial should be stopped or 
modified. 
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Monitoring for this study will be performed by the PI, co-Is and site PIs.  
• 
On-site visits once per year 
• 
Virtual calls once per month 
• 
Regular review of data, at least every 6 months (including enrollment, outcome/safety 
assessments, loss to follow-up, missing data and other key data variables). 
  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Standardized in-person training on study procedures and data collection steps will be provided to all 
staff involved in data collection. Staff will receive refresher training remotely. The quality of the data 
collected will be periodically assessed centrally by the Data Center to ensure that they are free of data 

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entry errors, missing, or nonsensical results. The periodic assessment will occur both within and across 
trial sites. Reports will be generated (see data management system section below) and reviewed at least 
once every 6 months to ensure high quality data and internal trial validity. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
We will develop a web-based online electronic data management system for this trial. The system 
(accessible from any computer with internet access) guides study staff through our recruitment and 
informed consent procedures, study interventions and handles the randomization of study participants. 
The electronic system will be also used to securely record and transmit trial data (endpoints, safety 
events) from local sites to the Data Center at the University of Pittsburgh. The system is pre-
programmed with skip patterns, drop-down menus, check-off boxes, and other error checking routines 
that monitor forms for out-of-range values and missing data. 
 
10.1.9.2 STUDY RECORDS RETENTION  
Study records should be retained for a minimum of 2 years after the patient last visit. These documents 
should be retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the sponsor, if applicable. 
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality
Rescue Medicine - 
glucagon protocol.doc Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working days of 
the scheduled protocol-required activity.  All deviations must be addressed in study source documents, 
reported to the PI.  Protocol deviations must be sent to the reviewing Institutional Review Board (IRB) 
per their policies. The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements. Further details about the handling of protocol deviations will be included in the MOP.  
 
Date of Deviation (Month/Day/Year) 
 
Enrollment of an ineligible participant 
 
Failure to collect informed consent/assent 
 
Failure to collect baseline surveys or lab results 
(e.g. HbA1c) 
 

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Failure to place or collect baseline CGM sensor 
data during run-in phase 
 
Randomization of an ineligible participant (or 
participant who did not complete all stages of 
run-in phase) 
 
Missed clinic visit  
 
Missed home visit for CGM sensor 
replacement  
 
Failure to download sensor data (e.g. due to 
staff omission) 
 
Participant failed to titrate insulin during 4 
week titration period 
 
Participant discontinued study medication 
 
Cross-over of insulin (i.e. AH or HA) 
 
Failure to collect follow-up HbA1c  
 
Failure to replace or collect follow-up CGM 
sensor data  
 
Breach of confidentiality 
 
Participant began using any non-study CGM 
device 
 
 
 
Other 
 
 
 
Is the participant eligible to continue on 
study? (Yes or No) 
 
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
This trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted 
to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.  
Data from this study may be requested from other researchers 3 years after the completion of the 
primary endpoint by contacting the PI. Individual de-identified data may be made available in a public 
repository if consent has been obtained from study participants. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study leadership 
in conjunction with the University of Pittsburgh has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 

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10.2 ADDITIONAL CONSIDERATIONS 
No interaction with human subjects will occur until after IRB/ethical approval by both the University of 
Pittsburgh and local IRBs. 
 
 
 

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10.3 ABBREVIATIONS 
The list below includes abbreviations utilized in this template.  However, this list should be customized for 
each protocol (i.e., abbreviations not used should be removed and new abbreviations used should be 
added to this list). 
 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS 
Least-squares Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 

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SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Affected Section 
Description of Change  
Brief Rationale 
3.1 
26 Aug 
2023 
1.2, 1.3 
Decreased number of 
sensors from 6 to 2 starting 
at the 6 month f/u clinic 
visit 
To make successful 
completion of all home 
visits (where sensors are 
changed and data 
scanned). 
3.1 
26 Aug 
2023 
1.1, 2.1, 6.2.1, 6.5.1, 
9.4.5, 9.4.7, 10.1.5 
Added language about 
Tanzania and Iraq 
 
4.1 
17 Nov 
2022 
1.2, 1.3 
Added an additional CGM 
sensor to 3 month clinic 
visit and 1 home visit 14 
days after 
Recommended by 
DSMB, to collect sensor 
data earlier during 
follow-up, in case there 
are loss of participants. 
4.1 
17 Nov 
2022 
2.3.1; 2.3.3 
Added other potential 
risks (skin rash/infection; 
risk of low or high blood 
sugar due to change(s) in 
insulin regimen). 
Recommended by MSF 
ERB, and to better align 
with information 
already contained in the 
Informed Consent 
document. 
4.1 
17 Nov 
2022 
5.4 
Rescreened participants 
will be assigned a new 
STUDY ID number. 
To align with practices 
from the Clinical Trial 
and Data Coordination 
Center. 
4.1 
17 Nov 
2022 
6.3 
Dr. Joyce Chang to replace 
Dr. Althouse as lead study 
biostatistician 
Dr. Althouse left the 
University of Pittsburgh 
4.2 
13Dec 2022 
1.3 
Corrected the number of 
home visits (4) 
Prior version had 
duplicate Home Visit 
#3s. 
4.3 
11Jan2023 
1.3 
Added row for CGM 
device acceptability 
questionnaire; relabeled 
CGM to “CGM sensor” 
Timing and frequency of 
this survey was not on 
the previous Schedule of 
Activities. 
4.3 
11Jan2023 
8.4.2 
Changed reporting 
requirement from 2 to 7 
business days 
Updated timely 
reporting of 
unanticipated problems 
to align with 
recommendations of 
DSMB 
5.0 
3April2023 
9.4.2 
Incomplete or missing 
CGM sensor data 
Pre-specifies how the 
primary and sensitivity 
analyses will handle 
cases of partial or 
incomplete glucose data 
from CGM sensors 
during follow-up. 
5.1 
13Sept2023 
4.1; 6.1.2 
Revised formulation and 
timing of NPH, regular 
Reflects most up to date 
information about the 

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and glargine insulins used 
in the study 
specific insulins 
available for use in local 
sites and also to ensure 
that nighttime NPH is 
given independently of 
pre-dinner regular in 
patients receiving basal 
bolus regimens. 
 
 
 
 
 
 
 
Various 
Deleted mention of Iraq 
site 
The MSF clinics in Iraq 
will be closing soon and 
not likely to serve as 
local sites for this study. 
 
 
10.1.10 
Protocol Deviation 
Removed participant 
withdrawal from the list 
of deviations in the 
Table since participants 
may withdrawal from 
the study. 
5.2 
 
6.1.2. 
Further additions added to 
usual care insulin 
Better reflect local 
realities on the ground in 
terms of what insulins are 
being dispensed, as well 
as the timing, frequency 
and route of 
administration. 
 
 
4.1 
Added a space 
Grammatical error 
5.3 
 
10.1.10 
Removed CGM sensor error 
as a protocol deviation. 
CGM sensor errors are 
relatively common, 
typically not due to fault 
by the patient or research 
staff, and therefore should 
not be considered a 
deviation from the study 
protocol. 
 
 
4.1. 
Clarified that insulin 
glargine is only available in 
glass cartridges. 
To reflect local insulins 
being dispensed for trial 
participants, and also to 
match with language in 
Section 6.1.2. 
 
 
6.1.2. 
Clarified that NPH insulin 
may be administered via a 
reusable pen in Bangladesh 
To reflect local clinical 
practice 
5.4 
 
1.3 
Clarified in select cases, 
participants or caregivers 
may remove CGM sensors 
on their own, with pick up 
and delivery arranged via 
reliable courier service. 
Reports of widespread 
public transit outages in 
Bangladesh due to 
upcoming presidential 
elections and political 
instability may require 
certain home visits to be 
completed remotely. 
 
 
10.1.10 
Removed use of intranasal 
glucagon as a protocol 
deviation 
Use of a rescue 
medication for severe 
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clinically appropriate 
and should not be 
considered a protocol 
deviation. 
5.5 
17 Feb 
2024 
6.1.2 
Clarified that regular 
insulins changed from 
glass vials to cartridges for 
all participants in 
Bangladesh after 28 
January, 2024 
To reflect changes in 
insulin formulation and 
mode of delivery 
(reusable pen) for 
regular insulins in 
Bangladesh 
6.0 
17 July 
2024 
1.3; 2.3.2; 2.3.3; 
6.5.1 
Added that glucagon may 
also be provided as an 
auto-injector 
Due to supply shortages 
and manufacturer’s 
recent divestment of the 
intranasal spray 
glucagon product, we 
needed to supply 
participants with 
glucagon in a different 
formulation (glucagon 
auto-injectors). 
 
 
 
 
 
 
 
 

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11 REFERENCES  
Include a list of relevant literature and citations for all publications referenced in the text of the protocol.  
Use a consistent, standard, modern format, which might be dependent upon the required format for the 
anticipated journal for publication (e.g., N Engl J Med, JAMA, etc.).  The preferred format is International 
Committee of Medical Journal Editors (ICMJE). Include citations to product information such as 
manufacturer’s IB, package insert, and device labeling.  
 
Examples: 
 
• 
Journal citation 
Veronesi U, Maisonneuve P, Decensi A. Tamoxifen: an enduring star. J Natl Cancer Inst. 2007 Feb 
21;99(4):258-60. 
• 
Whole book citation 
Belitz HD, Grosch W, Schieberle P. Food chemistry. 3rd rev. ed. Burghagen MM, translator. Berlin: 
Springer; 2004. 1070 p. 
• 
Chapter in a book citation 
Riffenburgh RH. Statistics in medicine. 2nd ed. Amsterdam (Netherlands): Elsevier Academic 
Press; c2006. Chapter 24, Regression and correlation methods; p. 447-86. 
• 
Web Site citation 
Complementary/Integrative Medicine [Internet]. Houston: University of Texas, M.D. Anderson 
Cancer Center; c2007 [cited 2007 Feb 21]. Available from: 
http://www.manderson.org/departments/CIMER/. 
• 
Electronic Mail citation 
Backus, Joyce. Physician Internet search behavior: detailed study [Internet]. Message to: Karen 
Patrias. 2007 Mar 27 [cited 2007 Mar 28]. [2 paragraphs] 
• 
References to package insert, device labeling or investigational brochure 
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