Clinical trial NCT00658021
Conditions: Type 2 Diabetes
Keywords: diabetes adolescents exenatide Astra Zeneca
Sponsor: AstraZeneca
Start date: 2008-05-30; Completion date: 2020-04-01
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to test the hypothesis that glycemic control, as measured by change in hemoglobin A1c (HbA1c) from baseline to endpoint, with exenatide is superior to that of placebo after 28 weeks of treatment in adolescent patients with type 2 diabetes who are naïve to antidiabetes agents, or patients who are being treated with metformin, an SU, or a combination of metformin and an SU

Detailed description:

Arms: arm 1: Subcutaneous injection, twice a day arm 2: Subcutaneous injection, twice a day arm 3: Subcutaneous injection, twice a day
Interventions: intervention 1: Placebo intervention 2: Exenatide intervention 3: Exenatide
Intervention descriptions: intervention 1: Subcutaneous injection, twice a day intervention 2: Subcutaneous injection, 5 µg, twice a day intervention 3: Subcutaneous injection,10 µg, twice a day

Protocol documents:
Prot_000.pdf: 
H8O-MC-GWBQ(e) Clinical Protocol 
Page 1 
 
 
 
1. Protocol H8O-MC-GWBQ(e) 
Safety and Efficacy of Exenatide as Monotherapy and 
Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes 
 
Confidential Information 
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Amylin Pharmaceuticals, LLC or its subsidiaries 
and should not be copied by or distributed to persons not involved in the clinical 
investigation of exenatide, unless such persons are bound by a confidentiality agreement 
with Amylin Pharmaceuticals, LLC or its subsidiaries. 
Exenatide (LY2148568) 
This Phase 3, multicenter, double-blind, placebo-controlled, randomized, three-arm trial is 
designed to compare the effects of exenatide (5 µg and 10 µg, both administered twice 
daily [BID]) versus placebo (BID) with respect to glycemic control as measured by 
hemoglobin A1c in approximately 195 adolescent patients with type 2 diabetes.  Patients 
will have inadequate glycemic control and will be either antidiabetic drug-naïve, defined as 
treatment with diet and exercise alone, or receiving treatment with oral antidiabetic agent(s) 
(with or without diet and exercise).  Patients are to be treated with study drug for 28 weeks.   
Amylin Pharmaceuticals, LLC 
San Diego, California USA 92121 
Protocol Approved by Lilly:  15 January 2008 
Amendment (a) Approved by Lilly:  21 May 2008 
Amendment (b) Approved by Lilly:  09 February 2011 
Amendment (c) Approved by Lilly:  29 May 2012 
Amendment (d) Approved by Amylin/AZ:  16 May 2013 
Amendment (e) Approved by Amylin/AZ: 13 Oct 2017 
 


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Page 2 
 
 
2. Table of Contents 
Protocol H8O-MC-GWBQ(e) 
Safety and Efficacy of Exenatide as Monotherapy and 
Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes 
Section 
Page 
1. 
Protocol H8O-MC-GWBQ(e) Safety and Efficacy of Exenatide as 
Monotherapy and Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes ..........................................................................................1 
2. 
Table of Contents ....................................................................................................................2 
3. 
Abbreviations and Definitions .................................................................................................7 
4. 
Introduction ...........................................................................................................................10 
4.1. 
Exenatide ..........................................................................................................................10 
4.2. 
Study Rationale ................................................................................................................12 
5. 
Objectives ..............................................................................................................................13 
5.1. 
Primary Objective .............................................................................................................13 
5.2. 
Secondary Objectives .......................................................................................................13 
6. 
Investigational Plan ...............................................................................................................14 
6.1. 
Summary of Study Design................................................................................................14 
6.1.1. 
Screening (Visit 1) ...................................................................................................15 
6.1.1.1. 
Height .................................................................................................................16 
6.1.1.2. 
Pubertal Assessment ...........................................................................................16 
6.1.2. 
Placebo Lead-In Period (Visit 2) .............................................................................16 
6.1.3. 
Randomization and Treatment Initiation (Visit 3) ...................................................17 
6.1.4. 
Telephone Contact (Visits 4, 6, 8, and 10) ...............................................................18 
6.1.5. 
Interim and Final Treatment Visits (Visit 5, 7, 9, and 11) .......................................18 
6.1.6. 
Early Discontinuation Visit ......................................................................................19 
6.1.7. 
Unscheduled Visit Due to Loss of Glycemic Control ..............................................19 
6.1.8. 
Discussion of Design and Control ...........................................................................19 
7. 
Study Population ...................................................................................................................21 
7.1. 
Inclusion Criteria ..............................................................................................................21 
7.1.1. 
Disease Diagnostic Criteria ......................................................................................21 
7.2. 
Exclusion Criteria .............................................................................................................22 
7.2.1. 
Rationale for Exclusion of Certain Study Candidates .............................................23 


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7.3. 
Rescreening ......................................................................................................................23 
7.4. 
Discontinuations ...............................................................................................................24 
7.4.1. 
Discontinuation of Study Sites .................................................................................25 
7.4.2. 
Discontinuation of the Study ....................................................................................25 
8. 
Treatment ...............................................................................................................................26 
8.1. 
Treatments Administered .................................................................................................26 
8.2. 
Materials and Supplies .....................................................................................................26 
8.3. 
Method of Assignment to Treatment ................................................................................27 
8.4. 
Rationale for Selection of Doses in the Study ..................................................................27 
8.5. 
Selection and Timing of Doses .........................................................................................27 
8.5.1. 
Metformin ................................................................................................................28 
8.5.2. 
Sulfonylurea .............................................................................................................28 
8.5.3. 
Special Treatment Considerations: Hypoglycemia ..................................................28 
8.5.4. 
Special Treatment Considerations:  Laboratory Measures ......................................29 
8.5.4.1. 
Carcinoembryonic Antigen and Calcitonin ........................................................29 
8.6. 
Blinding ............................................................................................................................29 
8.7. 
Concomitant Therapy .......................................................................................................30 
8.8. 
Treatment Compliance .....................................................................................................30 
9. 
Efficacy and Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements ........................................................................................31 
9.1. 
Efficacy Measures ............................................................................................................31 
9.1.1. 
Primary Efficacy Measure .......................................................................................31 
9.1.2. 
Secondary Efficacy Measures ..................................................................................31 
9.2. 
Safety Evaluations ............................................................................................................31 
9.2.1. 
Adverse Events ........................................................................................................32 
9.2.1.1. 
Serious Adverse Events ......................................................................................33 
9.2.2. 
Other Safety Measures .............................................................................................34 
9.2.3. 
Safety Monitoring ....................................................................................................34 
9.2.4. 
Complaint Handling .................................................................................................34 
9.3. 
Sample Collection and Testing .........................................................................................35 
9.3.1. 
Samples for Standard Laboratory Testing ...............................................................35 
9.3.2. 
Stored Samples .........................................................................................................35 
9.3.3. 
Collection Procedures ..............................................................................................36 
9.4. 
Appropriateness of Measurements ...................................................................................36 
10. Data Quality Assurance .........................................................................................................37 
10.1. Direct Data Entry and Computerized Systems .................................................................37 
11. Sample Size and Statistical Methods .....................................................................................38 
11.1. Determination of Sample Size ..........................................................................................38 


H8O-MC-GWBQ(e) Clinical Protocol 
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11.2. Statistical and Analytical Plans ........................................................................................38 
11.2.1. 
General Considerations ............................................................................................38 
11.2.2. 
Patient Disposition ...................................................................................................39 
11.2.3. 
Patient Characteristics ..............................................................................................39 
11.2.4. 
Concomitant Therapy ...............................................................................................39 
11.2.5. 
Treatment Compliance .............................................................................................39 
11.2.6. 
Primary Outcome and Methodology ........................................................................39 
11.2.7. 
Efficacy Analyses - Secondary Endpoints ...............................................................40 
11.2.8. 
Safety Analyses ........................................................................................................41 
11.2.8.1. 
Study Drug Exposure .........................................................................................41 
11.2.8.2. 
Adverse Events ...................................................................................................41 
11.2.8.3. 
Laboratory and Vital Signs Analyses .................................................................41 
11.2.8.4. 
Episodes of Hypoglycemia .................................................................................41 
11.2.8.5. 
Pubertal Assessments .........................................................................................42 
11.2.9. 
Subgroup Analyses ..................................................................................................42 
11.2.10. Interim Analyses ......................................................................................................42 
12. Informed Consent, Ethical Review, and Regulatory Considerations ....................................43 
12.1. Informed Consent .............................................................................................................43 
12.2. Ethical Review..................................................................................................................43 
12.3. Regulatory Considerations ...............................................................................................44 
12.3.1. 
Investigator Information ..........................................................................................44 
12.3.2. 
Protocol Signatures ..................................................................................................44 
12.3.3. 
Final Report Signature .............................................................................................44 
13. References .............................................................................................................................45 
 
 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 5 
 
 
List of Figures 
Figure 
Page 
Figure GWBQ.1. 
Illustration of study design for Protocol H8O-MC-GWBQ. ........................15 
 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 6 
 
 
List of Attachments 
Attachment 
Page 
Attachment 1. 
Protocol GWBQ Study Schedule .......................................................................47 
Attachment 2. 
Protocol GWBQ Clinical Laboratory Tests .......................................................52 
Attachment 3. 
Protocol GWBQ 
American Diabetes Association:  Diagnosis of Diabetes Mellitus* ......................................54 
Attachment 4. 
Protocol GWBQ 
Lifestyle Modification Program .............................................................................................55 
Attachment 5. 
Protocol GWBQ 
Estimated Glomerular Filtration Rate ....................................................................................57 
Attachment 6. 
Protocol Amendment H8O-MC-GWBQ(e) Summary  
Safety and Efficacy of Exenatide as Monotherapy and Adjunctive Therapy to Oral 
Antidiabetic Agents in Adolescents with Type 2 Diabetes ...................................................58 


H8O-MC-GWBQ(e) Clinical Protocol 
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3. Abbreviations and Definitions 
ADA 
American Diabetes Association 
ANCOVA 
Analysis of covariance 
Audit 
A systematic and independent examination of the trial-related activities and 
documents to determine whether the evaluated trial-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), good 
clinical practice (GCP), and the applicable regulatory requirement(s). 
BMI 
Body mass index 
Blinding/Masking 
A procedure in which one or more parties to the trial are kept unaware of the 
treatment assignment(s).  Single-blinding usually refers to the patient(s) being 
unaware, and double-blinding usually refers to the patient(s), investigator(s), 
monitor(s), and in some cases, select Sponsor personnel being unaware of the 
treatment assignment(s). 
CDE  
Certified Diabetes Educator  
CEA 
Carcinoembryonic antigen 
CMH 
Cochran-Mantel-Haenszel 
CRF/eCRF 
Case Report Form (sometimes referred to as Clinical Report Form).  A printed or 
electronic form for recording study participants’ data during a clinical study, as 
required by the protocol. 
Complaint  
A complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, purity, durability, reliability, safety or 
effectiveness, or performance of a drug or drug delivery system. 
Compliance  
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements. 
Confirmation  
A process used to confirm that laboratory test results meet the quality 
requirements defined by the laboratory generating the data and that Amylin is 
confident that results are accurate.  Confirmation will either occur immediately 
after initial testing or will require that samples be held to be retested at some 
defined time point, depending on the steps required to obtain confirmed results. 
DMC  
Data Monitoring Committee  
Drug Naïve 
No previous exposure to oral antidiabetic drugs and treatment with diet and 
exercise alone. 
ECG  
Electrocardiogram  
End of Study (Trial) 
End of study (trial) is the date of the last visit or last scheduled procedure shown 
in the Study Schedule for the last active patient in the study. 
EU 
European Union 
FSG  
Fasting serum glucose  


H8O-MC-GWBQ(e) Clinical Protocol 
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GCP  
Good clinical practices  
GLMM 
Generalized linear mixed model 
GLP-1 
Glucagon-like peptide 1 
HbA1c 
Glycated hemoglobin 
HOMA-B  
Homeostasis model assessment of beta cell function  
HOMA-S  
Homeostasis model assessment of insulin sensitivity  
IB 
Investigator’s Brochure  
ICD 
Informed Consent Document 
IRB/ERB  
Institutional review board/ethical review board:  a board or committee 
(institutional, regional, or national) composed of medical professional and 
nonmedical members whose responsibility is to verify that the safety, welfare, 
and human rights of the subjects participating in a clinical trial are protected. 
IV  
Intravenous  
IVRS  
Interactive voice response system  
IND  
Investigational New Drug application  
Intention to Treat 
(ITT) 
The principle that asserts that the effect of a treatment policy can be best assessed 
by evaluating on the basis of the intention to treat a subject (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence 
that subjects allocated to a treatment arm should be followed up, assessed and 
analyzed as members of that arm irrespective of their compliance to the planned 
course of treatment. (continued) 
Interim Analysis  
Any analysis intended to compare treatment arms at any time prior to the formal 
completion of a trial. 
Investigator  
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is 
conducted by a team of individuals at a trial site, the investigator is the 
responsible leader of the team and may be called the principal investigator. 
LMP  
Lifestyle modification program  
LOCF  
Last observation carried forward  
LS  
Least squares  
Legal 
Representative  
An individual, judicial, or other body authorized under applicable law to consent, 
on behalf of a prospective subject, to the patient's participation in the clinical 
trial. 
MAR  
Missing at random  
MedDRA  
Medical dictionary for regulatory activities  
MMRM  
Mixed-model repeated measures  
Patient  
A subject with a defined disease  


H8O-MC-GWBQ(e) Clinical Protocol 
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Per-protocol 
The set of data generated by the subset of patients who sufficiently complied with 
the protocol to ensure that these data would be likely to exhibit the effects of 
treatment, according to the underlying scientific model. 
OGTT 
Oral glucose tolerance test 
QD 
Once daily 
QT 
Interval on electrocardiogram between the beginning of the Q wave and end of 
the T wave 
QTc 
QT corrected for heart rate 
RD 
Registered dietitian 
RQA 
Research Quality Assurance 
SAP 
Statistical Analysis Plan 
SC  
Subcutaneous  
SMBG 
Self-monitored blood glucose 
Sponsor  
Throughout this protocol, unless otherwise specified, the term “Amylin” is used 
to refer to Amylin Pharmaceuticals, LLC.  Amylin is a wholly owned subsidiary 
of AstraZeneca PLC (“AZ”).  AZ will take responsibility for the conduct of 
Clinical Study GWBQ. 
Study Entry Terms 
Screen  
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical trial.  In this 
study, screening involves invasive or diagnostic procedures and/or tests (for 
example, blood draws).  For this type of screening, informed consent for these 
screening procedures and/or tests shall be obtained; this consent may be separate 
from obtaining consent for the study. 
Enter/Consent  
The act of obtaining informed consent for participation in a clinical trial from 
patients deemed eligible or potentially eligible to participate in the clinical trial.  
Patients entered into a trial are those who sign the informed consent document 
directly or through their legally acceptable representatives. 
 
Enroll/Randomize 
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial 
are those who have been assigned to a treatment. 
SU 
Sulfonylurea 
TZD 
Thiazolidinedione 
US 
United States 


H8O-MC-GWBQ(e) Clinical Protocol 
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Protocol H8O-MC-GWBQ(d) 
Safety and Efficacy of Exenatide as Monotherapy and 
Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes 
4. Introduction 
4.1. Exenatide 
Exenatide (BYETTA) is the first in a class of medicines called incretin mimetics.  Exenatide 
enhances glucose-dependent insulin secretion by the pancreatic beta cell, suppresses 
inappropriately elevated glucagon secretion, and slows gastric emptying.  Exenatide has been 
approved for use in the United States (US) as an adjunctive therapy to diet and exercise for 
adults with type 2 diabetes with inadequate glycemic control and in the European Union (EU) for 
adults with type 2 diabetes with inadequate glycemic control despite treatment with metformin, a 
sulfonylurea (SU), or combination of metformin, thiazolidinedione (TZD), and an SU.  BYETTA 
is administered twice daily, subcutaneously (SC), at least 6 hours apart, before the 2 main meals 
of the day. 
Incretins, such as glucagon-like peptide 1 (GLP-1), enhance glucose-dependent insulin secretion 
and exhibit other antihyperglycemic actions following their release into the circulation from the 
gut (Drucker 2001).  When administered in vivo, exenatide, a 39 amino acid peptide, mimics 
certain antihyperglycemic actions of GLP-1.  Exenatide has been shown to bind to and activate 
the known human GLP-1 receptor in vitro, which leads to an increase in both glucose-dependent 
synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms 
involving cyclic adenosine monophosphate and/or other intracellular signaling pathways.  
Exenatide promotes insulin release from beta cells in the presence of elevated glucose 
concentrations.  
Exenatide improves glycemic control by reducing fasting and postprandial glucose 
concentrations in patients with type 2 diabetes through the following multiple mechanisms of 
action: 
• Insulin secretion:  Exenatide has acute effects on pancreatic beta cell 
responsiveness to glucose and leads to insulin release only in the presence of 
elevated glucose concentrations (Parkes et al. 2001; Kolterman et al. 2003).  This 
insulin secretion subsides as blood glucose concentrations decrease and approach 
euglycemia.  In healthy individuals, robust insulin secretion occurs during the first 
10 minutes following intravenous (IV) glucose administration.  This secretion, 
known as the “first-phase insulin response,” is characteristically absent in most 
patients with type 2 diabetes.  The loss of the first-phase insulin response is an 
early beta cell defect in type 2 diabetes.  Administration of exenatide at 
therapeutic plasma concentrations restored first-phase insulin response to an IV 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 11 
 
 
bolus of glucose in patients with type 2 diabetes.  Both first-phase insulin 
secretion and second-phase insulin secretion were significantly increased in 
patients with type 2 diabetes treated with exenatide compared with saline 
(p<.001 for both). 
• Glucagon secretion:  In patients with type 2 diabetes, exenatide suppresses 
glucagon secretion and lowers serum glucagon concentrations during periods of 
hyperglycemia (Gedulin et al. 1999).  Lower glucagon concentrations lead to 
decreased hepatic glucose output and decreased insulin demand.  However, 
exenatide does not impair the normal glucagon response to hypoglycemia (Degn 
et al. 2004).  
• Gastric emptying:  Exenatide slows gastric emptying, thereby reducing the rate at 
which meal-derived glucose appears in the circulation (Jodka et al. 1998; 
Kolterman et al. 2003).  
• Food intake:  In both animals and humans, administration of exenatide has been 
shown to reduce food intake (Edwards et al. 2001).  
The effect of exenatide is immediate with respect to its effect on hyperglycemia in the fasting 
state.  In addition, a single dose of exenatide in patients with type 2 diabetes significantly reduces 
the abnormal rise in postprandial glucose concentrations. 
The main risks associated with exenatide treatment include mild or moderate nausea (for 
approximately half of treated patients) that is more frequent at the initiation of therapy and an 
increased risk of mild or moderate hypoglycemia if the patient is also using an SU.  
Approximately 43% of adult patients taking exenatide exhibit a temporal rise in antibodies to 
exenatide, which are mostly of low titer (<1/125).  In about 3% of all patients in the three 30-
week registration trials, the formation of antibodies to exenatide at high titers was associated 
with failure to achieve adequate improvement in glycemic control.  Postmarketing reports have 
linked exenatide use to acute pancreatitis and to altered renal function.  As it is eliminated by the 
kidneys, exenatide should not be used by patients with severe renal impairment or end-stage 
renal disease.   
Type 2 diabetes accounts for approximately 45% of all new cases of diabetes in adolescents 
(Dietz and Robinson 2005).  Evidence has shown that a diagnosis of type 2 diabetes in 
childhood, coupled with inadequate glycemic control, increases the risk of early mortality as well 
as early end organ damage (Cavallo 2006).  The current study will investigate the safety and 
efficacy of exenatide in the treatment of type 2 diabetes in adolescents, and will provide 
important information on the potential clinical use of exenatide in that population. 
More detailed information about the known benefits and risks of exenatide may be found in the 
Investigator’s Brochure (IB). 


H8O-MC-GWBQ(e) Clinical Protocol 
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4.2. Study Rationale 
Insulin and metformin are currently the only approved drugs for the treatment of type 2 diabetes 
in adolescents.  It is important to identify additional safe and effective diabetes therapies for this 
age group.  The current study will include patients who are naïve to antidiabetes drug therapy, 
defined as treatment with diet and exercise alone, and patients previously treated with 
metformin, an SU, or both (with or without diet and exercise).  Although SU use is not an 
approved therapy for adolescents, published reports have described its clinical use in this age 
group (Bloomgarden 2004; Von and Hewett 2007).  Since a monotherapy indication for 
exenatide exists in the US for treatment of adults with type 2 diabetes, such use might also be of 
benefit in adolescents with type 2 diabetes.   
A recent study (Study 2993-124) in 13 adolescent patients with type 2 diabetes investigated the 
pharmacokinetics, pharmacodynamics, safety, and tolerability of exenatide in patients between 
the ages of 10 and 16 with type 2 diabetes and an average body mass index (BMI) of 
32.5 (range: 23.2 to 40.8).  Consistent with clinical trials in adults, exenatide 5 µg nearly 
eliminated postprandial glucose excursions in adolescents.  Exenatide was well-tolerated, with 
1 patient who experienced moderate gastrointestinal events.  No hypoglycemic events were 
reported.  Thus, it appears that the pharmacokinetics, pharmacodynamics, and tolerability of 
exenatide 5 µg in adolescents are comparable to those observed in adults.  Therefore, the 5- and 
10-µg doses of exenatide will be included in this study, both compared with placebo. 
 


H8O-MC-GWBQ(e) Clinical Protocol 
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5. Objectives 
5.1. Primary Objective 
The primary objective of this study is to test the hypothesis that glycemic control, as measured 
by change in hemoglobin A1c (HbA1c) from baseline to endpoint, with exenatide is superior (in 
at least 1 of the exenatide treatment arms), to that of placebo after 28 weeks of treatment in 
adolescent patients with type 2 diabetes who are naïve to antidiabetes agents, or patients who are 
being treated with metformin, an SU, or a combination of metformin and an SU.  
5.2. Secondary Objectives  
The secondary objectives of the study are to compare exenatide 5 µg twice daily and exenatide 
10 µg twice daily versus each other and versus placebo with regards to: 
• the proportion of patients achieving an HbA1c at endpoint of <7%, ≤6.5%, and 
<6.5% 
• body weight 
• fasting serum glucose (FSG) 
• self-monitored blood glucose (SMBG) measurements before and 2 hours after the 
two main meals of the day 
• fasting serum insulin concentrations 
• the incidence and rate of hypoglycemia 
• beta-cell function and insulin sensitivity as measured by homeostasis model 
assessments (HOMA-B, HOMA-S) (Matthews et al. 1985) 
• the proportion of patients discontinuing the study due to failure to maintain 
glycemic control 
• safety and tolerability including reporting of adverse events, antibodies to 
exenatide, calcitonin, carcinoembryonic antigen (CEA), vital signs, 
electrocardiograms (ECGs), laboratory measurements, urinalysis, and pubertal 
assessment 


H8O-MC-GWBQ(e) Clinical Protocol 
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6. Investigational Plan 
6.1. Summary of Study Design 
Study H8O-MC-GWBQ is a multicenter, double-blind, placebo-controlled, randomized, parallel, 
3-arm trial.  Approximately 195 adolescents, ages 10 to 17 years inclusive, with type 2 diabetes 
will be enrolled.  However, the number of patients ≥17 years of age will be limited to no more 
than 10% of patients in each treatment arm.  The patients will be naïve to antidiabetes agents, or 
they will be receiving oral treatment with metformin, an SU, or a combination of metformin and 
an SU at the time of enrollment.  Randomization will be stratified by the patient’s background 
diabetes therapy and screening HbA1c.  The study will commence with a 1-week, single-blind, 
injectable placebo lead-in period before patients are randomly assigned to add injectable 
exenatide or injectable placebo to their existing diabetes treatment.  Patients will be randomly 
assigned to 1 of 3 treatment arms:  exenatide 5 µg twice daily, exenatide 10 µg twice daily, or 
placebo twice daily (volume of injection equivalent to exenatide 5 µg or exenatide 10 µg).  
During the first 4 weeks after randomization, all patients assigned to treatment will receive 
exenatide 5 µg twice daily or equivalent placebo volume twice daily.  A starting dose of 
exenatide 5 µg twice daily and titration to exenatide 10 µg twice daily has been shown to 
mitigate the incidence of nausea.  At the end of 4 weeks post-randomization, patients assigned to 
the exenatide 10 µg twice daily treatment arm, or equivalent placebo volume, are then to increase 
their dose from 5 µg twice daily to 10 µg twice daily, or equivalent placebo volume.  Study drug 
will be administered within 60 minutes before morning and evening meals (or the 2 main meals 
of the day, approximately 6 hours or more apart) for 28 weeks.  
All patients will be expected to participate in a simplified lifestyle modification program (LMP) 
throughout this study (Attachment 4).  The simplified lifestyle modification program will include 
both dietary education and physical activity components.  At the clinic visits, the patients will 
meet with a study registered dietitian (RD) or certified diabetes educator (CDE) who will review 
the patient’s dietary history and physical activity record.  The LMP will be reinforced at each 
visit. 
Patients who are discontinued due to loss of glycemic control will be offered alternative 
antidiabetes therapy at the discretion of the investigator. 
Figure GWBQ.1 illustrates the study design. 
 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 15 
 
 
 
Figure GWBQ.1. 
Illustration of study design for Protocol H8O-MC-GWBQ. 
A brief discussion of the major procedures during the study follows.  The Study Schedule 
(Attachment 1) contains a detailed list of the study events.  Clinic visits occur at Visits 1, 2, 3, 5, 
7, 9, and 11.  Telephone visits occur at Visits 4, 6, 8, and 10.  There is a potential for up to 6 
additional study-site visits during the safety follow-up period (see Protocol Addendum 4 for 
details).  
6.1.1. Screening (Visit 1) 
At Visit 1, parent or legal guardian informed consent and patient assent will be obtained and 
patients will be screened.  The screening includes medical history (including preexisting 
conditions and concomitant medications), laboratory measures, and physical examination 
(including measurement of height, weight, waist/hip circumference, vital signs, pubertal 
assessment, and ECG) for eligibility to participate in the study.  Patients will be assigned an 
identification number that will remain in effect throughout the study, with the exception of 
patients who are rescreened due to being above the upper bound of HbA1c (see Section 7.3 
Rescreening).  Patients will continue their oral agent(s), if any, throughout the study (refer to 
Placebo 
Lead-in 
(BID) 
Usual Oral 
Antidiabetic 
Therapya
Screening
Randomization
Abbreviations: BID = twice a day
a Metformin (Met) or Sulfonylurea (SU) or combination of Met and SU, with or without diet and exercise, or naïve to 
antidiabetic agents defined as being treated with diet and exercise alone
b The volume of placebo is equivalent to 5µg or 10µg exenatide
c Scheduled telephone visit
Treatment Period
Visit
1
2
3
4c
5
6c
7
8c
9
10c
11
Week of 
Treatment
-3
-1
0
2
4
8
12
16
20
24
28
5 µg
5 µg
Exenatide 
(BID)
Exenatide 10 µg (BID)
Exenatide 5 µg (BID) 
Placebob (BID)
Placebob 
(BID)
Lifestyle Modification 
Program


H8O-MC-GWBQ(e) Clinical Protocol 
Page 16 
 
 
Section 8.5 for more information).  Visit 1 may take place on 2 different dates to accommodate 
the fasting procedure.  If a patient has not fasted prior to arrival for this visit, the site will request 
that they return in a fasting state within one week for the collection of a glucose and C-peptide 
specimen.  A urine pregnancy test will be performed locally on all female patients of child-
bearing potential.  If the urine pregnancy test at Visit 1 is positive, a serum pregnancy test will be 
performed centrally to confirm the result. 
6.1.1.1. Height 
Height will be measured at each clinic visit throughout the study, preferably at the same time of 
day.  Measurements will be made with the patient standing and without shoes using a standard 
wall-mounted stadiometer.  The instrument should be calibrated using a standard calibration rod.  
Preferably, the same observer should measure the patients throughout the study, using the same 
instrument.  Any change of instrument during the study should be documented, and 
cross-calibration between the 2 instruments should be performed by measurement of the 
standardized calibration rod.   
6.1.1.2. Pubertal Assessment 
Pubertal development should be assessed at the required visits using the Tanner scale.  
6.1.2. Placebo Lead-In Period (Visit 2) 
At Visit 2, all patients who have met enrollment criteria will begin a 1-week, single-blind, 
injectable placebo lead-in period to familiarize the patients to injections.  At this visit, patients 
will receive an injection pen of placebo.  Patients and/or their responsible adult party (parent or 
legal guardian) will be instructed on how to use the injection pen.  As part of the pen instruction, 
at this clinic visit the patient or responsible adult will inject a dose of placebo and they will be 
instructed that this demonstration injection has no active drug.  During the 1-week lead-in period, 
the patients will inject study drug, placebo, SC into the abdomen within 60 minutes before the 
morning and evening meals (or before the 2 main meals of the day, approximately 6 hours or 
more apart) beginning on the evening of Visit 2.  Patients will receive a glucose meter and 
glucose monitoring supplies for the measurement of their glucose levels during the study.  
Patients will be instructed on how to use the glucose meter, how to monitor their glucose, and 
how to recognize and treat hypoglycemia.  Patients will be counseled at each visit, whether by 
telephone or at an actual clinic visit, by a qualified person (i.e., RD or CDE) to follow an LMP 
that consists of suggested standard dietary recommendations and recommended level of exercise 
throughout the study (Attachment 4).  Patients will be asked to measure their glucose at home 
before and 2 hours after the beginning of the 2 main meals of the day on 3 days during the week 
before clinic Visits 3 and 11. 
Additionally, patients’ vital signs, height, pubertal status, and body weight will be measured at 
Visit 2 and each clinic visit through the remainder of the study.  A urine pregnancy test will be 
performed locally on all females of child-bearing potential at Visit 2 and each clinic visit 
throughout the remainder of the study.  If the urine pregnancy test at Visit 2 or any clinic visit 
throughout the remainder of the study is positive, a serum pregnancy test will be performed 
centrally to confirm the result. 


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At Visit 2 and continuing at clinic visits 3, 5, 7, and 9, patients will be given diaries to record 
episodes of hypoglycemia, illnesses, and concomitant medications.  The patient will also be 
given at least 3 food worksheets and 3 exercise worksheets on which to record dietary and 
activity information at these visits.  Patients will return the completed diaries and food and 
exercise worksheets beginning at Visit 3 and at each subsequent clinic visit.  At each subsequent 
clinic visit, the patients will be given new diaries and worksheets.  Investigative staff will review 
the diaries at the clinic visit and transfer appropriate data to electronic case report forms 
(eCRFs), while the RD or CDE reviews the completed worksheets per the LMP (Attachment 4).   
Patients will be instructed to return used and unused study drug containers at each subsequent 
clinic visit.  
6.1.3. Randomization and Treatment Initiation (Visit 3) 
At Visit 3 (study baseline), patients should arrive at the study site after an overnight fast of at 
least 8 hours and should omit their morning study drug injection, oral antidiabetes medications, 
and concomitant medications prior to arriving so that fasting laboratory assessments can be 
performed.  In addition, laboratory assessments for carcinoembryonic antigen (CEA) and 
calcitonin will be performed at baseline. 
Patients will be randomly assigned to 1 of 3 treatment arms:  exenatide 5 µg twice daily, 
exenatide 10 µg twice daily, or placebo twice daily in a double-blind manner.  Patients 
randomized to placebo will be assigned to take the volume equivalent to exenatide 5 µg or to 
take the volume equivalent to exenatide10 µg.  However, the data for all placebo patients will be 
later combined into 1 group (regardless of injection volume) for analysis purposes.  Patients will 
be randomized to treatment in the proportion of 2:2:1:1 (exenatide 5 µg twice daily; exenatide 
10 µg twice daily; placebo volume equivalent of exenatide 5 µg twice daily; placebo volume 
equivalent exenatide of 10 µg twice daily, respectively) and stratified by screening HbA1c 
values (≤8% and >8%) as well as background diabetes therapy (drug naïve, metformin only, SU 
only and metformin+SU) to ensure a balanced distribution of patients within these strata across 
the treatments.  Patients will receive injection pens of exenatide or placebo.  Patients will be 
reinstructed on how to use their injection pen; however, they will not administer their first dose 
of the assigned therapy until the evening of Visit 3 (within 60 minutes before their evening 
meal).  Dosing of patients participating in the pharmacokinetic addendum at Visit 3 will be 
altered from that in the main protocol.  Patients will administer their first dose of the assigned 
therapy at Visit 3 (approximately 15 minutes before receipt of first meal at the clinic).  Patients 
taking part in the pharmacokinetic addendum are not required to take an evening dose as per 
protocol.  All injections of study drug (placebo and exenatide) will be SC into the abdomen.   
For approximately the first 4 weeks of therapy (until visit 5), patients assigned to both exenatide 
5 µg, 10 µg and both placebo groups will inject, either exenatide 5 µg or equivalent volume of 
placebo, within 60 minutes before the morning and evening meals (or the two main meals of the 
day, approximately 6 hours or more apart).  After visit 5, patients assigned to exenatide 10 µg 
and its matching placebo will begin injecting 10 µg twice daily. 


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In the week prior to Visits 3 and 11, patients will be asked to perform pre- and 2-hour 
postprandial blood glucose measurements at the 2 main meals of the day on 3 separate days.  
These glucose measurements should be recorded along with study drug dose in the patient 
diaries.  In addition to these requested glucose measurements, patients will be encouraged to 
measure daily fasting glucose values at home.  The diaries are considered source documents and 
are to be returned to the investigator at the clinic visit.  If a patient fails to perform any of the 
aforementioned measurements, this will not constitute a protocol violation. 
Also occurring at Visits 3 and 11, will be the collection of CEA and calcitonin. 
6.1.4. Telephone Contact (Visits 4, 6, 8, and 10) 
Study site staff will contact patients by phone to review study medication administration, 
reinforce lifestyle interventions, and answer study questions, as needed.  All adverse events and 
concomitant medications will be collected via telephone and documented.  The date of last 
menses will be collected from all female patients of child-bearing potential.  If the patient has 
missed a menstrual period, she will come into the clinic immediately to have a urine pregnancy 
test performed. 
6.1.5. Interim and Final Treatment Visits (Visit 5, 7, 9, and 11) 
Following randomization, patients should attend regular study visits at the intervals described in 
the Study Schedule (Attachment 1).  Efficacy and safety data will be collected at these study 
visits.  
Beginning with Visit 5, patients randomized to exenatide 5 µg will continue administering 
exenatide 5 µg twice daily while patients assigned to exenatide 10 µg will increase their 
exenatide dose to 10 µg twice daily.  Patients randomized to placebo will remain on placebo 
volume equivalent to exenatide 5 µg twice daily or increase their placebo dose to the equivalent 
of exenatide 10 µg twice daily according to treatment assignment.  Continuing for the duration of 
the study, patients should inject the assigned dose of exenatide or the equivalent volume of 
placebo within 60 minutes before the morning and evening meals (or before the 2 main meals of 
the day, approximately 6 hours or more apart).   
At Visit 11, (or the early discontinuation visit), patients will participate in end-of-study treatment 
measures (see Study Schedule) (Attachment 1).  At this visit, patients should return all diaries, 
study drug, and used and unused study drug devices.  The patients will not receive exenatide or 
placebo; however, a treatment regimen, as deemed clinically appropriate, should be initiated.  
Investigative staff should complete a study summary page for each patient who will not 
participate in the safety follow up addendum (see Protocol Addendum 4 for details). 
At Visit 11 (or the early discontinuation visit), patients should arrive at the study site after an 
overnight fast of at least 8 hours and should omit their morning study drug injection, oral 
antidiabetes medications, and concomitant medications prior to arriving at the study site so that 
fasting laboratory assessments can be performed. 
Additional contacts between the patient and the investigator may occur at any time. 


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6.1.6. Early Discontinuation Visit 
If a patient discontinues after randomization but prior to completion of the study treatment 
period, the patient will be asked to return as soon as possible to the study site for an early 
discontinuation visit.  The early discontinuation visit procedures are described in detail in the 
Study Schedule (Attachment 1).  The patients will not receive exenatide or placebo; however, a 
treatment regimen, as deemed clinically appropriate, should be initiated.  Investigative staff 
should complete a study summary page for each patient.  Patients who discontinue after 
randomization but prior to completion of the study treatment period should continue with the 
safety follow-up addendum unless the patient is lost to follow-up or withdraws consent.  Patients 
who do not have height assessments at study-site visits over a 6-month interval prior to 
discontinuation of study medication will enter the safety follow-up period (Protocol 
Addendum 4). 
6.1.7. Unscheduled Visit Due to Loss of Glycemic Control 
If a patient experiences loss of glycemic control during the treatment period as indicated by 
fasting blood glucose >250 mg/dL (13.9 mmol/L) or non-fasting glucose >300 mg/dL 
(16.7 mmol/L) for 4 days during a 7-day period, as measured by home SMBG, the patient will be 
instructed to return to the clinic for a confirmatory fasting or non-fasting glucose (measured by a 
local laboratory).  If that fasting glucose is >250 mg/dL (13.9 mmol/L), or non-fasting glucose is 
>300 mg/dL (16.7 mmol/L), the patient will immediately start early discontinuation procedures 
and this unscheduled visit will be considered an early discontinuation visit (Section 6.1.6, Early 
Discontinuation Visit).  However, if the confirmatory fasting glucose is ≤250 mg/dL 
(13.9 mmol/L), or non-fasting glucose is ≤300 mg/dL (16.7 mmol/L), the patient will remain in 
the study and continue to follow the study schedule and confirmatory blood glucose value will be 
documented in the patient’s chart.   
In addition, if increase in absolute HbA1c is ≥0.5% from baseline at 2 consecutive scheduled 
visits which are at least one month apart prior to study completion, the patient will discontinue. 
6.1.8. Discussion of Design and Control 
This study is designed to support the efficacy and safety of exenatide as a treatment for type 2 
diabetes in adolescent patients who are naïve to antidiabetes agents, or who are being treated 
with metformin, an SU, or combination metformin and an SU.  
Approximately 195 patients will be enrolled.  Patients will be eligible to participate if they are 
not achieving adequate glycemic control (HbA1c 6.5% to 10.5%, inclusive) with metformin, an 
SU, or metformin and an SU, or diet and exercise only.  Patients will be stratified to treatment 
assignment based on diabetes therapy at enrollment and screening HbA1c.  The three-arm design 
is intended to allow comparison of exenatide at doses of 5 µg twice daily and 10 µg twice daily 
with placebo twice daily. 
The primary endpoint for treatment will be assessed at 28 weeks.  This timing is intended to 
allow patients to achieve a stable, representative HbA1c on study treatment.  It is expected that 
exenatide will be more efficacious than placebo when added to the patient’s current diabetes 


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therapy.  Consequently, the study is designed to show superiority of exenatide compared with 
placebo.  Fasting serum glucose, fasting serum insulin concentrations, and body weight 
assessments will also be used to support the assessment of overall metabolic efficacy.   
Site visits and telephone contacts are included in the study to provide opportunities for patients 
to discuss any questions that they have regarding study drug, injections, or study procedures.   
Investigators will be instructed to maintain patients on stable doses of metformin and an SU so 
that treatment arm differences can be attributed to study treatment rather than other agents.  For 
patients using an SU, the SU dose may be reduced if hypoglycemic episodes occur, and 
eventually stopped, if hypoglycemia continues.   
For some patients, glycemic control may decline.  Therefore, it is important that the adolescent 
patients in this study whose HbA1c significantly deteriorates receive active therapy.  As a result, 
any patient whose absolute HbA1c value increases by ≥0.5% from baseline at 2 consecutive 
scheduled visits which are at least one month apart, despite standard counseling and education 
available to all study participants at each visit, will be discontinued from the study.  Another 
criterion for discontinuation due to loss of glycemic control will be based on home glucose 
monitoring.  A patient whose fasting blood glucose is >250 mg/dL (13.9 mmol/L) or non-fasting 
glucose is >300 mg/dL (16.7 mmol/L) for 4 days during a 7-day period, as measured by home 
SMBG, will return to the clinic for a confirmatory fasting or non-fasting glucose (measured by a 
local laboratory).  If the confirmatory fasting glucose is >250 mg/dL (13.9 mmol/L), or non-
fasting glucose is >300 mg/dL (16.7 mmol/L), the patient will be discontinued.  If the 
confirmatory fasting glucose is ≤250 mg/dL (13.9 mmol/L) or non-fasting glucose is 
≤300 mg/dL (16.7 mmol/L) the patient will remain in the study and continue to follow the study 
schedule. 


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7. Study Population 
A sufficient number of individuals will be screened to enroll at least 195 patients (65 per 
treatment arm).  This number is deemed sufficient to allow for approximately 50 subjects per 
treatment arm to complete treatment.   
7.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria: 
[1] are a male or a female between ages 10 to 17 years, inclusive. The number of 
patients ≥17 years of age will be limited to no more than 10% of patients in 
each treatment arm 
[2] have a history of type 2 diabetes with the original diagnosis based on at least 
one American Diabetes Association (ADA) diagnostic criteria (Section 7.1.1)   
[3] have been treated with metformin, an SU, or both metformin and an SU (with 
or without diet and exercise), for at least 3 months or are naïve to anti-diabetes 
agents and being treated with diet and exercise alone.  The dose of oral 
agent(s) should be stable for the 30 days prior to the screening visit 
[4] have fasting C-peptide >0.6 ng/mL 
[5] have no antibodies to glutamic acid decarboxylase (GAD65) or islet cell 
antigen (ICA512) 
[6] have HbA1c between 6.5% and 10.5%, inclusive 
[7] present an appropriately signed assent form 
[8] a parent or adult guardian agrees in writing to participate in the patient’s 
treatment by signing a consent form 
[9] both the patient and parent or responsible adult guardian are able to 
understand and comply with a lifestyle modification program 
[10] the investigator determines that patient and parent or responsible adult 
guardian are able to fully participate in and likely to complete the trial.  
7.1.1. Disease Diagnostic Criteria  
For the purposes of this study, patients with type 2 diabetes are defined by: 
• diagnosis of type 2 diabetes, as determined by ADA diagnostic criteria and 
antibody testing, documented and confirmed in the patient’s medical record, 
which includes laboratory determinations consistent with one or more of the 
following in the patient’s medical history:  
o fasting blood glucose ≥126 mg/dL (7.0 mmol/L) 
o random blood glucose ≥200 mg/dL (11.1 mmol/L) 


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o two-hour OGTT (Oral Glucose Tolerance Test) ≥200 mg/dL (11.1 
mmol/L) 
AND one or more of the following: 
o no antibodies to GAD65 
OR 
o no antibodies to islet cell antigen (ICA512) 
7.2. Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
[11] are the children or immediate family members of either Amylin, Bristol-
Myers Squibb, or AstraZeneca employees or investigator site personnel 
directly affiliated with this study.  Immediate family is defined as a spouse, 
parent, child, or sibling, whether biological or legally adopted  
[12] have received treatment within the last 60 days with a drug that has not 
received regulatory approval for any indication at the time of study entry  
[13] have previously been exposed to exenatide or, completed or withdrawn from 
this study or any other study investigating exenatide 
[14] are unwilling or unable to inject the study medication  
[15] have a genetic syndrome or disorder other than diabetes known to affect 
glucose tolerance 
[16] have a known allergy or hypersensitivity to exenatide or excipients contained 
in the agent 
[17] have used an alpha-glucosidase inhibitor, a meglitinide, or pramlintide for 
more than 1 week during the 3 months prior to screening 
[18] currently use inhaled steroids at a dose equal to or above 1000 µg Flovent 
(fluticasone propionate) daily 
[19] have used oral steroids within the last 60 days or more than 20 days use within 
the past year 
[20] have used a TZD within 120 days prior to screening 
[21] have used any weight loss medication(s) within 30 days of screening 
[22] are sexually active female of childbearing potential who is unwilling to 
appropriately use TWO methods of birth control (for example, use of oral 
contraceptives; condoms with contraceptive foam; or abstinence) for the 
duration of the study 
[23] are female who is pregnant or planning to become pregnant within 6 months 
of study screening 


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[24] are female who is lactating. 
[25] have history of renal disease, or serum creatinine >1.6 mg/dL (141.4 µmol/L) 
(males) or >1.4 mg/dL (123.8 µmol/L) (females) 
[26] have hepatic dysfunction, defined by aspartate (AST) or alanine (ALT) 
transaminase >3.0 times the upper limit of normal (ULN) 
[27] have had at least 1 episode of diabetic ketoacidosis after receiving antidiabetes 
medication.  A history of diabetic ketoacidosis at the time of diagnosis will 
not be an exclusion criterion 
[28] have physical limitations that prevent participation in lifestyle intervention 
[29] have admitted use of anabolic steroids within the past 60 days 
[30] have an active or untreated malignancy, or have been in remission from 
clinically significant malignancy (other than in situ carcinomas of the cervix) 
for less than 5 years 
[31] have investigator-determined significant organ system illness or condition, 
including but not limited to psychiatric or developmental disorder that prevent 
participation in lifestyle intervention 
[32] fail to satisfy the investigator of suitability to participate for any other reason 
[33] have used insulin for more than 10 weeks during the 3 months prior to 
screening  
7.2.1. Rationale for Exclusion of Certain Study Candidates 
Exclusion Criterion [11] reduces the potential bias that may be introduced at the study site.  
Exclusion Criterion [12] eliminates drugs that cannot be mapped to a standard drug dictionary, or 
for which little data are known to analyze the potential relationship of adverse events or drug 
interactions.  Exclusion Criterion [13] eliminates the possibility of having two sets of data for 
one patient. 
Exclusion Criteria [14] through [33] include clinical situations that may prevent patients from 
completing the protocol, or may influence the effect of the study regimens, or are serious 
conditions that pose a risk for morbidity or mortality.  
7.3. Rescreening 
Patients who have an HbA1c value less than 0.2% of the lower bound of the criteria for inclusion 
may be rescreened one more time within 2 weeks of the initial screening visit.  For example, a 
patient who has an HbA1c value of 6.3% or 6.4% at the initial screening visit is eligible for 
rescreening. 
Alternatively, patients who have an HbA1c greater than the upper bound of 10.5% may be 
rescreened one more time at a later date if, in the investigator’s opinion, the patient may meet 
this criterion following application of an acceptable diabetes regimen (for example, increased 
diet and exercise).  Patients who are rescreened due to being above the upper bound of HbA1c 


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for study inclusion more than 2 weeks after their initial study screening will be required to be 
rescreened for all eligibility criteria. 
Rescreened patients who meet the HbA1c criteria for inclusion at the rescreen visit will not be 
documented as screen failures for HbA1c criteria.  For these patients, the HbA1c value that is 
within the inclusion criteria obtained at the rescreening visit will be used as the screening HbA1c 
value.  Rescreened patients who fail to meet HbA1c criteria at the rescreen visit will be 
documented as screen failures. 
Rescreening of patients for reasons other than HbA1c criterion will not be allowed; however, 
laboratory samples deemed by the lab as not acceptable for testing (for example, clotted 
hematology specimen) may be re-drawn within 2 weeks of the initial screening visit. 
7.4. Discontinuations 
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, that patient will continue in the study unless, in the 
opinion of the Sponsor’s physician responsible for the study, the patient should be discontinued 
for safety reasons.  The Sponsor or its designees must be contacted. 
In addition, patients will be discontinued from the treatment period of the study in any of the 
following circumstances:  
• if the patient experiences a loss of glycemic control, as evidenced by: 
o increase in absolute HbA1c ≥0.5% from baseline at 2 consecutive 
scheduled visits which are at least 1 month apart, prior to study 
completion 
o fasting blood glucose >250 mg/dL (13.9 mmol/L) or non-fasting glucose 
>300 mg/dL (16.7 mmol/L) for 4 days in a 7-day period as measured by 
SMBG.  The patient will return to the clinic for a confirmatory fasting 
glucose, if possible, or a non-fasting glucose.  If by local laboratory 
measurement a fasting glucose is >250 mg/dL (13.9 mmol/L) or a non-
fasting glucose is >300 mg/dL (16.7 mmol/L), the patient will be 
discontinued from the study  
• if a female patient becomes pregnant 
• if the patient misses more than 10 consecutive days of study therapy 
• if the patient misses more than 10 consecutive days of oral antidiabetes therapy 
• if metformin or an SU is added or altered for more than 10 consecutive days or 10 
days in a 30-day period after study entry 
• if a patient uses excluded concomitant medications (Section 7.2, Exclusion 
Criteria) 


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• if the investigator decides that the patient should be withdrawn.  If this decision is 
made because of a serious adverse event or a clinically significant laboratory 
value, the study drug is to be discontinued and appropriate measures are to be 
taken.  The Sponsor or its designee is to be notified immediately 
• if the patient or attending physician requests that the patient is withdrawn from 
the study 
• if the investigator or the Sponsor, for any reason, stops the study or stops the 
patient’s participation in the study. 
Patients who discontinue the study drug and/or study early will have early discontinuation 
procedures performed as shown in the Study Schedule (Attachment 1) and be placed on 
appropriate active antidiabetes therapy.  Patients who discontinue study drug administration prior 
to Visit 11 will enter the safety follow-up period.  Refer to the safety follow-up addendum for 
guidance. 
7.4.1. Discontinuation of Study Sites 
Study site participation may be discontinued if the Sponsor, the investigator, or the institutional 
review board (IRB) of the site judges it necessary for any reason. 
7.4.2. Discontinuation of the Study 
The study will be discontinued if the Sponsor judges it necessary for any reason. 


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8. Treatment 
8.1. Treatments Administered  
This study involves a comparison of exenatide 5 µg twice daily and exenatide 10 µg twice daily 
compared with placebo twice daily.   
The investigator or his/her designee is responsible for explaining the correct use of the 
investigational agent(s) to the patient and parent or responsible adult guardian, verifying that 
instructions are followed properly, maintaining accurate records of study drug dispensing and 
collection, and returning all unused medication to the Sponsor or its designee at the end of the 
study. 
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug injection pen so that the situation can be assessed.   
8.2. Materials and Supplies 
The primary study material is exenatide (0.25 mg/mL), a clear, colorless, sterile, preserved 
solution for SC injection.  It consists of exenatide in sodium acetate buffer, pH 4.5, containing 
4.3% mannitol as an iso-osmolality modifier and 0.22% metacresol as a preservative.  
Placebo is the same sterile, preserved solution; however, the active ingredient, exenatide, is 
omitted. 
Exenatide solution for injection in prefilled pens for twice daily injections has been approved in 
the US since 2005 under NDA 021773 and in the European Union since 2006, as Byetta® 
Marketing Authorisation Numbers EU/1/06/362/001-004.  In addition to the commercial product 
Byetta, a clinical trials presentation, hereafter referred to as “exenatide solution for injection 1.2 
mL and 2.4 mL”, is available to facilitate blinding in clinical trials. 
As the manufacturer (Ypsomed AG) of the reusable injection pen (Ypsopen U100) has ceased 
production of the device, a switch to the Byetta Commercial Like Clinical (CLC) prefilled 
injection pen is needed. 
Exenatide solution for injection 1.2 mL and 2.4 mL is provided by AstraZeneca for the STARZ 
study, also known as D5550C00002, and H80-MC-GWBQ.  Due to the expiry of the previous 
Ypsopen presentation, the Byetta CLC prefilled injection pen will be made available to this 
clinical trial. 
The currently used Ypsopen U100 reusable injection pen expires in Oct 2018. As patients enroll 
in a 28 week treatment period, no patient will be randomized to this drug presentation after 31 
March 2018. After the switch have been initiated all new patients entering the study will be 
recruited/randomized to the Byetta CLC prefilled injection pen. 
 
 


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Study medication will be provided in an injection pen. Study medication will be self-
administered.  Proper measures have been taken to ensure that exenatide and placebo are 
indistinguishable.  
Patients will be provided with commercially available blood glucose meters and test strips for 
use during the study.  Other necessary study supplies will be provided, as needed. 
Labels for study agents will comply with the regulatory requirements of the countries 
participating in the study. 
8.3. Method of Assignment to Treatment  
At Visit 1, each patient will receive the next consecutive patient number from a block of patient 
numbers assigned to the investigator.  At Visit 3, patients will be randomly assigned to 1 of 3 
treatment arms:  exenatide 5 µg twice daily, exenatide 10 µg twice daily, or placebo twice daily.  
Patients will be assigned to the 3 treatment arms by a computer-generated randomized sequence 
using interactive voice response system (IVRS) with equal probability to 1 of 3 treatment arms.  
Patients will be randomized to treatment in the proportion of 2:2:1:1 (exenatide 5 µg twice daily; 
exenatide 10 µg twice daily; placebo volume equivalent of 5 µg exenatide twice daily; and 
placebo volume equivalent 10 µg exenatide twice daily, respectively) and stratified by screening 
HbA1c values (≤8% and >8%) as well as background diabetes therapy to ensure a balanced 
distribution of patients within these strata across the treatments.  
8.4. Rationale for Selection of Doses in the Study 
A pharmacodynamics and pharmacokinetics study (2993-124) demonstrated that single doses of 
exenatide 2.5 µg and 5 µg were safe and well tolerated in the adolescent population tested, 
producing reductions in post-prandial plasma glucose, serum insulin and plasma glucagon 
concentrations.  The pharmacokinetics of exenatide is well characterized in adolescents receiving 
a single 5 µg dose.  Also, in those subjects with quantifiable exenatide levels in response to the 
2.5 µg and 5 µg doses, exposure was generally dose proportional. 
Given the similarity in exposure, tolerability and pharmacodynamic effects between that study 
and previous studies in adults, the exenatide doses of 5 µg and 10 µg twice daily were selected 
for the current study. 
8.5. Selection and Timing of Doses 
Following randomization, all patients will begin administering either exenatide or placebo.  
Patients should inject exenatide 5 µg or the equivalent volume of placebo SC into the abdomen 
within 60 minutes before the morning and evening meals (or before the 2 main meals of the day, 
approximately 6 hours or more apart) for 4 weeks and continue administering exenatide 5 µg or 
placebo equivalent volume or increase their exenatide dose to 10 µg or placebo equivalent 
volume, according to assigned treatment.  Study drug should not be administered after a meal.  If 
a dose is missed, the treatment should be resumed with the next scheduled dose.  


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8.5.1. Metformin 
Metformin will be continued throughout the study at the same dose and schedule as before study 
entry. 
Although a patient should not change his or her metformin dosage after entering the study, 
changes will be allowed due to illness for up to 10 consecutive days or 10 days in a 30-day 
period. 
In addition, if a patient requires a procedure involving the injection of a contrast dye, the patient 
should stop metformin therapy prior to, or at the time of the procedure.  Patients should not take 
metformin within 48 hours after the procedure, but may resume therapy after renal function has 
been evaluated and found to be normal.  
8.5.2. Sulfonylurea  
The concomitant SU will be continued throughout the study at the same dose and schedule as 
before study entry.  The SU dosage may be decreased in response to hypoglycemia.   
If the patient is receiving a fixed-dose combination of metformin and an SU, the SU dosage may 
be decreased in response to hypoglycemia; however, the metformin dosage should remain 
unchanged.  If a fixed-dose combination is available that would permit reduction of an SU 
dosage (as described above) without a change in metformin dosage, a fixed-dose combination 
pill can be used.  If a fixed-dose combination does not meet these criteria, the metformin and SU 
should be administered as separate pills.   
8.5.3. Special Treatment Considerations: Hypoglycemia  
Patients will record hypoglycemic episodes in study diaries provided by the Sponsor via the 
investigative sites.  Patients will be encouraged to check their glucose level when signs or 
symptoms arise, prior to treating the event.  Hypoglycemic events will be analyzed according to 
standard definitions of hypoglycemia. 
Confirmed hypoglycemic episodes will be defined as follows in this study: 
Minor hypoglycemia:   
• any time a patient feels that he or she is experiencing a sign or symptom 
associated with hypoglycemia that is either self-treated by the patient or 
resolves on its own  
and 
• has a concurrent fingerstick blood glucose <3.0 mmol/L (54 mg/dL).   
Major hypoglycemia:   
• any episode with symptoms consistent with hypoglycemia resulting in 
loss of consciousness or seizure that shows prompt recovery in response 
to administration of glucagon or glucose  
or 


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• documented hypoglycemia (blood glucose <3.0 mmol/L [54 mg/dL]) 
requiring the assistance of another person because of severe impairment 
in consciousness or behavior (whether or not symptoms of hypoglycemia 
are detected by the patient).   
Signs and symptoms of hypoglycemia not confirmed with blood glucose values will be reported 
separately from confirmed episodes described above. 
The patient should record the glucose meter reading, associated symptoms, and treatment in the 
study diary. 
Events of hypoglycemia will be closely monitored.  If the patient is on an SU and 1 
hypoglycemic event or 2 suspected hypoglycemic events occur, the investigator should consider 
reducing the patient’s SU dosage by approximately 50%.  If additional confirmed or suspected 
hypoglycemic events occur, the investigator may consider additional 50% reductions of the 
patient’s SU dosage, with discontinuation of the SU therapy as appropriate.   
8.5.4. Special Treatment Considerations:  Laboratory Measures 
8.5.4.1. Carcinoembryonic Antigen and Calcitonin 
Patients will be assessed for the tumor marker CEA and calcitonin levels at visits 3 and 11 or 
early discontinuation.  Calcitonin levels will be measured to determine the possible effect of 
exenatide on thyroid c-cell function. 
8.6. Blinding 
This is a double-blinded study; that is, the patient, the investigator and sponsor of all 3 parties are 
blinded to the assigned treatment.  The study also includes a single-blind placebo lead-in period 
where only the patients are blinded to the treatment.  In addition, the Sponsor will be blinded to 
post-baseline measurements of the primary efficacy variable, HbA1c and antibodies to exenatide 
data. 
Emergency unblinding for adverse events may be performed through an IVRS, which may 
supplement or take the place of emergency codes generated by a computer drug-labeling system.  
This option may be used ONLY if the patient’s well being requires knowledge of the patient’s 
treatment assignment.  All calls resulting in an unblinding event are recorded and reported by the 
IVRS. 
The investigator should make every effort to contact the Sponsor’s clinical research physician 
prior to unblinding a patient’s treatment assignment.  If a patient’s treatment assignment is 
unblinded, the Sponsor must be notified immediately by telephone. 
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study.  In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from the Sponsor’s clinical 
research physician for the patient to continue in the study. 


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8.7. Concomitant Therapy 
Patients will not be allowed to take any of the listed excluded medications during the treatment 
period (Section 7.2, Exclusion Criteria). 
For oral medications that are dependent on threshold concentrations for efficacy, such as 
antibiotics, patients should be advised to take those drugs at least 1 hour before study drug 
injection.  If such drugs are to be administered with food, patients should be advised to take them 
with a meal or snack when study drug is not administered.  Concomitant medications should not 
be taken or administered on the morning of prescheduled clinic visits. 
It may be possible that due to an emergency, some patients will require treatment with insulin.  If 
the period exceeds 10 days during a 3-month period, then the decision to keep the patient in the 
study should be made after consultation between the investigator and the Sponsor’s clinical 
research physician.  Each situation will be considered separately, in order to differentiate 
between real clinical needs and non-compliance.  The decision will be documented by a note to 
the investigator’s file.   
8.8. Treatment Compliance 
The investigator will assess the compliance of the patient at each visit based on a review of the 
patient’s glycemic control, adherence to the visit schedule, completion of patient diaries, and any 
other parameters the investigator deems necessary.  For patients deemed noncompliant, initial 
actions will include education, training, and reinforcement of the importance of compliance with 
the protocol.  No specific study data will be collected for analysis of treatment compliance.  Any 
deviation from the prescribed dosage regimen will be recorded in the eCRF. 
A patient will be discontinued if he or she misses more than 10 consecutive days of study 
medication (exenatide or placebo) during the study, misses more than 10 consecutive days of 
oral antidiabetes therapy during the study, or if the patient’s dose of metformin or SU (for 
reasons other than hypoglycemia) is altered for more than 10 consecutive days or 10 days in a 
30-day period after study entry. 
 


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9. Efficacy and Safety Evaluations, Sample Collection and 
Testing, and Appropriateness of Measurements 
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1). 
9.1. Efficacy Measures  
9.1.1. Primary Efficacy Measure  
The primary efficacy measure is the change in HbA1c from baseline to 28 weeks of treatment in 
adolescent patients with type 2 diabetes who are naïve to antidiabetes agents or patients who are 
being treated with metformin, an SU, or combination of metformin and an SU after treatment 
with exenatide or placebo. 
9.1.2. Secondary Efficacy Measures  
The following secondary efficacy measures will be collected at the times shown in the Study 
Schedule (Attachment 1).  
• proportion of patient achieving an HbA1c <7%, ≤6.5%, and <6.5% 
• body weight 
• FSG 
• SMBG measurements before and 2 hours after the 2 main meals of the day  
• fasting serum insulin concentrations 
• beta-cell function and insulin sensitivity as measured by homeostasis model 
assessment (HOMA-B, HOMA-S) (Matthews et al. 1985) 
• proportion of patients who discontinue the study due to failure to maintain 
glycemic control. 
9.2. Safety Evaluations 
The following safety measures will be collected at times shown in the schedule of events 
(Attachment 1): 
• adverse events (serious and nonserious) 
• incidence and frequency of hypoglycemic events  
• laboratory measurements (including clinical chemistry, calcitonin, CEA and 
hematology and urinalysis) 
• antibodies to exenatide 
• ECGs 
• vital signs 


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• pubertal assessment 
• height. 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting the Sponsor or its designee to any event that seems unusual, even if this event 
may be considered an unanticipated benefit to the patient.   
The investigator is responsible for the appropriate medical care of patients during the study. 
For adverse events that are serious, or that cause the patient to discontinue before completing the 
study, the investigator remains responsible for following these events using an appropriate health 
care option.  The patient should be followed until the event is resolved or explained.  Frequency 
of follow-up evaluation is left to the discretion of the investigator. 
9.2.1. Adverse Events 
The Sponsor has standards for reporting adverse events that are to be followed regardless of 
applicable regulatory requirements that may be less stringent.  A clinical trial adverse event is 
any untoward medical event associated with the use of a drug or drug delivery system in humans, 
whether or not it is considered related to a drug or drug delivery system. 
Lack of drug effect is not an adverse event in clinical trials because the purpose of the clinical 
trial is to establish drug effect. 
Cases of pregnancy that occur during maternal or paternal exposures to study drug or drug 
delivery system should be reported.  Data on fetal outcome and breast-feeding are collected for 
regulatory reporting and drug safety evaluation. 
Study site personnel will record the occurrence and nature of each patient’s pre-existing 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.   
During the study, site personnel will record any change in the condition(s) and the occurrence 
and nature of any adverse events.  
After the informed consent and assent documents are signed, all adverse events related to 
protocol procedures are reported to the Sponsor or its designee via eCRF. 
All adverse events occurring after the patient receives the first dose of study drug must be 
reported to the Sponsor or its designee via eCRF. 
Study site personnel will record any daily dosage that exceeds the maximum dosage in the 
protocol or in the relevant reference safety document (for example, clinical dosage section for 
humans in the Investigator Brochure); whichever is greater, via eCRF. 
Investigators will be instructed to report to the Sponsor or its designee their assessment of the 
potential relatedness of each adverse event to protocol procedure, study drug, and/or injection 
pen via eCRF.   


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Study site personnel must alert the Sponsor or its designee within 24 hours of the investigator 
unblinding a patient’s treatment arm assignment for any reason. 
If a patient's dosage is reduced or treatment is discontinued as a result of an adverse event, study 
site personnel must clearly report to the Sponsor or its designee via eCRF the circumstances and 
data leading to any such dosage reduction or discontinuation of treatment.  
Any clinically significant labs or vital sign measurements that result in a diagnosis should be 
reported to the Sponsor or its designee using the “Adverse Events/Pre-existing Condition” page 
of the eCRF.  In cases where the investigator notices an unanticipated benefit to the patient, 
study site personnel should report “unexpected benefit” with the actual event term to the Sponsor 
or its designee via eCRF (for example, the complete actual term would be “unexpected benefit—
sleeping longer”). 
9.2.1.1. Serious Adverse Events 
Serious adverse event collection begins after the patient has signed informed consent and has 
received study drug.  If a patient experiences a serious adverse event after signing informed 
consent, but prior to receiving study drug, the event will NOT be collected unless the 
investigator feels the event may have been caused by a protocol procedure.  
Study site personnel must alert the Sponsor or its designee of any serious adverse event within 24 
hours of investigator awareness of the event via a Sponsor-approved method.  Alerts issued via 
telephone are to be immediately followed with official notification on study-specific serious 
adverse event forms.  A serious adverse event is any adverse event from this study that results in 
one of the following outcomes: 
• death  
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (that is, immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• considered significant by the investigator for any other reason. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
The Sponsor or its designee will be alerted to a study-specific outcome as a serious adverse event 
only if the investigator deems it to be related to use of the study drug or injection pen or by a 
protocol procedure. 
When a condition related to the injection pen necessitates medical or surgical intervention to 
preclude either permanent impairment of a body function or permanent damage to a body 
structure, the serious outcome of “required intervention” will be assigned. 


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Serious adverse events occurring within 30 days after the last dose of study drug will be 
collected, regardless of the investigator's opinion of causation.  Thereafter, serious adverse 
events are not required to be reported unless the investigator feels the events were related to 
either study drug, drug delivery system, or a protocol procedure.  For information on the 
collection of serious adverse events during the safety follow-up period, please see Protocol 
Addendum 4.  
9.2.2. Other Safety Measures  
Twelve-lead ECGs will be obtained according to the Study Schedule (Attachment 1).  ECGs are 
to be performed locally. 
The ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at 
the site as soon as possible after the time of ECG collection, and ideally while the patient is still 
present, for immediate patient management and to determine whether the patient meets entry 
criteria.  If a clinically significant increase in the QTc interval from baseline is present, then the 
investigator should assess the patient for symptoms (such as palpitations, near syncope, 
syncope).  The physician must document his/her review of each ECG. 
Patients will record hypoglycemic episodes in study diaries provided by the Sponsor via 
investigative sites.  Patients will be encouraged to check their glucose level when signs or 
symptoms arise (as described in Section 8.5.3) before treating the event and record the glucose 
meter reading, associated symptoms, and treatment in the study diary.   
Pubertal assessment will be summarized based on Tanner Scale.  
9.2.3. Safety Monitoring 
The Sponsor’s clinical research physician or scientist will monitor safety data throughout the 
course of the study.   
The Sponsor’s clinical research physician or scientist will review serious adverse events within 
time frames mandated by company procedures and will review trends, laboratory analytes, and 
adverse events at periodic intervals.   
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring committee (DMC); (a group created to 
advise the Sponsor regarding the continuing safety of study participants and the continuing 
validity and scientific merit of the trial) can conduct additional analyses of the safety data. 
9.2.4. Complaint Handling 
The Sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements. 
Complaints related to unblinded comparator drugs or concomitant drugs/drug delivery systems 
are reported directly to the manufacturers of those drugs/devices in accordance with the package 
insert. 


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For blinded studies, all product complaints associated with material packaged, labeled, and 
released by the Sponsor will be reported via product complaint forms. 
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study: 
• recording a complete description of the product complaint reported and any 
associated adverse events using the study-specific complaint forms provided for 
this purpose 
• faxing the completed product complaint form within 24 hours to the Sponsor or 
its designee 
• determining when a drug/drug delivery system is to be returned for investigation.   
If the investigator believes that an adverse event is related to the drug delivery system, but the 
patient has not communicated a complaint, the investigator should assume a complaint and report 
the product complaint to the Sponsor or its designee within 24 hours. 
9.3. Sample Collection and Testing  
Attachment 2 lists the specific tests performed for this study. 
9.3.1. Samples for Standard Laboratory Testing 
Blood samples will be collected at the times specified in the Study Schedule (Attachment 1).  
Standard clinical laboratory tests, including chemistry, hematology, and urinalysis panels will be 
performed and analyzed by a central laboratory.  A urine pregnancy test will be performed 
locally at all clinic visits for females of childbearing potential.  If the urine pregnancy test at any 
clinic visit is positive, a serum pregnancy test will be performed centrally to confirm the result. 
Laboratory analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
Investigators must document their review of each laboratory report. 
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Certain samples may be retained for a longer period, if necessary, to 
comply with applicable laws, regulations, or laboratory certification standards.   
9.3.2. Stored Samples 
At Visits 3 and 11, or if the patient exits the study early (after Visit 3 but prior to Visit 11), blood 
samples will be drawn and the serum and plasma will be stored and may be used for future 
testing to support investigation of the primary and secondary endpoints of the study or for other 
markers of metabolic or cardiovascular interest.  A sponsor-designated referral laboratory will 
perform any testing of the stored samples.  Results of stored sample testing will not be reported 
to investigative sites.   
Stored samples will retain the patient identifier (for example, trial patient numbers) and, 
therefore, will not be stored indefinitely.  Samples will be stored at a Sponsor designated site for 


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a maximum of 3 years after last patient visit for the study; any sample remaining at that time will 
be destroyed. 
9.3.3. Collection Procedures  
Blood (sampled by venipuncture) and urine will be collected from patients during the course of 
the study.  All lab specimens will be collected at the times specified in Study Schedule 
(Attachment 1). 
9.4. Appropriateness of Measurements 
All efficacy assessments included in this study are generally regarded as reliable and accurate 
assessments of diabetes control.  Safety assessments will be consistent with good clinical 
practice (GCP) guidelines. 


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10. Data Quality Assurance 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do the 
following: 
• provide instructional material to the study sites, as appropriate 
• conduct a start-up training session to instruct the investigators and study 
coordinators.  This session will give instruction on the protocol, the completion of 
the eCRFs, and study procedures 
• make periodic visits to the study site 
• be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
• review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection 
• conduct a quality review of the database.   
In addition, the Sponsor or its representatives may periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Amylin or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs. 
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the Sponsor, applicable regulatory agencies, and applicable ethical 
review boards (ERBs) with direct access to original source documents. 
10.1. Direct Data Entry and Computerized Systems 
An electronic data capture system will be used in this trial.  Some or all of a patient’s data (for 
example, a rating scale, daily dosing schedule, patient diary, event diary) may be directly entered 
into the system on an eCRF (for example, personal desk assistant or by means of IVRS) at the 
time that the information is obtained.  In these instances where there is no prior written or 
electronic record of the data, the eCRF (for example, personal desk assistant, or by means of 
IVRS) will serve as the source document.   
Electronic case report form data will be encoded and stored in a clinical trial database.   
Any data for which the eCRF will serve as the source document will be identified and 
documented by each site in that site’s study file. 
Data from complaint forms submitted to the Sponsor will be encoded and stored in the global 
product complaint management system. 


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11. Sample Size and Statistical Methods 
11.1. Determination of Sample Size 
Approximately 195 patients diagnosed with type 2 diabetes will participate in this study.  
Approximately 65 patients will be randomized to receive placebo and 130 patients will be 
randomized to receive exenatide (65 per exenatide treatment arm).  A sample of 65 patients per 
treatment arm would provide >95% power to reject the null hypothesis of no difference among 
treatments assuming true mean changes in HbA1c of -0.7, -0.5, and 0 for patients receiving 
exenatide 10 µg twice daily, exenatide 5 µg twice daily, and placebo twice daily, respectively 
(based on results of previous Studies 2993-112, 
, H8O-MC-GWAA, 
H8O-MC-GWAD).  This power computation also assumes a common standard deviation of 
1.0% and a two-sided significance level of 0.05.  Assuming the same true mean changes in 
HbA1c, common standard deviation, and two-sided significance level, 65 patients per treatment 
arm would also provide >95% power to detect a difference between 10 µg exenatide twice daily 
and placebo treatments, and 80% power to detect a difference between 5 µg exenatide twice 
daily and placebo with a Fisher Protected Testing procedure (Hayter 1986). 
Due to an approximate 23% discontinuation rate in the exenatide arms (based on results from 
2993-112), 65 patients randomized per treatment arm will be sufficient to observe 50 completers 
per treatment arm.   
11.2. Statistical and Analytical Plans 
11.2.1. General Considerations 
All of the data will be entered, verified, and archived at Amylin Pharmaceuticals, LLC or its 
delegate.  All data listings, summaries, and analyses will be performed under the guidance and 
approval of the assigned statisticians.  A detailed statistical analysis plan (SAP) will be 
developed before database lock.  The full analysis set will use the intent-to-treat (ITT) principle 
and include the data from all randomized patients who received at least 1 dose of study drug. 
Although, patients randomly assigned to placebo will be assigned to take the volume equivalent 
to 5 µg exenatide twice daily, or to take the volume equivalent to 10 µg exenatide twice daily, 
those patients will be combined into 1 group for analysis purposes. 
Multiplicity adjustments for the primary analysis will be performed using Fisher Protected 
Testing procedure.  No imputation of missing data will be performed with the exception of the 
last observation carried forward (LOCF) of post-baseline values in change from baseline to 
endpoint analyses.  All tests of treatment effects will be conducted at a two-sided significance 
level of 0.05 unless otherwise stated.   
Supportive analyses will be performed on the per-protocol analysis set.  Per-protocol patients 
will be randomized to study drug, adhere to the inclusion/exclusion criteria, and have a Week 28 
HbA1c measurement. 
CCI


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Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it affects the primary analysis.  Any other change to the data analysis methods 
described in the protocol and the justification for making the change will be described in the SAP 
as well as the clinical study report. 
11.2.2. Patient Disposition 
The primary reasons for discontinuation will be listed and summarized as frequencies and 
percentages for all patients by the treatment arm and by visit. 
11.2.3. Patient Characteristics 
Categorical variables (for example, gender and ethnic origin) will be summarized by frequencies 
and percentages.  Continuous variables (for example, age, body weight, and baseline HbA1c) 
will be summarized by means, standard deviations, and extremes (minimum and maximum). 
11.2.4. Concomitant Therapy  
Summaries as well as patient listings of concomitant drug therapy will be provided. 
11.2.5. Treatment Compliance  
No specific study data will be collected for analysis of treatment compliance. 
11.2.6. Primary Outcome and Methodology 
The primary outcome is the change in HbA1c from baseline to treatment endpoint at 28 weeks.  
The ITT analysis set will be used to demonstrate superiority of exenatide to placebo. 
The method for the primary efficacy analysis will be a mixed model repeated measures 
(MMRM) ANCOVA under the assumption that data are missing at random (MAR).  The model 
will include change in HbA1c as the dependent variable and treatment, screening HbA1c strata 
(≤8% and >8%), baseline HbA1c, background diabetes therapy strata (drug naïve, metformin, an 
SU, and a combination of metformin and an SU), week of visit, and treatment-by-week 
interaction as fixed effects and patient as the random effects.  The plan for determining a 
covariance structure to be used for this model will be described in the SAP.  All post-baseline 
measurements of the change in HbA1c will be included in the analysis with no imputation of 
missing data other than that inherent in the MMRM model.  If the last efficacy measurement is 
collected at a visit for which the efficacy measurement is not planned to be collected, the 
measurement collected at the early termination visit will be mapped to the following planned 
visit.  Using SAS® PROC MIXED, least squares (LS) means and 95% confidence interval will 
be produced from the model to estimate the magnitudes of treatment effects.  The p-value for the 
overall test for differences among treatments will be obtained directly from the MMRM analysis.  
Pairwise comparisons between each exenatide treatment and placebo will be obtained from the 
MMRM model.  Inferences will be based on the estimate of the treatment difference at Week 28.  
Superiority of exenatide treatment to placebo with regard to change in HbA1c will be concluded 
if the p-value adjusted using the Fisher Protected Testing procedure for at least one of the 
exenatide treatment arms is less than 0.05.   


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An analysis of covariance (ANCOVA) with change in HbA1c as the dependent variable and 
treatment, screening HbA1c strata (≤8% and >8%), baseline HbA1c, and background diabetes 
therapy strata (drug naïve, metformin, an SU, and a combination of metformin and an SU) as the 
independent variables will be done to provide further supportive evidence of superiority of 
exenatide to placebo.  Least squares (LS) means and 95% confidence interval will be produced 
from the model to estimate the magnitudes of treatment effects.  The p-value for the overall test 
for differences among treatments will be obtained directly from the ANCOVA.  Pairwise 
comparisons between each exenatide treatment and placebo will be obtained from the ANCOVA 
model.  For the purpose of supporting the primary analysis, inferences will be based on the 
estimate of the treatment difference at Week 28 (LOCF).  Superiority of exenatide treatment to 
placebo with regard to change in HbA1c will be concluded if the p-value adjusted using the 
Fisher Protected Testing procedure for at least one of the exenatide treatment arms is less than 
0.05.   
11.2.7. Efficacy Analyses - Secondary Endpoints 
In addition to the primary efficacy analysis for superiority in HbA1c, the efficacy measures (both 
actual and change values) will be summarized at baseline, endpoint, and, if measured, at each 
visit.   
Other secondary efficacy measures include: 
• proportion of patient achieving an HbA1c at endpoint of <7%, ≤6.5%, and <6.5 % 
• body weight 
• FSG 
• SMBG measurements before and 2 hours after the 2 main meals of the day 
• fasting serum insulin concentrations 
• beta-cell function and insulin sensitivity as measured by homeostasis model 
assessment (HOMA-B, HOMA-S) (Matthews et al. 1985) 
• proportion of patients who discontinue the study due to failure to maintain 
glycemic control. 
Similar to the analysis for HbA1c, the continuous secondary efficacy measures will be 
summarized by treatment and by visit, and treatments will be compared using an MMRM 
analysis where multiple post-baseline measurements are collected.  If only an endpoint 
measurement is collected, an ANCOVA model will be used.  As in the analyses of HbA1c, 
inferences will be based on the estimate of the treatment difference at Week 28 for the MMRM 
analysis, and at Week 28 (LOCF) for the ANCOVA analysis.  Treatment comparisons and LS 
estimates will be reported only for scheduled visits.  Furthermore, the proportion of patients 
reaching HbA1c <7%, ≤6.5%, and <6.5%, as well as the proportion of patients who discontinue 
due to failure to maintain glycemic control (termination reason = “loss of glycemic control”), 
will be summarized and compared by treatment using the Cochran-Mantel-Haenszel (CMH) test, 
where screening HbA1c strata (≤8% and >8%) and background diabetes therapy strata will serve 


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as the stratification factors.  In addition a Generalized Linear Mixed Model (GLMM) analysis 
will be done using the binary HbA1c outcome (achieved vs. not achieved HbA1c goal) as the 
dependent variable.  Details of analyses will be specified in the SAP.   
11.2.8. Safety Analyses 
Descriptive statistics of changes from baseline, measured from Visit 3 (Week 0) for clinical 
chemistry, hematology, urinalysis, CEA, calcitonin, and vital signs will be generated.  Physical 
examinations (including height and pubertal assessments) and ECGs will be summarized and 
listed.   
Antibodies to exenatide data will be listed and summarized. 
11.2.8.1. Study Drug Exposure 
Exposure to each therapy during the treatment period of the study will be calculated for each 
patient and summarized by treatment arm. 
11.2.8.2. Adverse Events 
Adverse events will be summarized by presenting patient incidence and event frequency in each 
system organ class and in each preferred term defined by the Medical Dictionary for Regulatory 
Activities (MedDRA), by treatment.  Adverse events will be collected if they occur during or 
after the administration of randomized study medication at Visit 3 (Week 0) through study 
completion (Week 28) or early termination, if applicable. 
Adverse events will be summarized as treatment-emergent adverse events.  Treatment-emergent 
adverse events will be defined as those occurring on or after randomization or worsened through 
study completion, and will be analyzed by treatment and summarized.  Adverse events that occur 
on or after Visit 2 (Week -1) through Visit 3 (Week 0) will be classified as pretreatment (non-
treatment-emergent) and will be listed only.  All adverse events will be listed by patient, visit, 
preferred term, treatment arm, severity, and relationship to the treatment.  The frequency and 
percentage of treatment-emergent adverse events will be presented for each treatment arm. 
11.2.8.3. Laboratory and Vital Signs Analyses 
Categorical changes in laboratory analyses (clinical chemistry and hematology, calcitonin, CEA 
and urinalysis) will be evaluated by examining the proportion of patients whose test values are 
outside the reference ranges at their final visit.  The treatment effect on change from baseline in 
laboratory analytes and vital signs will be assessed using descriptive statistics. 
11.2.8.4. Episodes of Hypoglycemia 
The distribution of hypoglycemic episodes and hypoglycemia incidence will be summarized by 
treatment.  Hypoglycemia rate (adjusted for duration of exposure to study drug therapy) will be 
summarized by treatment.  Similar reports will be created for daytime and nocturnal 
hypoglycemia episodes.  A method of analysis to compare treatments will be described in the 
SAP. 


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11.2.8.5. Pubertal Assessments 
Pubertal assessments (based on Tanner scale) will be performed at Visits 1, 2, 3, 5, 7, 9, and 11 
(or at early discontinuation visit prior to Visit 11).  Details of analyses of pubertal assessment 
data will be specified in the SAP. 
11.2.9. Subgroup Analyses  
Analyses of population subgroups of interest (gender, or BMI) will be performed.  Other 
subgroup analyses may be performed if deemed appropriate.  Subgroup analyses will be 
described in detail in the SAP. 
11.2.10. Interim Analyses 
Three safety analyses are planned for this trial beginning when at least 25% of the patients have 
been randomized.  In order to minimize the operational and statistical bias that result from 
performing a safety assessment, the assessment for this study will be conducted under the 
auspices of a DMC.  The purpose of the DMC is to advise the Sponsor regarding the continuing 
safety of study participants and the continuing validity and scientific merit of the trial. 
Details regarding the safety updates will be given in the Data Monitoring Committee Charter. 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 43 
 
 
12. Informed Consent, Ethical Review, and Regulatory 
Considerations 
12.1. Informed Consent 
The investigator is responsible for ensuring that the patient understands the risks and benefits of 
participating in the study, including answering any questions the patient may have throughout the 
study and sharing in a timely manner any new information that may be relevant to the patient's 
willingness to continue his or her participation in the trial. 
The informed consent document (ICD) will be used to explain the risks and benefits of study 
participation to the patient in simple terms before the patient is entered into the study, and to 
document that the patient is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study.   
The investigator is responsible for ensuring that informed consent is given by each patient or 
legal representative.  This includes obtaining the appropriate signatures and dates on the ICD 
prior to the performance of any protocol procedures and prior to the administration of study drug.   
A legal representative must give informed consent for a child to participate in this study.  In 
addition to informed consent given by the legal representative, the child may be required to give 
documented assent, if applicable. 
As used in this protocol, the term "informed consent" includes all consent and assent given by 
patients or their legal representatives. 
12.2. Ethical Review 
The Sponsor must agree with all ICDs before they are submitted to the ERB and are used at 
investigative sites(s).  All ICDs must be compliant with the International Conference on 
Harmonisation guideline on GCP.  Informed consent obtained under special circumstances may 
occur only if allowed by local laws and regulations and performed in accordance with a written 
process approved by the Sponsor.   
Documentation of ERB approval of the protocol and the ICD must be provided to the Sponsor 
before the study may begin at the investigative site(s).  The ERB(s) will review the protocol as 
required.   
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.   
The study site’s ERB(s) should be provided with the following: 
• the current IB or package labeling and updates during the course of the study 
• ICD 
• relevant curricula vitae. 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 44 
 
 
12.3. Regulatory Considerations 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCP and the applicable laws and 
regulations.  The investigator, head of the medical institution, or designee will promptly submit 
the protocol to applicable ERB(s). 
Exenatide is being studied in the US under a US Investigational New Drug (IND) application.  
The US IND number is 57,725. 
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient's name to protect the patient’s identity when reporting adverse events and/or other trial-
related data. 
12.3.1. Investigator Information 
Physicians who treat diabetes mellitus in adolescents will participate as investigators in this 
clinical trial. 
12.3.2. Protocol Signatures 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Sponsor’s representative. 
12.3.3. Final Report Signature 
The clinical study report coordinating investigator will sign the final clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.   
The investigator with the most enrolled patients will serve as the clinical study report 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by the Sponsor to serve as the clinical study report coordinating 
investigator. 
The Sponsor’s responsible medical officer will sign the final clinical study report for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study. 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 45 
 
 
13. References 
American Diabetes Association. 2007. Standards of medical care in diabetes. Diabetes Care 
30(1):S4-S41. 
Bloomgarden ZT. 2004. Type 2 diabetes in the young.  The Evolving Epidemic. Diabetes Care. 
27(4):998-1010. 
Cavallo J. 2006. Who has diabetes? JDRF Countdown. Spring 10-19. 
Degn KB, Brock B, Juhl CB, Djurhuus CB, Grubert J, Kim D, Han J, Taylor K, Fineman M, 
Schmitz O. 2004. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-
dependent insulin secretion and counterregulation duration hypoglycemia. Diabetes 53:2397-
2403. 
Dietz WH, Robinson TN. 2005. Overweight children and adolescents. NEJM 352:2100-2109. 
Drucker DJ. 2001. Minireview: the glucagon-like peptides. Endocrinology 142:521-7. 
Edwards CM, Stanley SA, Davis R, Brynes AE, Frost GS, Seal LJ, Ghatei MA, Bloom SR. 
2001. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in 
healthy volunteers. Am J Physiol Endocrinol Metab 281:E155–E161. 
Gedulin B, Jodka L, Hoyt J. 1999. Exendin-4 (AC2993) decreases glucagon secretion during 
hyperglycemic clamps in diabetic fatty Zucker rats. Diabetes 48(1 Suppl):A199. Abstract 
0864. 
Hayter AJ. 1986. The maximum familywise error rate of Fisher’s least significant difference test. 
J American Statistical Association 396:1000-1004. 
Jodka C, Gedulin BR, Young AA. 1998. Exendin-4 potently regulates gastric emptying in rats. 
Diabetes 47(1 Suppl):403A. Abstract 1543. 
Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA, Taylor K, Kim D, 
Aisporna M, Wang Y, Baron AD. 2003. Synthetic exendin-4 (exenatide) significantly reduces 
postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol 
Metab 88:3082-3089. 
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F; 
Chronic Kidney Disease Epidemiology Collaboration. Using standardized serum creatinine 
values in the modification of diet in renal disease study equation for estimating glomerular 
filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247–54. 
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, Kusek JQ, Eggers P, 
Van Lente F, Greene T, Coresh K for the CKD-EPI (Chronic Kidney Disease Epidemiology 
Collaboration).  A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009 
May 5;150(9):604-612. 
Little RJA, Rubin DB. 2002. Statistical analysis with missing data. 2nd ed. Hoboken (NJ): John 
Wiley & Sons, Inc. 
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. 1985. 
Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma 
glucose and insulin concentrations in man. Diabetologia 28(7):412-419. 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 46 
 
 
MyPlate Plan. 2011.  Alexandria, VA: United States Department of Agriculture.  Available at: 
http://www. ChooseMyPlate.gov.  Accessed on 26 January 2012. 
Parkes DG, Pittner R, Jodka C, Smith P, Young A. 2001. Insulinotropic actions of exendin-4 and 
glucagon-like peptide-1 in vivo and in vitro. Metabolism 50(5):583-589. 
Schwartz GJ, Gauthier B. 1985. A simple estimate of glomerular filtration rate in adolescent 
boys. J Pediatr 106(3): 522-526. 
Schwartz GJ, Feld LG, Langford DJ. 1984. A simple estimate of glomerular filtration rate in full-
term infants during the first year of life. J Pediatr 21(6):654-660. 
Schwartz GJ, Haycock GB, Edelmann CM Jr., Spitzer A. 1976. A simple estimate of glomerular 
filtration rate in children derived from body length and plasma creatinine. Pediatrics 
58(2):259-263.  
Von KT, Hewett ML. 2007. Type 2 diabetes in children and adolescents.  Screening, diagnosis 
and management. JAAPA 20(3): 51-54. 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 47 
 
 
Attachment 1. Protocol GWBQ Study Schedule


H8O-MC-GWBQ(e) Clinical Protocol 
 
Page 48 
 
Study Schedule, Protocol H8O-MC-GWBQ — Treatment Period 
Visit 
1¥ 
2 
3 
4‡ 
5 
6‡ 
7 
8‡ 
9 
10‡ 
11 
UV† 
ED*** 
Time relative to Visit 3 (weeks) 
-3 
-1 
0 
2 
4 
8 
12 
16 
20 
24 
28 
 
 
Visit Interval (± weeks)* 
1 
1 
0 
1 
1 
1 
1 
1 
1 
1 
1 
 
 
Informed consent/assent** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient number assigned 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study drug/injection pen 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Collect study drug 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Collect injection pen 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Dispense glucose meter/supplies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Instruct on glucose meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Instruct on hypoglycemia 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Instruct on/reinforce lifestyle modification plana 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Placebo injection demonstration under staff 
supervisionb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Telephone contact 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Injection/pen training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (12-lead)c 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Heightd 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Waist/Hip circumferencee 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Weight/SBP/DBP/HR 
X 
X 
X 
 
X 
 
X 
 
X 
   
X 
 
X 
Physical examination  
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pubertal Assessments 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
(continued) 


H8O-MC-GWBQ(e) Clinical Protocol 
 
Page 49 
 
Study Schedule, Protocol H8O-MC-GWBQ — Treatment Period (Continued) 
Visit 
1¥ 
2 
3 
4‡ 
5 
6‡ 
7 
8‡ 
9 
10‡ 
11 
UV† 
ED*** 
Time relative to Visit 3 (weeks) 
-3 
-1 
0 
2 
4 
8 
12 
16 
20 
24 
28 
 
 
Visit Interval (± weeks)* 
1 
1 
0 
1 
1 
1 
1 
1 
1 
1 
1 
 
 
Clinical assessments (continued): 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events/Pre-existing conditionsf 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Distribute study diaries/food and exercise 
worksheets 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Collect study diaries/food and exercise 
worksheets 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Transfer diary information to eCRF: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre- and 2-hr post-prandial glucoseg 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Hypoglycemic episodes h 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Injectable therapy dose (day prior to visit)i 
 
 
 
 
 
 
 
 
 
 
X 
 
Xj 
OAD dose (day prior to visit) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Date of first dose of study drug recorded 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Date of final dose of study drug recorded 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Remind patient to fast prior to next clinic visit 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Laboratory assessmentsk: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Chemistry 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Stored Samples 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Pregnancy testl 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Fasting C-peptide 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting insulin 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Fasting glucose 
X 
 
X 
 
 
 
 
 
 
 
X 
X† 
X 
Random (non-fasting) glucose 
 
 
 
 
 
 
 
 
 
 
 
X† 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Hemoglobin A1c 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Calcitonin 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
(continued) 
 


H8O-MC-GWBQ(e) Clinical Protocol 
 
Page 50 
 
Study Schedule, Protocol H8O-MC-GWBQ — Treatment Period (Continued) 
Visit 
1¥ 
2 
3 
4‡ 
5 
6‡ 
7 
8‡ 
9 
10‡ 
11 
UV† 
ED*** 
Laboratory Assessmentsk (continued): 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time relative to Visit 3 (weeks) 
-3 
-1 
0 
2 
4 
8 
12 
16 
20 
24 
28 
 
 
Visit Interval (± weeks)* 
1 
1 
0 
1 
1 
1 
1 
1 
1 
1 
1 
 
 
CEA 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Glutamic acid decarboxylase (GAD65) 
antibodiesm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Islet cell antigen (ICA512) antibodiesm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Antibodies to exenatiden 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Date of last menseso 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Patient Summary 
 
 
 
 
 
 
 
 
 
 
Xp 
 
X 
Perform procedure as indicated unless time interval is shaded. 
Abbreviations:  CEA= carcinoembryonic antigen: eCRF = electronic case report form; DBP = diastolic blood pressure; ECG = electrocardiogram; ED = early 
discontinuation visit; HR = heart rate; OAD = oral antidiabetic drug; SBP = systolic blood pressure; UV= unscheduled visit due to loss of glycemic control; 
X = performed at this visit. 
a A qualified person (i.e., registered dietitian [RD] or certified diabetes educator [CDE]) will introduce and reinforce the lifestyle modification program to the 
patient on an individual basis beginning at visit 2.  At Visit 2 patients will receive 3 food and exercise worksheets that are to be completed and returned at 
Visit 3.  At each subsequent clinic visit, the patients will be given new diaries and worksheets.  Beginning at Visit 3, and continuing at each subsequent clinic 
or telephone visit, the RD/CDE will reinforce the lifestyle modification program with each patient until the study is complete. 
b Patient (or parent or guardian) will administer a single placebo dose using the study device under the supervision of study site staff for instruction purposes 
only. 
c ECGs will be performed locally. 
d Patient’s height will be measured without shoes, with a wall mounted stadiometer. 
e The patient should be standing with their feet 25-30 cm apart, with their arms hanging naturally at the sides.  The measurer should stand to the side of the 
patient, and fit the tape snugly around the waist on bare skin. Take the measurement at end-expiration with the measuring tape positioned in a horizontal plane 
(horizontal to the floor) at the level of the top of the bony iliac crest (minimum waist). The hip circumference should be measured at the widest area of the 
buttocks. 
f At visit 1, only pre-existing conditions will be collected.  Pre-existing conditions will not be collected at any other visit. 
g Patient should complete and record self monitored blood glucose testing on 3 days in the week prior to clinic Visits 3 and 11. 
h Hypoglycemic episodes will be collected at all clinic visits (beginning at Visit 3). They will be discussed during the telephone visits 
i Patients should not administer injectable therapy (exenatide or placebo) prior to visiting the study site on the day of visit.  
j Only applies if the early discontinuation occurs at or after Visit 4 or any subsequent visit. 
k Patients should fast about 8 hours prior to visiting the study site on the day of visit 3 and visit 11.   


H8O-MC-GWBQ(e) Clinical Protocol 
 
Page 51 
 
Study Schedule, Protocol H8O-MC-GWBQ — Treatment Period (Concluded) 
l Pregnancy test to be administered to females of childbearing potential.  All pregnancy tests performed at clinic visits will be urine pregnancy tests performed 
locally.  If the urine pregnancy test at any clinic visit is positive, a serum pregnancy test will be performed centrally to confirm the result. 
m A positive result will be reconfirmed by a second test at screening, as false positives have occurred.  
n Blood samples will be collected for antibodies to exenatide analysis.  Samples that test positive for antibodies to exenatide may be subjected to further 
immunologic characterization. 
o Female patients of childbearing potential only.  If the patient has missed a menstrual period, she will come into to the clinic immediately to have a urine 
pregnancy test performed. 
p Only patients who have achieved the final height requirement of a change of less than 5 mm between Visit 3 and Visit 11 of the treatment period will be 
summarized at Visit 11 and will not participate in the safety follow-up addendum.   
* All procedures are to be completed prior to next visit. 
** Patients who are17 years of age at the time of screening that reach age of majority (as applicable in their country) during the study will be asked to re-consent. 
***Patients who discontinue early from the study treatment period should continue into the safety follow-up addendum unless the patient is lost to follow-up, 
withdraws consent, or achieved final height criteria of a change of less than 5 mm during the treatment period. 
¥ Visit 1 may take place in 2 different dates to accommodate the fasting procedure. If a patient comes for visit 1 non-fasting then the site will request the patient 
return in a fasting state within a week to draw the fasting blood glucose and c-peptide. 
‡ Visits 4, 6, 8, and 10 are telephone visits where the LMP is reinforced and all adverse events and concomitant medications will be documented. 
† At the unscheduled visit (UV) associated with loss of glycemic control, fasting or non-fasting glucose testing will be done locally, at which time the 
investigator will decide whether the patient will begin early discontinuation procedures or continue in the trial. 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 52 
 
 
Attachment 2. Protocol GWBQ Clinical Laboratory Tests 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 53 
 
 
Clinical Laboratory Testsa 
 
 
Hematology: 
Clinical Chemistry 
Hemoglobin 
Serum Concentrations of: 
Leukocytes (WBC) 
Alanine aminotransaminase (ALT/SGPT) 
 
Aspartate aminotransaminase (AST/SGOT) 
Serum Pregnancy Testb 
Creatinined 
 
 
Urine Pregnancy Testf 
 
 
 
Fasting Insulin  
Fasting Glucose  
 
 
Urinalysis:  
Hemoglobin A1c 
Specific Gravity 
 
PH 
Fasting C-peptidec 
Protein 
 
Glucose 
Antibodies to exenatidee 
Ketones 
 
Bilirubin 
Stored Samples 
Urobilinogen 
 
Blood 
Islet cell antigen (ICA512) antibodiesc 
 
 
 
Calcitonin 
 
 
 
Carcinoembryonic antigen (CEA) 
 
 
 
Glutamic acid decarboxylase (GAD65) antibodiesc 
a Assayed by designated laboratory. 
b Will be performed when a urine pregnancy test at any clinic visit is positive.  
c Screening test only. 
d Creatinine measurements will be used to calculate patient glomerular filtration rate by the Schwartz equation. 
e Blood samples will be collected for antibodies to exenatide analysis.  Samples that test positive for antibodies to 
exenatide may be subjected to further immunologic characterization. 
f Urine pregnancy test will be performed by local lab. 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 54 
 
 
Attachment 3. Protocol GWBQ 
American Diabetes Association:  Diagnosis of Diabetes 
Mellitus* 
1.  Symptoms of diabetes plus casual plasma glucose concentration greater than or equal to 
200 mg/dl (11.1 mmol/L).  
Casual is defined as any time of day without regard to time since last meal.  The classic 
symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. 
 
OR 
2.  Fasting plasma glucose greater than or equal to 126 mg/dl (7mmol/L).  
Fasting is defined as no caloric intake for at least 8 hours.  
 
OR  
3.  2-h Plasma glucose greater than or equal to 200 mg/dl (11.1 mmol/L) during an OGTT.   
The test should be performed as described by the World Health Organization, using a glucose 
load containing the equivalent of 75g anhydrous glucose dissolved in water. 
NOTE:   
In the absence of unequivocal hyperglycemia, in order to make a diagnosis of diabetes mellitus, 
these criteria should be confirmed by repeat testing on a different day.   
The OGTT is not recommended for routine clinical use, but may be required in the evaluations 
of patients with impaired fasting glucose or when diabetes is still suspected despite a normal 
FPG. 
The use of the hemoglobin A1c (A1C) for the diagnosis of diabetes is not recommended at this 
time. 
*ADA’s Clinical Practice Recommendations 2007 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 55 
 
 
Attachment 4. Protocol GWBQ 
Lifestyle Modification Program 
A simplified lifestyle modification program (LMP) will be recommended for all patients 
participating in study GWBQ.  The LMP consists of a diet and exercise component suggested to 
be followed throughout the duration of the study.  This program will address the dietary and 
physical activity needs of the individual.  A qualified person (i.e.) Registered Dietitian (RD) or 
Certified Diabetes Educator (CDE) will meet with the patient and parent or guardian at each 
scheduled clinic visit.  The LMP will be reinforced at each visit. 
The study LMP for sites located in the U.S. will be based on the “MyPlate Plan”, a program 
designed by the United States Department of Agriculture and available to the public at 
www.ChooseMyPlate.gov.  The qualified person at each site will enter each patient’s age, 
gender, weight and height into the SuperTracker program calculator.  The program will calculate 
the total daily calories recommended to be consumed to promote at least minimal weight loss 
and to meet growth needs.  The MyPlate Plan will also be used to calculate the number of daily 
meal servings from each food group in the plan.   
The qualified person can individualize the MyPlate Plan using clinical judgment to promote 
compliance with the meal plans and physical activity throughout the study.  At each clinic visit, 
individualized tools can be given to the patient with a copy retained by the qualified person. 
For countries other than the US, the study LMP will be based on the “MyPlate Plan” or other 
locally applicable plan. 
Visit 2 (Beginning of the placebo lead-in period)   
The qualified person will meet with the patient and parent or guardian beginning at Visit 2 of the 
study.  The qualified person will introduce and review the MyPlate with the patient and 
parent/guardian, explaining the recommended number of calories, food groups, portion sizes, and 
individualizing the plan to aid patient compliance.  The patient will be given at least three food 
and exercise worksheets.  The patient will be instructed to complete a minimum of one of the 
worksheets with at least two weekdays and one weekend day of food consumption and exercise. 
The patient will be instructed to complete the worksheet prior to Visit 3 and bring the worksheet 
with them to the next clinic visit.   
The qualified person will instruct the patients on the importance of a minimum of 60 minutes of 
daily exercise (walking, jogging, biking, hiking, sport activity, etc) and limiting sedentary 
activities (watching TV, video games) to one hour or less daily.   
Visit 3 (Randomization) through Visit 10  
The qualified person will meet with the patient and parent/guardian to collect and review the 
food and exercise worksheets, during clinic visits.  The qualified person will evaluate adherence 
to the LMP and address any areas of concern.  The patient’s weight will be noted at each clinic 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 56 
 
 
visit to help assess diet and exercise compliance.  The qualified person will re-instruct patient on 
problem areas, as appropriate.  The qualified person will reinforce positive changes and 
encourage the patient to adhere to both the diet and exercise recommendations.  The patient will 
be given at least three food and exercise worksheets.  The patient will be instructed to complete a 
minimum of two of the worksheets with at least two weekdays and one weekend day of food 
consumption and exercise.  The patient will be instructed to complete the worksheets prior to the 
clinic visit and bring the worksheets with them to the next clinic visit.  During the phone visits 
the patient may speak with the qualified person on the LMP if requested. 
Visit 11 (End of study treatment) 
The qualified person will meet with the patient and parent/guardian and collect the food and 
exercise worksheets.  The patient should be encouraged to maintain a healthy lifestyle after the 
patient ends study treatment and enters the safety follow-up period, at the discretion of the 
investigator.  
Footnote: Failure to return food and exercise worksheets will not, at any time, be considered a protocol violation. 
 


H8O-MC-GWBQ(e) Clinical Protocol 
Page 57 
 
 
Attachment 5. Protocol GWBQ 
Estimated Glomerular Filtration Rate  
Note:  The central laboratory applies the formula and reports the value in its calculated form.   
Standard Schwartz Formula for Estimated Glormerular Filtration Rate (GFR)a 
For glomerular filtration rate in mL/min/1.73 m2 
GFR = kb × height(cm)/serum creatinine (mg/dL) 
a Schwartz GJ et al, 1976; Schwartz et al, 1984; Schwartz et al, 1985. 
b k= 0.55 in male children aged 2 -12 years and all female children and adolescents up to age 17 years ; k= 0.65 for 
adolescent males aged 13-17 years. 
 
Modification of Diet in Renal Disease (MDRD) Formula for Estimated Glomerular 
Filtration Rate (GFR) in Adults 
• 
GFR (mL/min/1.73 m2) = 175 x (serum creatinine)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American) 
 
CKD-EPI Formula for Estimated Glomerular Filtration Rate (GFR) in Adults 
GFR (mL/min/1.73 m2) =  141 x min(Scr/k,1)a  x  max(Scr/k,1) -1.209  x_ 0.993Age  x_[1.018 if 
female] x 1.159 if black] 
 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 1 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
 
Amendment (a) to Protocol Addendum 
H8O-MC-GWBQ(3) 
Safety and Efficacy of Exenatide as Monotherapy and 
Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes 
 
 
 
 
 
 
Confidential Information 
 
The information contained in this protocol addendum is confidential and is  
intended for the use of clinical investigators. It is the property of Amylin Pharmaceuticals, 
LLC or its subsidiaries and should not be copied by or distributed to persons not involved 
in the clinical investigation of (LY2148568), unless such persons are bound by a 
confidentiality agreement with Amylin Pharmaceuticals, LLC or its subsidiaries. 
 
 
 
 
 
Exenatide (LY2148568) 
 
 
 
 
 
 
 
 
 
 
Amylin Pharmaceuticals, LLC 
San Diego, California USA 92121 
 
Protocol Addendum (3) Approved by Lilly: 01-Feb-2011 GMT 
Amendment (a) to Protocol Addendum (3) Approved by Amylin/AZ: 16 May 2013 
 
 
 
 
 
 
This addendum is to be performed in addition to all procedures required by protocol 
H8O-MC-GWBQ or any subsequent amendments to that protocol. 
 
 
 
 
 
 
 
 
 
 
 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 2 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
Amendment (a) to Protocol Addendum 
H8O-MC-GWBQ(3) 
Safety and Efficacy of Exenatide as Monotherapy and 
Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes 
 
Table of Contents 
Section 
Page 
 
Rationale for Addendum .............................................................................................................4 
 
Protocol Additions ......................................................................................................................5 
Laboratory Tests.......................................................................................................................5 
Pharmacokinetic Sampling .....................................................................................................5 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 3 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
 
Table of Contents (concluded) 
List of Protocol Addendum Attachments 
 
Attachment 
Page 
 
Attachment 1. 
Protocol Addendum GWBQ (3) Study Schedule for PK Samples .....................6 
 
Attachment 2. 
Protocol Addendum GWBQ (3) Sampling Summary ........................................7 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 4 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
 
Rationale for Addendum 
 
To provide a thorough quantification of the pharmacokinetic (PK) disposition of exenatide in 
adolescents and allow assessment of safety endpoints relative to maximum plasma exenatide 
concentrations observed in adolescent patients, additional PK samples will be collected. Optimal 
design analysis has demonstrated that data from a limited number of subjects in the current 
study, combined with existing PK data from Amylin Study 2993-124, will provide a robust 
characterization of exenatide PK in adolescents.  At least 36 subjects  (12 from each treatment 
arm) enrolled in Study H8O-MC-GWBQ will be incorporated into the population PK analyses. 
 
 Group A:  PK samples will be collected once at Visit 3 at 2 hours post dose.  This 
group will consist of at least 24 subjects, evenly divided among treatment groups 
(placebo twice daily:  8 subjects, exenatide 5 mcg twice dailly:  8 subjects, and 
exenatide 10 mcg twice daily:  8 subjects). This is to allow for the  assessment of 
Cmax in the adolescent population.

 Group B: PK samples will be collected twice during Visit 3: once at 30 minutes 
post dose and once at 4 hours post dose.  This group will consist of at least 12 
subjects, evenly divided among treatment groups (placebo twice daily:  4 subjects, 
exenatide 5 mcg twice daily: 4 subjects, and exenatide 10 mcg twice daily: 4 
subjects). 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 5 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
 
Protocol Additions 
 
Laboratory Tests 
 
Pharmacokinetic Sampling 
Additional PK sampling will be performed at Visit 3 in a subset of subjects.  At least 36 subjects, 
from the US, will be chosen from select sites and randomly assigned to 1 of 2 groups: 
 
 Group A:  PK samples will be collected once at Visit 3 at 2 hours post dose.  This 
group will consist of at least 24 subjects, evenly divided among treatment groups 
(placebo twice daily:  8 subjects, exenatide 5 mcg twice daily:  8 subjects, and 
exenatide 10 mcg twice daily:  8 subjects).

 Group B: PK samples will be collected twice during Visit 3: once at 30 minutes post 
dose and once at 4 hours post dose.  This group will consist of at least 12 subjects, 
evenly divided among treatment groups (placebo twice daily:  4 subjects, exenatide 
5 mcg twice daily: 4 subjects, and exenatide 10 mcg twice daily: 4 subjects). 
 
Dosing of subjects on the PK addendum at Visit 3 will be altered from that in the main protocol. 
Subjects will administer their first dose of the assigned therapy at Visit 3 (approximately 15 min 
before receipt of first meal at the clinic) 
 
Subjects participating in the PK addendum are not to take their evening dose on the day of Visit 3. 
 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
 
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 2 years following last patient visit for the study. 
 
At the visits and times specified in the Study Schedule, venous blood samples (Attachment 1) 
will be collected (Attachment 2).  Blood samples will be used to determine the plasma 
concentrations of LY2148568.  The actual date and time (24-hour clock time) of each 
sampling will be recorded. 
 
A maximum of 2 samples may be drawn at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor. Instructions for the collection and 
handling of blood samples will be provided by the sponsor. 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 6 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
 
Attachment 1. Protocol Addendum GWBQ (3) Study Schedule 
for PK Samples 
 
 
 
 
Study Schedule for PK Samples, Protocol Addendum H8O-MC-GWBQ(3) 
 
CRF Visit No.: 
V3 
Time relative to V3 (baseline) - days 
0 
Procedure 
PK informed consent signed 
X 
Venous blood PK samplesa,b 
X 
a    PK samples must be collected only after the subject signs the PK informed consent document. 
b    Group A: PK samples will be collected once at Visit 3 at 2 hours post dose. This group will consist of 24 
subjects, evenly divided among treatment groups (placebo twice daily:  8 subjects, exenatide 5 mcg twice daily: 
8 subjects, and exenatide 10 mcg twice daily: 8 subjects). 
•   Group B: PK samples will be collected twice during Visit 3: once at 30 minutes post dose and once at 4 hours 
post dose. This group will consist of 12 subjects, evenly divided among treatment groups (placebo twice daily: 
4 subjects, exenatide 5 mcg twice daily: 4 subjects, and exenatide 10 mcg twice daily: 4 subjects).. 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 7 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
 
Attachment 2. Protocol Addendum GWBQ (3) Sampling 
Summary 
 
 
 
 
This table summarizes the maximum number of venipunctures samples and volumes for all PK 
sampling during the study.  Fewer samples may actually be taken, but this will not require a 
protocol amendment. 
 
Protocol H8O-MC-GWBQ Sampling Summary 
 
Purpose 
Sample 
Type 
Maximum Amount 
per Sample 
Maximum 
Number Samples 
Maximum Total 
Amount 
Drug concentration: Group A: 
PK samples 
Blood 
4 mL 
1 +2 additional 
samples if 
warranted 
12 mL 
Drug Concentration Group B: 
PK samples 
Blood 
4 mL 
2+2 additional 
samples if 
warranted 
16mL 
 


H8O-MC-GWBQ(3) Clinical Protocol Addendum 
Page 8 
LY2148568 
PK Addendum 
Amendment (a) to Addendum (3) 
 
 
 
Revised Protocol Addendum Sections 
Global change:  References to Eli Lilly and Company as Sponsor for this study have been replaced with 
Amylin Pharmaceuticals, LLC (Amylin). 
 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 1 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
1. Amendment (a) to Protocol Addendum H8O-MC-GWBQ(4) 
Safety and Efficacy of Exenatide as Monotherapy and 
Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes 
 
 
 
Confidential Information 
The information contained in this protocol addendum is confidential and is intended for the 
use of clinical investigators.  It is the property of Amylin Pharmaceuticals, LLC or its 
subsidiaries and should not be copied by or distributed to persons not involved in the 
clinical investigation of exenatide unless such persons are bound by a confidentiality 
agreement with Amylin Pharmaceuticals, LLC or its subsidiaries.  This document and its 
associated attachments are subject to United States Freedom of Information Act (FOIA) 
Exemption 4.  
Exenatide (LY2148568) 
Amylin Pharmaceuticals, LLC 
San Diego, California USA 92121 
Protocol Addendum (4) Electronically Signed and Approved by Lilly:  29 May 2012 
Amendment (a) to Protocol Addendum (4) Approved by Amylin/AZ:  16 May2013 
 
 
This addendum is to be performed in addition to all procedures required by protocol 
H8O-MC-GWBQ or any subsequent amendments to that protocol. 
 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 2 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
2. Table of Contents 
Amendment (a) to Protocol Addendum H8O-MC-GWBQ(4) 
Safety and Efficacy of Exenatide as Monotherapy and 
Adjunctive Therapy to Oral Antidiabetic Agents in 
Adolescents with Type 2 Diabetes 
Section 
Page 
1. 
Amendment (a) to Protocol Addendum H8O-MC-GWBQ(4) Safety 
and Efficacy of Exenatide as Monotherapy and Adjunctive Therapy 
to Oral Antidiabetic Agents in Adolescents with Type 2 Diabetes .........................................1 
2. 
Table of Contents ....................................................................................................................2 
3. 
Rationale for Addendum .........................................................................................................5 
4. 
Protocol Additions ...................................................................................................................6 
4.1. 
Long-Term Safety Follow-Up Objective ...........................................................................6 
4.2. 
Summary of Study Design..................................................................................................6 
4.2.1. 
Safety Follow-Up Period (Visits 801 to 806) ............................................................7 
4.2.1.1. 
Patients Previously Completing the Protocol or Early 
Withdrawal ...........................................................................................................8 
4.3. 
Exclusion Criteria ...............................................................................................................8 
4.4. 
Treatments Administered ...................................................................................................8 
4.5. 
Concomitant Therapy .........................................................................................................8 
4.5.1. 
Safety Evaluations ......................................................................................................8 
4.6. 
Statistical and Analytical Plans ..........................................................................................9 
4.6.1. 
General Considerations ..............................................................................................9 
 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 3 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
Table of Contents  
 
List of Figures 
Page 
Figure GWBQ(4) 1. Illustration of study design for Protocol Addendum H8O-MC-
GWBQ(4). ....................................................................................................7 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 4 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
Table of Contents (concluded) 
 
List of Protocol Addendum Attachments 
Attachment 
Page 
Attachment 1. 
Addendum GWBQ(4)  
Study Schedule Safety Follow-Up Period .........................................................10 
 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 5 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
3. Rationale for Addendum 
In response to a request from the European Medicines Agency Paediatric Committee, patients 
will be observed in a long-term safety follow-up period following discontinuation of study drug 
administration.  Patients will return to the clinic every 6 months for evaluation on safety 
measures.  Patients will be followed for up to 3 years after the completion of the treatment 
period, or until the difference between 2 consecutive height measurements at 6-month intervals is 
less than 5 mm (whichever occurs first).  Patients who have achieved the final height 
requirement of a change of less than 5 mm between Visit 3 and Visit 11 of the treatment period 
will be excluded from the safety follow-up period.  Patients who do not have height assessments 
at study-site visits over a 6-month interval prior to discontinuation of study medication will enter 
the safety follow-up period.  Long-term follow-up of patients will allow observation of ongoing 
development and growth on an individual patient basis and a description of the occurrence of 
selected adverse events (AEs) in pediatric patients in the absence of study drug treatment 
following up to 28 weeks of study drug administration. 
 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 6 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
4. Protocol Additions 
4.1. Long-Term Safety Follow-Up Objective 
The objectives of the safety follow-up period are as follows: 
 To describe safety parameters over time following discontinuation of study drug 
administration, including the following: 
 Adverse events of special interest (AESIs) 
 Ongoing prescription medication 
 Height and weight 
 Tanner pubertal stage 
 Carcinoembryonic antigen (CEA) concentration 
 Calcitonin concentration 
4.2. Summary of Study Design 
Following discontinuation of study drug administration, patients with a height difference of at 
least 5 mm between Visit 3 and Visit 11 will enter the safety follow-up period.  Patients who 
discontinue study drug administration prior to Visit 11 will also enter the safety follow-up 
period.  During this period, patients will return to the study site at approximately 6-month 
intervals for a period of up to 3 years or until the difference between 2 height measurements over 
a 6-month interval is less than 5 mm (whichever comes first).  Patients who do not have height 
assessments at study-site visits over a 6-month interval prior to discontinuation of study 
medication will enter the safety follow-up period.  Patients will not receive any study drug but 
may be treated with a diabetes treatment regimen deemed appropriate by the investigator or 
healthcare provider.  During the safety follow-up period, the following will occur:  AESIs and 
ongoing prescription medications will be reviewed; height, weight, and Tanner pubertal stage 
will be assessed; and CEA and calcitonin concentrations will be measured.  Refer to the Study 
Schedule (Attachment 1) for more information.   
Patients who have achieved the final height requirement of a change of less than 5 mm between 
Visit 3 and Visit 11 of the treatment period will be excluded from the safety follow-up period. 
Patients who completed the protocol prior to this addendum will be evaluated for inclusion in the 
safety follow-up period where possible (Section 4.2.1.1).   
The entire study design including the safety extension period is illustrated in Figure GWBQ(4) 1. 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 7 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
Abbreviations:  BID = twice a day 
a Metformin (Met) or sulfonylurea (SU) or combination of Met and SU, with or without diet and exercise, or naïve 
to antidiabetic agents defined as being treated with diet and exercise alone. 
b The volume of placebo is equivalent to 5 μg or 10 μg exenatide. 
c Scheduled telephone visit. 
d Patients will return to the study site at approximately 6-month intervals for a period of up to 3 years or until the 
difference between 2 height measurements over a 6-month interval is less than 5 mm (whichever comes first).  
Patients who do not have height assessments at study-site visits over a 6-month interval prior to discontinuation of 
study medication will enter the safety follow-up period.  Patients will not receive any study drug but may be 
treated with a diabetes treatment regimen deemed appropriate by the investigator or healthcare provider. 
Figure GWBQ(4) 1. Illustration of study design for Protocol Addendum H8O-MC-GWBQ(4). 
4.2.1. Safety Follow-Up Period (Visits 801 to 806) 
During the safety follow-up period, patients may return to the study site at 6-month intervals 
(±2 weeks) for a period of up to 36 months (up to 6 clinic visits).  The first visit (Visit 801) 
during the safety follow-up period is to occur 6 months after discontinuation of study drug 
administration or Visit 11, whichever comes first.  Fasting is not required prior to any of the 
study visits during the safety follow-up period.   
All patients will undergo the following procedures during each safety follow-up period visit: 
 Review of ongoing prescription medications  
 Review of AESIs (see 4.5.1) will be conducted using an AESI questionnaire and will be 
recorded in the electronic case report form [eCRF])  
 Assessment of body weight and height 
End of Study 
Visit             1
2        3        4c
5         6c
7        8c
9        10c
801 to 806
Week of 
Study         -3
-1          0        2
4
8         12       16       20        24        
Screening
Randomization
Treatment Period
Safety Follow-up Period d
Lifestyle Modification Program
Usual Oral 
Antidiabetic
Therapy a
Placebo 
Lead-in 
(BID)
Exenatide BID (10 ug)
Exenatide BID (5 ug)
Placebo BID b
Exenatide 
BID (5 ug)
BID (5 ug)
Placebo 
BID b
End of Treatment Period
Early Withdrawal Patients d
Variable        


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 8 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
 Assessment of Tanner pubertal stage 
 Blood samples will be collected to assess the following: 
o Calcitonin 
o CEA concentration 
Patients will discontinue participation in the safety follow-up period after 3 years or once they 
have a height difference of less than 5 mm between two 6-month interval visits. 
Study procedures will be performed at Visits 801 to 806 according to the Study Schedule 
(Attachment 1). 
4.2.1.1. Patients Previously Completing the Protocol or Early Withdrawal 
Patients who previously completed the protocol or withdrew early from the study will be 
evaluated for participation in the safety follow-up period.  Patients who completed the 28-week 
study and grew less than 5 mm during the treatment period (between Visits 3 and 11) will be 
excluded, while early withdrawal patients will be included in the safety follow-up period.  
Patients who are eligible to participate in the safety follow-up will be contacted to return to the 
clinic and parent or legal guardian informed consent and patient assent will be obtained.  Patients 
will be observed until either they achieve the height requirement or it has been 3 years since their 
last dose in the treatment period.  Patients will not receive study drug during the 3-year follow-
up period and will be allowed to go on any diabetes treatment regimen deemed appropriate by 
the investigator or healthcare provider. 
4.3. Exclusion Criteria 
[34] 
Patients who completed the 28-week study and grew less than 5 mm during the treatment 
period (between Visits 3 and 11) will be excluded from participation in the safety follow-up 
period. 
4.4. Treatments Administered 
No study drug treatment will be administered during the safety follow-up period. 
4.5. Concomitant Therapy 
During the safety follow-up period, patients will be treated at the discretion of their healthcare 
provider, with no medication restrictions.   
4.5.1. Safety Evaluations 
Assessment of body weight, height, vital signs, Tanner pubertal stage, calcitonin concentration, 
and CEA concentration in the safety follow-up period will be performed as described in the main 
protocol. 
Review of medications during the safety follow-up period will focus on ongoing prescription 
medications. 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 9 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
Adverse events of special interest will be assessed at all visits during the safety follow-up period, 
and the eCRF will be completed if it is determined that the patient has experienced 1 or more of 
the listed AESIs.  The AESIs are as follow: 
 Hematological malignancies 
 Thyroid neoplasms 
 Pancreas neoplasms 
 Aplastic anemia 
 Pancreatitis 
 Pregnancy and pregnancy outcomes (including congenital anomalies) 
This list may be updated if additional AESIs are identified. 
Other serious and non-serious adverse events will be done through routine postmarketing 
spontaneous reporting and according to the relevant medication(s) the patient is receiving (which 
may or may not include exenatide).  Pregnancies that occur during the safety follow-up period 
should be reported and followed to term. 
4.6. Statistical and Analytical Plans 
4.6.1. General Considerations 
Safety data will be listed for the safety follow-up population, which will consist of all patients 
who participate in at least 1 safety follow-up period visit. 
Data collected in the safety follow-up period is for descriptive purposes and is not associated 
with a predefined hypothesis or test.  Missing data will not be imputed. 
 


H8O-MC-GWBQ(4) Clinical Protocol Addendum 
Page 10 
 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
Attachment 1.  Addendum GWBQ(4)  
Study Schedule Safety Follow-Up Period


LY2148568 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
 
Page 11 
Study Schedule, Protocol Addendum H8O-MC-GWBQ(4) – Safety Follow-Up Period 
Visit (at intervals of approximately 6 months ± 2 weeks)a  
801 
802 
803 
804 
805 
806 
ED 
Informed consent/assentb 
X 
 
 
 
 
 
 
Clinical Assessments: 
 
 
 
 
 
 
 
Heightc,d 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Tanner pubertal assessment  
X 
X 
X 
X 
X 
X 
X 
AESIs 
X 
X 
X 
X 
X 
X 
X 
Ongoing prescription medications 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessmentse: 
 
 
 
 
 
 
 
Calcitonin 
X 
X 
X 
X 
X 
X 
X 
CEA 
X 
X 
X 
X 
X 
X 
X 
Patient Summaryf 
 
 
 
 
 
X 
X 
Abbreviations:  AESIs = adverse events of special interest; CEA = carcinoembryonic antigen; ED = early discontinuation.   
a All procedures are to be completed prior to next visit. 
b Required only for patients previously completing the protocol who have returned to the clinic for evaluation.   
c Patients will continue to return to the clinic at 6-month intervals for safety evaluation for up to 3 years or until the difference between 2 consecutive height 
measurements is less than 5 mm (whichever occurs first). 
d Patient’s height will be measured without shoes, with a wall-mounted stadiometer. 
e Assayed by Sponsor-designated laboratory. 
f Patient Summary will be completed at the visit where the difference between 2 consecutive height measurements is less than 5 mm if this criterion occurs 
before the 3-year period ends.   


LY2148568 
Safety Follow-up Addendum 
Amendment (a) to Addendum (4) 
 
Revised Protocol Addendum Sections 
Global change:  References to Eli Lilly and Company as Sponsor for this study have been 
replaced with Amylin Pharmaceuticals, LLC (Amylin). 
 

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
H8O-MC-GWBQ
Edition Number
2.0
Date
22th April 2020
Safety and Efficacy of Exenatide as Monotherapy and Adjunctive 
Therapy to Oral Antidiabetic Agents in Adolescents with Type 2 
Diabetes


2
TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
TABLE OF CONTENTS......................................................................................................2
LIST OF ABBREVIATIONS................................................................................................5
AMENDMENT HISTORY...................................................................................................7
STUDY DETAILS..............................................................................................8
1.1
Study objectives..................................................................................................8
1.1.1
Primary objective................................................................................................8
1.1.2
Secondary objectives...........................................................................................8
1.1.3
Exploratory objectives ........................................................................................9
1.2
Study design .......................................................................................................9
1.3
Number of patients............................................................................................11
ANALYSIS SETS ............................................................................................12
2.1
Definition of analysis sets .................................................................................12
2.1.1
All Patients analysis set.....................................................................................12
2.1.2
Intent-to-Treat  analysis set ...............................................................................12
2.1.3
Full analysis set.................................................................................................12
2.1.4
Evaluable analysis set .......................................................................................13
2.1.5
Safety analysis set.............................................................................................13
2.1.6
Safety follow-up analysis set.............................................................................13
2.1.7
Pharmacokinetic (PK) analysis set ....................................................................13
2.2
Violations and deviations..................................................................................13
PRIMARY AND SECONDARY VARIABLES ...............................................14
3.1
Primary efficacy variable ..................................................................................14
3.2
Secondary efficacy variables.............................................................................14
3.3
Exploratory efficacy variables...........................................................................15
3.4
Safety variables.................................................................................................15
3.5
Exploratory safety variables..............................................................................16
3.6
Definition of study variables .............................................................................16
3.6.1
Study baseline...................................................................................................16
3.6.2
End of study treatment measurement.................................................................16
3.6.3
Change and percent change from baseline.........................................................16
3.6.4
Rescue therapy..................................................................................................17
3.6.5
Early discontinuation visit.................................................................................17
3.6.6
Study periods....................................................................................................18
ANALYSIS METHODS...................................................................................18
4.1
General principles.............................................................................................18
4.1.1
Statistical notations and presentations ...............................................................18
4.1.2
Hypothesis testing significance level.................................................................19
4.1.3
Handling of missing data...................................................................................19


3
4.1.3.1
Missing efficacy data ........................................................................................19
4.1.3.2
Missing baseline and demographic data ............................................................20
4.1.3.3
Missing safety data ...........................................................................................20
4.1.3.4
Premature discontinuation.................................................................................20
4.1.4
Handling of data post rescue medication ...........................................................20
4.1.5
Statistical modelling..........................................................................................21
4.2
Analysis methods..............................................................................................21
4.2.1
Study disposition and baseline demographics....................................................21
4.2.1.1
Patient disposition.............................................................................................21
4.2.1.2
Demographics and baseline characteristics........................................................22
4.2.1.3
Medical/surgical history....................................................................................26
4.2.1.4
Prior and concomitant medications....................................................................26
4.2.2
Treatment compliance.......................................................................................27
4.2.3
Exposure...........................................................................................................27
4.2.4
Efficacy analysis...............................................................................................28
4.2.4.1
Estimands .........................................................................................................28
4.2.4.2
Analysis of primary variable .............................................................................31
4.2.4.3
Sensitivity and supplementary analyses for primary endpoint............................32
4.2.4.4
Analysis of secondary variables ........................................................................34
4.2.4.5
Analysis of exploratory efficacy variables.........................................................38
4.2.5
Safety analyses .................................................................................................39
4.2.5.1
Adverse events..................................................................................................39
4.2.5.2
Hypoglycemic episodes ....................................................................................40
4.2.5.3
Antibodies to exenatide.....................................................................................41
4.2.5.4
Laboratory data (including CEA and calcitonin concentrations) ........................41
4.2.5.5
Vital signs.........................................................................................................42
4.2.5.6
ECG..................................................................................................................43
4.2.5.7
Height...............................................................................................................43
4.2.5.8
Tanner pubertal assessment...............................................................................43
4.2.6
Pharmacokinetic analyses .................................................................................43
4.3
Conventions......................................................................................................43
4.3.1
Visit assignments for efficacy variables ............................................................44
4.3.2
Visit assignment for safety variables .................................................................45
4.3.3
Rules for safety observations.............................................................................47
4.3.3.1
Multiple safety assessments ..............................................................................47
4.3.3.2
Adverse events at patient level..........................................................................47
4.3.3.3
Adverse event at event level..............................................................................48
INTERIM ANALYSES ....................................................................................49
CHANGES OF ANALYSIS FROM PROTOCOL ............................................49
REFERENCES .................................................................................................50
APPENDIX ......................................................................................................51
Appendix 1
Study schedule – treatment period .................................................................51
Appendix 2
Study schedule – long-term safety follow-up period ......................................53
Appendix 3
Partial date conventions for AEs....................................................................54


4
Appendix 4
Partial date conventions for CMs...................................................................55
Appendix 5
Preferred terms for potentially immune-related AEs ......................................57
Appendix 6
Criteria for potentially clinically significant laboratory tests ..........................59
Appendix 7
Criteria for potentially significant vital signs .................................................60
LIST OF TABLES
Table 1 Important Protocol Deviations................................................................................14
Table 2 Demographics and baseline characteristics .............................................................22
Table 3 Estimand framework...............................................................................................28
Table 4 Dummy variables ...................................................................................................34
Table 5 Visit Windows: FSG, FSI, HOMA-B and HOMA-S...............................................44
Table 6 Visit Windows: Failure to maintain glycemic control .............................................44
Table 7 Visit Windows: Antibodies to exenatide and vital signs..........................................45
Table 8 Visit Windows: Body weight, height, BMI and Tanner pubertal assessment ...........46
Table 9 Visit Windows: Laboratory data, ECG, waist circumference and hip circumference46
Table 10 Visit windows: Hypoglycemic episodes................................................................47
LIST OF FIGURES
Figure 1 Study Design.........................................................................................................11


5
LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
AE
Adverse events
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BMI
Body mass index
CCT
Concomitant Therapy
CDE
Certified diabetes educator
CEA
Carcinoembryonic antigen
CFBL
Change from baseline
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMH
Cochran-Mantel-Haenszel
CRF
Case report form
CSP
Clinical study protocol
CSR
Clinical study report
CTMS
Clinical trial management system
CV
Coefficient of variation
DAE
AE Leading to Treatment Discontinuation
DBL
Database lock
DMC
Data Monitoring Committee
DRM
Data Review Meeting
EBID
Exenatide twice daily
ECG
Electrocardiogram
ED
Early discontinuation
eGFR
Estimated glomerular filtration rate
FAS
Full analysis set
FSG
Fasting serum glucose
FSI
Fasting serum insulin
GCV
Geometric coefficient of variation
GSD
Geometric standard deviation
HbA1c
Glycated hemoglobin A1c
HOMA-B
Homeostasis model assessments – beta-cell functions


6
Abbreviation or special 
term
Explanation
HOMA-S
Homeostasis model assessments – insulin sensitivity
ICH
International Conference on Harmonisation
ITT
Intent-to-Treat
LLN
Lower limit of normal range
LMP
Lifestyle modification program
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
MMRM
Mixed model repeated measures
MNAR
Missing not at random
OAM
Oral anti-diabetic medication
OC
Observed case
PBO
Placebo
PD
Protocol deviations
PK
Pharmacokinetic
PT
Preferred term
QD
Once daily
QW
Once weekly
RD
Registered dietitian
SAP
Statistical Analysis Plan
SD
Standard deviation
SI
Standard International (Unit)
SMBG
Self-monitored blood glucose
SOC
System organ class
SU
Sulfonylurea
TEAE
Treatment emergent adverse events
ULN
Upper limit of normal range
WHODD
World Health Organization Drug Dictionary


7
AMENDMENT HISTORY
Date
Brief description of change
22th April 2020
Due to change of company for the analysis of this study from Amylin Pharmaceuticals, 
LLC to IQVIA, the Statistical Analysis Plan has been fully rewritten from Version 1.0.
Rewritten to be consistent with Study D5551C00002 where appropriate.
Summaries and analysis of long-term safety follow-up period included.
Due to power considerations, efficacy analysis comparisons will be between both 
exenatide treatment arms combined versus placebo. 
Updated to allow for possibility of analysis of treatment period data and safety follow-up 
period data separately
Important Protocol Deviation #1 has been amended to consider screening time, rather 
than enrolment.
Baseline definition and end of study treatment measurement have been updated.
Columns for the EBID treatment groups have been swapped.
Updated to only consider informed consent, and not assent.
Race and Region has been updated.
Ethnic group has been deleted.
Country has been sorted in alphabetical order.
Medications will be presented for ITT and safety follow-up analysis set.
MI definition has been extended and additional table for primary analysis has been 
added.
Post-treatment AE definition has been updated to account for the overlap between 
TEAEs and previous post-treatment AE definition.
Shift from baseline to the worst value for lab parameters has been deleted.
Total bilirubin upper limit updated.
PK and antibodies data will only be listed.


8
STUDY DETAILS
The scope of this statistical analysis plan (SAP) is to describe the planned summaries and 
analyses of data collected during this study. The study comprises a treatment period (Week 0 to 
Week 28) and a long-term safety follow-up period (after completion/early discontinuation (ED) 
of the treatment period, for 3 years or until the difference between 2 consecutive height 
measurements at 6-month intervals is less than 5 mm if earlier).
On entry to this study, patients will have inadequate glycemic control and will be either 
antidiabetic drug-naïve, defined as treatment with diet and exercise alone, or receiving treatment 
with oral antidiabetic agent(s), either metformin, a sulfonylurea (SU), or a combination of 
metformin and an SU (with or without diet and exercise). 
Refer to Appendices 1 and 2 for schedules for both periods.  Reporting of treatment period data 
may be performed before reporting of safety follow-up period data.
1.1
Study objectives
1.1.1
Primary objective
The primary objective of the treatment period is to test the hypothesis that glycemic control, as 
measured by change in glycated hemoglobin A1c (HbA1c) from baseline to endpoint, with 
exenatide 5 µg twice daily or 10 µg twice daily (Total EBID) is superior to that of placebo 
(PBO), after up to 28 weeks of study drug treatment, in adolescent patients with type 2 diabetes.
The primary objective of the safety follow-up period is to assess ongoing development and 
growth following up to 28 weeks of study drug treatment in adolescent patients with type 2 
diabetes and to document the following: 

Adverse events of special interest

Prescription medications

Body weight, height and Tanner pubertal stage

Carcinoembryonic antigen (CEA) concentration

Calcitonin concentration
1.1.2
Secondary objectives 
The secondary objectives are:

To compare the effects of EBID to those of PBO, after up to 28 weeks of study drug 
treatment, in adolescents with type 2 diabetes, on the following:

Proportion of patients achieving HbA1c goals

Body weight


9

Fasting serum glucose (FSG) concentrations 

Fasting serum insulin (FSI) concentrations 

Self-monitored blood glucose (SMBG) measurements before and 2 hours after the two 
main meals of the day 

Beta-cell function (HOMA-B) and insulin sensitivity (HOMA-S) as measured by 
homeostasis model assessments (HOMA)

Proportion of patients discontinuing the study due to failure to maintain glycemic 
control 

To assess the safety and tolerability of up to 28 weeks of EBID treatment, in adolescents 
with type 2 diabetes, on the following:

Adverse events

Incidence and rate of hypoglycemia 

Antibodies to exenatide

Laboratory measurements (including CEA and calcitonin concentrations)

Vital signs and physical examination including Tanner pubertal stage

Electrocardiograms (ECGs)
1.1.3
Exploratory objectives 

To assess the pharmacokinetics (PK) of EBID treatment, in adolescents with type 2 diabetes 
who participated in the PK sub-study
1.2
Study design
This is a multicenter, double-blind, placebo-controlled, randomized, parallel, 3-arm trial.  
Approximately 195 adolescents, ages 10 to 17 years inclusive, with type 2 diabetes will be 
enrolled.  The number of patients aged 17 years of age will be limited to no more than 10% of 
patients in each treatment arm.  Patients will be naïve to antidiabetic agents, or they will be 
receiving oral treatment with metformin, an SU, or a combination of metformin and an SU at the 
time of enrolment. Randomization will be stratified by the patient’s background diabetes therapy 
and screening HbA1c.  The study will commence with a 1-week, single-blind, injectable placebo 
lead-in period before patients are randomly assigned to add injectable exenatide or injectable 
placebo to their existing diabetes treatment.  Patients will be randomly assigned to 1 of 
3 treatment arms:  exenatide 5 µg twice daily, exenatide 10 µg twice daily, or placebo twice daily 
(volume of injection equivalent to exenatide 5 µg or exenatide 10 µg).  During the first 4 weeks 
after randomization, all patients assigned to treatment will receive exenatide 5 µg twice daily or 
equivalent placebo volume twice daily.  A starting dose of exenatide 5 µg twice daily and 
titration to exenatide 10 µg twice daily has been shown to mitigate the incidence of nausea.  At 
the end of 4 weeks post-randomization, patients assigned to the exenatide 10 µg twice daily 
treatment arm, or equivalent placebo volume, are then to increase their dose from 5 µg twice 
daily to 10 µg twice daily, or equivalent placebo volume.  Study drug will be administered 


10
within 60 minutes before morning and evening meals (or the 2 main meals of the day, 
approximately 6 hours or more apart) for 28 weeks. 
All patients will be expected to participate in a simplified lifestyle modification program (LMP) 
throughout this study.  The simplified lifestyle modification program will include both dietary 
education and physical activity components.  At the clinic visits, the patients will meet with a 
registered dietitian (RD) or certified diabetes educator (CDE) who will review the patient’s 
dietary history and physical activity record.  The LMP will be reinforced at each visit.
Patients who have discontinued the study due to loss of glycemic control will be offered 
alternative antidiabetic therapy at the discretion of the investigator.
In response to a request from the European Medicines Agency Pediatric Committee, patients will 
be observed in a long-term safety follow-up period following discontinuation of study drug 
administration. Patients will return to the clinic every 6 months for evaluation of safety 
measures. Patients will be followed for up to 3 years after the completion of the treatment period, 
or until the difference between 2 consecutive height measurements at 6-month intervals is less 
than 5mm (whichever occurs first). Patients who have achieved the final height requirement of a 
change of less than 5mm between Visit 3 (Week 0) and Visit 11 (Week 28/Early 
Discontinuation) of the treatment period will be excluded from the safety-follow up period. 
Patients who do not have height assessments at study-site visits over a 6-month interval prior to 
discontinuation of study medication will enter the safety follow-up period. 


11
Figure 1 Study Design
1.3
Number of patients
Approximately 195 patients diagnosed with type 2 diabetes were planned to be enrolled. 
Approximately 65 patients were to be randomized to receive placebo and 130 patients were to be 
randomized to receive exenatide (65 per exenatide treatment arm). A sample of 65 patients per 
treatment arm would provide >95% power to reject the null hypothesis of no difference among 
treatments assuming true mean changes in HbA1c of -0.7, -0.5, and 0 for patients receiving 
exenatide 10 μg twice daily, exenatide 5 μg twice daily, and placebo twice daily, respectively 
(based on results of previous Studies 2993-112, 
, H8O-MC-GWAA, H8O-
MC-GWAD). This power computation also assumes a common standard deviation of 1.0% and a 
two-sided significance level of 0.05. Assuming the same true mean changes in HbA1c, common 
standard deviation, and two-sided significance level, 65 patients per treatment arm would also 
provide >95% power to detect a difference between 10 μg exenatide twice daily and placebo 
CCI


12
treatments, and 80% power to detect a difference between 5 μg exenatide twice daily and 
placebo with a Fisher Protected Testing procedure (Hayter 1986). 
Due to an approximate 23% discontinuation rate in the exenatide arms (based on results from 
2993-112), 65 patients randomized per treatment arm would be enough to observe 50 completers 
per treatment arm. Patients will be eligible to participate if they are not achieving adequate 
glycemic control (i.e. HbA1c at screening is 6.5% to 10.5%, inclusive) with metformin, an SU, 
or metformin and an SU, or diet and exercise only. Patients will be stratified to treatment 
assignment based on diabetes therapy at enrolment and screening HbA1c. The three-arm design 
was intended to allow comparison of exenatide at doses of 5 μg twice daily and 10 μg twice daily 
with placebo twice daily. 
Due to the availability of other more conveniently administered therapies e.g. oral, once daily 
(QD), or once weekly (QW), recruitment to this study has been slow/difficult despite extensive 
efforts by the sponsor.  The planned number of patients will take unreasonably long to recruit so 
a decision was made with agreement by the European Medicines Agency and Food and Drug 
Administation to stop recruitment and to pool patients from both exenatide arms and compare the 
pooled arm with placebo. With a total of 122 patients randomized (Total EBID:Placebo 2:1), the 
study should have approximately 87% power to detect a difference between Total EBID and 
placebo assuming the true mean changes in HbA1c are -0.7, -0.5, and 0 for patients receiving 
exenatide 10 µg BID, exenatide 5 µg BID, and placebo BID, respectively. The combined effect 
of the Total EBID doses compared to placebo (mean difference) is assumed to be -0.6 with a 
common standard deviation of 1% at the 5% significance level without consideration of patient 
discontinuation and impact on effect size. An assumed effect size of -0.455 was considered in 
power calculation.  
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
All Patients analysis set
The All Patients analysis set will include all patients who provided written informed consent.  
This set will be used for listings and summaries of patient disposition and pre-randomized 
treatment adverse events.
2.1.2
Intent-to-Treat  analysis set
The Intent-to-Treat (ITT) analysis set will include all randomized patients. ITT patients will be 
analyzed in accordance to their planned treatment group.  This set will be used for listings and 
summaries of demographic and baseline characteristics.
2.1.3
Full analysis set
The Full analysis set (FAS) will consist of all randomized patients who receive at least one dose 
of randomized study medication.  Full analysis set patients will be analyzed in accordance to 


13
their planned treatment group.  This set will be used for listings and summaries of non-HbA1c 
efficacy data.
2.1.4
Evaluable analysis set
The Evaluable analysis set will consist of all randomized patients who received at least 1 dose of 
randomized study medication and have a baseline and at least 1 post-baseline HbA1c assessment. 
Evaluable patients will be analyzed in accordance to their planned treatment group. This set will 
be used for listings and summaries of HbA1c efficacy data.
2.1.5
Safety analysis set
The Safety analysis set consists of all patients who received at least 1 dose of randomized study 
medication.   
Patients will be analyzed and presented in accordance to the actual treatment received, regardless 
of planned treatment assignment. If a patient receives at least one dose of exenatide treatment 
during the assessment period, they will be analyzed and presented in accordance with the actual 
exenatide treatment received no matter what arm they were randomized to. If a patient 
randomized to the placebo arm receives exenatide at doses of both 5 μg twice daily and 10 μg 
twice daily, they will be analyzed and presented in the 10 μg twice daily treatment group. 
This set will be used for listings and summaries of safety data during the treatment period.
2.1.6
Safety follow-up analysis set
The safety follow-up (SFU) analysis set consists of all patients who have at least 1 safety follow-
up period assessment Visit 801 (6 months after Week 28/ED) to Visit 806 (3 years after Week 
28/ED).
This set will be used for listings and summaries of safety data during the safety follow-up period.
2.1.7
Pharmacokinetic (PK) analysis set
The PK analysis set will consist of all patients who receive at least 1 dose of EBID, for whom at 
least 1 evaluable post-dose PK concentration assessment is available, and do not deviate from the 
clinical study protocol (CSP) in ways that would significantly affect the PK analyses, as 
determined at the final protocol deviations meeting prior to unblinding of this study. Patients will 
be presented in accordance to the actual treatment received.
This set will be used for listing of PK data.
2.2
Violations and deviations
AstraZeneca use ICH E3 terminology for protocol deviations (PD), which are all important 
deviations related to study inclusion or exclusion criteria, conduct of the trial, patient 
management or patient assessment.  
Important deviations may include deviations pertaining (but not limited) to those presented in 
Table 1.
These protocol deviations will be programmatically derived (where possible) and presented in a 
listing. In addition, protocol deviations attributed to these criteria reported in the IQVIA Clinical 
Trial Management System (CTMS) for all patients randomized by IQVIA in this study will be 
reported in the Clinical Study Report (CSR). No additional per protocol analyses are planned.


14
Table 1 Important Protocol Deviations
(*) PD will only be presented from the CTMS as not possible to fully identify programmatically.
This list is not intended to be all-inclusive. Other protocol deviations may be identified by the 
study team during on-going review of the study conduct prior to treatment unblinding.
PRIMARY AND SECONDARY VARIABLES
3.1
Primary efficacy variable
The primary efficacy endpoint for the treatment period is the change in HbA1c from baseline 
Visit 3 (Week 0) to Visit 11 (Week 28).
3.2
Secondary efficacy variables 
The following are the secondary efficacy endpoints: 

Change in HbA1c from baseline Visit 3 (Week 0) to each intermediate visit as 
applicable
Number
Important protocol deviations criteria
1
Randomized patients without type 2 diabetes or central laboratory HbA1c 
obtained at screening not within ± 0.2% of the protocol-specified HbA1c range
2
Randomized patients not satisfying the target population baseline 
antihyperglycemic therapy requirement
3
Randomized patients who were treated with any systemic corticosteroid therapy 
for ≥5 consecutive days during randomized treatment
4
Randomized patients who received no (or incorrect) study medication at any 
time during the 28-week treatment period (*). 
5
Patients assigned to the incorrect IVRS randomization stratification factor as 
compared to the HbA1c test result at screening (≤8.0% or >8.0%) or 
background diabetes therapy (drug naïve, metformin only, SU only and 
metformin + SU)
6
Missed the background anti-diabetic medication for ≥10 consecutive days in 
the last three months of the study (*)
7
No valid baseline HbA1c
8
No single valid on-treatment HbA1c
9
Randomized patients who are not compliant with study medication 
administration requirements (dose, frequency) (*)


15

Proportion of patient achieving HbA1c goals of <7%, ≤6.5%, and <6.5% at Visit 11 
(Week 28) and each intermediate visit as applicable

Change in body weight from baseline Visit 3 (Week 0) to Visit 11 (Week 28), and to 
each intermediate visit as applicable

Change in FSG from baseline Visit 3 (Week 0) to Visit 11 (Week 28)

Change in FSI from baseline Visit 3 (Week 0) to Visit 11 (Week 28)

Change in SMBG measurements before and 2 hours after the 2 main meals of the day 
on 3 days during the week before Visit 3 (Week 0) and Visit 11 (Week 28) 

Change in HOMA-B and HOMA-S as measured by homeostasis model assessment 
from baseline Visit 3 (Week 0) to Visit 11 (Week 28)

Proportions of patients discontinuing the study, due to failure to maintain glycemic 
control at Visit 11 (Week 28), and to each intermediate visit as applicable
3.3
Exploratory efficacy variables
The exploratory efficacy endpoints are:

Change in body mass index (BMI) from baseline Visit 3 (Week 0) to Visit 11 (Week 28), 
and to each intermediate visit as applicable

Change in body weight and BMI percentile from baseline Visit 3 (Week 0) to Visit 11 
(Week 28), and to each intermediate visit as applicable. The body weight and BMI 
percentiles will be determined based on the standardized growth chart for boys and girls 
(2000 CDC Growth Charts)

Change in hip and waist circumference from baseline Visit 3 (Week 0) to Visit 11 (Week 
28)
3.4
Safety variables
Safety endpoints during the treatment period are:

Incidence of treatment-emergent adverse events (TEAEs; see section 4.2.5.1) and 
hypoglycemic events (see section 4.2.5.2) over the treatment period

Antibodies to exenatide, physical examination (height), laboratory measurements 
(clinical chemistry, hematology and urinalysis including calcitonin and CEA 
concentrations), vital signs (blood pressure and heart rate) and ECGs (overall assessment) 
from screening Visit 1 (Week -3) or baseline Visit 3 (Week 0) to Visit 11 (Week 28), and 
to each intermediate visit as applicable

Tanner pubertal stage at baseline Visit 3 (Week 0), Visit 5 (Week 4), Visit 7 (Week 12), 
Visit 9 (Week 20) and Visit 11 (Week 28)


16
Safety endpoints during the follow-up period are:

Adverse events of special interest

CEA and calcitonin concentrations

Prescription medications

Body weight, height and Tanner pubertal stage
3.5
Exploratory safety variables
The exploratory safety endpoint is change in estimated glomerular filtration rate (eGFR) from 
baseline Visit 3 (Week 0) to Visit 11 (Week 28).
3.6
Definition of study variables
Refer to Section 4.3 for details on conventions such as visit windowing and handling of duplicate 
assessments.
3.6.1
Study baseline
The baseline measurement is defined as the last non-missing (either numerical or character) 
value, including values from unscheduled visits, collected on or prior to the first dose of study 
medication in the double-blind treatment period on/at Visit 3 (Week 0). Assessments carried out 
on the date of the first dose are assumed to have been done pre-dose unless time information 
indicates otherwise. 
The baseline measurement for demographic and baseline characteristic data in patients who do 
not get treated is defined as the last non-missing value collected on or prior to Visit 3 (Week 0).
If the last non-missing value ties with another non-missing value happening at the same day and 
time (or same day, if time is not collected) then the mean of the values will be used.
If the baseline value is missing for a given variable, change from baseline will be missing. 
Baseline for BMI will be calculated from last non-missing values for height and weight, even if 
they were at separate dates.
3.6.2
End of study treatment measurement
For completers, end of study treatment measurement is the last non-missing post-baseline 
measurement obtained at or prior to Visit 11 (Week 28).
If patient discontinues prior to Week 28 (Visit 11), then the end of study treatment measurement 
is the last non-missing post-baseline measurement obtained at or prior to ED visit.
If patient discontinues prior to Week 28 (Visit 11) and there is no ED visit, then the end of study 
treatment measurement is the last dose date +1 (or + 30 days if discontinued due to SAEs and 
other clinically significant or related AEs).
3.6.3
Change and percent change from baseline
Change from baseline to any post-baseline Week t is defined as follows:
CWeek t = MWeek t - Mbaseline,


17
Where:
−CWeek t is the change from baseline at Week t,
−MWeek t is the measurement at Week t,
−Mbaseline is the baseline measurement.
Percent change from baseline to any post-baseline Week t is defined as follows:
PWeek t =100×(MWeek t - Mbaseline) / Mbaseline.
If the baseline value is zero, the percent change will be missing.
3.6.4
Rescue therapy
Rescue therapy is defined as any new antidiabetic concomitant medication or changes to 
background oral-diabetic medication, for exacerbation of diabetes.
Treatment with insulin may be given for emergency reasons during the treatment period. If the period 
of insulin use exceeds 10 days during a 3-month period, then a decision to discontinue study 
treatment will be made after consultation between the investigator and the Sponsor’s clinical research 
physician.  
Background oral antidiabetic medication (metformin and SU) were to be continued throughout the 
study at the same dose and schedule as before study entry. However, metformin dosage could be 
adjusted for up to 10 consecutive days or 10 days in a 30-day period and the SU dosage could be 
decreased in response to hypoglycemia.
Changes in background metformin and SU will be programmatically derived from the 
concomitant therapy (CCT) oral anti-diabetic medication (OAM) CRFs and reviewed by the 
clinical team prior to unblinding. Increases identified as potential rescue episodes will be queried 
at the site-level to determine whether rescue therapy or not.
New antidiabetic medication will be programmatically identified from the CCT OAM CRFs 
where the Anatomical Therapeutic Chemical (ATC) code begins with “A10”.
A rescue episode will be defined as the first unique rescue therapy entry on the CCT OAM CRFs 
as derived as above. If a patient has multiple entries, the first will be considered the point at 
which the patient was rescued. 
For patients who require initiation of rescue therapy and continue study treatment, only data 
before initiation of rescue therapy will be included in the primary efficacy analysis. If HbA1c is 
measured before rescue therapy, then we will include the HbA1c measurement. If HbA1c is 
measured on the date of first rescue therapy but no time information is available, then HbA1c 
will be included in the primary efficacy analysis. Sensitivity analyses including data after 
initiation of rescue therapy will be carried out to test the robustness of the missing data 
assumption.
3.6.5
Early discontinuation visit
If a patient discontinues after randomization but prior to completion of the study treatment 
period, the patient will be asked to return as soon as possible to the study site for an early 
discontinuation (ED) visit. The patients will not receive exenatide or placebo; however, a 
treatment regimen, as deemed clinically appropriate, should be initiated. Investigative staff 


18
should complete a study summary page for each patient. Patients who discontinue early from the 
study treatment period should continue into the safety follow-up addendum unless the patient is 
lost to follow-up, withdraws consent, or achieved final height criteria of a change of less than 5 
mm during the treatment period.
3.6.6
Study periods
The following definitions will be used to assign data to the correct study period. For details on 
which data will be presented in outputs for each endpoint, refer to Section 4.2.
Pre-treatment period: defined as the period prior to the date of the first dose of randomized study 
medication. All data for patients who do not receive randomized study medication will be 
considered pre-treatment.
Treatment period: defined as the date of first dose of randomized study medication to date of the 
Week 28 visit, or the ED visit for patients who discontinue the study prior to Week 28. 
Safety follow-up period: defined as the day after the Visit 11 (Week 28) visit, or the day after the 
ED visit for patients who discontinue the study prior to Visit 11 to the date of completion of the 
Safety follow-up study (typically after 3 years or once the patient has a height difference of less 
than 5 mm between two 6-month interval visits).  The safety follow-up period will only be defined 
for patients who enter the safety follow-up period.
See Section 4.1.3 for details on missing data handling.
ANALYSIS METHODS
4.1
General principles
All statistical evaluations, as well as summaries and tabulations, will be done by qualified 
personnel at IQVIA. Before unblinding, following clean file declaration (database lock), all 
decisions on the evaluability of the data for each individual patient will be made and documented 
and each patient will be assigned to the appropriate analysis set.
Statistical analysis software (SAS) version 9.4 or later will be used to generate all statistical 
analyses, data summaries and listing.
4.1.1
Statistical notations and presentations
Although patients randomly assigned to placebo will be assigned to take the volume equivalent to 5 
μg exenatide twice daily or to take the volume equivalent to 10 μg exenatide twice daily, all patients 
assigned to placebo will be combined into 1 group for analysis purposes. Descriptive summaries will 
present treatment groups separately, as follows:
5 μg EBID
10 μg EBID
Total EBID
Placebo
Total
EBID Exenatide twice daily 
Total EBID is the pool of the 10 μg and 5 μg EBID doses. Total (over all treatments) will not be 
included in efficacy and safety endpoint outputs.


19
Summaries including data from the safety follow-up period will be presented by the actual 
treatment group during the randomized period.
All efficacy and safety variables will be summarized using descriptive statistics as appropriate.  
Continuous variables will be summarized by descriptive statistics including n (number of 
patients with available data), arithmetic mean, standard deviation (SD), median, minimum value 
and maximum value.  The mean and median will be presented with one more decimal place than 
the original data; the standard deviation with two more decimal places than the original data; and 
minimum and maximum values with the same number of decimal places as the original data. 
Categorical variables will be summarized using frequency tables (number of patients and 
percentage of patients in each category).  Unless otherwise stated, percentages will be calculated 
out of the analysis set total for the treatment group.  Percentages will be rounded to one decimal 
place.
For log transformed data, the following descriptive statistics will be presented: n (number of 
patients with available data), geometric mean, geometric coefficient of variation (GCV%), 
geometric standard deviation factor (GSD), arithmetic mean, standard deviation, coefficient of 
variation (CV%), median, minimum and maximum value. 
GCV (%) will be calculated as


1
exp
100
2 

s
where s is the SD of the data on a log scale.  
Individual data will be presented in patient listings. All patient data listings will be sorted by 
treatment and patient identifier ID.  The first 3 digits of the patient ID denotes the center number 
and the next 4 digits denotes the individual patient number. 
4.1.2
Hypothesis testing significance level
Statistical tests, where performed, will be conducted at a 2-sided significance level of 5%. Where 
appropriate, model-based point estimates, together with their 95% confidence intervals will be 
presented along with the 2-sided p-values for the tests. 
No adjustments for multiplicity (including hierarchical testing) will be made for the primary, 
secondary and exploratory variables.
4.1.3
Handling of missing data
4.1.3.1
Missing efficacy data
Missing data in this study may result from patients discontinuing from the study prematurely or 
missing intermediate visits or selected assessments while remaining on study.  Every effort will 
be made to obtain the CSP-required data for all study assessments that are scheduled for all 
patients who have been enrolled. Data collected after initiation of rescue therapy will be 
excluded from most efficacy analyses (see Section 4.2.4 for details) and therefore these data will 
effectively be handled as missing in analyses. For efficacy analyses, in general missing 
observations will not be imputed, except those inherited from the mixed model repeated 
measures (MMRM) which implicitly assumes that data are missing at random (MAR).  
Sensitivity of the primary analysis will be performed using pattern mixture model imputation for 
missing values and details of this imputation is provided in Section 4.2.4.3. 


20
Missing at Random (MAR) refers to missingness that is independent of missing responses, 
conditionally on observed responses and covariates. As the imputation strategy should always 
consider the dropout patterns and the time-course of the efficacy measurements by treatment, the 
pre- and post- withdrawal values will be assessed to understand the impact of dropouts on the 
efficacy results. The primary efficacy endpoint of HbA1c data will be visually examined to 
explore the missingness patterns by (1) plotting each individual patient’s HbA1c change 
trajectory in completers, side-by-side with those from the early study drug withdrawal, and by 
(2) plotting the early study drug withdrawal’s last HbA1c change data, overlaid with the box plot 
by visit from completer population.  
For categorical endpoints HbA1c goals of <6.5%, ≤6.5% and <7% at 28 weeks, any patient with 
missing HbA1c value at 28 weeks will be considered as failed to meet HbA1c <6%, ≤6.5% and 
<7%, respectively, at endpoint (28 Weeks). 
4.1.3.2
Missing baseline and demographic data
For demographic and baseline characteristics, each variable will be analyzed and/or summarized 
using the available data. For continuous variables, missing data will be indicated in the “n” count 
and for categorical variables, patients with missing data will be included in the “Total” count and 
denominator for percentages.
4.1.3.3
Missing safety data
Safety analyses will be conducted on the observed case (OC) only. 
However, imputation of missing or partial AE and concomitant medication onset/start, and 
end/stop dates will be used to determine the status of each AE and the previous/concomitant 
status of each medication. See Appendices 3 and 4 for the method of imputation of 
missing/partial AE/concomitant onset/start and end/stop dates. Missing/partial start/stop dates 
will appear as is (i.e., without imputation) in the patient data listings, but will be imputed to 
permit the proper tabulation of AE and concomitant medications data.
In addition, in case of missing AE severity, AE causality, or AE seriousness, a worst-case 
approach will be used. For missing severity, the AE will be considered severe; for missing 
causality, the AE will be considered as possibly-related to study drug; for missing seriousness, 
the AE will be considered serious.
4.1.3.4
Premature discontinuation
Patients who discontinue study medication prior to Visit 11 (Week 28) should enter the safety 
follow-up period, unless they have a height difference of less than 5 mm over a 6-month interval 
at study-site visits prior to discontinuation of study medication. 
Patients who discontinue the study prematurely should have all early termination visit procedures 
done at the time of study discontinuation.   
4.1.4
Handling of data post rescue medication
Instances of patients receiving rescue medication is defined in Section 3.6.4.
Efficacy
For all efficacy endpoints data collected after the first administration of rescue therapy will be 
excluded from the descriptive statistical summary and inferential statistical analyses.


21
However, data collected after initiation of rescue medication will be included in several 
sensitivity and supportive analyses for the primary analysis to provide a comprehensive view of 
the treatment effect (see more details in Section 4.2.4.3). 
Safety
Because patients can continuously receive study medication concurrent with the rescue therapy, 
all safety data (except eGFR) collected during the rescue medication use will be summarized 
together with data collected prior to the rescue therapy. The exploratory analysis of eGFR will be 
repeated twice (once including data after rescue therapy and once excluding data after rescue 
therapy).  
4.1.5
Statistical modelling
In general, continuous variables will be analyzed using a MMRM if multiple post-baseline 
measurements are collected. If only an endpoint measurement is collected, analysis of covariance 
(ANCOVA) will be used. The MMRM/ANCOVA analysis will be treated as the primary 
analysis method for continuous efficacy endpoints. The statistical analysis of categorical 
variables will be done using a stratified Cochran-Mantel-Haenszel (CMH) test.
Standard diagnostic approaches will be used to verify that the key statistical assumptions of the 
MMRM/ANCOVA and CMH test hold.
If the distributional assumptions of the MMRM for the primary analysis do not hold, alternative 
models will be explored using appropriate transformed data.
4.2
Analysis methods
4.2.1
Study disposition and baseline demographics
Unless otherwise stated, for patient disposition and baseline demographics outputs, percentages 
will be calculated out of the total number of patients in the analysis set displayed in the output, 
overall and by treatment group (i.e., each denominator will also include the number of patients 
with missing/unknown values for the endpoint).
4.2.1.1
Patient disposition
Patient disposition information for all patients who provided informed consent, including counts 
and percentages of patients who entered placebo lead-in, were randomized, received randomized 
treatment, completed the treatment period, entered the safety follow-up period and completed the 
safety follow-up period, will be summarized.  Patients who were not randomized (including 
reasons for non-randomization), patients who did not receive randomized treatment, patients who 
discontinued the randomized treatment period early (including reasons for early discontinuation), 
patients who did not enter the safety follow-up period (including reasons for not entering) and 
patients who discontinued the safety follow-up period early (including reasons for early 
discontinuation), will be summarized overall and for each treatment group. 
No percentage will be displayed for number of patients who provided informed consent. The 
denominator for percentages for the patients entered placebo lead-in will be the number of 
patients who provided informed consent. The denominator for other percentages will be the total 
number of patients in the ITT analysis set, overall and by treatment group. A listing of patient 


22
disposition will be provided, including reasons for early discontinuation and reasons for not 
entering safety follow-up.
The number and percentage of patients in each analysis set will also be reported overall and by 
treatment group. The denominator for percentages will be the total number of patients in the ITT 
analysis set, overall and by treatment group. 
4.2.1.2
Demographics and baseline characteristics
Demographic and baseline characteristics will be summarized for the ITT, FAS, evaluable, 
safety and SFU analysis sets overall and by treatment as per below table. 
Table 2 Demographics and baseline characteristics
Demographic and baseline characteristics
Categories
Age years (continuous)
Age group 1 (years) (categorical)
<10
10 to 17
>17
Age group 2 (years) (categorical)
<10
10 to 12
13 to 16
> 16
Sex
Male
Female
Race
White 
Black or African American
Asian
Native Hawaiian or Other Pacific Islander
American Indian or Alaska Native
Hispanic
Other


23
Demographic and baseline characteristics
Categories
Region
Africa
Asia
Europe
Latin America
USA
Country
Brazil
India
Mexico 
Republic of Korea
Russia
South Africa
USA 
Height (cm), (continuous)
Weight (kg), (continuous)
Body Mass Index (BMI) (kg/m2), 
(continuous)
Height population percentile group 
(categorical)
<3
3 to <85
85 to <97
≥97
Weight population percentile group 
(categorical)
<3
3 to <85
85 to <97
≥97
BMI population percentile group (categorical)
<3


24
Demographic and baseline characteristics
Categories
3 to <85
85 to <97
≥97
Waist Circumference (cm), (continuous)
Hip Circumference (cm), (continuous)
Baseline HbA1c %, (continuous)
HbA1c stratum
≤8.0%
>8.0%
Background Diabetes therapy
Naïve
Metformin
SU
Metformin + SU
Duration of Diabetes (years), (continuous)
Duration of Diabetes (years), (categorical)
<1
≥1 to ≤5
>5
Baseline FPG (fasting serum glucose), 
mg/dL, (continuous)
Baseline FPG (fasting serum glucose), 
mmol/L, (continuous)
ECG
Abnormal
    Clinically significant
    Not clinically significant
Normal
Baseline eGFR (mL/min/1.732) (continuous) 
(Bedside Schwartz equation)


25
Demographic and baseline characteristics
Categories
Baseline eGFR (mL/min/1.732)
(Bedside Schwartz equation)
≥125
<125
Baseline eGFR (mL/min/1.732) (continuous)
(CKD-Epi equation)
Baseline Tanner Stage (repeat for each of 
Pubic hair-female, breast-female, pubic hair-
male, genitals-male, overall) 
Stage 1
Stage 2
Stage 3
Stage 4
Stage 5
Patient’s age (years) and ECG will be taken from the Case Report Form (CRF) at screening.
If a patient switches to a different site during the study, the patient will be summarized at the site 
he/she originally enrolled in, regardless of when the patient switched sites.
Region will be categorized as following:
Africa - South Africa
Europe - Russia
Asia - India, Republic of Korea
Latin America - Brazil, Mexico
USA - USA.
BMI will be calculated as the ratio of patient’s weight (in kilograms) to the square of the patient’s 
height (in meters): BMI = kg/m². The Investigator-calculated BMI will not be summarized or 
listed. Height is collected in cm and will be converted to meters before calculating BMI by dividing 
by 100. 
Percentile of body weight, height and BMI percentile will be determined based on the 
standardized growth chart for boys and girls. 
Values and percentiles will be listed for height, body weight and BMI.
Duration of diabetes (years) will be calculated using the screening visit date and the date of 
diabetes diagnosis (see below).


26
If date of diabetes diagnosis is…
Then duration of diabetes (years) is…
Complete date
(Date of screening – Date of diabetes 
diagnosis + 1) / 365.25
Partial date
(a) Year and month are not missing, but day 
is missing
(b) Year is not missing, but month and date 
are both missing
(b1) Year of diabetes diagnosis is 
different from the year of screening 
(b2) Year of diabetes diagnosis is the 
same as year of screening
(a) Impute missing day 1st of the month, then 
use complete date rule
(b1) Difference between year of diabetes 
diagnosis and year of screening
(b2) 2/12 (2 months)
4.2.1.3
Medical/surgical history
All medical/surgical history (pre-existing conditions) by each system organ class (SOC) and 
preferred term (PT) will be summarized by treatment group for the safety analysis set in 
accordance to the terminology of the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA) available at database lock (DBL).
Conditions will be defined as pre-existing if the start date is on or before the date of informed 
consent.
Percentages will be calculated out of the total number of patients in the analysis set displayed in 
the output, overall and by treatment group.
4.2.1.4
Prior and concomitant medications
All medications will be coded using the latest version of WHO Drug Dictionary (WHODD) 
available at DBL. 
Medications will be classified as:

Pre-treatment medication: Medications stopped prior to first dose of randomized study 
medication (or all medications recorded for patients who did not receive randomized study 
medication) 

Prior concomitant medication: Medications started prior to and that continue past the first 
dose of randomized study medication.

New concomitant medication:  Medications with a start date on or after the first dose of 
randomized study medication up to but not including Visit 11 (Week 28/ED) 

Post-treatment medications: Medications with a start date on or after last dose of study 
medication 


27
A listing of all medications will be produced.
The number and percentage of patients receiving prior concomitant and new concomitant 
medications will be summarized by treatment and ATC classification (level 4) for the ITT 
analysis set. Prior concomitant and new concomitant medications will be combined for summary 
tables. This will be repeated for the safety follow-up analysis set.
Prior antidiabetic concomitant medications will be summarized separately by reported term for 
the ITT and safety follow-up analysis sets.
Rescue therapy will be summarized by ATC classification (level 4) and generic term for the ITT 
and safety follow-up analysis set.
A listing of rescue medications will be provided. 
Pre-treatment medications and post-treatment medications will be summarized separately by 
treatment and ATC classification (level 4) for the ITT analysis set. Post-treatment prescription 
medications will also be summarized by actual treatment during the randomized period, ATC 
classification (level 4) and generic term for the safety follow-up analysis set.
Medications with start/stop dates that are partially/completely missing will be imputed as 
described in Appendix 4.
Review of unique combinations of ATC code classifications and generic terms captured will be 
performed by a physician prior to database lock to confirm prohibited medication use including 
the following:

alpha-glucosidase inhibitors, meglitinide or pramlintide 

inhaled steroids at a dose equal to or above 1000 μg Flovent ® (fluticasone propionate) 
daily

oral steroids

thiazolidinedione 
Prohibited medications will be listed.
4.2.2
Treatment compliance
No specific study data was collected for analysis of study medication treatment compliance.  
4.2.3
Exposure
Exposure to study medication will be presented for the treatment period (Week 0 to Week 28) for 
the safety analysis set and for the safety follow-up analysis set.
Duration of exposure in days will be calculated as the date on the last dose CRF form (STR_LD) 
minus the date on the first dose CRF form (STR_FD) + 1.
Dose interruptions will not be taken into consideration for calculation of duration of exposure.
The mean, SD, median, minimum, and maximum duration of exposure will be provided by 
treatment group.  Duration of exposure will also be categorized into fixed intervals as follows, 
with number of patients and percentage summarized by treatment group:
1-13, 14-27, 28-55, 56-83, 84-111, 112-139, 140-167, 168-195, ≥196 days


28
In addition, duration of exposure will also be summarized by country and treatment group.
4.2.4
Efficacy analysis
4.2.4.1
Estimands
Estimands for the study are defined in Table 3. Intercurrent events (IE) that may occur during the 
study are receipt of rescue therapy, IP discontinuation and study withdrawal.
Table 3 Estimand framework
Attributes
Estimand
Population
Variable
Intercurrent event (IE) 
strategy
Population-
level summary
Primary
Evaluable
Change in 
HbA1c from 
baseline to 
Week 28 
All IEs: Data after event 
excluded. Hypothetical 
approach due to missing 
at random (MAR) 
assumption of MMRM 
analysis.
Least squares 
mean difference 
in CFBL at 
Week 28 
between Total 
EBID and PBO
Sensitivity to 
primary
Evaluable
Change in 
HbA1c from 
baseline to
Week 28
All IEs: Data after event 
excluded. Hypothetical 
approach using multiple 
imputation (MI) pattern 
mixture modelling.
Least squares 
mean difference 
in CFBL at 
Week 28 
between Total 
EBID and PBO
Supplementary 
to primary
Evaluable
Change in 
HbA1c from 
baseline to 
Week 28
Rescue and IP 
discontinuation: Data 
after event included. 
Treatment policy 
approach
Withdrawal from study 
prior to Week 28: 
Hypothetical approach 
due to MAR assumption 
of MMRM analysis
Least squares 
mean difference 
in CFBL at 
Week 28 
between Total 
EBID and PBO


29
Attributes
Estimand
Population
Variable
Intercurrent event (IE) 
strategy
Population-
level summary
Sensitivity to 
supplementary 
of primary
Evaluable
Change in 
HbA1c from 
baseline to 
Week 28
Rescue and IP 
discontinuation: Data 
after event included. 
Treatment policy 
approach
Withdrawal from study 
prior to Week 28: 
Hypothetical approach 
using MI pattern mixture 
modelling
Least squares 
mean difference 
in CFBL at 
Week 28 
between Total 
EBID and PBO
Secondary 1
Evaluable
Proportions of 
patients having 
HbA1c goals of 
<7%, ≤6.5%, 
and <6.5% at 
Week 28
All IEs: Data after event 
excluded. Composite 
approach used, with 
patients with missing 
data at endpoint treated 
as non-responders
Difference in 
proportion of 
responders at 
Week 28 
between Total 
EBID and PBO
Sensitivity to 
secondary 1
Evaluable
Proportions of 
patients having 
HbA1c goals of 
<7%, ≤6.5%, 
and <6.5% at 
Week 28 
All IEs: Data after event 
excluded. Hypothetical 
approach using MI 
pattern mixture 
modelling
Difference in 
proportion of 
responders at 
Week 28 
between Total 
EBID and PBO
Secondary 2
Evaluable
Change in 
HbA1c from 
baseline to 
Week 28 and 
each 
intermediate 
visit 
All IEs: Data after event 
excluded. Hypothetical 
approach due to missing 
at random (MAR) 
assumption of MMRM 
analysis
Least squares 
mean difference 
in CFBL at 
Week 28 and 
each 
intermediate 
visit between 
Total EBID and 
PBO


30
Attributes
Estimand
Population
Variable
Intercurrent event (IE) 
strategy
Population-
level summary
Sensitivity to 
secondary 2
Evaluable
Change in 
HbA1c from 
baseline to 
Week 28 and 
each 
intermediate 
visit
All IEs: Data after event 
excluded. Hypothetical 
approach using multiple 
imputation (MI) pattern 
mixture modelling
Least squares 
mean difference 
in CFBL at 
Week 28 and 
each 
intermediate 
visit between 
Total EBID and 
PBO
Continuous 
secondary and 
exploratory 
efficacy 
endpoints 
measured post-
baseline at a 
single endpoint
Full 
analysis set 
Change in XX* 
from baseline to 
Week 28
All IEs: Data after event 
excluded. Hypothetical 
approach due to missing 
at random (MAR) using 
MI ANCOVA analysis
Least squares 
mean difference 
in CFBL at 
Week 28 
between Total 
EBID and PBO
Other 
continuous 
secondary and 
exploratory 
efficacy 
endpoints 
Full 
analysis set
Change in 
HbA1c from 
baseline to 
Week 28 and 
each 
intermediate 
visit 
All IEs: Data after event 
excluded. Hypothetical 
approach due to missing 
at random (MAR) 
assumption of MMRM 
analysis.
Least squares 
mean difference 
in CFBL at 
Week 28 and 
each 
intermediate 
visit between 
Total EBID and 
PBO
Exploratory
Safety
Change in 
eGFR from 
baseline to 
Week 28 by 
baseline eGFR 
category
All IEs: Data after event 
excluded. Hypothetical 
approach due to MAR 
assumption of MMRM 
analysis.
Least squares 
mean difference 
in CFBL at 
Week 28 
between Total 
EBID and PBO
Sensitivity to 
exploratory
Safety
Change in 
eGFR from 
baseline to 
Week 28 by 
baseline eGFR 
category 
Rescue and IP 
discontinuation: Data 
after event included. 
Treatment policy 
approach. 
Least squares 
mean difference 
in CFBL at 
Week 28 
between Total 
EBID and PBO


31
Attributes
Estimand
Population
Variable
Intercurrent event (IE) 
strategy
Population-
level summary
Withdrawal from study 
prior to Week 28: 
Hypothetical approach 
due to MAR assumption 
of MMRM analysis.
*where XX are FSG, FSI, SMBG, HOMA-B, HOMA-S, hip and waist circumference.
4.2.4.2
Analysis of primary variable
The MMRM analysis of the primary endpoint in the Evaluable analysis set will be considered the 
primary analysis.
The primary efficacy analysis will compare treatment groups (Total EBID vs. PBO) with respect 
to change in HbA1c from baseline Visit 3 (Week 0) to Visit 11 (Week 28) using the MMRM 
approach. The model will include change in HbA1c as the dependent variable and treatment, 
baseline HbA1c, background diabetes therapy strata (drug naïve, metformin only, SU only, and 
metformin + SU), week of visit, baseline HbA1c-by-week interaction and treatment-by-week 
interaction as the fixed effects. The variance - covariance structure to be used for this modelling 
will be unstructured (UN); if the model does not converge with unstructured variance –
covariance matrix, then autoregressive order 1 (AR [1]) and heterogeneous autoregressive order 
1 (ARH [1]) structures will be tried and the covariance structure will be decided based on model 
convergence status and the Akaike information criterion. The restricted maximum likelihood 
(REML) method will be used for parameter estimation. The least squares (LS) mean, 2-sided 
95% confidence interval, and p-value of the difference in the change of HbA1c between the 
Total EBID and PBO groups at Visit 11 (Week 28) will be provided. The mean (SD) observed 
HbA1c at baseline and Week 28 will also be given by treatment group.
HbA1c data from post-baseline visits (including ED) will potentially be included in the MMRM 
analysis. In addition, if a patient’s last available measurement during the 28-week assessment 
period is from an unscheduled visit or ED visit, the value will be programmatically mapped to 
the next closest scheduled visit and potentially included in the MMRM analysis. See Section 
4.1.3 for details on missing data handling and Section 4.2.4.1 for details on handling of data after 
IEs.
For patients who initiate rescue medication or discontinue IP and continue study participation, 
only data before initiation of rescue medication or up to and including date of discontinuation 
from IP will be included in the MMRM/ANCOVA analysis. If there is evidence that a 
measurement was taken prior to initiation of rescue medication, then this data will be included. If 
the measurement was taken on the date of initiation of rescue medication but time information is 
not available, then the measurement will be included. Data collected after discontinuation of IP 
will be excluded from analyses for all secondary efficacy endpoints.
Summaries and analysis of the primary endpoint will be performed in the Evaluable analysis set.


32
Assessment of homogeneity of treatment effect:
The homogeneity of treatment effect will be assessed by adding treatment by baseline interaction 
and treatment by strata interaction to the primary MMRM model as described in Section 4.2.4.2. 
The same covariance structure as used for the primary analysis will be used for this model. The 
p-value for the interaction effects will be explored to identify the potential trend for non-
homogeneity.
Descriptive summary of primary efficacy variable by visit
Actual, change and percent change from baseline values of HbA1c will be summarized using 
descriptive statistics by visit and treatment group. Plots of mean ± standard error of mean for the 
change from baseline in HbA1c by visit and treatment group will be provided. Only OC 
summaries will be provided.
Subgroup analysis
The primary endpoint, change from baseline in HbA1c at week 28, will be summarized 
descriptively for subgroups of interest listed below. No statistical analyses will be conducted.

Sex

Age group: two different definitions. 
o
Age (years) <10, 10 to 12, 13 to 16, >16 
o
Age (years) <10, 10 to 17, and >17

Race
Actual, change and percent change from baseline values of HbA1c will be summarized using 
descriptive statistics by visit and treatment group for each subgroup of the Evaluable analysis set. 
OC summaries will be provided.
4.2.4.3
Sensitivity and supplementary analyses for primary endpoint
To further support the primary endpoint analysis and to examine the influence of missing data 
due to drop-out and/or receiving rescue therapy, sensitivity and supplementary estimands 
described in Section 4.2.4.1 are defined and will be addressed using an MMRM analysis at Week 
28. 
An imputation sensitivity analysis will test the assumption of MAR that is made by the MMRM 
analysis. For this purpose, a model that assumes missing not at random (MNAR) will be used, 
whereby assumptions for the missing data “stress test” the MAR assumptions of the primary 
analysis, by positing outcomes that, while clinically plausible, are likely to be worse for the Total 
EBID group than the outcomes assumed by MAR. A plausible stress test could assume that the 
outcome for the Total EBID treatment is somewhat worse than would be predicted by MMRM 
from the study data. Such a stress test would appropriately disadvantage the estimate of 
treatment effect, compared to the estimate of the primary analysis. In this way the MAR 
assumption of the primary analysis could be stress tested.
If this is so, the proposed MNAR sensitivity analysis, which assumes that the trajectory of 
withdrawals from the Total EBID group, regardless of reason for withdrawal, is as bad as that of 
PBO patients, is quite conservative and a reasonable stress test of the already somewhat 
conservative MAR assumption of a common trajectory for withdrawals. Note that this approach 
constitutes a pattern mixture model (Molenberghs and Kenward, 2007). The patterns here are 


33
defined by the time of withdrawal combined with the treatment group. The time of withdrawal is 
used in the definition of the pattern to allow the estimate to take account of the improvement 
over time that tends to be observed in all patients. By the end of the study earlier withdrawals are 
likely to have improved somewhat more from their last observation, than late withdrawals. 
Specifically, for patients who drop out after visit t, the change from baseline at visit t + n will be 
assumed to be the mean for visit t plus the difference in the means of the PBO group at visits t 
and t + n, given the study data. Then, the overall estimate of treatment effect is obtained by 
averaging the estimates across the dropout patterns, according to the proportions of dropouts 
occurring at each visit. Note that in this analysis, PBO missing observations are imputed 
assuming MAR and follow the pattern of observed PBO observations, and missings for the Total 
EBID group are assumed MNAR.
In summary, the pattern mixture models will be implemented by multiple imputation via the 
following steps; 
Step 1: Non-monotone missing data (usually relatively infrequent) will be imputed using the 
MCMC option of SAS PROC MI with treatment, baseline HbA1c, background diabetes 
therapy strata (drug naïve, metformin only, SU only, and metformin +SU) and value of the 
endpoint at each visit. This will create a monotone missing pattern in the dataset within each 
treatment group. This step will create 1000 imputed datasets. 
Step 2: The values for each pattern will be imputed via the chained equation method, using SAS 
PROC MI option MONOTONE REG (). The MNAR imputation is achieved by using only 
appropriate study data for each pattern. For example, to impute for time t if the EBID missing data 
has the trajectory of PBO, include only PBO observations up to and including time t, plus only 
observations from patients in the EBID group that have observations up to but not beyond time t-
1. First, all missings for the first post-baseline visit are imputed, then missings for the next visit 
are imputed using observed data plus the missings just imputed; and so on to the final visit. The 
covariates used in the model will be baseline HbA1c, background diabetes therapy strata (drug 
naïve, metformin only, SU only, and metformin +SU) and HbA1c measured at time t-1.
Step 3: The imputed data from Step 1 and Step 2, along with observed data will be analyzed 
using an MMRM model for the outcome of change from baseline  with treatment, baseline 
HbA1c, background diabetes therapy strata (drug naïve, metformin only, SU only, and 
metformin +SU), week of visit, baseline HbA1c-by-week interaction and treatment-by-week 
interaction as the fixed effects. The variance - covariance structure to be used for this 
modelling will be unstructured (UN). The estimates from multiple imputed datasets will be 
combined using Rubin’s combination rules for statistical inference (Rubin, 1987) using PROC 
MI ANALYZE.
The seed used will be 88281 for both steps 1 and 2.
At Step 1, if a categorical covariate has more than 2 levels, then dummy coding has to be 
performed to present it as either 0/1 or 1/2. If categorical variable has X categories (X>2) then 
we would create X-1 dummy variables, using the rule described in the table below.


34
Table 4 Dummy variables
Category
Dummy 
variable 1
Dummy 
variable 2
…
Dummy 
variable X-1
A
1
0
0
B
0
1
0
…
0
0
0
X-1
0
0
1
X
0
0
0
A supplemental to the primary analysis and a sensitivity to the supplemental of the primary 
analysis will also be performed. In these analyses, data after rescue medication use or date of 
IP discontinuation will be included in the MMRM analysis and MI pattern mixture modelling.
Further sensitivity analysis will be as described in section 4.2.4.2, where it will compare active 
treatment group doses vs Placebo (EBID vs. PBO).
4.2.4.4
Analysis of secondary variables
Summary statistics and frequency tables will be provided for all secondary endpoints by visit and 
treatment for the Full analysis set during the treatment period (see Section 3.6.5 for treatment 
period definition), unless otherwise stated. 
As for the primary analysis, data including the ED visit where applicable will be included in the 
MMRM/ANCOVA and CMH analysis for secondary analysis variables. Data collected from an 
ED visit will be mapped to the next closest scheduled visit. For patients who initiate rescue 
medication and continue study participation, data collected after the initiation of rescue 
medication will be excluded from analyses. Data collected after discontinuation of IP will be 
excluded from analyses for all other secondary efficacy endpoints.
Change in HbA1c from baseline Visit 3 (Week 0) to each intermediate visit
The MMRM method for change in HbA1c will be used until Week 28 and to each intermediate 
visit, using the Evaluable analysis set, which is the same approach as stated in Section 4.2.4.2.
The least squares mean (LSM) change from baseline and SE bar by visit will be presented in a 
figure by treatment group. The p-value for the difference between treatment groups by visit will 
also be provided in the figure.
Actual, change and percent change from baseline values of HbA1c will be summarized using 
descriptive statistics by visit and treatment group for the Evaluable analysis set.  OC summaries 
will be provided. 
HbA1c measures will be listed. 


35
Proportions of patients achieving HbA1c goals
Proportions of patients having HbA1c goals of <7%, ≤6.5%, and <6.5% at Week 28 will be 
compared between treatments (Total EBID vs. PBO) using the Evaluable analysis set via the 
CMH procedure, in which screening HbA1c strata and background diabetes therapy strata will 
serve as the stratification factors. 
A bar chart of the percentage of patients achieving HbA1c goals of <7%, ≤6.5%, and <6.5% by 
treatment group will be provided along with p-values.
The number and percentage of patients having HbA1c goals of <7%, ≤6.5%, and <6.5% will be 
summarized by visit and treatment group for the Evaluable analysis set. 
Any Evaluable patient without HbA1c value at the endpoint will be considered as not achieving 
HbA1c goal at endpoint. The denominator will be the total number of Evaluable patients in the 
treatment group, and the numerator will be the number of patients achieving HbA1c <7%, 
≤6.5%, and <6.5%. 
As a sensitivity analysis, also in the Evaluable analysis set, the probabilities of patients reaching 
HbA1c targets of <7%, ≤6.5%, and <6.5% will be analyzed to Week 28 using the CMH 
procedure, with missing data imputed using MI pattern mixture model imputation. HbA1c and 
background diabetes therapy strata will serve as the stratification factors. The imputed HbA1c 
data for the sensitivity analysis of the primary endpoint will be used for this analysis.
Similar outputs (bar chart including p-values and summary of the numbers and percentage of 
patients having HbA1c goals by visit and treatment group) will be produced for the Evaluable 
analysis set for this sensitivity analysis.   
Change in body weight, FSG and FSI from baseline Visit 3 (Week 0)
The same MMRM approach (as used for the primary analysis) will be used to analyze the change 
in body weight from baseline Visit 3 (Week 0) to Week 28, and each intermediate visit. Baseline 
body weight will replace baseline HbA1c and screening HbA1c strata will be included in these 
models.
Since only baseline and endpoint FSG and FSI measurements are collected, these endpoints will 
be analyzed by multiple imputation based on the assumption that missing data are MAR via the 
following steps:
Step 1: Non-monotone missing data (expected to be infrequent) will be imputed using the 
MCMC option of SAS PROC MI with treatment, baseline FSG/FSI, screening HbA1c strata 
(8% and >8%) and background diabetes therapy strata (drug naïve, metformin only, SU only, 
and metformin +SU) and value of the endpoint at each visit. This will create a monotone 
missing pattern in the dataset within each treatment group. This step will create 1000 imputed 
datasets. 
Step 2: After a monotone missing pattern is created for the data, PROC MI using MONOTONE 
REGRESSION will be used to impute missing post-baseline values. The covariates used in the 
model will be treatment, baseline FSG/FSI, screening HbA1c strata (8% and >8%) and 
background diabetes therapy strata (drug naïve, metformin only, SU only, and metformin +SU) 
and value of the endpoint at each visit. This is MAR imputation.


36
Step 3: The imputed data from Step 1 and Step 2, along with observed data will be analyzed 
using separate ANCOVA models for each imputed dataset with change from baseline in 
FSG/FSI as the dependent variable and  treatment, baseline FSG/FSI, screening HbA1c strata 
(8% and >8%) and background diabetes therapy strata (drug naïve, metformin only, SU only, 
and metformin +SU) as fixed effects. Parameter estimates (LS means and standard errors) and 
variance/covariance matrix will be obtained for each of the multiple imputed datasets. 
Step4: The estimates from multiple imputed datasets will be combined using Rubin’s 
combination rules for statistical inference (Rubin, 1987) using PROC MI ANALYZE.
The seed used will be 88281 for both steps 1 and 2.  The number of imputed datasets may be 
reduced depending on the extent of missing data.
The residuals from the ANCOVA model will be plotted against the quartiles from standard 
Normal distribution for each of the imputed datasets. A Kolmogorov–Smirnov normality test 
will be conducted for the residuals. If deviation from normality is noted in the ANCOVA model 
or imputation diagnostics including trace and autocorrelation plots indicate issues with the 
multiple imputation then alternative approaches will be discussed e.g. analysis of variance 
(ANOVA), number of imputed datasets etc. 
Actual values and change from baseline will be summarized using descriptive statistics by visit 
and treatment group for the Full analysis set. OC summaries will be provided where appropriate. 
Body weight, FSG and FSI measures will be listed.
Change in SMBG measurements from baseline Visit 3 (Week 0) 
In both the seven days prior to Visit 3 (Week 0) and the seven days prior to Visit 11 (Week 28), 
patients will be asked to perform 4-point SMBG profiles (pre- and 2-hour post-prandial 
measurements at the 2 main meals of the day) on 3 separate days. SMBG profiles will be 
summarized as follows.
Only complete pairs of pre-prandial and post-prandial SMBG concentrations will be used. If 
measurements are taken for more than 2 main meals of the day, then the latest 2 meals of the day 
will be used that have both a pre-prandial and post-prandial measurement. If measurements were 
taken on more than 3 separate days in a period, then the latest 3 days of measurements that have 
both a pre-prandial and post-prandial measurement prior to the visit will be used. If data are 
missing for a meal, then the remaining available data will be used.  Thus, summary measures 
will be calculated provided the patient had a least one complete pair of measurements in the 
period.
Mean SMBG will be calculated as the mean of SMBG concentrations (pre- and post-prandial) 
over the 2 main meals over 3 separate days, where complete pairs of both pre-prandial and post-
prandial measurements for a given meal are present. Mean SMBG at baseline Visit 3 (Week 0) 
and Visit 11 (Week 28) as well as the change in overall daily mean from baseline Visit 3 (Week 
0) to Visit 11 (Week 28) will be summarized using descriptive statistics by treatment group for 
the Full analysis set.
Post-prandial excursions will be calculated as the difference between the pre-prandial and post-
prandial blood glucose concentrations (post-prandial – pre-prandial) and averaged (mean) over 
the 2 main meals over the 3 separate days in each period. Mean post-prandial excursions at 


37
baseline Visit 3 (Week 0) and Visit 11 (Week 28) as well as the change from baseline values will 
be summarized using descriptive statistics by treatment group. 
The mean pre-prandial (post-prandial) SMBG concentration will be defined as the average 
(mean) measurement over the 2 main meals over 3 separate days in each period.  Mean pre-
prandial (post-prandial) SMBG concentrations at baseline Visit 3 (Week 0) and Visit 11 (Week 
28) as well as the change from baseline values will be summarized using descriptive statistics by 
treatment group.
The same multiple imputation ANCOVA approach (as used for the analysis of FSG and FSI) 
will be used to analyze change from baseline Visit 3 (Week 0) to Visit 11 (Week 28) for each of 
the 4 SMBG summary measures (overall, pre-prandial, post-prandial, post-prandial excursions). 
Change in beta-cell function (HOMA-B) and insulin sensitivity (HOMA-S) from baseline 
Visit 3 (Week 0) to Visit 11 (Week 28)
The effects of the study medications on HOMA will be examined. The pancreatic beta-cell 
function (HOMA-B) and peripheral and hepatic insulin sensitivity (HOMA-S) will be computed 
from a computerized HOMA model, the HOMA Calculator (Matthews et al 1985). The HOMA 
Calculator, developed by Diabetes Trials Unit at the Oxford Center for Diabetes, Endocrinology, 
and Metabolism, is a computer algorithm that takes account of variations in hepatic and 
peripheral glucose resistance, increases in the insulin secretion curve for plasma glucose 
concentrations above 10 mmol/L (180 mg/dL), and the contribution of circulating proinsulin 
(e.g., C-peptide) to estimate the steady state beta-cell function and insulin sensitivity, as 
percentages of a normal reference population. The model assumes %HOMA-B and %HOMA-S 
values of 100% in normal young adults as a recalibration. 
HOMA parameters will be log transformed (natural logarithmic transformation). The observed 
values and change from baseline for these parameters will be summarized by visit using 
descriptive statistics (n, geometric mean, geometric coefficient of variation: GCV%, geometric 
standard deviation factor: GSD, arithmetic mean, standard deviation, coefficient of variation: 
CV%, median, minimum and maximum value) for the Full analysis set. 
The same multiple imputation ANCOVA approach (as used for the analysis of FSG and FSI) 
will be used to analyze change from baseline Visit 3 (Week 0) to Visit 11 (Week 28) for HOMA-
B and HOMA-S.
All HOMA parameters will be analyzed on a logarithmic scale (natural logarithmic 
transformation), and then back-transformed to the original scale for result presentation using the 
following formulae:
Geometric Mean= exp(mean(log (X)))
SE of Geometric Mean = Geometric Mean* SE of Mean (log (X))
LS means will be back-transformed in the same way.
Separate tables of back-transformed and non-transformed results will be provided.
Homeostasis results will be listed.
Proportions of patients discontinuing the study due to failure to maintain glycemic control 
at Visit 11 (Week 28), and at each intermediate visit


38
Patients should be discontinued from the study if the patient experiences a loss of glycemic 
control, as evidenced by:

Increase in absolute HbA1c ≥0.5% from baseline at 2 consecutive scheduled visits which 
are at least 1 month apart, prior to study completion 
and/or

Fasting blood glucose >250 mg/dL (13.9 mmol/L) or non-fasting glucose >300 mg/dL 
(16.7 mmol/L) for 4 days in a 7-day period as measured by SMBG. The patient will 
return to the clinic for a confirmatory fasting glucose, if possible, or a non-fasting 
glucose. If by local laboratory measurement a fasting glucose is >250 mg/dL (13.9 
mmol/L) or a non-fasting glucose is >300 mg/dL (16.7 mmol/L), the patient will be 
discontinued from the study.
A patient who discontinues because of loss of glycemic control should have discontinuation 
reason “Loss of Glucose Control” on their Disposition form. In addition, early patients in the 
study may have also discontinued due to glycemic control but only stated this on the Adverse 
Event form.
For the purposes of this analysis a patient will be deemed as having discontinued due to loss of 
glycemic control if they satisfy at least one of the following criteria:
(a) They have discontinuation reason “Loss of glucose control” on SUM CRF form.
(b) They have an adverse event with lower level MedDRA terms “Loss of glucose control” 
or “Hyperglycaemia” leading to study drug discontinuation.
The proportion of patients who discontinue the study due to failure to maintain glycemic control 
will be summarized using frequencies and percentages by visit for the Full analysis set. OC
summaries will be provided.
A listing of patients with loss of glycemic control will be produced.
4.2.4.5
Analysis of exploratory efficacy variables
Analysis of all exploratory endpoints will be performed for the Full analysis set unless otherwise 
specified. 
The same MMRM approach (as used for the primary analysis) will be used to analyze the change 
in BMI, body weight percentiles and BMI percentiles from baseline Visit 3 (Week 0) to Week 
28, and each intermediate visit. 
The same multiple imputation ANCOVA approach (as used for the analysis of FSG and FSI) 
will be used to analyze change from baseline Visit 3 (Week 0) to Visit 11 (Week 28) for waist 
and hip circumference.
Baseline values, the values at each visit, and changes from baseline values will be summarized 
for BMI, percentiles of body weight, percentiles of BMI, hip circumference and waist 
circumference by treatment. OC summaries will be provided.
Exploratory efficacy variables will be listed.


39
4.2.5
Safety analyses
4.2.5.1
Adverse events
Adverse events (AE) will be classified in accordance to the MedDRA dictionary. All adverse 
events will be coded using the latest available version of MedDRA by the database lock. 
AEs starting (or worsening) after Week 28/ED but considered by the Investigator as clinically 
significant and as related to study medication or study procedure, and serious adverse events
(SAE) occurring within 30 days of the last administration of study medication will be recorded 
on the AE CRF and reported in the AE listing.
Treatment-emergent AEs (TEAE) are defined as AEs starting (or worsening) after the first dose 
of study medication through the end of the treatment + 1 day (or + 30 days for SAEs and other 
clinically significant or related AEs), including AEs collected after patients initiate glycemic 
rescue therapy. For patients who discontinue study medication before Week 28, the end of the 
treatment refers to the date of the ED visit even if last study medication was before this date. 
Adverse events with a start date prior to the first administration of study medication will be 
classified as pre-treatment (non-treatment emergent) and will be listed only.
Post-treatment AEs are defined as AEs that start (or worsen) during the off-treatment period 
(safety follow-up period) defined as the day after the Visit 11 (Week 28/ED) + 1 day (or + 30 
days for SAEs and other clinically significant or related AEs) to the date of completion of the 
safety follow-up period. As per protocol only adverse events of special interest (AESIs) will be 
collected in long term extension.
On-treatment AEs (TEAEs) will be summarized for 28-week treatment period as defined below.
An overall summary of number and percentage of patients experiencing at least 1 TEAE will be 
presented for EBID and PBO. The AE summary will include the number and percentage of 
patients experiencing any AE, any SAE, any AE possibly related to study drug, study procedure 
or study device as judged by the investigator, any AE leading to treatment discontinuation, and 
any fatal AE.  
Additionally, all TEAEs will be summarized for each treatment group as follows:

AEs summarized by SOC, PT, intensity (Mild, Moderate, Severe), possibly related to 
study drug (No, Yes) and outcome 

SAEs summarized by SOC and PT, intensity (Mild, Moderate, Severe), possibly related 
to study drug (No, Yes)

AEs leading to treatment discontinuation (DAE) summarized by SOC and PT

Frequent AEs (AE with at least 5% incidence in any treatment) summarized by preferred 
term

Non-serious frequent AEs summarized by SOC and PT

Adverse events of special interest by SOC and PT
Summaries will be presented for the treatment period (Safety analysis set). 
Any AE that is recorded as the reason for study discontinuation will be considered a DAE 
regardless of the date recorded.


40
Potentially immune-related AEs will be listed and identified using the PTs given in Appendix 5.
Tables of key patient information for SAEs and AEs leading to discontinuation of study 
medication will be provided. Adverse events will be listed.
The number of AEs and number of SAEs will be summarized for the treatment period.
The denominator for summaries will be the number of patients included in the analysis set by 
treatment group and total. 
Selected AEs have been identified as AESIs. During the safety follow-up period, only AESIs 
will be recorded in the CRF.
The AESIs recorded are as follows:

Hematological malignancies

Thyroid neoplasms

Pancreas neoplasms

Aplastic anemia

Pancreatitis

Pregnancy and pregnancy outcomes (including congenital anomalies)
This list may be updated if additional AESIs are identified.  All AESIs will be listed.
AESIs will be summarized by system organ class (SOC), PT, intensity (Mild, Moderate, Severe), 
seriousness and outcome by the actual treatment during the randomized period for the Safety 
follow-up analysis set.
4.2.5.2
Hypoglycemic episodes
Confirmed hypoglycemic episodes will be defined as follows: 
Minor hypoglycemia: 

Any time a patient feels that he or she is experiencing a sign or symptom associated with 
hypoglycemia that is either self-treated by the patient or resolves on its own
and

Has a concurrent fingerstick blood glucose <3.0 mmol/L (54 mg/dL). 
Major hypoglycemia: 

any episode with symptoms consistent with hypoglycemia resulting in loss of consciousness 
or seizure that shows prompt recovery in response to administration of glucagon or glucose 
or 

documented hypoglycemia (blood glucose <3.0 mmol/L [54 mg/dL]) requiring the 
assistance of another person because of severe impairment in consciousness or behavior 
(regardless of whether symptoms of hypoglycemia are detected by the patient).


41
Episodes will be categorized into major or minor following medical review of the hypoglycemic data 
by an AstraZeneca or IQVIA physician.
Incidence of hypoglycemic episodes will be summarized by whether they are major or minor and 
by when the episodes occurred (night-time will be defined to be between 11pm and 5 am) using 
frequencies and percentages of patients with at least one episode of hypoglycemia occurring 
during the study. The number of episodes per patient will be classified into categories (0, 1 to 2, 
3 to 4, ≥5), and summarized using frequencies by treatment group and visit for the Safety 
analysis set.  
Similar analyses will be performed for confirmed hypoglycemic episodes (those with a blood 
glucose record) and unconfirmed hypoglycemic episodes (those reported into study database 
without corroborating blood glucose record).
Minor and Major hypoglycemia rate (adjusted for duration of exposure to study drug therapy = the 
date of last dose of IP – date of first dose of IP +1) will be summarized by treatment. 
The number and percentage of patients with any confirmed and unconfirmed hypoglycemic 
episodes will also be summarized by baseline sulfonylurea use (yes/no) and treatment.
Hypoglycemic events will be listed.
4.2.5.3
Antibodies to exenatide 
A patient is said to have treatment emergent antibodies to exenatide at a visit if the antibody test 
is positive after the first injection of study medication following a negative or missing antibody 
measurement prior to the first injection of study medication, or the titer is increased by at least 3 
dilutions from a detectable measurement prior to the first injection of study medication.
Patients with antibodies to exenatide during the treatment, as well as incidence of negative, any 
positive, low positive (<625), and high positive (≥625) will also be summarized descriptively by 
visit. 
4.2.5.4
Laboratory data (including CEA and calcitonin concentrations)
Continuous laboratory parameters will be summarized in standardized international (SI) and US 
units. The visit windows described in Section 4.3.2 will be used. There will be no imputation for 
missing values.
All hematology, clinical chemistry and urinalysis results will be listed by treatment group, 
patient, and visit, including scheduled and unscheduled/repeat measurements. Laboratory 
assessments that are outside of normal ranges will be flagged. Separate listings of laboratory 
values above/below the upper/lower limit of the reference range will be produced. The central 
laboratory or local laboratory (for assessments measured at a local laboratory) reference ranges 
will be used. The observed values at each visit to Visit 11 (Week 28) and change from baseline 
values will be summarized for each of the quantitative laboratory assessments by treatment 
group for the Safety analysis set. For categorical parameters, shift tables from baseline to each 
visit to Visit 11 (Week 28) will be produced by treatment group for the Safety analysis set.  
Tumor marker CEA and calcitonin levels will also be summarized by visit for the Safety follow-


42
up analysis set. These summaries will include observed values at each visit from Visit 3 (Week 
0) through Visit 11 (Week 28) to end of the safety follow-up period and change from baseline by 
actual treatment group during the randomized period and overall.
Number and percentage of laboratory results that are potentially clinically significant (see 
Appendix 6) will be listed and summarized by analyte name and criteria for each treatment group 
for the safety analysis set. A listing of calcitonin values >100 ng/L will be produced.
Estimated glomerular filtration rate (eGFR) will be derived based using the Bedside Schwartz 
formula (Schwartz, 2009):
eGFR = 41.3 * (Height in meters / Serum creatinine in mg/dL)
A table of observed and change from baseline in eGFR values will be provided. This will be 
provided both overall and by baseline eGFR, hyperfiltrating versus non-hyperfiltrating, where 
hyperfiltration is defined as an eGFR ≥125 ml/min/1.73m2.
An ANCOVA analysis of change in eGFR from baseline to Week 28 by baseline eGFR 
(hyperfiltrating: ≥125 ml/min/1.73m2 versus non-hyperfiltrating: <125 ml/min/1.73m2) will be 
provided. The same multiple imputation approach as stated in Section 4.2.4.4 will be used. The 
model will include treatment, screening HbA1c strata (≤8%, >8%), background diabetes therapy 
strata (drug naïve, metformin only, SU only, and metformin + SU), baseline eGFR as the fixed 
effects. The least squares mean, 2-sided 95% confidence interval, and p-value of the difference 
in the endpoints of interests between Total EBID and PBO groups will be presented. This 
analysis will be done both excluding data after initiation of rescue therapy and separately 
including data after initiation of rescue therapy.
eGFR will also be calculated using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) formula (Levey et al, 2009):
eGFR = 141 × min(Scr/κ, 1)α  × max(Scr/κ, 1) -1.209 × 0.993Age × [1.018 if female,  x 1.159
if black]
where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and 
-0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of 
Scr/κ or 1.
eGFR using the CKD-EPI equation will be summarized at baseline and may be analyzed as a 
sensitivity analysis.
Strip Sign for Selected Laboratory Data
For selected laboratory test values that have been received with a qualifier as a part of the result 
(>, , <, or ), a process to strip the qualifier will be applied and the resulting numeric values 
will be used for data analysis. The raw value with operator will remain as such in the database 
and will be used when listed. 
4.2.5.5
Vital signs
Vital signs (systolic and diastolic blood pressure and heart rate) will be summarized by visit and 
treatment group for the safety analysis set.  Observed and change from baseline values will be 
summarized for each visit where appropriate. This summary will be repeated by age group (<12 
years, ≥12 years). 


43
Number and percentage of vital signs that are potentially clinically significant (see Appendix 7 ) 
will be summarized by parameter, category, treatment group and age group (<12 years, ≥12 
years). Individual patient data for patients with marked abnormality criteria will be listed.
Vital signs parameters will be listed.
4.2.5.6
ECG
A shift table from screening Visit 1 (Week -3) to Visit 11 (Week 28/ED) will be produced 
showing the number and percentage of patients in each overall interpretation category (normal, 
abnormal not clinically significant, abnormal clinically significant) by treatment for the safety 
analysis set.
A listing of clinically significant abnormal ECGs will be produced.
4.2.5.7
Height
Baseline values (and percentiles), the values (and percentiles) at each visit and changes from 
baseline values (and percentiles) will be summarized by actual treatment during the randomized 
period for both the Safety analysis set and for Safety follow-up analysis set.
Height at all visits will be listed.
4.2.5.8
Tanner pubertal assessment
A shift table of change in pubertal stage from baseline Visit 3 (Week 0) will be produced for the 
safety analysis set (to Week 28, and each intermediate visit) and for the safety follow-up set (to 
up to 3-years, and each intermediate visit). 
Each pubertal assessment category (pubic hair – females, breasts – females, pubic hair – males 
genitals – males and overall) will be summarized separately.
A listing of Tanner pubertal stage data will also be provided.
4.2.6
Pharmacokinetic analyses
The PK analysis set is defined in Section 2.1.6.
The exclusion of any patients from the PK analysis will be agreed by the study physician, 
statistician and PK Scientist during the data review meeting (DRM).  The exclusion of 
concentration data from the PK analysis for an individual time point will be documented by the 
PK Scientist including the reason(s) for exclusion.  These individual concentration data will be 
listed.
Plasma exenatide concentrations will be listed.
4.3
Conventions
All visits scheduled during the 28-week treatment period should occur within ± 7 days of the 
scheduled date relative to Visit 3 (Week 0) per the CSP.  All visits during the safety follow-up 
period should occur within 6 months ± 2 weeks of the previous visit.


44
Patients do not always adhere strictly to the visit timing in the CSP. Therefore, the designation of 
visits during the treatment period will be based on the day of evaluation relative to the start of the 
treatment period (day of study medication = Day 1) rather than the nominal visit recorded in the 
CRF. Designation of visits during the safety follow-up period will be based on the day of 
evaluation relative to the last date of the treatment period (Visit 11/ED).  
To assign a measurement to a Week t during the study, the first step is to select all measurements 
falling within the study period. Mutually exclusive relative day windows are used to determine 
the Week t measurement. These relative day windows are defined to provide derived visits that 
correspond to the post-baseline time points specified in the CSP. Visit windows are listed below.
4.3.1
Visit assignments for efficacy variables
Selection of SMBG measurements is discussed in section 4.2.4.4.
Table 5 Visit Windows: HbA1c
Visit
Week
Period
Target Day
Day range
3
0
TP
1
Baseline
5
4
TP
29
2-56
7
12
TP
85
57-112
9
20
TP
141
113-168
11
28
TP
197
169-last day of TP
TP: Treatment period.
Table 5 Visit Windows: FSG, FSI, HOMA-B and HOMA-S
Visit
Week
Period
Target Day
Day range
3
0
TP
1
Baseline
11
28
TP
197
2-last day of TP
TP: Treatment period.
Table 6 Visit Windows: Failure to maintain glycemic control
Visit
Week
Period
Target Day
Day range
3
0
TP
1
Baseline
4
2
TP
15
2-21
5
4
TP
29
22-42


45
Visit
Week
Period
Target Day
Day range
6
8
TP
57
43-70
7
12
TP
85
71-98
8
16
TP
113
99-126
9
20
TP
141
127-154
10
24
TP
169
155-182
11
28
TP
197
183-last day of TP
TP: Treatment period.
4.3.2
Visit assignment for safety variables
Table 7 Visit Windows: Antibodies to exenatide and vital signs
Visit
Week
Period
Target Day
Day range
3
0
TP
1
Baseline
5
4
TP
29
2-56
7
12
TP
85
57-112
9
20
TP
141
113-168
11
28
TP
197
169-last day of TP
TP: Treatment period. 


46
Table 8 Visit Windows: Body weight, height, BMI and Tanner pubertal assessment
Visit
Week
Period
Target Day
Day range
3
0
TP
1
Baseline
5
4
TP
29
2-56
7
12
TP
85
57-112
9
20
TP
141
113-168
11
28
TP
197
169-last day of TP
801
+26
SFU
+183
last day of TP+1-273
802
+52
SFU
+365
274-454
803
+78
SFU
+546
455-636
804
+104
SFU
+729
637-820
805
+130
SFU
+911
821-l001
806/ED
+156
SFU
+1093
1002-last day of SFU
TP: Treatment period. SFU: Safety follow-up period (+ denotes relative to Visit 11/ED)
Table 9 Visit Windows: Laboratory data, ECG, waist circumference and hip 
circumference
Visit
Week
Period
Target Day
Day range
3
0
TP
1
Baseline
11
28
TP
197
2-last day of TP
801
+26
SFU
+183
last day of TP+1-273
802
+52
SFU
+365
274-454
803
+78
SFU
+546
455-636
804
+104
SFU
+729
637-820
805
+130
SFU
+911
821-l001
806/ED
+156
SFU
+1093
1002-last day of SFU
TP: Treatment period. SFU: Safety follow-up period (+ denotes relative to Visit 11/ED). Only 
CEA and calcitonin measured during SFU


47
Table 10 Visit windows: Hypoglycemic episodes
Visit
Week
Period
Target Day
Day range
3
0
TP
1
Baseline
4
2
TP
15
2-21
5
4
TP
29
22-42
6
8
TP
57
43-70
7
12
TP
85
71-98
8
16
TP
113
99-126
9
20
TP
141
127-154
10
24
TP
169
155-182
11
28
TP
197
183-last day of TP
TP: Treatment period.
Collected at clinic visits but discussed during telephone visits
4.3.3
Rules for safety observations
4.3.3.1
Multiple safety assessments
The assessments for laboratory parameters will be based only on central laboratory values if 
results for both local and central labs exist. 
For the baseline visit window see section 3.6.1. For other visit windows rules below apply. 
For laboratory efficacy parameters, if a patient has more than one measurement (scheduled or 
unscheduled) included within a relative day window, the assessment closest to the target day and 
time (the target time is always assumed to be 8:00 am) will be used. In case of ties between 
observations located on different sides of the target day and time, the later assessment will be 
used. In case of ties located on the same side of the target day and time (i.e. more than 1 value 
for the same day and time), the mean of the values will be used.
For non-laboratory efficacy parameters, if a patient has more than one measurement (scheduled 
or unscheduled) included within a relative day window, the assessment closest to the target day
will be used. In case of ties between observations located on different sides of the target day, the 
later assessment will be used. In case of ties located on the same side of the target day (i.e., more 
than 1 value for the same day), the mean of the values will be used.
4.3.3.2
Adverse events at patient level
When a patient has the same adverse event, based on SOC/PT, reported multiple times in a single 
analysis period, the patient will only be counted once at the SOC/PT level in adverse event 
frequency tables.


48
When a patient has the same adverse event, based on preferred terminology, reported multiple 
times in a single analysis period, the following criteria, in order of precedence, will be used to 
select the event to be included in summary tables:
1.
Relationship to study medication
2.
Intensity of event
3.
Onset date and time
When assessing relationship to study medication, relationship is reported by the Investigator into 
2 categories - related and not related. Related events will take precedence over not related events 
in determining the event to include in summary tables.
More intense events will take precedence over less intense events in determining the event to 
include in summary tables.
Earlier onset date-time events will take precedence over late onset date-time events in 
determining the onset to include in summary tables.
When reporting adverse events by intensity, in addition to providing a summary table based on 
the event selection criteria detailed above, summary tables will also be provided based on the 
most intense event during the analysis period - independent of relationship to study medication. 
For these tables, the following criteria, in order of precedence, will be used to select the event to 
be included in summary tables:
1.
Intensity of event
2.
Onset date and time
4.3.3.3
Adverse event at event level
At event level, each unique AE record will be counted. Unique AE record can be obtained by 
collapsing all AE records following a standard algorithm described below. 
To ensure that multiple events for the same patient are counted accurately in the summaries, a 
methodology for collapsing AE records and reporting for the analysis will be followed as below. 
For each patient and PT, AE records will be collapsed into a single record (unique AE) when:
1.
Multiple AE records have the same onset date,
2.
The onset date of an event record is either the same day or 1 day later than the resolution 
date of a preceding event record (contiguous events),


49
3.
The onset date of an event record is after the onset date and prior to or on the resolution date 
of a preceding event record (overlapping events).
The unique AE record will contain the earliest onset date, latest resolution date (if available), 
highest intensity, relationship (yes/no), and highest action taken in the following order (highest 
to lowest): drug discontinued, drug interrupted, none. In addition, the unique AE record will be 
classified as a SAE if at least 1 AE record was classified as a SAE and the unique AE record will 
be classified as requiring treatment if at least 1 AE record required treatment.
INTERIM ANALYSES
Three safety analyses were planned for this trial beginning when at least 25% of the patients have 
been randomized. To minimize the operational and statistical bias that result from performing a 
safety assessment, the assessment for this study were to be conducted under the auspices of a Data 
Monitoring Committee (DMC). The purpose of the DMC was to advise the Sponsor regarding the 
continuing safety of study participants and the continuing validity and scientific merit of the trial.  
Details regarding the safety updates are given in the Data Monitoring Committee Charter.  No 
interim safety analyses were in fact performed.
CHANGES OF ANALYSIS FROM PROTOCOL
The CSP does not specify eGFR as an endpoint, nor is it provided by the laboratory. However, 
since eGFR could provide important information it will be derived and analyzed as stated in 
Section 4.2.4.5 of this SAP.
In addition to the protocol-specified analysis, hypoglycemia will be summarized by baseline 
sulfonylurea use (yes/no) and treatment. 
No Generalized Linear Mixed Model (GLMM) analysis will be done using the binary HbA1c 
outcome (achieved vs. not achieved HbA1c goal) as the dependent variable. 
No per-protocol analysis for supportive analyses will be done.
Due to the lack of data and extent of missing data, efficacy analyses will be pooled across the 5 µg 
and 10 µg twice daily exenatide doses for statistical testing (Total EBID). Thus, the Fisher 
Protected Testing produced for the primary analysis will not be required.
For the analysis of SMBG, pre and post measurement for the same meal (lunch/dinner) is changed 
to be generically 2 main meals (i.e. allowing breakfast) and changed to allow data from consecutive 
days to be used (as many patients had only consecutive days data recorded).
Due to lack of data, plasma exenatide concentrations and antibodies will only be listed.


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REFERENCES
Matthews et al 1985
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC.  Homeostasis 
model assessment: insulin resistance and β-cell function from fasting plasma glucose and 
insulin concentrations in man. Diabetologia 28(7):412-419.
Molenberghs and Kenward, 2007
Molenberghs and M.G Kenward. Missing Data in Clinical Studies, p221. John Wiley and Sons, 
2007
Rubin, 1987
Rubin D. Multiple Imputation for Nonresponse in Surveys. John Wiley and Sons, 1987
Schwartz, 2009
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. J Am Soc 
Nephrol. 2009 Mar;20(3):629-37
Levey et al, 2009
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T, Coresh J. A New Equation to Estimate Glomerular Filtration Rate. 
Ann Intern Med. 2009; 150:604-612. 
2000 CDC Growth Charts
2000 CDC Growth Charts for the United States: Methods and Development
http://www.cdc.gov/growthcharts/cdc_charts.htm


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APPENDIX
Appendix 1
Study schedule – treatment period 


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Appendix 2
Study schedule – long-term safety follow-up period


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Appendix 3
Partial date conventions for AEs
Missing type
Action
If only the day part of the AE onset date is 
missing 
If the month and year are the same as that of 
first dose of study medication, the date of first 
dose of study medication will be used as the 
onset date of the AE.  Otherwise, the first day 
of the month will be used to complete the onse
date of the AE  
If the day and month parts of the AE onset 
date are missing 
If the year is the same as that of the first dose 
of study medication, the date of the first dose 
of study medication will be used as the onset 
date of the AE.  Otherwise, January 1st will be 
used to complete the onset date of the AE.
If the AE onset date is completely missing and
end date missing, or after first dose of study 
medication
The date of the first dose of study medication 
will be used as the onset date of the AE.
If only the day part of the AE end date is 
missing 
The last day of the month will be used to 
complete the end date of the AE.  
If the day and month parts of the AE end date
are missing
December 31st will be used to complete the end
date of the AE.  
If the end date of the AE is completely missing 
and the AE is not ongoing, and the onset date of 
the AE occurs after the date of the first dose of 
study medication, 
Then the onset date of the AE will be used as 
the AE end date.  Otherwise, the date of the 
first dose of study medication will be used as 
the AE end date.


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Appendix 4
Partial date conventions for CMs
START 
DATE
STOP 
DATE
Action
Known
Known
If stop date < study med start date, assign as pre-treatment 
If stop date ≥ study med start date and start date < study med 
start date, assign as prior concomitant 
If stop date ≥ study med start date and start date < study med 
stop date and start date ≥ study med start date, assign as new 
concomitant
If start date ≥ study med stop date, assign as post-treatment
Partial
Impute stop date as latest possible date (ie, last day of month if 
day unknown or 31st December if day and month are unknown), 
then:
Follow the same algorithm above for a known start date and 
known stop date.
Missing
If stop date is missing could never be assumed a pre-treatment 
medication
If start date < study med start date, assign as prior concomitant 
If start date ≥ study med start date and start date < study med 
stop date, assign as new concomitant
If start date ≥ study med stop date, assign as post-treatment
Partial
Known
Impute start date as earliest possible date (ie, first day of month 
if day unknown or 1st January if day and month are unknown), 
then:
Follow the same algorithm above for a known start date and 
known stop date.
Partial
Impute start date as earliest possible date (ie, first day of month 
if day unknown or 1st January if day and month are unknown) 
and impute stop date as latest possible date (ie, last day of 
month if day unknown or 31st December if day and month are 
unknown), then:
Follow the same algorithm above for a known start date and 
known stop date.


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START 
DATE
STOP 
DATE
Action
Missing
Impute start date as earliest possible date (ie, first day of month 
if day unknown or 1st January if day and month are unknown), 
then:
If stop date is missing could never be assumed a pre-treatment 
medication
Follow the same algorithm above for a known start date and 
missing stop date.
Missing
Known
If stop date < study med start date, assign as pre-treatment
If stop date ≥ study med start date, assign as prior concomitant
Partial
Impute stop date as latest possible date (ie, last day of month if 
day unknown or 31st December if day and month are unknown), 
then:
Follow the same algorithm above for a missing start date and 
known stop date.
Missing
Assign as prior concomitant


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Appendix 5
Preferred terms for potentially immune-related AEs
Allergic bronchitis
Immediate post-injection 
reaction
Rash
Allergic colitis
Injection site dermatitis
Rash erythematous
Allergic cough
Injection site eczema
Rash follicular
Allergic cystitis
Injection site erythema
Rash generalised
Allergic keratitis
Injection site 
hypersensitivity
Rash macular
Allergic oedema
Injection site induration
Rash maculo-papular
Allergic otitis media
Injection site inflammation
Rash maculovesicular
Allergic pharyngitis
Injection site macule
Rash papular
Allergic respiratory 
symptom
Injection site nodule
Rash pruritic
Alveolitis allergic
Injection site oedema
Rash pustular
Anaphylactic reaction
Injection site papule
Rash vesicular
Anaphylactic shock
Injection site 
photosensitivity reaction
Reaction to excipient
Anaphylactoid reaction
Injection site pruritus
Reaction to preservatives
Anaphylactoid shock
Injection site pustule
Reversible airways 
obstruction
Angioedema
Injection site rash
Scleral oedema
Arthralgia
Injection site reaction
Scleritis allergic
Arthritis
Injection site recall reaction
Skin oedema
Arthritis allergic
Injection site streaking
Intestinal angioedema
Asthma
Injection site swelling
Stevens-Johnson syndrome
Auricular swelling
Injection site urticaria
Stridor
Bronchial hyperreactivity
Injection site vesicles
Suffocation feeling
Bronchial oedema
Joint effusion
Swelling face
Bronchospasm
Joint swelling
Swollen tongue
Circumoral oedema
Laryngeal obstruction
Throat tightness
Conjunctival oedema
Laryngeal oedema
Tongue oedema
Corneal oedema
Laryngitis allergic
Tongue pruritus
Dermatitis
Laryngotracheal oedema
Toxic epidermal necrolysis


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Dermatitis allergic
Lip oedema
Toxic skin eruption
Diffuse cutaneous 
mastocytosis
Lip swelling
Tracheal obstruction
Drug eruption
Local swelling
Tracheal oedema
Drug hypersensitivity
Localised oedema
Type I hypersensitivity
Drug reaction with 
eosinophilia 
and systemic symptoms
Mechanical urticaria
Type II hypersensitivity
Encephalopathy allergic
Nasal oedema
Type III immune complex 
mediated reaction
Eosinophilia
Nephritis allergic
Type IV hypersensitivity 
reaction
Eosinophilic oesophagitis
Oculorespiratory syndrome
Urticaria
Epiglottic oedema
Oedema mouth
Urticaria cholinergic
Erythema multiforme
Oedema mucosal
Urticaria chronic
Erythema nodosum
Oesophageal oedema
Urticaria contact
Eye oedema
Orbital oedema
Urticaria papular
Eye swelling
Oropharyngeal swelling
Urticaria physical
Eyelid oedema
Palatal oedema
Urticaria pigmentosa
Face oedema
Periarthritis
Urticaria pressure
Gastrointestinal oedema
Periorbital oedema
Urticaria thermal
Gingival oedema
Pharyngeal oedema
Urticaria vesiculosa
Gingival swelling
Photosensitivity allergic 
reaction
Urticaria vibratory
Haemorrhagic urticaria
Photosensitivity reaction
Visceral oedema
Hereditary angioedema
Pruritus
Wheezing
Hypersensitivity
Pruritus allergic
Idiopathic urticaria
Pruritus generalised


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Appendix 6
Criteria for potentially clinically significant laboratory tests
Parameter
Lower Limit 
Upper Limit
Percent Decrease 
from Baseline
Percent Increase 
from Baseline
Hematology
Hemoglobin
<0.6 x LLN
>1.3 x ULN
> 25%
>30%
Leukocytes (WBC)
<0.5 x LLN
>2.0 x ULN
> 60%
>100%
Chemistry
Alanine aminotransferase 
(ALT)
N/A
>3.0 x ULN
N/A
>300%
Aspartate aminotransferase
(AST)
N/A
>3.0 x ULN
N/A
>300%
Creatinine
N/A
>2.0 × ULN
N/A
>100%
Total bilirubin
N/A
>2.0 x ULN
N/A
>300%
LLN: Lower limit of normal value provided by the central laboratory
ULN: Upper limit of normal value provided by the central laboratory


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Appendix 7
Criteria for potentially significant vital signs 
Age: 6 - <12 years
Marked abnormality criteria
Vital signs variables
Units
Low
High
Heart Rate
Value
bpm
<60
>95 
Value – Baseline
bpm
>20
Baseline – Value
bpm
>10
Systolic Blood Pressure
Value
mmHg
<100
>120
Value – Baseline
mmHg
>10
Baseline – Value
mmHg
>10
Diastolic Blood Pressure
Value
mmHg
<60
>75
Value – Baseline
mmHg
>10
Baseline – Value
mmHg
>10
Age: ≥12 years
Marked abnormality criteria
Vital signs variables
Units
Low
High
Heart Rate
  Value
bpm
<55
>85 
  Value – Baseline
bpm
>20
  Baseline – Value
bpm
>10
Systolic Blood Pressure
  Value
mmHg
<110
>135
  Value – Baseline
mmHg
>10
  Baseline – Value
mmHg
>10
Diastolic Blood Pressure
  Value
mmHg
<65
>85
  Value – Baseline
mmHg
>10


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Marked abnormality criteria
Vital signs variables
Units
Low
High
Heart Rate
  Baseline - Value
mmHg
>10


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