Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL). A Randomized, Placebo Controlled Clinical Trial to Evaluate Cardiovascular Outcomes After Treatment With Exenatide Once Weekly in Patients With Type 2 Diabetes Mellitus.
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: AstraZeneca

1
PPD
PPD

7$%/(2)&217(176
7,7/(3$*( 
7$%/(2)&217(176 
35272&2/$0(1'0(176800$5<2)&+$1*(6 
/,672)$%%5(9,$7,216 
&/,1,&$/678'<35272&2/ 
 
,1752'8&7,21 
 
%DFNJURXQG 
 
5DWLRQDOHIRU&RQGXFWRIWKH6WXG\ 
 
678'<2%-(&7,9(6$1'+<327+(6(6 
 
3ULPDU\2EMHFWLYH 
 
6HFRQGDU\2EMHFWLYHV 
 
$GGLWLRQDO2EMHFWLYHV 
 
75,$/*29(51$1&( 
 
75,$/'(6,*1 
 
'HVLJQ'HVFULSWLRQ 
 
7ULDO'XUDWLRQ 
 
3RVW7ULDO$FFHVVWR7KHUDS\ 
 
75,$/3238/$7,21 
 
,QFOXVLRQ&ULWHULD 
 
([FOXVLRQ&ULWHULD 
 
75,$/3/$1 
 
7ULDO3URFHGXUHV2YHUYLHZ 
 
3UH(QUROOPHQWDQG(QUROOPHQW3URFHGXUHV 
 
0HWKRGRI$VVLJQLQJ3DWLHQWVWR7UHDWPHQW*URXSV9LVLW 
 
7UHDWPHQWV$GPLQLVWHUHG 
 
&RQFRPLWDQW7KHUDS\ 
 
3UHFDXWLRQVWR0LQLPL]H5DWHVRI+\SRJO\FHPLD 
 
/DERUDWRU\DQG$QWKURSRPHWULF0HDVXUHPHQWV 
 
&DOFLWRQLQ6DPSOH&ROOHFWLRQ 
 
*HQHWLFDQG%LRPDUNHU6DPSOH&ROOHFWLRQ 
 
5HVRXUFH8WLOL]DWLRQ4XDOLW\RI/LIH'DWDIRU(FRQRPLF(YDOXDWLRQ 
2

 
7HPSRUDU\RU3HUPDQHQW'LVFRQWLQXDWLRQRI7ULDO0HGLFDWLRQ 
 
3HUPDQHQW'LVFRQWLQXDWLRQRI7ULDO0HGLFDWLRQ3HU3URWRFRO 
 
7ULDO7HUPLQDWLRQ9LVLW 
 
3RVW7UHDWPHQW7HOHSKRQH&RQWDFW 
 
:LWKGUDZDORI&RQVHQW 
 
/RVWWR)ROORZ8S 
 
%UHDNLQJWKH%OLQG 
 
7ULDO+RWOLQH 
 
75,$/0(',&$7,216 
 
7ULDO0HGLFDWLRQ6XSSO\ 
 
)RUPXODWLRQ3DFNDJLQJDQG6WRUDJH 
 
'LVSHQVLQJRI7ULDO0HGLFDWLRQ 
 
'RVH$GPLQLVWUDWLRQ3URFHGXUHV5RXWHDQG6FKHGXOH 
 
5DQGRPL]DWLRQ6FKHGXOHDQG%OLQGLQJ3URFHGXUHV 
 
'UXJ$FFRXQWDELOLW\ 
 
()),&$&<$66(660(176 
 
3ULPDU\(IILFDF\(QGSRLQW 
 
6HFRQGDU\(IILFDF\(QGSRLQWV 
 
$GGLWLRQDO(IILFDF\(QGSRLQWV 
 
67$7,67,&$/0(7+2'6 
 
%DVHOLQH&KDUDFWHULVWLFV 
 
6DPSOH6L]H 
 
5DQGRPL]DWLRQ 
 
3ULPDU\+\SRWKHVLV 
 
3ULPDU\$QDO\VLV 
 
6HFRQGDU\(IILFDF\$QDO\VHV 
 
$QDO\VLV3RSXODWLRQV 
 
,QWHQW7R7UHDW3RSXODWLRQ 
 
3HU3URWRFRO3RSXODWLRQ 
 
6DIHW\3RSXODWLRQ 
 
6DIHW\'DWD$QDO\VLV 
 
6XEJURXS$QDO\VHV 
 
,QWHULP$QDO\VHV 
3

 
(FRQRPLF$QDO\VLV 
 
6$)(7<$66(660(176 
 
'HILQLWLRQV 
 
$GYHUVH(YHQW$VVHVVPHQW 
 
5HFRUGLQJDQG5HSRUWLQJ$GYHUVH(YHQWV 
 
5HFRUGLQJ$GYHUVH(YHQWV 
 
6DIHW\5HSRUWLQJ 
 
6SRQVRU5HVSRQVLELOLW\IRU5HSRUWLQJ6HULRXV$GYHUVH(YHQWV 
 
&DOFLWRQLQ0RQLWRULQJ 
 
2YHUGRVH 
 
'HILQLWLRQRIDQ2YHUGRVHIRU7KLV3URWRFRO 
 
5HSRUWLQJRI2YHUGRVH 
 
5HSRUWLQJRI3UHJQDQF\ 
 
8QEOLQGLQJ 
 
(7+,&$/$1'/(*$/$63(&76 
 
*HQHUDO,QIRUPHG&RQVHQW 
 
&RQVHQWDQG&ROOHFWLRQRI6SHFLPHQVIRU*HQHWLFDQG*HQRPLF$QDO\VLV 
 
&RQVHQWDQG&ROOHFWLRQRI%LRPDUNHU6SHFLPHQV 
 
(WKLFV&RPPLWWHHRU,QVWLWXWLRQDO5HYLHZ%RDUG 
 
(WKLFDO&RQGXFWRIWKH6WXG\ 
 
5HJXODWRU\$XWKRULW\$SSURYDOV$XWKRUL]DWLRQV 
 
&RQILGHQWLDOLW\ 
 
5HFRUGV 
 
5HFRUGV5HWHQWLRQ 
 
&DVH5HSRUW)RUPV 
 
75,$/0$1$*(0(17*29(51$1&(&200,77((6 
 
([HFXWLYH&RPPLWWHH(& 
 
2SHUDWLRQV&RPPLWWHH2& 
 
5HPLWRI2SHUDWLRQV&RPPLWWHH 
 
'DWD6DIHW\0RQLWRULQJ%RDUG'60% 
 
&OLQLFDO(YHQWV&RPPLWWHH&(& 
 
6WUDWHJLF$GYLVRU\&RPPLWWHH 
4


',6&/2685(2)'$7$38%/,&$7,216$1'&/,1,&$/678'<
5(3257

5()(5(1&(6
/,672)$33(1',&(6
$SSHQGL[&OLQLFDO(YHQWV/LVW 
$SSHQGL[7ULDO3ODQ3URWRFRO%&% 
$SSHQGL[3URWRFRO$PHQGPHQW6XPPDU\RI&KDQJHV
$SSHQGL[3URWRFRO$PHQGPHQW6XPPDU\RI&KDQJHV 
$SSHQGL[3URWRFRO$PHQGPHQW6XPPDU\RI&KDQJHV 
$SSHQGL[3URWRFRO$PHQGPHQW6XPPDU\RI&KDQJHV 
$SSHQGL[3URWRFRO$PHQGPHQW6XPPDU\RI&KDQJHV 
5

EXSCEL Protocol Amendment 06
PROTOCOL AMENDMENT 06: SUMMARY OF CHANGES
Exenatide QW Clinical Study Protocol D5551C00003, BCB109
PROTOCOL TITLE:
A 
RANDOMIZED, 
PLACEBO 
CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE CARDIOVASCULAR OUTCOMES AFTER TREATMENT WITH EXENATIDE ONCE 
WEEKLY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Protocol Number:
D5551C00003, BCB109
Amendment Number:
06
Amendment Purpose:
Date: 09 March 2016
The purpose of this non-substantial amendment is two-fold:
1.
to update the protocol based on US Food and Drug Administration (FDA) recommendation for the study
analysis, and
2.
to update the procedures for handling all Clinical Events (as defined in Protocol Appendix 1) to be
consistent throughout the study.
As per the protocol, the EXenatide Study of Cardiovascular Event Lowering Trial (EXSCEL) Executive Committee 
will monitor the accrual of the aggregate number of adjudicated primary endpoint events (confirmed cardiovascular-
related death, nonfatal myocardial infarction or nonfatal stroke) and will determine the primary endpoint event cut-
off date (i.e., the date at which the anticipated number of events is expected to have accrued).  The primary 
statistical analysis was initially planned to include all adjudicated cardiovascular events with onset dates up to and 
including the primary endpoint event cut-off date.  As per FDA recommendation, the primary statistical analysis has 
been updated to include all adjudicated primary endpoint events with onset dates up to and including the Trial 
Termination Visit date (rather than the primary endpoint event cut-off date).  Any events occurring between the 
Trial Termination Visit and the safety follow-up phone call (scheduled 70 days after last dose of study medication) 
will not be adjudicated and will not be included in the primary analysis, as agreed by the FDA.  The FDA also made 
recommendations for updating the censoring strategy, which has been incorporated in the protocol amendment.
The procedure for serious adverse event (SAE) reporting described in Protocol Section 10.3.1 and Protocol 
Appendix 1 will be updated to reflect that Clinical Events (as defined in Protocol Appendix 1) occurring after the 
primary endpoint event cut-off date (e.g., during either the time period up to the Trial Termination Visit or during 
the safety follow-up period) will continue to be collected and reported in the same way as they have been throughout 
the study.  There will be no switch to collecting and managing Clinical Events as SAEs after the primary endpoint 
cut-off date as previously described in the protocol.  
This amendment will also address administrative changes in the study.
Administrative Changes:
!
To inform that as of January 2015, the EXSCEL Executive Committee co-chair, 
, has
been replaced by 
!
To inform that while Amylin LLC remains the sponsor for the study, as of 1 February 2014, Amylin LLC is
wholly owned by AstraZeneca.
!
To inform that as part of the ownership transfer of Amylin, a new study code D5551C00003 was generated to
comply with AstraZeneca internal procedures.  Trial reference codes H80-MC-GWDQ, BCB109 and
D5551C00003 refer to the same clinical study, known as EXSCEL.
In the table below, the changes in individual sections are presented in the revised text with all deletions addressed as 
a strikethrough and all additions shown in bold.
6
PPD
PPD

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
3 Trial 
Governance
EXSCEL is a multinational pragmatic trial that 
will be conducted at approximately 800 sites 
worldwide.  It will be run jointly by the Duke 
Clinical Research Institute (DCRI) and the 
University of Oxford Diabetes Trials Unit 
(DTU) Academic Research Organizations 
(AROs), in an academic collaboration with 
Amylin Pharmaceuticals, LLC (Amylin), a 
wholly owned subsidiary of Bristol-Myers 
Squibb.  EXSCEL will be Co-Chaired by 
 
 and sponsored 
and funded by Amylin.
The EXSCEL Executive Committee (EC) will 
have overall responsibility for the oversight and 
management of the trial (Figure 1).  The EC 
will consist of senior independent academic 
representatives who are experts in their field 
and sponsor representatives.  It will be 
Co-Chaired
 
EXSCEL is a multinational pragmatic trial that 
will be conducted at approximately 800 sites 
worldwide. It will be run jointly by the Duke 
Clinical Research Institute (DCRI) and the 
University of Oxford Diabetes Trials Unit 
(DTU) Academic Research Organizations 
(AROs), in an academic collaboration with 
Amylin Pharmaceuticals, LLC (Amylin), a 
wholly owned subsidiary of AstraZeneca
Bristol-Myers Squibb. EXSCEL will be Co-
Chaired by
 
sponsored and funded by 
Amylin.
The EXSCEL Executive Committee (EC) will 
have overall responsibility for the oversight and 
management of the trial (Figure 1). The EC will 
consist of senior independent academic 
representatives who are experts in their field and 
sponsor representatives. It will be Co-Chaired 
by 
4.1 Design 
Description
Paragraph 2
Approximately 14,000 patients meeting all 
enrollment criteria will be recruited in to the 
trial over approximately a five year period, 
randomly allocated to treatment with either 
EQW 2 mg or matching placebo subcutaneous 
injections once weekly in a 1:1 ratio, and 
followed until the requisite number of primary 
endpoint events have been reported.  The trial is 
planned to continue until 1360 patients with 
positively adjudicated primary endpoint events 
have been accrued, or until the independent 
Data Safety Monitoring Board (DSMB) advises 
otherwise.  It is anticipated that the EXSCEL 
Executive Committee will monitor the accrual 
of the aggregate number of adjudicated primary 
endpoint events and will determine the primary 
endpoint event cut-off date (i.e., the date at 
which the anticipated number of events is 
expected to have accrued); all patients will be 
expected to have follow-up through this date 
(see Section 6).
Approximately 14,000 patients meeting all 
enrollment criteria will be recruited in to the trial 
over approximately a five year period, randomly 
allocated to treatment with either EQW 2 mg or 
matching placebo subcutaneous injections once 
weekly in a 1:1 ratio, and followed until the 
requisite number of primary endpoint events 
have been reported. The trial is planned to 
continue until 1360 patients with positively 
adjudicated primary endpoint events have been 
accrued, or until the independent Data Safety 
Monitoring Board (DSMB) advises otherwise. It 
is anticipated that the EXSCEL Executive 
Committee will monitor the accrual of the 
aggregate number of adjudicated primary 
endpoint events and will determine the primary 
endpoint event cut-off date (i.e., the date at 
which the anticipated number of events is 
expected to have accrued).  Based on the 
primary endpoint event cut-off date, a 
window of time for conduct of the Trial 
Termination Visit will be established; all 
patients will be expected to have follow-up 
through this date until the Trial Termination 
Visit (see Section 6).
7
PPD
PPD
PPD
PPD

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
4.2 Trial 
Duration
It is anticipated that enrollment will occur over 
approximately a five year period, and that an 
additional 2 to 3 years may be required to 
accumulate the requisite number of patients 
with positively adjudicated primary endpoint 
events, for a total duration of up to 
approximately 7.5 years, unless the trial is 
terminated earlier. All patients who discontinue 
study medication, but have not withdrawn 
consent to participate in the study, will be 
followed up, if possible, for the full study 
period and will have their vital status 
ascertained, if possible, as of the data cut-off 
date for primary endpoint events.
It is anticipated that enrollment will occur over 
approximately a five 5-year period, and that an 
additional 2 to 3 years may be required to 
accumulate the requisite number of patients with 
positively adjudicated primary endpoint events, 
for a total duration of up to approximately 
7.5 years, unless the trial is terminated earlier. 
All patients who discontinue study medication, 
but have not withdrawn consent to participate in 
the study, will be followed up, if possible, for the 
full study period and will have their vital status 
ascertained, if possible, as of the Trial 
Termination Visit data cut-off date for primary 
endpoint events.
6.1 Trial 
Procedures -
Overview
Paragraph 3:
The trial is planned to continue until 
1360 patients with positively adjudicated 
primary endpoint events have been accrued.  It 
is anticipated that the EXSCEL Executive 
Committee will monitor the accrual of the 
aggregate number of adjudicated primary 
endpoint events and will determine the primary 
endpoint event cut-off date (i.e., the date at 
which the anticipated number of events is 
expected to have accrued; all patients will be 
expected to have follow-up through this date).  
Based on the primary endpoint event cut-off 
date, a window of time for conduct of the Trial 
Termination Visit will be established.
Paragraph 3:
The trial is planned to continue until 
1360 patients with positively adjudicated 
primary endpoint events have been accrued. It is 
anticipated that the EXSCEL Executive 
Committee will monitor the accrual of the 
aggregate number of adjudicated primary 
endpoint events and will determine the primary 
endpoint event cut-off date (i.e., the date at 
which the anticipated number of events is 
expected to have accrued) all patients will be 
expected to have follow-up through this date).
Based on the primary endpoint event cut-off 
date, a window of time for conduct of the Trial 
Termination Visit will be established. All 
patients will be expected to have follow-up 
until this visit.
8

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
Paragraphs 5 and 6:
After the Trial Termination Visit patients will 
be contacted by telephone to check for any 
serious adverse experiences and hospitalizations 
that occurred within 70 days after the 
administration of the last dose of trial 
medication.  Patients who have discontinued 
trial medication 70 or more days prior to the 
Trial Termination Visit will not need to have 
the telephone contact visit performed.  These 
patients will have their final assessment of 
serious adverse experiences and hospitalizations 
completed at the Trial Termination Visit.
Note that all serious adverse experiences, 
hospitalizations, and reportable study events 
with an onset date after the primary endpoint 
event cut-off date established by the study 
Executive Committee will be managed as 
serious adverse experiences (see Section 
10.3.1).
Paragraphs 5 and 6:
After the Trial Termination Visit patients will be 
contacted by telephone to check for any Clinical 
Events, serious adverse experiences and 
hospitalizations that occurred within 70 days 
after the administration of the last dose of trial 
medication. Note that any events occurring 
between the Trial Termination Visit and the 
safety follow-up phone call will not be 
adjudicated and will not be included in the 
primary analysis. Patients who have 
discontinued trial medication 70 or more days 
prior to the Trial Termination Visit will not need 
to have the safety follow-up telephone contact 
visit performed. These patients will have their 
final assessment of Clinical Events, serious 
adverse experiences and hospitalizations 
completed at the Trial Termination Visit.
Clinical Events (as defined in Protocol 
Appendix 1) will continue to be collected and 
reported in the same way as they have been 
throughout the entire study (i.e., prior to the 
cut-off date) Note that all serious adverse 
experiences, hospitalizations, and reportable 
study events with an onset date after the primary 
endpoint event cut-off date established by the 
study Executive Committee will be managed as 
serious adverse experiences (see Section 10.3.1).
9

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
6.13 Trial 
Termination Visit
Investigators will be informed by the DCRI and 
DTU Coordinating Centers as to when the Trial
Termination Visit is to be completed, and will 
schedule all patients for the Trial Termination
Visit. Based on the primary endpoint event cut-
off date, a window of time for conduct of the
Trial Termination Visits will be established; this 
window will be a period of time following the
primary endpoint event cut-off date. At the 
Trial Termination Visit, all patients must be
discontinued from trial medication; the 
investigator should ensure that the patient 
receives appropriate standard of care. For 
procedural details of the Trial Termination 
Visit, refer to Appendix 2.  
….
If a patient fails to return or otherwise becomes 
difficult to contact, it is the investigator’s
responsibility to make every effort to maintain 
contact so that at the end of the trial the patient
can be located to determine status and to obtain 
necessary information for serious adverse
experience reporting and/or endpoint 
adjudication as of the primary endpoint event 
cut-off date.
Investigators will be informed by the DCRI and 
DTU Coordinating Centers as to when the Trial
Termination Visit is to be completed, and will 
schedule all patients for the Trial Termination
Visit. Based on the primary endpoint event cut-
off date, a window of time for conduct of the
Trial Termination Visits will be established; this 
window will be a period of time following the 
primary endpoint event cut-off date. All patients 
will be expected to have follow-up until this 
visit. At the Trial Termination Visit, all patients 
must be discontinued from trial medication; the 
investigator should ensure that the patient 
receives appropriate standard of care. For 
procedural details of the Trial Termination Visit, 
refer to Appendix 2.  
….
If a patient fails to return or otherwise becomes 
difficult to contact, it is the investigator’s
responsibility to make every effort to maintain 
contact so that at the end of the trial the patient
can be located to determine status and to obtain 
necessary information for serious adverse
experience reporting and/or endpoint 
adjudication as of the Trial Termination Visit
primary endpoint event cut-off date.
6.14 Post-
Treatment 
Telephone 
Contact
After the Trial Termination Visit, patients will 
be contacted by telephone to check for any
serious adverse experiences and hospitalizations 
that occurred within 70 days after the
administration of the last dose of trial 
medication. For patients who have been 
discontinued from trial medication for more 
than 70 days as of the Trial Termination Visit, 
the Trial Termination Visit will be the final 
study follow-up. Note that all serious adverse 
experiences, hospitalizations, and reportable 
study events with an onset date after the 
primary endpoint event cut-off date established 
by the study Executive Committee will be 
managed as serious adverse experiences (see 
Section 10.3.1).
After the Trial Termination Visit, patients will 
be contacted by telephone to check for any 
Clinical Events, serious adverse experiences 
and hospitalizations that occurred within 70 days 
after the administration of the last dose of trial 
medication. For patients who have been 
discontinued from trial medication for more than 
70 days as of the Trial Termination Visit, the 
Trial Termination Visit will be the final study 
follow-up. Clinical Events (as defined in 
Protocol Appendix 1) will continue to be 
collected and reported in the same way as 
they have been throughout the entire study
(i.e., prior to the cut-off date) Note that all 
serious adverse experiences, hospitalizations, 
and reportable study events with an onset date 
after the primary endpoint event cut-off date 
established by the study Executive Committee 
will be managed as serious adverse experiences
(see Section 10.3.1).
8.3 Additional 
Efficacy 
Endpoints
•
Number of episodes of severe 
hypoglycemia requiring medical assistance.
•
Number of episodes of severe hypoglycemia 
requiring medical assistance.
10

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
9.5 Primary 
Analysis
The primary statistical analysis will be based 
upon adjudicated CV events with patients who
discontinue prematurely from treatment 
followed until the end of the study, i.e. until the 
requisite number of primary composite events 
has been accrued. It is anticipated that the 
Executive Committee will monitor the accrual 
of the aggregate number of primary composite 
CV events to determine the primary endpoint 
event cut-off date (i.e., the date at which the 
anticipated number of events is expected to 
have accrued). All patients will be expected to 
have follow-up through this date. Analysis of 
the primary composite cardiovascular outcome 
will be based on the time from randomization to 
the occurrence of the first event, with patients 
analyzed according to their randomized 
treatment. The primary analysis will include all 
adjudicated CV events with onset dates up to 
and including the primary endpoint event cut-
off date.
The primary statistical analysis will be based 
upon adjudicated CV events with patients who 
discontinue prematurely from treatment followed 
until the end of the study, i.e. the Trial 
Termination Visit and until the requisite 
number of primary composite events has been 
accrued. It is anticipated that the Executive 
Committee will monitor the accrual of the 
aggregate number of primary composite CV 
events to determine the primary endpoint event 
cut-off date (i.e., the date at which the 
anticipated number of events is expected to have 
accrued). Based on the primary endpoint 
event cut-off date, a window of time for 
conduct of the Trial Termination Visit will be 
established.  All patients will be expected to 
have follow-up through this date until this visit. 
Analysis of the primary composite 
cardiovascular outcome will be based on the 
time from randomization to the occurrence of the 
first event, with patients analyzed according to 
their randomized treatment. The primary 
analysis will include all adjudicated CV events 
with onset dates up to and including the Trial 
Termination Visit primary endpoint event cut-
off date. Note that any event occurring 
between the Trial Termination Visit and the 
safety follow-up date (70 days after the 
administration of the last dose of trial 
medication) will not be adjudicated and will 
not be included in the primary analysis.  
Events occurring during this period will be 
summarized descriptively.  
9.7.1 Intent-To-
Treat Population
The ITT population consists of all randomized 
patients.  Evaluation will include all events 
which occurred from randomization to the 
primary endpoint event cut-off date, regardless 
of the time interval between patient 
discontinuation of study drug and final contact.  
Patients who do not have any events during the 
study will be censored at the primary endpoint 
event cut-off date.  Every effort will be made to 
collect CV events through the primary endpoint 
event cut-off date even in those who have 
discontinued study medication or the study.  For 
the ITT population, patients will be analyzed as 
randomized.
The ITT population consists of all randomized 
patients. Evaluation will include all events which 
occurred from randomization to the Trial 
Termination Visit primary endpoint event cut-
off date, regardless of the time interval between 
patient discontinuation of study drug and final 
contact.  Patients who do not have any events 
during the study will be censored at the Trial 
Termination Visit primary endpoint event cut-
off date.  Every effort will be made to collect CV 
events through until the Trial Termination 
Visit primary endpoint event cut-off date even in 
those who have discontinued study medication 
or the study.  For the ITT population, patients 
will be analyzed as randomized.
11

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
9.7.1.1 On-
Treatment 
Analysis
An on-treatment analysis using the ITT 
population will be performed for the primary 
and secondary analyses as sensitivity analyses.
This analysis will include only those events that 
occurred within 70 days of the last dose of study 
medication or the primary endpoint event cut-
off date, whichever occurs first. The patients 
will be analyzed according to the treatment 
group to which they were randomized.
An on-treatment analysis using the ITT 
population will be performed for the primary and 
some secondary endpoints as sensitivity 
analyses. This analysis will include only those
events that occurred through within 70 days of
the last dose of study medication or the Trial 
Termination Visit primary endpoint event 
cutoff date, whichever occurs first. The patients 
will be analyzed according to the treatment 
group to which they were randomized. The 
on-treatment censoring scheme will also be 
applied for analysis for on-treatment + n 
days, where n=7, 30, and 70.
9.7.2 Per-
Protocol 
Population
The Per-Protocol population consists of all 
randomized patients who have taken at least one 
dose of study medication and will include in 
their analysis all data collected prior to any 
major protocol violations (or primary endpoint 
event cut-off date, whichever occurs first), such 
as:
!
Initiation of an open-label prohibited 
medication, i.e. a GLP-1 receptor agonist. 
Evaluation will include all data up to the 
day of the initiation of the prohibited 
medication.
!
Early discontinuation from study 
medication.  Evaluation will include events 
which occurred from randomization to 70 
days after the last dose of study medication 
or the primary endpoint event cut-off date, 
whichever occurs first.
The Per-Protocol population consists of all 
randomized patients who have taken at least one 
dose of study medication and will include in 
their analysis all data collected prior to any 
major protocol violations (or the Trial 
Termination Visit primary endpoint event cut-
off date, whichever occurs first), such as:
!
Initiation of an open-label prohibited 
medication, i.e. a GLP-1 receptor agonist. 
Evaluation will include all data up to the day 
of the initiation of the prohibited 
medication.
!
Early discontinuation from study 
medication.  Evaluation will include events 
which occurred from randomization to 70 
days after the last dose of study medication 
or the Trial Termination Visit primary 
endpoint event cut-off date, whichever 
occurs first.
9.8 Safety Data 
Analysis
Safety parameters will be summarized and 
presented in tables for the safety population.  
Serious adverse events will be listed and 
tabulated by high level group terms (HGLT), as 
assigned by the MedDRA dictionary.
Safety parameters will be summarized and 
presented in tables for the safety population.
Serious adverse events will be listed and 
tabulated as described in the SAP by high level 
group terms (HGLT), as assigned by the 
MedDRA dictionary.
12

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
9.9 Subgroup 
Analyses
Subgroup analyses for the primary CV 
composite endpoint will be performed on the 
ITT population in order to explore whether the 
treatment effect on the risk of developing CV 
events is consistent across subgroups.  The 
following subgroups will be assessed:
!
Class of AHA therapy at entry (mono or 
combination)
!
Race (Black, Caucasian, Asian, Other)
!
Region (North/South America, Europe or 
South Africa, Rest of world)
!
Gender (Male, Female)
!
Age (<65 or ≥65)
!
Baseline HbA1c (<8.0% or ≥8/0%)
!
Baseline BMI (<30 or ≥30 kg/m2)
!
Duration of diabetes (<5 years or ≥5 years)
!
Baseline eGFR (<60 mL/min or ≥60 
mL/min)
!
History of previous cardiovascular event 
(e.g., previous MI or stroke)
Subgroup analyses for the primary CV 
composite endpoint will be performed on the 
ITT population in order to explore whether the 
treatment effect on the risk of developing CV 
events is consistent across subgroups.  The 
following subgroups will be assessed:
!
Class of AHA therapy at entry (mono or 
combination)
!
Race (Indian [American] or Alaska 
Native, Asian, Black, Native Hawaiian or 
Other Pacific Islander, White, Hispanic, 
Other (Black, Caucasian, Asian, Other)
!
Geographic region (North America, Latin 
America, Europe and Asia Pacific) 
(North/South America, Europe or South 
Africa, Rest of world)
!
Gender (Male, Female)
!
Age (<65 or ≥65)
!
Baseline HbA1c (<8.0% or ≥8./0%)
!
Baseline BMI (<30 or ≥30 kg/m2)
!
Duration of diabetes (<5, 5-14, ≥15 years or 
≥5 years)
!
eGFR groups (in mL/min/1.73 m2)
∀
(<60 or ≥60)
∀
Stage 1: 90+, Stage 2: 60-89, Stage 3: 
30-59, Stage 3a: 45-59, 
Stage 3b: 30-44, Stage 4: 15-29, Stage 
5: <15  Baseline eGFR (<60 mL/min or 
≥60 mL/min)
!
History of previous cardiovascular event 
(e.g., previous MI or stroke)
13

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
9.11 Economic 
Analysis
The primary objective of the economic analysis 
is to collect sufficient data from the trial 
participants on resource use and quality of life 
to undertake cost-effectiveness analyses that are 
relevant to the major countries taking part in the 
study.  Resource use data on hospitalizations, 
visits and medications will be combined with 
appropriate national unit costs to calculate a 
cost per patient per year in the study.  Quality of 
life data from the EQ-5D will be combined with 
survival data to calculate quality adjusted time 
in the trial per patient.
Cost-effectiveness analyses will report the 
incremental cost per major CV outcome 
averted, CV related death averted, life-year 
gained and quality-adjusted life year gained, of 
including EQW in addition to usual care vs. 
usual care without EQW.  Analyses will be 
conducted within trial and using a lifetime 
perspective, with lifetime extrapolation 
performed using the UKPDS Outcomes Model 
or all patients still alive at the end of the study, 
using risk factor characteristics from the last 
available visit.  A full analysis plan for the 
economic analysis will be prepared and reported 
separately from this protocol.
The primary objective of the economic analysis 
is to collect sufficient data from the trial 
participants on resource use and quality of life to 
undertake cost-effectiveness analyses that are 
relevant to the major countries taking part in the 
study. Resource use data on hospitalizations, 
visits and medications will be combined with 
appropriate national unit costs to calculate a cost 
per patient per year in the study. Quality of life
data from the EQ-5D will be combined with 
survival data to calculate quality adjusted time in 
the trial per patient.
Cost-effectiveness analyses will report the 
incremental cost per major CV outcome averted, 
CV related death averted, life-year gained and 
quality-adjusted life year gained, of including 
EQW in addition to usual care vs. usual care 
without EQW. Analyses will be conducted 
within trial and using a lifetime perspective, with 
lifetime extrapolation performed using the 
UKPDS Outcomes Model or all patients still 
alive at the end of the study, using risk factor 
characteristics from the last available visit. A full 
analysis plan for the economic analysis will be 
prepared and reported separately from this 
protocol.
For the main clinical study report (CSR), the 
quality of life data will be summarized 
descriptively for baseline and changes from 
baseline by treatment.
14

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
10.3.1 Recording 
Adverse Events
SAEs will be recorded in the Clinical Events 
or SAE eCRF modules as appropriate (see 
Table 1) through the primary endpoint event 
cut-off date; ALL SAEs with onset dates 
AFTER the primary endpoint event cut-off date 
will be recorded in the SAE eCRF module. 
Guidelines for events which qualify as Clinical 
Events are provided in Appendix 1. Events to be 
recorded in the Clinical Events eCRF module 
include SAEs that are: (1) Obvious trial 
endpoints, (2) Cardiovascular Events of Interest, 
(3) Expected Events and Diabetic 
Complications.
Table 1
List of events to be recorded in each 
eCRF reporting module*
eCRF 
reporting 
module to 
be used
List of events to be recorded in this 
eCRF reporting module:
Clinical 
Event eCRF
(events with 
onset date up 
to and 
including the 
primary 
endpoint 
event cut-off 
date)
- Clinical Events that meet the criteria 
of an SAE (i.e. serious adverse event) 
and are listed in Appendix 1
- All non-serious (or serious) events 
of percutaneous coronary intervention 
(PCI), stress tests, severe 
hypoglycemia, diabetic eye disease, 
foot ulcer, microalbuminuria, 
macroalbuminuria, 
hyperlipidemia/dyslipidemia, 
hypertension, or gout
- All neoplasia events
- All pancreatitis events
SAE eCRF
- Any event meeting the criteria of an 
SAE (see Section 10.1 for definition 
of SAE) that are not listed in 
Appendix 1 and all events above with 
an onset date after the primary 
endpoint event cut-off date
- All episodes of pancreatitis
- All episodes of any type of 
neoplasia/cancer
- Any AE or SAE resulting from an 
overdose of study drug
- Any event that is recorded in the 
Clinical Event eCRF, that the 
investigator considers a SUSAR, with 
the exception of possible Primary or 
Secondary trial endpoints (i.e. all 
events listed in Appendix 1, Section I)
* Trial sites will be provided with an ‘EXSCEL 
Event Reporting’ flow chart that can be referenced 
to help identify which events should be reported in 
which eCRF reporting module.
SAEs will be recorded in the Clinical Events or 
SAE eCRF modules as appropriate (see Table 1) 
throughout the trial (including the 70 day 
safety wash-out period after last dose of study 
medication) through primary endpoint event 
cut-off date; ALL SAEs with onset dates 
AFTER the primary endpoint event cut-off date 
will be recorded in the SAE eCRF module.
Guidelines for events which qualify as Clinical 
Events are provided in Appendix 1. Events to be 
recorded in the Clinical Events eCRF module 
include SAEs that are: (1) Obvious trial 
endpoints, (2) Cardiovascular Events of Interest, 
(3) Expected Events and Diabetic 
Complications.
Table 1
List of events to be recorded in each 
eCRF reporting module*
eCRF 
reporting 
module to be 
used
List of events to be recorded in this 
eCRF reporting module:
Clinical 
Event eCRF
(events with 
onset date up 
to and 
including the 
primary 
endpoint 
event cut-off 
date)
- Clinical Events that meet the criteria 
of an SAE (i.e. serious adverse event) 
and are listed in Appendix 1
- All non-serious (or serious) events 
of percutaneous coronary intervention 
(PCI), stress tests, severe 
hypoglycemia, diabetic eye disease, 
foot ulcer, microalbuminuria, 
macroalbuminuria, 
hyperlipidemia/dyslipidemia, 
hypertension, or gout
- All neoplasia events
- All pancreatitis events
SAE eCRF
- Any event meeting the criteria of an 
SAE (see Section 10.1 for definition of 
SAE) that are not listed in Appendix 1 
and all events above with an onset date 
after the primary endpoint event cut-
off date
- All episodes of pancreatitis
- All episodes of any type of 
neoplasia/cancer
- Any AE or SAE resulting from an 
overdose of study drug
- Any event that is recorded in the 
Clinical Event eCRF, that the 
investigator considers a SUSAR, with 
the exception of possible Primary or 
Secondary trial endpoints (i.e. all 
events listed in Appendix 1, Section I)
* Trial sites will be provided with an ‘EXSCEL 
Event Reporting’ flow chart that can be referenced 
to help identify which events should be reported in 
which eCRF reporting module.
15

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
10.3.2 Safety 
Reporting
The DSMB will monitor the totality of collected 
safety data (i.e. events recorded on both the 
Clinical Events and SAE eCRFs) on a semi-
annual basis regardless of event classification.
SAEs recorded on the Clinical Events eCRF 
represent those events which are components of 
the composite CV endpoint, other trial 
endpoints, potential components of the CV 
endpoint that require adjudication or are 
expected sequelae of T2DM. SAEs recorded as 
Clinical Events, including death related to an 
event in the Clinical Events List, will not be 
reported to the Sponsor, regulatory agencies or 
ethics committees, regardless of relationship to 
trial medication even though they may be 
considered possibly, probably or definitely 
drug-related and meet SAE criteria.  In addition 
to the un-blinded review by the DSMB, events 
reported via this module that may be associated 
with a trial endpoint will be adjudicated by the 
CEC. As described above, all SAEs that are not 
included in the Clinical Events List and 
“Clinical Events” with onset dates after the 
primary endpoint event cut-off date will be 
recorded by the investigator in the SAE eCRF 
module. These events must be recorded in this 
module (or faxed to the number provided on the 
SAE report form if EDC is unavailable) within 
24 hours of a trial site becoming aware of the 
event. Any SAEs meeting the definition of a 
SUSAR will be subject to expedited reporting 
as per current legislation. Brief information on 
the clinical course of the event, treatment, and 
relevant diagnostic, laboratory or other 
investigations will be collected on the eCRF.
All episodes of pancreatitis and neoplasia will 
be treated as SAEs and will be collected and 
reported in the SAE eCRF module. All events 
recorded in the SAE eCRF module will be 
reported to the appropriate regulatory agencies 
in a manner and timeframe consistent with all 
applicable laws and regulations (Section 
10.3.3). All SUSARS will be reported in an 
expedited manner with the exception of possible 
trial endpoints as detailed in Section I of 
Appendix 1, which will be handled as Clinical 
Events.
The DSMB will monitor the totality of collected 
safety data (i.e. events recorded on both the 
Clinical Events and SAE eCRFs) on a semi-
annual basis regardless of event classification. 
SAEs recorded on the Clinical Events eCRF 
represent those events which are components of 
the composite CV endpoint, other trial 
endpoints, potential components of the CV 
endpoint that require adjudication or are 
expected sequelae of T2DM. SAEs recorded as 
Clinical Events, including death related to an 
event in the Clinical Events List, will not be 
reported to the Sponsor, regulatory agencies or 
ethics committees, regardless of relationship to 
trial medication even though they may be 
considered possibly, probably or definitely drug-
related and meet SAE criteria. This will be 
applicable throughout the duration of trial 
including the 70 day wash-out period. There 
will be no switch to collecting and reporting 
Clinical Events as SAEs.  Thus, the exemption 
from routine SAE reporting of events listed in 
Protocol Appendix 1 will remain for the 
entire trial duration, including the safety 
wash-out phase.  In addition to the un-blinded 
review by the DSMB, events reported via this 
module that may be associated with a trial 
endpoint will be adjudicated by the CEC. As 
described above, all SAEs that are not included 
in the Clinical Events List and “Clinical Events”
with onset dates after the primary endpoint event 
cut-off date will be recorded by the investigator 
in the SAE eCRF module. These events must be 
recorded in this module (or faxed to the number 
provided on the SAE report form if EDC is 
unavailable) within 24 hours of a trial site 
becoming aware of the event. Any SAEs 
meeting the definition of a SUSAR will be 
subject to expedited reporting as per current 
legislation. Brief information on the clinical 
course of the event, treatment, and relevant 
diagnostic, laboratory or other investigations will 
be collected on the eCRF. All episodes of 
pancreatitis and neoplasia will be treated as 
SAEs and will be collected and reported in the 
SAE eCRF module. All events recorded in the 
SAE eCRF module will be reported to the 
appropriate regulatory agencies in a manner and 
timeframe consistent with all applicable laws 
and regulations (Section 10.3.3). All SUSARS
will be reported in an expedited manner with the 
exception of possible trial endpoints as detailed 
in Section I of Appendix 1, which will be 
handled as Clinical Events.
16

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 05 TEXT
AMENDMENT 06 TEXT
12.1 Executive 
Committee (EC)
The EC will be responsible for overall 
management and oversight of the trial.  The EC 
will be composed of senior independent 
academic representatives who are experts in 
their field and representatives from the sponsor.  
The Committee will be 
-
 
 
n EC charter will outline 
the committee membership and structure and 
delineate operating procedures.
The EC will be responsible for overall 
management and oversight of the trial. The EC 
will be composed of senior independent 
academic representatives who are experts in their 
field and representatives from the sponsor. The 
Committee will be
 
. An EC 
charter will outline the committee membership 
and structure and delineate operating procedures.
Appendix 2 
TRIAL PLAN 
(PROTOCOL 
BCB109)
Table 1
Footnote 9:
[9] Patients will be contacted by telephone to 
check for any serious adverse experiences and 
hospitalizations that occurred within 70 days 
after the administration of the last dose of trial 
medication.  Note that all serious adverse 
experiences, hospitalizations, and reportable 
study events with an onset date after the 
primary endpoint event cut-off date established 
by the study Executive Committee will be 
managed as serious adverse experiences (see 
Section 10.3.1).
Table 1
Footnote 9:
[9] Patients will be contacted by telephone to 
check for any Clinical Events, serious adverse 
experiences and hospitalizations that occurred 
within 70 days after the administration of the last 
dose of trial medication. Note that all serious 
adverse experiences, hospitalizations, and 
reportable study events with an onset date after 
the primary endpoint event cut-off date 
established by the study Executive Committee 
will be managed as serious adverse experiences 
(see Section 10.3.1).
17
PPD
P
P
PPD

EXSCEL Protocol Amendment 06
LIST OF ABBREVIATIONS
ACS
Acute coronary syndrome 
AE
Adverse Event 
AHA
Antihyperglycemic agent
Amylin Amylin Pharmaceuticals, LLC
ARO
Academic Research Organization
BP
Blood Pressure 
CEC
Clinical Events Committee
CHF
Congestive heart failure
CI
Confidence Interval
CRO
Contract Research Organization
CSR
Clinical Study Report
CV
Cardiovascular
CVD
Cardiovascular disease 
DBP
Diastolic blood pressure 
DCRI
Duke Clinical Research Institute
DSMB Data Safety Monitoring Board 
DTU
Diabetes Trials Unit
EC
Executive Committee
ECG
Electrocardiogram 
EDC
Electronic Data Capture
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate 
EQW
Exenatide once weekly
EQ-5D EuroQol 5 Dimensions
FDA
Food and Drug Administration 
GCP
Good Clinical Practice
HbA1c
Hemoglobin A1c 
HLGT
High level group term
IFU
Instructions for use
IRB
Institutional Review Board
ITT
Intent-to-Treat
MDRD Modification of Diet in Renal Disease Study Group method for eGFR
MI
Myocardial infarction
OC
Operations Committee
PCI
Percutaneous coronary intervention
SAE
Serious Adverse Event 
SUSAR Suspected Unexpected Serious Adverse Reaction
SBP
Systolic blood pressure 
T2DM
Type 2 diabetes mellitus
TC
Total cholesterol
TG
Triglycerides
TIA
Transient ischemic attack
UKPDS United Kingdom Prospective Diabetes Study
18

EXSCEL Protocol Amendment 06
CLINICAL STUDY PROTOCOL
1
INTRODUCTION
1.1
Background
Type 2 diabetes mellitus is a leading public health issue. Often regarded as a mild disease, it is 
the fourth leading cause of death in developed countries and the number of people worldwide
with diabetes is predicted to exceed 300 million by the year 2025.1  Diabetes remains the leading 
cause of blindness, end stage renal disease, and lower extremity amputations and confers a two 
to four times greater risk of heart disease and strokes.
The majority of people with type 2 diabetes mellitus (T2DM) die as a result of cardiovascular 
disease (CVD). Epidemiological analysis of UKPDS data from patients with newly-diagnosed 
T2DM showed that potentially modifiable risk factors for CVD were a raised LDL cholesterol, a 
low HDL cholesterol, hyperglycemia, hypertension, and smoking.2 Elevated glucose levels were 
also the major determinant of microvascular complications. A number of trials in people with 
T2DM have shown that their CVD risk can be reduced by lowering LDL cholesterol,3,4 blood 
pressure,5,6 glycated hemoglobin,7,8 or all three risk factors.9
1.2
Rationale for Conduct of the Study
Exenatide, a GLP-1 receptor agonist, has been shown in randomized clinical trials to improve 
glycemic control, augment endogenous insulin secretion, to reduce blood pressure and promote 
weight loss with a meta-analysis of exenatide twice-daily (BYETTA) trials10 showing a trend to 
lower relative risk for CV events versus pooled comparators of 0.70 (95% confidence interval 
0.38 - 1.31). BYETTA (exenatide) injection is currently available in the US and in many 
countries worldwide for people with type 2 diabetes who are unable to achieve good glycemic 
control with common oral therapies. The addition of BYETTA to titrated basal insulin therapy
has also been demonstrated to improve glycemic control without an increased risk of 
hypoglycemia
in 
patients 
receiving 
concomitant 
diet/exercise, 
metformin, 
or 
metformin+pioglitazone therapy (exenatide enhances insulin secretion in a glucose-dependent 
manner, thus minimizing the risk of hypoglycemia in the absence of an insulin secretagogue).11
Exenatide once weekly (EQW; BYDUREON), is an extended release formulation of exenatide 
that is administered once weekly rather than twice daily.  EQW has been approved by the US 
FDA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 
diabetes mellitus and in the European Union as an adjunct to metformin, a sulfonylurea (SU), a 
thiazolidinedione (TZD), a combination of metformin and SU, or a combination of metformin 
and TZD therapy to improve glycemic control in adult patients with type 2 diabetes mellitus.
In a 30-week, randomized, open-label trial, EQW treatment resulted in a significantly greater 
improvement in glycemic control, as measured by glycated hemoglobin (HbA1c), compared to 
exenatide administered twice daily.12  Furthermore, treatment with EQW for one year (52 weeks) 
showed net reductions of 2.0% in HbA1c, 0.06 mmol/l (2.2 mg/dl) LDL cholesterol, 6 mmHg in 
systolic blood pressure and 4 kg in body weight.13  Thus, EQW represents a novel therapeutic 
19

EXSCEL Protocol Amendment 06
approach to the treatment of T2DM that could potentially impact the occurrence of 
cardiovascular events in patients mediated by improvements in multiple CV risk factors, as well 
as reducing glycemia. 
EXSCEL (EXenatide Study of Cardiovascular Event Lowering) is a pragmatic, long-term, 
placebo-controlled, double-blinded trial which seeks to characterize the effects of EQW on 
cardiovascular-related outcomes in patients with type 2 diabetes when added to the current usual 
care for glycemic control in a standard care setting.
2
STUDY OBJECTIVES AND HYPOTHESES
2.1
Primary Objective
The primary objective of EXSCEL will be to evaluate the effect of EQW, used in addition to the 
current usual care for glycemic control, on major macrovascular events when administered to 
patients with type 2 diabetes.
Objective: To compare the impact of including EQW in addition to usual care vs. usual care
without EQW on major CV outcomes as measured by the primary CV composite endpoint of 
CV-related death, nonfatal myocardial infarction (MI), or nonfatal stroke.
Hypotheses:
Efficacy:  EQW, when used in addition to usual care, is superior to usual care without EQW
with regard to the risk of developing a confirmed event in the primary CV composite endpoint. 
Safety:  EQW, when used in addition to usual care, is non-inferior to usual care without EQW
with regard to the risk of developing a confirmed event in the primary CV composite endpoint.
2.2
Secondary Objectives
The secondary objectives of EXSCEL are to evaluate the effect of EQW treatment used in 
addition to the current usual care for glycemic control on:
1) All cause mortality
2) Each of the components of the primary composite CV endpoint
3) Hospitalization for acute coronary syndrome (ACS)
4) Hospitalization for congestive heart failure (CHF)
2.3
Additional Objectives
Additional objectives of EXSCEL are to evaluate the effect of EQW treatment used in addition 
to the current usual care for glycemic control on:
1) Revascularization procedures.  This will include percutaneous coronary intervention (PCI)
with or without stenting, coronary artery bypass grafting, revascularization and/or stenting 
for peripheral arterial disease, carotid endarterectomy, or carotid stenting
2) Time to initiation of first co-interventional agent (i.e., next antihyperglycemic agent [AHA]
or chronic insulin therapy)
3) Number of episodes of severe hypoglycemia
20

EXSCEL Protocol Amendment 06
4) Absolute values of and changes in markers of cardiovascular risk including: HbA1c, body 
weight, blood pressure, lipid profile
5) Quality of life assessed by the EQ-5D (EuroQol 5 Dimension) questionnaire
6) Medical resource use and total direct medical costs
7) Incremental cost-effectiveness analysis of exenatide once weekly as part of usual care 
compared with usual care without exenatide
3
TRIAL GOVERNANCE 
EXSCEL is a multinational pragmatic trial that will be conducted at approximately 800 sites 
worldwide. It will be run jointly by the Duke Clinical Research Institute (DCRI) and the 
University of Oxford Diabetes Trials Unit (DTU) Academic Research Organizations (AROs), in 
an academic collaboration with Amylin Pharmaceuticals, LLC (Amylin), a wholly owned 
subsidiary of AstraZeneca. EXSCEL will be Co-Chaired
and sponsored and funded by Amylin.
The EXSCEL Executive Committee (EC) will have overall responsibility for the oversight and 
management of the trial (Figure 1). The EC will consist of senior independent academic 
representatives who are experts in their field and sponsor representatives.  It will be Co-Chaired
by Professors Adrian Hernandez and Rury Holman (see Section 12.1).
Figure 1:
EXSCEL Governance
21
PPD

EXSCEL Protocol Amendment 06
4
TRIAL DESIGN
4.1
Design Description
EXSCEL will be a multinational, placebo-controlled, double-blind, randomized, parallel-group 
pragmatic clinical trial. Eligible patients will have type 2 diabetes with an HbA1c #6.5% and 
∃10.0 % on up to three (i.e., 0-3) oral antihyperglycemic agents (AHAs) or insulin either alone or 
in combination with up to 2 (i.e., 0-2) oral AHAs.  Patients enrolled will be at a wide range of 
CV risk with approximately 70% having had a prior CV event (see Section 6.3). 
Approximately 14,000 patients meeting all enrollment criteria will be recruited in to the trial 
over approximately a five year period, randomly allocated to treatment with either EQW 2 mg or 
matching placebo subcutaneous injections once weekly in a 1:1 ratio, and followed until the 
requisite number of primary endpoint events have been reported. The trial is planned to continue 
until 1360 patients with positively adjudicated primary endpoint events have been accrued, or 
until the independent Data Safety Monitoring Board (DSMB) advises otherwise.  It is anticipated 
that the EXSCEL Executive Committee will monitor the accrual of the aggregate number of 
adjudicated primary endpoint events and will determine the primary endpoint event cut-off date 
(i.e., the date at which the anticipated number of events is expected to have accrued). Based on 
the primary endpoint event cut-off date, a window of time for the conduct of the Trial 
Termination Visit will be established; all patients will be expected to have follow-up until the 
Trial Termination Visit (see Section 6).
The trial will assess the impact of EQW therapy upon CV outcomes in a large population from a 
heterogeneous group of countries and practice environments; patients will be enrolled in the 
Americas (North/South America), Europe and Asia/Australasia. Given that this population will 
be at elevated CV risk, it is anticipated that patients will see their usual care provider at least 
twice per year for routine care. Trial follow up will consist of a blend of trial visits and phone 
calls during the double-blind placebo-controlled treatment period. 
There is no requirement to achieve glycemic equipoise between randomized groups but all 
patients during the double-blind treatment period will have their AHA regimens adjusted as 
deemed necessary by their usual care provider with the addition or substitution of other AHAs, 
including insulin, but excluding GLP-1 receptor agonists, to achieve appropriate individualized 
glycemic goals in line with national guidelines. Adjustments in AHA medications are permitted 
any time after randomization, but usual care providers will be asked to avoid this until HbA1c
levels begin to reflect the initial effect of randomized study medication. Prior to randomization, 
it is anticipated that all patients will have received counseling regarding appropriate diet and 
level of physical activity as part of usual care for type 2 diabetes. Per usual care, HbA1c values 
should be measured locally. An NGSP (National Glycohemoglobin Standardization Program) 
certified HbA1c assay14 should be used if available.
4.2
Trial Duration
It is anticipated that enrollment will occur over approximately a 5-year period, and that an 
additional 2 to 3 years may be required to accumulate the requisite number of patients with 
positively adjudicated primary endpoint events, for a total duration of up to approximately 7.5 
22

EXSCEL Protocol Amendment 06
years, unless the trial is terminated earlier. All patients who discontinue study medication, but 
have not withdrawn consent to participate in the study, will be followed up, if possible, for the 
full study period and will have their vital status ascertained, if possible, as of the Trial 
Termination Visit.
4.3
Post Trial Access to Therapy
At the end of the trial, the sponsor will not continue to supply study drug to 
patients/investigators. The investigator should ensure that the patient receives appropriate 
standard of care to treat the condition under study according to national treatment guidelines.
5
TRIAL POPULATION
5.1
Inclusion Criteria
Each patient must meet the following criteria to be enrolled in this trial.
a) Patient has type 2 diabetes mellitus 
b) Patient will be able to see a usual care provider at least twice a year 
c) Patient has an HbA1c of #6.5 % and ∃10.0% and is currently using one of the following 
treatment regimens:
!
Treatment with up to three (i.e., 0-3) oral AHAs (concomitant use of DPP-4 inhibitors is 
permitted)
!
Insulin therapy, either alone or in combination with up to two (i.e., 0-2) oral AHAs (use of 
basal and prandial insulins is permitted in any combination of individual or premixed 
insulins)
All patients should be on a stable diabetes management regimen, as assessed by the 
investigator, at the time of enrollment.  
HbA1c values must be from within the 3 months prior to randomization.  If multiple values are 
available, the most recent reported value should be used.  A patient whose HbA1c is >10.0% 
may, at the discretion of the investigator, have their oral AHA or insulin therapy adjusted and be 
re-screened once for HbA1c randomization eligibility (#6.5 % and ∃10.0%).
d) Patients with any level of CV risk and meeting all other inclusion criteria may be enrolled. 
Recruitment will be constrained (see Section 6.3) such that approximately 30% will not have 
had a prior CV event and 70% will have had a prior CV event
A prior CV event is defined as at least one of the following:
!
History of a major clinical manifestation of coronary artery disease i.e. myocardial infarction, 
surgical or percutaneous (balloon and/or stent) coronary revascularization procedure, or 
coronary angiography showing at least one stenosis #50% in a major epicardial artery or 
branch vessel
!
Ischemic cerebrovascular disease, including: 
∀
History of ischemic stroke; strokes not known to be hemorrhagic will be allowed as part 
of this criterion; transient ischemic attacks (TIAs) are not included
23

EXSCEL Protocol Amendment 06
∀
History of carotid arterial disease as documented by #50 % stenosis documented by 
carotid ultrasound, magnetic resonance imaging (MRI), or angiography, with or without
symptoms of neurologic deficit
!
Atherosclerotic peripheral arterial disease, as documented by objective evidence such as 
amputation due to vascular disease, current symptoms of intermittent claudication confirmed 
by an ankle-brachial pressure index or toe brachial pressure index less than 0.9, or history of 
surgical or percutaneous revascularization procedure 
e) Female patients must not be breast feeding and agree to use an effective method of 
contraception or must not otherwise be at risk of becoming pregnant
f)
Patient understands the trial procedures, alternative treatments available, the risks involved 
with the trial, and voluntarily agrees to participate by providing written informed consent 
g) Patient agrees to provide permission to obtain all medical records necessary for complete 
data ascertainment during the follow-up period, and agrees to communication between the 
trial site and the usual care provider in order to facilitate routine care
h) Patient is 18 years or older at enrollment
5.2
Exclusion Criteria
Each patient meeting any of the following criteria will be excluded from this trial.
a) Patient has a diagnosis of type 1 diabetes mellitus, or a history of ketoacidosis
b) Patient has a history (#2 episodes) of severe hypoglycemia within 12 months of enrollment
c) Patient has ever been treated with an approved or investigational GLP-1 receptor agonist e.g.,
BYETTA (exenatide), 
BYDUREON 
(EQW), 
VICTOZA 
(liraglutide),
LYXUMIA 
(lixisenatide), albiglutide, taspoglutide, or dulaglutide
d) Patient is enrolled in another experimental protocol which involves the use of an 
investigational drug or device, or an intervention that would interfere with the conduct of the 
trial
e) Patient has a planned or anticipated revascularization procedure
f)
Pregnancy or planned pregnancy during the trial period  
g) Patient has medical history that indicates a life expectancy of <2 years or might limit the 
individual’s ability to take trial treatments for the duration of the trial 
h) Patient has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance which, in the opinion of the investigator or coordinator, might pose an 
unacceptable risk to the patient, confound the results of the trial e.g. if patient cannot comply 
with requirements of the trial, or likely to interfere with the patient’s participation for the full 
duration of the trial
i)
Patient has end-stage renal disease or an estimated glomerular filtration rate (eGFR) derived 
from serum creatinine (using the simple MDRD-4 formula) of <30 mL/min/1.73m2
(see Appendix 2)
j)
Patient has a known allergy or intolerance to exenatide
k) Patient has a history of gastroparesis
l)
Personal or family history of medullary thyroid cancer or MEN2 (Multiple Endocrine 
Neoplasia Type 2) or calcitonin level of > 40 ng/L at baseline
24

EXSCEL Protocol Amendment 06
NOTE: Serum for calcitonin measurement will be drawn at baseline.  Patients may be 
randomized and initiate study medication prior to the results of the calcitonin measure being 
available.  If a randomized patient is found to have an exclusionary serum calcitonin 
concentration, they will stop study medication and patients will continue to have follow-up and 
be part of the Intent-to-Treat analysis.
m) Patient has previously been randomized in EXSCEL
n) Patient has a history of pancreatitis
o) Is an employee of Amylin Pharmaceuticals, LLC, Bristol-Myers Squibb Company, or 
AstraZeneca
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
patients and that the results of the study can be used. It is imperative that patients fully meet all 
eligibility criteria.
6
TRIAL PLAN
6.1
Trial Procedures - Overview
A schedule of procedures to be performed during the trial is found in Appendix 2. The intent of 
this large, pragmatic, global trial is to integrate the trial-specific procedures into usual clinical 
care visits and to use routine clinical care assessments and laboratory values whenever possible 
as an efficient strategy for protocol implementation and data collection. At randomization (Visit 
1) patients will be provided with the patients’ instruction for use (IFU) and will be trained by 
study personnel to administer the study medication injection. Patients will be seen at one week 
(±3 days) and have their self-injection observed. Then patients will be seen at 2 months (± 2 
weeks) after randomization to again confirm competency with dosing study medication. The next 
visit will be six months (±1 month) after randomization. Thereafter, patients will be seen every 
six months (±1 month) until study close out (Figure 2).  
At all visits post randomization there will be an assessment of Clinical Events and Serious 
Adverse Events (see Section 10.3.1), as well as a review of concomitant medication, and 
adherence to study therapy. At semi-annual and annual visits, additional procedures will include 
blood pressure, body weight, heart rate, review of laboratory values and dispensing of study drug 
as described in Appendix 2.
The trial is planned to continue until 1360 patients with positively adjudicated primary endpoint 
events have been accrued.  It is anticipated that the EXSCEL Executive Committee will monitor 
the accrual of the aggregate number of adjudicated primary endpoint events and will determine 
the primary endpoint event cut-off date (i.e., the date at which the anticipated number of events 
is expected to have accrued).  Based on the primary endpoint event cut-off date, a window of 
time for conduct of the Trial Termination Visit will be established. All patients will be expected 
to have follow-up until this visit.
NOTE:  Patients who have temporarily or permanently discontinued trial medication should 
continue with their regular visit schedule.  ALL patients should have a Trial Termination Visit
(including patients who have previously discontinued trial medication).
25

EXSCEL Protocol Amendment 06
After the Trial Termination Visit patients will be contacted by telephone to check for any 
Clinical Events, serious adverse experiences and hospitalizations that occurred within 70 days 
after the administration of the last dose of trial medication.
Note that any events occurring 
between the Trial Termination Visit and the safety follow-up phone call will not be adjudicated 
and will not be included in the primary analysis. Patients who have discontinued trial medication 
70 or more days prior to the Trial Termination Visit will not need to have the safety follow-up 
telephone contact visit performed. These patients will have their final assessment of Clinical 
Events, serious adverse experiences and hospitalizations completed at the Trial Termination 
Visit.
Clinical Events (as defined in Protocol Appendix 1) will continue to be collected and reported in 
the same way as they have been throughout the entire study (i.e., prior to the cut-off date) (see 
Section 10.3.1).
Figure 2:
EXSCEL Study Design
6.2
Pre-Enrollment and Enrollment Procedures
Informed consent, and if feasible, randomization will occur at the initial trial visit for patients 
satisfying all inclusion and exclusion criteria.
Patients may qualify for enrollment based on 
recent laboratory data e.g. HbA1c within the last 3 months, obtained as part of usual care prior to 
Visit 1 (recommended guidance for management of serum creatinine values will be provided to 
each site). For patients who require a repeat visit e.g. key lab data not available at Visit 1, 
randomization will be delayed until all information is available.  It should be noted that patients 
may still be randomized at Visit 1 even if calcitonin results are pending.
~14,000 patients
PLACEBO ONCE WEEKLY
EXENATIDE ONCE WEEKLY
Randomization
Six monthly visits
after first year
1 w 2 mo 6 mo
1 y
Primary endpoint 
event cut-off date
(determined by EC)
Post-treatment 
safety follow-up 
contact (70 days 
after study drug 
discontinuation, 
if applicable)
Trial Termination Visit
(defined period after 
primary endpoint cut-off) 
26

EXSCEL Protocol Amendment 06
6.3
Method of Assigning Patients to Treatment Groups (Visit 1)
An Interactive Voice Response System (IVRS) will be used to enroll those patients satisfying all 
inclusion and exclusion criteria.
This automated system will randomize eligible patients and 
dispense double-blind trial medication.  Each site user will be given an identification number and 
a password to access the IVRS. Patients will be randomly allocated at Visit 1 in a 1:1 ratio, 
stratified by whether or not they have had a prior CV event, to receive one of the following t wo 
interventions:
Treatment 1:  EQW 2 mg subcutaneous injection, administered once weekly 
Treatment 2:  Matching placebo subcutaneous injection, administered once weekly
The IVRS will be programmed to ensure the expected overall proportion of randomized patients 
with a prior CV event is approximately 70%.  With transition to Amylin-labeled trial medication 
(beginning in 2013), the IVRS was programmed to ensure at least 80% of newly randomized
patients have a history of a prior CV event (previously was programmed to ensure approximately 
60% of patients had a prior CV event).
The generation of the randomized allocation schedule for trial treatment assignment will be the 
responsibility of the IVRS provider. Prior to database lock, these codes will be provided in strict 
confidence only to the facility packaging trial medication and to the DSMB independent 
statistical group. Immediately upon database lock the codes will be transmitted to the DTU and 
DCRI data management groups for incorporation into the trial database.
6.4
Treatments Administered
In accordance with standard guidelines for care in all countries participating in the trial, it is 
anticipated that all patients will receive counseling about appropriate diet and exercise 
interventions as part of usual care.
EQW and matching placebo will be supplied as subcutaneous injections and will be administered 
once weekly.  
As exenatide is not recommended for use in patients with end-stage renal disease or severe renal 
impairment, trial medication must be discontinued if a patient’s eGFR drops below 
30 mL/min/1.73 m2, based on two consecutive serum creatinine determinations (See Section 
6.12). As part of standard of care, serum creatinine should be, at minimum, among labs drawn 
annually.  If serum creatinine has not been performed on an annual basis, then study personnel 
should prompt usual care providers to perform serum creatinine measurement. 
If serum 
creatinine remains unavailable, then it should be performed at the next visit by study personnel.  
If the investigator recognizes that the eGFR has decreased sufficiently to necessitate trial 
medication cessation, he/she should determine whether or not repeat/confirmatory testing has 
occurred and undertake this if necessary. If the need for drug discontinuation is confirmed, the 
situation will be explained to the patient and the patient will be asked to stop the study drug and 
encouraged to continue follow up off study drug until the end of the trial. If deemed necessary 
by the investigator, an unscheduled visit can be performed to discuss study drug discontinuation 
and the importance of subsequent follow up. Drug discontinuation will be managed at the trial
27

EXSCEL Protocol Amendment 06
site through the IVRS system. Drug discontinuation visit procedures should be followed as 
outlined in Section 6.11. 
6.5
Concomitant Therapy
Concomitant medications will be used at the discretion of the usual care provider (or investigator 
if also the usual care provider), who will be informed of the patient’s enrollment in the trial, the 
use of blinded trial medication, and that use of GLP-1 receptor agonists is contraindicated during 
the trial period. If an open-label GLP-1 receptor agonist therapy is started whilst on study 
medication, then the investigator will inform the usual care provider about the possibility of 
double dosing and encourage the discontinuation of open-label GLP-1 agonist therapy.
However, if an open-label GLP-1 receptor agonist therapy remains, then study drug should be 
discontinued to avoid potential double dosing. Usual care providers will be encouraged to 
follow guidelines for care based upon local and institutional practice patterns and any relevant 
published practice guidelines. AHAs will be captured by name and total daily dose at the time of 
study visits, while other relevant concomitant medications may be collected only as drug classes. 
During the double-blind treatment period, investigators are expected to monitor patients’ AHA 
regimens and communicate with usual care providers, who will be responsible for adjusting the 
AHA regimen in order to achieve locally-appropriate HbA1c goals based on clinical care practice 
guidelines published by national and international societies. These goals will be individualized, 
with the understanding that currently applicable glycemic guidelines may vary among different 
geographic regions. With adherence to local custom and laws (including privacy regulations 
such as HIPAA), types of communication may be informal e.g. email or telephone exchanges, to 
enhance frequency and ease of two-way communication.
Usual care providers should be notified that adjustments to the AHA regimen are not 
recommended until HbA1c levels begin to reflect the effect of randomized therapy. Any AHA 
agent, with the exception of GLP-1 receptor agonists, is acceptable. If HbA1c goals are not met 
following adjustment with oral AHAs in patients not receiving insulin, an insulin regimen may 
be initiated, preferably without discontinuing or down-titrating some or all of the existing AHAs, 
as clinically appropriate. Patients already receiving insulin therapy may up-titrate insulin during 
the trial if necessary. Ideally, patients should generally remain on the baseline AHA therapies 
throughout the course of the trial, unless the baseline AHA is no longer clinically appropriate. 
However, this should be at the discretion of the usual care provider.  In addition, patients should 
be reminded to keep taking their blinded trial medication following initiation of insulin.
6.6
Precautions to Minimize Rates of Hypoglycemia
At the screening/randomization visit and all subsequent visits, the symptoms and appropriate 
management of hypoglycemia will be reviewed with patients. Patients who experience severe 
hypoglycemia will be asked to notify both their usual care provider, as well as trial personnel.  
Usual care providers will be responsible for the adjustment of non-trial AHA medications in 
order to prevent or minimize the occurrence of further hypoglycemia.  
All episodes of severe hypoglycemia will be reviewed and recorded. Severe hypoglycemia 
(hypoglycemia requiring assistance) refers to instances in which the patient was sufficiently 
28

EXSCEL Protocol Amendment 06
disoriented or incapacitated as to require help from either a family member or from medical 
personnel (whether or not this assistance was actually provided).  For example, if a family 
member or other bystander brought the patient a snack or drink to help raise his blood sugar even 
though the patient was capable of doing this himself, the episode would not be considered 
severe.  
Combination therapies with insulin and sulfonylurea have an increased risk of hypoglycemia.  To 
minimize this risk, patients whose diabetes is well controlled may require a reduction in the 
insulin or sulfonylurea dose when allocated study medication.  EXSCEL will employ both 
patient- and investigator-directed education to minimize the risk of hypoglycemia.  Patients 
receiving sulfonylurea/insulin combinations will be explicitly reminded of the symptoms and 
proper management of hypoglycemia before starting study drug.
6.7
Laboratory and Anthropometric Measurements
Laboratory values i.e. HbA1c, serum creatinine, lipid profile [LDL-C, TC, TG, HDL-C]) will be 
obtained where available as per the patient’s usual care assessments. Blood pressure, heart rate, 
height, and body weight will be collected by study personnel as indicated in Appendix 2.
6.8
Calcitonin Sample Collection
Serum calcitonin concentrations will be monitored throughout the patient’s participation in the 
trial (See Section 10.4).  Samples will be collected at baseline, annually and at the Trial 
Termination visit.  
6.9
Genetic and Biomarker Sample Collection
In a subset of sites, patients enrolled in the trial will be asked to consent separately to provide a 
whole blood sample for future pharmacogenomic analyses. The objective of collecting blood 
samples from which genetic analyses can be performed is to investigate the relationships 
between genetic make-up and clinical events. These samples will be drawn at baseline, or at any 
point in the trial at which consent is obtained from the patient.
In addition, a subset of patients enrolled in the trial will be asked to consent separately to provide 
one serum sample, one plasma sample, and one urine sample for future biomarker analyses. 
These specimens (preferably fasting) will be obtained at baseline (prior to drug exposure), year 1
and at the Trial Termination visit.
6.10
Resource Utilization Quality of Life Data for Economic Evaluation
As part of this trial, data will be collected to inform cost-effectiveness analyses that are relevant 
to major health care systems around the world. The economic analyses will be undertaken by a 
team led by the University of Oxford and Duke University. Resource use information will be 
collected from case report forms on number, type and duration of hospitalizations, number of 
outpatient physician visits, and use of antihyperglycemic and cardiovascular agents.  The EQ-5D 
instrument, consisting of 5 questions, will be used to measure health utilities which are essential 
to estimating quality-adjusted survival for the cost-effectiveness analysis. This instrument will 
be administered at baseline, at 6 months, at subsequent annual visits, and at the Trial Termination 
visit.
29

EXSCEL Protocol Amendment 06
An outline statistical analysis plan for this evaluation is reported in Section 9.11; a detailed 
analysis plan and study report will be developed and reported separately.
6.11
Temporary or Permanent Discontinuation of Trial Medication
Following randomization, it is expected that patients will remain on study medication for the 
duration of trial participation. However, it is recognized that patients may need to discontinue 
trial medication, in some cases permanently, for when protocol-specified reasons apply 
(Section 6.12), due to the judgment of the primary investigator or the decision of the patient.  
The Trial Hotline should be contacted whenever a site is considering interrupting or 
discontinuing trial medication (Section 6.18).
Unless resumption of trial medication is considered unsafe or is refused by the patient, the 
patient will be expected to resume regular use of the blinded trial medication after a period of 
temporary discontinuation.  Should a patient stop taking trial medication, either permanently or 
temporarily, the reasons for discontinuation and length of time the patient stopped taking trial
medication will be assessed and recorded.
All randomized patients who permanently discontinue trial medication should have a drug 
termination visit as part of their next scheduled study visit (unless a separate drug termination 
visit at that point is deemed necessary by the investigator). Necessary procedures are indicated 
in Appendix 2.  All efforts should be made to reinforce with patients that this would be a 
medication discontinuation visit, not a trial discontinuation visit; patients should continue with 
their regular visit schedule until the end of the trial, including semi-annual in-person visits, as 
well as the annual calcitonin measurement. If patients cannot attend visits in person, they will be 
followed via telephone contact for all subsequent visits.  
NOTE:  After trial medication is discontinued due to pregnancy, re-initiation of study 
medication can be considered following completion of the pregnancy and breastfeeding (if 
applicable).
6.12
Permanent Discontinuation of Trial Medication Per Protocol
Reasons for protocol-specified discontinuation from the trial medication are listed below. All 
patients will be followed until resolution i.e. return to baseline values or diagnosis determined, or 
new stable state established, based on investigator assessment, for any adverse event or 
laboratory safety test abnormality resulting in discontinuation.
a) Severe Hypoglycemia: repeated (2 or more) episodes since the prior trial visit of severe 
hypoglycemia i.e. in which patient required medical assistance, despite down-titration or 
interruption/discontinuation of non-trial AHAs.
!
Note:  The patient and the Investigator will notify the usual care provider of severe 
hypoglycemic events. The usual care provider should make a thorough attempt to down-
titrate and/or modify co-interventional and baseline therapies that may contribute to 
hypoglycemia before discontinuing blinded trial medication for hypoglycemia.
b) Any medical condition or personal circumstance which, in the opinion of the investigator, 
exposes the patient to additional risk by continuing in the trial or does not allow the patient to 
adhere to the requirements of the protocol. 
30

EXSCEL Protocol Amendment 06
c) Severe, 
irreversible 
renal 
dysfunction 
(confirmed 
by 
two 
consecutive 
eGFR 
<30 ml/min/1.73m2) or renal replacement therapy.
d) Annual calcitonin measurement #50 ng/L 
6.13
Trial Termination Visit
Investigators will be informed by the DCRI and DTU Coordinating Centers as to when the Trial 
Termination Visit is to be completed, and will schedule all patients for the Trial Termination 
Visit.  Based on the primary endpoint event cut-off date, a window of time for conduct of the 
Trial Termination Visits will be established; this window will be a period of time following the 
primary endpoint event cut-off date.  All patients will be expected to have follow-up until this 
visit.  At the Trial Termination Visit, all patients must be discontinued from trial medication; the 
investigator should ensure that the patient receives appropriate standard of care. For procedural 
details of the Trial Termination Visit, refer to Appendix 2.
NOTE:  All patients should have a Trial Termination Visit. Patients who have discontinued 
trial medication prior to the end of the trial must, at minimum, have a Trial Termination
telephone contact.
If a patient fails to return or otherwise becomes difficult to contact, it is the investigator’s 
responsibility to make every effort to maintain contact so that at the end of the trial the patient 
can be located to determine status and to obtain necessary information for serious adverse 
experience reporting and/or endpoint adjudication as of the Trial Termination Visit.
6.14
Post-Treatment Telephone Contact
After the Trial Termination Visit, patients will be contacted by telephone to check for any 
Clinical Events, serious adverse experiences and hospitalizations that occurred within 70 days 
after the administration of the last dose of trial medication. 
For patients who have been 
discontinued from trial medication for more than 70 days as of the Trial Termination Visit, the 
Trial Termination Visit will be the final study follow-up.  Clinical Events (as defined in Protocol 
Appendix 1) will continue to be collected and reported in the same way as they have been 
throughout the entire study (i.e., prior to the cut-off date) (see Section 10.3.1).
6.15
Withdrawal of Consent
Patients who request to discontinue study treatment will remain in the study and must continue to 
be followed for protocol specified follow-up procedures. The only exception to this is when a 
patient explicitly withdraws consent for any further contact with him/her or persons previously 
authorized by patient to provide this information. 
Patients should notify the investigator of the decision to withdraw consent from future follow-up 
in writing, whenever possible. The withdrawal of consent should be explained in detail in the 
medical records by the investigator and entered on the appropriate eCRF page. In the event that 
vital status (whether the patient is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
31

EXSCEL Protocol Amendment 06
When a patient withdraws consent from future follow-up prior to trial completion, all applicable 
activities scheduled for the final trial visit should be performed at that time (Section 6.13).
6.16
Lost to Follow-Up
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status. This includes follow-up with persons authorized by the patient as noted above as well as 
the usual care provider. Lost to follow-up is defined by the inability to reach the patient after a 
minimum of three documented phone calls, as well as lack of response by patient to one 
registered mail letter. All attempts should be documented in the patient’s medical records. If it is 
determined that the patient has died, the site will use permissible local methods to obtain the date 
and cause of death.
If an investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the patient’s informed consent, then the investigator may use a 
Sponsor-retained third-party representative to assist site staff with obtaining patient’s contact 
information or other public vital status data necessary to complete the follow-up portion of the 
study. Where specific consent has been obtained from the participant, the site staff and 
representative will consult publicly available sources, such as public health registries and 
databases, in order to obtain updated contact information. If after all attempts, the patient
remains lost to follow-up, then the last known alive date as determined by the investigator should 
be reported and documented in the patient’s medical records.
6.17
Breaking the Blind
The IVRS will be used to unblind patients to the randomized treatment assignment only if 
absolutely necessary. Disclosure envelopes will not be supplied with the clinical supplies. Drug 
identification information is to be unmasked ONLY if necessary for the welfare of the patient. 
Prior to unblinding, the investigator is required to speak with a trial hotline physician (Section 
6.18).  Patients whose treatment has been unblinded can continue to receive trial medication and 
can continue to be followed in the trial as described in this protocol.
6.18
Trial Hotline
Clinicians at DCRI and DTU operate the trial hotline. It is available at all times to answer urgent 
clinical questions from sites concerning enrolled patients as well as questions to determine 
whether a particular patient qualifies for enrollment or performance of study procedures.
7
TRIAL MEDICATIONS
7.1
Trial Medication Supply 
Investigational Materials will be provided by the Sponsor as EQW 2 mg and matching placebo.
7.2
Formulation, Packaging, and Storage
EQW (formulation AC2993 F17) is an extended release formulation of exenatide and consists of 
5% exenatide, sucrose, and 50:50 poly D,L lactic-co-glycolic acid (PLG).  The vial containing 
the white to off white dry powder (2.8 mg of exenatide in EQW microspheres to deliver 2 mg of 
exenatide) must be stored in a refrigerator between 2ºC and 8ºC (36°F and 46°F) and protected
32

EXSCEL Protocol Amendment 06
from light.
EQW matching placebo is the identical formulation with the active ingredient 
omitted.
The Microsphere Diluent for suspension of the EQW and matching placebo microspheres 
contains carboxymethylcellulose low viscosity, polysorbate 20, sodium chloride, and water for 
injection.  The Microsphere Diluent must be stored between 2°C and 25°C (36°F and 77°F). The 
EQW or matching placebo dose is prepared by reconstitution of the microspheres in the diluent 
provided. Specific instructions for dose preparation of the injection will be provided in the 
Instructions for Use (IFU). The reconstituted dose of study medication (EQW or matching 
placebo) should not be stored for future use. The injection must be administered immediately 
after preparation of the dose.
7.3
Dispensing of Trial Medication
Study materials will be provided to patients by the investigator, medically qualified 
subinvestigator, or other qualified study-site personnel.  Under no circumstance will the 
investigator or subinvestigators allow the study medication to be used other than as directed by 
the protocol or to be administered to any persons other than patients participating in the study.
A supply of study medication will be dispensed for each patient, according to their assigned 
treatment group (EQW or Placebo).  A 6 month supply of study medication will be distributed to 
patients at the study site during Visit 1 and at subsequent visits indicated in Appendix 2. Patients 
should bring used and unused study medication vials to the site at each visit so medication 
compliance can be assessed.
7.4
Dose Administration Procedures, Route, and Schedule
Doses of EQW or matching placebo are to be injected into subcutaneous (SC) tissue of the 
abdomen, thigh, or back of the upper arm. The site of injection should be rotated on a regular 
basis so that the same site is not used repeatedly. The same anatomical region can be used for 
the injection but the site should be rotated (e.g. different quadrants of the abdomen can be used 
in a weekly rotation).
At Visit 1 (Day 0), a medically qualified staff member will demonstrate the preparati on of EQW 
or matching placebo for the patient or a designated caregiver and will administer the first dose of 
study medication. 
Patients will subsequently self administer study medication (or have it 
administered by a caregiver) once weekly (± 3 days) relative to the date of the first dose of EQW 
or matching placebo (Visit 1 [Day 0]). Patients will be seen one week as well as two months 
after randomization to confirm competency with study medication.  On weeks with no scheduled 
study-site visits, patients may opt to return to the study site to have the injection procedure 
monitored by study-site personnel, although such visits will not be required. During scheduled 
study visits, patients must bring their study medication treatment kit with them to the clinic and 
will self administer EQW or matching placebo as directed by study-site personnel.
Adjustments to dosing regimens are not permitted.  If a patient is unable to tolerate study 
medication (e.g., patient experiences adverse events that are judged by the investigator to be 
unacceptable) the termination of study medication can be considered.
Patients who terminate 
33

EXSCEL Protocol Amendment 06
study medication will be followed up, per the protocol, for the remainder of the study unless the 
patient opts to withdraw consent for further follow-up.
7.5
Randomization Schedule and Blinding Procedures 
Patients who meet all study requirements based on inclusion and exclusion criteria will be 
randomized at Visit 1 (Day 0). Patients will be randomly assigned to 1 of 2 treatment groups 
(EQW or Placebo). Randomization will be in the ratio of 1:1 (EQW:Placebo) and will be carried 
out centrally in a manner blocked within site and stratified by whether a participant has or has 
not had a prior cardiovascular event, to achieve a balanced distribution of patients across 
treatment groups.
Sufficient study medication will be provided to the study site for enrollment of all patients. Study 
medication kits will be labeled with unique package numbers (this is not the patient
randomization number).  At Visit 1 (Day 0), study site personnel must contact the interactive 
voice response system (IVRS) to randomly assign patients.  The study-site personnel must call 
the IVRS at all subsequent visits (except Visits 2, 3 and Trial Termination) to record the visit and 
confirm the kit assignment. The calls to the IVRS will ensure the resupply of additional kits
required for upcoming visits. If medication is allocated to a patient incorrectly, the sponsor must 
be notified. At Trial Termination, the site must call the IVRS to record study termination.  The 
sponsor, the study-site personnel, and the patients will be blinded to treatment allocation.
7.6
Drug Accountability
Drug accountability will be the responsibility of the study-site personnel.  Upon receipt of study 
medication, study site personnel should open the shipment, verify that the amount and identity of 
the contents match that stated on the enclosed shipping form, indicate the condition of the 
contents on the form, and then sign and date the form. In addition, the study-site personnel must
contact IVRS to verify receipt of study medication. The sponsor (or designee) should be notified 
immediately about any irregularities, discrepancies, or damage.
A drug accountability log will be provided to record all study medication dispensed to or 
returned from each patient. Upon completion of the study, all used and unused EQW or 
matching placebo vials and copies of completed drug accountability logs should be returned to 
the sponsor (or designee). A clinical supplies return authorization form will be prepared by the 
clinical research associate at the closeout visit. The clinical supplies return form should be 
enclosed with the return drug shipment; however, if the site manager/CRA approves, the site can 
destroy the material instead of returning the used and unused study drug. The study site 
personnel must maintain documentation of any missing or unreturned study medication.
8
EFFICACY ASSESSMENTS
Trial endpoints will be defined based on clinical standards, regulatory precedent, and historical 
trials. The definitions of the events to be adjudicated by the Clinical Events Classification 
Committee (CEC) and the committee procedures will be included in the CEC Charter (Section 
12.4). Patients will be asked at each trial visit about procedures and hospitalizations which have 
taken place since they were last seen. 
34

EXSCEL Protocol Amendment 06
8.1
Primary Efficacy Endpoint
!
Time to first confirmed CV event in the primary composite CV endpoint
Defined as the time from randomization to first confirmed CV-related death, nonfatal MI or 
nonfatal stroke.  
8.2
Secondary Efficacy Endpoints
!
Time to all-cause mortality
Defined as time from randomization to death due to any cause. 
!
Time to first confirmed CV event for each component of the primary composite 
endpoint
Defined as time from randomization to a confirmed CV-related death, fatal or nonfatal MI, or 
fatal or nonfatal stroke. 
!
Time to hospitalization for acute coronary syndrome
Defined as time from randomization to a confirmed hospital admission for unstable angina, 
ST-elevation myocardial infarction or non-ST-elevation myocardial infarction.
!
Time to hospitalization for heart failure
Defined as time from randomization to hospital admission for congestive heart failure 
requiring treatment with increased oral or intravenous diuretics, inotropes, or vasodilator 
therapy. 
8.3
Additional Efficacy Endpoints
!
Time to revascularization procedure
Defined as time from randomization to time of first cardiovascular or peripheral 
revascularization procedure.  This will include percutaneous coronary intervention with or 
without stenting, coronary artery bypass grafting, revascularization and/or stenting for 
peripheral arterial disease, carotid endarterectomy, or carotid stenting.
!
Time to initiation of first co-interventional agent 
∀
Additional AHA
∀
Chronic insulin therapy
!
Absolute values and change from baseline in:
∀
HbA1c
∀
Body weight
∀
Blood pressure
∀
Lipid profile 
!
Quality of life assessed by the EQ-5D (EuroQol 5 Dimension) questionnaire
!
Medical resource use and total direct medical costs
!
Incremental cost-effectiveness analysis of exenatide once weekly as part of usual care 
compared with usual care without exenatide
35

EXSCEL Protocol Amendment 06
9
STATISTICAL METHODS
This section outlines the statistical analysis strategy related to the primary and secondary study 
objectives with the full details given in a separate Statistical Analysis Plan (SAP). 
If any 
substantive changes are made to these objectives or the statistical methods after the study has 
begun then the protocol will be amended, provided that it is prior to any unblinding, consistent 
with ICH Guideline E9. 
The study database will only be locked and unblinded once 
medical/scientific review has been performed, protocol violations have been identified and the 
data have been declared final and complete. The statistical analyses for this study will be the 
responsibility of the University of Oxford Diabetes Trials Unit. 
9.1
Baseline Characteristics
Demographic characteristics e.g. gender, age, race, body weight, will be summarized for each 
treatment group. In addition, duration of diabetes, alcohol intake, smoking status, cardiovascular 
medical history, baseline laboratory results and concomitant medications will be summarized by 
treatment group.
9.2
Sample Size
The primary endpoint is the time from randomization to the first confirmed CV event defined as 
a CV-related death, nonfatal MI or nonfatal stroke.  The study is designed to assess the primary 
efficacy objective of superiority of EQW to placebo through the following hypothesis:
H0:  upper limit of the 95% CI of the HR [exenatide:placebo] #1
versus
H1: upper limit of the 95% CI of the HR [exenatide:placebo] <1
In order to test the above hypothesis with 85% power and 2-sided α=0.05, a total number of 1360 
composite CV events are required assuming a risk reduction of 15% on EQW compared with
placebo.  With this number of events, the power will be much larger than 90% to assess the 
primary safety objective of non-inferiority of EQW compared with placebo.
In addition, with the following assumptions made for this study,
!
An annual composite cardiovascular primary endpoint event rate estimated to be around 
2.2% per year for the population to be enrolled
!
A planned accrual period of 5-6 years
!
An estimated annual lost-to-follow up rate of 1%
!
An anticipated treatment discontinuation rate of 5% per year
it is expected that a total of 14000 patients need to be randomized in a 1:1 ratio into EQW and 
placebo to achieve the targeted 1360 confirmed composite CV events.
9.3
Randomization
Randomization via an Interactive Voice Response System (IVRS) will be 1:1 EQW to Placebo, 
blocked within each site, and stratified by whether a participant has or has not had a prior 
cardiovascular event (see Section 5.1).
36

EXSCEL Protocol Amendment 06
9.4
Primary Hypothesis
The primary efficacy hypothesis is that EQW will be superior to placebo with respect to the 
primary composite cardiovascular endpoint, defined as the time from randomization to the first 
confirmed CV-related death, nonfatal MI or nonfatal stroke with the patients analyzed as 
randomized.
The primary safety hypothesis is that EQW will be non-inferior to placebo with respect to the 
primary composite cardiovascular endpoint, with patients analyzed as randomized.
9.5
Primary Analysis
The primary statistical analysis will be based upon adjudicated CV events with patients who 
discontinue prematurely from treatment followed until the end of the study, i.e. the Trial 
Termination Visit and until the requisite number of primary composite events has been accrued. 
It is anticipated that the Executive Committee will monitor the accrual of the aggregate number 
of primary composite CV events to determine the primary endpoint event cut-off date (i.e., the 
date at which the anticipated number of events is expected to have accrued). Based on the 
primary endpoint event cut-off date, a window of time for conduct of the Trial Termination Visit 
will be established.  All patients will be expected to have follow-up until this visit.  Analysis of 
the primary composite cardiovascular outcome will be based on the time from randomization to 
the occurrence of the first event, with patients analyzed according to their randomized treatment. 
The primary analysis will include all adjudicated CV events with onset dates up to and including 
the Trial Termination Visit date.  Note that any event occurring between the Trial Termination 
Visit and the safety follow-up date (70 days after the administration of the last dose of trial 
medication) will not be adjudicated and will not be included in the primary analysis. Events 
occurring during this period will be summarized descriptively.
Kaplan-Meier curves for time to the first occurrence of a primary composite endpoint event will 
be used to depict the accumulation of events over time for the EQW and placebo treatment 
groups. The hazard ratio for the time to first occurrence of the primary composite endpoint event
for the EQW treated group to that of the placebo treated group and its 95% confidence interval 
will then be estimated using a Cox proportional hazards model stratified by baseline CV risk 
group (prior CV event or no prior CV event) and using treatment group as covariate.
The primary safety hypothesis will be assessed by a non-inferiority analysis with the non-
inferiority margin of 1.30, i.e., non-inferiority will be concluded if the upper limit of the 
confidence interval is less than 1.30.
The primary efficacy hypothesis of superiority will be then assessed by the 95% confidence 
interval for the hazard ratio of EQW to placebo, i.e., superiority will be concluded if the 95% 
confidence interval does not include 1 (upper limit of 95% confidence interval < 1). 
9.6
Secondary Efficacy Analyses
The secondary efficacy endpoints are the time to confirmed occurrence of:
1) All cause mortality
37

EXSCEL Protocol Amendment 06
2) CV-related death
3) Fatal or nonfatal myocardial infarction
4) Fatal or nonfatal stroke
5) Hospitalization for acute coronary syndrome (ACS)
6) Hospitalization for congestive heart failure (CHF)
Details of the testing strategy of the secondary efficacy endpoints will be provided in the
Statistical Analysis Plan (SAP).
9.7
Analysis Populations
The three predefined analysis populations are:
1) The Intent to Treat (ITT) Population
2) The Per Protocol Population
3) The Safety Population
9.7.1
Intent-To-Treat Population
The ITT population consists of all randomized patients. Evaluation will include all events which 
occurred from randomization to the Trial Termination Visit date, regardless of the time interval 
between patient discontinuation of study drug and final contact. Patients who do not have any 
events during the study will be censored at the Trial Termination Visit date. Every effort will be 
made to collect CV events until the Trial Termination Visit date even in those who have 
discontinued study medication or the study.  For the ITT population, patients will be analyzed as 
randomized.
9.7.1.1
On-Treatment Analysis
An on-treatment analysis using the ITT population will be performed for the primary and 
secondary analyses as sensitivity analyses.  This analysis will include only those events that 
occurred through the last dose of study medication or the Trial Termination Visit date, whichever 
occurs first.  The patients will be analyzed according to the treatment group to which they were 
randomized.  The on-treatment censoring scheme will also be applied for analysis for on-
treatment + n days, where n=7, 30, and 70.
9.7.2
Per-Protocol Population
The Per-Protocol population consists of all randomized patients who have taken at least one dose 
of study medication and will include in their analysis all data collected prior to any major 
protocol violations (or the Trial Termination Visit date, whichever occurs first), such as: 
!
Initiation of an open-label prohibited medication, i.e. a GLP-1 receptor agonist.  Evaluation 
will include all data up to the day of the initiation of the prohibited medication.
!
Early discontinuation from study medication.  Evaluation will include events which occurred 
from randomization to 70 days after the last dose of study medication or the Trial 
Termination Visit date, whichever occurs first. 
!
Taking incorrect study medication for more than three months.
38

EXSCEL Protocol Amendment 06
All protocol violations will be specified in the statistical analysis plan prior to unblinding of the 
data. Events that occurred after protocol violation will be excluded from the analysis. Patients 
will be analyzed as randomized.
The primary safety and primary efficacy analyses will be repeated with the per-protocol 
population as sensitivity analyses.
9.7.3
Safety Population 
The safety population consists of all randomized patients who received at least 1 dose of study 
therapy; in addition, if a patient is found to have taken a study therapy for the entire duration of 
the study, different from that to which he/she was randomized, then the patient is counted in the 
treatment group of the drug he/she actually received. Serious AEs, including those which lead to 
discontinuation of study medication, occurring between randomization and 70 days after the last 
dose of study medication, will be summarized. For continuous safety parameters, at least one 
post-randomization measurement is required for inclusion in the analysis. To assess change from 
baseline, a baseline measurement is also required.
9.8
Safety Data Analysis
Safety parameters will be summarized and presented in tables for the safety population. Serious 
adverse events will be listed as described in the SAP.
9.9
Subgroup Analyses 
Subgroup analyses for the primary CV composite endpoint will be performed on the ITT 
population in order to explore whether the treatment effect on the risk of developing CV events 
is consistent across subgroups.  The following subgroups will be assessed:
!
Class of AHA therapy at entry (mono or combination)
!
Race (Indian [American] or Alaska Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Hispanic, Other)
!
Geographic region (North America, Latin America, Europe and Asia Pacific)
!
Gender (Male, Female)
!
Age (<65 or #65)
!
Baseline HbA1c (<8.0% or #8/0%)
!
Baseline BMI (<30 or #30 kg/m2)
!
Duration of diabetes (<5, 5-14, #15 years)
!
eGFR groups (in mL/min/1.73 m2)
∀
(<60 or #60)
∀
Stage 1: 90+, Stage 2: 60-89, Stage 3: 30-59, Stage 3a: 45-59, Stage 3b: 30-44, Stage 4: 
15-29, Stage 5: <15
!
History of previous cardiovascular event (e.g., previous MI or stroke)
The hazard ratios, 95% CIs, and appropriate summary statistics for each of the subgroups (by 
treatment group) will be provided and the hazard ratios examined for interaction effects. The 
39

EXSCEL Protocol Amendment 06
interaction effect would be treatment × stratified variable, in additive format with treatment + 
stratified variable. For example, the stratified variable means the categorical variable ‘Region’. 
9.10
Interim Analyses
The DSMB will undertake safety reviews of all available data every 6 months or more frequently 
if the committee deems it appropriate.
Two formal interim efficacy analyses are planned after approximately 453 and 906 primary 
composite CV events are adjudicated, corresponding to one-third and two-thirds, respectively, of 
the targeted 1360 primary composite CV events.  The analyses will test for superiority using a 
Haybittle-Peto spending function where the study termination guideline for overwhelming 
superiority will be p-value < 0.0001 for the first interim analysis and p-value <0.001 for the 
second interim analysis.  This will ensure a significance level of 0.0499 for the final analysis.
If the stopping boundary for efficacy is met at either of the interim analyses, the DSMB may 
recommend terminating the study earlier than planned.  The DSMB may, however, also advise 
terminating the study early for safety or ethical reasons.
The interim analyses will be performed by an independent statistical group.  Further details of 
the interim analyses are provided in the DSMB Charter.  
9.11
Economic Analysis
The primary objective of the economic analysis is to collect sufficient data from the trial 
participants on resource use and quality of life to undertake cost-effectiveness analyses that are 
relevant to the major countries taking part in the study. Resource use data on hospitalizations, 
visits and medications will be combined with appropriate national unit costs to calculate a cost 
per patient per year in the study. Quality of life data from the EQ-5D will be combined with 
survival data to calculate quality adjusted time in the trial per patient. 
Cost-effectiveness analyses will report the incremental cost per major CV outcome averted, CV-
related death averted, life-year gained and quality-adjusted life year gained, of including EQW in 
addition to usual care vs. usual care without EQW. Analyses will be conducted within trial and 
using a lifetime perspective, with lifetime extrapolation performed using the UKPDS Outcomes 
Model or all patients still alive at the end of the study, using risk factor characteristics from the 
last available visit. A full analysis plan for the economic analysis will be prepared and reported 
separately from this protocol.
For the main clinical study report (CSR), the quality of life data will be summarized 
descriptively for baseline and changes from baseline by treatment.
10
SAFETY ASSESSMENTS
10.1
Definitions
Adverse Event (AE)
An adverse event is defined as any unfavorable and unintended sign, symptom, disease or change 
in the structure, function, or chemistry of the body temporally associated with the use of the 
investigational product, whether or not considered related to the use of the product. 
Any 
40

EXSCEL Protocol Amendment 06
worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a 
preexisting condition which is temporally associated with the use of the investigational product, 
is also an adverse event.  Adverse events include those reported spontaneously by the patient or 
as the result of non-directed questioning from study site personnel.
Changes as a result of 
normal growth and development which do not vary significantly in frequency or severity from 
expected levels are not to be considered adverse events (e.g. the onset of menopause occurring at 
a physiologically appropriate time).  
Serious Adverse Event (SAE)
This is defined as any untoward medical occurrence or effect in a patient treated on a study 
protocol which does not necessarily have a causal relationship with the study treatment, that also, 
at any dose:
!
Results in death
!
Is life-threatening
!
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions
!
Requires in-patient hospitalization or prolongs existing hospitalization
!
Results in a congenital anomaly or birth defect
!
Is otherwise medically significant (i.e. withdrawal reactions, all accidental or intentional 
overdoses of study medication whether they result in an adverse event or not, or any event 
which the investigator considers significant but which is not covered by the above)
Suspected Unexpected Serious Adverse Reaction (SUSAR)
This is defined as a serious adverse event, the nature or severity of which is not consistent with 
the known study treatment information.  
10.2
Adverse Event Assessment
Adverse events will be monitored over the course of the trial, starting from the time of 
randomization and through the duration of the patient’s participation, including the 70 day 
post-trial medication follow-up period.  Adverse events reported by the patient will be evaluated 
by the investigator to determine if a given event meets the criteria for a serious event (described 
in Section 10.1).  Any adverse event that does not meet the definition of a serious event will be 
considered non-serious and will not be recorded in the eCRF, with the exception of events noted 
in Section 10.3.
10.3
Recording and Reporting Adverse Events
10.3.1
Recording Adverse Events
SAEs will be recorded in the Clinical Events or SAE eCRF modules as appropriate (see Table 
1) throughout the trial (including the 70 day safety wash-out period after last dose of study 
medication). Guidelines for events which qualify as Clinical Events are provided in Appendix 1. 
Events to be recorded in the Clinical Events eCRF module include SAEs that are: (1) Obvious 
41

EXSCEL Protocol Amendment 06
trial endpoints, (2) Cardiovascular Events of Interest, (3) Expected Events and Diabetic 
Complications.
In addition, non-serious adverse events of percutaneous coronary intervention (PCI), stress tests, 
severe hypoglycemia, diabetic eye disease, foot ulcer, microalbuminuria, macroalbuminurea, 
hyperlipidemia/dyslipidemia, hypertension, or gout also will be recorded in the Clinical Events 
eCRF module (see Appendix 1).
Any SAE which is not included among the expected events on the Clinical Events List will be 
recorded in the SAE eCRF module.  
Events of neoplasia and pancreatitis should be reported on the SAE eCRF even if the event does 
not meet seriousness criteria.
Note: The events listed in Appendix 1 are Clinical Events that are trial endpoints or expected 
events for this population, and do not generally fit the definition of a SUSAR, including those 
events with an outcome of death.  However, if the investigator’s assessment of an event is that it 
meets SUSAR criteria despite being listed as a Clinical Event, the event may be reported as a 
SUSAR via the SAE eCRF as long as it is not any of the possible trial endpoints listed in 
Appendix 1, Section I).
Table 1:
List of events to be recorded in each eCRF reporting module*
eCRF reporting module
to be used
List of events to be recorded in this eCRF reporting module:
Clinical Event eCRF
- Clinical Events that meet the criteria of an SAE (i.e. serious adverse event) and are 
listed in Appendix 1
- All non-serious (or serious) events of percutaneous coronary intervention (PCI), 
stress tests, severe hypoglycemia, diabetic eye disease, foot ulcer, microalbuminuria, 
macroalbuminuria, hyperlipidemia/dyslipidemia, hypertension, or gout
- All neoplasia events
- All pancreatitis events
SAE eCRF
- Any event meeting the criteria of an SAE (see Section 10.1 for definition of SAE)
that are not listed in Appendix 1
- All episodes of pancreatitis
- All episodes of any type of neoplasia/cancer
- Any AE or SAE resulting from an overdose of study drug
- Any event that is recorded in the Clinical Event eCRF, that the investigator considers 
a SUSAR, with the exception of possible Primary or Secondary trial endpoints (i.e. all 
events listed in Appendix 1, Section I)
* Trial sites will be provided with an ‘EXSCEL Event Reporting’ flow chart that can be referenced to help 
identify which events should be reported in which eCRF reporting module. 
The Clinical Events List will be reviewed and the eCRF will be completed during every visit to 
determine if a patient has experienced one or more of the listed events. SAEs should be 
42

EXSCEL Protocol Amendment 06
reviewed for all patients randomized regardless of whether the patient is currently on trial 
medication.
10.3.2
Safety Reporting
The DSMB will monitor the totality of collected safety data (i.e. events recorded on both the 
Clinical Events and SAE eCRFs) on a semi-annual basis regardless of event classification.  SAEs
recorded on the Clinical Events eCRF represent those events which are components of the 
composite CV endpoint, other trial endpoints, potential components of the CV endpoint that 
require adjudication or are expected sequelae of T2DM.  SAEs recorded as Clinical Events, 
including death related to an event in the Clinical Events List, will not be reported to the 
Sponsor, regulatory agencies or ethics committees, regardless of relationship to trial 
medication even though they may be considered possibly, probably or definitely drug-related 
and meet SAE criteria.
This will be applicable throughout the duration of trial including the 
70 day wash-out period.  There will be no switch to collecting and reporting Clinical Events as 
SAEs.  Thus, the exemption from routine SAE reporting of events listed in Protocol Appendix 1 
will remain for the entire trial duration, including the safety wash-out phase. In addition to the 
un-blinded review by the DSMB, events reported via this module that may be associated with a 
trial endpoint will be adjudicated by the CEC. As described above, all SAEs that are not 
included in the Clinical Events List will be recorded by the investigator in the SAE eCRF 
module.  These events must be recorded in this module (or faxed to the number provided on the 
SAE report form if EDC is unavailable) within 24 hours of a trial site becoming aware of the 
event.  Any SAEs meeting the definition of a SUSAR will be subject to expedited reporting as 
per current legislation.  Brief information on the clinical course of the event, treatment, and 
relevant diagnostic, laboratory or other investigations will be collected on the eCRF. 
All 
episodes of pancreatitis and neoplasia will be treated as SAEs and will be collected and reported 
in the SAE eCRF module.  All events recorded in the SAE eCRF module will be reported to the 
appropriate regulatory agencies in a manner and timeframe consistent with all applicable laws 
and regulations (Section 10.3.3). All SUSARS will be reported in an expedited manner with the 
exception of possible trial endpoints as detailed in Section I of Appendix 1, which will be 
handled as Clinical Events.
Note that pancreatitis and pancreatic neoplasms / malignancies are events of special interest for 
GLP-1 based therapies, such as exenatide.  As described above, all events of pancreatitis and all 
neoplasms (including pancreatic cancer) are to be reported on both the Clinical Events eCRF and 
the SAE eCRF, even if the event does not meet seriousness criteria. These events are reviewed 
by the DSMB and adjudicated by the CEC.
Additionally, any SAE considered by an investigator who is a qualified physician to be possibly, 
probably, or definitely related to the investigational product that is brought to the attention of the 
investigator after study closeout must be reported within the above timeline.  All patients with 
serious adverse events must be followed to assess outcome until resolution or until designated 
permanent.
43

EXSCEL Protocol Amendment 06
10.3.3
Sponsor Responsibility for Reporting Serious Adverse Events
The Sponsor will ensure that all appropriate regulatory agencies confirm that the approach for 
monitoring Clinical Events, described in the Safety Assessments Section is acceptable to them.  
SAEs that are not recorded as Clinical Events will be reported to regulatory agencies, IRB/IECs, 
and investigators in accordance with all applicable global laws and regulations.
10.4
Calcitonin Monitoring
Studies in rodents have indicated an increased incidence of thyroid C-cell tumors (adenomas, 
carcinomas) with EQW treatment. The relevance of these findings to human safety is currently 
unknown and is being investigated.  In clinical studies, there was no difference between 
exenatide (BID or once weekly) and comparators with respect to thyroid neoplasms.  A detailed 
summary of findings in rodents and clinical studies is available in the Exenatide Investigator 
Brochure. Measurement of calcitonin has been added to newly initiating clinical trials of EQW 
to characterize any effects of exenatide or comparator treatment on calcitonin levels over time to 
better assess evidence of a biologic effect on c-cells. In clinical trials, no difference in calcitonin 
was observed between exenatide and comparators.
Calcitonin concentrations will be monitored at baseline, annually and at the Trial Termination
visit.  Investigators and participants will be blinded to calcitonin values.  If the baseline value 
exceeds 40 ng/L, the site will be informed and directed to have the patient terminate study 
medication.  If a concerning calcitonin value (#50 ng/L) is identified during trial follow-up, the 
site investigator will be notified and they should call the Trial Hotline for advice, where they will 
be instructed to alert the usual care provider and permanently discontinue study medication.  
Calcitonin concentrations will be monitored by the DSMB, which will include a thyroid expert.  
10.5
Overdose
10.5.1
Definition of an Overdose for This Protocol
An overdose is defined as a patient taking more than 1 dose of study medication in the same day.  
In the event of an overdose, medical treatment may be needed since severe nausea and vomiting 
are possible.
The patient should be instructed to contact the investigational site, and/or 
healthcare provider in the event of an overdose.
10.5.2
Reporting of Overdose
If an adverse experience(s) is associated with (“results from”) the overdose of study medication, 
the adverse experience(s) is collected as a serious adverse experience, even if no other criteria for 
seriousness are met.
If a dose of study drug meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as an Event 
of Clinical Interest (ECI), using the terminology “accidental or intentional overdose without 
adverse effect.”
All reports of overdose with and without an adverse experience must be reported within 1 day of 
the site’s knowledge of the event.
44

EXSCEL Protocol Amendment 06
10.6
Reporting of Pregnancy
Although not considered an adverse experience, it is the responsibility of investigators or their 
designees to report any pregnancy in a patient (spontaneously reported to them) which occurs 
during the trial or within 70 days of completing the trial. All patients who become pregnant must 
stop taking blinded trial medication and be followed to the completion/termination of the 
pregnancy. All occurrences of pregnancy must be reported via the Pregnancy Surveillance
Form. If the pregnancy continues to term, the outcome (health of infant) must also be reported.
10.7
Unblinding
Breaking the blind is strongly discouraged and should only be requested if it is deemed necessary 
for the wellbeing or safety of the patient. Any Investigator requesting the unblinding of a patient 
will be asked to contact the trial hotline physician, available 24hrs/day to discuss the case and 
determine the course of action; however, it is the prerogative of the treating physician to insist 
that their patient should be unblinded.  Patients whose treatment has been unblinded can continue 
to receive trial medication and can continue to be followed in the trial as described in this 
protocol.
11
ETHICAL AND LEGAL ASPECTS
11.1
General Informed Consent
The investigator must obtain written documented consent to participate in the trial from each 
potential patient in his/her native language. Consent must be documented by the patient's dated 
signature on a Consent Form along with the dated signature of the person conducting the consent 
discussion. If the patient is illiterate, an impartial witness should be present during the entire 
informed consent reading and discussion. Afterward, the patient should sign and date the 
informed consent, if capable. The impartial witness should also sign and date the informed 
consent along with the individual who read and discussed the informed consent (i.e., trial staff 
personnel). A copy of the signed and dated consent form should be given to the patient.
The initial informed consent form, any subsequent revised written informed consent forms, and 
any written information provided to the patient must receive the IRB/IECs approval/favorable 
opinion in advance of use. The patient or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
patient’s willingness to continue participation in the trial. 
The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form.
The informed consent form will describe the regular two-way exchange of information that is 
expected to occur between trial physicians and the usual care physicians.  The informed consent 
form will also include a request that the patient provide permission for the collection of medical 
records and copies of relevant reports necessary for complete data collection even if trial 
medication is discontinued beforehand.
45

EXSCEL Protocol Amendment 06
11.2
Consent and Collection of Specimens for Genetic and Genomic 
Analysis
Patients providing informed consent will have a whole blood specimen collected for potential 
future genetic research. This is an optional activity, and only those patients who have consented 
to having this genetic sample collected may have this blood sample drawn. The approval of the 
consent form for analysis and the associated protocol procedures (e.g., collection of a blood 
sample) may, in some cases, proceed independently through Institutional Review Boards, Ethical 
Review Boards, Independent Ethical Review Committees (ERCs), Privacy Committees, etc., 
from the associated clinical trial.
11.3
Consent and Collection of Biomarker Specimens
Patients providing informed consent will have blood and urine samples, preferably fasting, 
collected at baseline (prior to drug exposure), Year 1, and at the Trial Termination visit. 
Biomarker samples will be stored in at least two aliquots for potential future proteomic and/or 
metabolomic analysis. This is an optional activity, and only those patients who have consented 
to having this biomarker sample collected may have this blood sample drawn. The approval of 
the consent form for analysis and the associated protocol procedures (e.g., collection of a blood 
sample) may, in some cases, proceed independently through Institutional Review Boards, Ethical 
Review Boards, Independent Ethical Review Committees (ERCs), Privacy Committees, etc., 
from the associated clinical trial.
11.4
Ethics Committee or Institutional Review Board
Documented approval from appropriate Ethics Committee(s) or Institutional Review Board(s)
must be obtained for all participating centers prior to study start, according to Good Clinical 
Practice (GCP), local laws, regulations and organizations. 
When necessary, an extension, 
amendment or renewal of the Ethics Committee approval must also be obtained. 
Ethics 
Committees, upon request, may be required to provide a list of the Ethics Committee members
involved in the vote and a statement to confirm that the Ethics Committee is organized and 
operates according to GCP and applicable laws and regulations. Modifications to the study 
protocol will not be implemented without the agreement of the Executive Committee and 
appropriate ethical approval.
11.5
Ethical Conduct of the Study
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the sponsor and investigator abide by GCP G uidelines.  
The study will also be carried out in keeping with applicable local law(s) and regulation(s).  This 
may include an inspection by the sponsor representatives and/or Regulatory Authority 
representatives at any time.  The investigator must agree to the inspection of study-related 
records by the Regulatory Authority/sponsor representatives, and must allow direct access to 
source documents to the Regulatory Authority/sponsor representatives.  The investigator must 
notify the sponsor promptly of any inspections scheduled by regulatory authorities, and promptly 
forward copies of inspection reports to the sponsor.
46

EXSCEL Protocol Amendment 06
All potential serious breaches must be reported to the sponsor immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
patients of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
11.6
Regulatory Authority Approvals/Authorizations
Regulatory Authority approvals/authorizations/notifications, where required, must be in place 
and fully documented prior to study start.
11.7
Confidentiality
All records identifying the patient will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. The patient will be 
identified only by a unique patient ID number on the eCRF.  All documents will be stored 
securely and kept in strict confidence in compliance with the Data Protection Act.
Study findings stored on a computer will be stored in accordance with local data protection laws.  
The patients will be informed in writing that representatives of the sponsor, Ethical Committees, 
Institutional Review Boards or Regulatory Authorities may inspect their medical records to 
verify the information collected, and that all personal information made available for inspection 
will be handled in strictest confidence and in accordance with local data protection laws.
When the results of the study are published, the patient’s identity will remain confidential.  The 
investigator will maintain a list to enable patients’ records to be identified.
11.8
Records
11.8.1
Records Retention
The investigator must retain all study records and source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by the sponsor, whichever is longer. The investigator must contact the sponsor prior to 
destroying any records associated with the study.
The sponsor will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, IRB). Notice of such 
transfer will be given in writing to the sponsor.
11.8.2
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
47

EXSCEL Protocol Amendment 06
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by the investigator or qualified physician who is a sub -investigator 
and who is delegated this task on the Delegation of Authority Form. For electronic CRFs, review 
and approval/signature is completed electronically through the electronic data capture tool. The 
investigator must retain a copy of the CRFs including records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet training requirements and 
must only access the electronic data capture tool using their unique user account. User accounts 
are not to be shared or reassigned to other individuals.
12
TRIAL MANAGEMENT/GOVERNANCE COMMITTEES
12.1
Executive Committee (EC)
The EC will be responsible for overall management and oversight of the trial. The EC will be 
composed of senior independent academic representatives who are experts in their field and 
representatives from the sponsor.  The Committee will be co-chaired 
 
   An EC charter will outline the 
committee membership and structure and delineate operating procedures.
The Executive Committee is the main decision-making body for the EXSCEL trial and is 
charged with the overall scientific, professional, and operational conduct of the trial.
The primary functions of the Executive Committee are to:
1. Review and approve the trial protocol and all protocol amendments.
2. Supervise the conduct of the trial in accordance with its responsibilities described in the trial 
protocol and committee charter. 
3. Review and approve the Statistical Analysis Plan. 
4. Oversee all trial subcommittees, including but not limited to: 
!
Clinical Endpoint Committee
!
Data Safety Monitoring Board 
!
Operations Committee 
!
Strategic Advisory Committee
5. Review and consider recommendations from the Data Safety Monitoring Board (DSMB). 
6. The Executive Committee will determine the time to terminate the trial, based on 
recommendations from the DSMB and other available information. The Executive Committee 
may also find it necessary to terminate the trial under certain circumstances, including but not 
limited to the following reasons: 
48
PPD

EXSCEL Protocol Amendment 06
!
Animal, human or toxicological test results, in the reasonable determination of the Executive 
Committee, support termination of the trial 
!
Ethical or patient safety issues occur that the Executive Committee feels support termination 
of the trial 
!
Extraordinary scientific, regulatory or other events that negatively impact the rationale for 
the trial such that the Executive Committee agrees it is appropriate to terminate the trial 
7. Review all sub-study requests and approve where appropriate. 
8. Consider, authorize as appropriate and prioritize requests for access to trial data and/or
genetic and biomarker samples for academic or other collaborations. 
After the Executive 
Committee disbands, DCRI, DTU and the sponsor will assume this responsibility. 
9. Approve the communication strategy on how to best communicate information about the 
progress of the trial. 
10. Ensure accurate, uniform, timely, and high quality reporting of the main trial and all 
approved sub-studies. 
11. Serve as the writing group who will prepare and submit for publication the primary 
manuscript describing the main trial results. All members of the Executive Committee will have 
access, in confidence to the draft manuscript describing the primary results paper. 
12. Assume the role of publications committee and review, authorize and prioritize proposals for 
publications which require trial or sub study data, samples, or genetic material and assign writing 
groups. 
13. Review and comment on any independent publications reporting results from the trial 
following the primary publication. 
12.2
Operations Committee (OC)
The Operations Committee (OC) is composed of Country Leads selected by the Executive 
Committee from investigators in each country with appropriate clinical trial experience. The OC 
will be co-chaired by the clinical coordinators from the Duke Clinical Research Institute (DCRI) 
and the Diabetes Trials Unit (DTU). Balance will be sought between cardiologists and 
endocrinologists. The primary role of the OC is to serve as the interface between the EC and the 
trial sites, and to assist in the progress of the trial at the regional level. Committee members will 
be instrumental in serving as ambassadors of the trial to encourage recruitment as well as ensure 
trial compliance by working with study personnel and mediating in country-specific issues. The 
committee will provide a means of transmitting any identified needs, concerns, or suggestions 
from the sites to the EC and assist in disseminating clinical or operational information to the 
sites. The functions and operating procedures of the OC are delineated in a charter. 
12.2.1
Remit of Operations Committee
Specific functions of the OC will include the following: 
1. All members will serve as regional leaders for site investigators. 
2. All members will serve as advocates for the trial. 
3. Country Leads will:
49

EXSCEL Protocol Amendment 06
a) Communicate with investigators in the Lead’s country to review country specific 
progress reports, including but not limited to recruitment/retention of patients, event 
reporting and data collection, and communication between sites and usual care providers. 
b) Liaise with the academic coordinating centers and global 
Contract Research 
Organizations (CROs) to review and attempt to resolve any operational issues raised 
within a region.
c) Support regulatory submissions, as needed in collaboration with the Sponsor’s 
Regulatory Affairs Department.
4. Committee Co-Chairs will: 
a) Compile country-specific performance metrics for presentation to the Executive 
Committee. 
b) Liaise with Country Leads, academic coordinating centers (DCRI and DTU project 
teams), sponsors and global AROs/CROs to implement trial policies.
12.3
Data Safety Monitoring Board (DSMB)
The DSMB will be composed of six senior academic individuals, including the DSMB Chair.  
There will be at least one member with high-level expertise for each of cardiology, 
endocrinology, and statistics.  An Independent Statistician (not affiliated with the DCRI, DTU, 
or the Sponsor) will also be in attendance.  All of these individuals will have long-standing 
experience in the operational, medical, and biostatistical aspects of international clinical trials.  
The DTU senior statistician assigned to the trial will oversee the provision of interim masked 
data sets for use by the DSMB and the DCRI/DTU trial coordinating centers.  DTU will transfer 
pre-agreed masked datasets to the Independent Statistician who will then prepare unmasked 
confidential reports for the DSMB, using treatment codes provided in advance by the IVRS 
vendor.  During the Open Session of the DSMB meetings, representatives of the Executive 
Committee may present updates on the trial status or the safety profile of exenatide, but will not 
be privy to discussions of the unmasked data conducted during the Closed Sessions and will not 
vote.  Proceedings and minutes of the Closed Session will be held in strict confidence and will 
not be shared outside the DSMB while the trial is ongoing.
The DSMB will be responsible for the interests of the patients and, to this end, will undertake 
regular reviews of the safety data.  The DSMB will have access to an agreed subset of the trial 
data as listed in the DSMB charter (updated as necessary during the trial) in an unblinded fashion 
throughout the trial duration. In addition, the DSMB will evaluate two interim analyses after 
approximately one-third and two-thirds of the total targeted number of primary composite CV 
events (see Sec 9.10 for details).
If the DSMB finds it necessary to recommend actions regarding interruption of the trial or 
changes to the protocol based on medical rationale that would make it unethical to continue the 
trial in its present form, those recommendations will be forwarded to the EC.  The details of the 
DSMB's functions and the early stopping rules will be delineated in a separate DSMB charter.
50

EXSCEL Protocol Amendment 06
12.4
Clinical Events Committee (CEC)
The events which constitute the principal endpoints of this trial will be adjudicated by the 
Clinical Events Classification Committee (CEC), coordinated through the Duke Clinical 
Research Institute (DCRI), which will be comprised of approximately 5-7 physicians and a 
coordinator.  The specific endpoints to be adjudicated include:  cause of death (cardiovascular-
related vs. non-cardiovascular), MI, stroke, acute coronary syndrome, pancreatitis, neoplasm, 
ventricular fibrillation/tachycardia, and CHF requiring hospitalization. Clinical reviewers will be
board certified or board eligible endocrinologists, cardiologists, neurologists, gastroenterologists, 
or physicians with clinical expertise and prior clinical event classification experience. The CEC 
will review clinical data and adjudicate safety and efficacy endpoints.  The CEC will adjudicate 
clinical events using pre-specified criteria and definitions.  The CEC will be blinded to the 
assigned trial medication. Sites will provide clinical information via the eCRF and also provide 
supplemental information from medical records, when needed. The CEC operations and endpoint 
criteria will be described in a separate charter.
12.5
Strategic Advisory Committee
The Strategic Advisory Committee will provide oversight for the operational conduct of the 
study across all participating institutions. It will be composed of senior management from the 
Sponsors, AROs and contracted CROs, who are experts in the operational aspects of the conduct 
of clinical trials and the EXSCEL Clinical Leads.
13
DISCLOSURE OF DATA, PUBLICATIONS, AND CLINICAL STUDY
REPORT
During the Trial all data derived from the Trial will be held by the AROs but with access for 
Sponsor to any data required for safety and regulatory purposes. At the time database lock 
occurs, the IVRS provider will provide the AROs with an electronic file containing the full 
randomization codes for upload to the electronic database.  The ARO will undertake the planned 
analyses and prepare and submit manuscripts for publication and presentation to academic 
meetings agreed by the Executive Committee. The Sponsor will have the right to comment on 
these but the final editorial control remains with the Executive Committee. The Executive 
Committee will draft the manuscript describing the main study results, and oversee publications 
requiring trial data, samples, or genetic material.
In addition, a CSR will be prepared for regulatory purposes.  The Signatory Investigator 
responsible for signing the CSR will be selected by the Sponsor in conjunction with the 
Executive Committee.
51

EXSCEL Protocol Amendment 06
14
REFERENCES
                                                          
1
King H, Aubert RE, Herman WH: Global Burden of Diabetes, 1995-2025.  Diabetes Care 
1998; 21:1414-1431.
2
UKPDS Group. Risk factors for coronary artery disease in non-insulin dependent diabetes 
(UKPDS 23). BMJ 1998; 316: 823–828. 
3
Collins R, Armitage J, Parish S, Sleight P, Peto R. MRC/BHF Heart Protection Study of 
cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-
controlled trial. Lancet 2003;361:2005-2016. 
4
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, 
Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH: Primary prevention of 
cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin 
Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet 2004; 
364:685–696.
5
UK Prospective Diabetes Study Group (UKPDS): Tight blood pressure control and risk of 
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 
317:703–713.
6
Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood-pressure lowering 
and low-dose aspirin in patients with hypertension: principal results of the Hypertension 
Optimal Treatment (HOT) randomized trial. Lancet 1998; 351:1755–1762.
7
Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in 
type 2 diabetes. N Engl J Med 2008;359:1577–1589. 
8
Ray KK, Seshasai SRK, Wijesuriya S, et al. Effect of intensive control of glu cose on 
cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of 
randomized controlled trials. Lancet 2009;373:1765–1772. 
9
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention 
on mortality in type 2 diabetes. N Engl J Med 2008;358:580-591. 
10 Shen L, Han J, Yushmanova I, Bruce S, Porter L. Cardiovascular safety of exenatide BID: an 
integrated analysis from long-term controlled clinical trials in subjects with type 2 diabetes.  
Diabetes 2009;58(Suppl 1):A96-97. Abstract 366-OR.
11 Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, Hoogwerf BJ, 
Rosenstock J. Use of twice-daily exenatide in basal insulin-treated patients with type 2 
diabetes: a randomized, controlled trial. Ann Intern Med 2011;154(2):103-112.
12 Drucker DJ, Buse JB, Taylor K, Kendall D, Trautmann M, Zhuang D, Porter L. Once 
Weekly vs Twice daily Exenatide for the Treatment of Type 2 Diabetes. Lancet 
2008;372(9645):1240-1250.
52

EXSCEL Protocol Amendment 06
                                                                                                                                                                                          
13 Buse J, Drucker D, Taylor K, Kim T, Wilhelm K, Kendall D, Trautmann M, Zhuang D, 
Porter L. Exenatide once weekly elicits sustained glycaemic control and weight loss over 52 
weeks. Diabetologia 2008;51(Suppl 1):S67. Abstract 146.
14 http://www.ngsp.org/prog/index.html
53

EXSCEL Protocol Amendment 06
APPENDIX 1
CLINICAL EVENTS LIST
Any clinical event listed in this appendix that meets the criteria of an SAE (unless indicated otherwise below) must 
be reported in the Clinical Event eCRF reporting module.
I.
Obvious Trial Endpoints 
(These events will prompt the investigator to complete an endpoint package which will then be adjudicated 
according to the Clinical Events Classification [CEC] charter)  
Death
!
Cardiovascular (CV) Death (i.e., fatal myocardial infarction [MI] / cerebrovascular accident 
[CVA] / congestive heart failure [CHF] / arrhythmia, cardiac arrest, death following CV 
intervention)
!
Non-CV Death
Nonfatal MI
Acute coronary syndrome
Nonfatal CVA
CHF requiring hospitalization
II. Cardiovascular Events of Interest
(Some of these events will result in prompts to answer additional questions in the eCRF – these questions will be 
designed to determine whether or not a primary or secondary outcome of interest has occurred) 
Atrial fibrillation/Atrial flutter
Ventricular fibrillation/tachycardia requiring intervention
Deep Vein Thrombosis (DVT)
Pulmonary embolism
Percutaneous Coronary Intervention (PCI) – (including non-serious events)
Coronary Artery Bypass Graft (CABG)
Coronary catheterization
Stress test (including non-serious events)
Abdominal aortic aneurysm/repair
Carotid endarterectomy/Carotid angioplasty and/or stenting
Any hospitalization due to cardiovascular events (i.e., whether or not the hospitalization was for an obvious 
trial endpoint)
Shock/hypotension
Accelerated or malignant hypertension/hypertensive urgency
Transient Ischemic Attack (TIA)
Syncope
Renal artery angioplasty and/or stenting
Other arterial angioplasty and/or stenting
III. Expected Events and Diabetic Complications
(Subcategories indicate potential additional information to be captured, usually as an indication of severity)
A. Peripheral Vascular Disease (PVD)
!
Limb PCI
!
Vascular surgery 
54

EXSCEL Protocol Amendment 06
!
Amputation
!
Surgical debridement of ulcer
B.
Gangrene
C.
Severe hypoglycemia (including non-serious events) / Hyperglycemia / Diabetic ketoacidosis / Hyperosmolar 
hyperglycemic nonketotic coma
D.
Diabetic eye disease (including non-serious events)
!
Photocoagulation or other laser therapy
!
Cataract extraction
!
Blindness
!
Enucleation
!
Steroid/Avastin injection
!
Scleral buckling or other retinal fixation procedure
E.
Diabetic neuropathy (including distal sensorimotor, focal/multifocal, or autonomic) (including non-serious 
events)
!
Foot ulcer
F.
Diabetic nephropathy (including non-serious events)
!
Microalbuminuria
!
Macroalbuminuria
G.
Renal failure
!
Acute renal failure, requiring or associated with hospitalization
!
Chronic renal failure, requiring peritoneal or hemodialysis, including creation of fistula or other vascular 
access for hemodialysis
!
Renal transplant
H.
Any hospitalization due to complications of DM
I.
Infections
!
Osteomyelitis
o
IV antibiotic therapy vs. debridement
!
Cellulitis
o
Oral vs. IV antibiotic therapy
!
Mucormycosis
!
Pneumonia
o
Community acquired vs. hospital acquired
o
Oral vs. IV antibiotic therapy
!
Bacteremia
!
Sepsis
!
Infected joints
o
Prosthetic joint
!
Complicated or serious urinary tract infection (UTI) / Pyelonephritis
o
Requiring hospitalization
!
Malignant external otitis
J.
Gastrointestinal (GI) conditions  
55

EXSCEL Protocol Amendment 06
!
Abdominal pain
!
Nausea / vomiting
!
Diarrhea
!
Fatty liver disease / Nonalcoholic steatohepatitis (NASH)
!
Cholecystitis / cholelithiasis
!
Elevated liver enzymes
K.
Metabolic Conditions Associated with Diabetes (including non-serious events)
!
Hyperlipidemia / dyslipidemia
!
Hypertension
!
Gout
56

EXSCEL Protocol Amendment 06
APPENDIX 2
TRIAL PLAN (PROTOCOL BCB109)
Table 1:
Trial Plan 
Treatment Initiation
Follow-up [4]
Drug or Study Termination
Evaluation
Screening
Day -1
Randomization 
Day 0
Visit 1 [1]
Week 1 and
Month 2 
Visit 2 and 3
Semi-
Annual
Annual
Drug 
Termination [5]
Trial 
Termination [8]
Post-
Treatment
Follow-up
Contact [9]
Informed Consent/HIPAA [2] and 
Stored Blood Sample Authorization
X
Medical History
X
Physical Examination
X
Height
X
Blood Pressure, Heart Rate and 
Body Weight
X
X
X
X
X
X
Calcitonin Blood Sample
X
X
X
Collect and review available 
information including most recent 
HbA1c, serum creatinine and lipid 
profile
X [6]
X
X
X
X
Randomization
X
If consent obtained, collect blood 
sample for genetic and genomic 
analysis
X [7]
If consent obtained, blood sample 
(serum and plasma) and urine 
sample for archive
X
Year 1 
only
X
Drug Dispensation
X
X
X
Used/Unused Vial Assessment
X
X
X
X
Clinical and SAE Event Assessment
X
X
X
X
X
X
X
Conmed Assessment
X
X
X
X
X
X
X
Confirm competency with 
injections [3]
X
EQ-5D Completion
X
Month 6 
only
X
X
[1]   Wherever possible the screening and randomization visit should be combined.
[2]   Informed Consent Form and if applicable, authorization to use and disclose protected health information.
[3]   Patients will return approximately 1 week (±3 days) as well as 2 months (± 2 weeks) after Day 0 to perform a self-injection under the observation of the 
clinical site to confirm competency with injection.  An additional visit can be considered at ~1 month if the patient is not able to adequately inject themselves.
[4]   Semi-annual (±1 month) and Annual Follow-up (±1 month) Visits will occur in reference to Visit 1 Day 0 for the duration of participation in the trial.
57

EXSCEL Protocol Amendment 06
[5]   Patients who terminate study medication are required to have a Drug Termination Visit as part of their next scheduled study visit (unless a separate drug 
termination visit at that point is deemed necessary by the investigator).  Patients will continue to be observed following the Drug Termination visit according to 
their planned visit schedule for the remainder of the trial.  All procedures for remaining Semi-annual and Annual Visits are to be followed with the exception of 
Drug Dispensation.
[6]   It is recommended that serum creatinine value draw dates be within 3 months of randomization but up to 12 months is acceptable (however, if > 6 months 
old and value is between 30-40mL/min/1.73m2 it is recommended that a new serum creatinine value is obtained as part of usual care).
[7]   Blood sample for genetic and genomic analysis may be collected at any time during the trial after consent is obtained.
[8]   For patients who have been discontinued from trial medication for more than 70 days as of the Trial Termination Visit, the Trial Termination Visit will be 
the final study follow-up.
[9]   Patients will be contacted by telephone to check for any Clinical Events, serious adverse experiences and hospitalizations that occurred within 70 days after 
the administration of the last dose of trial medication.  (see Section 10.3.1).
58

EXSCEL Protocol Amendment 06
APPENDIX 3
PROTOCOL AMENDMENT 01: SUMMARY OF CHANGES
Exenatide QW Clinical Study Protocol BCB109
PROTOCOL TITLE:
A 
RANDOMIZED, 
PLACEBO 
CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE CARDIOVASCULAR OUTCOMES AFTER TREATMENT WITH EXENATIDE ONCE 
WEEKLY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Protocol Number:
BCB109
Amendment Number:
01
Amendment Purpose:
Date: 11 November 2010
The purpose of Amendment 1 is to add annual and study termination calcitonin assessments and monitoring to the 
conduct of the trial.  Additional clarifications and edits are included.  Notable changes are detailed in the table 
below.
SECTION
ORIGINAL PROTOCOL TEXT
AMENDMENT 01 TEXT
Title Page
Amylin Pharmaceuticals, Inc. sponsors the 
Investigational New Drug Application in the 
US and Puerto Rico and transfers the clinical 
sponsor obligations to Lilly for the conduct 
of this study outside the US.  For 
investigative sites outside of the US and 
Puerto Rico, Lilly will serve as the study 
sponsor.  
Amylin Pharmaceuticals, Inc. sponsors the 
Investigational New Drug Application in the 
US and Puerto Rico and will serve as the 
sponsor for the Clinical Trial Application in 
Canada.  Amylin Pharmaceuticals, Inc. 
transfers the clinical sponsor obligations to 
Lilly for the conduct of this study outside the 
US, Puerto Rico and Canada.  For investigative 
sites outside of the US, Puerto Rico and 
Canada, Lilly will serve as the study sponsor.  
4.1 
Design 
Description
Eligible patients will have type 2 diabetes 
with a glycated hemoglobin (HbA1c) ≥7.0 % 
and ≤10.0 % on stable doses of up to three 
oral antihyperglycemic agents (AHAs) for at 
least 3 months i.e. no oral AHA adjustments 
in the past 3 months.
Eligible patients will have type 2 diabetes with 
a glycated hemoglobin (HbA1c) ≥7.0 % and 
≤10.0 % on stable doses of up to three (i.e. 0-3) 
oral antihyperglycemic agents (AHAs) for at 
least 3 months i.e. no oral AHA adjustments in 
the past 3 months.
5.1 
Inclusion Criteria
c.  Patient has an HbA1c of ≥ 7.0 % and ≤ 
10.0% on stable doses of up to three oral 
AHAs for at least 3 months i.e. no oral 
AHA adjustments in the past 3 months.
A patients whose HbA1c is > 10.0% may, 
at the discretion of the investigator, have 
their oral AHA therapy adjusted and be 
re-screened once for HbA1c randomization 
eligibility (≥ 7.0 % and ≤ 10.0%) 
following a 3-month period on stable 
AHA doses.
c.  Patient has an HbA1c of ≥ 7.0 % and ≤ 10.0% 
on stable doses of up to three (i.e. 0-3) oral 
AHAs for at least 3 months i.e. no oral AHA 
adjustments in the past 3 months.  
Concomitant use of DPP-4 inhibitors is 
permitted.
HbA1c values must be from within the 3 
months prior to randomization.  If multiple 
values are available, the most recent 
reported value should be used.  A patient 
whose HbA1c is > 10.0% may, at the 
discretion of the investigator, have their oral 
AHA therapy adjusted and be re-screened 
once for HbA1c randomization eligibility (≥ 
7.0 % and ≤ 10.0%) following a 3-month 
period on stable AHA doses.
5.1 
Inclusion Criteria
d.   Patients with any level of CV risk and 
meeting all other inclusion criteria may 
be enrolled. Recruitment will be 
constrained  such that 40% will not have 
had a prior CV event and 60% will have 
d.  Patients with any level of CV risk and 
meeting all other inclusion criteria may be 
enrolled. Recruitment will be constrained 
such that approximately 40% will not have 
had a prior CV event and 60% will have had 
59

EXSCEL Protocol Amendment 06
SECTION
ORIGINAL PROTOCOL TEXT
AMENDMENT 01 TEXT
had a prior CV event defined as at least 
one of the following:
a prior CV event defined as at least one of 
the following:
6.1 
Trial Procedures
Study Design Figure
The study design figure has been updated 
6.3  
Method of 
Assigning 
Patients to 
Treatment 
Groups (Visit 1)
This automated system will assign a unique 
allocation number to eligible patients and 
dispense double-blind trial medication.  
This automated system will randomize eligible 
patients and dispense double-blind trial 
medication. 
6.8 
Calcitonin 
Sample 
Collection
(this is a new subsection; subsequent 
subsections have been renumbered 
accordingly)
Serum calcitonin concentrations will be 
monitored throughout the patient’s participation 
in the trial.  Samples will be collected at 
baseline, annually and trial/early termination.
6.9 
Genetic and 
Biomarker 
Sample 
Collection
(previously 
Section 6.8)
These fasting specimens will be obtained at 
baseline (prior to drug exposure), and either 
at one year of treatment or at the time of drug 
discontinuation (if occurring within the first 
year).
These specimens (preferably fasting) will be 
obtained at baseline (prior to drug exposure), 
annually and trial/early termination.
6.12 
Early 
Discontinuation 
of Trial 
Medication
(previously 
Section 6.11)
Unless consent to follow the patient is 
specifically withdrawn, patients should 
continue to be followed as outlined in 
Section 6.14 until the end of the trial. When a 
patient withdraws consent prior to trial 
completion, all applicable activities 
scheduled for the final trial visit should be 
performed at that time.
Unless consent to follow the patient is 
specifically withdrawn, patients should 
continue with their regular visit schedule as 
outlined in Section 6.15 until the end of the 
trial. When a patient withdraws consent prior to 
trial completion, all applicable activities 
scheduled for the final trial visit should be 
performed at that time.
7.2 Formulation, 
Packaging, and 
Storage
The Microsphere Diluent must be stored 
between 2°C and 27°C (36°F and 81°F).  The 
EQW or matching placebo dose is prepared 
by reconstitution of the microspheres in the 
diluent provided.  Specific instructions for 
dose preparation of the injection will be 
provided in the Directions For Use (DFU).  
The Microsphere Diluent must be stored 
between 2°C and 25°C (36°F and 77°F).  The 
EQW or matching placebo dose is prepared by 
reconstitution of the microspheres in the diluent 
provided.  Specific instructions for dose 
preparation of the injection will be provided in 
the Patient Instructions For Use (PIU).  
7.3 
Dispensing of 
Trial Medication
Study materials will be provided to subjects 
by the investigator or medically qualified 
subinvestigator named on Form FDA 1572, 
or other qualified study-site personnel.  
Under no circumstance will the investigator 
or subinvestigators allow the study 
medication to be used other than as directed 
by the protocol or to be administered to any 
persons other than subjects participating in 
the study.
Study materials will be provided to subjects by 
the investigator, medically qualified 
subinvestigator or other qualified study-site 
personnel.  Under no circumstance will the 
investigator or subinvestigators allow the study 
medication to be used other than as directed by 
the protocol or to be administered to any
persons other than subjects participating in the 
study.
60

EXSCEL Protocol Amendment 06
SECTION
ORIGINAL PROTOCOL TEXT
AMENDMENT 01 TEXT
7.4 
Dose 
Administration 
Procedure, Route 
and Schedule
Doses of EQW or matching placebo are to be 
injected into subcutaneous (SC) tissue of the 
abdomen.  The site of injection should be 
rotated on a regular basis so that the same 
site is not used repeatedly.
Doses of EQW or matching placebo are to be 
injected into subcutaneous (SC) tissue of the 
abdomen, thigh or back of the upper arm.  The 
site of injection should be rotated on a regular 
basis so that the same site is not used 
repeatedly. The same anatomical region can be 
used for the injection but the site should be 
rotated (e.g. different quadrants of the abdomen 
can be used in a weekly rotation).
7.4 
Dose 
Administration 
Procedure, Route 
and Schedule
Subjects will be seen one week as well as 
one month after randomization to confirm 
competency with study medication.
Subjects will be seen one week as well as two 
months after randomization to confirm 
competency with study medication.
7.5 
Randomization 
Schedule and 
Blinding 
Procedures
The study-site personnel must call the IVRS 
at all subsequent visits (except Study 
Termination) to record the visit and confirm 
the kit assignment.
The study-site personnel must call the IVRS at 
all subsequent visits (except Visits 2, 3 and 
Study Termination) to record the visit and 
confirm the kit assignment
7.6
Drug 
Accountability
Drug accountability will be the responsibility 
of the study-site personnel.  Upon receipt of 
study medication, study site personnel should 
open the shipment, verify that the amount 
and identity of the contents match that stated 
on the enclosed shipping form, indicate the 
condition of the contents on the form, and 
then sign and date the form.  The study-site 
personnel should make a copy of the 
shipping form for the site's file, and return 
the original completed form to the sponsor 
(or designee).  In addition, the study-site 
personnel will contact IVRS to verify receipt 
of study medication.  
Drug accountability will be the responsibility of 
the study-site personnel.  Upon receipt of study 
medication, study site personnel should open 
the shipment, verify that the amount and 
identity of the contents match that stated on the 
enclosed shipping form, indicate the condition 
of the contents on the form, and then sign and 
date the form.  In addition, the study-site 
personnel will contact IVRS to verify receipt of 
study medication.  
9.8.3
Safety 
Population
Serious AEs and AEs leading to 
discontinuation of study medication, any of 
which occurred within 90 days after the last 
dose of study medication, will be collected.
Serious AEs, including those which lead to 
discontinuation of study medication, occurring 
between randomization and 90 days after the 
last dose of study medication, will be collected.   
10.1  Definitions
! Is otherwise medically significant (i.e. 
withdrawal reactions, all accidental or 
intentional overdoses whether they result 
in an adverse event or not, or any event 
which the investigator considers 
significant but which is not covered by the 
above.)
! Is otherwise medically significant (i.e. 
withdrawal reactions, all accidental or 
intentional overdoses of study medication 
whether they result in an adverse event or 
not, or any event which the investigator 
considers significant but which is not 
covered by the above.)
10.3 
Classification 
and Reporting of 
Adverse Events
Table 1. (additional footnote included to 
clarify collection of pancreatitis and 
neoplasia)
** All episodes of pancreatitis and neoplasia 
will be treated as SAEs and will be collected 
and reported as Ancillary Events.  
10.3 
Classification 
and Reporting of 
Adverse Events
As described in Section 10.1.1 all SAEs that 
are not included in the Clinical Events List 
will be recorded by the investigator as 
Ancillary Events.  These events must be 
recorded in this module within 1 day of a 
trial site becoming aware of the event.  Brief 
As described above, all SAEs that are not 
included in the Clinical Events List will be 
recorded by the investigator as Ancillary 
Events.  These events must be recorded in this 
module (or faxed to Lilly if EDC is 
unavailable) within 1 day of a trial site 
61

EXSCEL Protocol Amendment 06
SECTION
ORIGINAL PROTOCOL TEXT
AMENDMENT 01 TEXT
information on the clinical course of the 
event, treatment, and relevant diagnostic, 
laboratory or other investigations will be 
collected on the eCRF. Episodes of 
pancreatitis, diagnoses of thyroid carcinoma 
and pancreatic cancer will be collected and 
reported as Ancillary Events.  All Ancillary 
Events will be reported to the appropriate 
regulatory agencies in a manner and 
timeframe consistent with all applicable laws 
and regulations (Section 10.3.1). 
Additionally, any SAE considered by an 
investigator who is a qualified physician to 
be possibly, probably, or definitely related to 
the investigational product that is brought to 
the attention of the investigator after study 
closeout must be reported within the above 
timeline to Amylin/Eli Lilly.  All patients 
with serious adverse events must be followed 
to assess outcome until resolution or until 
designated permanent.
becoming aware of the event.  Brief 
information on the clinical course of the event, 
treatment, and relevant diagnostic, laboratory or 
other investigations will be collected on the 
eCRF. All episodes of pancreatitis and 
neoplasia will be treated as SAEs and will be 
collected and reported as Ancillary Events.  All 
Ancillary Events will be reported to the 
appropriate regulatory agencies in a manner 
and timeframe consistent with all applicable 
laws and regulations (Section 10.3.1). 
Note: Events which meet the criteria to be 
classified as an Ancillary Event which result in 
death and are deemed to be possibly related to 
study drug will be collected and reported as 
Ancillary Events.
Additionally, any SAE considered by an 
investigator who is a qualified physician to be 
possibly, probably, or definitely related to the 
investigational product that is brought to the 
attention of the investigator after study closeout 
must be reported within the above timeline to 
Amylin/Eli Lilly.  All patients with serious 
adverse events must be followed to assess 
outcome until resolution or until designated 
permanent.
10.4 
Calcitonin 
Monitoring
(this is a new subsection; subsequent 
subsections have been renumbered 
accordingly)
Studies in rodents have indicated an increased 
incidence of thyroid C-cell tumors (adenomas, 
carcinomas) with EQW treatment. The 
relevance of these findings to human safety is 
currently unknown and is being investigated.  
In clinical studies, there was no difference 
between exenatide (BID or once weekly) and 
comparators with respect to thyroid neoplasms.  
A detailed summary of findings in rodents and 
clinical studies is available in the Exenatide 
Investigator Brochure.   Measurement of 
calcitonin has recently been added to newly 
initiating clinical trials of EQW to characterize 
any effects of exenatide or comparator 
treatment on calcitonin levels over time to 
better assess evidence of a biologic effect on c-
cells.  In clinical trials, no difference in 
calcitonin was observed between exenatide and 
comparators.
Calcitonin concentrations will be monitored at 
baseline, annually and at trial/early termination.  
Investigators and participants will be blinded to 
calcitonin values.  If the baseline value exceeds 
100 ng/L, the site will be informed and directed 
to have the patient terminate study medication.  
If a concerning calcitonin value is identified 
during trial follow-up, the site investigator will 
62

EXSCEL Protocol Amendment 06
SECTION
ORIGINAL PROTOCOL TEXT
AMENDMENT 01 TEXT
be notified and will alert the usual care 
physician.  Calcitonin concentrations will be 
monitored by the DSMB, which will include a 
thyroid expert.  
10.5.2 Reporting 
of Overdose
(previously 
section 10.4.2)
If an adverse experience(s) is associated with 
(“results from”) the overdose of test drug, the 
adverse experience(s) is reported as a serious 
adverse experience, even if no other criteria 
for seriousness are met.
If an adverse experience(s) is associated with 
(“results from”) the overdose of study 
medication, the adverse experience(s) is 
collected as a serious adverse experience, even 
if no other criteria for seriousness are met.
10.6 
Reporting of 
Pregnancy
(previously 
Section 10.5)
All patients who become pregnant must stop 
taking blinded trial medication and be 
followed to the completion/termination of the 
pregnancy. If the pregnancy continues to 
term, the outcome (health of infant) must 
also be reported.
All patients who become pregnant must stop 
taking blinded trial medication and be followed 
to the completion/termination of the pregnancy. 
All occurrences of pregnancy must be reported 
via the Lilly Pregnancy/Breastfeeding Exposure 
Form. If the pregnancy continues to term, the 
outcome (health of infant) must also be 
reported.
11.3
Consent and 
Collection of 
Biomarker 
Specimens
Patients providing informed consent will 
have a fasting blood sample collected at 
baseline (prior to drug exposure), and either 
at one year of treatment or at the time of drug 
discontinuation (if occurring within the first 
year).
Patients providing informed consent will have a 
blood and urine samples, preferably fasting, 
collected at baseline (prior to drug exposure), 
annually, and at the time of trial termination.
12.3 
Data Safety 
Monitoring 
Board (DSMB)
The DSMB will be composed of five senior 
academic individuals, including the DSMB 
Chair.  
The DSMB will be composed of six senior 
academic individuals, including the DSMB 
Chair.
12.5 Strategic 
Advisory 
Committee
(this is a new subsection)
The Strategic Advisory Committee will provide 
oversight for the operational conduct of the 
study across all participating institutions.  It 
will be composed of senior management from 
the Sponsors, AROs and the contracted CRO, 
who are experts in the operational aspects of 
the conduct of clinical trials and the EXSCEL 
Clinical Leads.  
Appendix 2
Trial Plan 
(Protocol 
BCB109)
Please refer to Appendix 2 for specific 
changes.  
Please refer to Appendix 2 for specific changes.  
Significant changes are summarized below:
!
Calcitonin samples will be collected 
annually and at trial/early termination 
visits.
!
Heart rate will be measured at 
randomization, all six-monthly visits 
(e.g. semi-annual and annual), and 
drug or trial/early termination visits.
!
Clarification that consent is required 
for the biomarker assessment
!
Samples for future biomarker 
assessments will now be collected 
annually trial/early termination rather 
than at one year only.
63

EXSCEL Protocol Amendment 06
APPENDIX 4
PROTOCOL AMENDMENT 02: SUMMARY OF CHANGES
Exenatide QW Clinical Study Protocol BCB109
PROTOCOL TITLE:
A 
RANDOMIZED, 
PLACEBO 
CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE CARDIOVASCULAR OUTCOMES AFTER TREATMENT WITH EXENATIDE ONCE 
WEEKLY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Protocol Number:
BCB109
Amendment Number:
02
Amendment Purpose:
Date: 10 May 2011
The purpose of Amendment 02 is to allow insulin use prior to randomization, lower the calcitonin exclusion 
threshold to >40 ng/L, define the calcitonin exit threshold to be ≥50 ng/L, and clarify reporting of Clinical Events, 
Serious Adverse Events, and deaths.  Additional clarifications and edits are included.  Notable changes are detailed 
in the table below.
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
Title Page
IND Number added  
1.2 Rationale 
for Conduct of 
the Study
Exenatide, a GLP-1 receptor agonist, has been 
shown in randomized clinical trials to 
improve glycemic control, augment 
endogenous insulin secretion, to reduce 
blood pressure and promote weight loss with 
a meta-analysis of exenatide twice-daily 
(BYETTA) trials (9) showing a trend to 
lower relative risk for CV events versus 
pooled comparators of 0.70 (95% 
confidence interval 0.38 - 1.31).  BYETTA 
(exenatide) injection is currently available in 
the US and in many countries worldwide for 
people with type 2 diabetes who are unable 
to achieve good glycemic control with 
common oral therapies.  
Exenatide, a GLP-1 receptor agonist, has been 
shown in randomized clinical trials to 
improve 
glycemic 
control, 
augment 
endogenous insulin secretion, to reduce 
blood pressure and promote weight loss with 
a meta-analysis of exenatide twice-daily 
(BYETTA) trials (9) showing a trend to 
lower relative risk for CV events versus 
pooled 
comparators 
of 
0.70 
(95% 
confidence interval 0.38 - 1.31). BYETTA 
(exenatide) injection is currently available in 
the US and in many countries worldwide for 
people with type 2 diabetes who are unable 
to achieve good glycemic control with 
common oral therapies.  The addition of 
BYETTA to titrated basal insulin therapy 
(not currently an approved indication) has 
also been demonstrated to improve glycemic 
control without an increased risk of 
hypoglycemia 
in 
patients 
receiving 
concomitant diet/exercise, metformin, or 
metformin+pioglitazone therapy (exenatide 
enhances insulin secretion in a glucose-
dependent manner, thus minimizing the risk 
of hypoglycemia in the absence of an insulin 
secretagogue) (13).
64

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
4.1 Design 
Description
EXSCEL will be a multinational, placebo-
controlled, double-blind, randomized, 
parallel-group pragmatic clinical trial. 
Eligible patients will have type 2 diabetes 
with a glycated hemoglobin (HbA1c) ≥7.0% 
and ≤10.0 % on stable doses of up to three 
(i.e. 0-3) oral antihyperglycemic agents 
(AHAs) for at least 3 months i.e. no oral 
AHA adjustments in the past 3 months. 
Patients enrolled will be at a wide range of 
CV risk with approximately 60% having had 
a prior CV event.
EXSCEL will be a multinational, placebo-
controlled, 
double-blind, 
randomized, 
parallel-group 
pragmatic 
clinical 
trial. 
Eligible patients will have type 2 diabetes 
with a glycated hemoglobin (HbA1c) ≥7.0 
% and ≤10.0 % on stable doses of up to 
three (i.e. 0-3) oral antihyperglycemic 
agents (AHAs) for at least 3 months i.e. no 
oral AHA adjustments in the past 3 months. 
A stable dose of insulin (±20% of the 
scheduled total daily insulin dose), either 
alone or in combination with a stable dose 
of metformin for at least 3 months, will also 
be permitted. Patients enrolled will be at a 
wide range of CV risk with approximately 
60% having had a prior CV event. 
5.1 
Inclusion 
Criteria
c.  Patient has an HbA1c of ≥ 7.0 % and 
≤10.0% on stable doses of up to three (i.e. 
0-3) oral AHAs for at least 3 months i.e. no 
oral AHA adjustments in the past 3 months.  
Concomitant use of DPP-4 inhibitors is 
permitted.
HbA1c values must be from within the 3 
months prior to randomization.  If multiple 
values are available, the most recent 
reported value should be used.  A patient 
whose HbA1c
is > 10.0% may, at the 
discretion of the investigator, have their 
oral AHA therapy adjusted and be re-
screened once for HbA1c randomization 
eligibility (≥ 7.0 % and ≤ 10.0%) following 
a 3-month period on stable AHA doses.
c. Patient has an HbA1c of ≥ 7.0 % and ≤10.0% 
! A stable dose of up to three (i.e. 0-3) oral 
AHAs for at least 3 months will be allowed 
(i.e. no oral AHA adjustments in the past 3 
months).  
o Concomitant use of DPP-4 inhibitors is 
permitted.
o A stable dose of insulin (±20% of the 
scheduled total daily insulin dose) either 
alone or in combination with a stable 
dose of metformin for at least 3 months is 
permitted. The use of basal and prandial 
insulins is permitted in any combination 
of individual or premixed insulins. If the 
prescribed insulin regimen includes 
adjustments, the total dose should not 
vary by more than 20% from day to day 
over the preceding 3 months. 
HbA1c values must be from within the 3 
months prior to randomization.  If 
multiple values are available, the most 
recent reported value should be used.  A 
patient whose HbA1c is>10.0% may, at 
the discretion of the investigator, have 
their oral AHA or insulin therapy 
adjusted and be re-screened once for 
HbA1c randomization eligibility (≥ 7.0 % 
and ≤ 10.0%) following a 3-month period 
on stable AHA doses.
65

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
5.2 Exclusion 
Criteria
b. Patient has taken insulin within 2 weeks of 
screening visit or for greater than 1 week 
within 3 months of screening visit.  
l. Personal or family history of medullary 
thyroid cancer or MEN2 (Multiple Endocrine 
Neoplasia Type 2) or calcitonin level of 100
ng/L or greater.
o. No original protocol text; new to this version
b. Patient has a history (≥ 2 episodes) of severe 
hypoglycemia within 12 months of 
enrollment.
l. Personal or family history of medullary 
thyroid cancer or MEN2 (Multiple Endocrine 
Neoplasia Type 2) or calcitonin level > 40 
ng/L at baseline.
o. Is an employee of Eli Lilly and Company or 
Amylin Pharmaceuticals
66

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
6.5 
Concomitant 
Therapy
During the double-blind treatment period, trial 
investigators are expected to monitor 
patients’ AHA regimens and communicate 
with usual care physicians, who will be 
responsible for adjusting the AHA regimen in 
order to achieve locally-appropriate HbA1c
goals. These goals will be individualized, 
with the understanding that currently 
applicable glycemic guidelines may vary 
among different geographic regions. With 
adherence to local custom and laws 
(including privacy regulations such as 
HIPAA), types of communication may be 
informal e.g. email or telephone exchanges, 
to enhance frequency and ease of two-way 
communication.   In addition, the degree of 
locally-appropriate HbA1c goal-attainment at 
each site will be monitored centrally and sites 
with unusually low goal attainment will be 
advised accordingly.
Usual care providers should be notified that 
adjustments to the AHA regimen are not 
recommended until HbA1c levels begin 
reflect the effect of randomized therapy. Any 
AHA agent, with the exception of GLP-1 
receptor agonists, is acceptable.  If HbA1c 
goals are not met following adjustment with 
oral AHAs in patients not receiving insulin, 
an insulin regimen may be initiated, 
preferably without discontinuing or down-
titrating some or all of the existing AHAs, as 
clinically appropriate.  Ideally, patients 
should generally remain on the baseline AHA 
therapies throughout the course of the trial, 
unless the baseline AHA is no longer 
clinically appropriate. However, this should 
be at the discretion of the usual care provider.  
In addition, patients should be reminded to 
keep taking their blinded trial drug following 
initiation of insulin.
During the double-blind treatment period, trial 
investigators are expected to monitor 
patients’ AHA regimens and communicate 
with usual care physicians, who will be 
responsible for adjusting the AHA regimen in 
order to achieve locally-appropriate HbA1c
goals. The Executive Committee (EC) and 
Operations Committee (OC) will provide a
brief list of guidelines for usual care based on 
clinical care practice guidelines published by 
national and international societies that will 
be updated as knowledge about T2DM 
evolves over the course of the trial. These 
goals will be individualized, with the 
understanding that currently applicable 
glycemic guidelines may vary among 
different geographic regions. With adherence 
to local custom and laws (including privacy 
regulations such as HIPAA), types of 
communication may be informal e.g. email or 
telephone exchanges, to enhance frequency 
and ease of two-way communication.   In 
addition, the degree of locally-appropriate 
HbA1c goal-attainment at each site will be 
monitored centrally and sites with unusually 
low goal attainment will be advised 
accordingly.
Usual care providers should be notified that 
adjustments to the AHA regimen are not 
recommended until HbA1c levels begin 
reflect the effect of randomized therapy. Any 
AHA agent, with the exception of GLP-1 
receptor agonists, is acceptable.  If HbA1c 
goals are not met following adjustment with 
oral AHAs in patients not receiving insulin, 
an insulin regimen may be initiated, 
preferably without discontinuing or down-
titrating some or all of the existing AHAs, as 
clinically appropriate.  Patients already 
receiving insulin therapy may up-titrate 
insulin during the trial if necessary. Ideally, 
patients should generally remain on the 
baseline AHA therapies throughout the 
course of the trial, unless the baseline AHA is 
no longer clinically appropriate. However, 
this should be at the discretion of the usual 
care provider.  In addition, patients should be 
reminded to keep taking their blinded trial 
drug following initiation of insulin.
67

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
6.9 Genetic 
and Biomarker 
Sample 
Collection
In a subset of sites, patients enrolled in the trial 
will be asked to consent separately to provide 
a whole blood sample for future 
pharmacogenomic analyses. The objective of 
collecting blood samples from which genetic 
analyses can be performed is to investigate 
the relationships between genetic make-up 
and clinical events.  These samples will be 
drawn at baseline, or at any point in the trial 
at which consent is obtained from the patient.
Patients enrolled in the trial will be asked to 
consent separately to provide two blood and 
two urine samples for future biomarker 
analyses.  These specimens (preferably 
fasting) will be obtained at baseline (prior to 
drug exposure), annually and trial/early 
termination.
In a subset of sites, patients enrolled in the trial 
will be asked to consent separately to provide 
a whole blood sample for future 
pharmacogenomic analyses. The objective of 
collecting blood samples from which genetic 
analyses can be performed is to investigate 
the relationships between genetic make-up 
and clinical events.  These samples will be 
drawn at baseline, or at any point in the trial 
at which consent is obtained from the patient.
Patients enrolled in the trial will be asked to 
consent separately to provide one serum 
sample, one plasma sample, and one urine 
sample for future biomarker analyses.  These 
specimens (preferably fasting) will be 
obtained at baseline (prior to drug exposure), 
annually and trial/early termination. All 
samples will be divided and stored in 2 
aliquots at the Laboratory Corporation of 
America facility in Kannapolis, North 
Carolina, USA.
6.11 End of 
Trial Visit and 
Post Trial 
Telephone 
Contact
NOTE:  All patients should have an End of 
Trial Visit. (Patients who have discontinued 
trial drug must, at minimum, have an End of 
Trial telephone contact visit.)
NOTE:  All patients should have an End of 
Trial Visit. (Patients who have discontinued 
trial drug prior to the end of the trial must, 
at minimum, have an End of Trial telephone 
contact visit.)
6.12 Early 
Discontinuation 
of Trial 
Medication
Following randomization, it is expected that 
patients will remain on study medication for 
the duration of trial participation.  However, 
it is recognized that patients may need to 
discontinue trial medication, in some cases 
permanently, for protocol-specified reasons 
(Section 6.14), due to the judgment of the 
primary investigator or because the patient 
withdraws consent.  The Trial Hotline should 
be contacted whenever a site is considering 
interrupting or discontinuing trial drug 
(Section 6.17).  
Following randomization, it is expected that 
patients will remain on study medication for 
the duration of trial participation.  However, 
it is recognized that patients may need to 
discontinue trial medication, in some cases 
permanently, for protocol-specified reasons 
(Section 6.14), due to the judgment of the 
primary investigator or the decision of the 
patient.  The Trial Hotline should be 
contacted whenever a site is considering 
interrupting or discontinuing trial drug 
(Section 6.17).  
6.14 Permanent 
Discontinuation 
of Trial Drug 
Per Protocol
No original text
e)Annual calcitonin measurement ≥ 50 ng/L 
68

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
7.6  Drug 
Accountability
A drug disposition form will be provided to 
record all study medication dispensed to or 
returned from each subject.  Upon completion 
of the study, all used and unused remaining 
EQW or matching placebo, empty containers, 
and copies of completed drug disposition 
forms should be returned to the sponsor (or 
designee). 
A 
clinical 
supplies 
return 
authorization form will be prepared by the 
clinical research associate at the closeout 
visit. The clinical supplies return form should 
be enclosed with the return drug shipment.  
The study site personnel must maintain 
documentation of any missing or unreturned 
study medication.
A drug disposition form will be provided to 
record all study medication dispensed to or 
returned 
from 
each 
subject. 
 
Upon 
completion of the study, all used and unused 
remaining EQW or matching placebo, empty 
containers, and copies of completed drug 
disposition forms should be returned to the 
sponsor (or designee). A clinical supplies 
return authorization form will be prepared by 
the clinical research associate at the closeout 
visit. The clinical supplies return form should 
be enclosed with the return drug shipment; 
however, if the site manager/CRA approves, 
the site can destroy the material instead of 
returning the used and unused study drug.  
The study site personnel must maintain 
documentation of any missing or unreturned 
study medication.
10.1 
Definitions
Events meeting the above definition as SAEs 
and will be recorded in the safety trial 
database as either Clinical or Ancillary 
Events 
(definitions 
and 
criteria 
are 
summarized in Table 1).
Serious Adverse Event (SAE)
This is defined as any untoward medical 
occurrence or effect in a patient treated on a 
study protocol which does not necessarily 
have a causal relationship with the study 
treatment, that also, at any dose:
!
Results in death
!
Is life-threatening
!
Results in persistent or significant or 
disability/incapacity
!
Requires in-patient hospitalization or 
prolongs existing hospitalization
!
Results in a congenital anomaly or 
birth defect
!
Is otherwise medically significant (i.e. 
withdrawal reactions, all accidental or 
intentional 
overdoses 
of 
study 
medication whether they result in an 
adverse event or not, or any event 
which 
the 
investigator 
considers 
significant but which is not covered by 
the above.)
Text removed
Serious Adverse Event (SAE)
This is defined as any untoward medical 
occurrence or effect in a patient treated on a 
study protocol which does not necessarily 
have a causal relationship with the study 
treatment, that also, at any dose:
!
Results in death
!
Is life-threatening
!
Results in persistent or significant 
incapacity or substantial disruption of 
the ability to conduct normal life 
functions
!
Requires in-patient hospitalization or 
prolongs existing hospitalization
!
Results in a congenital anomaly or 
birth defect
!
Is otherwise medically significant (i.e. 
withdrawal reactions, all accidental or 
intentional 
overdoses 
of 
study 
medication whether they result in an 
adverse event or not, or any event 
which 
the 
investigator 
considers 
significant but which is not covered by 
the above.)
69

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
10.2 Adverse 
Events 
Assessment
Adverse events will be monitored over the 
course of the trial, starting from the time of 
randomization and through the duration of the 
subject’s participation, including the 90 day 
post-trial 
drug 
follow-up 
period 
or 
withdrawal.  Adverse events reported by the 
patient will be evaluated by the investigator 
to determine if a given event meets the 
criteria for a serious event (described in 
Section 10.1).  Any adverse event that does 
not meet the definition of a serious event will 
be considered non-serious and will not be 
recorded.
Adverse events will be monitored over the 
course of the trial, starting from the time of 
randomization and through the duration of the 
subject’s participation, including the 90 day 
post-trial 
drug 
follow-up 
period 
or 
withdrawal.  Adverse events reported by the 
patient will be evaluated by the investigator 
to determine if a given event meets the 
criteria for a serious event (described in 
Section 10.1).  Any adverse event that does 
not meet the definition of a serious event will 
be considered non-serious and will not be 
recorded in the eCRF, with the exception of 
events noted in Section 10.3.
10.3 Recording 
and Reporting 
Adverse 
Events
Original section structure
10.3 Classification and Reporting Adverse 
Events
10.3.1 Sponsor Responsibility for 
Reporting Serious Adverse Events
New section structure
10.3 Recording and Reporting Adverse Events
10.3.1 Recording Adverse Events
10.3.2 Safety Reporting
10.3.3 Sponsor Responsibility for 
Reporting Serious Adverse Events
70

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
10.3.1 
Recording 
Adverse 
Events
The classification of an SAE as a Clinical or 
Ancillary event is dependent on if the SAE is 
included 
in 
the 
Clinical 
Events 
List 
(Appendix 1).  The Clinical Events List is 
inclusive of SAEs that are: (1) components of 
the 
primary 
or 
secondary 
composite 
cardiovascular endpoints, (2) other trial 
endpoints, (3) potential components of the 
CV endpoint that are included among terms 
sent for review by the CEC; (4) expected 
sequelae of type 2 diabetes; (5) expected 
events based on information noted in the 
exenatide investigator brochure.  SAE which 
meet these criteria will be reported in the 
Clinical Events eCRF module.  SAE which 
are not included on the Clinical Events List 
will be considered Ancillary events and will 
be reported in the Ancillary Events eCRF 
module.
The Clinical Events List will be reviewed and 
the eCRF will be completed during every 
visit to determine if a patient has experienced 
one or more of the listed events.  SAE should 
be reviewed for all patients randomized 
regardless of whether the patient is currently 
on trial medication. 
SAEs will be recorded in the Clinical Events 
or SAE eCRF modules. Guidelines for 
events which qualify as Clinical Events are 
provided in Appendix 1. Events to be 
recorded in the Clinical Events eCRF
module 
include 
SAEs 
that 
are: 
(1) 
components of the primary or secondary 
composite cardiovascular endpoints, (2) other 
trial endpoints, (3) potential components of 
the CV endpoint that are included among 
terms sent for review by the CEC; (4) 
expected sequelae of type 2 diabetes  (Table 
1).  These events represent trial outcomes and 
expected events for this population.  In 
addition, non-serious adverse events of stress 
tests, severe hypoglycemia, diabetic eye 
disease, 
foot 
ulcer, 
microalbuminurea, 
proteinuria, hyperlipidemia / dyslipidemia, 
hypertension, and gout also will be recorded 
in the Clinical Events eCRF module (see 
Appendix I).
Any SAE which is not included among the 
expected events on the Clinical Events List 
will be recorded in the SAE eCRF module. 
Events of neoplasia and pancreatitis should 
be reported on the SAE eCRF even if the 
event does not meet serious criteria.
Note: The events listed in Appendix 1 are 
Clinical Events that are trial endpoints or 
expected events for this population, and do 
not generally fit the definition of a SUSAR,
including those events with an outcome of 
death.  However, if the investigator’s 
assessment of an event is that it meets 
SUSAR criteria despite being listed as a 
Clinical Event, the event may be reported as 
a SUSAR as long as it does not require 
adjudication.  If the investigator feels that a 
Clinical Event meets SUSAR criteria the 
SAE eCRF should be used to report the 
event.
The Clinical Events List will be reviewed and 
the eCRF will be completed during every 
visit to determine if a patient has experienced 
one or more of the listed events.  SAE should 
be reviewed for all patients randomized 
regardless of whether the patient is currently 
on trial medication.
71

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
10.3.2 Safety 
Reporting
(Formerly Section 10.3) SAE recorded on the 
Clinical Events eCRF represent those events 
which are components of the composite CV 
endpoint, other trial endpoints, potential 
components of the CV endpoint that require 
adjudication, expected sequelae of T2DM, or 
are expected based on information provided 
in the exenatide investigator brochure.  
Clinical events will be monitored by the 
DSMB and will not require expedited 
reporting to the sponsor even though they 
may be considered possibly, probably or 
definitely drug-related and meet SAE criteria.
Regardless of relationship to trial drug, 
Clinical Events will not be reported by the 
sponsor to regulatory agencies or ethics 
committees in an expedited manner, nor in 
the format of a line listing as part of an 
Annual Safety Report.  Events reported via 
this module will be regularly monitored by 
the DSMB and those which may be 
associated with a trial endpoint will be 
adjudicated by the CEC. 
As described above, all SAEs that are not 
included in the Clinical Events List will be 
recorded by the investigator as Ancillary 
Events.  These events must be recorded in 
this module (or faxed to Lilly if EDC is 
unavailable) within 1 day of a trial site 
becoming aware of the event.  Brief 
information on the clinical course of the 
event, treatment, and relevant diagnostic, 
laboratory or other investigations will be 
collected on the eCRF. All episodes of 
pancreatitis and neoplasia will be treated as 
SAEs and will be collected and reported as 
Ancillary Events.  All Ancillary Events will 
be reported to the appropriate regulatory 
agencies in a manner and timeframe 
consistent with all applicable laws and 
regulations (Section 10.3.1). 
Note: Events which meet the criteria to be 
classified as an Ancillary Event which result 
in death and are deemed to be possibly 
related to study drug will be collected and 
reported as Ancillary Events.
The DSMB will monitor the totality of 
collected safety data (i.e. events recorded on 
both the Clinical Events and SAE eCRFs) on 
a semi-annual basis regardless of event 
classification.  SAE recorded on the Clinical 
Events eCRF represent those events which 
are components of the composite CV 
endpoint, other trial endpoints, potential 
components of the CV endpoint that require 
adjudication or are expected sequelae of 
T2DM.  SAE recorded as Clinical Events, 
including death related to an event in the 
Clinical Events List, and will not be reported 
to the Sponsor, regulatory agencies or ethics 
committees, regardless of relationship to 
trial drug even though they may be 
considered possibly, probably or definitely 
drug-related and meet SAE criteria. In 
addition to the un-blinded review by the 
DSMB, events reported via this module that
may be associated with a trial endpoint will 
be adjudicated by the CEC. As described 
above, all SAEs that are not included in the 
Clinical Events List will be recorded by the 
investigator in the SAE eCRF module.  These 
events must be recorded in this module (or 
faxed to Lilly if EDC is unavailable) within 1 
day of a trial site becoming aware of the 
event.  Any SAEs meeting the definition of a 
SUSAR will be subject to expedited reporting 
as per current legislation.  Brief information 
on the clinical course of the event, treatment, 
and relevant diagnostic, laboratory or other 
investigations will be collected on the eCRF. 
All episodes of pancreatitis and neoplasia will 
be treated as SAEs and will be collected and 
reported in the SAE eCRF module.  All 
events recorded in the SAE eCRF module 
will be reported to the appropriate regulatory 
agencies in a manner and timeframe 
consistent with all applicable laws and 
regulations (Section 10.3.2). All SUSARS
will be reported in an expedited manner with 
the exception of those fulfilling the criterion 
of an efficacy endpoint (as detailed in Section 
1 of Appendix 1: Primary or Secondary Trial 
Endpoints) which will be handled as Clinical 
Events.
72

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
10.3.3 Sponsor 
Responsibility 
for Reporting 
Serious 
Adverse 
Events
(Formerly Section 10.3.1)
The Sponsor will ensure that all appropriate 
regulatory agencies confirm that the approach 
for monitoring Clinical Events, described in 
the Safety Assessments Section is acceptable 
to them.  All Ancillary SAE will be reported 
to 
regulatory 
agencies, 
IRB/IECs, 
and 
investigators 
in 
accordance 
with 
all 
applicable global laws and regulations.
The Sponsor will ensure that all appropriate 
regulatory agencies confirm that the approach 
for monitoring Clinical Events, described in 
the Safety Assessments Section is acceptable 
to them.  SAE that are not recorded as Clinical 
Events will be reported to regulatory agencies, 
IRB/IECs, and investigators in accordance 
with all applicable global laws and 
regulations.
10.4 Calcitonin 
Monitoring
Calcitonin concentrations will be monitored at 
baseline, annually and at trial/early 
termination.  Investigators and participants 
will be blinded to calcitonin values.  If the 
baseline value exceeds 100 ng/L, the site will 
be informed and directed to have the patient 
terminate study medication.  If a concerning 
calcitonin value is identified during trial 
follow-up, the site investigator will be 
notified and will alert the usual care 
physician.  Calcitonin concentrations will be 
monitored by the DSMB, which will include 
a thyroid expert.  
Calcitonin concentrations will be monitored at 
baseline, annually and at trial/early 
termination.  Investigators and participants 
will be blinded to calcitonin values.  If the 
baseline value exceeds 40 ng/L, the site will 
be informed and directed to have the patient 
terminate study medication.  If a concerning 
calcitonin value (≥50 ng/L) is identified 
during trial follow-up, the site investigator 
will be notified and will alert the usual care 
physician and study medication will be 
discontinued.  Calcitonin concentrations will 
be monitored by the DSMB, which will 
include a thyroid expert.  
10.7 Un-
blinding
No original text
Breaking the blind is strongly discouraged and 
should only be requested if it is deemed 
necessary for the wellbeing or safety of the 
patient. Any Investigator requesting the 
unblinding of a patient will be asked to 
contact the trial hotline physician, available 
24hrs/day to discuss the case and determine 
the course of action; however, it is the 
prerogative of the treating physician to insist 
that their patient should be unblinded.
73

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
12.4 Clinical 
Events 
Committee 
(CEC)
The events which constitute the principal 
endpoints of this trial will be adjudicated by 
the Clinical Events Classification Committee 
(CEC), coordinated through the Duke 
Clinical Research Institute (DCRI), which 
will be comprised of approximately 5-7 
physicians and a coordinator.  The specific 
endpoints to be adjudicated include:  cause of 
death (cardiovascular-related vs. non-
cardiovascular), MI, stroke, acute coronary 
syndrome, and CHF requiring hospitalization. 
Clinical reviewers will be board certified or 
board eligible endocrinologists, cardiologists, 
neurologists, gastroenterologists, or 
physicians with clinical expertise and prior 
clinical event classification experience. The 
CEC will review clinical data and adjudicate 
safety and efficacy endpoints.  The CEC will 
adjudicate clinical events using pre-specified 
criteria and definitions for the diagnoses of 
MI, stroke, acute coronary syndrome, and 
CHF requiring hospitalization.  The CEC will 
be blinded to the assigned trial drug. Sites 
will provide clinical information via the 
eCRF and also provide supplemental 
information from medical records, when 
needed. The CEC operations and endpoint 
criteria will be described in a separate 
charter. 
The events which constitute the principal 
endpoints of this trial will be adjudicated by 
the Clinical Events Classification Committee 
(CEC), coordinated through the Duke 
Clinical Research Institute (DCRI), which 
will be comprised of approximately 5-7 
physicians and a coordinator.  The specific 
endpoints to be adjudicated include:  cause of 
death (cardiovascular-related vs. non-
cardiovascular), MI, stroke, acute coronary 
syndrome, pancreatitis, neoplasm, ventricular 
fibrillation/tachycardia, and CHF requiring 
hospitalization. Clinical reviewers will be 
board certified or board eligible 
endocrinologists, cardiologists, neurologists, 
gastroenterologists, or physicians with 
clinical expertise and prior clinical event 
classification experience. The CEC will 
review clinical data and adjudicate safety and 
efficacy endpoints.  The CEC will adjudicate 
clinical events using pre-specified criteria and 
definitions.  The CEC will be blinded to the 
assigned trial drug. Sites will provide 
clinical information via the eCRF and also 
provide supplemental information from 
medical records, when needed. The CEC 
operations and endpoint criteria will be 
described in a separate charter. 
References
No original text
13. Buse JB, Bergenstal RM, Glass LC, 
Heilmann CR, Lewis MS, Kwan AY, 
Hoogwerf BJ, Rosenstock J. Use of twice-
daily exenatide in basal insulin-treated 
patients with type 2 diabetes: a 
randomized, controlled trial. Ann Intern 
Med. 2011;154(2):103-112.
Appendix 1
CLINICAL EVENTS LIST (TO BE 
INCORPORATED INTO ECRF)
The following list of events would be 
recorded in the eCRF at the time of the trial 
visit, but not reported to the Sponsor or 
regulatory agencies urgently regardless of 
relationship to trial drug. Included are trial 
endpoints as well as events that are expected 
to occur in this trial population. 
CLINICAL EVENTS LIST (TO BE 
RECORDED IN THE CLINICAL 
EVENTS eCRF)
Deleted existing text
74

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
Appendix 1
I. A.  Obvious trial endpoints (These events 
will prompt the investigator to complete an 
endpoint package which will then be 
adjudicated according to the Clinical Events 
Classification [CEC] charter)  
   
   Death
!
Cardiovascular (CV) Death (i.e., fatal 
myocardial infarction 
[MI]/cerebrovascular accident [CVA]/ 
congestive heart failure 
[CHF]/arrhythmia, cardiac arrest, death 
following CV intervention)
!
Non-CV Death
I.A.  Obvious trial endpoints (These events 
will prompt the investigator to complete an 
endpoint package which will then be 
adjudicated according to the Clinical Events 
Classification [CEC] charter)  
Death
!
Cardiovascular (CV) Death (i.e., fatal 
myocardial infarction 
[MI]/cerebrovascular accident [CVA]/ 
congestive heart failure 
[CHF]/arrhythmia, cardiac arrest, death 
following CV intervention)
!
Deleted existing text
Appendix 1
Section II. C. Hypoglycemia / Hyperglycemia 
/Diabetic ketoacidosis / Hyperosmolar 
hyperglycemic nonketotic coma
Section II. C. Severe hypoglycemia / 
Hyperglycemia /Diabetic ketoacidosis / 
Hyperosmolar hyperglycemic nonketotic coma
Appendix 1
No original text
Added  the term “(including non-serious 
events)” to the existing events:
-stress test
-diabetic eye disease
-diabetic neuropathy
-diabetic nephropathy
-metabolic conditions associated with diabetes
75

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 01 TEXT
AMENDMENT 02 TEXT
Appendix 1
III. Terms listed in the exenatide 
Investigator Brochure
A.
Allergic/Hypersensitivity Reactions
!
Injection site reactions
!
Pruritis and/or urticaria
!
Rash
!
Angioedema
!
Anaphylactic reaction
B.
Gastrointestinal reactions
!
Nausea
!
Vomiting and/or diarrhea 
resulting in dehydration
!
Abdominal distension or pain
!
Eructation
!
Constipation
!
Flatulence
!
Diarrhea 
C.
Renal and Urinary Disorders
!
Altered renal function, including 
acute or worsened chronic renal 
failure 
!
Renal impairment
!
Increased serum creatinine 
D.
Development of antibodies to 
exenatide
E.
For all other terms please refer to the 
current Investigator Brochure
Deleted Section III.
76

EXSCEL Protocol Amendment 06
APPENDIX 5
PROTOCOL AMENDMENT 03: SUMMARY OF CHANGES
Exenatide QW Clinical Study Protocol BCB109
PROTOCOL TITLE:
A 
RANDOMIZED, 
PLACEBO 
CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE CARDIOVASCULAR OUTCOMES AFTER TREATMENT WITH EXENATIDE ONCE 
WEEKLY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Protocol Number:
BCB109
Amendment Number:
03
Amendment Purpose:
Date: 23 April 2012
The purpose of Amendment 03 is to alter inclusion criteria to allow patients with an HbA1c ≥6.5% and using 
insulin, alone or in combination with oral antihyperglycemic medications, to be eligible to enroll in the study.  In 
addition, the requirement for patients to have been on a stable dose of oral antihyperglycemic medication has been 
removed.  Additional safety language regarding hypoglycemia has been included for patients using concomitant 
insulin and/or sulfonylurea.  In addition, patients discontinued due to pregnancy can resume study medication 
following completion of the pregnancy and cessation of breastfeeding (if applicable).  Finally, clarifications 
regarding events requiring adjudications were added.  Minor editorial changes have also been included to improve 
clarity and consistency.  Notable changes are detailed in the table below.
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Title Page
Amylin Pharmaceuticals, Inc.
 
Amylin Pharmaceuticals, Inc.
List of 
Abbreviations
None
CRO
Contract Research Organization
HLGT High level group term
IFU
Instructions for use
ITT
Intent-to-Treat
PCI
Percutaneous coronary intervention
TC
Total cholesterol
TG
Triglycerides
TIA
Transient ischemic attack
List of 
Abbreviations
EDC
Electronic Data Collection
EDC
Electronic Data Capture Collection
77
PPD
PPD
PPD

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 1.2
Rationale for 
Conduct of the 
Study
The addition of BYETTA to titrated basal 
insulin therapy (not currently an approved 
indication) has also been demonstrated to
improve glycemic control without an increased 
risk of hypoglycemia in patients receiving 
concomitant diet/exercise, metformin, or 
metformin+pioglitazone therapy (exenatide 
enhances insulin secretion in a 
glucose-dependent manner, thus minimizing 
the risk of hypoglycemia in the absence of an 
insulin secretagogue) (13). Exenatide once 
weekly (EQW), a new formulation of 
exenatide that is administered once weekly 
rather than twice daily, is under development 
and currently being reviewed by the US FDA.
The addition of BYETTA to titrated basal 
insulin therapy (not currently an approved 
indication) has also been demonstrated to 
improve glycemic control without an increased 
risk of hypoglycemia in patients receiving 
concomitant diet/exercise, metformin, or 
metformin+pioglitazone therapy (exenatide 
enhances insulin secretion in a 
glucose-dependent manner, thus minimizing 
the risk of hypoglycemia in the absence of an 
insulin secretagogue) (13). Exenatide once 
weekly (EQW), a new formulation of exenatide 
that is administered once weekly rather than 
twice daily, has been approved by the US FDA 
as an adjunct to diet and exercise to improve 
glycemic control in adults with type 2 diabetes 
mellitus and in the European Union as 
adjunctive therapy to improve glycemic control 
in patients with type 2 diabetes mellitus who 
are taking metformin, a sulfonylurea, or a 
combination of metformin and a sulfonylurea 
but have not achieved adequate glycemic 
control. is under development and currently 
being reviewed by the US FDA.
Section 2.2
Secondary 
Objectives
(4) Hospitalization for heart failure (CHF)
(4)
Hospitalization for congestive heart 
failure (CHF)
Section 3
Trial 
Governance
The EC will consist of approximately eleven 
individuals, comprising nine senior 
independent academic representatives who are 
experts in their field and two Alliance 
representatives.  
The EC will consist of approximately eleven 
individuals, comprising nine senior 
independent academic representatives who are 
experts in their field and two Alliance sponsor
representatives.  
Figure 1
Figure updated to clarify groups involved
Section 4.1
Design 
Description
Eligible patients will have type 2 diabetes with 
a glycated hemoglobin (HbA1c) ≥7.0 % and 
≤10.0 % on stable doses of up to three (i.e. 0-3) 
oral antihyperglycemic agents (AHAs) for at 
least 3 months i.e. no oral AHA adjustments in 
the past 3 months. A stable dose of insulin 
(±20% of the scheduled total daily insulin 
dose), either alone or in combination with a 
stable dose of metformin for at least 3 months, 
will also be permitted.
Eligible patients will have type 2 diabetes with 
a glycated hemoglobin (HbA1c) ≥7.0 % an 
HbA1c ≥6.5% and ≤10.0 % on stable doses of
up to three (i.e., 0-3) oral antihyperglycemic 
agents (AHAs) for at least 3 months i.e. no 
oral AHA adjustments in the past 3 months. A 
stable dose of or insulin either alone or in 
combination with up to 2 (i.e., 0-2) oral AHAs.
(±20% of the scheduled total daily insulin 
dose), either alone or in combination with a 
stable dose of metformin for at least 3 months, 
will also be permitted.
Section 4.1
Design 
Description
Per usual care, HbA1c values should be 
measured locally using a NGSP (National 
Glycohemoglobin Standardization Program) 
certified HbA1c assay (12).
Per usual care, HbA1c values should be 
measured locally. using a An NGSP (National 
Glycohemoglobin Standardization Program) 
certified HbA1c assay should be used if 
available (12).
78

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 4.2
Trial Duration
All patients that cease study medication will be 
followed up, if at all possible, for the full study 
period. All patients that withdraw from the trial 
will have their vital status ascertained, if at all 
possible, at the end of the trial.
All patients that discontinue cease study 
medication, but have not withdrawn consent to 
participate in the study, will be followed up, if 
possible, for the full study period All patients 
that withdraw from the trial and will have their 
vital status ascertained, if possible, at the end 
of the trial.
Section 5.1
Inclusion 
Criteria
c.
Patient has an HbA1c of ≥ 7.0 % and 
≤10.0%
! A stable dose of up to three (i.e., 0-3) 
oral AHAs for at least 3 months will 
be allowed (i.e. no oral AHA 
adjustments in the past 3 months).  
o
Concomitant use of DPP-4 
inhibitors is permitted.  
o
A stable dose of insulin (±20% of 
the scheduled total daily insulin 
dose) either alone or in 
combination with a stable dose of 
metformin for at least 3 months 
is permitted. The use of basal and 
prandial insulins is permitted in 
any combination of individual or 
premixed insulins. If the 
prescribed insulin regimen 
includes adjustments, the total 
dose should not vary by more 
than 20% from day to day over 
the preceding 3 months. 
HbA1c values must be from within the 3 
months prior to randomization.  If multiple 
values are available, the most recent reported 
value should be used.  A patient whose HbA1c
is>10.0% may, at the discretion of the 
investigator, have their oral AHA or insulin 
therapy adjusted and be re-screened once for 
HbA1c randomization eligibility (≥7.0 % and 
≤10.0%) following a 3-month period on stable 
AHA doses.
c.
Patient has an HbA1c of ≥6.5 % ≥ 7.0 %
and ≤10.0% and is currently using one of 
the following treatment regimens:
!
Treatment with up to three (i.e., 0-3) 
oral AHAs (concomitant use of DPP-4 
inhibitors is permitted).
!
Insulin therapy, either alone or in 
combination with up to two (ie., 0-2) 
oral AHAs (use of basal and prandial 
insulins is permitted in any 
combination of individual or premixed 
insulins)
All patients should be on a stable diabetes 
management regimen, as assessed by the 
investigator, at the time of enrollment.
! A stable dose of up to three (i.e., 0-3) 
oral AHAs for at least 3 months will 
be allowed (i.e. no oral AHA 
adjustments in the past 3 months).  
o
Concomitant use of DPP-4 
inhibitors is permitted.  
o
A stable dose of insulin (±20% of 
the scheduled total daily insulin 
dose) either alone or in 
combination with a stable dose of 
metformin for at least 3 months is 
permitted. The use of basal and 
prandial insulins is permitted in 
any combination of individual or 
premixed insulins. If the 
prescribed insulin regimen 
includes adjustments, the total 
dose should not vary by more 
than 20% from day to day over 
the preceding 3 months. 
HbA1c values must be from within the 
3 months prior to randomization.  If multiple 
values are available, the most recent reported 
value should be used.  A patient whose HbA1c
is>10.0% may, at the discretion of the 
investigator, have their oral AHA or insulin 
therapy adjusted and be re-screened once for 
HbA1c randomization eligibility (≥6.5 % 
≥7.0 % and ≤10.0%). following a 3-month 
period on stable AHA doses
79

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 5.1
Inclusion 
Criteria
o
History of ischemic stroke.  
Strokes not known to be 
hemorrhagic will be allowed as 
part of this criterion;
o
History of ischemic stroke; strokes
not known to be hemorrhagic will 
be allowed as part of this criterion;
transient ischemic attacks (TIAs) 
are not included
Section 5.2
Exclusion 
Criteria
None
Each patient meeting any of the following 
criteria will be excluded from this trial.
Section 5.2
Exclusion 
Criteria
i.
Patient has end-stage renal disease or an 
estimated glomerular filtration rate 
(eGFR) derived from serum creatinine 
(using the simple MDRD-4 formula) of 
<30 mL/min/1.73 m2.
i.
Patient has end-stage renal disease or an 
estimated glomerular filtration rate 
(eGFR) derived from serum creatinine 
(using the simple MDRD-4 formula) of 
<30 mL/min/1.73 m2 (see Appendix 2).
Section 5.2
Exclusion 
Criteria
NOTE: Serum for calcitonin measurement will 
be drawn at baseline.  Patients may be 
randomized and initiate study medication prior 
to the results of the calcitonin measure being 
available.  If a randomized patient is found to 
have an exclusionary serum calcitonin 
concentration, they will stop study medication 
and patients will continue to have follow-up 
for vital status and be part of the intention to
treat analysis.
NOTE: Serum for calcitonin measurement will 
be drawn at baseline.  Patients may be 
randomized and initiate study medication prior 
to the results of the calcitonin measure being 
available.  If a randomized patient is found to 
have an exclusionary serum calcitonin 
concentration, they will stop study medication 
and patients will continue to have follow-up 
and be part of the Intent-to-Treat intention to 
treat analysis.
Section 6.1
Trial Procedures
At baseline (Visit 1) patients will be provided 
with the patients’ instruction brochure and be 
trained by study personnel to administer the 
study medication injection.
At randomization baseline (Visit 1) patients 
will be provided with the patients’ instruction
for use (IFU) brochure and be trained by study 
personnel to administer the study medication 
injection.
Section 6.1
Trial Procedures
At semi-annual and annual visits, additional 
procedures will include blood pressure, body 
weight, review of routine laboratory values and
dispensing of study drug as described in 
Appendix 2.
At semi-annual and annual visits, additional 
procedures will include blood pressure, body 
weight, heart rate, review of laboratory values 
and dispensing of study drug as described in 
Appendix 2.
Section 6.2
Pre-Enrollment 
and Enrollment 
Procedures
Patients may qualify for enrollment based on 
recent laboratory data e.g. HbA1c within the 
last 3 months, obtained as part of usual care 
prior to Visit 1.
Patients may qualify for enrollment based on 
recent laboratory data e.g. HbA1c within the last 
3 months, obtained as part of usual care prior to 
Visit 1 (recommended guidance for 
management of serum creatinine values will be 
provided to each site).
Section 6.4
Treatments 
Administered
As part of standard of care, serum creatinine 
should be among labs drawn annually.
As part of standard of care, serum creatinine 
should be, at minimum, among labs drawn 
annually.
80

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 6.4
Treatments 
Administered
If the need for drug discontinuation is 
confirmed, the patient will be invited back to 
the trial site for an unscheduled visit to explain 
the situation, to stop the study drug and to 
encourage the patient to continue follow up off 
study drug until the end of the trial.
If the need for drug discontinuation is 
confirmed, the situation will be explained to the 
patient and the patient will be asked to stop the 
study drug and encouraged the patient will be 
invited back to the trial site for an unscheduled 
visit to explain the situation, to stop the study 
drug and to encourage the patient to continue 
follow up off study drug until the end of the 
trial.  If deemed necessary by the investigator, 
an unscheduled visit can be performed to 
discuss study drug discontinuation and the 
importance of subsequent follow up.
Section 6.6
Precautions to 
Minimize Rates 
of 
Hypoglycemia
At the screening/enrollment visit and all 
subsequent visits, the symptoms and 
appropriate management of hypoglycemia will 
be reviewed with participants.  
At the screening/randomization enrollment visit 
and all subsequent visits, the symptoms and 
appropriate management of hypoglycemia will 
be reviewed with patients. participants
Section 6.6
Precautions to 
Minimize Rates 
of 
Hypoglycemia
None
Combination therapies with insulin and 
sulfonylurea have an increased risk of 
hypoglycemia.  To minimize this risk, patients 
whose diabetes is well controlled may require a 
reduction in the insulin or sulfonylurea dose 
when allocated study medication.  EXSCEL 
will employ both patient- and investigator-
directed education to minimize the risk of 
hypoglycemia.  Patients receiving 
sulfonylurea/insulin combinations will be 
explicitly reminded of the symptoms and 
proper management of hypoglycemia before 
starting study drug.  The EXSCEL study team 
will also provide investigators with training 
materials to demonstrate best practice for 
minimizing hypoglycemia risk in these 
patients.
Section 6.7
Laboratory and 
Anthropometric 
Measurements
Blood pressure, heart rate, height, and body 
weight will be collected by study personnel as 
indicated in the flow chart.
Blood pressure, heart rate, height, and body 
weight will be collected by study personnel as 
indicated in Appendix 2. in the flow chart
Section 6.10
Resource 
Utilization 
Quality of Life 
Data for 
Economic 
Evaluation
This instrument will be administered at 
baseline, at 6 months and annually thereafter.
This instrument will be administered at 
baseline, at 6 months, at subsequent annual 
visits, and at the trial/early termination visit. 
and annually thereafter
Section 6.11
Trial/Early 
Termination 
Visit and Post 
Trial Telephone 
Contact
Section 6.11
End of Trial Visit and Post Trial Telephone 
Contact
Section 6.11
End of Trial Trial/Early Termination Visit and 
Post Trial Telephone Contact
81

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 6.11
Trial/Early 
Termination 
Visit and Post 
Trial Telephone 
Contact
End of Trial Visit
End of Trial Trial/Early Termination Visit
Section 6.12
Temporary 
Discontinuation 
of Trial 
Medication
Section 6.12
Early Discontinuation of Trial Medication
Section 6.12
Early Temporary Discontinuation of Trial 
Medication
Section 6.12
Temporary 
Discontinuation 
of Trial 
Medication
Unless resumption of trial medication is 
considered unsafe or is refused by the 
participant, the patient will be expected to 
resume regular use of the blinded trial 
medication.  Should a participant stop taking 
trial medication, either permanently or 
temporarily, the reasons for discontinuation 
and length of time the patient stopped taking 
trial medication will be assessed and recorded.  
All randomized patients who permanently 
discontinue trial medication should have a 
medication discontinuation visit (as described 
in Section 6.13) as soon as possible after 
stopping the trial drug.
Unless resumption of trial medication is 
considered unsafe or is refused by the patient,
participant the patient will be expected to 
resume regular use of the blinded trial 
medication after a period of temporary 
discontinuation.  Should a patient participant
stop taking trial medication, either 
permanently or temporarily, the reasons for 
discontinuation and length of time the patient 
stopped taking trial medication will be 
assessed and recorded.  All randomized 
patients who permanently discontinue trial 
medication should have a drug termination
medication discontinuation visit (as described 
in Section 6.13) as part of their next scheduled 
study visit (unless a separate drug termination 
visit at that point is deemed necessary by the 
investigator). as soon as possible after 
stopping the trial drug.
Section 6.12
Early 
Discontinuation 
of Trial 
Medication
None
NOTE:  After trial medication is discontinued 
due to pregnancy, re-initiation of study 
medication can be considered following 
completion of the pregnancy and breastfeeding 
(if applicable).
82

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 6.13
Permanent 
Discontinuation 
of Trial 
Medication 
Visit 
Procedures
All randomized patients who permanently 
discontinue trial medication should have a 
medication discontinuation visit as soon as 
possible after stopping the trial drug.  
Necessary procedures are indicated in the Flow 
Chart.  All efforts should be made to reinforce 
with patients that this would be a medication 
discontinuation visit, not a trial discontinuation 
visit. Patients will be asked to continue with all 
other trial follow up until the completion of the 
trial, including annual in-person visits and 
telephone calls, as well as the annual calcitonin 
measurement.  IVRS should be contacted to 
register the patient as discontinued only after 
all efforts have been exhausted to get patients 
back on trial drug if appropriate.
All randomized patients who permanently 
discontinue trial medication should have a drug 
termination medication discontinuation visit as 
part of their next scheduled visit (unless a 
separate drug termination visit is deemed 
necessary by the investigator). soon as possible 
after stopping the trial drug.  Necessary 
procedures are indicated in Appendix 2. the
Flow Chart.   All efforts should be made to 
reinforce with patients that this would be a 
medication discontinuation visit, not a trial
discontinuation visit. Patients will be asked to 
continue with all other trial follow up until the 
completion of the trial, including semi-annual 
in-person visits and/or telephone calls, as well as 
the annual calcitonin measurement.  IVRS 
should be contacted to register the patient as 
having discontinued study medication only 
after all efforts have been exhausted to get 
patients back on trial medication drug if 
appropriate.
Section 6.14
Permanent 
Discontinuation 
of Trial 
Medication Per 
Protocol
b)
Pregnancy, as confirmed by serum 
pregnancy test. 
Patient must stop taking blinded trial 
medication, and be followed if she 
becomes pregnant during the trial 
(Section 10.6)
Deleted; remaining items in list renumbered
Section 6.14
Permanent 
Discontinuation 
of Trial 
Medication Per 
Protocol
The usual care provider will be provided with 
standard guidance on down-titrating AHAs in 
the presence of hypoglycemia.
The usual care provider will be provided with 
standard guidance by the trial investigator on 
down-titrating AHAs in the presence of 
hypoglycemia.
Section 6.14
Permanent 
Discontinuation 
of Trial 
Medication Per 
Protocol
d)
Severe, irreversible renal dysfunction 
(eGFR <30 ml/min/1.73m2) or renal 
replacement therapy.
c)
Severe, irreversible renal dysfunction 
(confirmed by two consecutive eGFR 
<30 ml/min/1.73m2) or renal replacement 
therapy.
Section 6.15
Follow-up for 
Patients who 
Permanently 
Discontinue 
Trial Medication
End of Trial Visit
End of Trial Trial/Early Termination Visit
Section 7.2
Formulation, 
Packaging, and 
Storage
Specific instructions for dose preparation of 
the injection will be provided in the Patient 
Instructions for Use (PIU).
Specific instructions for dose preparation of the 
injection will be provided in the Patient 
Instructions for Use (IFU PIU).
83

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 7.4
Dose 
Administration 
Procedures, 
Route, and 
Schedule
Subjects who terminate study medication will 
be followed for the remainder of the study for 
the assessment of clinical events unless the 
subject opts to withdraw consent.
Patients Subjects who terminate study 
medication will be followed up, per the 
protocol, for the remainder of the study unless 
the patient subject opts to withdraw consent.
Section 7.6 
Drug 
Accountability
A drug disposition form will be provided to 
record all study medication dispensed to or 
returned from each subject.  Upon completion 
of the study, all used and unused remaining 
EQW or matching placebo, empty containers, 
and copies of completed drug disposition 
forms should be returned to the sponsor (or 
designee).
A drug accountability log disposition form will 
be provided to record all study medication 
dispensed to or returned from each patient
subject.  Upon completion of the study, all used 
and unused EQW or matching placebo vials
empty containers, and copies of completed drug 
accountability logs disposition forms should be 
returned to the sponsor (or designee).
Section 9.7
Secondary 
Analyses
5. Hospitalization for heart failure (CHF)
5.
Hospitalization for congestive heart 
failure (CHF)
Section 9.8.1
Intent-To-Treat 
Population
Every effort will be made to collect CV events 
to study termination even in those who have 
discontinued the study.  
Every effort will be made to collect CV events 
to study termination even in those who have 
discontinued study medication or the study.  
Section 9.8.2
Per Protocol 
Population
If a patient is found to have taken a study 
medication for the entire duration of the study 
that is different from that to which he/she was 
randomized then the patient is counted in the 
treatment group of the drug he/she actually 
received.  
If a patient is found to have taken a study 
medication for any the entire duration of the 
study that is different from that to which he/she 
was randomized, then the patient is counted in 
the treatment group of the drug he/she actually 
received.  
Section 9.10
Subgroup 
Analyses
!
Region (North/South America or Canada, 
Europe or South Africa, ROW)
!
Region (North/South America or Canada, 
Europe or South Africa, Rest of world
ROW)
Section 10.3.1
Recording 
Adverse Events
SAEs will be recorded in the Clinical Events 
or SAE eCRF modules.
SAEs will be recorded in the Clinical Events 
or SAE eCRF modules as appropriate (see 
Table 1).
Section 10.3.1
Recording 
Adverse Events
In addition, non-serious adverse events of 
stress tests, severe hypoglycemia, diabetic eye 
disease, foot ulcer, microalbuminurea, 
proteinuria, hyperlipidemia/dyslipidemia, 
hypertension, and gout also will be recorded in 
the Clinical Events eCRF module (see 
Appendix I).
In addition, non-serious adverse events of 
percutaneous coronary intervention (PCI), 
stress tests, severe hypoglycemia, diabetic eye 
disease, foot ulcer, microalbuminuria, 
proteinuria, macroalbuminuria, hyperlipidemia/
dyslipidemia, hypertension, or and gout also 
will be recorded in the Clinical Events eCRF
module (see Appendix 1).
84

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Section 10.3.1
Recording 
Adverse Events
Note: The events listed in Appendix 1 are 
Clinical Events that are trial endpoints or 
expected events for this population, and do not 
generally fit the definition of a SUSAR,
including those events with an outcome of 
death.  However, if the investigator’s
assessment of an event is that it meets SUSAR 
criteria despite being listed as a Clinical Event, 
the event may be reported as a SUSAR as long 
as it does not require adjudication.  If the 
investigator feels that a Clinical Event meets 
SUSAR criteria the SAE eCRF should be used 
to report the event.
Note: The events listed in Appendix 1 are 
Clinical Events that are trial endpoints or 
expected events for this population, and do not 
generally fit the definition of a SUSAR,
including those events with an outcome of 
death.  However, if the investigator’s 
assessment of an event is that it meets SUSAR 
criteria despite being listed as a Clinical Event, 
the event may be reported as a SUSAR via the 
SAE eCRF as long as it is not a possible
Primary or Secondary trial endpoint (i.e. all 
events listed in Appendix 1 Section I).  If the 
investigator feels that a Clinical Event meets 
SUSAR criteria the SAE eCRF should be used 
to report the event.
Table 1
Table format updated for clarity
Section 10.3.2
Safety 
Reporting
All SUSARS will be reported in an expedited 
manner with the exception of those fulfilling 
the criterion of an efficacy endpoint (as 
detailed in Section I of Appendix 1: Primary or 
Secondary Trial Endpoints) which will be 
handled as Clinical Events.
All SUSARS will be reported in an expedited 
manner with the exception of Primary and 
Secondary trial endpoints as detailed in 
Section I of Appendix 1, which will be handled 
as Clinical Events. fulfilling the criterion of an 
efficacy endpoint (as detailed in Section I of 
Appendix 1: Primary or Secondary Trial 
Endpoints) which will be handled as Clinical 
Events.
Section 10.4
Calcitonin 
Monitoring
If a concerning calcitonin value (≥50 ng/L) is 
identified during trial follow-up, the site 
investigator will be notified and will alert the 
usual care physician and study medication will 
be discontinued.  
If a concerning calcitonin value (≥50 ng/L) is 
identified during trial follow-up, the site 
investigator will be notified and they should 
call the Trial Hotline for advice, where they 
will be instructed to alert the usual care 
provider and permanently discontinue study 
medication.  and will alert the usual care 
physician and study medication will be 
discontinued.  
Section 10.5.1
Definition of an 
Overdose for 
This Protocol
The patient should be instructed to contact the 
investigational site, and/or healthcare provider 
in the event of an overdose 1 day of the trial 
site becoming aware of the event.
The patient should be instructed to contact the 
investigational site, and/or healthcare provider 
in the event of an overdose 1 day of the trial 
site becoming aware of the event.
Section 13
Disclosure of 
Data and 
Publications
The Executive Committee, which includes 
principal investigators, Sponsor 
representatives, academic cardiologists and 
academic endocrinologists, will draft the 
manuscript describing the main study results, 
and oversee publications requiring trial data, 
samples, or genetic material.
The Executive Committee, which includes 
principal investigators, Sponsor 
representatives, academic cardiologists and 
academic endocrinologists, will draft the 
manuscript describing the main study results, 
and oversee publications requiring trial data, 
samples, or genetic material.
Appendix 1
CLINICAL EVENTS LIST (TO BE 
RECORDED IN THE CLINICAL EVENTS 
eCRF)
CLINICAL EVENTS LIST (TO BE 
RECORDED IN THE CLINICAL EVENTS 
eCRF)
Any clinical event listed in this appendix that 
meets the criteria of an SAE (unless indicated 
otherwise below) must be reported in the 
Clinical Event eCRF reporting module.
85

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 02 TEXT
AMENDMENT 03 TEXT
Appendix 1
Percutaneous Coronary Intervention (PCI)
Percutaneous Coronary Intervention (PCI) –
including non-serious events
Appendix 1
C. Severe hypoglycemia / Hyperglycemia 
/Diabetic ketoacidosis / Hyperosmolar 
hyperglycemic nonketotic coma
C. Severe hypoglycemia (including 
non-serious events) / Hyperglycemia 
/Diabetic ketoacidosis / Hyperosmolar 
hyperglycemic nonketotic coma
Appendix 1
F. Diabetic nephropathy (including non-
serious events)
!
Microalbuminuria
!
Proteinuria
F. Diabetic nephropathy (including 
non-serious events)
! Microalbuminuria
! Macroalbuminuria Proteinuria
Appendix 1
G. Renal failure/peritoneal or 
hemodialysis/renal transplant (including 
creation of fistula or other vascular access 
for hemodialysis) 
G. Renal failure/peritoneal or 
hemodialysis/renal transplant (including 
creation of fistula or other vascular access 
for hemodialysis)
!
Acute renal failure, requiring or 
associated with hospitalization
!
Chronic renal failure, requiring 
peritoneal hemodialysis, including 
creation of fistula or other vascular 
access for hemodialysis
!
Renal transplant
Appendix 2
[5]  Patients who terminate study medication 
are required to have a Drug Termination 
Visit as soon as possible following the 
cessation of study medication.  Patients 
will continue to be observed following the 
Drug Termination visit according to their 
planned visit schedule for the remainder of 
the trial.  All procedures for remaining 
Semi-annual and Annual Visits are to be 
followed with the exception of Drug 
Dispensation.
[5] Patients who terminate study medication 
are required to have a Drug Termination 
Visit as part of their next scheduled study 
visit (unless a separate drug termination 
visit at that point is deemed necessary by 
the investigator). as soon as possible 
following the cessation of study 
medication. Patients will continue to be 
observed following the Drug Termination 
visit according to their planned visit 
schedule for the remainder of the trial.  All 
procedures for remaining Semi-annual and 
Annual Visits are to be followed with the 
exception of Drug Dispensation.
Appendix 2
None
[6]  It is recommended that serum creatinine 
value draw dates be within 3 months of 
randomization but up to 12 months is 
acceptable (however, if > 6 months old and 
value is between 30-40mL/min/1.73m2 it is 
recommended that a new serum creatinine 
value is obtained as part of usual care).
Appendix 2
None
[7]  Blood sample for genetic and genomic analysis 
may be collected at any time during the trial 
after consent is obtained.
Appendix 4
None
Added Protocol Amendment 02 Summary of 
Changes
86

EXSCEL Protocol Amendment 06
APPENDIX 6
PROTOCOL AMENDMENT 04: SUMMARY OF CHANGES
Exenatide QW Clinical Study Protocol BCB109
PROTOCOL TITLE:
A 
RANDOMIZED, 
PLACEBO 
CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE CARDIOVASCULAR OUTCOMES AFTER TREATMENT WITH EXENATIDE ONCE 
WEEKLY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Protocol Number:
BCB109
Amendment Number:
04
Amendment Purpose:
Date: 12 September 2012
The purpose of Amendment 04 is to change the sponsorship to include only Amylin Pharmaceuticals, LLC.  In 
addition, minor changes have been included in the safety section to clarify reporting of serious adverse events, given 
the change in sponsorship.  Notable changes are detailed in the table below.
SECTION
AMENDMENT 03 TEXT
AMENDMENT 04 TEXT
Global Change
Amylin Pharmaceuticals, Inc.
Amylin Pharmaceuticals, LLC
Title Page
Eli Lilly and Company
Title Page
Throughout this protocol, unless otherwise 
specified, the term “Lilly” is used to refer to 
Eli Lilly and Company and its affiliates, acting 
as a representative of Amylin Pharmaceuticals, 
Inc.  Amylin Pharmaceuticals, Inc. sponsors 
the Investigational New Drug Application in 
the US and Puerto Rico and will serve as the 
sponsor for the Clinical Trial Application in 
Canada.  Amylin Pharmaceuticals, Inc. 
transfers the clinical sponsor obligations to 
Lilly for the conduct of this study outside the 
US, Puerto Rico and Canada.  For investigative 
sites outside of the US, Puerto Rico and 
Canada, Lilly will serve as the study sponsor.  
The applicable party will hereinafter be 
referred to as the “sponsor”.
Amylin Pharmaceuticals, LLC sponsors the 
Investigational New Drug Application. 
List of 
Abbreviations
Alliance Amylin/Lilly exenatide consortium
Amylin Amylin Pharmaceuticals, Inc.
Amylin Amylin Pharmaceuticals, LLC
Section 3
Trial 
Governance
The EC will consist of approximately eleven 
individuals, comprising nine senior 
independent academic representatives who are 
experts in their field and two sponsor 
representatives.  
The EC will consist of approximately eleven 
individuals, comprising nine senior 
independent academic representatives who are 
experts in their field and sponsor 
representatives.  
Section 3
Trial 
Governance
EXSCEL will be Co-Chaire
 
 
ut sponsored and funded by 
Amylin on behalf of the Alliance (Amylin & 
Eli Lilly). 
EXSCEL will be Co-Chaired
 
 
ut sponsored and funded by 
Amylin. 
Section 5.2
Exclusion
Criteria
o. Is an employee of Eli Lilly and Company 
or Amylin Pharmaceuticals
o. Is an employee of Amylin Pharmaceuticals,
LLC
87
PPD
PPD

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 03 TEXT
AMENDMENT 04 TEXT
Section 10.3.2 
Safety Reporting
These events must be recorded in this module 
(or faxed to Lilly if EDC is unavailable) within 
24 hours of a trial site becoming aware of the 
event.  
These events must be recorded in this module 
(or faxed to the number provided on the SAE 
report form if EDC is unavailable) within 
24 hours of a trial site becoming aware of the 
event.  
Section 10.3.2 
Safety 
Reporting
Additionally, any SAE considered by an 
investigator who is a qualified physician to be 
possibly, probably, or definitely related to the 
investigational product that is brought to the 
attention of the investigator after study 
closeout must be reported within the above 
timeline to Amylin/Eli Lilly.  
Additionally, any SAE considered by an 
investigator who is a qualified physician to be 
possibly, probably, or definitely related to the 
investigational product that is brought to the 
attention of the investigator after study 
closeout must be reported within the above 
timeline. 
Section 10.6
Reporting of 
Pregnancy
All occurrences of pregnancy must be reported 
via the Lilly Pregnancy/Breastfeeding 
Exposure Form.  
All occurrences of pregnancy must be reported 
via the Pregnancy/Breastfeeding Exposure 
Form.  
Appendix 5
None
Added Protocol Amendment 03 Summary of 
Changes
88

EXSCEL Protocol Amendment 06
APPENDIX 7
PROTOCOL AMENDMENT 05: SUMMARY OF CHANGES
Exenatide QW Clinical Study Protocol BCB109
PROTOCOL TITLE:
A 
RANDOMIZED, 
PLACEBO 
CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE CARDIOVASCULAR OUTCOMES AFTER TREATMENT WITH EXENATIDE ONCE 
WEEKLY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Protocol Number:
BCB109
Amendment Number:
05
Amendment Purpose:
Date: 25 October 2013
Based on blinded review of accrued data, the event rate for the primary composite CV endpoint is approximately 2.2 
per 100 patient-year, which is less than the anticipated rate of 3.8 per 100 patient-year.  To achieve completion of 
the study within the commitment date of the FDA Post-Marketing Request, a number of measures will be taken in 
protocol amendment 05:
1.  The power of the study to achieve the primary objective of superiority of exenatide once weekly versus placebo 
with regard to the primary composite CV endpoint has been reduced from 90% to 85% resulting in a reduction of 
the targeted number of events from 1591 to 1360.
2.  The total number of patients to be enrolled in order to achieve the targeted number of events is being increased 
from 9500 to 14000.
3.  The proportion of patients enrolled with a prior history of a CV event is being increased from 60% to 80% (for 
newly enrolled patients).  Since more than 7000 patients have been enrolled under the 60:40 scheme, it is anticipated 
that the ratio of patients with prior history of CV event to those with no prior CV event will be approximately 70:30 
at study end.  It is anticipated that more than 4000 patients (around 30%) without any prior CV history will be 
enrolled in the study.
In addition, the following changes are being made throughout this protocol amendment:
4.  The secondary hypothesis of non-inferiority of exenatide once weekly compared with placebo with regard to the 
primary composite CV endpoint is updated to a primary safety hypothesis.
5.  The end of study procedures have been clarified.
6.  Clarifications have been made to the specifications around withdrawal of consent, lost-to-follow-up procedures, 
and the follow-up phone call for safety purposes after end-of-study discontinuation of study treatment.
7.  Update to planned interim analyses as specified in the DSMB charter.
8.  Administrative changes, such as, requirements for reporting of a potential serious breach of GCP, record 
retention, source documentation, case report form completion and the Clinical Study Report have been made.
Notable changes are detailed in the table below.
89

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
Throughout
Trial / Early Termination Visit
Trial Termination Visit
1.2  Rationale for 
Conduct of the 
Study
Exenatide once weekly (EQW), a new 
formulation of exenatide that is administered 
once weekly rather than twice daily, has been 
approved by the US FDA as an adjunct to diet 
and exercise to improve glycemic control in 
adults with type 2 diabetes mellitus and in the 
European Union as adjunctive therapy to 
improve glycemic control in patients with type 
2 diabetes mellitus who are taking metformin, a 
sulfonylurea, or a combination of metformin 
and a sulfonylurea but have not achieved 
adequate glycemic control. 
Exenatide once weekly (EQW; BYDUREON), is 
an extended release formulation of exenatide that 
is administered once weekly rather than twice 
daily.  EQW has been approved by the US FDA 
as an adjunct to diet and exercise to improve 
glycemic control in adults with type 2 diabetes 
mellitus and in the European Union as an adjunct 
to metformin, a sulfonylurea (SU), a 
thiazolidinedione (TZD), a combination of 
metformin and SU, or a combination of 
metformin and TZD therapy to improve 
glycemic control in adult patients with type 2 
diabetes mellitus. 
2.1  Primary 
Objective 
The primary objective of EXSCEL will be to 
evaluate the effect of EQW, used in conjunction 
with the current usual care for glycemic control, 
on major macrovascular events when 
administered to patients with type 2 diabetes.
Objective:  To compare the impact of including 
EQW as part of usual care vs. usual care 
without exenatide on major CV outcomes as 
measured by the primary CV composite 
endpoint of CV related death, nonfatal 
myocardial infarction (MI), or nonfatal stroke.
Hypothesis:  EQW, when used as part of usual 
care, is superior to usual care without exenatide 
with regard to the risk of developing a 
confirmed event in the primary CV composite 
endpoint. 
The primary objective of EXSCEL will be to 
evaluate the effect of EQW, used in addition to 
the current usual care for glycemic control, on 
major macrovascular events when administered 
to patients with type 2 diabetes.
Objective:  To compare the impact of including 
EQW in addition to usual care vs. usual care 
without EQW on major CV outcomes as 
measured by the primary CV composite endpoint 
of CV related death, nonfatal myocardial 
infarction (MI), or nonfatal stroke.
Hypotheses:
Efficacy:  EQW, when used in addition to usual 
care, is superior to usual care without EQW with 
regard to the risk of developing a confirmed 
event in the primary CV composite endpoint. 
Safety:  EQW, when used in addition to usual 
care, is non-inferior to usual care without EQW 
with regard to the risk of developing a confirmed 
event in the primary CV composite endpoint.
2.2  Secondary 
Objectives
The secondary objectives of EXSCEL are to 
evaluate the effect of EQW treatment used in 
conjunction with the current usual care for 
glycemic control on:
The secondary objectives of EXSCEL are to 
evaluate the effect of EQW treatment used in 
addition to the current usual care for glycemic 
control on:
2.3  Additional 
Objectives
Additional objectives of EXSCEL are to 
evaluate the effect of EQW treatment used in 
conjunction with the current usual care for 
glycemic control on:
Additional objectives of EXSCEL are to 
evaluate the effect of EQW treatment used in 
addition to the current usual care for glycemic 
control on:
90

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
3  Trial 
Governance 
EXSCEL is a multinational pragmatic trial that 
will be conducted in approximately 500 sites 
worldwide.  It will be run jointly by the Duke 
Clinical Research Institute (DCRI) and the 
University of Oxford Diabetes Trials Unit 
(DTU) Academic Research Organizations 
(AROs), in an academic collaboration with 
Amylin Pharmaceuticals, LLC (Amylin). 
EXSCEL will be Co Chaire
 
but sponsored and funded by 
Amylin.
The EXSCEL Executive Committee (EC) will 
have overall responsibility for the oversight and 
management of the trial (Figure 1).  The EC 
will consist of approximately eleven 
individuals, comprising nine senior independent 
academic representatives who are experts in 
their field and two sponsor representatives.  It 
will be Co-Chaired 
with other academic 
members comprising four further diabetologists 
and three further cardiologists.  Geographical 
balance will be sought.  Decision making will 
be by consensus.  
EXSCEL is a multinational pragmatic trial that 
will be conducted in approximately 800 sites 
worldwide.  It will be run jointly by the Duke 
Clinical Research Institute (DCRI) and the 
University of Oxford Diabetes Trials Unit 
(DTU) Academic Research Organizations 
(AROs), in an academic collaboration with 
Amylin Pharmaceuticals, LLC (Amylin), a 
wholly owned subsidiary of Bristol-Myers 
Squibb. EXSCEL will be Co Chaire
 
and sponsored and 
funded by Amylin.
The EXSCEL Executive Committee (EC) will
have overall responsibility for the oversight and 
management of the trial (Figure 1).  The EC will 
consist of senior independent academic 
representatives who are experts in their field and 
sponsor representatives.  It will be Co-Chaired 
 
(see Section 12.1).  
91
PPD
P
P
D
PPD
PPD

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
4.1  Design 
Description 
EXSCEL will be a multinational, placebo-
controlled, double-blind, randomized, parallel 
group pragmatic clinical trial.  Eligible patients 
will have type 2 diabetes with an HbA1c ≥6.5% 
and ≤10.0 % on up to three (i.e., 0-3) oral 
AHAs or insulin either alone or in combination 
with up to 2 (i.e., 0-2) oral AHAs.  Patients 
enrolled will be at a wide range of CV risk with 
approximately 60% having had a prior CV 
event.
Approximately 9500 patients meeting all 
enrollment criteria will be recruited in to the 
trial over an approximately three year period, 
randomly allocated to treatment with either 
EQW 2 mg or matching placebo subcutaneous 
injections once weekly in a 1:1 ratio, and 
followed up for a minimum of four years.  The 
trial will continue until adjudicated 1591 
primary endpoint events have been accrued, or 
until the independent Data Safety Monitoring 
Board (DSMB) advises otherwise.  
The trial will assess the impact of EQW therapy 
upon CV outcomes in a large population from a 
heterogeneous group of countries and practice 
environments.  Approximately one-third of 
patients will be enrolled in the Americas 
(North/South America & Canada), one-third in 
Europe and one-third in the Asia/Australasia.  
Given that this population will be at elevated 
CV risk, it is anticipated that patients will see 
their usual care provider at least twice per year 
for routine care.  Trial follow up will consist of 
a blend of trial visits and phone calls during the 
double-blind placebo-controlled treatment 
period, which is expected to provide an average 
5.5 patient years of follow up. 
EXSCEL will be a multinational, placebo-
controlled, double-blind, randomized, parallel 
group pragmatic clinical trial.  Eligible patients 
will have type 2 diabetes with an HbA1c ∀6.5% 
and #10.0 % on up to three (i.e., 0-3) oral 
antihyperglycemic agents (AHAs) or insulin 
either alone or in combination with up to 2 (i.e., 
0-2) oral AHAs.  Patients enrolled will be at a 
wide range of CV risk with approximately 70% 
having had a prior CV event (see Section 6.3).
Approximately 14,000 patients meeting all 
enrollment criteria will be recruited in to the trial 
over approximately a five year period, randomly 
allocated to treatment with either EQW 2 mg or 
matching placebo subcutaneous injections once 
weekly in a 1:1 ratio, and followed until the 
requisite number of primary endpoint events 
have been reported.  The trial is planned to 
continue until 1360 patients with positively 
adjudicated primary endpoint events have been 
accrued, or until the independent Data Safety 
Monitoring Board (DSMB) advises otherwise.  It 
is anticipated that the EXSCEL Executive 
Committee will monitor the accrual of the 
aggregate number of adjudicated primary 
endpoint events and will determine the primary 
endpoint event cut-off date (i.e., the date at 
which the anticipated number of events is 
expected to have accrued); all patients will be 
expected to have follow-up through this date 
(Section 6).
The trial will assess the impact of EQW therapy 
upon CV outcomes in a large population from a 
heterogeneous group of countries and practice 
environments; patients will be enrolled in the 
Americas (North/South America), Europe and 
Asia/Australasia.  Given that this population will 
be at elevated CV risk, it is anticipated that 
patients will see their usual care provider at least 
twice per year for routine care.  Trial follow up 
will consist of a blend of trial visits and phone 
calls during the double-blind placebo-controlled 
treatment period. 
92

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
4.2  Trial 
Duration
Minimum follow up for the last patient 
randomized will be 4 years unless the trial is 
terminated earlier.  All patients that discontinue 
study medication, but have not withdrawn 
consent to participate in the study, will be 
followed up if possible, for the full study period 
and will have their vital status ascertained, if 
possible, at the end of the trial.
It is anticipated that enrollment will occur over 
approximately a five year period, and that an 
additional 2 to 3 years may be required to 
accumulate the requisite number of patients with 
positively adjudicated primary endpoint events, 
for a total duration of up to approximately 7.5 
years, unless the trial is terminated earlier.  All 
patients who discontinue study medication, but 
have not withdrawn consent to participate in the 
study, will be followed up, if possible, for the 
full study period and will have their vital status 
ascertained, if possible, as of the data cut-off 
date for primary endpoint events.
4.3  Post Trial 
Access to 
Therapy
New Section in Amendment 05
At the end of the trial, the sponsor will not 
continue to supply study drug to 
patients/investigators. The investigator should 
ensure that the patient receives appropriate 
standard of care to treat the condition under 
study according to national treatment guidelines.
5.1  Inclusion 
Criteria
d.  Patients with any level of CV risk and 
meeting all other inclusion criteria may be 
enrolled. Recruitment will be constrained such 
that approximately 40% will not have had a 
prior CV event and 60% will have had a prior 
CV event
d.  Patients with any level of CV risk and 
meeting all other inclusion criteria may be 
enrolled. Recruitment will be constrained (see 
Section 6.3) such that approximately 30% will 
not have had a prior CV event and 70% will 
have had a prior CV event
5.2  Exclusion 
Criteria
c.  Patient has ever been treated with an 
approved or investigational GLP-1 receptor 
agonist e.g., BYETTA (exenatide), EQW, 
VICTOZA (liraglutide),or taspoglutide
o.  Is an employee of Amylin Pharmaceuticals, 
LLC. 
c.  Patient has ever been treated with an 
approved or investigational GLP-1 receptor 
agonist e.g., BYETTA (exenatide), 
BYDUREON (EQW), VICTOZA (liraglutide), 
LYXUMIA (lixisenatide), albiglutide, 
taspoglutide, or dulaglutide
o.  Is an employee of Amylin Pharmaceuticals, 
LLC, Bristol-Myers Squibb Company, or 
AstraZeneca 
5  Trial 
Population 
New addition in Amendment 05
Eligibility criteria for this study have been 
carefully considered to ensure the safety of the 
study patients and that the results of the study 
can be used. It is imperative that patients fully 
meet all eligibility criteria.
93

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
6.1  Trial 
Procedures -
Overview
New addition in Amendment 05
The trial is planned to continue until 1360 
patients with positively adjudicated primary 
endpoint events have been accrued.  It is 
anticipated that the EXSCEL Executive 
Committee will monitor the accrual of the 
aggregate number of adjudicated primary 
endpoint events and will determine the primary 
endpoint event cut-off date (i.e., the date at 
which the anticipated number of events is 
expected to have accrued; all patients will be 
expected to have follow-up through this date).  
Based on the primary endpoint event cut-off 
date, a window of time for conduct of the Trial 
Termination Visit will be established.
NOTE:  Patients who have temporarily or 
permanently discontinued trial medication 
should continue with their regular visit schedule.  
ALL patients should have a Trial Termination 
Visit (including patients who have previously 
discontinued trial medication). 
After the Trial Termination Visit patients will be 
contacted by telephone to check for any serious 
adverse experiences and hospitalizations that 
occurred within 70 days after the administration 
of the last dose of trial medication.  Patients who 
have discontinued trial medication 70 or more 
days prior to the Trial Termination Visit will not 
need to have the telephone contact visit 
performed. These patients will have their final 
assessment of serious adverse experiences and 
hospitalizations completed at the Trial 
Termination Visit.
Note that all serious adverse experiences, 
hospitalizations, and reportable study events 
with an onset date after the primary endpoint 
event cut-off date established by the study 
Executive Committee will be managed as serious 
adverse experiences (see Section 10.3.1).
6.3  Method of 
Assigning 
Patients to 
Treatment 
Groups (Visit 1)
New addition in Amendment 05
The IVRS will be programmed to ensure the 
expected overall proportion of randomized 
patients with a prior CV event is approximately 
70%.  With transition to Amylin-labeled trial 
medication (beginning in 2013), the IVRS was 
programmed to ensure at least 80% of newly 
randomized patients have a history of a prior CV 
event (previously was programmed to ensure 
approximately 60% of patients had a prior CV 
event).
94

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
6.5  Concomitant 
Therapy
During the double-blind treatment period, 
investigators are expected to monitor patients’ 
AHA regimens and communicate with usual 
care providers, who will be responsible for 
adjusting the AHA regimen in order to achieve
locally-appropriate HbA1c goals.  The 
Executive Committee (EC) and Operations 
Committee (OC) will provide a brief list of 
guidelines for usual care based on clinical care 
practice guidelines published by national and 
international societies that will be updated as 
knowledge about T2DM evolves over the 
course of the trial.  
During the double-blind treatment period, 
investigators are expected to monitor patients’ 
AHA regimens and communicate with usual care 
providers, who will be responsible for adjusting 
the AHA regimen in order to achieve locally-
appropriate HbA1c goals based on clinical care 
practice guidelines published by national and 
international societies.  
6.5  Concomitant 
Therapy
In addition, the degree of locally-appropriate 
HbA1c goal-attainment at each site will be 
monitored centrally and sites with unusually 
low goal attainment will be advised 
accordingly.
In addition, the degree of locally-appropriate 
HbA1c goal-attainment at each site will be 
monitored centrally and sites with unusually low 
goal attainment will be advised accordingly.
6.6   Precautions 
to Minimize 
Rates of 
Hypoglycemia
The EXSCEL study team will also provide 
investigators with training materials to 
demonstrate best practice for minimizing 
hypoglycemia risk in these patients.
The EXSCEL study team will also provide 
investigators with training materials to 
demonstrate best practice for minimizing 
hypoglycemia risk in these patients.
6.9  Genetic and 
Biomarker 
Sample 
Collection
Patients enrolled in the trial will be asked to 
consent separately to provide one serum sample, 
one plasma sample, and one urine sample for 
future biomarker analyses.  These specimens 
(preferably fasting) will be obtained at baseline 
(prior to drug exposure), annually and trial/early 
termination.  All samples will be divided and 
stored in 2 aliquots at the Laboratory 
Corporation of America facility in Kannapolis, 
North Carolina, USA.
In addition, a subset of patients enrolled in the 
trial will be asked to consent separately to 
provide one serum sample, one plasma sample, 
and one urine sample for future biomarker 
analyses.  These specimens (preferably fasting) 
will be obtained at baseline (prior to drug 
exposure), year 1 and at the Trial Termination 
visit.
95

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
6.11  Temporary 
or Permanent 
Discontinuation 
of Trial 
Medication
Amendment 04 Section 6.12 Temporary 
Discontinuation of Trial Medication, Section 
6.13 Permanent Discontinuation of Trial 
Medication Visit Procedures, and Section 6.15 
Follow-up for Patients who Permanently 
Discontinue Trial Medication, were combined 
in Amendment 05 Section 6.11
Following randomization, it is expected that 
patients will remain on study medication for the 
duration of trial participation. However, it is 
recognized that patients may need to discontinue 
trial medication, in some cases permanently, for 
when protocol-specified reasons apply (Section 
6.12), due to the judgment of the primary 
investigator or the decision of the patient.  The 
Trial Hotline should be contacted whenever a 
site is considering interrupting or discontinuing 
trial medication (Section 6.18).
Unless resumption of trial medication is 
considered unsafe or is refused by the patient, 
the patient will be expected to resume regular 
use of the blinded trial medication after a period 
of temporary discontinuation.  Should a patient 
stop taking trial medication, either permanently 
or temporarily, the reasons for discontinuation 
and length of time the patient stopped taking trial 
medication will be assessed and recorded.
All randomized patients who permanently 
discontinue trial medication should have a drug 
termination visit as part of their next scheduled 
study visit (unless a separate drug termination 
visit at that point is deemed necessary by the 
investigator).  Necessary procedures are 
indicated in Appendix 2.  All efforts should be 
made to reinforce with patients that this would 
be a medication discontinuation visit, not a trial 
discontinuation visit; patients should continue 
with their regular visit schedule until the end of 
the trial, including semi-annual in-person visits, 
as well as the annual calcitonin measurement.  If 
patients cannot attend visits in person, they will 
be followed via telephone contact for all 
subsequent visits.  
NOTE:  After trial medication is discontinued 
due to pregnancy, re-initiation of study 
medication can be considered following 
completion of the pregnancy and breastfeeding 
(if applicable).
6.12  Permanent 
Discontinuation 
of Trial 
Medication Per 
Protocol
Note:  The patient and the Investigator will 
notify the usual care provider of severe 
hypoglycemic events. The usual care provider 
should make a thorough attempt to down-titrate 
and/or modify co-interventional and baseline 
therapies that may contribute to hypoglycemia 
before discontinuing blinded trial medication 
for hypoglycemia. The usual care provider will 
be provided with standard guidance by the trial 
investigator on down-titrating AHAs in the 
presence of hypoglycemia.
Note:  The patient and the Investigator will 
notify the usual care provider of severe 
hypoglycemic events. The usual care provider 
should make a thorough attempt to down-titrate 
and/or modify co-interventional and baseline 
therapies that may contribute to hypoglycemia 
before discontinuing blinded trial medication for 
hypoglycemia.
96

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
6.13  Trial 
Termination Visit
6.14  Post-
Treatment 
Telephone 
Contact
Amendment 04 Section 6.11 Trial/Early 
Termination Visit and Post-Trial Telephone 
Contact was separated into sections 6.13 and 
6.14 in Amendment 05.  In addition, the timing 
of the post-treatment telephone contact was 
modified from 90 days to 70 days after the 
administration of the last dose of trial 
medication, if applicable.
6.13  Trial Termination Visit
Investigators will be informed by the DCRI and 
DTU Coordinating Centers as to when the Trial 
Termination Visit is to be completed, and will 
schedule all patients for the Trial Termination 
Visit.  Based on the primary endpoint event cut-
off date, a window of time for conduct of the 
Trial Termination Visits will be established; this 
window will be a period of time following the 
primary endpoint event cut-off date.  At the Trial 
Termination Visit, all patients must be 
discontinued from trial medication; the 
investigator should ensure that the patient 
receives appropriate standard of care. For 
procedural details of the Trial Termination Visit, 
refer to Appendix 2.
NOTE:  All patients should have a Trial 
Termination Visit. (Patients who have 
discontinued trial medication prior to the end of 
the trial must, at minimum, have a Trial 
Termination telephone contact.)
If a patient fails to return or otherwise becomes 
difficult to contact, it is the investigator’s 
responsibility to make every effort to maintain 
contact so that at the end of the trial the patient 
can be located to determine status and to obtain 
necessary information for serious adverse 
experience reporting and/or endpoint 
adjudication as of the primary endpoint event 
cut-off date.
6.14  Post-Treatment Telephone Contact
After the Trial Termination Visit, patients will 
be contacted by telephone to check for any 
serious adverse experiences and hospitalizations 
that occurred within 70 days after the 
administration of the last dose of trial 
medication.  For patients who have been 
discontinued from trial medication for more than 
70 days as of the Trial Termination Visit, the 
Trial Termination Visit will be the final study 
follow-up.  Note that all serious adverse 
experiences, hospitalizations, and reportable 
study events with an onset date after the primary 
endpoint event cut-off date established by the 
study Executive Committee will be managed as 
serious adverse experiences (see Section 10.3.1).
97

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
6.15  Withdrawal 
of Consent
New Section in Amendment 05
Patients who request to discontinue study 
treatment will remain in the study and must 
continue to be followed for protocol specified 
follow-up procedures. The only exception to this 
is when a patient explicitly withdraws consent 
for any further contact with him/her or persons 
previously authorized by patient to provide this 
information. 
Patients should notify the investigator of the 
decision to withdraw consent from future follow-
up in writing, whenever possible. The 
withdrawal of consent should be explained in 
detail in the medical records by the investigator 
and entered on the appropriate eCRF page. In the 
event that vital status (whether the patient is 
alive or dead) is being measured, publicly 
available information should be used to 
determine vital status only as appropriately 
directed in accordance with local law.
When a patient withdraws consent from future 
follow-up prior to trial completion, all applicable 
activities scheduled for the final trial visit should 
be performed at that time (Section 6.13).
98

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
6.16  Lost to 
Follow-Up
New Section in Amendment 05
All reasonable efforts must be made to locate 
patients to determine and report their ongoing 
status. This includes follow-up with persons 
authorized by the patient as noted above as well 
as the usual care provider. Lost to follow-up is 
defined by the inability to reach the patient after 
a minimum of three documented phone calls, as 
well as lack of response by patient to one 
registered mail letter. All attempts should be 
documented in the patient’s medical records. If it 
is determined that the patient has died, the site 
will use permissible local methods to obtain the 
date and cause of death.
If an investigator’s use of a third-party 
representative to assist in the follow-up portion 
of the study has been included in the patient’s 
informed consent, then the investigator may use 
a Sponsor-retained third-party representative to 
assist site staff with obtaining patient’s contact 
information or other public vital status data 
necessary to complete the follow-up portion of 
the study. Where specific consent has been 
obtained from the participant, the site staff and 
representative will consult publicly available 
sources, such as public health registries and 
databases, in order to obtain updated contact 
information. If after all attempts, the patient 
remains lost to follow-up, then the last known 
alive date as determined by the investigator 
should be reported and documented in the 
patient’s medical records.
6.17  Breaking 
the Blind
AND
10.7  Unblinding
New addition in Amendment 05
Patients whose treatment has been unblinded can 
continue to receive trial medication and can 
continue to be followed in the trial as described 
in this protocol.
8  Efficacy 
Assessments
Trial endpoints will be defined based on clinical 
standards, regulatory precedent, and historical 
trials. These definitions will be provided in a 
separate document, along with the description 
of the Clinical Events Classification Committee 
(CEC).  Patients will be asked at each trial visit 
about procedures and hospitalizations which 
have taken place since they were last seen.
Trial endpoints will be defined based on clinical 
standards, regulatory precedent, and historical 
trials. The definitions of the events to be 
adjudicated by the Clinical Events Classification 
Committee (CEC) and the committee procedures 
will be included in the CEC Charter (Section 
12.4).  Patients will be asked at each trial visit 
about procedures and hospitalizations which 
have taken place since they were last seen.
8.2  Secondary 
Efficacy 
Endpoints
Time to first confirmed CV event for each 
component of the primary composite endpoint
Defined as time from randomization to a 
confirmed CV-related death, nonfatal MI or 
nonfatal stroke.
Time to first confirmed CV event for each 
component of the primary composite endpoint 
Defined as time from randomization to a 
confirmed CV-related death, fatal or nonfatal 
MI, or fatal or nonfatal stroke.
99

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
8.2  Secondary 
Efficacy 
Endpoints
Time to hospitalization for heart failure
Defined as time from randomization to hospital 
admission for congestive heart failure requiring 
treatment with intravenous diuretics, inotropes, 
or vasodilator therapy.
Time to hospitalization for heart failure
Defined as time from randomization to hospital 
admission for congestive heart failure requiring 
treatment with increased oral or intravenous 
diuretics, inotropes, or vasodilator therapy.
9.2  Sample Size The planned sample size for this study is 9500 
patients, randomized 1:1 to each of the two 
treatment arms assuming:
•
An annual composite cardiovascular 
primary endpoint event rate estimated to be 
3.8% per year for the population to be enrolled. 
•
A planned accrual period of 3 years
•
A minimum treatment period of 4 years
•
An estimated annual lost-to-follow up rate 
of 1%
•
An anticipated treatment discontinuation 
rate of 5% per year
The number of cardiovascular primary endpoint 
events required is commensurate with a 90% 
power to detect a 15% relative risk decrease in 
the EQW group, i.e. a true hazard ratio of 0.85 
relative to placebo, with a two-sided 
alpha=0.05.  For an exponential maximum 
likelihood test of equality of survival curves, a 
total of 1591 composite cardiovascular events 
were calculated to be required using nQuery.
The primary endpoint is the time from 
randomization to the first confirmed CV event 
defined as a CV-related death, nonfatal MI or 
nonfatal stroke.  The study is designed to assess 
the primary efficacy objective of superiority of 
EQW to placebo through the following 
hypothesis:
H0:  upper limit of the 95% CI of the HR 
[exenatide:placebo] ≥ 1
versus
H1: upper limit of the 95% CI of the HR 
[exenatide:placebo] < 1
In order to test the above hypothesis with 85% 
power and 2-sided α=0.05, a total number of 
1360 composite CV events are required 
assuming a risk reduction of 15% on EQW 
compared with placebo.  With this number of 
events, the power will be much larger than 90% 
to assess the primary safety objective of non-
inferiority of EQW compared with placebo.
In addition, with the following assumptions 
made for this study,
•
An annual composite cardiovascular 
primary endpoint event rate estimated to be 
around 2.2% per year for the population to be 
enrolled
•
A planned accrual period of 5-6 years
•
An estimated annual lost-to-follow up rate 
of 1%
•
An anticipated treatment discontinuation 
rate of 5% per year
it is expected that a total of 14000 patients need 
to be randomized in a 1:1 ratio into EQW and 
placebo to achieve the targeted 1360 confirmed 
composite CV events.
100

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
9.4  Primary 
Hypothesis
The primary hypothesis is that EQW will be 
superior to placebo with respect to the primary 
composite cardiovascular outcome, with the 
participants analyzed according to their 
allocated treatment (intention to treat).
The primary efficacy hypothesis is that EQW 
will be superior to placebo with respect to the 
primary composite cardiovascular endpoint, 
defined as the time from randomization to the 
first confirmed CV-related death, nonfatal MI or 
nonfatal stroke with the patients analyzed as 
randomized.
The primary safety hypothesis is that EQW will 
be non-inferior to placebo with respect to the 
primary composite cardiovascular endpoint, with 
patients analyzed as randomized.
Secondary 
Hypothesis
This section (9.5) from Amendment 04 was 
deleted
Not applicable
101

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
9.5  Primary 
Analysis
Statistical analyses will be based upon 
adjudicated outcomes with patients who 
discontinue prematurely from treatment 
followed until the end of the study, i.e. until the 
requisite number of primary composite events 
has been accrued.  Analysis of the primary 
composite cardiovascular outcome will be based 
on the time from randomization to the 
occurrence of the first event, with participants 
analyzed according to their allocated treatment 
(intention to treat).
A log rank test will be performed first, with 
Kaplan-Meier curves for time to event used to 
depict the accumulation of events over time for 
the EQW and placebo treatment groups.  The 
hazard ratio for the time of occurrence of the 
composite endpoint for the EQW and placebo 
treated groups and its 95% confidence interval 
will then be estimated using a Cox proportional 
hazards model without covariate adjustment.  
Secondary Cox proportional hazards model 
analyses using covariate adjustments will also 
be performed as detailed in the SAP.
The primary statistical analysis will be based 
upon adjudicated CV events with patients who 
discontinue prematurely from treatment followed 
until the end of the study, i.e. until the requisite 
number of primary composite events has been 
accrued.  It is anticipated that the Executive 
Committee will monitor the accrual of the 
aggregate number of primary composite CV 
events to determine the primary endpoint event 
cut-off date (i.e., the date at which the 
anticipated number of events is expected to have 
accrued).  All patients will be expected to have 
follow-up through this date.  Analysis of the 
primary composite cardiovascular outcome will 
be based on the time from randomization to the 
occurrence of the first event, with patients 
analyzed according to their randomized 
treatment.   The primary analysis will include all 
adjudicated CV events with onset dates up to and 
including the primary endpoint event cut-off 
date.
Kaplan-Meier curves for time to the first 
occurrence of a primary composite endpoint 
event will be used to depict the accumulation of 
events over time for the EQW and placebo 
treatment groups.  The hazard ratio for the time 
to first occurrence of the primary composite 
endpoint event for the EQW treated group to that 
of the placebo treated group and its 95% 
confidence interval will then be estimated using 
a Cox proportional hazards model stratified by 
baseline CV risk group (prior CV event or no 
prior CV event) and using treatment group as 
covariate.
The primary safety hypothesis will be assessed 
by a non-inferiority analysis with the non-
inferiority margin of 1.30, i.e., non-inferiority 
will be concluded if the upper limit of the 
confidence interval is less than 1.30.
The primary efficacy hypothesis of superiority 
will be then assessed by the 95% confidence 
interval for the hazard ratio of EQW to placebo, 
i.e., superiority will be concluded if the 95% 
confidence interval does not include 1 (upper 
limit of 95% confidence interval < 1).
102

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
9.6  Secondary 
Efficacy 
Analyses
Secondary analyses will be conducted with 
participants analyzed according to their 
allocated treatment (intention to treat) with a 
Hochberg adjustment for multiple testing.  
These analyses will examine:
1.
All cause mortality
2.
Fatal or nonfatal myocardial infarction
3.
Fatal or nonfatal stroke
4.
Hospitalization for acute coronary 
syndrome (ACS)
5.
Hospitalization for congestive heart failure 
(CHF)
The secondary efficacy endpoints are the time to 
confirmed occurrence of:
1.
All cause mortality
2.
CV-related death
3.
Fatal or nonfatal myocardial infarction
4.
Fatal or nonfatal stroke
5.
Hospitalization for acute coronary syndrome 
(ACS)
6.
Hospitalization for congestive heart failure 
(CHF)
Details of the testing strategy of the secondary 
efficacy endpoints will be provided in the 
Statistical Analysis Plan (SAP).
9.7.1  Intent-To-
Treat Population
The ITT population consists of all randomized 
patients.  Evaluation will include all events 
which occurred from randomization to the date 
of final post-study telephone contact, regardless 
of the time interval between patient 
discontinuation of study drug and final contact.  
Patients who do not have any events during the 
study will be censored at the date of their final 
post-study telephone contact.  Every effort will 
be made to collect CV events to study 
termination even in those who have 
discontinued study medication or the study.  For 
the ITT population, any patient found to have 
taken a study medication for the entire duration 
of the study that is different from that to which 
he/she was randomized will be counted in the 
treatment group of the drug to which he/she was 
randomized.
The ITT population consists of all randomized 
patients.  Evaluation will include all events 
which occurred from randomization to the 
primary endpoint event cut-off date, regardless 
of the time interval between patient 
discontinuation of study drug and final contact.  
Patients who do not have any events during the 
study will be censored at the primary endpoint 
event cut-off date.  Every effort will be made to 
collect CV events through the primary endpoint 
event cut-off date even in those who have 
discontinued study medication or the study.  For 
the ITT population, patients will be analyzed as 
randomized.
9.7.1.1  On-
Treatment 
Analysis
New addition in Amendment 05
An on-treatment analysis using the ITT 
population will be performed for the primary and 
secondary analyses as sensitivity analyses.  This 
analysis will include only those events that 
occurred within 70 days of the last dose of study 
medication or the primary endpoint event cut-off 
date, whichever occurs first.  The patients will be 
analyzed according to the treatment group to 
which they were randomized.
103

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
9.7.2  Per-
Protocol 
Population
The Per-Protocol population consists of all 
randomized patients who have taken at least one 
dose of study medication and will include in 
their analysis all data collected prior to any 
major protocol violations such as: 
•
Initiation of an open-label prohibited 
medication i.e. a GLP-1 receptor agonist.  
Evaluation will include all data up to the day of 
the initiation of the prohibited medication.
•
Discontinuation from study medication.  
Evaluation will include events which occurred 
from randomization to 90 days after the last 
dose of study medication. 
•
Taking incorrect study medication for more 
than three months. 
All such protocol violations will be identified 
prior to unblinding of the data.  Events that 
occurred after protocol violation will be 
excluded from the analysis. If a patient is found 
to have taken a study medication for any 
duration of the study that is different from that 
to which he/she was randomized, then the 
patient is counted in the treatment group of the 
drug he/she actually received.  Patients who do 
not have any events during the study will be 
censored 90 days after the last dose of study 
medication.
The Per-Protocol population consists of all 
randomized patients who have taken at least one 
dose of study medication and will include in 
their analysis all data collected prior to any 
major protocol violations (or primary endpoint 
event cut-off date, whichever occurs first), such 
as: 
•
Initiation of an open-label prohibited 
medication i.e. a GLP-1 receptor agonist.  
Evaluation will include all data up to the day of 
the initiation of the prohibited medication.
•
Early discontinuation from study 
medication.  Evaluation will include events 
which occurred from randomization to 70 days 
after the last dose of study medication or the 
primary endpoint event cut-off date, whichever 
occurs first. 
•
Taking incorrect study medication for more 
than three months. 
All protocol violations will be specified in the 
statistical analysis plan prior to unblinding of the 
data.  Events that occurred after protocol 
violation will be excluded from the analysis. 
Patients will be analyzed as randomized.
The primary safety and primary efficacy 
analyses will be repeated with the per-protocol 
population as sensitivity analyses.
9.7.3  Safety 
Population
Serious AEs, including those which lead to 
discontinuation of study medication, occurring 
between randomization and 90 days after the 
last dose of study medication, will be collected.
Serious AEs, including those which lead to 
discontinuation of study medication, occurring
between randomization and 70 days after the last 
dose of study medication, will be summarized.
9.9  Subgroup 
Analyses
The subgroups will be divided by categories or 
by the tertiles for continuous variables.
The subgroups will be divided by categories or 
by the tertiles for continuous variables.
104

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
9.10  Interim 
Analyses
The DSMB will review available data every 6 
months or more frequently if the committee 
deems it appropriate as outlined in the DSMB 
Charter.  Stopping guidelines will be detailed in 
the DSMB Charter.  The overall alpha=0.05 will 
be preserved by limiting the number of interim 
superiority analyses conducted as detailed in the 
DSMB Charter.  The DSMB may, however, 
advise stopping the study before the minimum 
follow-up of 4 years has been achieved on 
ethical or safety grounds.
The DSMB will undertake safety reviews of all 
available data every 6 months or more frequently 
if the committee deems it appropriate.
Two formal interim efficacy analyses are 
planned after approximately 453 and 906 
primary composite CV events are adjudicated, 
corresponding to one-third and two-thirds, 
respectively, of the targeted 1360 primary 
composite CV events.  The analyses will test for 
superiority using a Haybittle-Peto spending 
function where the study termination guideline 
for overwhelming superiority will be p-value < 
0.0001 for the first interim analysis and p-value 
<0.001 for the second interim analysis.  This will 
ensure a significance level of 0.0499 for the final 
analysis.
If the stopping boundary for efficacy is met at 
either of the interim analyses, the DSMB may 
recommend terminating the study earlier than 
planned.  The DSMB may, however, also advise 
terminating the study early for safety or ethical 
reasons.
The interim analyses will be performed by an 
independent statistical group.  Further details of 
the interim analyses are provided in the DSMB 
Charter.  
10.2  Adverse 
Event 
Assessment
Adverse events will be monitored over the 
course of the trial, starting from the time of 
randomization and through the duration of the 
patient’s participation, including the 90 day post 
trial medication follow-up period or withdrawal.
Adverse events will be monitored over the 
course of the trial, starting from the time of 
randomization and through the duration of the 
patient’s participation, including the 70 day post 
trial medication follow-up period.
10.3.1  Recording 
Adverse Events
SAEs will be recorded in the Clinical Events or 
SAE eCRF modules as appropriate (see Table 
1).  Guidelines for events which qualify as 
Clinical Events are provided in Appendix 1.  
Events to be recorded in the Clinical Events 
eCRF module include SAEs that are: (1) 
components of the primary or secondary 
composite cardiovascular endpoints, (2) other 
trial endpoints, (3) potential components of the 
CV endpoint that are included among terms sent 
for review by the CEC; (4) expected sequelae of 
type 2 diabetes  (Table 1).  These events 
represent trial outcomes and expected events for 
this population.  
SAEs will be recorded in the Clinical Events or 
SAE eCRF modules as appropriate (see Table 1) 
through the primary endpoint event cut-off date; 
ALL SAEs with onset dates AFTER the primary 
endpoint event cut-off date will be recorded in 
the SAE eCRF module.  Guidelines for events 
which qualify as Clinical Events are provided in 
Appendix 1.  Events to be recorded in the 
Clinical Events eCRF module include SAEs that 
are: (1) Obvious trial endpoints, (2)  
Cardiovascular Events of Interest, (3) Expected 
Events and Diabetic Complications.
Table 1:  List of 
events to be 
recorded in each 
eCRF reporting 
module
SAE eCRF:
Any event meeting the criteria of an SAE (see 
Section 10.1 for definition of SAE) that are not 
listed in Appendix 1
SAE eCRF:
Any event meeting the criteria of an SAE (see 
Section 10.1 for definition of SAE) that are not 
listed in Appendix 1 and all events above with 
an onset date after the primary endpoint event 
cut-off date
105

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
10.3.2  Safety 
Reporting
As described above, all SAEs that are not 
included in the Clinical Events List will be 
recorded by the investigator in the SAE eCRF 
module.  
As described above, all SAEs that are not 
included in the Clinical Events List and “Clinical 
Events” with onset dates after the primary 
endpoint event cut-off date will be recorded by 
the investigator in the SAE eCRF module.  
10.3.2  Safety 
Reporting
New addition in Amendment 05
Note that pancreatitis and pancreatic neoplasms / 
malignancies are events of special interest for 
GLP-1 based therapies, such as exenatide.  As 
described above, all events of pancreatitis and all
neoplasms (including pancreatic cancer) are to 
be reported on both the Clinical Events eCRF 
and the SAE eCRF, even if the event does not 
meet seriousness criteria.  These events are 
reviewed by the DSMB and adjudicated by the 
CEC.
10.6  Reporting 
of Pregnancy
Although not considered an adverse experience, 
it is the responsibility of investigators or their 
designees to report any pregnancy in a patient 
(spontaneously reported to them) which occurs 
during the trial or within 90 days of completing 
the trial.  
Although not considered an adverse experience, 
it is the responsibility of investigators or their 
designees to report any pregnancy in a patient 
(spontaneously reported to them) which occurs 
during the trial or within 70 days of completing 
the trial.  
11.3  Consent 
and Collection of 
Biomarker 
Specimens
Patients providing informed consent will have a 
blood and urine samples, preferably fasting, 
collected at baseline (prior to drug exposure), 
annually, and at the time of trial termination.  
Patients providing informed consent will have 
blood and urine samples, preferably fasting, 
collected at baseline (prior to drug exposure), 
Year 1, and at the Trial Termination visit.  
11.5  Ethical 
Conduct of the 
Study
New addition in Amendment 05
The investigator must notify the sponsor 
promptly of any inspections scheduled by 
regulatory authorities, and promptly forward 
copies of inspection reports to the sponsor.
All potential serious breaches must be reported 
to the sponsor immediately. A serious breach is a 
breach of the conditions and principles of GCP 
in connection with the study or the protocol, 
which is likely to affect, to a significant degree, 
the safety or physical or mental integrity of the 
patients of the study or the scientific value of the 
study.
Personnel involved in conducting this study will 
be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study 
personnel where sanctions have been invoked or 
where there has been scientific misconduct or 
fraud (e.g., loss of medical licensure, 
debarment).
106

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
11.8  Records
New Section in Amendment 05
11.8.1
Records Retention
The investigator must retain all study records 
and source documents for the maximum period 
required by applicable regulations and 
guidelines, or institution procedures, or for the 
period specified by the sponsor, whichever is 
longer. The investigator must contact the 
sponsor prior to destroying any records 
associated with the study.
The sponsor will notify the investigator when the 
study records are no longer needed.
If the investigator withdraws from the study 
(e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee 
(e.g., another investigator, IRB). Notice of such 
transfer will be given in writing to the sponsor.
11.8.2
Case Report Forms
An investigator is required to prepare and 
maintain adequate and accurate case histories 
designed to record all observations and other 
data pertinent to the investigation on each 
individual treated or entered as a control in the 
investigation. Data that are derived from source 
documents and reported on the CRF must be 
consistent with the source documents or the 
discrepancies must be explained. Additional 
clinical information may be collected and 
analyzed in an effort to enhance understanding 
of product safety. CRFs may be requested for 
AEs and/or laboratory abnormalities that are 
reported or identified during the course of the 
study.
The investigator will maintain a signature sheet 
to document signatures and initials of all persons 
authorized to make entries and/or corrections on 
CRFs. 
The completed CRF, including any paper or 
electronic SAE/pregnancy CRFs, must be 
promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a sub-
investigator and who is delegated this task on the 
Delegation of Authority Form. For electronic 
CRFs, review and approval/signature is 
completed electronically through the electronic 
data capture tool. The investigator must retain a 
copy of the CRFs including records of the 
changes and corrections.
Each individual electronically signing electronic 
CRFs must meet training requirements and must 
only access the electronic data capture tool using 
their unique user account. User accounts are not 
to be shared or reassigned to other individuals.
107

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
12.1  Executive 
Committee (EC)
The EC will be composed of approximately 
eleven individuals consisting of nine senior 
independent academic representatives who are 
experts in their field and two representatives 
from the Alliance.  The Committee will be co-
chaired 
 
  The other academic 
members will comprise four further 
diabetologists and three further cardiologists.  
Geographical balance will be sought. Decision 
making will be by consensus.  An EC charter 
will delineate operating procedures.
The Executive Committee is the main decision-
making body for EQW and is charged with the 
overall scientific, professional, and operational 
conduct of the trial.
The EC will be composed of senior independent 
academic representatives who are experts in their 
field and representatives from the sponsor.  The 
Committee will be co-chaired
 
 
An EC charter will outline the 
committee membership and structure and 
delineate operating procedures.
The Executive Committee is the main decision-
making body for the EXSCEL trial and is 
charged with the overall scientific, professional, 
and operational conduct of the trial.
12.3  Data Safety 
Monitoring 
Board (DSMB)
DTU will transfer pre-agreed masked datasets 
to the Independent Statistician who will then 
prepare unmasked confidential reports for the 
DSMB, using treatment codes provided in 
advance by the Sponsor.  
In addition, the DSMB will evaluate interim 
analyses of the data every six months (or on an 
ad hoc basis if needed) to determine if it 
believes either the trial should be terminated 
early because the exenatide arm (with respect to 
the placebo arm) demonstrates (a) clear 
inferiority, i.e., it is not in patient's best interest 
to continue taking blinded therapy; or (b) clear 
superiority, i.e., it is not in patient's best interest 
to continue taking blinded placebo.
DTU will transfer pre-agreed masked datasets to 
the Independent Statistician who will then 
prepare unmasked confidential reports for the 
DSMB, using treatment codes provided in 
advance by the IVRS vendor.  
In addition, the DSMB will evaluate two interim 
analyses after approximately one-third and two-
thirds of the total targeted number of primary 
composite CV events (see Sec 9.10 for details).
13  Disclosure of 
Data, 
Publications, and 
Clinical Study 
Report
Following submission for publication of the 
main trial results, a copy of the database will be 
transferred to the Sponsor.  
New addition in Amendment 05:
Following submission for publication of the 
main trial results, a copy of the database will be 
transferred to the Sponsor.  
In addition, a Clinical Study Report (CSR) will 
be prepared for regulatory purposes.  The 
Signatory Investigator responsible for signing 
the CSR will be selected by the Sponsor in 
conjunction with the Executive Committee.
Appendix 1:  
Clinical Events 
List
List re-organized from:
I.  Primary or Secondary Trial Endpoints
     A.  Obvious Trial Endpoints
     B.  Cardiovascular Events of Interest
II.  Expected Events and Diabetic 
Complications
I.  Obvious Trial Endpoints
II.  Cardiovascular Events of Interest
III.  Expected Events and Diabetic 
Complications
108
PPD
PPD

EXSCEL Protocol Amendment 06
SECTION
AMENDMENT 04 TEXT
AMENDMENT 05 TEXT
Appendix 1:  
Clinical Events 
List (Obvious 
Trial Endpoints)
Death
!  Cardiovascular (CV) Death (i.e., fatal 
myocardial infarction [MI]/cerebrovascular 
accident [CVA]/ congestive heart failure 
[CHF]/arrhythmia, cardiac arrest, death 
following CV intervention)
Death
!  Cardiovascular (CV) Death (i.e., fatal 
myocardial infarction [MI] /cerebrovascular 
accident [CVA] / congestive heart failure 
[CHF] / arrhythmia, cardiac arrest, death 
following CV intervention)
!  Non-CV Death
Appendix 1:  
Clinical Events 
List (Expected 
Events and 
Diabetic 
Complications)
G.  Renal Failure
•
Chronic renal failure, requiring 
peritoneal hemodialysis, including creation 
of fistula or other vascular access for 
hemodialysis
G.  Renal Failure
•
Chronic renal failure, requiring 
peritoneal or hemodialysis, including 
creation of fistula or other vascular access 
for hemodialysis
Appendix 2:  
Trial Plan 
New addition in Amendment 05
Added “Post-Treatment Follow-up Contact”
Appendix 2:  
Trial Plan
Blood sample (serum and plasma) and urine 
sample for archive - specimens obtained at 
baseline (prior to drug exposure), annually and 
trial/early termination.  
Blood sample (serum and plasma) and urine 
sample for archive - specimens obtained at 
baseline (prior to drug exposure), Year 1 and at 
the Trial Termination visit.
Appendix 2:  
Trial Plan
EQ-5D Completion listed for “Drug 
Termination Visit”
EQ-5D Completion removed from “Drug 
Termination Visit” consistent with Section 6.10
Appendix 6
None
Added Protocol Amendment 04 Summary of 
Changes
109