Clinical trial NCT02299050
Conditions: Type 2 Diabetes
Keywords: Type 2 Diabetes T2DM Cycloset Glycemic Control GLP-1
Sponsor: The University of Texas Health Science Center at San Antonio
Start date: 2014-06-01; Completion date: 2018-04-30
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Purpose This study will examine the effect of the addition of Cycloset upon glucose metabolism (glycemic control including post prandial glucose metabolism) in individuals with inadequately controlled (HbA1c 7.5-10.0) type 2 diabetes (T2DM) who are already on Bydureon (exenatide once weekly) or Victoza (liraglutide once daily) as part of their standard care.

Both a mechanistic rationale and empirical experimental evidence implicate a beneficial interaction between bromocriptine and the incretin mimetics (GLP-1 analogs) upon postprandial hyperglycemia in insulin resistant states. One of the actions of the incretin mimetics such as the GLP-1 analogs is to stimulate postprandial beta cell insulin secretory response to plasma glucose (see drug labeling information; www.fda.gov). Thus the combination of Cycloset that is working as a post prandial insulin sensitizier with therapies that increase post prandial insulin would be expected to provide complimentary glucose lowering effects. To date, however, no such studies investigating the interactive effects of a GLP-1 analog and Bromocriptine-QR (QR=extended release) (Cycloset) have been conducted in humans.

Condition - Type 2 Diabetes. Intervention - Cycloset. Phase - Phase 4

Study Type: Interventional Study Design: Treatment, Single Group Assignment, Open Label, N/A, Safety/Efficacy Study

Official Title: Effect of Cycloset on Glycemic Control in Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy

Detailed description:
This is a single-site, prospective, cohort study that will assess the effect of Cycloset as add-on therapy in adult subjects with T2DM that is inadequately controlled (HbA1c 7.5% to 10.0%) on GLP-1 analog therapy with either exenatide (Bydureon) once weekly or liraglutide (Victoza) once daily.

Entry criteria will be checked at the screening visit. All qualified subjects will undergo baseline studies including non-invasive hemodynamic testing for assessment of aortic stiffness and pulse wave velocity, assessment of body weight composition by dual-energy X-ray absorptiometry (DXA), assessment of endothelial function using the Endo-PAT device, measurement of cytokines and inflammatory biomarkers in the peripheral blood and urine, assessment of oxidative stress and inflammatory markers in white blood cells isolated from a peripheral whole blood sample, a 5-hour mixed meal tolerance test (MMT) for assessment of postprandial glucose metabolism and 24-hour ambulatory BP monitoring.

Following completion of all the baseline studies as above, subjects will be started on Cycloset, 0.8 mg/day in addition to their stable dose of Bydureon (exenatide) (2mg/week) or Victoza (liraglutide) (1.2-1.8 mg/day), and the dose will be increased by 0.8 mg/day every week to a maximum of 3.2 mg/day, or as tolerated to a minimum of 2.4 mg/day.

Subjects will return at months 1, 2, 3, and 4 for interim medical history, body weight, HbA1c, and FPG (Fasting plasma glucose). Postural blood pressure measurements will be obtained with the subject lying down and then after standing for 5 minutes at each of the visits. At month 4, all of the baseline studies detailed above will be repeated.

All tests will be performed in the Clinical Research Center at the Texas Diabetes Institute/University of Texas Health Science Center, San Antonio.

Arms: arm 1: Drug - Cycloset Cycloset 2.4 -3.2 mg/day

Other Names:

Bromocriptine Mesylate Quick Release
Interventions: intervention 1: Cycloset
Intervention descriptions: intervention 1: Bromocriptine QR 0.8 mg tablet 0.8 mg/day with dose increased to a maximum of 3.2 mg/day or as tolerated to a minimum of 2.4 mg/day Other names: Cycloset, B-QR

Protocol documents:
Prot_SAP_000.pdf: 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Official Study Title: Effect of Cycloset on Glycemic Control In Type 2 
Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy 
 
NCT number: NCT02299050 
 
IRB Approval Date: 06-03-2015 
 
Unique Protocol ID: HSC20130330H 
 
 


 
Veroscience 
 
Sponsor 
VeroScience 
1334 Main Road 
Tiverton Road Island 
CLINICAL STUDY PROTOCOL 
Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients 
Inadequately Controlled on GLP-1 Analogue Therapy 
Date of Original Protocol  01May2013 
Single center study 
US sites only 
Principal Investigator 
Ralph DeFronzo MD 
Co-Investigators 
Eugenio Cersosimo MD PhD 
Curtis Triplitt, PharmD 
Mariam Alatrach, MD 
Christina Agyin, NP 
John Adams 
Signatory of the sponsor 
Anthony H Cincotta PhD 
President and Chief Scientific Officer 
Sponsor’s responsible medical expert 
Bindu Chamarthi, MD, MMSc 
Medical Director 
1334 Main Road 
Tiverton, RI 
Telephone: 401 816-0525 
Fax: 
401 816-0524 
E-mail: Bindu_Chamarthi@veroscience.com 
Sponsor’s Project Manager 
Donna Cowan 
Clinical Trial Operations 
1334 Main Road 
Tiverton, RI 
Telephone: 401 816-0525 
Fax: 
401 816-0524 
E-mail: Donna_Cowan@veroscience.com 
Veroscience Serious Adverse Event Reporting 
inVentiv Health Clinical 
5430 Data Court, Suite 200 
Ann Arbor, MI 48108 
T: 734-757-9731 
F: 866-880-9343 
http://www.inVentivHealthclinical.com 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
 
 
 
 
PROTOCOL OUTLINE ................................................................................................................................... 5 
 
STUDY SCHEDULE........................................................................................................................................ 8 
 
ABBREVIATIONS AND DEFINITIONS ........................................................................................................10 
 
1 
INTRODUCTION AND STUDY RATIONALE.....................................................................................11 
 
2 
STUDY OBJECTIVES ........................................................................................................................14 
 
2.1 
PRIMARY OBJECTIVE .......................................................................................................................14 
 
2.2 
SECONDARY OBJECTIVES ..............................................................................................................14 
 
3 
STUDY DESIGN, DURATION AND DATES ......................................................................................14 
 
3.1 
STUDY DESIGN .................................................................................................................................14 
 
3.2 
STUDY DURATION AND DATES.......................................................................................................17 
 
4 
SELECTION OF SUBJECTS .............................................................................................................17 
 
4.1 
NUMBER OF SUBJECTS ...................................................................................................................17 
 
4.2 
INCLUSION CRITERIA .......................................................................................................................18 
 
4.3 
EXCLUSION CRITERIA......................................................................................................................19 
 
5 
STUDY TREATMENTS.......................................................................................................................20 
 
5.1 
DETAILS OF STUDY TREATMENTS.................................................................................................20 
 
5.2 
SUPPLIES AND ACCOUNTABILITY..................................................................................................20 
 
5.3 
COMPLIANCE.....................................................................................................................................20 
 
5.4 
RUN-IN MEDICATION ........................................................................................................................20 
 
6 
PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS ....................................................20 
 
6.1 
PRIOR AND CONCOMITANT ILLNESSES........................................................................................20 
 
6.2 
PRIOR AND CONCOMITANT TREATMENTS ...................................................................................21 
 
7 
OVERVIEW OF DATA COLLECTION AND STUDY PROCEDURES...............................................22 


Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on 
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7.1 
STUDY PROCEDURES AND SCHEDULES ......................................................................................22 
 
7.2 
DESCRIPTION OF STUDY DAYS......................................................................................................22 
 
7.2.1  Screening - Visit 0 ...............................................................................................................................22 
 
7.2.2  Study Days – Treatment Period ..........................................................................................................22 
7.2.2.1 Baseline – Visit 1 (Week 0) ± 3 days..............................................................................................22 
7.2.2.2 Baseline – Visit 2 (Visit 1 + 7-10 days)..........................................................................................23 
7.2.2.3 Baseline – Visit 3 (Visit 2 + 3-5 days).............................................................................................23 
7.2.2.4 Call 1 (day 7) ..................................................................................................................................23 
7.2.2.5 Call 2 (day 14) ................................................................................................................................24 
7.2.2.6 Call 3 (day 21) ................................................................................................................................24 
7.2.2.7 Visit 4 (Month 1) ± 3 days...............................................................................................................24 
7.2.2.8 Visit 5 (Month 2) ± 3 days...............................................................................................................24 
7.2.2.9 Visit 6 (Month 3) ± 3 days...............................................................................................................25 
 
7.2.3  End of Study (Visits 7 and 8): Endpoint ..............................................................................................25 
7.2.3.1 Visit 7 (Month 4) ± 3 days...............................................................................................................25 
7.2.3.2 24 hour urine collection instructions will be given Visit 8 (Visit 7+ 3-5 days) .................................26 
 
7.2.4  Follow-up .............................................................................................................................................26 
 
7.3 
METHODS ..........................................................................................................................................26 
 
7.3.1  Primary efficacy data will be: Change from baseline in HbA1c and change from baseline in 
postprandial glucose metabolism. .......................................................................................................26 
 
7.3.2  Secondary efficacy data: Change from baseline in endothelial function, aortic compliance, 
body weight composition, blood pressure and oxidative stress/inflammatory markers. .....................26 
 
7.3.3  Safety Data..........................................................................................................................................27 
 
8 
ADVERSE EVENTS............................................................................................................................28 
 
8.1 
DEFINITIONS......................................................................................................................................28 
 
8.1.1  Adverse Event .....................................................................................................................................28 
 
8.1.2  Serious Adverse Event........................................................................................................................29 
 
8.1.3  Alert Terms and Other Reasons for Expedited Reporting to Pharmacovigilance...............................30 
 
8.2 
PERIOD OF OBSERVATION .............................................................................................................30 
 
8.3 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS BY INVESTIGATOR....................30 
 
8.4 
IMMEDIATE REPORTING BY INVESTIGATOR TO SPONSOR .......................................................31 
 
9 
WITHDRAWALS .................................................................................................................................33 
 
9.1 
WITHDRAWAL OF SUBJECTS ..........................................................................................................33 
 
9.2 
EMERGENCY SPONSOR CONTACT................................................................................................34 
 
9.3 
EMERGENCY IDENTIFICATION OF INVESTIGATIONAL PRODUCTS...........................................34 


Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on 
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9.4 
EMERGENCY TREATMENT ..............................................................................................................34 
 
10 
STATISTICAL PROCEDURES ..........................................................................................................35 
 
10.1   ANALYSIS VARIABLES......................................................................................................................35 
 
10.2   ANALYSIS POPULATIONS ................................................................................................................35 
 
10.3   SAMPLE SIZE .....................................................................................................................................35 
 
11 
REGULATORY REQUIREMENTS .....................................................................................................36 
 
11.1   GOOD CLINICAL PRACTICE .............................................................................................................36 
 
11.2   DELEGATION OF INVESTIGATOR DUTIES .....................................................................................36 
 
11.3   SUBJECT INFORMATION AND INFORMED CONSENT ..................................................................36 
 
11.4   CONFIDENTIALITY ............................................................................................................................37 
 
11.5   PROTOCOL AMENDMENTS .............................................................................................................37 
 
11.6   APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS ...................................37 
 
11.7   ONGOING INFORMATION FOR INDEPENDENT ETHICS COMMITTEE/ INSTITUTIONAL 
REVIEW BOARD ................................................................................................................................38 
 
11.8   CLOSURE OF THE STUDY ...............................................................................................................38 
 
11.9   RECORD RETENTION .......................................................................................................................38 
 
11.10 LIABILITY AND INSURANCE .............................................................................................................39 
 
11.11 FINANCIAL DISCLOSURE .................................................................................................................39 
 
12 
STUDY MONITORING AND AUDITING ............................................................................................40 
 
12.1   STUDY MONITORING AND SOURCE DATA VERIFICATION..........................................................40 
 
12.2   ON-SITE AUDITS................................................................................................................................40 
 
13 
DOCUMENTATION AND USE OF STUDY FINDINGS .....................................................................41 
 
13.1   DOCUMENTATION OF STUDY FINDINGS .......................................................................................41 
 
13.2   USE OF STUDY FINDINGS ...............................................................................................................41 
 
14 
DECLARATIONS OF SPONSOR AND INVESTIGATOR..................................................................43 
 
14.1   DECLARATION OF SPONSOR..........................................................................................................43 
 
14.2   DECLARATION OF INVESTIGATOR.................................................................................................43 


Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy 
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PROTOCOL OUTLINE 
 
 
 
Study number 
HSC20130330H 
 
Title 
 
Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately 
Controlled on GLP-1 Analogue Therapy 
 
 
Investigator(s), Study Site(s) 
 
Ralph A. DeFronzo, M.D. (defronzo@uthscsa.edu),  University of Texas Health 
Science Center San Antonio 
 
Sponsor-Funded, Single Center, Investigator Initiated Trial 
 
 
Study Duration and Dates 
The duration of this study is 
expected to be approximately 18 
months (10-month subject 
recruitment, up to 3 week screening 
phase, and 5-month treatment), with 
subject recruitment to start in May 
2014 and the last subject to finish in 
October 2015. 
Phase 
IV (Open 
label 
Cycloset 
added to 
usual 
diabetes 
treatment) 
 
 
Objectives 
 
Primary Objective: 
 
To examine the effect of the addition of Cycloset upon glucose metabolism (glycemic control 
including post prandial glucose metabolism) in individuals with inadequately controlled (HbA1c 
7.5-10.0) type 2 diabetes (T2DM) who are already on Bydureon (exenatide once weekly) or 
Victoza (liraglutide once daily) as part of their standard care. 
 
 
Secondary Objectives: 
 
Since Cycloset has been shown to reduce cardiovascular events in those over the age of 18 
with T2DM, we will also perform mechanistic studies evaluating for potential mechanisms for 
this cardiovascular benefit including non-invasive tests for the assessment of the effects of 
Cycloset therapy on endothelial function, aortic compliance, body weight composition, and 
inflammatory and oxidative stress markers. 
 
 
Study Design 
 
This is a single-site, prospective, cohort study that will assess the effect of Cycloset as add-on 
therapy in adult subjects with T2DM that is inadequately controlled (HbA1c 7.5% to 10.0%) on 
GLP-1 analog therapy with either exenatide (Bydureon) once weekly or liraglutide (Victoza) once 


Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy 
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daily. 
 
Entry criteria will be checked at the screening visit. All qualified subjects will undergo baseline 
studies including non-invasive hemodynamic testing for assessment of aortic stiffness and pulse 
wave velocity,  assessment of body weight composition by dual-energy X-ray absorptiometry 
(DXA),  assessment  of  endothelial  function  using  the  Endo-PAT  device,  measurement  of 
cytokines  and  inflammatory  biomarkers  in  the  peripheral  blood  and  urine,  assessment  of 
oxidative stress and inflammatory markers in white blood cells isolated from a peripheral whole 
blood sample, a 5-hour mixed meal tolerance test (MMT) for assessment of postprandial glucose 
metabolism and 24-hour ambulatory BP monitoring. 
 
Following completion of all the baseline studies as above, subjects will be started on Cycloset, 
0.8 mg/day in addition to their stable dose of Bydureon (exenatide) (2mg/week) or Victoza 
(liraglutide) (1.2-1.8 mg/day), and the dose will be increased by 0.8 mg/day every week to a 
maximum of 3.2 mg/day, or as tolerated to a minimum of 2.4 mg/day. 
 
Subjects will return at months 1, 2, 3, and 4 for interim medical history, body weight, HbA1c, and 
FPG. Postural blood pressure measurements will be obtained with the subject lying down and 
then after standing for 5 minutes at each of the visits. At month 4, all of the baseline studies 
detailed above will be repeated. 
All   tests   will   be   performed   in   the   Clinical   Research   Center   at   the   Texas   Diabetes 
Institute/University of Texas Health Science Center, San Antonio. 
 
 
 
Number Of Subjects 
 
Planned enrollment = 15 
 
 
Primary Subject Characteristics at Enrollment 
 
 
T2DM male or female subjects between the ages of 30 and 70 years with HbA1c between 7.5- 
10% on a diabetes therapeutic regimen consisting of stable doses of either exenatide (2 
mg/week) or liraglutide (1.2-1.8 mg/day) for at least 90 days prior to enrollment with or without 
metformin and/or pioglitazone and no other glucose lowering agents. 
 
 
Study Treatments 
 
Cycloset, 0.8 mg/day, with the dose increased by 0.8 mg/day every week to a maximum of 3.2 
mg/day, or as tolerated to a minimum dose of 2.4 mg/day, added on to usual diabetes therapy 
consisting of a stable dose for at least 90 days of exenatide (2mg/week)  or liraglutide (1.2-1.8 
mg/day). Subjects must be on either exenatide or liraglutide as part of their standard care to be 
eligible for study participation. 
 
 
Study Endpoints 
 
The primary endpoint is the effect of Cycloset on glycemic control and postprandial glucose 
metabolism. 


Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy 
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Secondary endpoints include the effects of Cycloset on endothelial function, aortic compliance,, 
body weight composition, blood pressure and markers of inflammation and oxidative stress. 
 
 
 
 
Statistical Procedures 
Sample Size Calculation: Assuming that Cycloset will cause a 0.6% reduction in HbA1c, we 
computed that 15 subjects provide 90% power to detect a 0.6% decrease from a baseline HbA1c 
of 8.0 ±0.5% at an alpha of 0.05. 
 
A statistical analysis plan (SAP), providing details of the analyses and presentation structure of 
the results, will be developed and finalized before the database is locked. 


 
7
Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue Therapy 
 
 
STUDY SCHEDULE 
Screening 
Period 
 
 
Baseline Period 
Treatment Period (16 weeks) 
 
 
 
 
End of 
 
 
 
 
 
End of Study 
Data collected and/or 
action 
Visit 0* 
Visit 1* 
Visit 2 
Visit 3 
Phone 
call 1 
Phone 
call 2 
Phone 
call 3 
Visit 4 
Visit 5 
Visit 6 
Study 
Visit  α 
 
Visit 8 α 
 
Week 
-3 to -1 
 
Informed Consent 
X 
 
Week 0 
(baseline) 
Visit 1 
+7-10 days 
Visit 2 
+3-5 days 
Day 7 
Day 14 
Day 21 
 
1 
Month 
 
2 
Months 
 
3 
Months 
 
4 
Months 
Visit 7 
+3-5 
days 
Entry Criteria                                   X                                       X 
Medical History 
X 
X 
X 
X 
X 
Physical Exam 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
ECG 
X 
Hematology and chemistry              X                                                                                                                                                                                          X 
Lipids                                               X                                                                                                                                                                                          X                    X 
HbA1c                                             X                                                                                                                                        X             X              X             X                    X 
Fasting plasma glucose                  X                                                                                                                                        X             X              X             X                    X 
Postural Blood Pressure                                                                                                                                                            X             X              X             X* 
Aortic compliance testing                                     X                                                                                                                                                                                             X* 
DXA for body composition 
X 
X 
measurements 
Assessment of endothelial 
1 
1 
function using Endo-PAT 
X 
X 
Blood sample for 
X 
measurement of 
X 
inflammatory biomarkers 
and isolation of WBCs 
Mixed Meal Tolerance test 
X 
X 
Ambulatory BP monitoring 
device set up 
X 
Return ABPM 
device 
X 
Return ABPM 
device 
24-hour urine collection 
instruction 
X 
Return 24 hour 
urine 
X (first dose same 
X 
Return 24 hour 
urine 
Cycloset Titration 
day as visit 3) 
X 
X 
X 
Discontinue 
Cycloset 
 
Concomitant meds                                                                                                         To be assessed throughout the study 
Adverse Events                                                                                                              To be assessed throughout the study 
Hypoglycemia                                                                                                                 To be assessed throughout the study 
Serious Adverse Events                                                                                                 To be assessed throughout the study 
Report serious adverse events to sponsor within 24 hours 
Mandatory Contact                                                                                       Weekly titration phone contacts as described in the protocol 
1 Endo-PAT conducted upon arrival to study site and at 90 minutes into the Mixed Meal Tolerance test 
*  These tests (DXA and Aortic compliance testing) may be done on either Visit 7 or Visit 8 
 
 
 
 
 
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Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on GLP-1 Analogue 
Therapy 
 
 
 
Mixed MEAL TOLERANCE TEST 
 
3-3H-Glu/ 
Time 
Glucose 
C-pep/Ins 
Glucagon 
FFA 
GLP-1/GIP 
(minutes) 
(0.5 ml) 
(6 ml) 
(3 ml) 
(2 ml) 
(2 ml) 
(3 ml) (2 ml) 
 
 
-180 
-180 
X 
start 3-3H-glucose 
X 
X 
X 
X 
X 
-30 
X 
X* 
-20 
X 
X* 
X 
X 
X 
X 
-10 
X 
X* 
X 
X 
X 
X 
-5 
X* 
0 
X 
X* 
X 
X 
X 
X 
X 
0 
Mixed meal with 1-14C- 
glucose 
15 
X 
X 
X 
30 
X 
X 
X 
X 
X 
45 
X 
X 
X 
60 
X 
X 
X 
X 
X 
X 
75 
X 
X 
X 
90 
X 
X 
X 
X 
X 
105 
X 
X 
X 
120 
X 
X 
X 
X 
X 
X 
135 
X 
X 
150 
X 
X 
X 
X 
X 
165 
X 
X 
180 
X 
X 
X 
X 
X 
195 
X 
X 
210 
X 
X 
X 
X 
X 
225 
X 
X 
240 
X 
X 
X 
X 
X 
X 
255 
X 
X 
X 
X 
X 
270 
X 
X 
X 
X 
X 
285 
X 
X 
X 
X 
X 
300 
X 
X 
X 
X 
X 
Number 
26 
26 
21 
16 
16 
3 
5 
Blood volume (ml) 13 
156 
63 
32 
32 
9 
10 
Total blood loss (ml) = 315 ml 
 
*  3-3H-glucose only 
 
 
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Clinical Study Protocol: Effect of Cycloset on Glycemic Control In Type 2 Diabetic Patients Inadequately Controlled on 
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ABBREVIATIONS AND DEFINITIONS 
 
 
 
 
ABPM 
Ambulatory Blood Pressure Monitoring 
 
AE 
Adverse Event 
BG 
Blood Glucose 
BMI 
Body Mass Index 
CRC 
Clinical Research Center 
 
CRF 
Case Report Form 
 
DM 
Diabetes Mellitus 
 
FPG 
Fasting Plasma Glucose 
GCP 
Good Clinical Practice 
GLP-1 
glucagon-like peptide 
HbA1c 
Hemoglobin A1C 
ICH 
International Conference on Harmonization 
 
IEC 
Independent Ethics Committee 
 
IRB 
Institutional Review Board 
 
IV 
Intravenous 
 
MMT 
Mixed Meal Tolerance test 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMBG 
Self-Monitored Blood Glucose 
 
T2DM 
Type 2 diabetes mellitus 
 
VS 
Vital Signs 


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1 INTRODUCTION AND STUDY RATIONALE 
 
A.  Summary 
 
Type 2 diabetes mellitus (T2DM) is a common metabolic cardiovascular disorder characterized 
by multiple pathophysiologic abnormalities (1). Quick release bromocriptine (Cycloset), a D2- 
dopamine receptor agonist sympatholytic agent, was approved by the U.S. Food and Drug 
Administration in 2009 for use as monotherapy and in combination with oral antidiabetic agents 
for the treatment of T2DM (2) in those with T2DM over the age of 18. In humans, Cycloset 
reduces the postprandial glucose excursion without augmenting insulin secretion or improving 
insulin sensitivity in muscle (3,4). These results suggest that Cycloset enhances hepatic 
sensitivity to insulin, perhaps by inhibiting central sympathetic outflow, and are consistent with 
results obtained in rodents (5). 
 
The glucagon-like peptide (GLP)-1 receptor agonists, liraglutide and exenatide, also reduce 
postprandial, as well as fasting, hyperglycemia following glucose ingestion (6,7). The reduction in 
postprandial hyperglycemia results from a delay in gastric emptying and enhanced suppression 
of hepatic glucose production secondary to increased insulin secretion and decreased glucagon 
secretion (6,8). To date, no study in man has examined combination therapy with a GLP-1 
receptor agonist and Cycloset. Since both agents work by reducing postprandial hyperglycemia 
and inhibiting post-meal HGP, although by different mechanisms, one might expect them to have 
an additive or even synergistic effect to reduce postprandial plasma glucose levels. In fact, a 
synergistic interaction between bromocriptine and exenatide has been demonstrated in the 
glucose intolerant, insulin resistant Syrian hamster (9). 
 
In the present study we will examine the effect of the addition of Cycloset therapy to inadequately 
controlled (HbA1c  7.5-10.0) T2DM patients on exenatide (Bydureon) once weekly or liraglutide 
(Victoza). Since Cycloset has been shown to reduce cardiovascular events in adults with T2DM 
(10), a beneficial effect that maybe associated with improved endothelial/vascular function, we 
also will measure endothelial function using the Endo-PAT instrument and assess aortic 
compliance using non-invasive hemodynamic testing. 
 
1. DeFronzo RA. Banting Lecture: From the triumvirate to the ominous octet: a new paradigm for the treatment of type 
2 diabetes mellitus. Diabetes 58:773-95, 2009. 
2. DeFronzo RA. Bromocriptine: a sympatholytic, D2-dopamine agonist for the treatment of type 2 diabetes. Diabetes 
Care 34:789-94, 2011. 
3. Pijl H, Ohashi S, Matsuda M, Miyazaki Y, Mahankali A, Kumar V, Pipek R, Iozzo P, Lancaster JL, Cincotta AH, 
DeFronzo RA. Bromocriptine. A novel approach to the treatment of type 2 diabetes. Diabetes Care 23:1154-1161, 
2000. 
4. Kamath V, Jones CN, Yip JC, Varasteh BB, Cincotta AH, Reaven GM, Chen YD. Effects of quick-release form of 
bromocriptine (Ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in 
obese nondiabetic hyperinsulinemic women. Diabetes Care 20:1697-701, 1997. 
5. Cincotta AH. Hypothalamic role in the insulin resistance syndrome. In Insulin Resistance Syndrome. Hansen B, 
Shaffrir E, Eds. London, Taylor and Francis, 2002, p. 271-312. 
6. Cervera A, Wajcberg E, Sriwijitkamol A, Fernandez M, Zuo P, Triplitt C, Musi N, DeFronzo RA, Cersosimo E. 
Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endo Metab 
294:E846-E852, 2008. 
7. Blonde L, Russell-Jones D. The safety and efficacy of liraglutide with or without oral antidiabetic drug therapy in type 
2 diabetes: an overview of the LEAD 1-5 studies. Diabetes Obes Metab 11:26-34, 2009. 


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8. Cersosimo E, Gastaldelli A, Cervera A, Wajcberg E, Mendez V, Sriwijilkamol A, Fernandez M, Zuo P, Petz R, Triplitt 
C, Musi N, DeFronzo RA. Effect of exenatide on splanchnic and peripheral glucose metabolism in type 2 diabetic 
subjects. J Clin Endocrinol Metab J Clin Endocrinol Metab 96:1763-70, 2011. 
9. Ezrohki M, Lou S, Trubitsyma Y, Cincotta AH. Synergism of dopamine agonist plus GLP-1 analog therapy on 
improvement of glucose intolerance in Syrian hamsters (Abstract). 
10. Gaziano JM, Cincotta AH, O'Connor CM, Ezrokhi M, Rutty D, Ma ZJ, Scranton RE. Randomized clinical trial of 
quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. 
Diabetes Care. 33:1503-1508. 2010 
11. Abdul-Ghani M, Jenkinson C, Richardson D, Tripathy D, DeFronzo RA. Insulin secretion and insulin action in 
subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration 
Genetic Epidemiology Study (VAGES). Diabetes 55:1430-1435, 2006. 
12. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with 
the euglycemic insulin clamp. Diabetes Care 22:1462-1470. 1999. 13. Ferrannini E, Simonson DC, Katz LD, Reichard 
G, Bevilacqua S, Barrett EJ, Olsson M, DeFronzo RA. The disposal of an oral glucose load in patients with non-insulin 
dependent diabetes. Metabolism 37:79-85, 1988. 
 
B.  Detailed Background 
 
Cycloset is a dopamine receptor agonist indicated as an adjunct to diet and exercise to improve 
glycemic control in adults with type 2 diabetes mellitus (T2DM).  Cycloset reduces glucose 
following each meal without raising plasma insulin levels.  As such, Cycloset may be acting as a 
postprandial insulin sensitizer and/or glucose regulator (Pijl et al 2000) to reduce postprandial 
hyperglycemia and may be expected to synergize with incretin mimetics that increase 
postprandial insulin levels. 
 
Available evidence indicates that Cycloset improves glycemic control in patients with type 2 
diabetes predominantly by improving postprandial responsiveness to insulin. Once daily morning 
Cycloset therapy increases insulin-stimulated glucose disposal as assessed by the euglycemic 
insulin clamp technique and it also reduces post load glucose levels following an oral glucose 
tolerance test without increasing plasma insulin levels in type 2 diabetes subjects (Pijl et al 2000). 
The selective effect of timed bromocriptine treatment on postprandial versus post-absorptive 
glucose metabolism is exemplified by its much more pronounced effect on glucose clearance 
during a hyperglycemic versus euglycemic insulin clamp (Ezrokhi et al, 2008). 
 
In clinical studies, Cycloset therapy has been shown to reduce postprandial glucose levels across 
the three standard meals of the day without increasing plasma insulin levels when used alone or 
in combination with sulfonylurea therapy (Cincotta et al, 1999). Among patients with type 
2 diabetes failing sulfonylurea therapy (two identically designed studies with; n= 494; baseline 
HbA1c of 9,3), the addition of Cycloset as compared to placebo resulted in reductions in post 
prandial glucose after 24 weeks of treatment (Cincotta 1999). 
 
Post prandial glucose exursions contribute to the excessive morbidity associated with type 2 
diabetes (Ceriello, 2008). The mechanism by which timed Cycloset elicits its postprandial 
glucose metabolism effect is believed to  involve its ability to normalize aberrant fuel sensing 
neurons in the hypothalamus that inappropriately induce insulin resistance respecting regulation 
of  hepatic glucose output, adipose lipolysis, and glucose disposal in liver and muscle. Under 
normal conditions, in response to a meal, fuel sensing neurons in the hypothalamus act via the 
neuroendocrine axis to improve insulin sensitivity in liver, adipose, and muscle after a meal to 
reduce hepatic glucose output and adipose lipolysis, and to increase glucose disposal in liver and 
muscle.  However, in insulin resistant states like T2DM, this fuel sensing mechanism is altered 
and no longer sends these meal-induced insulin sensitizing signals to the periphery but 


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rathersends signals that tend to oppose insulin action, and postprandial dysglycemia ensues 
(Cincotta 2002, Luo et al 2008). 
 
One of the actions of the incretin mimetics such as the GLP-1 analogs is to stimulate postprandial 
beta cell insulin secretory response to plasma glucose (see drug labeling information; 
www.fda.gov).  Thus the combination of Cycloset that is working as a post prandial insulin 
senstizier  with therapies that increase post prandial insulin would be expected to provide 
complimentary glucose lowering effects.  As described above, Cycloset has been shown to 
reduce postprandial glucose levels when used in combination with insulin secretagoues. In 
animal models of insulin resistance, the combination of bromocriptine  and a GLP-1 analog  was 
shown to work synergistically to improve glycemic control. The interactive effect of chronic (2 
week) bromocriptine treatment on glucose tolerant/insulin resistant animals that were 
administered a GLP-1 analog just prior to the glucose tolerance test (GTT) was assessed in a 2 
week study. Intraperitoneal administered bromocriptine or vehicle was administered daily for 2 
weeks at the onset of locomotor activity.  A GTT was performed on all animals on day 13. On the 
day of the GTT, each of the BC and vehicle groups was divided in half and administered either 
vehicle or Exendin 4 just prior to the initiation of the GTT. The combination of timed bromocriptine 
plus a GLP-1 analog produced marked improvement in the GTT of severely glucose intolerant 
hamsters, to an extent much greater than the sum of either therapy (Ezrokhi 2012). 
 
Therefore, both a mechanistic rationale and empirical experimental evidence implicate a 
beneficial interaction between bromocriptine and the incretin mimetics (GLP-1 analogs) upon 
postprandial hyperglycemia in insulin resistant states. To date, however, no such studies 
investigating the interactive effects of a GLP-1 analog and Bromocriptine-QR (Cycloset) have 
been conducted in humans.. 
 
Ceriello A, Colagiuri S. International Diabetes Federation guideline for management of postmeal glucose: a review of 
recommendations. (2008) Diabet Med. 25(10), 1151-1156. 
 
Cincotta AH, Meier AH. Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. (1996) 
Diabetes Care. 19(6), 667-670. 
 
Cincotta AH, Meier AH, Cincotta Jr M. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic 
subjects: a new approach in the treatment of diabetes. (1999) Expert Opin Investig Drugs. 8(10), 1683-1707. 
 
Cincotta, A. (2002). Hypothalamic role in insulin resistance and insulin resistance syndrome. In B. Hansen & E. Shafrir (Eds.), 
Frontiers in Animal Diabetes Research Series. (pp 271-312) London: Taylor and Francis 
 
DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. (1992) Diabetes Care. Mar;15(3):318- 
368. PubMed PMID: 1532777. 
 
Ferrannini E. Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. (1998) 
Endocr Rev. Aug;19(4):477-490. 
 
Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes. (2003) 
Diabetologia.  Jan;46(1):3-19. 
 
M. Ezrokhi, S. Luo, J. Cincotta, A.H. Cincotta. Timed dopamine agonist therapy induces a postprandial-selective insulin sensitivity. 
(2008) Diabetologia. 51:[Suppl1] S276 
Meier A, Cincotta A. Circadian rhythms regulate the expression of the thrifty genotype/phenotype. (1996) Diabetes Rev. 4, 464-487. 
Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. (2000) Diabetes Care. 23(8), 
1154-1161. 


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2   STUDY OBJECTIVES 
 
2.1   PRIMARY OBJECTIVE 
 
The objective of this study is to examine the effect of the addition of Cycloset on glycemic control 
in inadequately controlled (HbA1c 7.5-10.0) T2DM patients who are already on Bydureon 
(exenatide once weekly) or Victoza (liraglutide ) as part of their standard care. 
 
An  additional  co-primary  objective  of  the  study  is  to  examine  the  effect  of  Cycloset  on 
postprandial glucose metabolism. 
 
 
2.2   SECONDARY OBJECTIVES 
 
Secondary Efficacy 
 
To assess the potential beneficial effect of Cycloset on endothelial function, arterial stiffness, 
body weight composition, blood pressure, inflammation and oxidative stress. 
 
Safety 
 
The safety objectives of this study are to investigate the relative differences from baseline to end 
of study in: 
 
• 
Occurrence of hypoglycemia 
 
• 
Adverse events 
 
• 
Laboratory values: standard blood chemistry and hematology 
 
• 
Clinical values: physical examination, vital signs and weight. 
 
 
3   STUDY DESIGN, DURATION AND DATES 
 
3.1   STUDY DESIGN 
 
This is a single center prospective cohort study that will assess the effect of Cycloset  in in T2DM 
subjects who are inadequately controlled (HbA1c  7.5% to 10.0%) on GLP-1 analog therapy with 
either Bydureon (exenatide once weekly) or Victoza (liraglutide ). 
 
 
Subjects who meet the entry criteria will first undergo non-invasive hemodynamic testing for a 
baseline assessment of aortic compliance (Visit 1). Subjects will then come to the Clinical 
Research Center (CRC) at the Texas Diabetes Institute on the morning of Visit 2 following a 10- 
12 hour overnight fast and restriction from use of caffeine, tobacco, vitamins or medications that 
might affect vascular tone. Subjects will take their normal dose of exenatide or liraglutide in the 


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morning prior to this visit. At this visit, subjects will a non-invasive assessment of endothelial 
function using the Endo-PAT 2000 device Subjects will then receive a 5-hour MMT test. At 
approximately 90 minutes into the completion of the MMT test, a second Endo-PAT recording will 
be conducted.  Upon completion of the second Endo-PAT test, subjects will be placed on a 
continuous ambulatory BP monitor and asked to collect a 24 hour urine sample, which they will 
start the following morning. After completion of the 24-hour urine collection, subjects will return to 
the CRC for Visit 3. At this visit, the ambulatory BP data will be downloaded and the 24-hr urine 
sample will be stored. Subjects will also have a DXA scan performed for assessment of body 
weight composition and have blood samples drawn for the measurement of serum cytokines and 
inflammatory biomarkers and isolation of white blood cells at this visit. 
 
 
At Visit 3 subjects will be started on Cycloset, 0.8 mg/day in addition to their stable dose of 
Bydureon (exenatide) (2mg/week) or Victoza (liraglutide) (1.2-1.8 mg/day). Subjects will receive 
their first dose of Cycloset in the CRC and will be monitored for one hour after the dose before 
being sent home.  The Cycloset dose will then be increased by 0.8 mg/day every week to a 
maximum of 3.2 mg/day, or as tolerated to a minimum of 2.4 mg/day.   During the Cycloset 
titration phase subjects will be monitored by phone with weekly phone visits. Subjects who 
cannot tolerate at least 2.4 mg/day of Cycloset will be replaced. 
 
 
Subjects will return at months 1, 2, 3, (Visits 4, 5 and 6) for interim medical history, body weight, 
HbA1c, and FPG. At month 4 (End of Study Visits 7 and 8), all of the tests performed at Baseline 
Visits 1-3, including non-invasive hemodynamic testing for assessment of aortic compliance, 
DXA for assessment of body weight composition, Endo-PAT tests for assessment of endothelial 
function, MMT test, collection of blood samples for measurement of inflammatory/ oxidative 
stress markers and isolation of white blood cells, 24-hour ambulatory BP recording and collection 
of a 24-hour urine sample will be repeated as described above. Cycloset administration will be 
discontinued at the completion of Visit 8. 
 
Two weeks after Cycloset administration is discontinued subjects will return for Visit 10 and 
complete a final assessment of aortic compliance. There will be no additional follow up after Visit 
10. 
STUDY PROCEDURES 
Endo-PAT 
The Endo-PAT 2000 is a device that is used to assess endothelial vasodilator function in a rapid 
and non-invasive fashion. The device consist of two plethysmographic probes that are placed on 
the index finger of each hand and record endothelium-mediated changes in the digital pulse 
waveform known as the PAT ( Peripheral Arterial Tone) signal. Blood pressure cuff is then 
inflated to induce downstream peripheral hyperemia by occluding blood flow through the brachial 
artery for 5 minutes. The contra-lateral arm is used as a control. Endothelium-mediated changes 
in the PAT signal are elicited by creating a downstream hyperemic response. 
 
Briefly, the Endo-PAT measurements will be taken in a fasting state and be conducted in a quiet, 
dimly lit, temperature-controlled exam room to reduce fluctuations in vascular tone. The patient 
will remain supine and comfortable for 15 minutes so as to attain a cardiovascular steady-state 
with two arm-supporters along each of the patient's sides to support the patient’s arm. The index 


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finger will be used to place Endo-PAT probe for the study; however, if this finger is unsuitable, a 
different digit (except the thumb) may be used, as long as the same finger is used on both hands. 
Blood pressure will be measured using the control arm (the arm that is not occluded during the 
Endo-PAT study. A second blood pressure cuff will be placed on the arm to be occluded during 
the Endo-PAT study. The Endo-PAT device will be employed and the blood pressure cuff will be 
inflated at that time. During the procedure the patient will be asked to refrain from moving the 
fingers, as this will create mechanical artifacts. It is important for the patient to be relaxed 
throughout the study. During the test and while the arm cuff is inflated, subjects may feel some 
discomfort, numbness, or tingling. In case of incomplete occlusion the cuff may be inflated to a 
maximum of 300 mmHg. The measurement will be taken for 5 minutes. During that time, the 
blood pressure cuff will be rapidly inflated to a supra-systolic pressure of 60 mmHg above the 
patient's systolic pressure or 200 mmHg, whichever is higher. The complete cessation of blood 
flow to the hand is verified by the absence of a PAT signal from the occluded arm. After 5 
minutes  occlusion,  the  cuff  will  be  released  as  quickly as  possible  and  a five-minute  post 
occlusion measurements will be recorded. 
 
The Endo-PAT system calculates the response to reactive hyperemia and a PAT ratio is created 
using the post and pre occlusion values. These values are normalized to measurements from the 
contra-lateral arm, which serves as control for non-endothelial dependent systemic effects. The 
technique provides values for the calculation of a Reactive Hyperemia Index (RHI), which gives 
an indication of the endothelial vasodilator function. The RHI, in turn, correlates with the 
measurement of endothelial vasodilator function in the coronary arteries and thus predicts the 
potential unfavorable cardiovascular conditions and outcomes. 
 
 
Noninvasive Hemodynamic Assessment of Aortic Compliance 
 
Subjects will be rested in the supine position for 15 minutes. Measurements for the assessment 
of aortic pulse wave velocity (PWV) will then be taken immediately after measurement of brachial 
blood pressure. PWV is determined by simultaneous measurement of arterial pressure waves at 
the carotid and femoral arteries with sensitive pressure transducers place on the skin overlying 
the carotid and femoral arteries. This is a completely noninvasive procedure using previously 
described and published techniques (Circulation 2006; 113: 1213-1225). The surface distance 
from suprasternal notch to the distal (femoral) recording site is measured, and the pressure wave 
transit time is calculated using a foot-of-the-wave to foot- of-the-wave method. PWV is calculated 
by dividing the distance to the distal site by the pressure wave  transit  time.  Data are 
collected by a single trained observer, and the mean of at least 2 PWV measurements is taken 
for each subject. 
 
 
Meal Tolerance Test (MMT) 
Following a 10-12 hour overnight fast, catheters will be placed in the antecubital vein or hand 
vein, one for infusion of tritiated glucose and one for blood withdrawal. At -180 minutes baseline 
blood samples (see attached flow sheet) will be obtained and a prime (40 uCi x FPG/100) – 
continuous (0.40 uCi/min) will be started. Blood samples for determination of plasma, glucose, 
insulin, C-peptide, glucagon, FFA, glucagon-like peptide-1, and glucose-dependent insulinotropic 
polypeptide and tritiated glucose and 14C-glucose radioactivity will be obtained at -180, -30, -20, 
-10, and 0 minutes. At time zero subjects will ingest a mixed meal (75 grams of glucose, 25 
grams of fat, 20 grams of protein, 600 kcal) over 15-20 minutes. The glucose will be labeled with 


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100 uCi of 1-14C-glucose. Plasma samples for substrates, hormones, and radioactivity will be 
obtained every 15 minutes for 5 hours. Plasma samples for catecholamines (CA) will be collected 
at – 10, 0, 60, 120, and 240 minutes. 
 
Meal tolerance will be determined by calculating the glucose AUC (trapezoidal rule) during the 
MTT. Insulin secretion will be calculated as I0-300/G0-300, CP0-300/G0-300, and ISR0-300/G0- 
300, where ISR = insulin secretary rate (deconvolution of the plasma C-peptide curve). Beta cell 
function (11) will be calculated as the insulin secretion/insulin resistance (disposition) index: 
ISR0-300/G0-300  x  Matsuda  Index  of  insulin  sensitivity  (12).  The  same  measures  will  be 
examined for the following time intervals: -10, 0, 0-60, 0-120, 0-180, and 0-240. 
During the fasting postabsorptive state, the rate of HGP equals the rate of glucose uptake by all 
tissues in the body and is calculated as the tritiated glucose infusion rate (DPM/min) divided by 
the plasma tritiated glucose specific activity (DPM/mg). Following meal ingestion, non-steady 
state conditions prevail and the rates of total (RaT) and oral (RaO) glucose appearance in the 
systemic circulation are calculated using Steele’s equation from the 14C-glucose and 3H-glucose 
specific activities, respectively, as previously described (13). The difference between RaT and 
RaO yields the rate of endogenous HGP. Subtraction of RaO from 75 grams (ingested glucose 
load) gives the splanchnic (primarily reflects) glucose uptake. 
 
Dual-Energy X-ray Absorptiometry (DXA) 
 
After an overnight fast, a DXA scan for body composition scan will be performed using a Hologic 
DXA scanner.  Subjects will be resting comfortably in supine position in a quiet room and the 
entire body will be scanned. The acquired images will be integrated and analyzed by a software 
IBM computer program and total amount of fat and fat-free mass and total body water will be 
estimated. Total and regional fat and fat-free mass will be measured by a licensed radiology 
technician using a Discovery 010-1596 instrument from Hologic that is housed on the CRC at the 
Texas Diabetes Institute. 
 
 
3.2 STUDY DURATION AND DATES 
 
The duration of this study is expected to be 18 months, with subject recruitment proposed to start 
in May 2014 and end in October 2015. The actual overall study duration or subject recruitment 
period may vary. 
 
 
4 SELECTION OF SUBJECTS 
 
4.1 
NUMBER OF SUBJECTS 
 
15 subjects 


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4.2 INCLUSION CRITERIA 
1.  Type 2 diabetes male or female subjects between the ages of 30 and 70 years of age, 
inclusive, at Screening 
 
2.  BMI = 24-40 kg/m2 
 
3.  HbA1c = 7.5-10.0% 
 
4.  Stable body weight (±3-4lbs) over the preceding 3 months 
 
5.  Subjects currently receiving a stable dose of exenatide (2mg/week) or liraglutide (1.2-1.8 
mg/day) for at least 90 days prior to determination of baseline A1C and eligibility for 
enrollment in the study protocol. 
 
6.  Subjects with a daytime feeding/night time sleeping schedule 
 
7.  Subjects with no evidence of major organ system disease as determined by physical 
exam, history, and screening laboratory data 
 
8.  Women must be of non-childbearing potential as defined by one of the following: 
a.  Women >45 and < 60 years of age at Screening, who have been amenorrheic for 
at least 2 years 
b.  Women who have had a documented hysterectomy and/or bilateral oophorectomy 
c.   Women > 60 years of age 
 
9.  Females of childbearing potential with a negative pregnancy test at Screening and using 
one of the following forms of contraception for the duration of participation in the study 
(i.e., until Follow-up 7-14 days post last dose): 
a.  Oral contraceptive 
b.  Injectable progesterone 
c.   Subdermal implant 
d.  Spermicidal foam/gel/film/cream/suppository 
e.  Diaphragm with spermicide 
f. Copper or hormonal containing IUD 
g.  Sterile male partner vasectomized > 6 month pre-dosing. 
 
10. Evidence of a personally signed and dated informed consent document indicating that the 
subject has been informed of all pertinent aspects of the study 
 
11. Subjects must be willing and able to comply with scheduled visits, treatment, laboratory 
tests and study procedures. 


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4.3   EXCLUSION CRITERIA 
1.  Recent (i.e., within three (3) months prior to Screening) evidence or medical history of 
unstable concurrent disease such as: documented evidence or history of clinically 
significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, 
psychiatric, immunological, or clinically significant neurological disease. 
 
2.  No history of T2DM 
 
3.  BMI of less 24 and greater 40 kg/m2 
 
4.  Unstable body weight (change of greater than ±3-4lbs over the preceding 3 months 
 
5.  Subjects not currently receiving exenatide or liraglutide 
 
6.  Subjects participating in an excessively heavy exercise program 
 
7.  Subject with a feeding/sleeping schedule different from a daytime feeding/night time 
sleeping schedule 
 
8.  Subjects taking medications known to alter glucose metabolism (with the exception of any 
combination of metformin,pioglitazone, sulfonylureas, and insulin) or which affect brain 
neurosynaptic function are excluded. 
 
9.  Subjects with evidence of major organ system disease as determined by physical exam, 
history, and screening laboratory data 
 
10. Pregnant subjects or subjects unwilling to use birth control during their study enrollment 
 
11. Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening 12. 
Subjects that are allergic to bromocriptine or any of the other ingredients in Cycloset, or 
take ergot medicines, breastfeeding or have history of syncope or Type 1 diabetes 
mellitus0 
12. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results that, in the judgment 
of the investigator, would make the subject inappropriate for entry into this study subjects 
of reproductive potential 
 
Female subjects must not become pregnant during the study. Absence of pregnancy must be 
checked by serum pregnancy testing at the screening visit (Visit 0). 
 
Female subjects of childbearing potential must use a medically accepted contraceptive regimen. 
If a female subject becomes pregnant during the trial, she must be withdrawn and followed up 
until the outcome of the pregnancy is known. If pregnancy occurs, the investigator must contact 
the sponsor immediately for further instruction. Both the detection and the outcome of the 
pregnancy must be reported to the sponsor on special forms (“Drug Exposure Via Parent – Data 
Collection Form”), which will be provided to the investigator as needed. 


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5   STUDY TREATMENTS 
 
5.1   DETAILS OF STUDY TREATMENTS 
 
 
All subjects will receive Cycloset, 0.8 mg/day, with the dose increased by 0.8 mg/day every week 
to a maximum of 3.2 mg/day, or as tolerated to a minimum dose of 2.4 mg/day, added on to 
usual diabetes therapy consisting of a stable dose for at least 90 days of exenatide (2mg/week) 
or liraglutide (1.2-1.8 mg/day). Subjects must be on either exenatide or liraglutide as part of their 
standard care to be eligible for study participation. Subjects will maintain their maximum tolerated 
dose of Cycloset for the duration of the study. 
 
 
 
 
5.2   SUPPLIES AND ACCOUNTABILITY 
 
Cycloset tablets will be provided by the Sponsor.  Accountability will be performed at the study 
site at the end of each subject’s treatment period. 
 
5.3   COMPLIANCE 
 
Subjects will be instructed to bring their current, used and unused (vials) of study drug to every 
visit. 
 
5.4   RUN-IN MEDICATION 
 
There is no run-in period prior to enrollment. Subjects will remain on their current regimen of 
either exenatide or liraglutide. No medications known to alter glucose metabolism (with the 
exception of metformin and/or pioglitazone),or which effect brain neurosynaptic function are 
allowed. 
 
 
6   PRIOR AND CONCOMITANT ILLNESSES AND TREATMENTS 
 
6.1   PRIOR AND CONCOMITANT ILLNESSES 
 
Additional illnesses present at the time informed consent is given are regarded as concomitant 
illnesses and must be documented in the case report form. Relevant past illnesses must also be 
documented in the case report form. 
 
Illnesses first occurring or detected during the study, and worsening of a concomitant illness 
during the study, are to be regarded as adverse events and must be documented as such in the 
case report form. 


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6.2   PRIOR AND CONCOMITANT TREATMENTS 
 
All treatments being taken by the subjects on entry to the study or at any time during the study in 
addition to the study drug are regarded as concomitant treatments and must be documented on 
the appropriate pages of the case report form. 
 
Concomitant medications should be kept to a minimum during the study and adhere to the 
inclusion/exclusion criteria described above.  However, if these are considered necessary for the 
subject's welfare and are unlikely to interfere with the investigational products, they may be given 
at the discretion of the investigator and recorded in the case report form. 
 
Subjects on systemic corticosteroids will be excluded. 


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7 OVERVIEW OF DATA COLLECTION AND STUDY PROCEDURES 
 
 
7.1 STUDY PROCEDURES AND SCHEDULES 
 
The study will consist of a screening visit, followed by visits at week 0, months 1,2, 3, and 4  and 
a final visit two weeks after discontinuation of Cycloset. 
 
7.2 DESCRIPTION OF STUDY DAYS 
 
7.2.1 Screening - Visit 0 
 
Screening of subjects will occur at Visit 0. 
 
• 
Consent form will be signed 
 
• 
Each subject will be assigned a study subject number 
 
• 
Assessment of inclusion/exclusion criteria will be performed 
 
• 
Medical history, including demographic and background assessments will be documented in 
the CRF 
 
• 
Routine physical examination will be performed 
 
• 
ECG test will be performed 
 
• 
Blood will be taken for the determination of HbA1c, FPG, lipids, clinical chemistry variables 
(and serum pregnancy test for women of child-bearing potential); and hematology (see study 
schedule). Total amount of blood drawn at this visit will be approximately 20 ml. 
 
 
 
 
7.2.2 Study Days – Treatment Period 
 
 
 
 
7.2.2.1   Baseline – Visit 1 (Week 0) ± 3 days 
 
 
 
• 
Baseline assessment of aortic compliance 


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7.2.2.2   Baseline – Visit 2 (Visit 1 + 7-10 days) 
 
• 
Subjects will arrive in the morning after an overnight fast (defined as no caloric intake for 
10-12 hours) 
• 
Study entry criteria will be reviewed 
 
• 
All adverse events (including serious adverse events), hypoglycemia and concomitant 
medications since the last visit will be documented 
 
• 
Subject will be weighed. 
 
• 
Postural blood pressure measurements will be obtained first with the subject lying down 
and then repeated after 5 minutes of standing. 
 
• 
Endo-PAT will be performed t0 and t90 of meal tolerance test 
 
• 
5-hour Mixed Meal Tolerance test (MMT) will be conducted. 
 
• 
Blood samples will be drawn at various time points as detailed in the Study Design 
section and Study Schedule table above. Total amount of blood drawn at this visit will be 
approximately 350 ml. 
 
• 
Ambulatory Blood Pressure Monitoring (ABPM) device will be set up 
 
• 
24 hour urine collection instructions will be given 
 
 
7.2.2.3   Baseline – Visit 3 (Visit 2 + 3-5 days) 
 
• 
ABPM device will be returned and data downloaded. 
 
• 
24 hour urine collection will be returned 
 
• 
DXA for body composition will be conducted 
 
• 
Bloods for inflammatory markers and white blood cell isolation. Total amount of blood 
drawn at this visit will be approximately 20 ml. 
 
• 
First dose of Cycloset will be administered in the CRC with a one hour post dose 
observation period 
 
• 
Instructions for titration of Cycloset will be reviewed. 
 
 
7.2.2.4   Call 1 (day 7) 
 
• 
Study site will contact the subject by telephone to remind them to increase the dose of 
Cycloset to 2 tablets and assess tolerance. Subjects will be instructed to contact the study 
site if they experience intolerable nausea or vomiting. 


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• 
Assessment for any AE/SAE will be completed 
 
 
7.2.2.5   Call 2 (day 14) 
 
• 
Study site will contact the subject by telephone to remind them to increase the dose of 
Cycloset to 3 tablets and assess tolerance. Subjects will be instructed to contact the study 
site if they experience intolerable nausea or vomiting. 
 
• 
Assessment for any AE/SAE will be completed 
 
 
7.2.2.6   Call 3 (day 21) 
 
• 
Study site will contact the subject by telephone to remind them to increase the dose of 
Cycloset to 4 tablets and assess tolerance. Subjects will be instructed to contact the study 
site if they experience intolerable nausea or vomiting. 
 
• 
If at any time a subject is not able tolerate the next higher dose of Cycloset, they may stay 
at the current dose, providing it is at least 3 tablets per day. 
 
• 
Assessment for any AE/SAE will be completed 
 
• 
Subjects will schedule an appointment for the 1 month follow up visit on day 28 ± 3 days 
 
 
7.2.2.7   Visit 4 (Month 1) ± 3 days 
 
• 
Assessment for any AE/SAE will be completed 
 
• 
Medical history and weight will be taken 
 
• 
Postural blood pressure measurements will be obtained first with the subject lying down 
and then repeated after 5 minutes of standing. 
 
• 
Blood will be drawn for FPG and A1c. Total amount of blood drawn at this visit will 
approximately 10 ml. 
 
• 
Subject will be reminded to increase the dose of Cycloset to 4 tablets if appropriate 
 
 
7.2.2.8   Visit 5 (Month 2) ± 3 days 
 
• 
Assessment for any AE/SAE will be completed 
 
• 
Medical history and weight will be taken 
 
• 
Postural blood pressure measurements will be obtained first with the subject lying down 
and then repeated after 5 minutes of standing. 
 
• 
Blood will be drawn for FPG and A1c. Total amount of blood drawn at this visit will be 


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approximately 10 ml. 
 
• 
 
 
7.2.2.9 
Visit 6 (Month 3) ± 3 days 
 
• 
Assessment for any AE/SAE will be completed 
 
• 
Medical history and weight will be taken 
 
• 
Postural blood pressure measurements will be obtained first with the subject lying down 
and then repeated after 5 minutes of standing. 
 
• 
Blood will be drawn for FPG and A1c. Total amount of blood drawn at this visit will be 
approximately 10 ml. 
 
7.2.3   End of Study (Visits 7 and 8): Endpoint 
 
NOTE: Aortic compliance testing and DXA scan may be done on either Visit 7 or Visit 8). 
 
 
7.2.3.1   Visit 7 (Month 4) ± 3 days 
 
 
 
• 
Subjects will arrive in the morning after an overnight fast (defined as no caloric intake for 
10-12 hours) 
 
• 
Assessment for any AE/SAE will be completed 
 
 
 
• 
Medical history and weight will be taken 
 
• 
Postural blood pressure measurements will be obtained first with the subject lying down 
and then repeated after 5 minutes of standing 
 
• 
Assessment of aortic compliance may be conducted at this visit or on a separate day 
 
• 
DXA for body composition will be conducted 
 
• 
5-hour Mixed Meal Tolerance test (MMT) will be conducted. 
 
• 
Endo-PAT will be performed t0 and t90 of meal tolerance test 
 
• 
Blood samples will be drawn for lipids, HbA1c and fasting glucose 
 
• 
lood samples will also be drawn at various time points as part of the MMT test as detailed 
in the Study Design section and Study Schedule table above. Total amount of blood 
drawn at this visit will be approximately 350 ml. 


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• 
Ambulatory Blood Pressure Monitoring (ABPM) device will be set up 
 
 
7.2.3.2   24 hour urine collection instructions will be given Visit 8 (Visit 7+ 3-5 days) 
 
 
 
• 
Subjects will arrive in the morning after an overnight fast (defined as no caloric intake for 
10-12 hours) 
 
• 
Assessment for any AE/SAE will be completed 
 
• 
Assessment of aortic compliance will be conducted if not done at Visit 7 
 
• 
Blood samples will be drawn for lipids, HbA1c and fasting glucose. 
 
• 
ABPM device will be returned and data downloaded. 
 
• 
24 hour urine collection will be returned 
 
• 
DXA for body composition will be conducted if not done at Visit 7. 
 
• 
Bloods for inflammatory markers and white blood cell isolation. Total amount of blood 
drawn at this visit will be approximately 20 ml. 
 
• 
Cycloset will be discontinued 
 
 
7.2.4   Follow-up 
 
The study site will phone the subject on the day after visit 8  to follow-up on hypoglycemia and 
adverse events that occurred in the 24 hours after the last dose of study medication in this study. 
 
7.3   METHODS 
 
Data will be collected relating to primary and secondary efficacy variables and safety. 
 
A local laboratory will be utilized for collection and analysis of the laboratory tests associated with 
efficacy, and safety. Standardized guidelines for preparation, collection, and centralized analysis 
of blood and urine specimens will provide uniformity of the data and will avoid potential inter – 
laboratory variability due to inconsistent methodology. 
 
 
7.3.1 Primary efficacy data will be:  Change from baseline in HbA1c and change from 
baseline in postprandial glucose metabolism. 
 
 
 
7.3.2 Secondary efficacy data: Change from baseline in endothelial function, aortic 
compliance, body weight composition, blood pressure and oxidative stress/inflammatory 
markers. 


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7.3.3   Safety Data 
 
Safety will be assessed on the basis of an analysis of hypoglycemia events, adverse events, 
clinical chemistry, clinical hematology and clinical values; physical examination weight, and vital 
signs. 
 
Occurrence of hypoglycemia 
 
The general symptoms of hypoglycemia most subjects experience include one or more of the 
following: headache, dizziness, general feeling of weakness, drowsiness, confusion, paleness, 
irritability, trembling, sweating, rapid heartbeat and a cold, clammy feeling. In severe cases 
seizure, loss of consciousness and even lapse into coma can occur. 
 
Definitions of hypoglycemia events that must be recorded on the CRF hypoglycemia page: 
 
• 
Severe hypoglycemia - in which the assistance of another party is required (not merely 
requested), and either: 
 
• 
a recorded self monitored blood glucose of <36 mg/dL, or 
. 
• 
there was treatment with oral carbohydrates, intravenous glucose or glucagons 
and there was prompt response to that therapy. 
 
For further clarification, the definition for severe hypoglycemia included all episodes in 
which neurological impairment was severe enough to prevent self-treatment and which 
were thus thought to place subjects at risk for injury to themselves or others. Requires 
assistance means that the subject could not help her/himself. Someone being kind that 
assists the subject when not necessary does not qualify as “ assistance required”. 
 
• 
Mild to moderate documented hypoglycemia – events not considered severe (by the 
above definition) but with SMBG < 70 mg/dl. 
 
• 
Hypoglycemia  symptoms  with  or  without  SMBG  values  that  according  to  the 
Investigator represent true hypoglycemia 
 
Symptoms consistent with an adrenergic surge, such as those observed during 
hypoglycemia (headache, dizziness, general feeling of weakness, drowsiness, confusion, 
paleness, irritability, trembling, sweating, rapid heartbeat and/or a cold clammy feeling), 
but with a documented SMBG >70 mg/dL or no recorded SMBG value, are to be recorded 
on the hypoglycemia event page, if, in the opinion of the investigator/study coordinator, 
they represent true hypoglycemia. 
 
The following hypoglycemia events are considered serious adverse event (SAEs): 
 
A hypoglycemia event associated with: 
 
• 
Coma/loss of consciousness (“hypoglycemia coma”) or 
 
• 
Hypoglycemia seizure/convulsion (“hypoglycemia seizure”). 


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These serious hypoglycemia events need to be reported on an SAE form, as well as in the CRF 
hypoglycemia event and adverse event pages. 
 
 
 
 
Subjects will be instructed to record the following variables for events suspected of being 
hypoglycemia: date and time started, whether the event occurred after the subject went to bed 
and prior to waking, whether the event was associated with symptoms, whether assistance was 
required, and if so, whether there was prompt recovery after oral CHO, glucagon, or intravenous 
(IV) glucose was used, SMBG value with associated date and time, any special circumstances 
(e.g. exercise), date and time of last meal, and date and time of last dose of long-acting and/or 
rapid-acting insulin. The study coordinator will review the diaries with the subject at every visit. 
 
Adverse Events 
 
AE monitoring will be conducted at all study visits, as well as, all titration contacts. (Please refer 
to Section 8 for additional information regarding AEs.) 
 
 
8   ADVERSE EVENTS 
 
8.1   DEFINITIONS 
 
 
8.1.1   Adverse Event 
 
The term  adverse event covers any unfavorable and unintended sign, symptom, syndrome, or 
illness that develops or worsens during the period of observation in the clinical study.  Clinically 
relevant abnormal results of diagnostic procedures including abnormal laboratory findings (e.g., 
requiring unscheduled diagnostic procedures or treatment measures, or resulting in withdrawal 
from the study) are considered to be adverse events. 
 
Worsening of a sign or symptom of the condition under treatment will normally be measured by 
efficacy parameters.  However, if the outcome fulfills the definition of “serious adverse event”, it 
must be recorded as such (see Section 8.1.2). 
 
The adverse event may be: 
 
• 
A new illness 
 
• 
Worsening of a concomitant illness 
 
• 
An effect of the study medication, including comparator 
 
• 
A combination of two or more of these factors 
 
No causal relationship with the study medication or with the clinical study itself is implied by the 
use of the term “adverse event”. 
 
Adverse events fall into the categories “non-serious” and “serious” (see Section 8.1.2). 
 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 


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conditions that require surgery.  The condition for which the surgery is required is an adverse 
event, if it occurs or is detected during the study period. Planned surgical measures permitted by 
the clinical study protocol and the condition(s) leading to these measures are not adverse events, 
if the condition(s) was (were) known before the start of study treatment.  In the latter case the 
condition should be reported as medical history. 
 
Hypoglycemia events will be captured on a specific hypoglycemia CRF page and should 
not be considered an adverse event unless classified as a serious AE (see Section 7.3.3). 
Therefore, hypoglycemic events not classified, as serious adverse events do not need to 
be entered on the adverse event CRF page. 
 
 
8.1.2   Serious Adverse Event 
 
A serious adverse event is one that at any dose (including overdose): 
 
• 
Results in death 
 
1 
• 
Is life-threatening 
 
• 
Requires in subject hospitalization or prolongation of existing hospitalization 
2 
• 
Results in persistent or significant disability or incapacity 
 
• 
Is a congenital anomaly or birth defect 
3 
• 
Is an important medical event 
 
1 
“Life-threatening” means that the subject was at immediate risk of death at the time of the 
serious adverse event; it does not refer to a serious adverse event that hypothetically might have 
caused death if it were more severe. 
 
2 
“Persistent or significant disability or incapacity” means that there is a substantial disruption of a 
person’s ability to carry out normal life functions. 
 
3 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred.  Important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes listed in 
the definition above should also usually be considered serious.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in in-subject hospitalization, or the development of 
drug dependency or drug abuse.  A diagnosis of cancer during the course of a treatment should 
be considered as medically important.  The List of Critical Terms (1998 adaptation of WHO 
Adverse Reaction Terminology Critical Terms List, provided in the “Instructions for completing the 
‘Serious  Adverse  Event/Expedited  Report  from  a  Clinical  Trial’  form”)  should  be  used  as 
guidance  for  adverse  events  that  may  be  considered  serious  because  they  are  medically 
important. 
 
Clarification    of    the    difference    in    meaning    between    “severe”    and    “serious” 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 


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moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).   This is not the same as “serious”, which is 
based on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning.   Seriousness (not severity) serves as a guide for defining regulatory reporting 
obligations. 
 
 
8.1.3   Alert Terms and Other Reasons for Expedited Reporting to Pharmacovigilance 
 
No special events are subject to reporting as alert terms in this study. 
 
However, cases in which a “significant overdose” of the investigational product was taken and a 
non-serious adverse event or no adverse event occurred are to be reported to the sponsor in an 
expedited manner on a “Serious Adverse Event/Expedited Report from a Clinical Trial” form. 
 
In a context of this protocol, an overdose of study insulin should be reported only if the subject 
administered a significant larger than prescribed dose of insulin. The definition of a “significant 
overdose” of study insulin will be based on clinical judgment and will be at the discretion of the 
investigator. 
 
In addition, any pregnancy diagnosed in a female subject or in the female partner of a male 
subject during treatment with the investigational product must be reported to the sponsor 
immediately.   Information related to the pregnancy must be given on a “Drug Exposure Via 
Parent – Data Collection” form that will be provided by the sponsor. 
 
8.2   PERIOD OF OBSERVATION 
 
For the purposes of this study, the period of observation for collection of adverse events extends 
from the time the subject gives informed consent until 24 hours after the last dose of study 
medication was given. 
 
If the investigator detects a serious adverse event in a study subject after the end of the period of 
observation, and considers the event possibly related to prior study treatment, he or she should 
contact the sponsor to determine how the adverse event should be documented and reported. 
 
8.3 DOCUMENTATION AND REPORTING OF ADVERSE EVENTS BY 
INVESTIGATOR 
 
All adverse events that occur during the observation period set in this protocol (see Section 8.2) 
must be documented on the pages provided in the case report form in accordance with the 
instructions for the completion of adverse event reports in clinical studies.  These instructions are 
provided in the investigator’s study file and in the case report form itself. 
 
The following approach will be taken for documentation: 
 
• 
All adverse events (whether serious or non-serious, or considered as an alert term) must be 
documented on the “Adverse Event” page of the case report form. 
 
• 
If the adverse event is serious (see Section 8.1.2), the investigator must complete, in addition to 
the “Adverse Event” page in the case report form, a “Serious Adverse Event/Expedited Report 
from a Clinical Trial” form at the time the serious adverse event is detected. 


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• 
This form must be completed and faxed to the sponsor’s Pharmacovigilance department 
within 24 hours. 
 
• 
If the adverse event is listed as an alert term (see Section 8.1.3) even if the “alert term” is non- 
serious, the investigator must complete, in addition to the “Adverse Event” page in the case report 
form, a “Serious Adverse Event/Expedited Report from a Clinical Trial” form at the time the 
adverse event is detected. 
 
• 
This form must be completed and faxed to the sponsor’s Pharmacovigilance department 
within 24 hours. 
 
• 
When a “significant overdose” of the investigational product occurs without an adverse event or in 
other situations where the sponsor requires an expedited report without an adverse event (see 
Section 8.1.3), the investigator should only complete a “Serious Adverse Event/Expedited Report 
from a Clinical Trial” form.   Instructions on where to send this form will be provided by the 
sponsor.  In this case, there is no need to complete the “Adverse Event” page in the case 
report form. 
 
Every attempt should be made to describe the adverse event in terms of a diagnosis.  If a clear 
diagnosis has been made, individual signs and symptoms will not be recorded unless they 
represent atypical or extreme manifestations of the diagnosis, in which case they should be 
reported as separate events. If a clear diagnosis cannot be established, each sign and symptom 
must be recorded individually. 
 
All subjects who have adverse events, whether considered associated with the use of the 
investigational products or not, must be monitored to determine the outcome.  The clinical course 
of the adverse event will be followed up according to accepted standards of medical practice, 
even after the end of the period of observation, until a satisfactory explanation is found or the 
investigator considers it medically justifiable to terminate follow-up. Should the adverse event 
result in death, a full pathologist’s report should be supplied, if possible. 
 
All questions on the completion and supply of adverse event report forms and any further forms 
issued to the investigator at a later date to clarify unresolved issues should be addressed to the 
sponsor. 
 
 
 
 
 
 
8.4   IMMEDIATE REPORTING BY INVESTIGATOR TO SPONSOR 
 
Serious adverse events and adverse events that fulfill a reason for expedited reporting to 
Pharmacovigilance (alert term and/or “significant overdose”, as defined in Section 8.1.3) must be 
documented on a “Serious Adverse Event/Expedited Report from a Clinical Trial” form in 
accordance with the “Instructions for completing the ‘Serious Adverse Event/Expedited Report 
from a Clinical Trial’ form”. 
 
• 
This form must be completed and faxed to the sponsor’s Pharmacovigilance department 
within 24 hours. 


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The “Serious Adverse Event/Expedited Report from a Clinical Trial” form and the instructions are 
provided in the investigator’s study file. The sponsor will ensure that all legal reporting 
requirements are met. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and 
the investigational product(s). 
 
Information not available at the time of the initial report (e.g., an end date for the adverse event or 
laboratory  values  received  after  the  report)  must  be  documented  on  a  follow-up  “Serious 
Adverse Event/Expedited Report from a Clinical Trial” form. 
 
The “Instructions for completing the ‘Serious Adverse Event/Expedited Report from a Clinical 
Trial’ form” give more detailed guidance on the reporting of serious adverse events, adverse 
events that comply with alert terms, and adverse events initially reported as non-serious that 
become serious.  In the latter situation, when a non-serious event becomes serious, details must 
be forwarded immediately to the sponsor on a “Serious Adverse Event/Expedited Report from a 
Clinical Trial” form. 


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9   WITHDRAWALS 
 
9.1   WITHDRAWAL OF SUBJECTS 
 
Subjects may be withdrawn from the study (i.e. from any further study medication or study 
procedure) for the following reasons: 
 
• 
At their own request or at the request of their legally authorized representative* 
 
• 
If, in the investigator's opinion, continuation in the study would be detrimental to the 
subject's well-being 
 
• 
At the specific request of the sponsor 
 
* “Legally authorized representative” means an individual or judicial or other body authorized 
under applicable law to consent on behalf of a prospective subject to the subject’s participation in 
the procedure(s) involved in the research. 
 
Subjects must be withdrawn from the investigational product under the following circumstances: 
 
• 
Women who become pregnant 
 
• 
Women  of  childbearing  potential  who  discontinue  contraception  with the  intention  of 
becoming pregnant. 
 
In all cases, the reason for and date of withdrawal must be recorded in the case report form and 
in the subject's medical records.   The subject must be followed up to establish whether the 
reason  was  an  adverse  event,  and,  if  so,  this  must  be  reported  in  accordance  with  the 
procedures in Section 8. 
 
The investigator must make every effort to contact subjects lost to follow-up.  Attempts to contact 
such subjects must be documented in the subject’s records (e.g., times and dates of attempted 
telephone contact, receipt for sending a registered letter). 
 
Subject withdrawal due to deterioration of glycemic control 
 
Subjects with 2 consecutive fasting blood glucose values >275 mg/dl after completion of the 
study drug titration phase will be evaluated for withdrawal and initiation of rescue therapy at the 
discretion of the study investigators. Subjects that are withdrawn will be referred to their primary 
care physician or endocrinologist for further diabetes medication adjustments as needed. 
 
Replacement of subjects 
 
Subjects that are withdrawn within <2 months following completion of study drug titration will be 
replaced. As far as possible, for subjects who complete at least 2 months on a stable dose of the 
study drug following the study drug titration phase, all examinations scheduled for the final study 
day will be performed prior to withdrawal. Subjects who complete at least 2 months on a stable 
dose of the study drug following the study drug titration phase but are unable to complete the 
final study day procedures will also be replaced. 


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9.2   EMERGENCY SPONSOR CONTACT 
 
In emergency situations, the investigator should contact the sponsor by telephone at the number 
given on the title page of the protocol. 
 
9.3   EMERGENCY IDENTIFICATION OF INVESTIGATIONAL PRODUCTS 
 
This section is not applicable as this is an open-label study. 
 
9.4   EMERGENCY TREATMENT 
 
During and after a subject's participation in the trial, the investigator and/or institution should 
ensure that adequate medical care is provided to a subject for any adverse events, including 
clinically significant laboratory values, related to the trial.   The investigator and/or institution 
should inform a subject when medical care is needed for intercurrent illness(es) of which the 
investigator becomes aware. 


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10 STATISTICAL PROCEDURES 
 
10.1 ANALYSIS VARIABLES 
 
A statistical analysis plan (SAP), providing details of the analyses and presentation structure of 
the results, will be developed and finalized before the database is locked. 
 
 
 
 
10.2 ANALYSIS POPULATIONS 
 
 
 
 
Samples from all patients who complete the clinical study period will be assayed. 
Dropouts will be replaced as described in section 9.1. 
 
 
10.3 SAMPLE SIZE 
 
 
Assuming that Cycloset will cause a 0.6% reduction in HbA1c, 15 subjects would provide 90% 
power to detect a 0.6% decrease from a baseline HbA1c of 8.0 ±0.5% at an alpha of 0.05. 


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11 REGULATORY REQUIREMENTS 
 
11.1 GOOD CLINICAL PRACTICE 
 
This study is to be conducted according to globally accepted standards of good clinical practice 
(as defined in the ICH E6 Guideline for Good Clinical Practice, 1 May 1996), in agreement with 
the Declaration of Helsinki and in keeping with local regulations. 
 
11.2 DELEGATION OF INVESTIGATOR DUTIES 
 
The investigator will ensure that all persons assisting with the trial are adequately qualified, 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
trial-related duties and functions. 
 
The investigator will maintain a list of sub investigators and other appropriately qualified persons 
to whom he or she has delegated significant trial-related duties. 
 
11.3 SUBJECT INFORMATION AND INFORMED CONSENT 
 
Before being enrolled in the clinical study, subjects must consent to participate after the nature, 
scope, and possible consequences of the clinical study have been explained in a form 
understandable to them. 
 
An informed consent document that includes information about the study will be prepared and 
given to the subject.   This document will contain all the elements required by the ICH E6 
Guideline for Good Clinical Practice and any additional elements required by local regulations. 
The document must be in a language understandable to the subject and must specify who 
informed the subject. Where required by local law, the person who informs the subject must be a 
physician. 
 
After reading the informed consent document, the subject must give consent in writing.  The 
subject's consent must be confirmed at the time of consent by the personally dated signature of 
the subject and by the personally dated signature of the person conducting the informed consent 
discussions. 
 
If the subject is unable to read, oral presentation and explanation of the written informed consent 
form and information to be supplied to subjects must take place in the presence of an impartial 
witness.  Consent must be confirmed at the time of consent orally and by the personally dated 
signature of the subject or by a local legally recognized alternative (e.g., the subject's thumbprint 
or mark).  The witness and the person conducting the informed consent discussions must also 
sign and personally date the consent document. 
 
A copy of the signed consent document must be given to the subject.   The original signed 
consent document will be retained by the investigator. 


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“Legally authorized representative” means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective subject to the subject’s participation in the 
procedure(s) involved in the research. 
 
The investigator will not undertake any measures specifically required only for the clinical study 
until valid consent has been obtained. 
 
It is recommended that the investigator inform the subject’s primary physician about the subject’s 
participation in the trial if the subject has a primary physician and if the subject agrees to the 
primary physician being informed. 
 
11.4 CONFIDENTIALITY 
 
Subject names will not be supplied to the sponsor.  Only the subject number and subject initials 
will be recorded in the case report form, and if the subject name appears on any other document 
(e.g., laboratory report), it must be obliterated on the copy of the document to be supplied to the 
sponsor.  Study findings stored on a computer will be stored in accordance with local data 
protection laws.  The subjects will be informed that representatives of the sponsor, independent 
ethics committee (IEC)/ institutional review board (IRB), 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. 
 
The investigator will maintain a personal subject identification list (subject numbers with the 
corresponding subject names) to enable records to be identified. 
 
11.5 PROTOCOL AMENDMENTS 
 
Neither the investigator nor the sponsor will alter this clinical study protocol without obtaining the 
written agreement of the other.  Once the study has started, amendments should be made only in 
exceptional cases. The changes then become part of the clinical study protocol. 
 
11.6 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS 
 
Before the start of the study, the clinical study protocol, informed consent document, and any 
other appropriate documents will be submitted to the IEC/IRB with a cover letter or a form listing 
the documents submitted, their dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought.  If applicable, the documents will also be submitted to 
the authorities, in accordance with local legal requirements. 
 
Investigational products can only be supplied to the investigator after documentation on all 
ethical and legal requirements for starting the study has been received by the sponsor.  This 
documentation must also include a list of the members of the IEC/IRB and their occupation and 
qualifications.  If the IEC/IRB will not disclose the names of the committee members, it should be 
asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP.  Formal approval by the IEC/IRB should preferably mention the study title, study code, 
study site (or region or area of jurisdiction, as applicable), amendment number where applicable, 
and any other documents reviewed.  It must mention the date on which the decision was made 
and must be officially signed by a committee member. 


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Before the first subject is enrolled in the study, all ethical and legal requirements must be met. 
 
The IEC/IRB and, if applicable, the authorities must be informed of all subsequent protocol 
amendments and administrative changes, in accordance with local legal requirements. 
Amendments must be evaluated to determine whether formal approval must be sought and 
whether the informed consent document should also be revised. 
 
The investigator must keep a record of all communication with the IEC/IRB and, if applicable, 
between a coordinating investigator and the IEC/IRB.  This also applies to any communication 
between the investigator (or coordinating investigator, if applicable) and the authorities. 
 
11.7 ONGOING INFORMATION FOR INDEPENDENT ETHICS COMMITTEE/ 
INSTITUTIONAL REVIEW BOARD 
 
Unless otherwise instructed by the IEC/IRB, the investigator must submit to the IEC/IRB: 
 
• 
Information on serious or unexpected adverse events from the investigator’s site, as soon 
as possible 
 
• 
Expedited safety reports from the sponsor, as soon as possible 
 
• 
Periodic reports on the progress of the study 
 
11.8 CLOSURE OF THE STUDY 
 
The study must be closed at the site on completion.  Furthermore, the sponsor or the investigator 
has the right to close this study site at any time.  As far as possible, premature closure should 
occur after mutual consultation.  Depending on local legislation, it may be necessary to inform 
IEC/IRB and the regulatory authorities when the study site is closed. 
 
Study materials must be returned, disposed of or retained as directed by the sponsor. 
 
11.9 RECORD RETENTION 
 
The investigator must obtain approval in writing from the sponsor before destruction of any 
records. 
 
Essential  documents  should  be  retained  until  at  least  2 years  after  the  last  approval  of  a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  However, because of international regulatory 
requirements, the sponsor may request retention for a longer period. 
 
Essential documents include: 
 
• 
Signed informed consent documents for all subjects 
 
• 
Subject identification code list, screening log (if applicable) and enrollment log 
 
• 
Record of all communications between the investigator and the IEC/IRB 
 
• 
Composition of the IEC/IRB (or other applicable statement as described in Section 12.6) 


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• 
Record of all communications between the investigator and sponsor (or CRO) 
 
• 
List of sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant trial-related duties, together with their roles in the 
study and their signatures 
 
• 
Copies of case report forms and of documentation of corrections for all subjects 
 
• 
Investigational product accountability records 
 
• 
Record of any body fluids or tissue samples retained 
 
• 
All other source documents (subject medical records, hospital records, laboratory records, 
etc.) 
 
• 
All other documents as listed in section 8 of the ICH E6 Guideline for Good Clinical 
Practice (Essential Documents for the Conduct of a Clinical Trial) 
 
Normally, these records will be held in the investigator's archives.  If the investigator is unable to 
meet this obligation, he or she must ask the sponsor for permission to make alternative 
arrangements.  Details of these arrangements should be documented. 
 
11.10 LIABILITY AND INSURANCE 
 
Liability and insurance provisions for this study are given in separate agreements. 
 
11.11 FINANCIAL DISCLOSURE 
 
Before the start of the study, the investigator will disclose to the sponsor any proprietary or 
financial interests he or she might hold in the investigational products or the sponsor company as 
outlined in the financial disclosure form provided by the sponsor.  The investigator agrees to 
update this information in case of significant changes during the study or within one year of its 
completion.  The investigator also agrees that, where required by law or regulation, the sponsor 
may submit this financial information to domestic or foreign regulatory authorities in applications 
for marketing authorizations. 
 
Similar information will be provided by each sub-investigator to whom the investigator delegates 
significant study related responsibilities. 


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12 STUDY MONITORING AND AUDITING 
 
Monitoring and auditing procedures will be followed according to study site policy in order to 
comply with GCP guidelines. 
 
12.1 STUDY MONITORING AND SOURCE DATA VERIFICATION 
 
Monitoring will be done by personal visits from a representative of the sponsor (study monitor) 
who will check the case report forms for completeness and clarity, and crosscheck them with 
source documents.   In addition to the monitoring visits, frequent communications (letter, 
telephone,  and  fax),  by  the  study  monitor  will  ensure  that  the  investigation  is  conducted 
according to protocol design and regulatory requirements. 
 
Study close-out will be performed by the study monitor upon closure of the study. 
 
12.2 ON-SITE AUDITS 
 
Domestic and foreign regulatory authorities, the IEC/IRB, and an auditor authorized by the 
sponsor may request access to all source documents, case report forms, and other study 
documentation for on-site audit or inspection.   Direct access to these documents must be 
guaranteed  by  the  investigator,  who  must  provide  support  at  all  times  for  these  activities. 
Medical records and other study documents may be copied during audit or inspection provided 
that subject names are obliterated on the copies to ensure confidentiality. 


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13 DOCUMENTATION AND USE OF STUDY FINDINGS 
 
13.1 DOCUMENTATION OF STUDY FINDINGS 
 
 
A case report form will be provided for each subject. 
 
All protocol-required information collected during the study must be entered by the investigator, 
or designated representative, in the case report form.  Details of case report form completion and 
correction will be explained to the investigator.   If the investigator authorizes other persons to 
make entries in the case report form, the names, positions, signatures, and initials of these 
persons must be supplied to the sponsor. 
 
The investigator, or designated representative, should complete the case report form pages as 
soon as possible after information is collected, preferably on the same day that a study subject is 
seen for an examination, treatment, or any other study procedure.  Any outstanding entries must 
be completed immediately after the final examination.  An explanation should be given for all 
missing data. 
 
A source data location list will be prepared prior to study start.  This list will be filed in both the 
trial master file and the investigator study file and updated as necessary. 
 
The completed case report form must be reviewed and signed by the investigator named in the 
clinical study protocol or by a designated sub-investigator. 
 
The sponsor will retain the originals of all case report forms.  The investigator will retain a copy of 
all completed case report form pages. 
 
 
13.2 USE OF STUDY FINDINGS 
 
All information concerning the product as well as any matter concerning the operation of the 
sponsor, such as clinical indications for the drug, its formula, methods of manufacture and other 
scientific data relating to it, that have been provided by the sponsor and are unpublished, are 
confidential and must remain the sole property of the sponsor.  The investigator will agree to use 
the information only for the purposes of carrying out this study and for no other purpose unless 
prior written permission from the sponsor is obtained. 
The sponsor has full ownership of the original case report forms completed as part of the study. 
By signing the clinical study protocol, the investigator agrees that the results of the study may be 
used for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals.  The authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement. 
 
The sponsor will ensure that a final report on the study is prepared. 
 
The investigator (or coordinating investigator) will be required to sign a statement that he or she 


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confirms that, to the best of his or her knowledge, it accurately describes the conduct and results 
of the study. 
 
All materials, documents and information supplied by the sponsor to the investigator, and all 
materials, documents and information prepared or developed in the course of the study to be 
performed under this protocol, shall be the sole and exclusive property of the sponsor.  Subject to 
obligations of confidentiality, the investigator reserves the right to publish only the results of the 
work performed pursuant to this protocol, provided, however, that the investigator provides an 
authorized representative of the sponsor with a copy of any proposed publication for review and 
comment at least 45 days in advance of its submission for publication.  In addition, if requested, 
the investigator will withhold publication an additional 90 days to allow for filing a patent 
application or taking such other measures as sponsor deems appropriate to establish and 
preserve its proprietary rights. 
 
It is agreed that, consistent with scientific standards, publication of the results of the study shall 
be made only as part of a publication of the results obtained by the investigator performing the 
protocol. 


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14 DECLARATIONS OF SPONSOR AND INVESTIGATOR 
 
14.1 DECLARATION OF SPONSOR 
 
This clinical study protocol was subject to critical review and has been approved by the sponsor. 
The information it contains is consistent with: 
 
• 
The current risk-benefit evaluation of the investigational product 
 
• 
The moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki and the principles of GCP as described in the US Code of Federal 
Regulations, part 50, 54, 56, and 312, as well as in the ICH Guidelines, May 9, 1997. 
 
• 
The investigator will be supplied with details of any significant or new findings, including 
adverse events, relating to treatment with the investigational product. 
 
 
Sponsor Representative 
 
 
Date:    
 
Signature:    
 
 
Name (block letters):   
 
 
 
14.2 DECLARATION OF INVESTIGATOR 
 
I confirm that I have read the above protocol.  I understand it, and I will work according to the 
principles of GCP as described in 21 CFR parts 50, 54, 56, and 312 and according to applicable 
local requirements. 
 
 
Investigator 
 
 
Date:   
 
Signature:   
 
 
Name (block letters):