Conditions: Coronary Artery Disease Diabetes Mellitus
Keywords: coronary artery disease diabetes mellitus chronic kidney disease ticagrelor
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 101
Healthy volunteers: no

Brief summary:
Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. To date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although pharmacodynamic (PD) studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and coronary artery disease) CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.

Detailed description:
Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), which further enhances atherothrombotic risk. These observations underscore the importance of antiplatelet therapy for prevention of atherothrombotic recurrences in these high-risk patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic events. This may be in part due to the impaired pharmacokinetic (PK) and pharmacodynamic (PD) effects of clopidogrel in patients with DM and CKD. Since both DM and CKD represent pandemic public health problems, the prevalence of which will double over the next 20 years, identifying antiplatelet agents with more favorable PK/PD profiles is of key importance.

Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was consistent also among DM patients. In patients with CKD, ticagrelor led to an even greater relative risk reduction of ischemic events, including cardiovascular mortality, compared to patients without CKD. However, to date there has been no analysis on the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although PD studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is aimed to show the impact of CKD status among patients with DM and CAD on PD and PK profiles of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial.

Arms:
arm 1: Patients with chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days. arm 2: Patients with chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days. arm 3: Patients without chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days. arm 4: Patients without chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.

Interventions: intervention 1: ticagrelor
Intervention descriptions: intervention 1: Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version 2 
07/31/2018 
NCT02539160 
Impact of chronic kidney disease on the pharmacodynamic and pharmacokinetic 
effects of ticagrelor in patients with diabetes mellitus and coronary artery disease 
 
 
 
 
 
 
 
Dominick J Angiolillo, MD, PhD, FACC, FESC, FSCAI 
Director of Cardiovascular Research 
Associate Professor of Medicine 
Division of Cardiology 
University of Florida College of Medicine - Jacksonville 
655 West 8th Street 
Jacksonville, FL – 32209 
Tel: 904-2443933, Fax: 904-2443102 
dominick.angiolillo@jax.ufl.edu 


Protocol Version 2 
07/31/2018 
NCT02539160 
Project overview 
Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events. 
Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD), 
which further enhances atherothrombotic risk. These observations underscore the importance of 
antiplatelet therapy for prevention of atherothrombotic recurrences in these high-risk patients. 
Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However, despite its 
clinical benefit, patients with DM and CKD frequently experience recurrent atherothrombotic 
events. This may be in part due to the impaired pharmacokinetic (PK) and pharmacodynamic 
(PD) effects of clopidogrel in patients with DM and CKD. Since both DM and CKD represent 
pandemic public health problems, the prevalence of which will double over the next 20 years, 
identifying antiplatelet agents with more favorable PK/PD profiles is of key importance.  
Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent 
and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation, ticagrelor 
significantly reduced ischemic events to a greater extent than clopidogrel, a finding that was 
consistent also among DM patients. In patients with CKD, ticagrelor led to an even greater 
relative risk reduction of ischemic events, including cardiovascular mortality, compared to 
patients without CKD. However, to date there has been no analysis on the efficacy of ticagrelor 
in DM patients according to CKD status. Moreover, although PD studies showed enhanced 
platelet inhibition associated with ticagrelor, it is unknown how this may be affected by CKD 
status. Ultimately, how PK/PD profiles of different ticagrelor dosing regimens may be affected 
by DM and CKD status is also unknown. The proposed study is aimed to show the impact of 
CKD status among patients with DM and CAD on PD and PK profiles of ticagrelor used at 2 
doses (90mg bid and 60mg bid) in the setting of a prospective, randomized, cross-over trial. 


Protocol Version 2 
07/31/2018 
NCT02539160 
Background: 
Diabetes mellitus (DM) and chronic kidney disease (CKD) represent pandemic diseases and 
a major public health concerns because of their prevalence and poor cardiovascular prognosis (1-
3). DM is the most common cause of CKD and up to 40% of diabetic patients develop CKD (4). 
CKD was present in approximately one-third of patients with NSTE-ACS and was a powerful 
independent predictor of subsequent mortality (5). Importantly, patients with DM or CKD have a 
high thrombotic milieu and frequently experience recurrent atherothrombotic events (6-11). 
Multiple mechanisms may contribute to these observations, including accelerated platelet 
turnover rates (12,13). These observations underscore the importance of antiplatelet therapy for 
prevention of atherothrombotic recurrences in these high-risk patients. Clopidogrel is the most 
widely used platelet P2Y12 receptor inhibitor. However, despite its clinical benefit, patients with 
DM and CKD frequently experience recurrent atherothrombotic events. The high 
atherothrombotic recurrence rates in DM and CKD patients are partly due to the inadequate 
response to antiplatelet agents, in particular clopidogrel, which is enhanced with the co-existence 
of these disorders (14-17). Therefore, identifying antiplatelet agents with more favorable 
pharmacokinetic (PK) and pharmacodynamics (PD) profiles is of key importance.  
Ticagrelor represents an attractive strategy especially in high-risk patients, such as those 
with DM and/or CKD (18-20). Ticagrelor, a cyclopentyltriazolopyrimidines, is an oral, 
reversible, non-competitive P2Y12 receptor inhibitor with rapid onset and offset of action and 
provides a stronger and more consistent platelet inhibition than clopidogrel (21-23). Although 
ticagrelor is a direct acting agent, ~30% of its effects are attributed to a metabolite (AR-
C124910XX) derived from hepatic metabolism (23). In the large scale phase III PLATO (Platelet 
Inhibition and Patient Outcomes) trial conducted in ACS patients, ticagrelor, in addition to 


Protocol Version 2 
07/31/2018 
NCT02539160 
aspirin, was associated with a significant reduction in ischemic events, driven by a reduction in 
myocardial infarction (MI) and cardiovascular mortality, at 1-year compared with clopidogrel 
(24). Such benefit was irrespective of patient management (invasive vs non-invasive). Of note, 
this higher efficacy was associated with no differences in overall PLATO major bleeding, 
although there was an increased rate of non-coronary artery bypass graft bleeding (24). A 
predefined subgroup analysis of patients with DM (n=4,662) showed a non-significant reduction 
of the rate of the primary end point (14.1% vs. 16.2%; hazard ratio [HR]: 0.88; 95% confidence 
interval [CI]: 0.76-1.03), which however was consistent with the overall trial results (p for 
interaction: 0.49) (19). The benefit of ticagrelor was enhanced in patients with worse metabolic 
control, as defined per HbA1c levels above the median (19). In the subgroup of patients with 
CKD, ticagrelor led to an enhanced benefit, with a 23% relative risk reduction of the primary 
ischemic end point (compared with a nonsignificant 10% reduction in patients without CKD) and 
an even more remarkable 4.0% absolute and 28% relative risk reduction of all-cause mortality 
(20).  
The recently reported PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients 
With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-
Thrombolysis in Myocardial Infarction 54) expands upon the findings of the PLATO trial 
showing that prolonging dual antiplatelet therapy up to 3 years with aspirin and ticagrelor (tested 
at two different doses: 90 mg bid and 60 mg bid) among high-risk patients who experienced a MI 
in the prior 1-3 years significantly reduced the ischemic events albeit at the expense of increased 
bleeding complications (25). Patients required enrichment factors to be eligible for study entry 
which included DM and CKD; others were age >65 year, multiple prior MI, and multivessel 
disease which are all common features in patients with DM and/or CKD. Although both 


Protocol Version 2 
07/31/2018 
NCT02539160 
ticagrelor doses showed a similar magnitude of clinical efficacy, the 60 mg dose appeared to 
have a more favorable safety profile (25). In patients with DM, the benefits of long-term use of 
ticagrelor was consistent with the overall trial results (HR, 0.85; 95% CI, 0.71-1.03 in DM versus 
HR, 0.85; 95% CI, 0.73-0.99 in non-DM; p for interaction: 0.97). There was also no apparent 
heterogeneity in the efficacy of ticagrelor at either dose with respect to the presence or absence 
of CKD (HR, 0.81; 95% CI, 0.66-0.99 in CKD versus HR, 0.88; 95% CI, 0.76-1.03 in non-CKD; 
p for interaction: 0.48). Indeed more insights on the efficacy of ticagrelor in patients with DM, 
and how this may be affected by CKD status, is being evaluated in the ongoing THEMIS (Effect 
of Ticagrelor on Health Outcomes in DiabEtes Mellitus Patients Intervention) Study 
(NCT01991795).  
 
Significance and Rationale: 
The emerging role of ticagrelor as a key agent for the secondary prevention of ischemic 
events underscores the need for a comprehensive understanding of its PK and PD profiles in 
high-risk settings such as patients with DM and CKD. These assessments will provide important 
mechanistic insights to recently complete and ongoing clinical outcomes studies. Importantly, 
these assessments will allow to better understand the aspects of ticagrelor pharmacology which 
may differ from other P2Y12 inhibiting therapies. DM significantly affects the PK and PD of 
thienopyridine-class P2Y12 receptor blockers (16, 26-28). However, it is unknown if DM also 
modulates the plasma concentrations of ticagrelor and its CYP3A4-derived metabolite 
(ARC124910XX). Platelets from patients with CKD are exposed to higher levels of dinucleoside 
polyphosphates, which can act as an agonists of the P2Y12 receptor (29). Moreover, CKD per se 


Protocol Version 2 
07/31/2018 
NCT02539160 
may affect disposition process, efficacy or safety of drugs (30,31). However, ticagrelor does not 
need biotransformation and its clearance depends minimally on renal function (23).  
To date there has not been any analysis on the clinical efficacy of ticagrelor in DM patients 
with CKD. Moreover, although ticagrelor improved heightened platelet reactivity in DM 
patients, it is unknown how this may be affected by CKD status. Ultimately, whether PK/PD 
profiles of different ticagrelor dosing may be affected by CKD status in patients with DM is also 
unknown. 
 
Study aims 
The aim of the study is to assess the impact of CKD status on the PK and PD profile of 
ticagrelor among patients with DM and CAD. Moreover, how DM and CKD status can affect 
PK/PD profiles in patients treated with different dosing regimens of ticagrelor (60mg and 90 mg) 
will also be assessed.  
 
Study Population 
The study will be performed at the University of Florida Health Science Center at UF 
Health Jacksonville - Division of Cardiology. Patients will be recruited in the Cardiology Clinics 
of our institution and will be screened by Cardiology Research staff, who will verify that all 
candidates meet inclusion and exclusion criteria. Results from blood tests performed within the 
last 90 days will be considered valid for screening purposes. If these are not available, a blood 
sample will be collected for the screening phase. The research design will have common 
inclusion and exclusion criteria as described below.  


Protocol Version 2 
07/31/2018 
NCT02539160 
Inclusion criteria: 
 
Age >18 years. 
 
Type 2 DM, defined according to WHO definition, on treatment with oral hypoglycemic 
agents and/or insulin for at least 2 months without any changes in treatment regimen;  
 
Angiographically documented CAD.  
 
On treatment with low-dose aspirin (81mg/day) and clopidogrel (75mg/day) for at least 
30 days as part of standard of care.  
Exclusion criteria: 
 
Patients with end-stage renal disease on hemodialysis. 
 
Use of any antiplatelet therapy (except aspirin and clopidogrel) in past 30 days.  
 
Use of parenteral or oral anticoagulation in past 30 day.  
 
Active pathological bleeding.  
 
History of intracranial hemorrhage with prior hemorrhage stroke.  
 
Blood dyscrasia or bleeding diathesis.  
 
Any active malignancy.  
 
Platelet count < 80x106/µl.  
 
Hemoglobin <8 g/dl.  
 
Known hepatic dysfunction (known moderate and severe hepatic dysfunction). 
 
Hemodynamic instability.  
 
Known allergy or hypersensitivity to ticagrelor or any excipients. 
 
Pregnant / lactating females (women of childbearing age must use reliable birth control 
while in the study).  


Protocol Version 2 
07/31/2018 
NCT02539160 
 
Strong inhibitors of cytochrome CYP3A4 and potent inducers of cytochrome CYP3A4 
(to avoid interaction with ticagrelor): ketoconazole, itraconazole, voriconazole, 
clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and 
telithromizycin. 
 
Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker 
protection. 
 
Research design 
The proposed investigation is a prospective, randomized, cross-over, open-label, PD and PK 
study in which CAD patients with DM on low-dose (81mg) aspirin and standard-dose (75mg) 
clopidogrel will be prospectively recruited. Patients will be screened during their regularly 
scheduled outpatient visits and informed about the study. Patients will be stratified according to 
CKD status into CKD and non-CKD groups. CKD will be defined according to the functional 
definition of the KDIGO (Kidney Disease: Improving Global Outcomes) guidelines (CKD: 
glomerular filtrate rate [GFR] <60ml/min/1.73m2; non-CKD: GFR ≥ 60ml/min/1.73m2) (32,33). 
The rationale for considering the functional classification to initially stratify patients is in line 
with clinical studies showing the increased cardiovascular risk and markedly dysfunctional 
platelets according to GFR strata (10,11,16). For patient stratification, GFR will be estimated 
through the CKD-EPI (chronic kidney disease epidemiology collaboration) equation, as this is 
suggested by guidelines as the most accurate method to calculate GFR, especially for values in 
the normal range (above 60ml/min/1.73m2) (32,33). For comparison, GFR will also be calculated 
with the MDRD (modification of diet in renal disease) equation. In addition, as exploratory 
analysis, renal function will also be classified according to markers of kidney damage, in 


Protocol Version 2 
07/31/2018 
NCT02539160 
particular albuminuria, in order to obtain a more comprehensive information about CKD (32,33). 
Albuminuria will be evaluated as albumin-to-creatinine ration (ACR) expressed in mg/g, which 
is approximately equivalent to albumin excretion rate. According to KDIGO guidelines, CKD 
will be defined as ACR >30mg/g and non-CKD as ACR ≤30mg/g (32,33). Albuminuria will be 
measured on random untimed spot urine samples. DM will be defined according to World Health 
Organization criteria and all subjects with DM will need to be on treatment with oral 
hypoglycemic agents and/or insulin for at least 2 months without any changes in their regimen 
(34).  
After providing informed consent, eligible patients will be divided into CKD group and 
non-CKD group as described above. DM patients with CKD or without CKD will be randomized 
in a 1:1 fashion to one of the following treatment arms: 
A. standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-
over to low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 2) 
B. low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to 
standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2). 
After the 2 phases of treatment (maximal treatment period 20 days) patients will resume their 
standard DAPT with aspirin and clopidogrel (end of study treatment). 
 
After 7-10 days of treatment, patients will come for their blood sampling in the morning 
hours. In particular, patients will not assume their scheduled morning dose of study medication 
to allow assessment of trough levels of platelet reactivity. Patients will be administered the dose 
of the randomized treatment while at the clinic and blood sampling will be collected after 2 hours 


Protocol Version 2 
07/31/2018 
NCT02539160 
in order to assess peak levels of platelet reactivity. After completing the first phase of the 
randomized assignment, patients will initiate the second phase and start assuming assigned 
medication 12 hours the last dose.  
 
Blood for sampling will be collected at the following visits (a total of 5 assessments at 3 visits): 
a) baseline (24 hours after last clopidogrel MD): PD assessments 
b) after 7-10 days of ticagrelor therapy (phase 1-pre-crossover): PK and PD assessment will 
be assessed to define trough (12 ± 2 hours after last ticagrelor dose) and peak (2 hours 
after ticagrelor administration) activity 
c) after 7-10 days of ticagrelor therapy (phase 2-post-crossover): PK and PD assessment 
will be assessed to define trough (12 ± 2 hours after last ticagrelor dose) and peak (2 
hours after ticagrelor administration) activity.  
 
A flow diagram of the study is presented below.  


Protocol Version 2 
07/31/2018 
NCT02539160 
 
Blood sampling: Peripheral venous blood samples (20 mL) will be drawn through a short 
venous catheter inserted into a forearm vein and collected in citrate and serum tubes as 
appropriate for assessments. The first 2-4 mL of blood will be discarded to avoid spontaneous 
platelet activation. 
Laboratory assessments 
1. Whole blood vasodilator-stimulated phosphoprotein (VASP) 
2. VerifyNow P2Y12 point of care testing  
3. Light-transmittence aggregometry (LTA) 
4. Thromboelastography 
5. 
 Reticulated Platelets (RPs) 


Protocol Version 2 
07/31/2018 
NCT02539160 
6. Serum thromboxane B2 
 
7. PK assessment 
Description of laboratory assays 
1) Whole blood vasodilator-stimulated phosphoprotein (VASP): VASP phosphorylation 
(VASP-P) is a marker of P2Y12 receptor reactivity, which is the target for ticagrelor. VASP 
will be assessed according to standard protocol using labeled monoclonal antibodies by flow 
cytometry with the Platelet VASP-FCM kit (Biocytex Inc., Marseille, France) as previously 
described (16). PGE1 increases VASP-P levels by stimulation of adenylate cyclase. Binding 
of ADP to P2Y12 leads to Gi-coupled inhibition of adenylate cyclase. Therefore, the 
addition of ADP to PGE1-stimulated platelets reduces PGE1-induced VASP-P levels. If 
P2Y12 receptors are successfully inhibited by inhibitors, addition of ADP will not reduce the 
PGE1-stimulated VASP-P levels. The platelet reactivity ratio (PRI) will be calculated after 
measuring VASP-P levels after stimulation with PGE1 (MFI PGE1) and also PGE1 + ADP 
(MFI PGE1 + ADP). The P2Y12 reactivity ratio = ([MFI PGE1] – [MFI PGE1 + 
ADP]/[MFI PGE1]) x 100%. 
2) VerifyNow Point-of-care Testing: The VerifyNow (VN) System is a turbidimetric based 
optical detection system which measures platelet induced aggregation as an increase in light 
transmittance (Accumetrics, San Diego, CA) and will be utilized according to 
manufacturer’s instructions, as previously described (22). The assay is based on microbead 
agglutination and uses specific reagents for the pathways of interest. The VN-P2Y12 assay, 
by combining ADP+PGE1, measures changes in platelet function specific to P2Y12 receptor 
inhibitors. The assay is based upon the ability of activated platelets to bind fibrinogen. 
Fibrinogen-coated microparticles aggregate in proportion to the number of GP IIb/IIIa 


Protocol Version 2 
07/31/2018 
NCT02539160 
receptors expressed. Microbead aggregation is more rapid and reproducible if platelets are 
activated; therefore the reagents are incorporated into the assay channel to induce platelet 
activation without fibrin formation. Light transmittance increases as activated platelets bind 
and aggregate fibrinogen-coated beads. The instrument measures this change in optical 
signal and reports results in P2Y12 Reaction Units (PRU). 
3) Light transmittance aggregometry (LTA): Platelet aggregation will be performed using LTA 
according to standard protocols. Blood will be collected in citrated (3.8%) tubes. LTA will 
be assessed using platelet rich plasma (PRP) by the turbidimetric method in a 2-channel 
aggregometer (chrono-Log 490 Model, Chrono-Log Corp., Havertown) as previously 
described (16,22). Platelet agonists will include 5 and 20 µM ADP. PRP will be obtained as 
a supernatant after centrifugation of citrated blood at 1000 rpm for 10 minutes. The isolated 
PRP will be kept at 37° C before use. Platelet poor plasma (PPP) will be obtained by a 
second centrifugation of the blood fraction at 2800 rpm for 10 minutes. Light transmission 
will be adjusted to 0% with the PRP and to 100% for the PPP for each measurement. Curves 
will be recorded for 6 minutes and platelet aggregation will be determined as the maximal 
percent change in light transmittance from baseline using PPP as a reference. 
4) Thromboelastography (CORA® system): The CORA® system (Haemonetics Corporation, 
Braintree, MA, USA) is a new generation portable thrombelastography technology able to 
evaluate all phases of hemostasis, including time to clot formation, rate of clot formation, 
strength of clot and residual clot strength due to antiplatelet drugs, rate of clot lysis. Whole 
blood samples will be collected into non-gel heparin vacutainer tubes with ≥ 14.5 IU 
heparin/ mL blood, completely filled by vacuum. The PlateletMapping Cartridge are used to 
assess platelet function in patients who have received platelet inhibiting drugs. The 


Protocol Version 2 
07/31/2018 
NCT02539160 
PlateletMapping assay consists of a set of agonists, ADP and AA platelet agonists together 
with ActivatorF, which can measure the inhibition of platelet function. This assay 
specifically determines the MA (Maximum Amplitude, a measure of clot strength) and the 
reduction in MA due to antiplatelet therapy and reports it as a percentage of reduction in clot 
strength. The HKH reagent, a combination of kaolin and heparinase, generates test data for 
the uninhibited MA resulting from thrombin activation of the blood sample, while the 
heparinase neutralizes the effects of heparin. The HKH test provides measures of R 
(Reaction time; the amount of time between the start of the test and the beginning of 
coagulation), K (the speed of formation of the clot from R time to a specific clot strength), 
Angle (the speed of clot strengthening), LY30 (Percent lysis 30 minutes after MA is 
finalized) and MA parameters; the activatorF test provides the contribution of fibrin to the 
overall strength of the clot. This test value is used in the calculation of aggregation/inhibition 
for MA ADP and MA AA; the AA and ADP test provide measures of MA, percent 
inhibition and percent aggregation. 
5) Reticulated Platelets: Reticulated platelets (PRs) will be measured with a previously 
described flow cytometry assay (35,36), which is an appropriate method of measuring young 
platelets and platelet turnover that has been validated in multiple studies (37,38).  
6) Serum thromboxane B2: The concentration of serum thromboxane B2 (TXB2) will be 
measured by using the TXB2 EIA kit (Cayman Chemical Company, Ann Arbor, MI) 
according to the instructions of the manufacturer (39). Briefly, samples will be diluted with 
EIA buffer to bring their concentrations within the range of the standard curve. No other 
purification will be performed on any of the samples. A standard curve will be established by 
serial dilution of TXB2 between 1000 pg/mL and 7.8 pg/mL using EIA buffer as the matrix. 


Protocol Version 2 
07/31/2018 
NCT02539160 
The concentration of TXB2 in the samples will be calculated from a logistic 4-parameter fit 
of the standard concentrations versus percentage bound/maximum bound. 
7) Pharmacokinetic (PK) assay: Determination of plasma concentration of ticagrelor and its 
active metabolite (AR-C124910XX) will be assessed from blood samples taken at the same 
time points of PD analysis as previously described [40]. Blood samples for measurement of 
drug concentrations will be drawn through the same cannula used for PD sampling. The 
blood will be taken into lithium heparin tubes and placed on ice until centrifugation (2800 
rpm, 4°C, 10 min) within 30 min of sampling to collect the plasma, which will be transferred 
to plain polypropylene tubes and frozen upright at or below -20°C until analysis.  
 
Primary and secondary objectives 
The primary end point is the level of on-treatment platelet reactivity as assessed by VASP-
PRI after treatment with ticagrelor 90mg bid on top of aspirin (81mg/day) for 7-10 days. The 
primary hypothesis of our study is that in DM patients the presence of CKD is associated with 
lower platelet inhibition (assessed by PRI determined by VASP-P) compared with those without 
CKD.  
 
Additional objectives include: 
1) The comparison of PD measures following administration of ticagrelor 90 mg between 
CKD and non-CKD groups at each time point assessed with PRU determined by the 
VerifyNow P2Y12 assay, 5 and 20 µM ADP-induced platelet aggregation by LTA and 
clot kinetic assessed by CORA® system.  


Protocol Version 2 
07/31/2018 
NCT02539160 
2) The comparisons of level of platelet reactivity as assessed by multiple assays after 
treatment with ticagrelor 60 mg bid (on top of aspirin 81mg/day) for 7-10 days between 
the CKD and non-CKD groups. 
3) The comparison of plasma concentrations of ticagrelor and its metabolite between the 
DM patients with and without CKD after 7-10 days of ticagrelor (60 and 90 mg) 
treatment.  
4) The comparison of platelet inhibition by standard dose (90mg twice daily) versus low 
dose (60mg twice daily) of ticagrelor in DM patients with or without CKD. 
5) The comparison of the rates of high on-treatment platelet reactivity (HPR), defined as 
VASP-PRI ≥50%, PRU >208, 5 µM ADP-induced maximal platelet aggregation ≥46% 
or ADP induced MA >47 (41,42). 
6) To evaluate whether response to ticagrelor varies with the proportion of RPs in DM 
patients according to the CKD status. 
7) To assess the effects of different levels of P2Y12 inhibition with thromboxane levels.  
8) The comparison of PD and PK measures according to the CKD classification based on 
markers of kidney damage (ACR). 
 
Sample Size Computation and Power Analysis 
The primary hypothesis of our study is that in DM patients the presence of CKD is 
associated with lower platelet inhibition compared with those without CKD after administration 
of ticagrelor 90 mg bid. Under the assumption of 10% absolute difference in mean PRI between 
CKD and non-CKD groups, with a common standard deviation of 13.0% a sample size of 37 
patients per group will allow to detect a difference in platelet aggregation between the two 


Protocol Version 2 
07/31/2018 
NCT02539160 
cohorts with a 90% power and two-sided alpha=0.05 (22). Considering the two cohorts (CKD 
and non-CKD), 74 patients with a valid primary end point data will be needed. Assuming a 40% 
rate of invalid results due to hemolysis or drop-out, up to 102 patients will need to be 
randomized in the study. We anticipate to consent approximately 115 patients in order to reach 
the target number of patients. We have chosen a 10% absolute increase of PRI by VASP-P as 
reference value since this has been associated with a difference in clinical outcomes (43). 
 
Statistical analysis plan 
Categorical variables will be expressed as frequencies and percentages. Continuous 
variables will be presented as mean ± SD or median [IQR] when appropriate. Continuous 
variables will be analyzed for normal distribution with the Kolmogorov-Smirnov test. Student’s 
t-test will be used for comparison of normally distributed continuous variables. Wilcoxon test or 
Mann-Whitney’s U test will be used for comparisons of continuous variables not following a 
normal distribution. An analysis of covariance (ANCOVA) method with a general linear model, 
using baseline variables significantly different between groups as covariates, will be used to 
evaluate the overall difference between groups and all between-groups comparisons, in line with 
other PK and PD studies (22,24). Analysis of variance (ANOVA) will be used to evaluate 
intragroup comparisons. In line with recommendations for cross-over study designs, treatment 
effects will be evaluated considering the functional parameters observed in the overall patient 
population after the treatment regardless of the sequence in which patients received treatment. 
Patients who will successfully complete at least one treatment phase of the study will be 
considered for comparisons. The absolute between-treatment mean differences and 95% 
confidence intervals will be estimated in the two groups. In order to perform an unbiased 


Protocol Version 2 
07/31/2018 
NCT02539160 
estimation of the treatment effect, period and sequence effects, which may occur in crossover 
studies, will be evaluated. A p-value <0.05 will be considered statistically significant. Statistical 
analysis will be performed using a SPSS v22.0 software. 
 
Publication Strategy/Additional Information  
This study will be performed at the University of Florida Health Science Center at UF 
Health - Division of Cardiology. Patients will be recruited and consented at the Cardiology 
clinics in the UF Health system. Patients will be screened by cardiology research, who will 
verify that all candidates meet inclusion criteria. Subjects will be identified with a number and 
data collection sheets will all be stored in a locked area. Data will be kept for 6 years after 
enrollment ends to comply with HIPAA regulations. Patients will receive a handout with the 
names and telephone numbers of the doctors involved in the study. Patients will sign an informed 
consent relating to the study. Study subjects will be identified first (months 1-18): we expect to 
enroll 4-5 subjects monthly and complete enrollment in 18 months (total: 82 subjects enrolled). 
Months 19-20 will be implied for statistical analysis and months 21-22 for manuscript 
preparation. 
We anticipate no major problems with the described protocol since the approach is a 
straight forward prospective study and is based on well-established methods. However, since 
there is limited experience with to define platelet function in this specific subset, variability may 
be higher than expected and we cannot currently perform a detailed sample size calculation. We 
anticipate adding this to the protocol after inclusion of the study population has been completed. 
If the sample size after one year is estimated to be too small, additional patients will be included. 
This approach is in agreement with recommendations for pilot investigations (44). 


Protocol Version 2 
07/31/2018 
NCT02539160 
 
Possible Discomforts and Risk 
In clinical trials, the most common clinical side effects of ticagrelor were dyspnea (13.8%), 
headache (6.5%), cough (4.9%), dizziness (4.5%), nausea (4.3%), bradycardia (4.4%) 
principally. Infrequent events included intracranial hemorrhage (0.3%) and severe bradycardia 
requiring pacemaker insertion (0.9%). Patients considered to be at high risk of bradyarrhythmic 
events will be excluded. The most important adverse effect associated with the use of ticagrelor 
is bleeding. The risk of spontaneous bleeding with ticagrelor is 2.8% (24). However, such 
bleeding prevalence occurred in the setting of long-term (12-15 months) trials, while our study is 
limited to up to 14 ± 4 days of active treatment thus reducing the risk of bleeding complications. 
All clinical events described above, if they were to occur, as well as death, MI, stroke, and urgent 
revascularization procedure with PCI or coronary artery bypass grafting will be recorded. 
Bleeding data will be collected using PLATO definitions (24). Clinical events will be evaluated 
by a local committee, comprised of 2 faculty members (2 cardiologists), not directly involved in 
the research. In the event of a report of a serious adverse event (major bleeding – defined as life-
threatening: fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at 
least 5 g/dL, significant hypotension requiring intravenous inotropes, requiring surgical 
intervention, or requiring transfusion of 4 or more units of blood; non–life-threatening: 
substantially disabling, intraocular bleeding leading to vision loss, or requiring at least 2 units of 
blood; thrombocytopenia <50,000) the local committee will meet and antiplatelet treatment 
management will be managed according to physician recommendation. 
 


Protocol Version 2 
07/31/2018 
NCT02539160 
 
Definition of Adverse Events 
An adverse event is any unintended or undesirable experience that occurs during the course 
of the clinical investigation whether or not it is considered to be therapy related. This includes 
any newly occurring event or previous condition that has increased in severity or frequency since 
the initiation of study treatment. Adverse events will be followed until resolution while the 
patient remains on-study. Once the patient is removed from study, events thought to be related to 
the study therapy will be followed until resolution or until the patient starts a new treatment 
regimen. 
Serious adverse events (SAE): An adverse event occurring while on study and considered 
related (reasonable possibility that the study treatment caused the adverse experience) to the 
study treatment that results in the following outcomes: 
- Death 
- A life-threatening adverse experience. 
- A persistent or significant disability, incapacity, or is a congenital anomaly, or birth defect. 
- Requires inpatient hospitalization, or prolongation of existing hospitalization. 
The definition of serious adverse event also includes ‘important medical event’. Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient and/or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 


Protocol Version 2 
07/31/2018 
NCT02539160 
definition above. These should also usually be considered serious. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse. 
 
Reporting of serious adverse events  
A copy of the MedWatch/AdEERs report must be faxed to AstraZeneca at the time the 
event is reported to the FDA. It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the 
same time. 
Serious adverse events that do not require expedited reporting need to be reported to 
AstraZeneca quarterly either as individual case reports or as line-listings. When reporting to 
AstraZeneca, a cover page should accompany the MedWatch/AdEERs form indicating the 
following: 
 
External Sponsored Research (ESR) 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ESR reference number 
Investigative site must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications and if the SAE is related to disease 
progression, as determined by the principal investigator. 


Protocol Version 2 
07/31/2018 
NCT02539160 
Send SAE report and accompanying cover page by way of fax to AstraZeneca’s 
designated fax line: +1-302-886-4114. 
Serious adverse events that do not require expedited reporting to the FDA need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious adverse 
events.  
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a 
copy of the randomization code/ code break information or unblind those SAEs which require 
expedited reporting. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related 
to the investigational product. All SAEs will be documented. The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 
Possible benefits 
The present investigation is aimed to evaluate the differences on the functional impact of 
CKD on platelet inhibition by ticagrelor in DM patients. This study is not designed to evaluate 
differences in clinical benefit. However, differences in antiplatelet profiles will perhaps prompt 
further investigation of the clinical implication of this difference by means of a larger scale 
clinical study. 
 
Ethical and regulatory 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB for written 
approval. A copy of the written approval of the protocol and informed consent form must be 


Protocol Version 2 
07/31/2018 
NCT02539160 
received by AstraZeneca before recruitment of subjects into the study and shipment of 
AstraZeneca investigational product.  
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document. The 
investigator is to notify the IRB of deviations from the protocol or serious adverse events or 
unanticipated problems occurring at the site and other adverse event reports received from 
AstraZeneca, in accordance with local procedures.  
The investigator is responsible for obtaining annual IRB approval /renewal throughout the 
duration of the study. Copies of the investigator’s reports and the IRB continuance of approval 
must be sent to AstraZeneca. 
 
Labeling and storage 
The label will include the following information: Facility Name, Patient Name, Dose, 
Prescription Number, and Dispensing Date. In addition, the drug name will be included as 
“Investigational Drug”. The investigational drug will be stored in the Cardiovascular Research 
drug room. This area has limited and restricted access. 
  
Potential Financial Risks or Benefits 
 
None 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Astra Zeneca, the maker of ticagrelor. 


Protocol Version 2 
07/31/2018 
NCT02539160 
References 
1. Malmberg K, Yusuf S, Gerstein HC, et al. Impact of diabetes on long-term prognosis in 
patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS 
(Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation. 
2000;102:1014-9. 
2. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United 
States. JAMA. 2007;298:2038-47. 
3. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, 
cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. 
4. Sasso FC, De Nicola L, Carbonara O, et al. Cardiovascular risk factors and disease 
management in type 2 diabetic patients with diabetic nephropathy. Diabetes Care. 
2006;29:498-503. 
5. Goldenberg I, Subirana I, Boyko V, et al. Relation between renal function and outcomes in 
patients with non-ST-segment elevation acute coronary syndrome: real-world data from the 
European Public Health Outcome Research and Indicators Collection Project. Arch Intern 
Med. 2010;170:888-95. 
6. Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment 
strategies and future directions. Diabetes Care 2009;32:531–40. 
7. Ferreira IA, Mocking AI, Feijge MA, et al. Platelet inhibition by insulin is absent in type 2 
diabetes mellitus. Arterioscler Thromb Vasc Biol 2006;26:417–22. 
8. Muntner P, He J, Hamm L, et al. Renal insufficiency and subsequent death resulting from 
cardiovascular disease in the United States. J Am Soc Nephrol 2002;13:745–53. 


Protocol Version 2 
07/31/2018 
NCT02539160 
9. Hage FG, Venkataraman R, Zoghbi GJ, el al. The scope of coronary heart disease in patients 
with chronic kidney disease. J Am Coll Cardiol 2009;53:2129–40. 
10. Best PJ, Steinhubl SR, Berger PB, et al. The efficacy and safety of short- and long-term dual 
antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the 
Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 
2008;155:687–93. 
11. Dasgupta A, Steinhubl SR, Bhatt DL, et al. Clinical outcomes of patients with diabetic 
nephropathy randomized to clopidogrel plus aspirin versus aspirin alone (a post hoc analysis 
of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management, 
and avoidance [CHARISMA] trial).Am J Cardiol 2009;103:1359–63. 
12. Capodanno D, Patel A, Dharmashankar K, et al. Pharmacodynamic effects of different 
aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ 
Cardiovasc Interv. 2011;4:180-7. 
13. Himmelfarb J, Holbrook D, McMonagle E, Ault K. Increased reticulated platelets in dialysis 
patients. Kidney Int. 1997;51:834-9. 
14. Morel O, El Ghannudi S, Jesel L, et al. Cardiovascular mortality in chronic kidney disease 
patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 
inhibition by clopidogrel. J Am Coll Cardiol 2011; 57: 399–408. 
15. Angiolillo DJ, Bernardo E, Capodanno D, et al. Impact of chronic kidney disease on platelet 
function profiles in diabetes mellitus patients with coronary artery disease taking dual 
antiplatelet therapy. J Am Coll Cardiol 2010;55:1139–46. 


Protocol Version 2 
07/31/2018 
NCT02539160 
16. Angiolillo DJ, Jakubowski JA, Ferreiro JL, et al. Impaired responsiveness to the platelet 
P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery 
disease. J Am Coll Cardiol 2014;64:1005–14. 
17. Alexopoulos D, Panagiotou A, Xanthopoulou I, et al. Antiplatelet effects of prasugrel vs. 
double clopidogrel in patients on hemodialysis and with high on-treatment platelet reactivity. 
J Thromb Haemost 2011; 9: 2379–85. 
18. Alexopoulos D, Xanthopoulou I, Mavronasiou E, et al. Randomized assessment of ticagrelor 
versus prasugrel antiplatelet effects in patients with diabetes. Diabetes Care 2013;36:2211–
16. 
19. James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute 
coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient 
Outcomes (PLATO) trial. Eur Heart J. 2010;31:3006–16. 
20. James S, Budaj A, Aylward P, et al. Ticagrelor versus clopidogrel in acute coronary 
syndromes in relation to renal function: results from the Platelet Inhibition and Patient 
Outcomes (PLATO) trial. Circulation. 2010;122:1056-67. 
21. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and 
safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with 
atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 
2006;27:1038-47. 
22. Storey RF, Angiolillo DJ, Patil SB, et al. Inhibitory effects of ticagrelor compared with 
clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO 
(PLATelet inhibition and patient Outcomes) PLATELET substudy. J Am Coll Cardiol 
2010;56:1456-62. 


Protocol Version 2 
07/31/2018 
NCT02539160 
23. Angiolillo DJ. The evolution of antiplatelet therapy in the treatment of acute coronary 
syndromes: from aspirin to the present day. Drugs. 2012;72:2087-116. 
24. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute 
coronary syndromes. N Engl J Med. 2009;361:1045-57. 
25. Bonaca MP, Bhatt DL, Cohen M, et al. Long-Term Use of Ticagrelor in Patients with Prior 
Myocardial Infarction. N Engl J Med. 2015 Mar. [Epub ahead of print]. 
26. Patti G, Proscia C, Di Sciascio G. Antiplatelet therapy in patients with diabetes mellitus and 
acute coronary syndrome. Circ J. 2014;78:33-41.. 
27. Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral 
antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess 
improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-
Thrombolysis in Myocardial Infarction 38. Circulation 2008;118:1626–36.  
28. Erlinge D, Varenhorst C, Braun OO, et al. Patients with poor responsiveness to 
thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, 
but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol. 
2008;52:1968–77. 
29. Chang H, Yanachkov IB, Michelson AD et al. Agonist and antagonist effects of diadenosine 
tetraphosphate, a platelet dense granule constituent, on platelet P2Y1, P2Y12 and P2X1 
receptors. Thromb Res 2010;125:159–65. 
30. Morel O, Muller C, Jesel L, et al. Impaired platelet P2Y12 inhibition by thienopyridines in 
chronic kidney disease: mechanisms, clinical relevance and pharmacological options. 
Nephrol Dial Transplant. 2013;28:1994-2002. 


Protocol Version 2 
07/31/2018 
NCT02539160 
31. Capodanno D, Angiolillo DJ. Antithrombotic therapy in patients with chronic kidney disease. 
Circulation. 2012;125:2649-61. 
32. Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura M, Feldman 
HI. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the 
evaluation and management of CKD. Am J Kidney Dis. 2014;63:713-35. 
33. Levey AS, Becker C, Inker LA. Glomerular filtration rate and albuminuria for detection and 
staging of acute and chronic kidney disease in adults: a systematic review. JAMA. 
2015;313:837-46 
34. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: Report of a 
WHO/IDF consultation. 
http://www.who.int/diabetes/publications/diagnosis_diabetes2006/en/. Accessed on March 
2015. 
35. Michelson AD, Barnard MR, Krueger LA, Frelinger AL III, Furman MI. Evaluation of 
platelet function by flow cytometry. Methods 2000;21:259-70. 
36. Robinson M, MacHin S, Mackie I, Harrison P. In vivo biotinylation studies: specificity of 
labelling of reticulated platelets by thiazole orange and mepacrine. Br J Haematol 
2000;108:859-64. 
37. Koike Y, Yoneyama A, Shirai J, et al. Evaluation of thrombopoiesis in thrombocytopenic 
disorders by simultaneous measurement of reticulated platelets of whole blood and serum 
thrombopoietin concentrations. Thromb Haemost 1998;79:1106-10. 
38. Salvagno GL, Montagnana M, Degan M, et al. Evaluation of platelet turnover by flow 
cytometry. Platelets 2006;17:170-7. 


Protocol Version 2 
07/31/2018 
NCT02539160 
39. Eriksson AC, Jonasson L, Lindahl TL, Hedba¨ck B, Whiss PA. Static platelet adhesion, flow 
cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and 
clopidogrel in coronary artery disease: a randomised cross-over study. J Transl Med. 
2009;7:42. 
40. Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and 
safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with 
atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006; 
27:1038-47. 
41. Bonello L, Tantry US, Marcucci R, et al. Consensus and future directions on the definition of 
high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 
2010;56:919-33. 
42. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment 
platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am 
Coll Cardiol. 2013;62:2261-73. 
43. Bonello L, Mancini J, Pansieri M, et al. Relationship between post-treatment platelet 
reactivity and ischemic and bleeding events at 1-year follow-up in patients receiving 
prasugrel. J Thromb Haemost. 2012;10:1999-2005. 
44. Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: 
recommendations for good practice. J Eval Clin Pract 2004;10:307-12. 
 

ICF_001.pdf: 
 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
1
 
 
 
University of Florida – Jacksonville 
 
SUBJECT INFORMATION AND CONSENT FORM 
 
 
TITLE: 
Impact of chronic kidney disease on the pharmacodynamic and 
pharmacokinetic effects of ticagrelor in patients with diabetes 
mellitus and coronary artery disease. 
 
PROTOCOL NO.: 
ESR-15-10953 
 
WIRB® Protocol #20151832 
 
Clinicaltrials.gov identifier: NCT02539160 
 
SPONSOR: 
The University of Florida 
 
INVESTIGATOR: 
Dominick J. Angiolillo, MD, PhD 
 
655 West 8th Street 
 
Jacksonville, Florida 32209 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Dominick J. Angiolillo, MD, PhD 
 
904-244-3378 
 
904-244-0411 (24 hours) 
 
 
Name of person seeking your consent:  ____________________________________________ 
 
 
Place of employment & position:  _________________________________________________ 
 
 
Name of Participant (“Study Subject”) ____________________________________________ 
 
This consent form may contain words that you do not understand. Please ask the study doctor or 
the study staff to explain any words or information that you do not clearly understand. You may 
take home an unsigned copy of this consent form to think about or discuss with family or friends 
before making your decision. 
 


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
2
WHAT WILL BE DONE AS PART OF YOUR NORMAL CLINICAL CARE (EVEN IF 
YOU DID NOT PARTICIPATE IN THIS RESEARCH STUDY)? 
If you choose not to participate in this study, you will be treated and followed by your primary 
care team per normal standard of care. 
 
WHY IS THIS RESEARCH STUDY BEING DONE? 
You are being asked to participate in this study because you are a diabetic patient who had a stent 
implanted in the artery of your heart due to a blockage and because of this also you are taking a 
blood thinning medication called clopidogrel, commercially known as Plavix®, in addition to a 
low dose baby aspirin. You must be informed so you can decide whether you want to participate. 
 
Platelets are parts of your blood that stick together to help form a clot. The stickier your platelets 
are, the greater your chances of having heart attacks. Platelets from the patients with diabetes 
mellitus tend to stick together more, increasing the risk of having a heart attack. It is also known 
that if you have both diabetes and kidney disease your platelets are even stickier and your 
chances of having a heart attack even higher compared to patients with diabetes but without 
kidney disease. Importantly, diabetes is the most common cause of having kidney disease. In fact, 
around 20 to 30% of people with diabetes develop kidney disease. To prevent a heart attack, 
there are antiplatelet drugs (blood thinners) to keep your platelets from sticking together. 
clopidogrel (Plavix®) and ticagrelor (Brilinta®) are antiplatelet drugs used in the treatment of 
patients with coronary artery disease like yours. In large-scale clinical investigation, Brilinta® has 
shown greater clinical benefits than Plavix®. The finding was consistent also in patients with 
diabetes mellitus or kidney disease. However, it is unknown if Brilinta® could prevent platelets 
from sticking together in patients with both diabetes mellitus and kidney disease.  
 
In another large-scale clinical investigation, 60mg of Brilinta® was as effective as 90mg of 
Brilinta®, but with reduced side effects.  However, it is unknown if the 60mg dose of Brilinta is 
as effective on blocking platelets compared with the 90mg dose in patients with diabetes mellitus 
and kidney disease. 
 
The purpose of this study is to evaluate the effect of Brilinta® according to kidney function in 
diabetic patients and to evaluate the effects of two dosing regimens of Brilinta® (60mg and 
90mg). 
 
HOW MANY PEOPLE ARE EXPECTED TO TAKE PART IN THIS RESEARCH 
STUDY? 
Up to 115 people are expected to be consented to take part in this study. 
 
HOW LONG WILL YOU BE IN THIS RESEARCH STUDY? 
If you are eligible, you will be expected to take part in the research for up to 20 days.  
 


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
3
WHO CAN PARTICIPATE IN THIS STUDY?  
Your study doctor will determine if you are able to participate in this research study. Please feel 
free to ask the study doctor about the study requirements for participation. 
 
WHAT WILL BE DONE ONLY BECAUSE YOU ARE IN THIS RESEARCH STUDY? 
Your study doctor will fully explain the study, other possible treatments, and any known or 
possible side effects of participating in this study. If you consent to participate in this study, your 
study doctor will collect data from your medical records. You will be evaluated to see if you 
meet criteria to enter into the research protocol. If you are a woman of childbearing potential, a 
pregnancy test will be done prior to taking any antiplatelet medication. If you are found to be 
pregnant, you will not be randomized and your participation in this study will end. Nursing 
woman can’t participate in this study. 
 
Other study related procedures will include a physical. At the screening visit, if results from 
blood tests performed in the last 90 days are not available, blood will be collected for 
determination of complete blood count, HbA1c, and renal function. After undergoing screening, 
if you are eligible to participate you will come for a total of 3 visits for a total of 5 blood draws. 
Baseline platelet function tests will be done to see how sticky your platelets are. After this, you 
will be randomized (chosen, like the flip of a coin) to: 
 (1) switch to Brilinta® 90 mg tablet twice daily for 7-10 daysor 
 (2) switch to Brilinta® 60 mg tablet twice daily for 7-10 days. 
 
After 7-10 days you will be asked to come to our clinical site in the morning 12±2 hours after the 
last dose of Brilinta®. Blood draws will be performed before and 2 hours after administration of 
the study drug.  
 
After this first phase you will switch to the different dose of Brilinta® and keep it for 7-10 days 
(90mg of Brilinta® for 60mg users and 60mg of Brilinta® for 90mg users). After 7-10 days you 
will be asked to come to our clinical site in the morning 12±2 hours after the last dose of 
Brilinta®. Blood draws will be performed before and 2 hours after administration of the study 
drug. After this, the study will be over and you will resume your standard of care therapy.   
 
Approximately 30 cc (one ounce) of blood will be collected from you for the blood samples 
mentioned above by inserting a needle directly into your vein or from a catheter in your vein. 
 
WHAT ARE THE POSSIBLE DISCOMFORTS AND RISKS? 
Your study doctor will be responsible for reviewing and monitoring your well-being. 
 
The following are potential risks: 
 Blood drawing. There is the discomfort of blood drawing and you may experience 
bruising, and/or bleeding where the needle is inserted.  Occasionally some people 
become dizzy or feel faint 


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
4
 The most common side effects of Brilinta® are: shortness of breath, headache, cough, 
dizziness, nausea and bleeding that may be minor or life-threatening or fatal. During 
treatment with ticagrelor, dizziness and confusion have been reported. Therefore, patients 
who experience these symptoms should be cautious while driving or using machines. 
 Loss of confidentiality.   
 
To protect you from above concerns: 
 The blood tests will be drawn by experienced personnel 
 Patients who are known to have bleeding problems will not participate in this study to 
reduce this risk.   
 The data will be stored as secured coded access.  
 
This study may include risks that are unknown at this time. 
 
Taking part in more than one research study or project may further increase the risks to you. If 
you are currently enrolled or have recently taken part in another research study, you must tell the 
person reviewing this consent form with you. 
 
Throughout the study, the researchers will notify you of new information that may become 
available and might affect your decision to remain in the study.  
 
If you wish to discuss the information above or any discomforts you may experience, you may 
ask questions now or call the Principal Investigator or contact person listed on the front page of 
this form. 
 
WHAT ARE THE POSSIBLE BENEFITS TO YOU? 
Participation in this study may or may not help to improve your condition. It is also possible that 
your condition may worsen. There is no guarantee that you will personally benefit by 
participating in this research study. 
 
HOW COULD OTHERS POSSIBLY BENEFIT FROM THIS RESEARCH STUDY? 
Your participation in this study may help the investigators learn more about the effects of 
administering ticagrelor (Brilinta®) and may help other people in the future. 
 
HOW COULD THE RESEARCHERS BENEFIT FROM THIS RESEARCH STUDY? 
The sponsor is paying the University of Florida for conducting this research study. In general, 
presenting research results helps the career of a scientist.  Therefore, the study doctor may benefit 
if the results of this study are presented at scientific meetings or in scientific journals. 
 
CONFLICT OF INTEREST 
Dr. Angiolillo has received consulting fees from Astra Zeneca, the maker of ticagrelor, in the 
past 12 months.  Please feel free to ask any further questions you might have about this matter.  
 


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
5
IF YOU CHOOSE TO TAKE PART IN THIS STUDY, WILL IT COST YOU 
ANYTHING? 
The Sponsor will pay for the medical services that you receive as part of your participation in this 
study which are described in the section of the consent form headed by the question “What Will 
Be Done Only Because You Are In This Research Study”. This may include some medical 
services that you would have received if you were not in this study.  All other medical services 
will be billed to you or your insurance company.  You will be responsible for paying any 
deductible, co-insurance, or co-payments for those services, and for any non-covered or out-of-
network services. Some insurance companies may not cover costs associated with research 
studies.  Please contact your insurance company for additional information.  
 
WILL YOU BE PAID FOR TAKING PART IN THIS RESEARCH STUDY? 
You will be paid $15.00 in Visa debit cards for each completed study visit to help cover time and 
travel. It may take up to 48 hours to process your debit card. If you do not complete all of your 
visits you will be paid for the visits that were completed.  
 
If you are paid more than $75 for taking part in this study, your name and social security number 
will be reported to the appropriate University employees for purposes of making and recording the 
payment as required by law. You are responsible for paying income taxes on any payments 
provided by the study. If the payments total $600 or more or you are a nonresident alien, payment 
will be processed through the University of Florida Accounts Payable department and the 
University must report the amount you received to the Internal Revenue Service (IRS). The IRS is 
not provided with the study name or its purpose. If you have questions about the collection and use 
of your Social Security Number, please visit: http://privacy.ufl.edu/SSNPrivacy.html. 
 
Your payment for participation in this research study is handled through the University of 
Florida’s Human Subject Payment (HSP) Program.  Your information which will include your 
name, address, date of birth, and SSN (depending on amount of money you are paid) is protected.  
Access to the (HSP) Program site is limited to certain staff with the assigned security role.  You 
will be randomly assigned a specific identification (ID) number to protect your identity. 
 
The study team will provide you with an informational form called the Prepaid Card Facts 
document.  If you have any problems regarding your payment call the HSP Office (352) 392-
9057. 
 
WHAT IF YOU ARE INJURED BECAUSE OF THE RESEARCH STUDY? 
The sponsor and the Principal Investigator will determine whether your injury is related to your 
participation in this study. 
 
If you are injured as a direct result of your participation in this study, only professional medical 
care that you receive at the University of Florida Health Science Center will be provided without 
charge. Hospital expenses will be billed to you or your insurance. You will be responsible for any  


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
6
deductible, co-insurance, or co-payments. Some insurance companies may not cover costs 
associated with research studies. Please contact your insurance company for additional 
information.  
 
No additional compensation is routinely offered. The Principal Investigator and others involved 
in this study may be University of Florida employees. As employees of the University, they are 
protected under state law, which limits financial recovery for negligence.   
 
Please contact the Principal Investigator Dominick J. Angiolillo M.D. at (904) 244-3378 
weekdays between the hours of 8:00 a.m. and 5:00 p.m., after regular business hours, you may 
call (904) 244-0411 if you experience an injury or have questions about any discomforts that you 
experience while participating in this study. 
 
WHAT OTHER CHOICES DO YOU HAVE IF YOU DO NOT WANT TO BE IN THIS 
RESEARCH STUDY? 
If you choose not to participate in this study, you will still continue receiving your medical care 
just as you normally do.  You can receive the study drugs without participating in the study. 
 
DO YOU HAVE TO BE IN THIS STUDY? 
Your participation in this study is voluntary. You may decide not to participate or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which you 
are entitled. If you leave this study for any reason, please contact Dominick J. Angiolillo, M.D., 
Ph.D. at 904-244-3378 or 904-244-0411 (24 hours).  They will tell you how to stop your 
participation safely. 
 
CAN YOU BE WITHDRAWN FROM THIS RESEARCH STUDY? 
The FDA, your study doctor, your local institution, has the right to stop your participation in the 
study, or cancel the study, without your consent at any time. Your study doctor may take you off 
the study at any time for any of the following reasons:  
 if he/she decides it is in your best interest. 
 if you do not consent to continue in the study after being told of changes in the research 
that may affect you;  
 or for any reason. 
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES 
If you agree to participate in this study, the study doctor will create, collect, and use private 
information about you and your health. This information is called protected health information or 
PHI. In order to do this, the study doctor needs your authorization. The following section 
describes what PHI will be collected, used and shared, how it will be collected, used, and shared, 
who will collect, use or share it, who will have access to it, how it will be secured, and what your 
rights are to revoke this authorization.  
 


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
7
Your protected health information may be collected, used, and shared with others to determine if 
you can participate in the study, and then as part of your participation in the study. This information 
can be gathered from you or your past, current or future health records, from procedures such as 
physical examinations, x-rays, blood or urine tests or from other procedures or tests. This 
information will be created by receiving study treatments or participating in study procedures, or 
from your study visits and telephone calls.  More specifically, the following information may be 
collected, used, and shared with others:  
 
 Complete past medical history to determine eligibility criteria  
 Records of physical exams 
 Laboratory, x-ray, MRI, and other test results 
 Records about study medications or drugs 
 
This information will be stored in locked filing cabinets or in computers with security passwords.  
 
Some of the information collected could be included in a "limited data set" to be used for other 
research purposes.  If so, the limited data set will include only information that does not directly 
identify you. For example, the limited data set cannot include your name, address, telephone 
number, social security number, or any other photographs, numbers, codes, or so forth that link 
you to the information in the limited data set.  If limited data sets are created and used, 
agreements between the parties creating and receiving the limited data set are required in order to 
protect your identity and confidentiality and privacy. 
 
Your PHI may be collected, used, and shared with others to make sure you can participate in the 
research, throughout your participation in the research, and to evaluate the results of the research 
study.  More specifically, your PHI may be collected, used, and shared with others for the 
following study-related purpose(s): 
 
 to determine the effectiveness of the study drug in treating patients with coronary artery 
disease and diabetes, with or without kidney disease 
 to evaluate a possible new use for the study drug  
 
Once this information is collected, it becomes part of the research record for this study. 
 
Only certain people have the legal right to collect, use and share your research records, and they 
will protect the privacy and security of these records to the extent the law allows. These people 
include: 
 
 the study doctor, and research staff associated with this project 
 other professionals at the University of Florida or Shands Hospital that provide study-
related treatment or procedures 
 The University of Florida Institutional Review Board  


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
8
Your PHI may be shared with: 
 
 The study sponsor The University of Florida and AstraZeneca Company. 
 United States and foreign governmental agencies who are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health and Human 
Services, and the Office of Human Research Protections 
 Government agencies who are responsible for overseeing public health concerns such as the 
Centers for Disease Control and federal, state and local health departments 
 Western Institutional Review Board 
 Your insurance company for purposes of obtaining payment 
 
Every attempt will be made to protect your right to privacy within legal limits.  However, records 
associated with your participation in the study, including medical histories (case histories) which 
may identify you, and this informed consent signed by you, will be made available for inspection 
by the Western Institutional Review Board® (WIRB®), AstraZeneca company or designee 
(including any persons or companies which are contracted by AstraZeneca company to have 
access to the research information during and after the study, such as the monitor(s) and 
auditor(s)), the US Food and Drug Administration (FDA), and state and other local authorities.  
Because of the need to release information to these parties, absolute confidentiality cannot be 
guaranteed.  In addition, the results of treatment and laboratory data may be published for 
scientific purposes, but your identity will not be disclosed. By signing a written informed consent 
form, you are authorizing such access. 
 
Otherwise, your research records will not be released without your permission unless required by 
law or a court order. It is possible that once this information is shared with authorized persons, it 
could be shared by the persons or agencies who receive it and it would no longer be protected by 
the federal medical privacy law.   
 
Your PHI will be used and shared with others until the end of study.   
 
This information will be destroyed 2 years after research is conducted or longer per University of 
Florida and/or FDA requirements. 
 
You may not be allowed to see or copy certain information in your medical records collected in 
connection with your participation with this study while the research is in progress if the research 
includes treatment. When the research study is completed you will have access to inspect or copy 
your records with certain exceptions under applicable law. 
 
You are not required to sign this consent and authorization or allow researchers to collect, use 
and share your PHI. Your refusal to sign will not affect your treatment, payment, enrollment, or 
eligibility for any benefits outside this research study. However, you cannot participate in this 
research unless you allow the collection, use and sharing of your protected health information by 
signing this consent and authorization. 


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
9
You have the right to review and copy your protected health information. However, we can make 
this available only after the study is finished. 
 
You can revoke your authorization at any time before, during, or after your participation in this 
study.  If you revoke it, no new information will be collected about you. However, information 
that was already collected may still be used and shared with others if the researchers have relied 
on it to complete the research. You can revoke your authorization by giving a written request 
with your signature on it to the study doctor.   
 
Your withdrawal must be made in writing and sent to Dominick J. Angiolillo, M.D. Ph.D., 655 
West 8th Street, Jacksonville, Florida 32209. 
 
NEW INFORMATION ON THE STUDY DRUG 
You will be informed about any new information, such as adverse reactions (side effects) that 
could affect your decision to continue in this study. You may be asked to sign a new consent 
form if that should occur. 
 
WHAT IF I BECOME PREGNANT DURING THE STUDY? 
If you are pregnant or nursing before you enroll in the study, you may not participate in the study.   
 
WHERE CAN I FIND INFORMATION ABOUT THE STUDY? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.   
 
WHO WOULD YOU CALL IF YOU HAVE ANY QUESTIONS? 
If you have questions about the study, please ask us before signing this form. If you require 
further general information regarding the research study, if at any time you feel you have had 
a research-related injury or reaction to the study drug, or if you have questions, concerns or 
complaints about the research please contact: 
 
Dominick J. Angiolillo, M.D., Ph.D. at 904-244-3378 or 904-244-0411 (24 hours). 
 
If you have questions about your rights as a research subject or if you have questions, concerns or 
complaints about the research, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, Washington  98374-2115 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail: Help@wirb.com 
 
or 


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
10
The University of Florida IRB in Jacksonville at (904) 244-9478. 
 
WIRB is a group of people who perform independent review of research.  
 
WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or if 
you wish to talk to someone other than the research staff. 
 
CONSENT TO PARTICIPATE IN THIS RESEARCH STUDY 
I have been informed about this study’s purpose, procedures, possible benefits and risks. I have 
also been told alternatives to being in the study and how my protected health information will be 
collected, used, and shared with others. I have been given the opportunity to ask questions. My 
questions have all been answered satisfactorily. I agree to be in this research study. I have 
received a copy of this form. 
 
By signing this consent form, I have not given up any of my legal rights. 
 
I authorize the release of my medical records for research or regulatory purposes to those agencies 
listed under the Authorization section of this consent form.  
 
 
 
 
Name of Participant (Print) 
Date 
 
 
 
 
Signature of Participant 
 
 
As an investigator or the investigator’s representative, I have explained to the participant the 
purpose, the procedures, the possible benefits, and the risks of this research study, the alternative 
to being in the study; and how the subject’s protected health information will be collected, used, 
and shared with others: 
 
 
 
 
 
 
Printed Name of Person Conducting Informed Consent Discussion Position 
 
 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion 
Date