A Mechanistic Study in Patients With Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet Response to Antiplatelet Therapy (CKD-Platelet Study)
Phase: PHASE3
Conditions: Chronic Kidney Diseases, Heart Attack, Stroke, Ischemic
Sponsor: University of Arkansas

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 1 of 43 
Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered 
Platelet Response to Antiplatelet Therapy 
 
Principal Investigator: 
Nishank Jain, MD 
University of Arkansas for Medical Sciences 
Medical Specialties, College of Integrated Clinical Enterprise 
4301 W. Markham Street 
Little Rock, AR 72205-71 
Telephone: (501)686-5295 
E-mail: NJain2@uams.edu 
 
Sub-Investigator(s): 
John M. Arthur, MD 
University of Arkansas for Medical Sciences 
Internal Medicine, Nephrology 
4301 W. Markham Street 
Little Rock, AR 72205 
Telephone: 501-686-5295 
E-mail: JMArthur@uams.edu 
 
Biostatistician: 
Wan Fei 
University of Arkansas for Medical Sciences 
College of Public Health 
4301 W. Markham Street 
Little Rock, AR 72205-7199 
Telephone: (501)686-5353 
E-mail: FWan@uams.edu 
 
Medical Monitor: 
Nithin Karakala, MD 
University of Arkansas for Medical Sciences 
Department of Internal Medicine, Nephrology 
4301 W. Markham Street 
Little Rock, AR 72205-7199 
Telephone: (501)686-5295 
E-mail: NKarakala@uams.edu 
 
Study location(s): 
University of Arkansas for Medical Sciences 
 
Sponsor: 
University of Arkansas for Medical Sciences 
 
Funding Source:  
ASN Foundation for Kidney Research 
Joseph V. Bonventre Career Development Grant 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 2 of 43 
TABLE OF CONTENTS 
1.0 
STUDY SCHEMA .................................................................................................. 5 
2.0 
STUDY SUMMARY ............................................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ........................................................................ 9 
3.1 
Disease Background .......................................................................................................9 
3.2 
Product Background .................................................................................................... 10 
3.3 
Rationale ...................................................................................................................... 12 
4.0 
STUDY OBJECTIVES ......................................................................................... 13 
4.1 
Aim 1 ............................................................................................................................ 13 
4.2 
Aim 2: ........................................................................................................................... 13 
4.3 
Primary Objectives ....................................................................................................... 13 
4.4 
Secondary Objectives .................................................................................................. 13 
5.0 
STUDY POPULATION ........................................................................................ 14 
5.1 
Inclusion Criteria for CKD subjects .............................................................................. 14 
5.2 
Exclusion Criteria for CKD patients and Healthy Control Subjects: ............................ 14 
5.3 
Accrual Goal ................................................................................................................ 15 
5.4 
Recruitment Plan ......................................................................................................... 16 
5.5 
Participant Compensation ............................................................................................ 16 
6.0 
INVESTIGATIONAL PRODUCT ........................................................................... 17 
6.1 
Test Article ..................................................................... Error! Bookmark not defined. 
6.2 
Treatment Dosage and Administration ........................................................................ 18 
6.3 
Concomitant Medications/Treatments ......................................................................... 19 
6.4 
Duration of Therapy ..................................................................................................... 19 
6.5 
Duration of Follow Up .................................................................................................. 19 
6.6 
Removal of Patients from Protocol Therapy ................................................................ 20 
7.0 
STUDY PROCEDURES ....................................................................................... 20 
7.1 
VISIT 1 (Screening visit) .............................................................................................. 20 
7.2 
Visit 2 – Baseline Visit (for all subjects) ....................................................................... 22 
7.3 
Mid-Treatment Telephone Call .................................................................................... 24 
7.4 
Visit 3 (Last visit) .......................................................................................................... 24 
7.5 
Schedule of Events ...................................................................................................... 25 
7.6 
Removal of Subjects from the Study ........................................................................... 26 
8.0 
ADVERSE EVENTS ............................................................................................ 26 
8.2 
Adverse Event Monitoring ............................................................................................ 26 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 3 of 43 
8.3 
Definitions .................................................................................................................... 27 
8.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting .................... 28 
8.5 
Reporting Requirements for Adverse Events .............................................................. 28 
8.6 
Unblinding Procedures ................................................................................................ 28 
8.7 
Sample Collection Guidelines ...................................................................................... 29 
8.8 
Assay Methodology...................................................................................................... 29 
8.9 
Specimen Banking ....................................................................................................... 32 
9.0 
STATISTICAL CONSIDERATIONS ...................................................................... 32 
9.1 
Study Design/Study Endpoints .................................................................................... 32 
9.2 
Sample Size and Accrual ............................................................................................. 32 
9.3 
Data Analyses Plans .................................................................................................... 33 
10.0 
STUDY MANAGEMENT ...................................................................................... 34 
10.1 Institutional Review Board (IRB) Approval and Consent ............................................. 34 
10.2 Data Management and Monitoring/Auditing ................................................................ 35 
10.3 Adherence to the Protocol ........................................................................................... 35 
10.4 Amendments to the Protocol ....................................................................................... 35 
10.5 Record Retention ......................................................................................................... 35 
10.6 Obligations of Investigators ......................................................................................... 35 
REFERENCES ................................................................................................................... 36 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 4 of 43 
ABBREVIATIONS 
ACS - Acute coronary syndrome 
ADP - Adenosine-5 diphosphate 
AE - Adverse Event 
ANOVA - Analysis of Variance 
ANCOVA - Analysis of Covariance 
APA - Anti platelet agent 
BMI - Body Mass Index 
CV - Cardiovascular 
CKD - Chronic Kidney Disease 
CKD-ND - Non-dialysis dependent CKD 
CKD-EPI - Chronic Kidney Disease Epidemiology Collaboration 
GFR - Glomerular filtration rate 
IL - Interleukin 
IPA - Inhibition of platelet aggregation 
IRB - Institutional Review Board 
NKF - National Kidney Foundation 
NSAIDs - Non-steroidal anti-inflammatory drugs 
PCI - Percutaneous coronary interventions 
PPIs - Protein pump inhibitors 
PE - Physical examination 
PI - Principal Investigator 
RCT - Randomized Clinical Trial 
RPA - Residual platelet aggregability 
SNPs - Single Nucleotide Polymorphisms 
SD - Standard Deviation 
TNF - Tumor necrosis factor 
TRI - Translational Research Institute 
UAMS - University of Arkansas for Medical Sciences 
UPIRTSO - Unanticipated Problems Involving Risk to Subjects or Others 
WBPA - Whole blood platelet aggregation 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 5 of 43 
1.0 
STUDY SCHEMA 
 
 
 
Study Flow Aim 1: describes the different steps of the study in chronological order for Aim1 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 6 of 43 
 
 
 
Study Flow Aim 2: describes the different steps of the study in chronological order for Aim 2 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 7 of 43 
2.0 
STUDY SUMMARY 
Title 
A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to 
Investigate Altered Platelet Response to Antiplatelet Therapy 
Short Title 
CKD Platelet Study  
Protocol Number 
227997 
Phase 
Phase III 
Methodology 
The study will be conducted in two phases. During the first phase of the 
study, CKD patients will be enrolled and will be randomized in two 
treatment groups (ticagrelor or clopidogrel) in a double blind manner. 
Healthy controls will be enrolled in the second phase of the study; they will 
receive open label study drugs. We want to recruit 20 positive controls from 
the UAMS hospital. 
Study Duration 
2 years and 3 months for subjects’ recruitment. 
2 years for data analysis. Total of 4 years and 3 months 
Study Center(s) 
CKD patients will be enrolled at the University of Arkansas for Medical 
Sciences (UAMS) renal clinic. Healthy controls will be recruited using the 
data from the UAMS Translational Research Institute (TRI) Research 
Participant Registry. We are also planning to recruit CKD and controls from 
Little Rock VA as a second site. Positive controls will be recruited from the 
UAMS hospital. 
Objectives 
Aim 1: Determine the mean changes from baseline in ADP-induced whole-
blood platelet aggregation (WBPA) values and markers of platelet 
activation and inflammation in CKD patients on aspirin who are randomly 
assigned to ticagrelor or clopidogrel in double-blind fashion. Double blind 
randomization. 
Aim 2: Determine the mean changes from baseline in ADP-induced WBPA 
values and markers of platelet activation and inflammation after treatment 
with ticagrelor plus aspirin in chronic kidney disease (CKD) patients 
compared with non-CKD controls. Open label treatment. 
Aim 3: Recruit 20 active controls that are in the hospital who have had a 
heart attack or stroke.  The data from the active controls group will be used 
to exhibit relevance of findings that represent similarities with already 
known abnormalities in positive controls and absence of them in negative 
controls.  
Number of Subjects 
Accrual goal is 81 participants (54 CKD patients and 27 healthy controls) 
and 20 positive controls 
Diagnosis and Main 
Inclusion Criteria 
CKD 4 and 5 subjects: Presence of CKD with an estimated GFR of <30 
mL/min/1.73 m2 for a period of ≥3 months. Not on dialysis 
Healthy Controls: These subjects will have an estimated GFR ≥60 
mL/min/1.73 m2. 
Positive controls will be patients with acute heart attack or acute stroke 
admitted to UAMS. They will not go through the intervention. They will only 
provide blood sample once. 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 8 of 43 
Study Product(s), Dose, 
Route, Regimen 
CKD participants will be double-blind randomized in these two arms: 
Arm 1 - Ticagrelor, 90 mg twice daily (one pill in the morning and one pill 
in the evening) + Aspirin 81 mg/day. Ticagrelor is the test treatment. 
Arm 2 - Clopidogrel, 75 mg/day in the morning and a matching placebo 
in the evening + Aspirin 81 mg/day. Clopidogrel is the reference treatment. 
Participants (Arm1/ Arm2) are required to take the oral treatment for a total 
of two weeks plus one half day. 
Healthy control participants will be asked to take Ticagrelor, 90 mg twice 
daily (one pill in the morning and one pill in the evening) and aspirin 81 
mg/day. Open label treatment. Participants are required to take the oral 
treatment for a total of two weeks plus one half day. 
Positive controls will not be part of the study intervention. 
Duration of administration 
Participants are required to take the daily oral treatment for a total of two 
weeks plus one half day (Exclude positive controls). 
Statistical Methodology 
Aim 1. We will use summary statistics to describe the distribution of the 
data. Post-treatment ADP-induced WBPA value in ohms (Ω) will be the 
primary outcome variable. We will use an analysis of covariance 
(ANCOVA) model to compare the treatment effects of ticagrelor vs. 
clopidogrel in CKD patients because this approach has higher statistical 
power than other methods to analyze drug effects. The primary outcome 
variable will be modeled as the dependent variable. The secondary 
outcome variables, including percentage of inhibition in platelet 
aggregation (IPA), residual platelet aggregability (RPA), adverse events at 
2-weeks, 1, 6 and 12 months will be compared using Chi-square test. For 
the exploratory analyses, we will 1) compare proportions of metabolic 
phenotypes of CYP polymorphisms between groups with Fisher’s exact 
test, 2) correlate WBPA values with cytokines, and drug/metabolite levels, 
and 3) measure two-way interactions between the exploratory markers and 
the study drug on the primary outcome variable. 
Aim 2. Summary statistics will be used to describe data distribution. Two-
sample t-test or Mann-Whitney test will be used to compare markers 
between groups. For the primary outcome, a mixed effects linear model will 
be used to compare mean change in WBPA to therapy between groups. 
The model will have group factor, treatment factor (repeated, pre vs. post), 
and interaction between group and treatment. The pair effect and subject 
effect will be random factors to control for the clustering within matched 
pairs and within each subject. Other confounders except sex and DM will 
be adjusted in the analyses. All available data will be included in the 
analyses; the mixed model can accommodate cases with missing data. 
RPA and adverse events will be compared as Aim 1 as part of the 
secondary outcomes analyses. 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 9 of 43 
3.0 
BACKGROUND AND RATIONALE 
3.1 
Disease Background 
Patients with chronic kidney disease (CKD) are at four-times higher risk of experiencing 
thrombotic cardiovascular (CV) events such as acute coronary syndrome (ACS) than the 
general population, and this risk increases with worsening kidney disease.1-4 As a result, 
one in five of the millions of CKD patients in the U.S. is prescribed aspirin and an oral 
P2Y12 inhibitor (e.g., clopidogrel and ticagrelor) to reduce future events.5,6 Despite 
treatment with clopidogrel, the most commonly used oral P2Y12 inhibitor, patients with 
stages 1–3 and stages 4–5 CKD are at, respectively, two- and four-times higher risk of 
thrombotic CV events or death than individuals without CKD.7,8 Residual platelet 
aggregability (RPA) while on clopidogrel treatment, as determined by mean changes in 
adenosine diphosphate (ADP) induced whole blood platelet aggregation (WBPA) from 
baseline, is a novel modifiable risk factor associated with increased risk for thrombotic CV 
events or death.9,10 Clopidogrel is a prodrug that requires metabolism by cytochrome P450 
(CYP) enzyme to become active.9,10 We reported that a higher proportion of patients with 
stages 4–5 non–dialysis dependent CKD (CKD-ND) demonstrated residual platelet 
aggregability on-clopidogrel treatment than patients without CKD, (56% vs. 8.3%, p=0.01), 
independent of metabolic phenotypes of CYP polymorphisms.11 Our work generated the 
hypothesis that a baseline defect in WBPA may result from advanced kidney disease and 
may not be completely inhibited with a P2Y12 inhibitor. Ticagrelor, a newer oral P2Y12 
inhibitor, is an active drug.12 Recent clinical trials in the general population translated this 
favorable pharmacokinetic difference into greater clinical benefit from ticagrelor than 
clopidogrel by reporting a 15% reduced risk of future thrombotic CV events.12 However, 
use of ticagrelor over clopidogrel in CKD-ND patients raises efficacy concerns despite its 
more favorable pharmacokinetic profile because CKD can alter drug metabolism and its 
interaction with the target receptor.13-15 Previous studies that explored antiplatelet effects 
of ticagrelor in CKD were limited to dialysis patients and suffered from lack of 
randomization or blinding.16-18 Surprisingly, scarce data exist to establish the antiplatelet 
efficacy of ticagrelor and its potential benefit when compared with clopidogrel in CKD-ND 
patients, precisely those at highest risk for thrombotic CV events.19 Clinical practice 
guidelines remain ambiguous about identifying the preferred oral anti platelet agents 
(APAs) for CKD patients but endorse ticagrelor use in “high risk” ACS patients.20,21 As a 
result, ticagrelor use is growing exponentially. It is therefore imperative to establish if 
ticagrelor is able to 1) demonstrate greater antiplatelet effects than clopidogrel in CKD-ND 
patients and 2) inhibit platelet function in CKD-ND as effectively as in non-CKD individuals; 
it is also important to 3) explore mechanisms to explain the poor response to APAs in CKD 
patients. We hypothesize that CKD-ND patients treated with ticagrelor will experience 1) 
greater mean changes in platelet function (i.e., greater platelet inhibition) than when treated 
with clopidogrel, but 2) lesser mean changes in platelet function (lesser platelet inhibition) 
than non-CKD controls treated with ticagrelor. 
 
Advanced kidney disease is a special clinical condition with multiple defects in the 
hemostatic pathway that raise serious concerns about the efficacy of ticagrelor in CKD-ND 
patients.14,22 First, CKD may cause alterations in platelet surface receptors and impair their 
ability to undergo conformational changes upon activation.15 Because ticagrelor binds 
reversibly to a site on the P2Y12 receptor remote from the ADP-binding site and 
subsequently blocks ADP binding to the receptor via allosteric modulation, binding of the 
ligand (ticagrelor) to its receptor (P2Y12) and the resultant allosteric modulation of the 
receptor may be altered in the milieu of kidney disease. Second, ADP-induced platelet 
aggregation may be higher in CKD and may not be completely inhibited by a P2Y12 
inhibitor that acts on this pathway.11 Finally, CKD may alter CYP enzyme function and 
result in lower levels of a drug or its active metabolite in blood.13 For these reasons, the 
differences between ticagrelor and clopidogrel may not translate into clinical benefits in 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 10 of 43 
CKD-ND patients comparable to those reported in the general population. The current 
proposal will fill this knowledge gap by comparing the antiplatelet effects of ticagrelor and 
clopidogrel in a double-blind, parallel-design randomized controlled trial (RCT) involving 
CKD-ND patients (Aim 1). We will also investigate if presence of kidney disease alters 
antiplatelet responses to ticagrelor in CKD-ND patients vs. non-CKD controls (Aim 2 and 
sub-aims). 
 
3.2 
Product Background 
Clopidogrel is a FDA approved drug. Clopidogrel is a prodrug, requiring metabolism by 
cytochrome P450 (especially CYP2C19) to become active (5-thiol metabolite) before 
irreversibly blocking ADP binding to the platelet P2Y12 receptor.23 The requirement for 
multiple steps for a drug to become active may be disadvantageous in CKD because 1) 
genetic polymorphisms in CYP2C19 result in high inter- and intra-individual variability in 
antiplatelet action and 2) CKD may alter the CYP450 system and affect conversion of a 
prodrug to its active metabolite.23,24 Observational studies reported that CKD vs. non-CKD 
patients had residual platelet aggregability, as defined by higher post-treatment platelet 
aggregability, when treated with aspirin plus clopidogrel.11,25-28 Our preliminary studies 
extended these findings and demonstrated in a prospective trial that a higher proportion of 
non–dialysis dependent stages 4–5 CKD (CKD-ND) than non-CKD patients had residual 
platelet aggregability, when treated with aspirin plus clopidogrel (56% vs. 8.3%, p=0.01), 
independent of CYP2C19 polymorphisms. Our work generated the hypothesis that there 
may be a baseline defect in the ADP pathway in advanced kidney disease to potentially 
explain the poor efficacy of P2Y12 inhibitors in CKD-ND patients. 
 
Ticagrelor is a FDA approved drug. Ticagrelor has the most desirable pharmacological 
properties among the oral P2Y12 inhibitors. Ticagrelor and its metabolite AR-C124910XX 
(primarily using the CYP3A4) are active.29,30 The drug reversibly blocks ADP binding to the 
P2Y12 receptor.31 In the general population, this pharmacokinetic difference translates into 
greater antiplatelet effects for ticagrelor than clopidogrel, with reduced inter- and intra-
individual variability.32,33 A recent RCT reported higher efficacy for ticagrelor than 
clopidogrel, each taken together with aspirin, in reducing CV events and mortality.34 
However, these trials excluded CKD-ND patients, precisely those at the highest risk of 
thrombotic CV events. In the subgroup with early-stage CKD (defined as creatinine 
clearance <60 mL/min), use of ticagrelor was associated with a 23% reduction in mortality 
and future CV events.12 This subgroup analysis suggests that ticagrelor may be superior 
to clopidogrel in CKD patients. Recent studies exploring the antiplatelet effects of ticagrelor 
in CKD were limited by lack of controls, high dropout rates, or failure to enroll patients with 
advanced CKD-ND (estimated GFR <30 mL/min/1.73m2). There are no controlled studies 
to compare ticagrelor and clopidogrel in CKD-ND patients. 
 
Clinical practice guidelines emphasize that providers should be aware of treatment 
strategies to choose newer APAs other than clopidogrel when appropriate. However, the 
guidelines remain ambiguous about the preferred APA in CKD-ND patients. Furthermore, 
guidelines endorse the use of the newer P2Y12 inhibitors for percutaneous coronary 
interventions (PCIs) that are “high-risk” procedures. Because PCIs in CKD-ND patients are 
considered high risk, there has been an exponential rise in ticagrelor prescriptions since 
its approval by FDA in 2011. Therefore, the proposed studies are critical to advancing this 
understudied field. A well-designed mechanistic study will be the first step to investigate 
antiplatelet efficacy of ticagrelor in these high-risk patients. 
 
Product safety data in healthy volunteers and CKD patients. In a randomized, open-
label, cross-over, trial conducted by Teng et al. among healthy volunteers comparing 
pharmacokinetic and pharmacodynamics effects of ticagrelor to clopidogrel. Ticagrelor and 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 11 of 43 
clopidogrel with aspirin was well tolerated overall by healthy volunteers. There were no 
serious adverse events or death reported during the study (total duration 34 days, two 10-
day intervention periods interspersed by a washout period of 14 days). There were no 
changes in complete blood count, vital signs or other lab parameters in healthy volunteers 
except increased bleeding time. In addition, following adverse events were reported: 
 
Study drug 
n 
Adverse events 
Outcome 
Ticagrelor 
3 
Moderate epistaxis, 
hematoma, petechaie, 
gingivitis or urticaria 
Discontinued study 
drug 
Ticagrelor 
4 
Headache, petechaie 
Continued study drug 
Clopidogrel 
2 
Nausea and flatulence 
Continued study drug 
 
Similar tolerability and no serious adverse events were noted on ticagrelor in healthy 
volunteers by Husted et al. (Br J Clin Pharmacol 70: 65–77, 2010). The adverse events 
reported in this study by healthy volunteers were as follows: 
 
Study drug 
n 
Adverse events 
Outcome 
Ticagrelor 
4 
Myalgias or gingival 
bleeding 
Continued study drug 
Clopidogrel 
2 
Gingival bleeding 
Continued study drug 
 
Most of the side effects reported in the two studies may be due to: 
1) 
Higher doses of ticagrelor (200 mg twice daily or 300 mg twice daily); 
2) 
Prolonged period of therapy (>14 days); 
3) 
Cross-over design with repeated drug exposure (treat with ticagrelor for 10 days, 
washout period of 14 days and then treat again for 10 days). 
 
Other large RCTs have reported rare side effects for the products as follows: 
 
 
Aspirin may cause some, all or none of the side-effects listed below: 
Common side effects (<10%) of aspirin are ulcers and bleeding of the stomach and 
intestines, which could happen if you are taking aspirin for long time. This study 
requires only 2 weeks’ treatment with aspirin which limits your risk. 
Rare side effects (<1%) are ringing in the ears, breathing problems, swelling and 
allergic problems. Reye’s syndrome (fever, rash, vomiting, headaches and lethargy) 
is also reported, which however, occurs more commonly in children and those with 
a known allergy to aspirin. 
 
 
Clopidogrel may cause some, all or none of the side-effects listed below: 
Common side effects (<10%) of clopidogrel are bleeding that occurs in 3.5-6.1% of 
the patients. Less common side effects are bleeding from stomach in approximately 
2% of the patients and 2.7% of the patients when combined with aspirin. Any 
bleeding requiring hospitalization and blood transfusion occurs in 0.8% of patients 
on clopidogrel. 
Rare side effects of clopidogrel (<1%) are low blood counts (low white cell count, low 
red cell count, low platelets); damage to liver (hepatitis, liver failure), bleeding in 
brain; bleeding in the eyes (0.05%); breathing problems such as pneumonia. 
 
 
Aspirin and clopidogrel have been used together safely in some patients in 
previous studies to reduce risk of heart attack. The risk of bleeding does increase 
minimally as compared to using either drug alone. However, the risk low do to the 
short duration of the treatment (only 2 weeks). 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 12 of 43 
 
 
Ticagrelor may cause some, all or none of the side effects listed below: 
Common side effects of ticagrelor are bleeding from any site that can occur in up to 
4% of patients. Other reported side effects seen >10% of the time is dyspnea (14%). 
Approximately 1–10% of patients may develop ECG abnormality, dizziness, nausea, 
and increases in serum creatinine or serum uric acid levels. 
Rare side effects of ticagrelor (<1%) are angioedema, atrioventricular block, 
bradycardia, gout, hypersensitivity, and skin rash. As ticagrelor has an FDA-required 
boxed warning regarding risk factors for bleeding, we are excluding all those patients 
meeting exclusion criteria. In addition, ticagrelor and clopidogrel are metabolized by 
cytochrome P450 liver enzymes, especially CYP2C19 and CYP3A4. Therefore, we 
are excluding any patients with liver disease to minimize risks of bleeding. Neither 
clopidogrel nor ticagrelor requires renal dosing for low GFR. 
 
Potential major drug-drug interactions of aspirin, clopidogrel or ticagrelor with the 
following drugs: 
• 
Antithrombotic drugs, like Ranolazine, Aggrenox and Cilostazol. Taking these 
medicines with the study drugs could potentially increase risk of bleeding. 
• 
Non-steroidal anti-inflammatory drugs (NSAIDs). These medicines can reduce the 
function of platelets and cause bleeding complications. Subjects will be asked to do 
not take any NSAIDs during the study. 
• 
Medicines for acid reflux called Proton pump inhibitors (PPIs), fish oil, Vitamin E and 
herbal supplements. 
 
Anticipated safety of controls/CKD in our study: Given above reasons, our protocol will 
use safest possible strategy - lower dose for 14 days without cross over. We anticipate 
lower number of adverse events in the healthy volunteers and CKD. 
 
3.3 
Study Rationale 
Of the nearly 13 million patients with chronic kidney disease (CKD) in the U.S., nearly one-
third experience thrombotic cardiovascular (CV) events, such as acute coronary syndrome 
(ACS).4,35-38 Risk of such events rises with advancing kidney failure. Furthermore, the CKD 
population is the fastest growing among chronic diseases, and the number of CKD patients 
undergoing percutaneous coronary interventions (PCIs) has increased by 50% in the last 
decade.4,38 Patients experiencing ACS and/or undergoing PCIs are subsequently 
prescribed the combination of aspirin, 81 mg/day, and an oral P2Y12 inhibitor (e.g., 
clopidogrel, ticagrelor) to reduce future CV events. Currently, at least one in five CKD 
patients is prescribed these drugs. Yet CKD patients continue to have thrombotic CV 
events, such as coronary in-stent thrombosis, despite treatment. 
 
Scientific Premise. Use of clopidogrel plus aspirin became standard of care for patients 
with ACS after the publication of two large randomized, controlled trials (RCTs), which 
excluded patients with advanced CKD and enrolled very few with early-stage CKD. Despite 
treatment with clopidogrel, patients with stages 1–3 and 4–5 CKD are at, respectively, two- 
and four-times higher risk of thrombotic CV events than those without CKD. 7,8,10,39 The 
landmark trials of oral P2Y12 inhibitors systematically excluded CKD-ND patients, 
precisely those who are at a higher risk for thrombotic CV events. Our previous work 
showed that the baseline ADP pathway of platelet aggregation in CKD-ND patients may 
be abnormal. Further, the ADP pathway may not be completely inhibited by clopidogrel, 
possibly due to altered platelet aggregation in advanced CKD. These findings raise 
questions regarding the antiplatelet efficacy of ticagrelor in CKD-ND patients, despite its 
more favorable pharmacokinetic profile than that of clopidogrel, because it targets the 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 13 of 43 
same pathway that may be abnormal in advanced CKD. The current proposal addresses 
these knowledge gaps by comparing the antiplatelet effects of ticagrelor and clopidogrel, 
the most commonly used oral P2Y12 inhibitor, in a double blind, parallel-design RCT 
involving CKD-ND patients (Aim 1). In addition, we will investigate if kidney disease alters 
the antiplatelet response to ticagrelor in CKD-ND patients vs. controls without CKD (Aim 
2). We will also measure the metabolic phenotypes of CYP2C19/CYP3A4 and drug and 
active metabolite levels, using mass spectrometry, to explore mechanisms responsible for 
the poor efficacy of APAs in CKD-ND patients (exploratory aim). 
 
Impact of the proposed study: In summary, the results of this study will be informative 
and move the field forward regardless of whether the hypothesis is proven to be true. 
Completion of the proposed trials will advance the understudied field of platelet dysfunction 
in CKD while elucidating novel mechanisms underlying the poor efficacy of APAs in CKD 
patients. Most important, it will provide urgently needed data to power future, larger trials 
to determine if newer P2Y12 inhibitors are efficacious and will improve outcomes in CKD-
ND patients, a group at disproportionately higher risk than the general population for CV 
events, where traditional risk factor modification interventions have failed to do so. 
 
4.0 
STUDY OBJECTIVES 
4.1 
Aim 1: Determine the mean changes from baseline in ADP-induced whole-blood 
platelet aggregation (WBPA) values and markers of platelet activation and 
inflammation in CKD-ND patients on aspirin who are randomly assigned to ticagrelor 
or clopidogrel in double-blind fashion. 
4.2 
Aim 2: Determine the mean changes from baseline in ADP-induced WBPA values 
and markers of platelet activation and inflammation after treatment with ticagrelor 
plus aspirin in CKD-ND patients compared with non-CKD controls. 
4.3 
Primary Objectives: 
Aim 1: To determine mean changes from baseline in ADP-induced whole blood 
platelet aggregation (WBPA) values and markers of platelet activation in non-
dialysis CKD patients on aspirin who are randomly assigned to ticagrelor or 
clopidogrel in a double-blind fashion. We will randomly assign 54 CKD patients (GFR 
<30 mL/min/1.73m2), stratified by diabetes mellitus presence and treated with aspirin, 81 
mg/day, to receive either ticagrelor, 90 mg twice daily, or clopidogrel, 75 mg/day, and 
placebo, for 2 weeks. WBPA values and P-selectin expression on platelet surface will be 
measured before and after treatment and compared between groups. The post-treatment 
WBPA will be the primary outcome variable. 
 
Aim 2: To determine mean changes from baseline in WBPA values and markers of 
platelet activation and inflammation after treatment with ticagrelor plus aspirin in 
non-dialysis CKD patients compared with non-CKD controls. We will recruit 27 non-
CKD controls (GFR ≥60 mL/min/1.73 m2 and no other evidence of kidney damage). The 
post-treatment WBPA will be the primary outcome variable. 
 
4.4 
Secondary Objectives: 
Aim 1:  
The secondary outcomes will include the proportion with IPA, RPA and 
adverse events (i.e. bleeding, CV events, hospitalizations, and deaths etc.) at 
2 weeks, 30 days, 6 months and 12 months between groups. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 14 of 43 
Sub-aim 1: To investigate mechanisms for WBPA differences between treatment groups, 
we will measure a) the metabolic phenotypes of CYP to analyze interaction 
effects with treatment on changes in WBPA; and b) the drug and metabolite 
levels and the levels of circulating inflammatory cytokines to correlate them 
with changes in WBPA. 
 
Aim 2:  
The secondary outcomes will include the proportion with IPA, RPA and 
adverse events (i.e., bleeding, CV events, hospitalizations, deaths etc.) at 2 
weeks, 30 days, 6 months and 12 months between groups. 
 
Sub-aim 2: To investigate mechanisms for WBPA differences between groups, we will 
measure a) the metabolic phenotypes of CYP to analyze interaction effects 
with treatment on changes in WBPA; b) the drug and metabolite levels and the 
levels of circulating inflammatory cytokines to correlate them with changes in 
WBPA; and c) uremic toxins. 
Aim3: 
Recruit 20 active controls that are in the hospital who have had a heart attack 
or stroke. To compare baseline platelet flow cytometry data from CKD with 
non-CKD controls and positive controls.  
 
5.0 
STUDY POPULATION 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled in the study. Study 
treatment may not begin until a subject is enrolled. 
 
5.1 
Inclusion Criteria for CKD subjects 
• 
Males and females, age-18 years and older 
• 
Non-dialysis CKD patients: Presence of CKD with an estimated GFR of <30 
mL/min/1.73 m2 for a period of ≥3 months, as defined by the National Kidney 
Foundation (NKF) and determined with the CKD-EPI creatinine-based formula 
• 
Ability to understand and sign informed consent after the nature of the study has 
been fully explained 
 
Inclusion Criteria for Healthy Controls 
• 
Males and females, age-18 years and older 
• 
These subjects will have an estimated GFR ≥60 mL/min/1.73 m2 as determined by 
the CKD-EPI creatinine-based formula and a urine albumin-to-creatinine ratio <30 
mg/g as defined by the National Kidney Foundation 
• 
Ability to understand and sign informed consent after the nature of the study has 
been fully explained. 
Inclusion criteria for positive controls for AMI (Sarma et al. Circulation. 2002;105:2166-
2171) 
• 
Patients admitted with ischemic symptoms (for e.g., chest pain) with EKG changes 
and positive troponin within 1 day 
 
Inclusion criteria for positive controls for acute ischemic stroke (Schmalbach et al. 
Cerebrovasc Dis 2015;39:176–180) 
• 
Patients admitted with acute ischemic stroke to blood draw within 1 day 
 
5.2 
Exclusion Criteria for CKD patients and Healthy Control Subjects: 
• 
Inability to sign consent and HIPAA form. Legal Authorized Representatives are not 
allowed to sign the consent form. 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 15 of 43 
• 
Unwillingness or inability to participate in the protocol or comply with any of its 
components. 
• 
Subjects unable or unwilling to stop taking: 
o 
Aspirin and other antithrombotic agents, like cilostazol, ranolazine, aggrenox, 
prasugrel, warfarin, xarelto, pradaxa, eliquis. 
o 
Glycoprotein IIb/IIIa antagonist (abciximab-ReoPro, eptifibatide-Integrilin, 
tirofiban-Aggrastal) 
o 
NSAIDs and PPIs 
o 
Fish oil, Vitamin E and herbal supplements 
• 
Acute kidney injury superimposed on CKD 
• 
Kidney transplant or any other solid organ transplant recipient 
• 
End-stage kidney disease on maintenance dialysis (peritoneal or hemodialysis) 
• 
Nephrotic syndrome defined as nephrotic range proteinuria, hypoalbuminemia, 
hyperlipidemia and generalized edema 
• 
Recent hospitalization or surgery <3 months 
• 
Acute coronary or cerebrovascular event in the last 12 months 
• 
Blood dyscrasias, active bleeding, or bleeding diathesis 
• 
Gastrointestinal bleeding in the last 6 months 
• 
Recent treatment (<30 days) with a glycoprotein IIb/IIIa antagonist (Integrelin). 
• 
Hematocrit <25%, white blood cell count >20,000/μL, or platelet count <50,000/μL 
• 
Any active malignancy or liver disease. 
• 
Pregnancy 
• 
Positive urine pregnancy test in a woman of childbearing potential prior to study 
entry. A female of childbearing potential is any woman who meets the following 
criteria: 
o 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
o 
Has not been naturally postmenopausal for at least 12 consecutive months 
(i.e., has had menses at any time in the preceding 12 consecutive months). 
• 
Patients must not be nursing due to the potential for congenital abnormalities and 
the potential of this regimen to harm nursing infants. 
 
Exclusion criteria for positive controls of AMI (Sarma et al. Circulation. 2002;105:2166-
2171) 
• 
Exclude if CABG of PCI in the last 6 months 
• 
Exclude if receiving any antiplatelet therapy other than aspirin 
 
Exclusion criteria for positive controls of acute stroke (Schmalbach et al. Cerebrovasc Dis 
2015;39:176–180) 
• 
Exclude if intracranial hemorrhage 
• 
Exclude if receiving any antiplatelet therapy other than aspirin 
 
5.3 
Accrual Goal 
Roughly, one in 5 patients with CKD is already on antiplatelet agents; therefore, 4 out of 
every 5 patients will be potential candidates. To complete recruitment of 54 subjects in 13 
months, it is necessary to randomize four subjects over each 4-week interval. If 75% of 
those who are enrolled and sign consent forms come for Visit 1, about 6 subjects need to 
be enrolled/consented every 4 weeks to qualify for randomization. Therefore, nine patients 
will need to be screened every 4 weeks to find six not taking an oral antiplatelet agent. If 
we assume a conservative 50% refusal rate, 18 patients will need to be screened every 4 
weeks (4/week) for four to be randomized. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 16 of 43 
The recruitment goal will be 4–5 controls per month to be completed in 4-6 months. 
Potential healthy control subjects will be contacted using the TRI participant research 
registry (AR research). Less than 10% are expected to respond and come for screening 
visit and meet eligibility criteria for controls. We estimate that nearly 200 contacted potential 
subjects will be identified, of which nearly 10% (i.e., n=20) will be enrolled as controls in 
the study. We will also planning to recruit Veterans from the Little Rock VA as a second 
site.  
 
Positive controls will be recruited from the UAMS hospital. We plan to recruit 20 
consecutive patients who meet inclusion/exclusion criteria. 
5.4 
Recruitment Plan 
Potential participants with CKD stages 4-5 will be enrolled in the study at the UAMS and 
Little Rock VA Renal Clinic targeting new and existing patients. We will speak with the 
possible subjects after their clinical visit with the kidney doctor and will go over the consent 
process and if possible, we will perform the screening visit. A flyer with a brief description 
of the study will be posted in the waiting area and visit room of the UAMS Renal clinic. 
Flyer has been included in the application. 
Healthy control subjects will be recruited using the data from the UAMS TRI Research 
Participant Registry. People recruited through the AR Research website, can choose to be 
contacted by the researchers by e-mail or letter or telephone call. We will contact the 
possible participants in relation to their preference (e-mail, call or letter). The letter, e-mail 
and call scripts have been included in the application. We will include the consent form and 
HIPAA authorization with the recruitment e-mail or mail, in this way the possible 
participants have time to go over a more detailed description of the research study and 
make a better-informed decision during the consent process. Veterans will also be 
approached through Little Rock VA and the details of recruitment activities at Little Rock 
VA are written in VA protocol. 
Study will be advertised on the Translational Research Institute Facebook’s page and on 
UAMS social media accounts to increase enrollment. 
The message and graphic that will be posted in social media is included in the submission. 
 
 
 
We will recruit positive controls as quickly as possible depending on the admissions on a 
given weekday.  
5.5 
Participant Compensation 
Visit 1 (Screening visit) 
We will not conduct in-person screening visit for controls due to COVID-19 pandemic. The 
CKD subjects will be performed either after their clinical appointment with the renal doctors 
or on telephone to minimize contact. Both healthy control and CKD subjects will not receive 
a compensation for the screening visit.  
 
Visit 2 (Baseline visit). For all participants: 
At the end of this visit, the subjects will receive a Walmart gift card for a value of $25. We 
will also validate the UAMS parking ticket. 
 
Visit 3 (Last visit). For all participants: 
At the end of this visit, the participant will receive a Walmart gift card for a value of $100. 
Moreover, we will validate the UAMS parking ticket. 
 
The participants that withdraw or are removed from the study will not receive gift cards for 
visits that they do not attend. We will give the Walmart gift card at the end of each visit and 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 17 of 43 
if the subject does not come to the scheduled visit, we will not give the subject 
compensation for that specific visit. All information concerning payment (amount, schedule 
and type of payment) will be discussed in the informed consent document. Receipts of the 
payment will be stored with the consent process note. 
 
Positive controls will have only one visit for blood draw. They will be given $50 Walmart gift 
card after completing blood draw. 
 
6.0 
INVESTIGATIONAL PRODUCT 
6.1 
Study Drugs 
Clopidogrel is a FDA approved drug. Clopidogrel is a prodrug, requiring metabolism by 
cytochrome P450 (especially CYP2C19) to become active (5-thiol metabolite) before 
irreversibly blocking ADP binding to the platelet P2Y12 receptor. 
 
Ticagrelor is a FDA approved drug. Ticagrelor has the most desirable pharmacological 
properties among the oral P2Y12 inhibitors. Ticagrelor and its metabolite AR-C124910XX 
(primarily using the CYP3A4) are active. The drug reversibly blocks ADP binding to the 
P2Y12 receptor. In the general population, this pharmacokinetic difference translates into 
greater antiplatelet effects for ticagrelor than clopidogrel, with reduced inter- and intra-
individual variability. 
 
6.1.1 
Dispensing 
For CKD subjects: Ticagrelor/clopidogrel/placebo will be dispensed by the UAMS 
investigational pharmacy in a double-blind manner using blister pack with morning 
(AM) and evening (PM) dosing labels. Each subject will receive open label aspirin 
in the same blister pack labeled AM. The blister pack will be labeled appropriately 
with subject ID, IRB number for the study protocol. UAMS research pharmacy will 
put the blister package in a specific second container reporting the administration 
instructions for the participant. The study drugs will be dispensed for 14 days plus 
one extra day, for a total of 15 days. 
 
The research staff will pick up the study drug from the research pharmacy. Dr Jain 
or other research staff member with clinical background (doctors or nurses) will 
give the study drugs to the participant. At the end of the treatment, left over pills 
will be returned to the research pharmacy for destruction. 
 
For Control subjects: Ticagrelor and aspirin will be dispensed by the UAMS 
investigational pharmacy in an open label fashion. The blister pack will be labeled 
appropriately with subject ID, IRB number for the study protocol and the 
instructions for the subjects. The study drugs will be dispensed for 14 days plus 
one extra day for a total of 15 days. The research personnel will pick up the study 
drugs from the research pharmacy and will return the left over pills after last visit 
to the research pharmacy for destruction. 
 
Positive controls will not be part of the intervention study. 
 
6.1.2 
Treatment Compliance 
Treatment compliance will be determined by asking the participants to bring the 
blister pack of the study drugs to the final visit. We will perform pill count to ensure 
adherence. Based on the remaining pills, we will calculate proportion of days the 
study drug was not taken by a subject and record it as non-adherence in 
percentage. Moreover, during the mid-treatment phone call we will ask the 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 18 of 43 
participants the pill count consumed. Pill non-adherence is defined as the ingestion 
of <80% or >110% of study drug recorded during Visit 3. Reasons for 
noncompliance will be sought and recorded, and subjects who are noncompliant 
with pills or visits will be counseled and reeducated about the importance of 
compliance and will also receive additional telephone calls to remind them about 
compliance between visit 2 and visit 3.  
 
6.2 
Treatment Dosage and Administration 
Intervention for CKD Participants. Randomization, Blinding and Intervention Aim 1. 
Stratified randomization will be used to ensure the balance between two treatments in the 
strata defined by diabetic status. All eligible CKD patients who provide written informed 
consent will be classified into a particular stratum (diabetics or non-diabetics) and then 
randomized in double-blind fashion to receive either 2 weeks of ticagrelor (90 mg twice 
daily) or clopidogrel (75 mg/day in the morning, plus a matching placebo once daily at 
night) in a 1:1 ratio. To minimize imbalance in treatment allocation and to maximize power, 
a computerized random number generator will be used to create a blocked randomization 
list separately for diabetic and non-diabetic strata. Block size, variable for each stratum, 
will be determined by the statistician and revealed to the research pharmacist but not to 
the research personnel. 
 
Matching placebo will be compacted by the research pharmacist to conceal frequency of 
dosing for clopidogrel. All study pills will be placed in larger identical capsules in blister 
pack (labeled AM and PM) to conceal allocation and frequency of dosing. 
 
The research pharmacist will randomize all eligible CKD participants in a double-blind 
fashion way in two arms: 
• 
Ticagrelor 90 mg twice daily + Aspirin 81 mg once daily 
• 
Clopidogrel (75 mg once daily) + placebo once daily + Aspirin 81 mg once daily 
 
 
Intervention for Healthy Control Participants. Open Label Intervention - Aim 2 
Overall, healthy controls will be recruited to match 1:1 for age and sex with subjects in 
the Ticagrelor arm. No randomization will be performed for the healthy controls subjects. 
We want to improve the pace of enrollment in the study as it is a two-year grant and the 
funds expire in June 2021 after getting NCE. With this in mind, we want to start enrolling 
controls concurrent to CKD patients. We will keep track of average age of recruited CKD 
subjects and proportion of males enrolled in the CKD arm. This will allow us to recruit 
some controls with similar average age and sex. We feel confident that this strategy will 
be able to match subjects with CKD to controls without CKD for age and sex in the end 
when the trial concludes.  
UAMS research pharmacist will provide ticagrelor and aspirin for the healthy control 
participants. We will enroll healthy controls in this open-label study together with the CKD’s 
recruitment for Aim 1.  
 
Healthy control participants will be asked to take ticagrelor, 90 mg twice daily (one pill in 
the morning and one pill in the evening) and aspirin 81 mg/day. Participants are required 
to take the oral treatment for a total of two weeks plus one half day. 
 
All subjects will be asked to take the specific oral treatment daily for a total of 2 weeks plus 
one half day as instructed. 
 
Regiment Description 
Agent 
Dose 
Route 
Schedule 
Cycle Length  

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 19 of 43 
Ticagrelor 
90 mg  
Oral 
AM and PM 
2 weeks (14 
days) 
 
Clopidogrel 
75 mg 
Oral 
AM 
Placebo (to 
conceal frequency 
of clopidogrel 
dosing) 
-- 
Oral 
PM 
Aspirin 
81 mg 
Oral 
AM 
 
6.3 
Concomitant Medications/Treatments 
As reported in the exclusion criteria, subjects will not be included in the study if: 
• 
Concomitant use of antiplatelet agents other than aspirin or antithrombotic agents 
• 
Recent treatment (<30 days) with a glycoprotein IIb/IIIa antagonist 
• 
Unwilling to stop NSAIDs, PPIs, Aspirin (if they are taking it for primary CV 
prevention), Fish oil, Vitamin E and herbal supplements 
 
6.4 
Duration of Therapy 
Treatment is to continue for two weeks plus one half day or until: 
• 
Inter-current illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s). Any adverse event attributed to blinded study drug 
that in the opinion of the PIs would obviate the reinstitution of drug, such as bleeding 
requiring hospitalization or transfusion 
• 
Patient decides to withdraw from the study 
• 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• 
Pregnancy 
 
Each stopping point will be documented and the participant notified to discontinue and 
return study drugs. The participant will be scheduled for a close-out visit to arrange follow-
up with his or her personal physician as indicated. A stopping point will be reported to the 
IRBs not more than 5 working days after the study staff becomes aware of the problem. If 
the stopping point is a serious adverse event, it will be reported within 2 working days. 
 
Data Safety and Monitoring Plan 
Routine data reports will be provided by the PIs to the IRB every 6 months and will include 
laboratory data and clinical data on study drug side effects. Non-routine data reports will 
be provided as needed and include data on serious adverse events, stop points, unblinding 
episodes, pill non-adherence, and loss to follow-up. The PIs will report any serious adverse 
events to the IRBs not more than 2 working days after study staff become aware of the 
event, and unanticipated problems will be reported not more than 5 working days after 
study staff become aware of the problem. We have included a medical monitor, Dr. 
Karakala, as part of the protocol. He will be responsible for monitoring of serious adverse 
events and to identify safety concerns during the study. 
 
6.5 
Duration of Follow Up 
Telephone follow up will occur at 30-days, 6-months and 12-months post randomization to 
obtain information about patients’ health. Specifically, we will collect discharge summaries 
for any hospitalizations, procedure notes/operative notes for any procedures that may 
occur or death summary for any death that may occur during follow up. If there are any 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 20 of 43 
unexplained adverse events, UAMS electronic medical records will be reviewed or records 
of non-UAMS care will be obtained to report adverse events by the research personnel. 
The medical records that will be reviewed and/or requested are related to hospitalization 
and/or procedure that can be associated to study-related adverse events. Data will be 
collected over the course of 12 months following enrollment. 
The telephone script is included in the application. 
 
Positive controls will not be followed with phone calls. 
 
6.6 
Removal of Patients from Protocol Therapy 
Stopping Points. All potential stopping points will be reviewed by the PIs prior to 
designation. A subject can leave the trial or be withdrawn if any one of the following occurs: 
 
1) 
Any adverse event attributed to blinded study drug that in the opinion of the PIs would 
obviate the reinstitution of drug, such as bleeding requiring hospitalization or 
transfusion. 
2) 
Intolerable side effects and the subject decides to withdraw. 
3) 
Pregnancy. 
4) 
The subject is unwilling or unable to continue with study protocol and procedures. 
 
Each stopping point will be documented and the participant notified to discontinue and 
return study drug. The participant will be scheduled for a close-out visit to arrange follow-
up with his or her personal physician as indicated. A stopping point will be reported to the 
IRBs not more than 5 working days after the study staff becomes aware of the problem. If 
the stopping point is a serious adverse event, it will be reported not more than 2 working 
days afterward. 
 
7.0 
STUDY PROCEDURES 
7.1 
VISIT 1 (Consent Process and Screening Procedures) 
7.1.1 
Informed Consent (for all subjects) 
CKD subjects. The medical records of patients will be reviewed to evaluate if they are 
eligible to be part of the study. For subjects enrolled in the study, assessments performed 
for clinical indications (not exclusively to determine study eligibility) may be used for 
baseline values even if the assessments were done before informed consent was obtained. 
Research staff will go over the consent process with the potential CKD subject after their 
clinical appointment at the renal clinic. If the subject does not have enough time to go over 
the consent process, but he/she is interested in our study, we will provide the subject with 
a printed copy of the ICF and we will perform the consent process on the phone. 
 
Healthy control subjects. To minimize contact with potential subjects (COVID-19 
pandemic), the consent process and screening questionnaire will be performed on the 
phone. After the phone conversation, research staff will e-mail the consent form to the 
potential subject for review and inform the subjects that a printed copy of the consent form 
will be provided during the baseline visit for signature. Moreover, subject will be informed 
that during baseline we evaluate their kidney functionality to determine eligibility (blood 
draw and urine collection). 
 
Phone consent process will be documented in the process note. Signed consent form will 
be obtained from each subjects enrolled in the study during the screening and/or baseline 
visit. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 21 of 43 
7.1.2 
Eligibility Questionnaires 
CKD subjects. We will ask permission to collect data related from UAMS medical 
records. This will avoid an extra blood draw. We will collect: 
 
• 
Laboratory data: Comprehensive metabolic panel. Complete blood count, 
Serum phosphate levels, Urine albumin to creatinine ratio, serum uric acid 
level. 
• 
Clinical data: Vital signs, body mass index. 
• 
Demographic data: age; gender; race; ethnicity. 
• 
Medical history: 
o 
Diabetes mellitus (defined as a fasting blood glucose level ≥126 mg/dL 
and/or use of hypoglycemic agents); 
o 
Hyperlipidemia (defined by use of lipid-lowering agents, or total 
cholesterol level ≥ 240 mg/dL or a serum LDL level ≥160 mg/dL); 
o 
Hypertension (defined as four office blood pressure readings 
averaging ≥140/90 mm Hg and/or use of antihypertensive drugs); 
o 
Current smoking (defined as any cigarette smoking in the past 30 
days) status will be recorded as data. Smoking status is not an 
exclusion criterion. 
o 
Nephrotic syndrome (spot urine protein-to-creatinine ratio >3, serum 
albumin concentration <3 g/dl, serum total cholesterol >200 mg/dl and 
generalized edema). 
• 
Medication in use (aspirin, clopidogrel, warfarin, prasugrel, beta-blockers, 
proton pump inhibitors, calcium antagonist, nitrates and statins). 
Pregnancy test. Performed at screening visit for CKD subjects. 
In a female of childbearing potential, perform urine pregnancy test. The test must 
be negative for subject to be eligible for inclusion. Research staff will perform the 
pregnancy test in the urine sample collected by the subject. Results of the 
pregnancy test will be recorded in the consent process note. 
CKD and Healthy Control Subjects will be asked to complete the following 
questionnaires: 
• 
Concomitant Medication Form (see questionnaire 1) 
• 
Demographic Form (see questionnaire 2) 
• 
Past Medical History Form (see questionnaire 3) 
• 
COVID-19 questionnaire 
Healthy control subjects will complete the questionnaires on the phone. 
All the subjects will be asked to schedule an in person visit “Visit 2 –Baseline”. 
Washout Period. Subjects will be asked to: 
 
• 
Stop taking for two weeks the following drug/supplement: 
o 
Aspirin (if they are taking it) for primary CV prevention 
o 
Vitamin E and herbal supplements 
o 
Nonsteroidal anti-inflammatory drugs 
o 
Fish oil 
o 
Proton pump inhibitors 
• 
Stop drinking alcohol 12 hours before each visit 
• 
Do not eat or smoke for at least 6 hours before the blood test during Visit 2. 
 
If the subject is taking aspirin, the baseline visit can be scheduled only after the washout 
period (plus 7 days). For the subjects that are not taking aspirin before the study, the 
baseline visit will be scheduled any time after the screening visit as specified also in the 
baseline section of the protocol. 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 22 of 43 
We will send to all the subject an e-mail or mail with instruction for the baseline visit, date, 
time of the visit and the location of the Visit 2. E-mail and mail script included in this 
application. 
 
Eligibility of healthy control will be determined only after baseline visit. 
 
Positive controls will sign consent after meeting inclusion/exclusion criteria. The research staff will ask the 
patient questions about their medical history, social history, physical history, and the medications that they 
are currently taking. The Stanford 7-Day Physical Activity Recall questionnaire will be used to assess the 
patient’s physical activity. 
Visit 2 – Baseline Visit (for all subjects) 
Baseline Visit 2 will be scheduled 2 weeks (+7 days) from the screening Visit 1. In case an 
eligible subject is not taking aspirin we will schedule visit 2 without the washout period. 
These participants do not need to wait for 2 weeks (+7 days) before the baseline visit 2. 
The Baseline Visit 2 can be scheduled any time after the screening visit for those subjects 
that are not taking aspirin before being in the research study. 
If an eligible subject is taking the following: 
• 
Vitamin E and herbal supplements 
• 
Nonsteroidal anti-inflammatory drugs 
• 
Fish oil 
• 
Proton pump inhibitors 
The baseline visit can be scheduled any time after the screening visit. 
 
If the participant is not eligible, research staff will contact the subject by phone and notify 
that he/she is not eligible to be part of the study. 
 
7.1.3 
Medical History 
• 
Review any medical problems since the screening visit. 
• 
We will also ask questions in order to perform COVID-19 screening if the 
last screening was done 2 weeks ago. 
 
 
7.1.4 
Review of medication in use 
Record any concomitant medication. Confirm that the subject has not taken in the 
past 2 weeks any of the following drugs: 
• 
Aspirin (if they are taking it) for primary CV prevention 
• 
Vitamin E and herbal supplements 
• 
Nonsteroidal anti-inflammatory drugs 
• 
Fish oil 
• 
Proton pump inhibitors 
 
Confirm that the subject stopped eating and smoking at least 6 hours before the 
visit and stopped drinking alcohol 12 hours before the visit. 
 
Record any symptoms occurred since the screening visit. 
 
7.1.5 
Diet and Physical Activity Questionnaire 
An interviewer-administered assessment of diet and exercise with a modified 24-
hour Dietary Recall Questionnaire and the Stanford 7-Day Physical Activity Recall 
Questionnaire will be performed to ensure dietary consistency which may affect 
platelet aggregability. Questionnaire forms included in the application. 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 23 of 43 
 
7.1.6 
Blood draw and urine collection  
For all subjects_ seven blood tubes will be drawn from trained staff members (total 
of 40 ml of blood). Blood will be used to evaluate: 
• 
Complete blood count (CBC). UAMS Clinical Lab. 
• 
Uric Acid, creatinine and lipid panel. UAMS Clinical Lab 
• 
Comprehensive Metabolic panel. UAMS Clinical Lab. 
• 
Complete Blood Count. UAMS Clinical Lab. 
• 
Serum phosphate. UAMS Clinical Lab. 
• 
Serum uric acid level. UAMS Clinical Lab. 
• 
HbA1c. UAMS Clinical Lab. 
• 
Levels of circulating cytokines including, but not limited to interleukin-1beta, 
IL-6, TNF-alpha 
• 
WBPA 
• 
Circulating drug/metabolites 
• 
DNA extraction and analyze of polymorphisms in relevant SNPs. 
: 
Moreover, subjects will be provided with a sterile urine collection cup by the 
research staff. Urine collected will be send to UAMS lab for evaluation of kidney 
functionality. Part of the same urine sample will be used for pregnancy test in 
woman of childbearing age (as described below). 
 
For all subjects, blood draw need to be done in fasting condition. Participants will 
be instructed by research staff to not eat and smoke for at least 6 hours and to 
avoid alcoholic beverage 12 hours before the blood test. 
 
 
7.1.7 
Pregnancy test. Performed at baseline visit for healthy control and CKD patients 
if necessary.. 
In a female of childbearing potential, perform urine pregnancy test. The test must 
be negative for subject to be eligible for inclusion. Research staff will perform the 
pregnancy test in the urine sample collected by the subject. Results of the 
pregnancy test will be recorded in the consent process note. 
 
 
7.1.8 
Double blind randomization for CKD 
CKD participants will be randomized by a research pharmacist in a double-blind 
fashion way in two arms: 
• 
Ticagrelor 90 mg twice daily (AM and PM) + Aspirin 81 mg once daily (AM) 
• 
Clopidogrel 75 mg once daily (AM) + placebo once daily (PM) + Aspirin 81 
mg once daily (AM) 
7.1.9 
Open label for healthy control: 
Recruitment of healthy controls will start together with the recruitment for CKD 
subjects. Healthy control participants will receive: 
• 
Ticagrelor 90 mg twice daily (AM and PM) + Aspirin 81 mg once daily (AM) 
 
Intervention for healthy controls will be open-label. Control subjects will be 
recruited matching 1:1 for age and sex the CKD subjects in the ticagrelor arm. 
 
At the end of the baseline-Visit 2, clinical research staff will provide the participant 
with the appropriate drug to cover the 2 weeks treatment period. 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 24 of 43 
 
In summary for both CKD and healthy controls, each subject will take the study 
drugs for 14 days at home and they will come for the last visit on the 15th day in 
the morning. During the last visit, we will ask the subject to take one more morning 
dose of the study drugs (15th day) as shown in the table below: 
 
 
 
 
7.1.10 Healthy control subjects eligibility 
If the subject is eligible, research staff will contact the subject to inform them 
about their eligibility and to start taking the study drugs as instructed during the 
baseline visit.  
If the subject is not eligible, research staff will contact the subject by phone and 
notify that he/she is not eligible to be part of the study. If the participant’s lab test 
results show abnormal values, the subject will be provided with the lab test results 
and he/she will be asked to discuss about the results with his/her primary 
physician. We will instruct the not-eligible subject to return the study drug to the 
research staff. 
7.1.11 Instruction to subjects about last visit 
Instruct subjects that they need to take the last dose of prescribed research drug 
during the last visit-Visit 3. Describe procedures that are going to happen during 
the last visit. Remind the subjects to collect the empty pill pocket and bring them 
back to the last visit as a proof of the total number of pills they had. 
 
7.2 
Mid-Treatment Telephone Call (7-10 days after Baseline-Visit 2): 
• 
Record when subject started taking the study treatment; 
• 
Record any adverse event; 
• 
Make sure that the participant did not take any of the following: 
o 
Vitamin E and herbal supplements 
o 
Nonsteroidal anti-inflammatory drugs 
o 
Fish oil 
o 
Proton pump inhibitors 
• 
Schedule the date for the last visit-Visit 3 in relation to when they started taking the 
study drugs. We will send to the subject an e-mail or mail regarding date, time of the 
visit and the location of the last visit-Visit 3. E-mail and mail script are included in this 
application. 
• 
Remind the subject to: 
o 
Stop eating and smoking at least 6 hours before the last visit-Visit 3; 
o 
Stop drinking alcoholic beverages 12 hours before the last visit-Visit 3; 
o 
Bring back the pill pocket (empty/used/not used) at the last visit-Visit 3; 
• 
Remind the participant that the last pill must be taken during the last visit-Visit 3. 
• 
Record the number of pills taken by participant since the start of the treatment. 
 
7.3 
Visit 3 (Last visit)  
7.3.1 
Physical exam will be performed only on the last visit 
Vital signs (temperature and blood pressure), height and weight 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 25 of 43 
 
7.3.2 
Review of medication in use 
Record any concomitant medication. Confirm that the subject has not taken the 
following drugs: 
• 
Vitamin E and herbal supplements 
• 
Nonsteroidal anti-inflammatory drugs 
• 
Fish oil 
• 
Proton pump inhibitors 
 
Confirm that the subject stopped eating and smoking 6 hours before the visit and 
stopped drinking any alcoholic beverage 12 hours before the visit. 
 
7.3.3 
Record any adverse events that occurred 
7.3.4 
Pill count to verify compliance with the study. In order to verify compliance, 
participants are requested to bring back the used study drug containers at 
the last visit 
7.3.5 
Blood draw 
• 
Time point 0: Draw seven tubes of blood (about 42 ml) by peripheral 
venipuncture. 
• 
Time point 1: Subjects will be asked to take the last dose of prescribed drug 
• 
Time point 2: After 3 hours from taking the last dose of prescribed research 
drug, we will draw two tubes of blood (about 12 ml) by peripheral 
venipuncture 
 
Blood collected at time point 0 will be used to evaluate: 
• 
Complete blood count (CBC), serum creatinine and serum uric acid. UAMS 
lab will evaluate them 
• 
Levels of circulating cytokines including, but not limited to interleukin-1beta, 
IL-6, TNF-alpha 
• 
WBPA 
• 
Drug/metabolite. 
 
Blood collected at time point 2 will be used to evaluate drug/metabolite. 
7.3.6 
Diet and Physical Activity Questionnaire will not be collected on this visit 
 
7.4 
Follow Up Calls 
Follow up calls will be done 4 weeks (±3 days), 26 weeks (±3 days) and 52 weeks (±3 
days) after the baseline visit (Visit 2). At each phone call we will ask the participant about 
any hospitalization, any procedure related to heart and blood vessels a stroke. If so, we 
will ask date and location of hospitalization and/or procedures. The medical records that 
will be reviewed and/or requested are related to hospitalization and/or procedure that can 
be associated to study-related adverse events. Data will be collected over the course of 12 
months following enrollment. 
 
7.5 
Schedule of Events 
The following table reports steps during different visits and follow up calls: 
 
 
Screening 
Treatment 
Follow up 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 26 of 43 
Weeks 
0 
2 
3 
4 
6 
28 
54 
Visit 
Visit 1 
Baseline 
V2 
Mid-
Treatment 
phone call 
Last 
Visit 3 
Phone 
call 1 
Phone 
call 2 
Phone 
call 3 
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
 
 
 
 
 
Vital Sign 
 
 
 
X 
 
 
 
History, medication 
review  
X 
X 
X 
X 
 
 
 
Diet and Physical 
Activity Questionnaire 
 
X 
 
 
 
 
 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Blood draw 
 
X 
 
X 
 
 
 
Urine collection 
 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Pill Count 
 
 
 
X 
 
 
 
Schedule of events table: Follow up calls will be done 4 weeks (±3 days), 26 weeks (±3 days) 
and 52 weeks (±3 days) after the baseline visit (Visit 2). 
7.6 
Removal of Subjects from the Study 
Patients can be taken off the study treatment and/or study at any time at their own request, 
or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation will be documented and may 
include: 
• 
Patient voluntarily withdraws from treatment (follow-up permitted);  
• 
Patient withdraws consent (termination of treatment and follow-up); 
• 
Patient is unable to comply with protocol requirements; 
• 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
• 
Treating physician judges that continuation on the study would not be in the patient’s 
best interest; 
• 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
 
8.0 
ADVERSE EVENTS 
8.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. Additionally, certain adverse events must be 
reported in an expedited manner to allow for optimal monitoring of subject’s safety and 
care. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 27 of 43 
8.3 
Definitions 
8.3.1 
Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention. 
 
In this study, we will monitor adverse events from the changes in blood laboratory 
parameters as recorded in the lab test from the final lab draw or other patient 
reported events. We will call each subject after 7-10 days from the baseline visit in 
order to verify any adverse event recorded during the first part of the treatment. 
 
8.3.2 
Severity of Adverse Events 
The severity of adverse events will be graded as follows 
Mild: 
the event causes discomfort without disruption of normal daily 
activities. 
Moderate: the event causes discomfort that affects normal daily activities. 
Severe: 
the event makes the patient unable to perform normal daily activities 
or significantly affects his/her clinical status. 
 
8.3.3 
Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that meets one or more of the following criteria: 
 
8.3.3.1 Results in death. 
 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
8.3.3.2 Is life-threatening (the patient was at risk of death at the time of the event; 
it does not refer to an event that hypothetically might have caused death 
if it were more severe). 
 
8.3.3.3 Requires 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization for ≥ 24 hours. 
 
8.3.3.4 Results in persistent or significant disability or incapacity 
 
8.3.3.5 Is a congenital anomaly/birth defect 
 
8.3.3.6 Is an important medical event 
 
8.3.3.7 Any event that does not meet the above criteria, but that in the judgment 
of the investigator jeopardizes the patient, may be considered for reporting 
as a serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of 
“Serious Adverse Event“. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 28 of 43 
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
8.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the adverse event. 
 
Step 2: Determine whether the adverse event is related to the protocol therapy. 
 
Attribution categories are as follows: 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Step 3: Determine the prior experience of the adverse event. 
 
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in the current known adverse events. 
 
Step 4: Determine whether the adverse event is a Serious Adverse Event 
 
8.5 
Reporting Requirements for Adverse Events 
8.5.1 
Expedited Reporting 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study. 
 
The IRB must be notified within 10 business days of any Unanticipated Problems 
Involving Risk to Subjects or Others” (UPIRTSO). A UPIRTSO is defined as any 
problem, event or new information that is: 
1) 
Unanticipated or unexpected; 
2) 
Related to the research; and 
3) 
Involves new or increased risks to subjects or others. 
 
8.5.2 
Routine Reporting 
All other adverse events - such as those that are expected, or are unlikely or 
definitely not related to the study participation - are to be reported annually as part 
of regular data submission. 
 
8.6 
Unblinding Procedures 
While the safety of the subject always comes first, it is still important to seriously consider 
if unblinding the study therapy is necessary to ensure a subject’s safety. In most cases, 
the unblinding will be part of managing an SAE, and will be reported with the SAE, however, 
in cases where unblinding was not associated with an SAE, such actions should be 
reported in a timely manner. While there is no regulation governing this timeline, it is 
suggested to use the same timeline requirements for investigator reporting of SAEs. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 29 of 43 
8.7 
Sample Collection Guidelines 
Samples from participants will be handled, processed by research staff members. The 
blood tubes and the urine containers will be labeled with the unique study number 
corresponding to the subject and they will be stored in a double container with ice until the 
end of the collection period. 
 
Blood and urine samples from participants will be transported by authorized and trained 
staff members to the UAMS Biomedical Building II (Bio-Med II) in Dr. Arthur’s laboratory 
(room #638-2) where they will be processed for long-term storage. The samples will be 
transported to the Bio-Med II building using a double container system that will be labeled 
as Biohazard container. Bio-Med II building can be accessed only by authorized personal 
using an access card. The freezer is locked and the key will be stored in a separate locked 
room. 
 
Blood and urine samples from participants will be centrifuged, and will be aliquoted in 
cryovials for long-term storage at -80°C. Each cryovial will be labeled only with the unique 
study number. De-identified DNA extracted from blood sample will be frozen banked in Dr. 
Arthur’s laboratory (room #638-2) and analyzed at the Pharmacogenomics Lab VA Little 
Rock (G-128). VA sub-award with scope of work is included in this amendment. 
 
Only authorized staff members will be able to access the protected file that associates the 
assigned unique study number to the identifiers of the participant. 
 
8.8 
Assay Methodology 
WBPA. Ten mL of whole blood will be collected in 3.2% sodium citrate (9:1 ratio) for platelet 
aggregation test by ex vivo whole blood impedance (WB) platelet aggregometry via a 
Chrono-log aggregometer. This instrument uses electrical impedance in whole blood. 
Blood from all subjects will be tested within 3 hours of collection at Dr. Jerry Ware Platelet 
laboratory at UAMS BioMed II building, 2nd floor. Whole blood platelet aggregation induced 
by 2 μg/ml collagen, 10 and 20 μM ADP, 0.5 and 0.25 mM arachidonic acid, thrombin and 
ristocetin will be tested. 
 
Rationale for using whole blood aggregometry: This is a method developed 20 years after 
the first aggregation test used in laboratory practice to assess platelet function involving 
platelet rich plasma. This method is superior to optical method: a) it is more sensitive and 
faster; b) evaluates platelets in physiological milieu in the presence of red blood cells and 
white blood cells known to affect platelet function and; c) does not require centrifugation 
which results in some platelet injury. The specimen is placed in a plastic cuvette containing 
magnetic stir bar. It is incubated at 37 degree Celsius for 5 minutes in wells prior to testing. 
An AC voltage in millivolt range is applied to the circuit, which creates stable resistance 
value during equilibrium with the formation of monolayer of platelets covering wires. After 
introducing agonists, platelets aggregate, which increases resistance to electrical flow, 
measured in ohms. ATP secretion is measured using firefly luciferin-luciferase reaction. 
Whole blood platelet aggregometry method allows larger platelets to be present and can 
potentially use thrombocytopenic samples and icteric/lipemic/hemolyzed samples. 
Previous studies have used optical aggregometry or multi-plate analyzers and Platelet 
Function Analyzer (PFA)-100 which are sub-optimal for testing and the results may not be 
reproducible. 
 
P-selectin by Flow Cytometry: Whole citrate blood will be fixed and mixed with antibodies 
(BD Biosciences) to measure P-selectin expression on the platelet surface by flow 
cytometry (UAMS Flow Cytometry Core Facility). P-selectin (CD62P) is a membrane 
glycoprotein stored in platelet granules. Upon platelet activation, granules are released, 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 30 of 43 
and P-selectin is expressed on the platelet surface. P-selectin by flow cytometry is a classic 
and specific marker of platelet activation. 
 
Cytokines analyses: Plasma will be frozen at –80 °C. Levels of circulating cytokines will be 
measured on batched frozen samples by Proteome Profiler Human Cytokine Array kit (R 
& D Systems, Catalog # ARY005B). Since studies investigating mechanisms of platelet 
aggregability in CKD patients are limited, and to not limit our inquiry to just a few cytokines, 
we are using a commercial cytokine array kit that detects 36 human circulating cytokines, 
chemokines and acute phase reactants simultaneously. It includes, but is not limited to, 
plasma interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. 
 
Rationale for Using Multiplex Cytokine Array: Platelet activation is linked to inflammation. 
Typical measures of inflammation are plasma IL-1β, IL-6 and TNF-α levels. Although P2Ys 
reduce levels of circulating cytokines in the general population,40 these changes have not 
been evaluated in the CKD population. Furthermore, some of the circulating cytokines, 
especially, IL-6 and TNF-α were implicated in decreasing metabolism of certain drugs in 
CKD patients.41 Finally, IL-6 and TNF-α were reported to be predictors of CV events in non-
dialysis CKD patients42,43 but it remains unclear if these cytokines and other unknown 
cytokines explain the poor efficacy of P2Ys in this high risk patient population. Therefore 
we decided to use the multiplex kit. 
 
Drug and metabolite levels: We will measure the trough- and peak- drug/metabolite levels 
by multiple reaction monitoring. Due to the highly reactive nature of the active thiol 
metabolite of clopidogrel, it cannot be reliably measured. We will instead measure both the 
intact drug and the inactive carboxylic acid metabolite (Figure 1). A mixed mode solid 
phase extraction (SPE) plate will be used for processing the plasma samples. Briefly, the 
plasma samples will be diluted in an aqueous buffer and loaded onto the SPE well-plate 
and washed with a water methanol solution, and finally eluted with 5% NH4OH in 60:40 
IPA:ACN. The intact clopidogrel will be measured by monitoring the 322 to 212 transition 
and its carboxylic acid metabolite will use the 308 to 198 transition, both in the positive ion 
mode.60 These will be measured using a Thermo Scientific Quantiva triple quadrupole 
mass spectrometer that is coupled to a Waters nanoAcquity UPLC. The system will operate 
at a flow rate of 50 ul/min using a 1mm x 10cm BEH C18 column with 1.7 um particles. 
Measuring ticagrelor will be performed in the negative ion mode with the 521 to 361 and 
the 477 to 361 transitions for drug and metabolite, respectively. The concentration of each 
drug will be determined by comparing the areas of the internal standards to the unlabeled 
drug in the plasma and the relationship to each standard curve and validated using GLP 
standards. 
 
Rationale for Measurement of Levels of Drugs and Their Metabolites by Mass 
Spectrometry: To investigate if the favorable pharmacokinetic profile of ticagrelor over 
clopidogrel is seen in non-dialysis CKD patients as in the general population, we will 
measure levels of drugs (clopidogrel and ticagrelor) and metabolites (carboxylic acid 
metabolite for clopidogrel and AR-C124910XX for ticagrelor) using mass spectrometry. 
Phase I and II studies of the two drugs reported achievement of steady state concentrations 
of drug and metabolite concentrations within 2 weeks regardless of loading dose.23,44 So, 
we should be able to determine levels of drugs and metabolites in 2 weeks. 
 
Rationale for Measuring Trough and Peak Drug and Metabolite Levels: Trough drug and 
metabolite levels at 2 weeks of antiplatelet therapy are stable and accurate compared to 
their peak levels.30,45,46 Therefore, we chose to measure the trough levels. In addition, we 
will measure peak levels 3 hours after the administration of the drug at Visit 2. This will 
ensure unbiased results and minimize variability. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 31 of 43 
Measurement of uremic toxins: On Visit 1, the plasma sample will be de-proteinized by 
acetonitrile precipitation at physiological pH,47 followed by concentrating it down to a small 
volume and dissolving it in the liquid chromatography mobile phase. A sensitive and 
selective MRM method was reported for quantifying p-cresol sulfate in human plasma by 
using m/z 187->80 and 187->107 transition.48 Similarly, an MRM method was reported for 
quantification of indoxyl sulfate.49 Both molecules will be detected in the same sample at 
physiological pH in negative ion mode. In addition, similar MRM methods exist for 
trimethylammonium N-oxide,50 albeit in a positive ion mode. Stable isotopic dilution will be 
used to validate the method in a few patients prior to applying it to the whole group. Stable 
isotopic dilution is the gold standard of quantification of low molecular weight metabolites 
and achieves the highest accuracy. Also, the TSQ Quantum mass spectrometer allows for 
20 ms polarity switching without any loss of the signal. Therefore, it is expected that 
implementation of these MRM methods will occur in a way that would result in quantification 
of the three toxins in the same run for the same 0.5 mL plasma sample. 
 
Rationale for indoxyl sulfate, guanidine succinic acid and p-cresol sulfate measurements. 
Widely known uremic toxins are indoxyl sulfate and p-cresol sulfate. Although animal 
studies have reported these uremic toxins to be pro-thrombotic,51 there are no controlled 
human studies to investigate their association with changes in platelet function and levels 
of drug and metabolite. This will be novel to the proposed study. 
 
CYP Polymorphims Measurement by blood sample collection, storage, DNA Extraction, 
Quantification, and Quality Assessment:   
 
Sample collection: 8.5 mL of blood will be collected into PAXgene Blood DNA Tubes, 
which contain a proprietary blend of reagents that both prevents blood coagulation and 
stabilizes white blood cells. These tubes will be stored at -70degrees C refrigerator at 
Arthur’s lab. All DNA samples will be sent to PAL, G128, Research Service, Little Rock VA 
in a batch where DNA will be isolated from the tubes using appropriate buffers supplied in 
the PAXgene Blood DNA Kit.  
 
For DNA isolation, the blood is transferred to processing tubes (supplied already filled 
with cell lysis buffer), and the solution is mixed to lyse red and white blood cells. Cell nuclei 
and mitochondria are pelleted by centrifugation, washed, and resuspended in digestion 
buffer. Protein contaminants are removed by incubation with a protease. DNA is 
precipitated in isopropanol, washed in 70% ethanol, dried, and resuspended in 
resuspension buffer. DNA will be extracted from whole-blood using the PAXgene Blood 
DNA System (Qiagen, Valencia, CA).  Highly pure genomic DNA will be obtained. DNA 
quantity and quality will be ascertained by RNAseP Quantitation™ (Applied Biosystems, 
Life Technologies, Carlsbad, CA) with fluorescence detection using an ABI7900HT Real-
Time Quantitation System (Applied Biosystems, Life Technologies, Carlsbad, CA) 
according to the manufacturer’s protocol. DNA samples are normalized to 50ng/µl and 
200ng per sample is required for analysis by microarray. 
 
Performing Pharmacogenetic analyses by microarray:  Each DNA sample will undergo 
whole-genome 
amplification, 
enzymatic 
end-point 
fragmentation, 
precipitation, 
resuspension and hybridization to microarrays for 20 hours at 48°C according to the 
manufacturer’s procedures (Illumina, Inc., San Diego, CA).  Microarrays used for 
Pharmacogenetics analyses are the Infinium® Human Gloval Screening Arrays V2  
(Illumina, Inc., San Diego, CA) which feature more than 17,220 PGx polymorphisms 
covering all genes listed on the PharGKB and CPIC-17 websites plus 800,000 additional 
markers per sample., After single-base extension and staining, beadchips are scanned 
using the Illumina iScan system and Autoloader2.  Analysis of Pharmacogenetic data:  
Preliminary data analyses to assess internal quality control will be performed with 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 32 of 43 
GenomeStudio V2 software using Genotyping Module 2.0.2 (llumina, Inc.).   Reproducibility 
between intentional replicates and gender calls will be determined.  Samples with call rates 
below 0.99 will be repeated and SNPs with GenTrain scores below 0.4 will be clustered 
manually.  GenomeStudio software can export a custom report with only PGx data. 
   
 
8.9 
Specimen Banking 
Blood and urine samples of the participants will be stored indefinitely for possible future 
use, only if participants consented for future use of the samples. The samples and health 
information stored for future research will be labeled only with study ID number and they 
will not have any identifiable information. The genetic material collected from participants 
will not be store for future research. All genetic material will be used only for this study and 
any left over at the end of the study will be discharged. Banking these samples and health 
information for future use is fundamental for understanding the correlation between the 
kidney functionality and several other diseases. We can use these samples to correlate 
kidney function/dysfunction with a broad spectrum of diseases in the future. The plasma 
from the blood and the supernatant collected from the urine samples of the participants will 
be stored in a -80°C freezer in Dr. Arthur’s laboratory in the Biomedical Building II UAMS 
on the 6th floor. The Bio-Med II building can be accessed only by authorized personal using 
an access card. The freezer is locked and the key will be stored in a separate locked room. 
Future use of these samples which is not specifically described here for the current study 
will require additional approval from the IRB or designation by the IRB as non-human 
subjects research. We are planning to use these samples for research purposes until they 
are completely consumed. Genetic tests: The DNA sample will be frozen for analyses of 
polymorphisms affecting metabolism of the study drugs. 
 
Specimens will be stored indefinitely or until they are used up. If future use is denied or 
withdrawn by the patient, best efforts will be made to stop any additional studies and to 
destroy the specimens. 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Study Design/Study Endpoints 
Statistical Considerations Summary statistics will be used to describe the data 
distribution. Median (interquartile range) and mean (SD) will be reported for markers as in 
Aim 1 for both groups (CKD vs. non-CKD) pre- and post-therapy. Two-sample t-test or 
Mann-Whitney test will be used to compare markers between groups at baseline. A mixed 
effects model will be used to compare WBPA (change) to ticagrelor and aspirin therapy 
between groups. The model will have group factor, ticagrelor treatment factor (repeated, 
pre vs. post), and interaction between group and treatment. The pair effect and subject 
effect will be random factors to control for the clustering within matched pairs and within 
each subject. Potential confounders (age and BMI) will be adjusted in the models. 
Differential response to ticagrelor treatment will be evaluated by testing the null hypothesis 
that there is no significant interaction term by using F-test statistics. In an exploratory 
analysis, levels of ticagrelor and its active metabolite will be compared between groups. 
Finally, two-way interactions between the metabolic phenotypes of CYP3A4 and CKD 
group on WBPA will be investigated. 
 
9.2 
Sample Size and Accrual 
Sample-size Calculation and Power Considerations. We used baseline measurements of 
WBPA from our previous work. For CKD-ND and non-CKD patients at baseline, we 
reported mean (SD) WBPA of 11.32 (5.14) Ω and 7.67 (3.52) Ω, respectively. We 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 33 of 43 
calculated post-treatment WBPA values in CKD-ND and non-CKD patients (at 75% IPA) 
to be 2.88 Ω and 2.77 Ω. We used the linear mixed effects model to compare between-
group (CKD vs. non-CKD) differences in ticagrelor treatment effect, where matched pair 
will be a random effect. With a fixed sample size of 27 pairs at a 2-sided α of 0.05, the 
power for detecting a difference of at least 4 Ω in mean WBPA changes between CKD and 
controls with an F test will be 91.3%. 
 
9.3 
Data Analyses Plans 
Data analyses plan for Aim 1 
Aim1 Primary Objectives Analysis Plan. Summary statistics will be used to describe the 
distribution of the data. Median (interquartile range) and mean (plus standard deviation 
[SD]) will be reported for all variables. An analysis of covariance (ANCOVA) model will be 
used in the primary analysis to compare treatment effects of ticagrelor vs. clopidogrel in 
CKD patients because this approach has higher statistical power than other methods to 
analyze drug effects.56 Post-treatment ADP-induced WBPA values in ohms (Ω) will be 
modeled as the dependent variable (the primary outcome measure). Specifically, we will 
use the WBPA values drawn after 3 hours of the drug administration at Visit 2. Baseline 
measurement of WBPA, diabetic status (1- diabetics; 0-non-diabetics) and a binary 
treatment variable (1-ticagrelor arm; 0-clopidogrel arm) will be included as independent 
variables. The coefficient associated with the treatment variable will be the parameter of 
interest. Under the assumption that there are no significant differences in baseline 
measurements between groups (due to randomization), this coefficient will reflect the mean 
difference in WBPA values (or difference in mean change from baseline) between groups. 
In the case of missing data, we will do a complete case analysis and compare estimates 
by using imputation of the means or the mixed-effects model approach. We will also 
calculate the following secondary outcome measures between the groups and compare 
between groups by Chi-square test: 
 
1) 
Percentage of inhibition in platelet aggregation (IPA) is the ratio of the difference 
in baseline and post-treatment values divided by the baseline value of WBPA. 
2) 
Residual platelet aggregability (RPA) is defined as those with IPA < 75% on 
treatment. 
3) 
Pre-specified adverse events at 2-weeks, at 30-days, at 6-months and at 12-
months including any bleeding (skin bruising, nose bleeds, major bleedings), CV 
events, hospitalizations or death 
 
Aim 1 Secondary Objectives Analysis Plan. We will report summary statistics of drug 
and metabolite levels. We will test correlations between changes in WBPA values in the 
treatment arms and levels of drug and metabolites. We will perform summary statistics of 
cytokine levels. We will correlate changes in levels of circulating cytokines before and after 
treatment with changes in WBPA values in the two treatment arms and drug/metabolite 
levels. In addition, we will use one-way ANOVA to analyze interaction of cytokines with 
treatment group to modify IPA. For statistical analysis, we will collapse CYP2C19 groups 
based on metabolic phenotypes based on previous published studies including our 
preliminary work. Proportions of metabolic phenotypes of CYP polymorphisms will be 
compared between groups with Chi Square or Fisher’s exact test. Two-way interactions 
between the metabolic phenotypes and the study drug on the outcome measure will be 
investigated. Specifically, we will test interaction of poor (vs. wild) and rapid (vs. wild) 
metabolic phenotype of CYP2C19 with the study drug on IPA (Visit 2 from Visit 1). We will 
conduct analyses similar to CYP2C19 for CYP3A4/5 alleles after collapsing them as binary 
variables. 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 34 of 43 
Data analyses plan for Aim 2 
Aim 2 Primary objective Analysis Plan. Summary statistics will be used to describe the 
data distribution. Median (interquartile range) and mean (SD) will be reported for markers 
as in Aim 1 for both groups (CKD vs. non-CKD) pre- and post-therapy. Two-sample t-test 
or Mann-Whitney test will be used to compare markers between groups at baseline. For 
the primary outcome measure, a mixed effects linear model will be used to compare mean 
change in WBPA to ticagrelor and aspirin therapy between groups. The model will have 
group factor, ticagrelor treatment factor (repeated, pre vs. post), and interaction between 
group and treatment. The pair effect and subject effect will be random factors to control for 
the clustering within matched pairs and within each subject. Models will be adjusted for 
potential confounders (age and BMI) that were not used in matching. Differential response 
to ticagrelor treatment will be evaluated by testing the null hypothesis that there is no 
significant interaction term by using F-test statistics. All available data will be included in 
the analyses; the mixed model can accommodate cases with incomplete data. Data 
transformations will be employed if needed to meet analysis assumptions. 
 
Aim 2 Secondary Objectives Analysis Plan. Secondary outcomes will be analyzed as 
Aim 1. Summary statistics will be performed. Student’s t-test or Wilcoxon rank sum test will 
be used to compare continuous and Chi-Square test to compare categorical variables 
between groups. Any two-way interactions of CYP polymorphisms (present/absent) and 
CKD status on IPA after treatment will be investigated. Similar interactions will be analyzed 
between uremic toxins and CKD status on changes in WBPA values and levels of 
drug/metabolite.  
 
Aim 3 Primary Objectives Analysis Plan.  We will collect data on CBC, CMP, lipid 
panel, A1c, phosphorus, uric acid and urine microalbumin/creatinine ratio from positive 
controls medical chart as these are routinely done on admitted patients. We will also 
perform platelet function analysis along with flow cytometry to analyze platelet phenotype 
as already outlined in the protocol for the other two groups. 
10.0 
STUDY MANAGEMENT 
10.1 
Institutional Review Board (IRB) Approval and Consent 
This study will be conducted in accordance with all applicable government regulations 
and University of Arkansas for Medical Sciences research policies and procedures. This 
protocol and any amendments will be submitted and approved by the UAMS Institutional 
Review Board (IRB). 
 
The formal consent of each subject, using the IRB-approved consent form, will be obtained 
before the subject is submitted to any study procedure. All subjects for this study will be 
provided a consent form describing this study and providing sufficient information in 
language suitable for subjects to make an informed decision about their participation in this 
study. The person obtaining consent will thoroughly explain each element of the document 
and outline the risks and benefits, alternate treatment(s), and requirements of the study. 
The consent process will take place in a quiet and private room, and subjects may take as 
much time as needed to make a decision about their participation. Participation privacy will 
be maintained and questions regarding participation will be answered. No coercion or 
undue influence will be used in the consent process. This consent form must be signed by 
the subject or legally acceptable surrogate, and the individual obtaining the consent. A 
copy of the signed consent will be given to the participant, and the informed consent 
process will be documented in each subject’s research record. 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 35 of 43 
10.2 
Data Management and Monitoring/Auditing 
All study subject material from participants will be assigned a unique identifying code or 
number. The key to the code (the instrument associating the data with subject identity) will 
be kept in a locked file in the principal investigator’s office, if hardcopy, or on a password-
protected UAMS server, both located behind locked doors in a restricted access area of 
the UAMS campus. Only those individuals listed as investigators for this protocol will have 
access to the code and information that identifies the subject in this study. 
 
10.3 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and well-
being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol. Investigators may only implement a 
deviation from or a change to the protocol to eliminate an immediate hazard(s) to subjects 
without prior IRB approval. 
 
10.4 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator. It should also be noted that when an amendment 
to the protocol substantially alters the study design or the potential risk to the patient, a 
revised consent form might be required. 
 
10.5 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and approval, 
signed patient consent forms). All study records will be retained in accordance with 
applicable institutional and applicable regulatory requirements. 
 
10.6 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with applicable regulatory requirements. The Principal Investigator is 
responsible for personally overseeing the treatment of all study subjects. The Principal 
Investigator must assure that all study site personnel, including sub-investigators and other 
study staff members, adhere to the study protocol and all applicable regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 36 of 43 
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Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 37 of 43 
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23. Mullangi 
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25. 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. 
Journal of the American College of Cardiology. 2010;55(11):1139-1146. 
26. Htun P, Fateh-Moghadam S, Bischofs C, et al. Low responsiveness to clopidogrel increases risk among 
CKD patients undergoing coronary intervention. Journal of the American Society of Nephrology : JASN. 
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27. Park S, Kim W, Park C, Kang W, Hwang S, Kim W. A Comparison of Clopidogrel Responsiveness in 
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32. Siller-Matula JM, Akca B, Neunteufl T, et al. Inter-patient variability of platelet reactivity in patients 
treated with prasugrel and ticagrelor. Platelets. 2016;27(4):373-377. 
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inhibition of ADP-induced platelet aggregation in patients with atherosclerotic disease regardless of 
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34. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary 
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36. Kumar N, Baker CS, Chan K, et al. Cardiac survival after pre-emptive coronary angiography in 
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Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 38 of 43 
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40. Storey RF. The P2Y12 receptor as a therapeutic target in cardiovascular disease. Platelets. 
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bioanalytical 
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pharmacokinetics/pharmacodynamics, and update on recent trends in drug-drug interaction studies. 
Biomed Chromatogr. 2009;23(1):26-41. 
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52. Wallentin L, James S, Storey RF, et al. Effect of CYP2C19 and ABCB1 single nucleotide 
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53. Li M, Hu Y, Li H, et al. No Effect of SLCO1B1 and CYP3A4/5 Polymorphisms on the Pharmacokinetics 
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https://www.pharmgkb.org/variant/rs776746. Accessed on February 6, 2017. 
55. Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity 
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56. Borm GF, Fransen J, Lemmens WA. A simple sample size formula for analysis of covariance in 
randomized clinical trials. J Clin Epidemiol. 2007;60(12):1234-1238. 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 39 of 43 
Concomitant Medication Form (Questionnaire 1) 
Subject ID #:   _______________ 
 
 
Date of visit ___ ___ /___ ___ / ___ ___                                           
Ask the participant if they are taking: 
• 
Antithrombotic Agents (mark yes or no): 
Aspirin 
Cilostazol 
Ranolazine 
Aggrenox 
Prasugrel 
Pradaxa 
Eliquis 
Warfarin 
Xarelto 
 
 
• 
Herbal supplements and antiplatelet agents (mark yes or no): 
 
 
 
Coumadin 
Fish Oil 
Vitamin E 
Herbal supplements 
 
 
• 
Non-steroidal anti-inflammatory drugs (NSAIDS) (mark yes or no):  
 
Motrin 
Advil 
Aleve 
Mobic 
Naprosyn 
Goody Powder 
Lodine 
Celebrex 
 
Ibuprofen 
BC 
Powder 
Pamprin  
 
 
 
• 
Proton Pump Inhibitors (mark yes or no): 
 
Protonix 
(Pantoprazole) 
Nexium 
(Esomeprazole) 
Prevacid 
(Lansoprazole) 
Prilosec 
(Omeprazole) 
Aciphex 
(rabeprazole) 
 
If participant is taking any of the above medications complete: 
 
For screening visit use only (visit 1) 
Those already on 
___________ 
Dose of (current) 
 
------------------mg 
 
How long on it? -------------------------- 
Primary prevention __ ___ 
Stop date of ___________between 
screening and baseline visit: 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 40 of 43 
Secondary prevention (exclude) ___ 
___ ___ /___ ___ / ___ ___ 
Those already on 
___________ 
Dose of (current) 
 
------------------mg 
 
How long on it? -------------------------- 
Primary prevention __ ___ 
Secondary prevention (exclude) ___ 
Stop date of ___________between 
screening and baseline visit: 
 
___ ___ /___ ___ / ___ ___ 
Those already on 
___________ 
Dose of (current) 
 
------------------mg 
 
How long on it? -------------------------- 
Primary prevention __ ___ 
Secondary prevention (exclude) ___ 
Stop date of ___________between 
screening and baseline visit: 
 
___ ___ /___ ___ / ___ ___ 
  
If the participant is taking any of the above medications, ask the participant if he/she agree to 
stop taking them: 
 
 YES, the participant can stop taking 
these medication 
 NO, the participant can NOT stop 
taking these medications 
Continue the study 
Participant can NOT continue the 
study 
 
 
Ask the participant about any other medication that is taking: 
 
Medication name† 
Total daily 
dose  
Route 
Med type 
Type of 
change 
Date of 
change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
†Screening visit: list all medications patient is currently taking.  All other visits: list any change during the 
period from the last visit  

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 41 of 43 
  1. Beta blockers 
7. TCA`s 
13. Narcotics 
19. Laxative/stool softner 
  2. ACEI & ARB`s 
8. SSRI    
14. Antihistamines                      20. Phosphate binders 
  3. Calcium channel blockers 
9. Antipsychotics                         15. Antibiotics                             21. Antiplatelets                  
  4. Diuretics 
10. Hypnotic/sedatives 
16. Steroids 
22. Anticoagulants 
  5. Other antihypertensives 
11. Hypoglycemics 
17. HAART 
23. Antiarhythmics 
  6. Statins                                   12. NSAID`s                                18. PPI 
24. Others 
 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 42 of 43 
Demographic Form (Questionnaire 2) 
Subject ID #:   _______________                                                                                               IRB # 227997 
                                                                                                            Date of visit ___ ___ /___ ___ / ___ 
___   
 
DOB (date of birth) 
 
        __ __ /__ __ / __ __  __ __   
 
Age   ________ 
 
Gender 
 
□M (1)                        □F (0) 
 
 
Race(check 1 or more) 
 
□African-American / black (1) 
□American-Indian/Alaska native(2) 
 
□Asian (3)          □White (4) 
□Native 
Hawaiian/Pacific 
islander(5) 
 
Ethnicity 
 
□Hispanic (1) 
 
□Non-hispanic (0) 
Obesity 
□ BMI ≥30  
□ BMI ≥25 and <30 
□ BMI <25 
 
Education 
□ High school or below 
□ Undergraduate school 
□ Graduate school  
□ Postgraduate training 
 
Employment 
□ Unemployed 
□ Self employed 
□ Employed 
 
Health insurance 
□ Medicare 
□ Medicaid 
□ Private 
□ Unisured 
 
 
 
 

Study Title: A Mechanistic Study with Non-Dialysis Chronic Kidney Disease to Investigate Altered Platelet 
Response to Antiplatelet Therapy 
PI: Jain Nishank, M.D. 
Institution: University of Arkansas for Medical Sciences 
 
Version No.:13 
IRB# 227997 
Date: 02/22/2021 
Page 43 of 43 
Past Medical History Form (Questionnaire 3) 
Subject ID #:   _______________ 
 
 
 
 
Date of visit ___ ___ /___ ___ / ___ ___                                           
 
PMH 
Cause CKD 
□DM (1)                □HTN (2)                  □unknown (3)   
□multifactorial (4)           □PKD (5)                 □RAS (6)  
 □ GN (7)         □ other (8)                                                 
 
DM  
      □yes (1)                                          □No ( 0)        
 
HTN 
      □yes (1)                                          □No ( 0)        
 
CVA in last 12 months 
      □yes (1)                                          □No ( 0)        
 
HIV  
      □yes (1)                                          □No ( 0)        
 
MI or CABG or PCI in last 12 months 
      □yes (1)                                          □No ( 0)        
 
MI or CABG or PCI > 12 months 
      □yes (1)                                          □No ( 0)        
 
CHF 
      □yes (1)                                          □No ( 0)        
 
CVA (remote) 
      □yes (1)                                          □No ( 0)        
 
CAD  
      □yes (1)                                          □No ( 0)        
 
LungDz 
      □yes (1)                                          □No ( 0)        
 
LiverDz 
      □yes (1)                                          □No ( 0)        
 
PVD 
      □yes (1)                                          □No ( 0)        
 
Cancer  
      □yes (1)                                          □No ( 0)        
 
DepressionHx 
      □yes (1)                                          □No ( 0)        
 
Surgery (within 3 month) 
      □yes (1)                                          □No ( 0)        
 
Recent bleeding episode 
      □yes (1)                                          □No ( 0)        
 
Bleeding disorder 
      □yes (1)                                          □No ( 0)        
Social history 
 
 
 
DrugAbuse  
      □yes (1)                                          □No ( 0)        
 
Alcohol 
      □yes (1)                                          □No ( 0)        
 
Tobacco 
      □yes (1)                                          □No ( 0)        
 
Married 
      □yes (1)                                           □No ( 0)   
      □Divorced (2)                                       □Widowed (3) 
 
Lives Alone  
      □yes (1)                                          □No ( 0)        
 
Employed 
      □yes (1)                                          □No ( 0)        
 
 
 
Allergies 
   □yes (1)                               □No ( 0)       specify medication           ______________________ 
Any other 
Conditions? 
   □yes (1)                               □No ( 0)      please specify _______________________________