Clinical trial NCT01467466
Conditions: Acute Renal Failure Kidney Disease Coronary Artery Disease
Keywords: renal cardiovascular kidney heart clinical trial double-blind multi-site trial randomized drug treatment IV solutions antioxidant
Sponsor: VA Office of Research and Development
Start date: 2013-10-07; Completion date: 2017-10-17
Enrollment: 5177 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
The purpose of this research study is to compare the effectiveness of intravenous isotonic sodium bicarbonate with intravenous isotonic sodium chloride and oral N-acetylcysteine (NAC) with oral placebo for the prevention of serious adverse outcomes following angiographic procedures in high-risk patients.

Detailed description:
The intravascular administration of iodinated contrast media for diagnostic imaging is a common cause of acute kidney injury (AKI) and a leading cause of iatrogenic renal disease. Contrast-induced AKI is associated with serious adverse outcomes including death, need for dialysis, prolonged hospitalization, and acceleration in the rate of progression of underlying chronic kidney disease. The benefit of IV isotonic bicarbonate compared to IV isotonic saline and of N-acetylcysteine for the prevention of contrast-induced AKI and associated adverse outcomes remains unclear. The purpose of this trial is to compare the effectiveness of IV isotonic sodium bicarbonate with IV isotonic sodium chloride and oral NAC with placebo for the prevention of serious adverse outcomes in 7,680 high-risk patients scheduled to undergo coronary or non-coronary angiography. Using a 2 x 2 factorial design, patients will be randomized to receive: 1) either peri-procedural IV isotonic sodium bicarbonate or peri-procedural IV isotonic saline and 2) either oral NAC or oral placebo prior to and for 5 days following the angiographic procedure. The primary study endpoint is a composite outcome comprised of death, need for acute dialysis, or persistent decline in kidney function within 90 days following the index angiogram.

Arms: arm 1: IV isotonic saline and oral placebo drug capsule arm 2: IV isotonic saline and oral N-acetylcysteine drug capsule arm 3: IV isotonic bicarbonate and oral placebo drug capsule arm 4: IV isotonic bicarbonate and oral N-acetylcysteine drug capsule
Interventions: intervention 1: IV isotonic saline intervention 2: IV isotonic bicarbonate intervention 3: N-acetylcysteine intervention 4: Placebo
Intervention descriptions: intervention 1: The investigators will administer 3 ml/kg of isotonic saline over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic saline over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic saline (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure. intervention 2: The investigators will administer 3 ml/kg of isotonic bicarbonate over 1 hour at an infusion rate of not less than 1 mL/kg per hour and not more than 3 mL/kg per hour prior to the angiographic procedure, 1-1.5ml/kg per hour during angiography, and 6 ml/kg of isotonic bicarbonate over 4 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour and not more than 1.5 mL/kg per hour. Providers will retain discretion to administer larger volumes of isotonic bicarbonate (up to a maximum of 12 mL/kg) over durations of up to 12 hours pre and 12 hours post-procedure. intervention 3: NAC will be administered at a dose of 1200mg orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days. intervention 4: A placebo study drug capsule will be administered orally 1 hour prior to angiography, 1 hour following the procedure, and then twice daily for the next 4 days.

Protocol documents:
Prot_002.pdf: 
Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
 
 
 
 
 
VA COOPERATIVE STUDY # 578 
PREVENTION OF SERIOUS ADVERSE EVENTS 
FOLLOWING ANGIOGRAPHY (PRESERVE): 
 
 
 
A DEPARTMENT OF VETERANS AFFAIRS COOPERATIVE STUDY 
 
 
TABLE OF CONTENTS 
EXECUTIVE SUMMARY .............................................................................................. 1 
FIGURE 1 - OVERVIEW OF STUDY DESIGN .......................................................... 3 
ABBREVIATIONS .......................................................................................................... 4 
I. 
INTRODUCTION ............................................................................................... 5 
II. 
STUDY HYPOTHESES AND OBJECTIVES ................................................. 6 
III. 
BACKGROUND ................................................................................................. 8 
IV. 
SIGNIFICANCE OF THE PROPOSED RESEARCH TO THE VA .......... 26 
V. 
OVERVIEW OF STUDY DESIGN ................................................................. 29 
VI. 
STUDY POPULATION AND PATIENT RECRUITMENT ........................ 32 
VII. 
STUDY PROCEDURES ................................................................................... 36 
VIII. 
POTENTIAL PITFALLS OF THE PROPOSED STUDY DESIGN 
AND ALTERNATIVE STUDY DESIGN CONSIDERATIONS .................. 57 
IX. 
FEASIBILITY OF RECRUITMENT ............................................................. 68 
X. 
ANTICIPATED BARRIERS TO RECRUITMENT AND 
STRATEGIES TO ADDRESS POTENTIAL UNDER-ENROLLMENT .. 70 
XI. 
FUTURE ANCILLARY STUDIES ................................................................. 72 
XII. 
HUMAN SUBJECTS ........................................................................................ 73 
XIII. 
DATA MANAGEMENT .................................................................................. 76 
XIV. 
QUALITY CONTROL PROCEDURES ........................................................ 83 
XV. 
GOOD CLINICAL PRACTICES ................................................................... 87 
XVI. 
STUDY MONITORING AND AUDITING PLANS ..................................... 88 
XVII. BIOSTATISTICAL CONSIDERATIONS ..................................................... 95 
XVIII. STUDY ORGANIZATION AND ADMINISTRATION ............................. 108 
XIX. 
PUBLICATIONS ............................................................................................ 110 
XX. 
REFERENCES ................................................................................................ 112 
 
 
1. 
Informed Consent Form Template 
2. 
HIPAA Authorization Template 
3. 
Drug Information Report 
 
APPENDICES 
 
 
 
 
CSP#578 PRESERVE Protocol v1.8 
Table of Contents 
Effective Date:  05/01/2019 


Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
 
 
 
 
EXECUTIVE SUMMARY 
The intravascular administration of iodinated contrast media for diagnostic imaging is a common 
cause of acute kidney injury (AKI) and a leading cause of iatrogenic renal disease. Multiple 
studies have demonstrated that contrast-induced AKI (CIAKI) is associated with increased short- 
term mortality, prolonged hospitalization, increased medical resource utilization, and adverse 
long-term outcomes. CIAKI is a unique form of renal disease in that it is universally iatrogenic, 
its risk factors and pathophysiology are well-characterized, and its inciting event is highly 
predictable. All of these characteristics make CIAKI particularly amenable to preventive 
interventions. 
 
Intravenous (IV) isotonic fluid is the principal intervention with documented effectiveness for 
the prevention of CIAKI. Over the past half-decade, clinical trials have focused on the 
comparative effectiveness of IV sodium bicarbonate (bicarbonate) and IV sodium chloride 
(saline). While several trials demonstrated bicarbonate to be more effective than saline for the 
prevention of CIAKI, other trials reported no difference between these two IV fluids. Another 
preventive intervention for CIAKI that has received substantial attention over the past decade is 
peri-procedural administration of N-acetylcysteine (NAC), an anti-oxidant agent with 
vasodilatory properties. Published results regarding the efficacy of NAC are inconsistent. 
Multiple meta-analyses attempting to reconcile the conflicting studies on these interventions 
have themselves, been inconclusive. Consequently, there remains clinical equipoise regarding 
the superiority of bicarbonate (compared to saline) and role of NAC for the prevention of CIAKI. 
 
We believe that there are three reasons that past trials and meta-analyses have not provided clear 
evidence to guide the use of bicarbonate and NAC for the prevention of CIAKI. First, all of the 
published clinical trials enrolled relatively small numbers of patients and most assumed 
unrealistically large effect sizes for the tested interventions. As a result, these studies were 
underpowered to detect biologically plausible, yet clinically important benefits of these 
interventions and were particularly susceptible to false positive and false negative results. Second, 
many trials included patients at low-risk for CIAKI, which resulted in relatively few primary 
study events and diminished the ability to discern the effects of these interventions in 
 
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higher-risk subjects, in whom they would theoretically have the greatest clinical utility. Third, 
and most importantly, nearly all prior trials used small absolute and/or relative increases in 
serum creatinine (SCr) as the primary study endpoint rather than serious, adverse patient- centered 
outcomes thought to represent downstream consequences of CIAKI (e.g., mortality, need for 
acute dialysis, or persistent decline in kidney function). While a multitude of studies have 
demonstrated that minor increases in SCr following angiography are associated with serious 
adverse events, it is unknown whether the prevention of small increases in  SCr  following contrast 
administration results in a reduction in clinically important patient-centered outcomes. 
 
To assess the comparative effectiveness of bicarbonate and saline and the benefit of NAC, we 
propose to conduct a multicenter, randomized, clinical trial designed and adequately powered to 
evaluate these interventions for the prevention of clinically important, adverse, patient-centered 
outcomes in high-risk Veterans undergoing cardiac and non-cardiac angiography. In this trial, 
7,680 patients scheduled to undergo coronary or non-coronary angiography who are at increased 
risk of developing CIAKI and experiencing serious downstream outcomes (i.e., diabetics with 
eGFR <60 ml/min/1.73 m2 or any patient with eGFR <45 ml/min/1.73 m2) will be enrolled. 
Using a 2 x 2 factorial design, patients will be randomized to receive: 1) either IV isotonic 
sodium bicarbonate or IV isotonic saline and 2) either oral NAC or oral placebo prior to and 
following the angiographic procedure. We will assess the effectiveness of bicarbonate compared 
to saline and NAC compared to placebo for the prevention of a composite primary endpoint 
consisting of clinically significant, patient-centered events including death, need for acute 
dialysis, or persistent decline in kidney function, all within 90 days following the index 
angiogram. As a secondary outcome, we will assess differences in the development of CIAKI, 
defined by an increase in SCr of at least 0.5 mg/dL and/or 25% at 4 days following angiography. 
By enrolling a large population of high-risk Veterans and comparing the effectiveness of these 
interventions for the prevention of clinically relevant outcomes, the findings of this trial will 
definitively establish the role of bicarbonate and of NAC for the prevention of serious, adverse 
patient-centered events following angiography and will help inform the care delivered to a very 
large and growing population of patients undergoing angiographic procedures within the VA 
Healthcare System and the broader medical community. 


Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
 
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FIGURE 1 - OVERVIEW OF STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
bicarbonate 
vs. 
 
 
 
allocation 
 
 
 
 
 
 
 
 


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ABBREVIATIONS 
 
AKI 
acute kidney injury 
ACS 
acute coronary syndrome 
BNP 
brain natriuretic peptide 
oC 
degrees centigrade 
CI 
confidence interval 
CIAKI 
contrast-induced acute kidney injury 
CKD 
chronic kidney disease 
CSP 
Cooperative Studies Program 
CSPCC 
Cooperative Studies Program Coordinating Center 
CSPCRPCC Cooperative Studies Program Clinical Research Pharmacy Coordinating Center 
CVA 
cerebrovascular accident 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ESRD 
end-stage renal disease 
HF 
heart failure 
HR 
hazard ratio 
IV 
intravenous 
LOS 
length of stay 
MAVERIC 
Massachusetts Veterans Epidemiology Research and Information Center 
MI 
myocardial infarction 
NAC 
n-acetylcysteine 
NaCl 
sodium chloride 
NaHCO3 
sodium bicarbonate 
NSTEMI 
non-ST elevation myocardial infarction 
OR 
odds ratio 
PCI 
percutaneous coronary intervention 
ROS 
reactive oxygen species 
RR 
relative risk 
RRT 
renal replacement therapy 
SCr 
serum creatinine 
STEMI 
ST-elevation myocardial infarction 


Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
 
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I. 
INTRODUCTION 
Contrast-induced acute kidney injury (CIAKI) is defined by an abrupt loss of kidney function 
following the intravascular administration of iodinated contrast media. CIAKI occurs in a 
substantial proportion of high-risk patients following angiography and is associated with serious, 
adverse, short and long-term outcomes. CIAKI is one of the few preventable forms of acute 
kidney injury and substantial advancements in our understanding of its risk factors and 
pathogenesis have informed research efforts to identify 
safe and effective preventive 
interventions. 
 
The cornerstone of preventive care for CIAKI is the administration of peri-procedure IV isotonic 
fluid. Recent clinical trials and meta-analyses suggest that IV isotonic sodium bicarbonate 
(bicarbonate) is more effective than IV isotonic sodium chloride (saline). However, these studies 
have significant limitations and definitive conclusions regarding the superiority of bicarbonate 
compared to saline have not been reached. Another promising preventive strategy is the provision 
of anti-oxidant therapy using N-acetylcysteine (NAC). Although some clinical trials and meta-
analyses of NAC support its effectiveness, conclusive evidence is lacking due to limitations 
of the studies to date. Consequently, there continues to be clinical equipoise on the superiority 
of bicarbonate compared to saline and on the benefit of NAC for the prevention of CIAKI. 
Moreover, because the majority of past studies focused only on endpoints defined by short-
term changes in kidney function, it is unknown whether the purported beneficial effects of these 
two interventions on the prevention of CIAKI translate into meaningful reductions in serious, 
adverse, patient-centered outcomes such as death, need for dialysis, or persistent decline in kidney 
function. Therefore, we propose to conduct a multicenter, randomized clinical trial to assess the 
effectiveness of IV isotonic bicarbonate compared with IV isotonic saline and oral NAC 
compared with oral placebo for the prevention of serious, adverse outcomes in high-risk 
Veterans undergoing coronary or non-coronary angiography. 


Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
 
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II. 
STUDY HYPOTHESES AND OBJECTIVES 
A. 
Study hypotheses 
1. 
Compared to peri-procedural infusion of IV isotonic saline, peri-procedural infusion of 
IV isotonic sodium bicarbonate will decrease 90-day morbidity (i.e., need for acute dialysis, 
persistent decline in kidney function) and mortality in high-risk patients undergoing coronary or 
non-coronary angiography. The decrease in 90-day morbidity and mortality associated with 
sodium bicarbonate administration in high-risk patients will be mediated by a reduction in the 
incidence of contrast-induced acute kidney injury within 4 days of angiography. 
 
2. 
Administration of NAC in the peri-procedural period will decrease 90-day morbidity (i.e., 
need for acute dialysis, persistent decline in kidney function) and mortality in high-risk patients 
undergoing coronary or non-coronary angiography. The decrease in 90-day morbidity and 
mortality associated with NAC administration in high-risk patients will be mediated by a 
reduction in the incidence of contrast-induced acute kidney injury within 4 days of angiography. 
 
B. 
Study objectives 
1. 
Primary Objectives 
a. To assess the effectiveness of IV isotonic sodium bicarbonate compared with IV 
isotonic saline for the prevention of 90-day adverse outcomes (i.e., death, need for 
acute dialysis, persistent decline in kidney function) in high-risk patients undergoing 
coronary or non-coronary angiography. 
b. To assess the effectiveness of NAC compared with placebo for the prevention of 90- 
day adverse outcomes (i.e., death, need for acute dialysis, persistent decline in kidney 
function) in high-risk patients undergoing coronary or non-coronary angiography. 
 
2. 
Secondary Objectives 
a. Sodium bicarbonate versus saline 
i. To assess the effectiveness of IV isotonic sodium bicarbonate compared with IV 
isotonic saline for the prevention of CIAKI, defined by an increase in serum 
creatinine of ≥0.5 mg/dL and/or ≥25% at 4 days, in high-risk patients undergoing 
coronary or non-coronary angiography. 


Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
 
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 Effective:   05/01/2019 
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ii. To assess the effectiveness of IV isotonic sodium bicarbonate compared with IV 
isotonic saline for the prevention of the following outcomes within 90 days of 
coronary or non-coronary angiography in high-risk patients: 
a) death 
b) renal endpoints including need for acute dialysis or persistent decline in 
kidney function 
c) hospitalization with 
acute 
coronary 
syndrome, 
heart 
failure, or 
cerebrovascular accident 
d) all-cause hospitalization 
 
 
b. NAC versus placebo 
i. To assess the effectiveness of NAC compared with placebo for the prevention of 
CIAKI, defined by an increase in serum creatinine of ≥0.5 mg/dL and/or ≥25% at 
4 days, in high-risk patients undergoing coronary or non-coronary angiography. 
ii. To assess the effectiveness of NAC compared with placebo for the prevention of 
the following outcomes within 90 days of coronary or non-coronary angiography 
in high-risk patients: 
a) death 
b) renal endpoints including need for acute dialysis or persistent decline in 
kidney function 
c) hospitalization 
with 
acute 
coronary 
syndrome, 
heart 
failure, or 
cerebrovascular accident 
d) all-cause hospitalization 
 
 
3. 
Tertiary Objective 
To explore the comparative effectiveness of IV isotonic sodium bicarbonate versus IV 
isotonic saline and NAC versus placebo for the prevention of the following outcomes in 
high-risk patients within one year following coronary or non-coronary angiography: 
a. end-stage renal disease 
b. death 


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III. 
BACKGROUND 
A. 
CIAKI: Definition, incidence, risk factors, and outcomes 
1. 
Definition, incidence, and risk factors for CIAKI 
Contrast-induced acute kidney injury (CIAKI) is defined as a sudden decline in kidney function 
following the intravascular administration of iodinated contrast media for diagnostic imaging.1-3 
While the threshold level of kidney injury used to define CIAKI varies across studies, the 
definition employed most commonly in research and clinical practice is an increase in the serum 
creatinine concentration (SCr) of at least 0.5 mg/dL and/or 25% within 3-4 days of contrast 
exposure.4-6 Precise estimates of the incidence of CIAKI following angiography vary 
considerably based on patient characteristics, procedural factors, and the threshold change in SCr 
used to define this condition.4, 7 We recently found that CIAKI occurred in 8.5% of clinically 
stable Veterans with eGFR <60 ml/min/1.73 m2 undergoing non-urgent coronary angiography 
and 13.2% of clinically stable Veterans with eGFR <60 ml/min/1.73 m2 undergoing non-urgent, 
non-coronary angiography.8 Some studies demonstrate that up to 33% of very high-risk patients 
develop this condition following contrast-enhanced procedures.9 This finding is particularly 
important given that more than 51,000 coronary and non-coronary angiograms are performed 
yearly within the VA Healthcare System involving patients at increased risk for CIAKI. 
Past research has elucidated the principal patient and procedure-related risk factors for CIAKI 
(Table 1). Underlying kidney dysfunction is recognized as the most important risk factor for the 
development of CIAKI, with increasing levels of renal impairment associated with escalating 
levels of risk.10  The presence of diabetes 
mellitus substantially amplifies the risk for 
CIAKI in patients with concomitant renal 
disease.10-13 Patients 
with intravascular 
volume depletion are also susceptible to 
renal injury from iodinated contrast, as are 
patients  with  advanced  heart  failure.10   In 
Table 1 - Principal risk factors for CIAKI 
 
• Underlying renal insufficiency 
• Diabetes mellitus* 
• Intravascular volume depletion 
• Congestive heart failure 
• Volume of contrast used 
• Hyper-osmolal contrast media 
• Intra-arterial contrast administration 
 
*amplifies risk in the setting of renal insufficiency 
both clinical states, decreased effective circulating volume and reduced renal perfusion potentiate 
renal vasoconstriction following the administration of intravascular contrast. The risk of CIAKI 
increases with larger volumes of administered contrast.14, 15  It is also believed that the risk for 


Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
 
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CIAKI is greater following intra-arterial contrast administration than intravenous administration. 
Recognition of these major risk factors has helped providers more accurately identify which 
patients are most likely to develop CIAKI and has informed research efforts to assess the 
effectiveness of preventive interventions for this iatrogenic condition. 
 
2. 
Association of CIAKI with clinically meaningful, patient-centered outcomes 
a. 
Short-term mortality associated with CIAKI 
Observational studies demonstrate an association between CIAKI (defined by small absolute 
and/or relative changes in SCr) and increased short-term mortality.11, 16-22 In a retrospective 
study, Levy et al. found that the incidence of in-hospital death among 183 hospitalized patients 
who developed CIAKI (defined by an increase in SCr of ≥25% to at least 2.0 mg/dL) was 34% 
compared to 7% in 174 matched controls without CIAKI (unadjusted OR=6.5, p<0.001).16 In 
analyses that accounted for underlying severity of illness, CIAKI remained a strong predictor of 
in-hospital death (OR=5.5, p<0.001). A subsequent study by McCullough et al. of 1,826 patients 
who underwent percutaneous coronary intervention (PCI) found an incidence of in-hospital 
mortality of 7.1% among patients who developed CIAKI (defined by an increase in SCr of 
>25%) compared to 1.1% in those without this change in SCr (p<0.0001).11  In patients who 
developed CIAKI that required renal replacement therapy, in-hospital mortality was 35.7%. Six 
additional studies, including an analysis by our group of over 27,000 patients reported an 
independent association of CIAKI with short-term mortality (Table 2). 17-22 
 
Table 2 - Association of CIAKI with short-term mortality 
Study 
authors 
Number of 
patients 
Definition of 
CIAKI 
Adjusted 
ORa 
95% CI 
Bartholomew et al.17 
20,479 
↑ SCr ≥1.0 mg/dL 
22 
16 - 31 
From et al.18 
3,236 
↑ SCr ≥25% or ≥0.5 mg/dL 
3.4 
2.6 - 4.4 
Gruberg et al.20 
439 
↑ SCr >25% 
3.9 
2.0 - 7.6 
Levy et al.16 
357 
↑ SCr ≥25% to ≥2.0 mg/dL 
5.5 
2.9 - 13.2 
McCullough et al.11 
1,826 
↑ SCr >25% 
6.6 
3.3 - 12.9 
Rihal et al.21 
7,586 
↑ SCr >0.5 mg/dL 
10.8 
6.9 - 17.0 
Shema et al.22 
1,111 
↑ SCr ≥50% or ↓ eGFR ≥25% 
3.9 
1.2 - 12.0 
Weisbord et al.19 
27,608 
↑ SCr 0.25-0.5 mg/dL 
1.8 
1.4 - 2.5 
a OR denotes odds ratio for death 


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While consistent in demonstrating a strong relationship between small changes in SCr and short- 
term mortality, seven of these eight studies were retrospective analyses and hence, susceptible to 
ascertainment bias in the assessment of post-procedure SCr and to potential problems with 
missing data.11, 16-19, 21, 22 However, prospective studies confirm these findings.23, 24 A clinical 
trial by Marenzi et al. found that patients who developed CIAKI (defined by an increase in SCr 
of ≥25%) had a significantly increased incidence of in-hospital mortality compared to patients 
without this decline in renal function (26% v. 1.4%, p<0.001).23 An even more recent trial of 
patients undergoing coronary angiography by Maioli et al. demonstrated that in-hospital 
mortality among patients who developed CIAKI (defined by an increase in SCr of ≥0.5 mg/dL) 
was markedly higher than among patients who did not develop this post-procedure complication 
(11.1% v. 0.2%, p=0.001).24 Thus, data from observational studies and clinical trials support an 
association of small post-angiography decrements in renal function with short-term mortality. 
 
b. 
Prolonged hospitalization and increased costs associated with CIAKI 
A series of retrospective studies and clinical trials also document an association of CIAKI with 
other clinically-relevant short-term outcomes.17, 19, 25-28 In our recent analysis of over 27,000 
patients who underwent coronary angiography, a rise in SCr of 0.25 - 0.5 mg/dL was associated 
with a prolongation in hospital length of stay after adjusting for underlying severity of illness.19 
Progressively larger increases in SCr were associated with even longer lengths of stay. 
Bartholomew and colleagues found that patients who developed CIAKI after PCI were 15 times 
more likely to have their hospitalization prolonged more than four days.17 In a clinical trial 
comparing IV fluids for the prevention of CIAKI, Adolph and colleagues found that patients 
with a post-angiography increase in SCr of ≥25% or ≥0.5 mg/dL remained in the hospital a mean 
of two days longer than patients without such an increase in SCr.25 This extended length of 
hospital stay results in increased healthcare expenditures as documented in an observational 
study by our group.27, 28 In our analysis of 598 diabetics with CKD undergoing coronary 
angiography, CIAKI (defined by a rise in SCr of ≥50%) was independently associated with a 2- 
fold increase in hospital costs.27, 28 A study by Subramanian et al. that used a decision analytic 
model reported that CIAKI results in an average increase in hospital-related costs of more than 
$10,300 and 1-year costs in excess of $11,800.26 Based on the number of angiograms performed 
across the United States, there may be 110,000 cases of angiography-associated CIAKI yearly 


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nationwide, with a cumulative cost of CIAKI of greater than $1.2 billion.26, 29 Collectively, these 
data indicate that CIAKI is associated with prolonged hospitalization and substantial medical 
resource utilization, underscoring the significant economic implications of this iatrogenic 
condition. 
 
c. 
Long-term adverse outcomes associated with CIAKI 
In addition to increased short-term complications, CIAKI defined by small increases in SCr has 
also been linked with long-term mortality in recent studies (Table 3). 21, 30-34 Solomon et al. 
demonstrated that CIAKI following angiography (defined by an increase in SCr of ≥0.3 mg/dL) 
was associated with a greater than 3-fold increased risk of major adverse outcomes (death, 
stroke, myocardial infarction, end-stage renal disease requiring renal replacement therapy) at 1- 
year of follow up.33 In an analysis by Harjai et al. of 985 patients who underwent PCI, CIAKI 
(defined by an increase in SCr of ≥0.5 mg/dL) was independently associated with increased 
mortality at 24 months of follow-up (HR=2.6; 95% CI: 1.5-4.4).31 Four additional studies found 
an independent association of CIAKI with long-term mortality, although the study by Roghi et 
al. demonstrated a trend toward increased long-term mortality that did not reach statistical 
significance in multivariable analyses. 21, 30, 32, 34 
 
Table 3 - Association of CIAKI with long-term mortality 
Study 
authors 
Number of 
Patients 
Definition of 
CIAKI 
Follow-up 
(months) 
Adjusted 
HR 
95% CI 
Brown et al.34 
7,856 
↑SCr ≥0.5 mg/dL 
90 
3.1 
2.4 - 4.0 
Goldenberg et al.30 
78 
↑SCr ≥0.5 mg/dL or ≥25% 
60 
2.7 
1.7 - 4.5 
Harjai et al.31 
985 
↑SCr ≥0.5 mg/dL 
24 
2.6 
1.5 - 4.4 
Rihal et al.21 
7,075 
↑ SCr >0.5 mg/dL 
6 
a 
a 
Roghi et al.32 
2,860 
↑SCr ≥0.5 mg/dL 
24 
1.8 
1.0 - 3.4 
Solomon et al.33 
294 
↑SCr ≥0.3 mg/dL 
12 
3.2 b 
1.1 - 8.7 
HR denotes hazard ratio for death 
a HR not reported: 6-month mortality of 9.8% with CIAKI v. 2.3% without CIAKI (p<0.0001) 
b reflects incident rate ratio of death, CVA, AMI, ESRD requiring renal replacement therapy 
Past studies have also documented an association of CIAKI with more rapid progression of 
underlying CKD. Goldenberg and colleagues examined downstream outcomes among 78 
patients with CKD and found that patients who manifested a transient post-procedure rise in SCr 
of ≥25% or ≥0.5 mg/dL following coronary angiography experienced a larger decrement in 


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eGFR two years following the procedure compared to patients without these small post- 
angiography increases in SCr (∆ eGFR = – 20 ± 11 ml/min/1.73 m2 v. – 6 ± 16 ml/min/1.73 m2, 
p=0.02).30 In a study by Maioli et al., patients who developed CIAKI (defined by a rise in SCr of 
≥0.5 mg/dL) had a 0.2 mg/dL higher mean SCr at one month post-angiography compared to 
patients who had not developed CIAKI (p=0.001).24 Ribichini et al. demonstrated that patients 
who developed CIAKI following coronary angiography were more than five times as likely to 
manifest a ≥25% reduction in eGFR at 30 days compared to patients without CIAKI (OR=5.5, 
95% CI: 2.2–13.3).35 Finally, James et al. recently reported that patients who developed mild 
CIAKI following coronary angiography had a nearly 5-fold increased risk of experiencing a 
sustained reduction in kidney function at 90 days (adjusted OR=4.74, 95% CI: 3.92-5.74).36 
Patients who developed more severe CIAKI had a greater than 17-fold increased risk of persistent 
renal injury at 90 days following angiography (adjusted OR=17.3, 95% CI: 12.0-24.9), supporting 
a graded relationship between the severity of CIAKI and risk for sustained renal damage at 
90 days. In this study, CIAKI was also associated with an increased risk of accelerated decline in 
kidney function, defined as a loss of eGFR >4 ml/min/1.73 m2 per year over 2-3 years of follow 
up (OR=2.9, 95% CI: 2.2-3.7), as well as a markedly increased risk of ESRD over this same 
period of follow-up (OR=13.8, 95% CI: 7.4–25.9).36 Collectively, these findings indicate that 
CIAKI, defined by small decrements in renal function, is associated with adverse long-term 
outcomes and more compromised renal function months to years following angiography. 
 
d. 
Other data supporting a likely link between CIAKI and adverse outcomes 
It is important to note that there are several lines of evidence that support the hypothesis that 
transient changes in SCr following angiography may mediate adverse renal and non-renal 
outcomes. First, mild AKI stemming from causes other than iodinated contrast (e.g., post-cardiac 
surgery, post-vascular surgery, following acute MI, medication-related) is independently 
associated with adverse outcomes including mortality and the development of ESRD.37-40 Lassnig 
et al. demonstrated that increases in SCr of <0.6 mg/dL following cardiothoracic surgery were 
independently associated with a nearly 2-fold increase in 30-day mortality (HR=1.92, 95% CI: 
1.34-2.77).38 Similarly, in a study of over 87,000 patients, Newsome and colleagues demonstrated 
that increases in SCr of 0.3 to 0.5 mg/dL following acute MI were independently associated 
with an increased risk for ESRD (HR = 2.36, p<0.05) and long-term mortality (HR= 


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1.26, p<0.05).40 Second, in animal models, there is persistent alteration in gene expression 
affecting the renal microvasculature and contributing to tissue calcification, inflammation, and 
fibrosis following recovery from ischemia-reperfusion injury.41-46 Vascular dropout and renal 
fibrosis resulting from sustained injury to the renal microvasculature have been shown to be 
persistent sequelae of transient AKI and are believed to mediate a progressive and chronic 
decline in kidney function.47 Moreover, immune up-regulation and T-cell infiltration of the 
kidney occur several weeks after ischemic renal injury and may be associated with long-term 
structural renal damage.48 These downstream effects of transient AKI provide a biological basis 
for the link between mild decrements in SCr and progression of chronic kidney disease. Third, 
experimental models have demonstrated that transient ischemic renal injury is associated with 
the development of acute lung injury, cardiac apoptosis, and decreased heart function.49, 50 Such 
extra-renal manifestations of transient AKI provide biological plausibility to the proposed link 
between AKI and adverse cardiovascular outcomes. 
 
e. 
Importance of studying hard, patient-centered outcomes 
Despite the abundance of epidemiological and experimental data associating small changes in 
SCr   with   adverse   renal   and   extra-renal 
outcomes, the evidence remains inadequate 
to warrant the use of small changes in SCr as 
a surrogate primary endpoint in large 
transformative 
clinical 
trials. 
Although 
serious, 
downstream 
events 
following 
angiography occur as a consequence of 
CIAKI, they may also develop independent 
of this intermediate event, as many of the 
clinical conditions that predispose patients to 
the development of CIAKI 
(e.g., CKD, 
diabetes mellitus, heart failure) are also 
independently associated with mortality and 
other   adverse   outcomes   (Figure   2).   In 
Figure 2 - Potential pathways to adverse 
patient-centered outcomes following angiography 
 
 
 
 
 
 
 
 
 
 
 
 


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addition, not all episodes of CIAKI lead to clinically consequential sequelae. For this reason, we 
believe that it is most appropriate for a definitive trial of interventions for the prevention of 
CIAKI to demonstrate effectiveness in reducing serious, adverse, patient-centered outcomes 
rather than merely focusing on the amelioration of small changes in SCr. This view has been 
echoed by regulatory agencies including the United States Food and Drug Administration, which 
has indicated that small changes in SCr following contrast administration would not be an 
acceptable endpoint for trials seeking to register pharmaceutical agents for the indication of 
prevention  of  CIAKI.51   While  demonstrating  the  prevention  of  CIAKI  is  important  for 
understanding the natural history of this condition, the prevention of more patient-centered 
outcomes is required for transformative clinical trials. Thus, our proposed primary endpoint is 
comprised of adverse, patient-centered events with the development of CIAKI serving as a key 
secondary endpoint. 
 
B. 
Pathophysiology and prevention of CIAKI 
1. 
Pathophysiology of CIAKI 
Three principal mechanisms are thought to underlie the nephrotoxicity of iodinated contrast 
media (Figure 3).52 First, the intravascular administration of iodinated contrast leads to transient 
systemic     vasodilatation     that     is 
followed by intense constriction of 
intra-renal 
vascular 
beds. 
Vasoconstriction in the outer renal 
medulla, which has a particularly low 
baseline oxygen tension, leads to a 
mismatch   of   oxygen   supply   and 
demand resulting in ischemic tubular 
injury.53-55 Second, iodinated contrast 
is directly toxic to renal tubular 
epithelial   cells.7,   56,   57    Third,   the 
administration of iodinated contrast results in the generation of reactive oxygen species (ROS), 
which contribute to renal tubular cell injury.58-60 Research elucidating these pathophysiologic 
processes has informed the development of interventions for the prevention of CIAKI. 


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2. 
Prevention of CIAKI 
Renal injury resulting from iodinated contrast is potentially preventable. Procedures that utilize 
intravascular contrast are usually scheduled in advance, providing sufficient time to implement 
preventive measures. Moreover, patients at increased risk for CIAKI are easily identifiable by 
the presence of known clinical risk factors. Past efforts to find effective preventive strategies for 
CIAKI have focused on four principal approaches: 1) use of less nephrotoxic contrast agents; 2) 
provision of pre-emptive renal replacement therapy to remove contrast from the circulation; 3) 
utilization of pharmacologic agents to counteract the nephrotoxic effects of contrast media; and 
4) expansion of the intravascular space and enhanced diuresis with IV fluids. 
 
 
Over the past 25 years, there has been considerable progress in developing less nephrotoxic 
contrast agents.61 In the late 1980s, low-osmolal contrast replaced the considerably more 
nephrotoxic high-osmolal agents, resulting in a decreased incidence of CIAKI.12, 62 Over the past 
decade, several trials have compared the renal effects of iso-osmolal and low-osmolal contrast 
media.63-65 While these studies have yielded conflicting data regarding the relative risks of 
CIAKI with low versus iso-osmolal contrast media, it is clear that the incidence of CIAKI 
remains substantial in high-risk patients despite the use of these less nephrotoxic agents.66-69 
 
Renal replacement therapies for the prevention of CIAKI have been largely ineffective, and in 
some instances, “prophylactic” hemodialysis has been associated with harm.70-72 The 
interpretation of studies of hemofiltration for the prevention of CIAKI has been confounded by 
the use of change in SCr, a variable that is directly impacted by hemofiltration, as the primary 
study endpoint.73, 74 As a result, use of dialysis or hemofiltration to prevent CIAKI is not 
currently recommended.75 
 
Trials of pharmacologic agents, including furosemide, dopamine, fenoldopam, calcium channel 
blockers, and mannitol have failed to demonstrate benefit and in some cases have documented an 
increased risk of CIAKI.9, 76-80 Studies on the benefit of natriuretic peptides, aminophylline, 
theophylline, statins, and ascorbic acid are mixed, yet the paucity of data on these interventions 
and potential safety concerns with natriuretic peptides, aminophylline, and theophylline has led 
experts to recommend against their routine use.81 Based on a more complete understanding of the 


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pathophysiology of CIAKI, recent research has focused on assessing two specific preventive 
strategies: 1) the administration of IV fluids and 2) the use of antioxidant agents, most notably 
N-acetylcysteine (NAC). 
 
3. 
Intravenous fluids for the prevention of CIAKI 
Intravascular volume expansion with IV fluids is believed to have two actions that protect 
against the development of CIAKI. First, expansion of the intravascular space is thought to blunt 
the vasoconstrictive effect of contrast on the renal medulla due to the suppression of vasopressin, 
inhibition of the renin-angiotensin axis, and increased synthesis of vasodilatory renal 
prostaglandins.82-86 Second, by decreasing the concentration and viscosity of contrast media in 
the tubular lumen, IV fluids are believed to attenuate the direct toxic effect of contrast agents on 
tubular epithelial cells.87 
 
Several randomized clinical trials established the current evidence basis for the use of IV fluids 
to prevent CIAKI and provided preliminary data on the effect of IV fluid composition. In 1994, 
Solomon et al. tested the prophylactic effect of IV fluid alone or in combination with IV mannitol 
or furosemide.79 Patients with CKD undergoing coronary angiography  were randomized to 
receive IV 0.45% (half-isotonic) saline alone prior to and following angiography 
or in 
combination with either 25 gm of IV mannitol or 80 mg of IV furosemide prior to contrast 
administration. The incidence of CIAKI among patients who received IV fluids alone was 11% 
compared to 28% in the IV fluid plus mannitol group and 40% in subjects who received 
furosemide in addition to IV fluids (p=0.02 for comparison with IV fluid alone). While this trial 
did not include a control group of patients who did not receive IV fluid, Trivedi et al. 
subsequently confirmed the benefit of IV fluid in a small clinical trial of patients undergoing 
non-emergent coronary angiography.88 Subjects in this study were randomized to receive either 
IV isotonic saline for 12 hours prior to and 12 hours following angiography or unrestricted oral 
fluids. The study was stopped at an interim analysis after 53 of 160 potential subjects had been 
enrolled when the rate of CIAKI was found to be nearly 10-fold higher in the oral fluid group 
compared to the IV saline group (34.6% v. 3.7%, p=0.005). The effect of tonicity of IV fluids on 
the development of CIAKI was assessed by Mueller and colleagues. Low-risk patients 
undergoing  coronary  angiography  were  randomized  to  receive  peri-procedural  IV  volume 


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expansion with either 0.45% (half-isotonic) saline or 0.9% (isotonic) saline.89 The overall rate of 
CIAKI was greater in patients who received half-isotonic saline compared to those who were 
administered isotonic saline (2% v 0.7%, P=0.04). On the basis of this study, it has generally 
been accepted that isotonic saline is superior to hypotonic saline for the prevention of CIAKI. 
 
a.         Clinical trials and meta-analyses of bicarbonate versus saline to prevent CIAKI 
Recent research on IV fluids for the prevention of CIAKI has focused on identifying the optimal 
fluid composition; specifically, whether isotonic sodium bicarbonate (bicarbonate) is superior to 
isotonic sodium chloride (saline) for the prevention of CIAKI. One of the principal factors 
believed to be associated with the development of CIAKI is the generation of reactive oxygen 
species (ROS) in the kidney following contrast-induced ischemic injury to renal tubular cells 
(see Figure 3 above). Moreover, important clinical risk factors for CIAKI, including chronic 
kidney disease, diabetes, intravascular volume depletion, and heart failure are themselves 
associated with enhanced ROS formation.60, 90-92 ROS are believed to contribute to a number of 
pathophysiologic processes that result in CIAKI-associated tubular damage. First, ROS are 
associated with the depletion of intracellular energy stores used for cellular reparative 
processes.93, 94 Second, ROS may play an important role in potentiating intra-renal ischemia by 
generating and/or augmenting the effects of vasoconstrictors, including isoprostane, angiotensin 
II, and endothelin-I.95-97 Third, ROS decrease the concentration and availability of the potent 
vasodilator nitric oxide, which leads to abnormal endothelial function, dysregulation of the renal 
microcirculation, and augmented renal hypoxia.90, 98, 99 Fourth, ROS are hypothesized to impair 
cellular responses to ischemic injury.100 Based on animal studies, the generation of ROS in the 
kidney is enhanced in acidic urine, and both ROS generation and tubular injury are attenuated by 
urinary alkalinization.101 The theoretical underpinnings of the benefit of IV sodium bicarbonate 
for the prevention of CIAKI are based on the principal that urinary alkalinization with IV 
administration of bicarbonate will decrease the generation of ROS following contrast 
administration and mitigate these ROS-associated pathophysiologic processes that damage renal 
tubular cells. Over the past six years, ten clinical trials that compared IV isotonic bicarbonate 
with IV isotonic saline for the prevention of CIAKI have been published in the peer-reviewed 
literature. Six trials demonstrated a lower incidence of CIAKI with bicarbonate administration, 
whereas four showed no significant differences (Table 4).24, 25, 102-109 


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The disparate results of these ten clinical trials led to a proliferation of systematic reviews and 
meta-analyses comparing the effectiveness of bicarbonate and saline.110-120 Of the eleven meta- 
analyses published to date, ten have reported a reduction in CIAKI with bicarbonate compared to 
saline.111-120 However, these meta-analyses also describe substantial study heterogeneity and 
publication bias, which limited the ability of the investigators to draw definitive conclusions. Ten 
of these meta-analyses cite the need for large, adequately powered, multicenter, randomized 
trials comparing the effects of these two IV fluids on the prevention of CIAKI, and many suggest 
the need for such a study to be designed to detect differences in important patient-centered 
outcomes rather than merely focusing on the small changes in SCr used to define CIAKI.111-120 


 
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Table 4 - Clinical trials comparing IV isotonic bicarbonate and IV isotonic saline to prevent CIAKI 
 
 
Authors 
Number 
of 
patients Diabetes 
Baseline SCr 
(mg/dL) 
Definition of 
10 outcome 
Frequency of 
CIAKI 
bicarbonate 
Frequency of 
CIAKI 
saline 
Dialysis Death 
PDKFa 
Assumed 
effect size of 
bicarbonate 
Positive studies 
Briguori et al.103 
219 
52% 
2.0 
↑ SCr ≥25% 
1.9% 
9.9% 
1% 
NA 
NA 
86% 
Masuda et al.104 
59 
31% 
1.3 
↑ SCr ≥0.5mg/dL or ≥25% 
6.6% 
34.5% 
7% 
3% 
NA 
85% 
Merten et al.105 
119 
48% 
1.7-1.9 
↑ SCr ≥25% 
1.7% 
13.6% 
0% 
NA 
NA 
66% 
Ozcan et al.106 
176 
45% 
1.4 
↑ SCr ≥0.5mg/dL or ≥25% 
4.2% 
16.6% 
1% 
NA 
NA 
NR 
Pakfetrat et al.107 
192 
30% 
1.1 
c 
4.2% 
12.5% 
NA 
NA 
NA 
NR 
Recio-Mayoral et 
al.108 
111 
30% 
1.0 
↑ SCr ≥0.5mg/dL 
1.8% 
21.8% 
4% 
4.5% 
NA 
85% 
Negative studies 
Adolph et al.25 
145 
34% 
1.5-1.6 
↑ SCr ≥0.5mg/dL or ≥25% 
4.2% 
2.7% 
0% 
NA 
NA 
87% 
Brar et al.102 
353 
44% 
1.5 
↓ eGFR ≥25% 
13.3% 
14.6% 
2% b 
2% b 
19% b 
66% 
Maioli et al.24 
502 
24% 
1.2 
↑ SCr ≥0.5mg/dL 
10% 
11.5% 
<1% 
1% 
NA 
50% 
Vasheghani et ald 109 
265 
22% 
1.6-1.6 
↑ SCr ≥0.5mg/dL or ≥25% 
7.4% 
5.9% 
NA 
NA 
NA 
71% 
NA denotes not assessed; NR denotes not reported 
a PDKF denotes persistent decline in kidney function 
b outcomes assessed 2 weeks to 6 months following angiography 
c three definitions of CIAKI assessed; differences between bicarbonate and saline based on ↑ SCr ≥0.3 mg/dL 
d bicarbonate administered as 75 ml of 8.4% sodium bicarbonate added to 1 liter isotonic saline (i.e., hypertonic bicarbonate) 
 
 
 
 
 


 
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In an effort to reconcile the incongruent clinical trial findings, multiple systematic reviews and 
meta-analyses have been performed to analyze the collective results of these studies.119, 121-137 In 
one of the more recent of these meta-analyses, Kelly and colleagues included 26 trials 
encompassing 3,393 patients.138 Based on the pooled data, they calculated a 38% reduction in the 
risk of CIAKI associated with NAC (RR=0.62; 95% CI: 0.44-0.88). Although the investigators 
reported heterogeneity among the pooled studies, they found no evidence of publication bias. In 
another meta-analysis of 22 trials encompassing 2,746 patients published just 3 months earlier, 
Gonzalez et al. found significant heterogeneity among the trials.127 In a cluster analysis, the 
investigators were able to divide the trials into two clusters that had minimal heterogeneity. One 
cluster that included trials in which NAC was found to be protective, was defined by an observed 
decline in SCr following contrast administration in the patients treated with NAC. In the studies 
included in the other cluster, there was no fall in SCr in the NAC-treated patients and no overall 
benefit for the prevention of CIAKI. The investigators concluded that NAC was not effective for 
the prevention of CIAKI. Thus, the conclusions of multiple meta-analyses of NAC are as disparate 
and inconclusive as the findings of the clinical trials that comprise these pooled analyses. 
 
4. 
Clinical trials and meta-analyses of NAC for the prevention of CIAKI 
The rationale for the use of NAC for the prevention of CIAKI relates to its capacity to scavenge 
ROS, reduce the depletion of glutathione, and stimulate the production of vasodilatory mediators 
including nitric oxide.139, 
140 Studies in animal models of AKI demonstrate that the 
administration of NAC reduces oxidative damage, attenuates outer renal medullary 
vasoconstriction, and decreases renal injury.139, 141 These animal studies provided the scientific 
basis for clinical trials of NAC for the prevention of CIAKI. 
 
Tepel et al. first described the efficacy of NAC for the prevention of CIAKI in humans a decade 
ago.142 This trial randomized 83 patients undergoing computed tomography to receive 600 mg of 
NAC or placebo twice daily on the day prior to and the day of the procedure. Significantly fewer 
subjects treated with NAC developed CIAKI compared to patients in the placebo arm (2% v. 
21%, p=0.01). A multitude of trials evaluating NAC for the prevention of CIAKI have since been 
published and have yielded highly conflicting results (Table 5). 23, 142-166 
 


 
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Table 5 - Randomized clinical trials comparing NAC and placebo to prevent CIAKI 
 
Authors 
NAC dose 
Number of 
patients 
Definition 
10 outcome 
% CIAKI 
NAC 
% CIAKI 
Control 
Dialysis 
Death 
PDKFa 
Assumed 
effect size NAC 
Positive studies 
Baker et al167 
b 
80 
↑ SCr ≥25% 
5% 
21% 
0% 
NR 
NR 
c 
Balderramo et al163 
1200 mg po x 2 
61 
↑ SCr ≥0.5 mg/dL 
3% 
7.1% 
NR 
NR 
NR 
90% 
Diaz-Sandoval et al160 
600 mg po x 4 
54 
↑ SCr ≥25%/0.5 mg/dL 
8% 
45% 
NR 
NR 
NR 
NR 
Drager et al159 
600 mg po x 4 
24 
mean Δ CrCl 
NR 
NR 
NR 
NR 
NR 
NR 
Kay et al146 
600 mg po x 4 
200 
↑ SCr ≥25% 
4% 
12% 
0% 
0% 
NR 
c 
MacNeill et al156 
600 mg po x 5 
43 
↑ SCr ≥25% 
5% 
32% 
NR 
NR 
NR 
NR 
Marenzi et al23 
d 
352 
↑ SCr ≥25% 
11.6% 
33% 
2.6% 
6% 
NR 
50% 
Miner et al166 
e 
171 
↑ SCr ≥25% 
9.6% 
22.2% 
2% 
5.5% 
NR 
50% 
Ochoa et al155 
1000 mg po x 2 
80 
↑ SCr ≥25%/0.5 mg/dL 
8% 
25% 
NR 
NR 
NR 
c 
Shyu et al151 
400 mg po x 4 
121 
↑ SCr ≥0.5 mg/dL 
3.3% 
24.6% 
0.8% 
NR 
NR 
c 
Tepel et al142 
600 mg po x 4 
83 
↑ SCr ≥0.5 mg/dL 
2% 
12% 
0% 
NR 
NR 
NR 
Negative studies 
Allaqaband et al150 
600 mg po x 4 
80 
↑ SCr ≥0.5 mg/dL 
17.7% 
15.3% 
NR 
NR 
NR 
NR 
Amini et al165 
600 mg po x 4 
87 
↑ SCr ≥25%/0.5 mg/dL 
11.1% 
14.3% 
NR 
NR 
NR 
90% 
Azmus et al161 
600 mg po x 4 
399 
↑ SCr ≥25%/↓eGFR 50% 
7.1% 
8.4% 
0.5% 
NR 
NR 
65% 
Berwanger et al168 
1200 mg po x 4 
2,308 
↑ SCr ≥25% 
12.7% 
12.7% 
0.3% 
2.0% 
NR 
30% 
Briguori et al144 
600 mg po x 4 
183 
↑ SCr ≥25% 
6.5% 
11% 
0.5% 
NR 
NR 
NR 
Carbonnel et al164 
600 mg IV x 4 
216 
↑ SCr ≥25%/0.5 mg/dL 
10.3% 
10.1% 
0% 
3.7% 
NR 
NR 
Coyle et al145 
600 mg po x 4 
137 
mean Δ SCr 
NR 
NR 
NR 
NR 
NR 
c 
Durham et al149 
1200 mg po x 2 
79 
↑ SCr ≥0.5 mg/dL 
26.3% 
22% 
2.5% 
NR 
NR 
NR 
Fung et al148 
400 mg po x 6 
91 
↑ SCr ≥25%/↓eGFR 50% 
13.3% 
17.4% 
0% 
NR 
NR 
90% 
Goldenberg et al158 
600 mg po x 6 
80 
↑ SCr ≥0.5 mg/dL 
10% 
8% 
0% 
0% 
NR 
90% 
Gomes et al147 
600 mg po x 4 
156 
↑ SCr ≥0.5 mg/dL 
10.4% 
10.1% 
1.3% 
4.5% 
NR 
50% 
Kefer et al157 
1200 mg IV x 2 
104 
↑ SCr ≥25%/0.5 mg/dL 
3.8% 
5.9% 
0% 
NR 
NR 
NR 
Oldemeyer et al154 
1500 mg po x 4 
96 
↑ SCr ≥25%/0.5 mg/dL 
8.2% 
6.4% 
0% 
NR 
NR 
NR 
Rashid et al153 
1000 mg IV x 1 
94 
↑ SCr ≥25%/0.5 mg/dL 
6.5% 
6.3% 
NR 
NR 
NR 
90% 
Sandhu et al152 
600 mg po x 4 
106 
↑ SCr ≥0.5 mg/dL 
5.7% 
0% 
NR 
NR 
NR 
NR 
Webb et al162 
500 mg IV x 1 
487 
↓ CrCl >5ml/min 
23.3% 
20.7% 
0% 
2.5% 
NR 
50% 
NR denotes not reported 
a PDKF denotes persistent decline in kidney function 
b 150 mg/kg IV x 1 hr pre and 50 mg/kg IV x 4 hrs post-angiography 
c effect size based on difference in mean change of SCr 
d 2 NAC groups: standard dose = 600 mg IV and 600 mg po x 4; high dose = 1200 mg IV and 1200 mg po x 4 
e 2000 mg po either x2 or x3 


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As with the trials comparing bicarbonate and saline for the prevention of CIAKI, the primary 
endpoints in all of the trials of NAC were based on small changes in SCr. This includes the most 
recently published ACT trial, which compared oral NAC to oral placebo in 2,308 patients 
undergoing angiography.168 While this study did not demonstrate a benefit to NAC for the 
prevention of CIAKI, a small minority of patient-participants had underlying CKD (N=367) and 
hence, most were at minimal risk for renal injury. While approximately half of the trials of NAC 
tracked short-term need for dialysis, few assessed other clinically-relevant, adverse outcomes 
such as death or persistent decline in kidney function and none were powered to assess the 
effectiveness of NAC in preventing these patient-centered outcomes. One trial by Marenzi et al. 
demonstrated that in addition to preventing CIAKI, NAC was associated with a reduction in 
death and the need for dialysis.23 Thus, there is a paucity of data on the effectiveness of NAC for 
the prevention of serious, adverse, patient-centered events following angiographic procedures. 
 
5. 
Interaction between bicarbonate and NAC 
There are limited data evaluating the interaction between bicarbonate and NAC in the prevention 
of CIAKI.103, 108, 118, 119, 169 Using an experimental model, Romano et al. found no interaction 
between bicarbonate and NAC in the prevention of renal tubular cell apoptosis following exposure 
to iodinated contrast media.169 In a recent systematic review and meta-analysis of IV sodium 
bicarbonate for the prevention of CIAKI, Zoungas et al. identified four studies which included 
data on 983 patients that evaluated combined treatment with sodium bicarbonate and NAC.118 
They observed no difference in the incidence of CIAKI following sodium bicarbonate 
administration with or without concomitant administration of NAC (p for heterogeneity = 0.73). 
Similar results were also seen in a meta-analysis by Brown et al.119 
 
6. 
Summary of limitations of prior studies that evaluated bicarbonate and NAC for the 
prevention of CIAKI 
We believe that there are common limitations of past trials comparing isotonic sodium 
bicarbonate to isotonic saline and prior trials evaluating NAC for the prevention of CIAKI. First, 
all of the published studies have been relatively small. The median number of patients enrolled in 
the trials comparing bicarbonate to saline was 184 (IQR 119, 265), while the median number of 
patients enrolled in the trials of NAC was 96 (IQR 80, 183). These small sample sizes mean that 
the individual studies only had adequate statistical power to detect clinical effects of such 


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magnitude that they are unlikely to be biologically plausible, while failing to detect benefits that 
were smaller and more plausible, yet still clinically meaningful. Second, all of the studies used 
small, short-term changes in SCr as their primary endpoint. While these changes in SCr have 
been used to define CIAKI, they have not been validated as a surrogate endpoint for patient- 
centered outcomes, including death, need for dialysis or persistent decline in kidney function. 
None of the trials to date has been designed with sufficient statistical power to detect differences 
in these clinically meaningful, patient-centered outcomes. Finally, many of the studies enrolled 
patients at relatively low-risk for the development of CIAKI, further diminishing the likelihood 
that a relatively small study could detect a meaningful clinical benefit. These limitations were 
well summarized by Bagshaw et al. in a 2006 review of the use of NAC in preventing CIAKI: 
“…given the clinical trial data published to date, meta-analyses cannot resolve the uncertainty 
engendered by 19 small [randomized clinical trials] with heterogeneous results for a surrogate 
outcome (change in serum creatinine level rather than “harder” end points, such as need for 
dialysis  or  mortality)…Ultimately,  a  much  larger  trial  with  high  methodologic  quality that 
involved multiple centers to achieve sufficient power to study clinically meaningful outcomes is 
needed…….” 170 We believe these comments are equally applicable to the primary studies and 
meta-analyses comparing bicarbonate to saline. 
 
C. 
Clinical implications of the equipoise on the effectiveness of bicarbonate and NAC 
The lack of consensus on the role of bicarbonate and NAC for the prevention of CIAKI is 
evident from the inconsistent use of prophylactic regimens in clinical practice. We recently 
completed a prospective, observational study of 239 Veterans with CKD who underwent non- 
emergent coronary or non-coronary angiography.171 Nearly 20% of patients did not receive any 
peri-procedural  IV  fluid.  Of  patients  who  received  pre-procedure  IV  fluid,  66%  received 
bicarbonate and 34% received hypotonic or isotonic saline. Of patients who received post- 
procedure IV fluid, 44% were administered bicarbonate and 56% received hypotonic or isotonic 
saline. One hundred and eighty-six (78%) of the 239 patients received NAC. However, 24 (12%) 
patients who received NAC did not receive any IV fluid, despite the absence of any studies 
conclusively and definitively demonstrating the effectiveness of NAC. 
 
In this same study, we surveyed 87 VA providers on their knowledge of the effectiveness of 
different interventions for the prevention of CIAKI.172  Nearly half of providers (48%) reported 


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that bicarbonate is ineffective for the prevention of CIAKI or were unsure of its effectiveness, 
while 54% reported NAC to be effective, 24% reported NAC to be ineffective, and 22% were 
unsure of its effectiveness. These observations reflect the clinical equipoise on the comparative 
effectiveness of bicarbonate and saline and benefit of NAC. 
 
There are also data suggesting that that the failure to establish a solid evidence basis for the 
prevention of CIAKI and its adverse medical outcomes has contributed to the under-utilization of 
clinically indicated coronary angiograms in patients with CKD. Chertow and colleagues 
conducted an analysis of more than 55,000 patients to assess whether patients with CKD who 
were diagnosed with an acute MI underwent coronary angiography at a rate comparable to 
patients with intact kidney function.173 While the provision of coronary angiography was 
associated with a significant reduction in mortality (OR=0.62; 95% CI: 0.54-0.70), those with 
CKD deemed to be appropriate candidates for this procedure were less than half as likely to 
undergo angiography compared to patients without CKD (OR=0.47; 95% CI: 0.40-0.52). 
Although the authors did not systematically examine the reasons for under-utilization of 
angiography in individuals with CKD, they posited that concern for the development of CIAKI 
may explain this finding. A subsequent study by Han et al., which included 45,343 patients with 
non-ST elevation MI, of whom 6,560 had moderate to advanced CKD, reported that the presence 
of CKD was independently associated with a nearly 50% decreased likelihood of undergoing 
coronary  angiography  with  PCI  (adjusted  OR=0.52;  95%  CI:  0.34-0.80).  The  investigators 
concluded that fear of CIAKI was a principal reason for this finding.174 Finally, a recent study by 
Goldenberg et al. examined utilization of and outcomes after coronary angiography in over 
13,000 patients with non-ST elevation ACS, more than one-third of whom had CKD. While the 
use of coronary angiography in patients with CKD was associated with a 36% lower risk of in- 
hospital mortality, considerably fewer patients with CKD underwent this procedure compared to 
patients without CKD (49.9% v. 67.8%, p<0.001).175 One of the conclusions drawn by the 
investigators was that measures for the prevention of CIAKI should be implemented to facilitate 
the delivery of appropriate care to patients with CKD. 
 
The clinical equipoise and absence of consensus on the comparative effectiveness of bicarbonate 
and saline and benefit of NAC is perhaps best exemplified by two recent clinical practice 
guidelines. The European Society of Intensive Care Medicine advocates the administration of IV 


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isotonic 
sodium bicarbonate 
rather 
than IV 
isotonic 
sodium chloride 
(grade 
2B 
recommendation), yet recommends against the use of N-acetylcysteine (grade 2B 
recommendation) for the prevention of CIAKI.176 In contrast, while guidelines from the Kidney 
Disease: Improving Global Outcomes (KDIGO) initiative recommend that providers administer 
isotonic IV crystalloid to prevent CIAKI, they specifically do not differentiate between use of 
sodium bicarbonate or sodium chloride (grade 1A recommendation).177 Moreover, the KDIGO 
guidelines recommend the use of NAC (grade 2C recommendation) for the prevention of CIAKI. 
Thus, two clinical practice guidelines differ substantially in regard to their recommendations for 
the use of bicarbonate and NAC to prevent CIAKI. 
 
D. 
Summary 
CIAKI is a common complication of angiographic procedures in high-risk patients and is 
associated with serious adverse outcomes. Greater understanding of its risk factors and 
pathophysiology has informed research on preventive strategies. Although the two most 
promising preventive interventions are isotonic sodium bicarbonate and NAC, multiple clinical 
trials evaluating these interventions have yielded highly conflicting results. Past trials have been 
limited by the enrollment of inadequate numbers of patients based on implausibly large effect 
sizes; the inclusion of patients at relatively low risk for adverse outcomes; and the reliance on 
small and transient changes in SCr as a surrogate study endpoint, rather than clinically 
meaningful, patient-centered events. Finally and most importantly, past studies of preventive 
strategies were not designed or powered to determine the impact of bicarbonate or NAC on 
serious, adverse, patient-centered outcomes. The absence of a consensus on the benefit of these 
interventions has led to non-uniform implementation of these measures in clinical practice and 
may be a factor in the under-utilization of clinically indicated and potentially life-saving 
angiographic procedures in patients with CKD. Considered collectively, these observations 
underscore the need for a large, adequately powered, multicenter clinical trial to assess the 
effectiveness of bicarbonate compared to saline and NAC compared to placebo for the 
prevention of serious, adverse, patient-centered outcomes in high-risk patients undergoing 
angiographic procedures. 


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IV. 
SIGNIFICANCE OF THE PROPOSED RESEARCH TO THE VA 
Approximately 3.6 million coronary and non-coronary angiograms are performed in the United 
States each year.29 Using conservative estimates of the incidence of CIAKI in this broad patient 
population, which includes individuals with and without underlying risk factors for CIAKI, we 
estimate that there are at least 110,000 cases of angiography-associated CIAKI in the United 
States on an annual basis.2, 12, 29 In addition to the serious medical outcomes associated with 
CIAKI reviewed above, the financial costs of this condition are substantial. A single episode of 
CIAKI is associated with an average one-year cost in excess of $11,800.26 Applying this estimate 
to the calculated number of angiography-associated cases of CIAKI yields an annual cost estimate 
for this iatrogenic complication of approximately $1.3 billion. Given the associated morbidity, 
mortality, and financial costs, CIAKI has been identified as an important public health problem. 
The National Quality Forum, a national non-profit organization that aims to improve healthcare 
quality for Americans by setting national priorities and goals for quality improvement, 
has 
included prevention of CIAKI as one of 34 recommendations for safe clinical practice that 
should be universally implemented.178 
 
Within the VA Healthcare System, there are more than 51,000 coronary and non-coronary 
angiograms performed each year involving Veterans with chronic kidney disease (CKD). As a 
result, there are likely many thousands of Veterans who develop angiography-associated CIAKI 
each year. Several epidemiological and clinical observations suggest that the incidence of CIAKI 
following angiography is likely to increase substantially within the VA Healthcare System. First, 
CKD, which is a principal risk factor for CIAKI and other adverse events following angiography, 
affects more than 550,000 Veterans nationwide and due to an aging Veteran population, is likely 
to substantially increase in prevalence over the next decade. Second, diabetes mellitus, which 
amplifies the risk for CIAKI in patients with underlying CKD and is an independent predictor of 
adverse outcomes following angiography, affects over 1,000,000 patients within the VA and is 
increasing in prevalence. Third, patients with CKD who undergo magnetic resonance 
angiography  with  gadolinium-based  contrast  agents  have  been  shown  to  be  at  risk  for 
nephrogenic systemic fibrosis, a debilitating and potentially fatal disorder.179  As a result, many 
patients who in years past would have undergone magnetic resonance angiography will now 
likely undergo conventional angiography with iodinated contrast, increasing the number of 
patients at risk for CIAKI and angiography-related adverse events. In fact, a recent study by Kim 


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et al. confirmed that following the initial public health advisory in 2006 regarding the association 
of gadolinium-based contrast agents with nephrogenic systemic fibrosis, there was a 71% 
decrease in the number of gadolinium contrast-enhanced MRI procedures performed within the 
VA Healthcare System among Veterans with eGFR <30 ml/min/1.73 m2.180 Thus, a large and 
growing number of high-risk Veterans will be undergoing angiographic procedures that will 
place them at risk for CIAKI and its serious, adverse sequelae. The findings of this proposed 
comparative effectiveness trial to prevent serious, adverse patient-centered outcomes will be 
directly applicable to this large and growing population of Veterans. 
 
The proposed clinical trial is focused on angiographic procedures because the risk for CIAKI and 
its associated serious, adverse downstream outcomes is believed to be greater following intra- 
arterial compared to intravenous injection of iodinated contrast. However, intravenous 
administration of iodinated contrast also poses a risk for adverse events in Veterans with advanced 
CKD. There are many more contrast-enhanced computed tomography scans performed each year 
within the VA than angiographic procedures. While many thousands of Veterans likely develop 
CIAKI annually following angiography, a considerably larger number of patients likely develop 
this condition following contrast-enhanced computed tomography. Findings from the proposed 
trial will be applicable to the tens of thousands of Veterans with advanced CKD who undergo 
contrast-enhanced computed tomography scans each year and will inform the delivery of 
preventive care to this additional large and growing patient population. 
 
We previously demonstrated that the use of bicarbonate and NAC in high-risk Veterans 
undergoing angiography is highly variable.8 This prior study found that providers administer 
NAC in lieu of IV fluids in a substantial proportion of patients at risk for CIAKI. This sub- 
optimal care can be explained by the documented uncertainty of VA providers on the 
effectiveness of bicarbonate and NAC.172 The proposed comparative effectiveness trial will 
resolve the clinical equipoise regarding these interventions and facilitate the uniform 
implementation of evidence-based preventive care to Veterans undergoing angiographic 
procedures. 
 
By determining the effectiveness of bicarbonate compared to saline and of NAC compared to 
placebo, the findings of this clinical trial will provide a solid evidence basis that VA providers 


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will be able to use to decrease the incidence of serious, adverse, patient-centered outcomes in the 
large and growing population of Veterans who are at-risk for preventable complications of 
contrast administration. 


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V. 
OVERVIEW OF STUDY DESIGN 
The proposed comparative effectiveness study is a multicenter, randomized, double-blind clinical 
trial that will use a 2 x 2 factorial design to assess the effectiveness of IV isotonic sodium 
bicarbonate compared to IV isotonic saline and NAC compared to placebo for the prevention of 
serious, adverse, patient-centered outcomes in high-risk patients undergoing coronary or non- 
coronary angiography. The primary hypotheses to be tested are that isotonic bicarbonate is more 
effective than saline and that NAC is more effective than placebo for the prevention of serious 
morbidity and mortality following coronary and non-coronary angiography in high-risk 
Veterans. Each of these two hypotheses are of equal importance as there is clinical equipoise on 
both the comparative effectiveness of bicarbonate and saline and the benefit of NAC. Moreover, 
despite the lack of any data establishing the efficacy of NAC in the absence of concomitant IV 
fluids, our data indicate that as many as 12% of high-risk Veterans receive this anti-oxidant in 
lieu of any IV fluids (vide supra).8  We believe that the beneficial effects of these interventions 
on adverse outcomes will be mediated through a reduction in the development of CIAKI. 
 
 
Patients will be enrolled if, at the time of angiography, they have underlying CKD with an eGFR 
<60 ml/min/1.73 m2 and a diagnosis of diabetes mellitus, or an eGFR <45 ml/min/1.73 m2 
regardless of whether or not they have diabetes mellitus. Eligible patients who consent to 
participate will be randomized prior to angiography to receive: 1) IV isotonic bicarbonate or IV 
isotonic saline and 2) oral NAC or oral placebo. Randomization will be stratified by site. At least 
3 ml/kg of the IV isotonic study crystalloid solution (sodium bicarbonate or saline) will be 
infused over a minimum of 1 hour at an infusion rate of not less than 1 mL/kg per hour and not 
more than 3 mL/kg per hour immediately prior to the angiographic procedure; 1-1.5ml/kg per 
hour will be infused during angiography; and at least 6 ml/kg will be administered during over at 
least  2 hours at an infusion rate of not less than 1 mL/kg per hour and not more than  3 mL/kg 
per hour following the procedure. This approach will ensure the provision of a minimum necessary 
volume of IV fluid, yet permit providers to administer additional study IV fluid as they deem 
clinically appropriate based on their assessment of individual patients. In patients who are obese 
(BMI >30 kg/m2) and weigh more than 125 kg, calculated rates of fluid administration should be 
capped based on a weight of 125 kg. NAC or placebo will be administered in an oral dose of 
1200 mg twice daily beginning on the day of angiography and continuing for a total of 5 days. 


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The primary study outcome will be a 90-day composite end-point comprised of death, need for 
acute dialysis, or persistent decline in kidney function, defined based on an increase in SCr at 90 
days of ≥50% relative to baseline. The development of CIAKI, defined by an increase in SCr of 
≥0.5 mg/dL and/or ≥25% at 4 days following contrast administration will be assessed as a 
secondary outcome. As additional secondary outcomes, we will evaluate death, the renal 
components of the primary composite endpoint (i.e., need for acute dialysis, persistent decline in 
kidney function), hospitalization with major adverse cardiac events (i.e., ACS, HF, CVA), and 
all-cause hospitalization. We will assess the development of ESRD and mortality at 1 year as a 
tertiary (exploratory) outcome. 
 
Based on analyses of over 25,000 Veterans with CKD who underwent angiography within the 
VA Healthcare System, we estimate that the baseline incidence of our primary study endpoint 
among eligible patients is 8.7%. Using this rate in the control arms of our study allows us to 
more conservatively estimate the overall event rate to be 7.6%. Considering these estimates, an 
intervention effect size of 25%, the absence of an interaction between our two interventions, a 
two-sided alpha of 0.025, and anticipated loss to follow-up of 3%, 7,680 patients (1,920 patients 
per treatment cell) will be required to test the primary hypothesis with 90% power. Thirty-three 
VA sites will be expected to enroll an average of 100 patients per year during the 2½ year 
recruitment period. 


 
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Table 6 - Overview of data collection 
Screening 
and 
Eligibility 
Pre- 
angiography 
Post- 
angiography 
(prior to 
discharge) 
12 hours – 4 
days 
post- 
angiography 
4 days 
post- 
angiography 
5-8 days post- 
angiography 
35-49 days 
post- 
angiography 
90 days post 
angiography 
1-Year post 
angiography 
Informed consent obtained 
X 
Clinical care SCr 
X a 
X 
Eligibility criteria 
X b 
Study Scr 
X d 
X d 
X d 
Subject contact info, military history 
X 
Medications 
X 
X 
X e 
Weight, blood pressure 
X c 
Urine protein, albumin, Cr 
X i 
Hemoglobin,   glucose,   electrolytes, 
BUN, HCO3 
a 
X a, h 
Hemoglobin A1C (if diabetic) 
X g, h 
Demographics 
X h 
Medical comorbidities 
X h 
Non-study IV fluid administration 
X 
X 
Urine pH 
X 
Procedural data/complications 
X 
Post-angiography events 
X 
X e 
NAC pill count 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
Assessment of 10 outcome 
X 
Assessment of 20 outcomes 
Xf 
X 
Assessment of ESRD 
X 
Assessment of long-term mortality 
X 
a denotes labs or procedures performed as part of routine clinical care by providers within 30 days prior to angiography 
b eligibility based on eGFR calculated from SCr performed as part of routine clinical care within 30 days prior to angiography.  If no Scr measurement was taken 
within 30 days prior to angiography, the patient’s consent will be sought and if obtained, a blood sample will be drawn for Scr measurement at the site’s VA 
laboratory to determine eligibility. 
c blood pressure denotes measurement taken as part of routine clinical care within 3 days prior to angiography; weight is most recent weight in medical record or 
by patient report or coordinator measurement 
d denotes SCr sent to central study laboratory for endpoint ascertainment 
e denotes information collected on subjects who remain hospitalized following angiography or who return to the hospital within 4 days of angiography 
f denotes assessment of CIAKI based on 4-day study SCr 
g denotes labs performed as part of routine clinical care by providers within 1 year prior to angiography 
h depending on the time constraints prior to angiography, this data may be collected immediately following the angiography procedure. 
i denotes urine sample collected prior to contrast administration and tested in the site’s VA laboratory 
 
 
 
 


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VI. 
STUDY POPULATION AND PATIENT RECRUITMENT 
A. 
Study population 
The study population will consist of outpatients and inpatients undergoing coronary or non- 
coronary angiography at any of the study sites who are at high risk for the development of 
CIAKI and its serious, adverse medical outcomes. Since a major risk factor for CIAKI and 
subsequent adverse clinical events following angiography is the presence of decreased kidney 
function, and at any given level of kidney function the risk is increased in patients with diabetes 
mellitus,  we  will  enroll  patients  with  an  estimated  glomerular  filtration  rate  (eGFR)  <60 
mL/min/1.73  m2   who  have  diabetes  mellitus,  as  well  as  patients  who  have  an  eGFR  <45 
mL/min/1.73 m2 regardless of whether or not they have diabetes mellitus.11-13, 181 To optimize the 
recruitment of patients at particularly high risk for adverse events following angiography, we 
will include patients undergoing urgent procedures and those with non-decompensated heart 
failure (i.e., heart failure that is not being treated with inamrinone, milrinone, dobutamine or 
nesiritide, isolated ultrafiltration therapy, and/or an intra-aortic balloon pump) at the time of their 
procedure. 
 
1. 
Inclusion criteria 
 Planned elective or urgent coronary or non-coronary angiography with iodinated contrast 
media in which it is anticipated that there will be an interval of ≥3 hours between the 
identification of the indication for angiography and the time of the planned procedure. 
(Procedures in which this interval is anticipated to be <3 hours will be considered emergent 
and these patients will be excluded – see exclusion criteria below) 
 Pre-angiography eGFR <60 ml/min/1.73 m2 with diabetes mellitus or 
pre-angiography eGFR <45 ml/min/1.73 m2 with or without diabetes mellitus 
o eGFR will be calculated using the 4-variable Modification of Diet in Renal Disease 
(MDRD) formula. The specific 4-variable MDRD formula used will depend on 
whether the screening SCr value was measured using an IDMS- traceable or non-
IDMS traceable laboratory methodology. This screening SCr will be measured as 
part of routine clinical care within 30 days prior  to angiography.182 For patients 
with multiple pre-procedure SCr values in this 30- day time frame, we will base 
eligibility on the SCr measured as part of routine 


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clinical care most proximate to the index angiogram that was obtained prior to the 
initiation of study IV fluids. Our past research and recent queries of VA clinical 
sites nationwide indicates that 91-95% of Veterans undergoing angiography have 
a SCr measured within 30 days prior to angiography. 
o Diabetes  mellitus  will  be  defined  as 
current  use  of  oral  hypoglycemic 
medications and/or insulin and/or : 
 Hgb A1C value of ≥ 6.5% within the previous 12 months or: 
 Medical record documentation of end-organ diabetic disease (e.g., diabetic 
retinopathy, diabetic nephropathy and/or diabetic neuropathy). 
 Ability to provide informed consent 
 
 
2. 
Exclusion criteria 
 Currently  receiving  hemodialysis,  peritoneal  dialysis,  continuous  renal  replacement 
therapy, or sustained low efficiency dialysis (SLED) 
 Stage 5 CKD (eGFR <15 mL/min/1.73 m2) 
 Unstable baseline SCr (if known) at the time of angiography defined by a change in SCr 
of ≥25% over the 3 days prior to angiography 
 Decompensated heart failure requiring any of the following therapies at the time of 
angiography (we are excluding these patients because IV fluid administration may be 
contraindicated): 
o IV milrinone, inamrinone, dobutamine, or nesiritide 
o Isolated ultrafiltration therapy 
o Intra-aortic balloon pump 
 Emergent angiography procedures defined as an anticipated duration of <3 hours between 
the identification of the indication for angiography and the time of the planned procedure. 
We are excluding these patients due to the limited time to collect necessary research data 
and to ensure that research procedures do not interfere with time-sensitive clinical care. 
 Receipt of intravascular iodinated contrast within the 5 days preceding angiography 
 Receipt of oral or IV NAC within the 48 hours preceding angiography 
 Known allergy to NAC 
 Known anaphylactic allergy to iodinated contrast media 


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 Age <18 years 
 Pregnancy 
 Prisoner 
 Ongoing participation in an unapproved concurrent interventional study 
Eligible patients who indicate at the time of recruitment an unwillingness to comply with the 96- 
hour and 90-day outcome assessments will also be excluded. 
 
B. 
Screening and patient recruitment 
Requisite waivers of HIPAA authorization and informed consent for screening will be obtained 
in order to allow study coordinators to review angiography logs/schedules in advance to identify 
patients scheduled for coronary or non-coronary angiography and assess their electronic medical 
records for eligibility. After the study is introduced to the patient by an individual participating in 
their care, research personnel will contact potentially eligible subjects to describe the study and 
complete the screening process. 
 
Based on our past study of Veterans undergoing angiography and recent queries of VA clinical 
sites nationwide, more than 90% of patients will have had a SCr measured as part of routine care 
within 30 days prior to angiography. For the small number of patients who have not had a SCr 
measured within 30 days, research personnel will contact them as stated above and, if they are 
agreeable, administer informed consent and then obtain a screening SCr prior to angiography to 
assess eligibility based on their underlying level of kidney function. 
 
We will require that potentially eligible female subjects who are able to have children (not 
considered post-menopausal [had a menstrual period within previous 12 months], not had tubal 
ligation, a hysterectomy or bilateral oophorectomy) and are sexually active, have a negative 
pregnancy test before being enrolled in the study. 
 
We believe that even for urgent angiograms for indications such as non-ST elevation MI or 
peripheral vascular occlusion, there will be sufficient time (>3 hours) prior to the procedure to 
determine eligibility, obtain consent, perform randomization, and implement the study 
interventions. Including these subjects will help ensure the recruitment of a high-risk patient 


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population. No adult patient (age ≥18 years) will be excluded from participating based on age, 
gender, race, ethnicity, or sexual preference. 


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VII. 
STUDY PROCEDURES 
A. 
Assessment of pre-procedure renal function 
Based on the structure of healthcare delivery within the VA Healthcare System in which patients 
frequently travel long distances to large VA Medical Centers for procedures such as angiograms, 
the SCr measured by the treating provider as part of routine clinical care prior to the procedure 
may be performed at a different VA laboratory than the SCr measured by the treating provider 
after the procedure. While an increasing majority of VA laboratories are using a standardized, 
IDMS-traceable method of measuring SCr, not all VA laboratories are using this calibrated 
methodology. Therefore, there may be inter-laboratory variation in SCr values due to differences 
in laboratory instrumentation and the lack of use of standardized methods of calibration. To 
reliably and accurately assess the development of persistent decline in kidney function 
(component of the primary endpoint) and CIAKI (secondary endpoint), it is essential that pre- 
and post-procedure SCr measurements for this purpose be standardized. We will therefore utilize 
a central laboratory to measure the pre-procedure study SCr and follow-up SCr values for 
endpoint ascertainment. 
 
The timing of the pre-procedure study SCr (reference SCr) measurement used to assess these 
outcomes is also critical as the administration of IV fluids may lead to hemodilution and artifactual 
lowering of SCr. In addition, variation in intravascular volume status affects renal function, 
particularly in patients with underlying CKD. Therefore, we will standardize the timing 
of 
assessment of the reference SCr for endpoint ascertainment. This sample will be obtained 
following patient enrollment and immediately prior to the initiation of study IV fluids and study 
drug capsules to avoid any potential effects of study interventions on the baseline SCr level. This 
reference SCr sample will be distinct from the baseline pre-procedure SCr measured by the 
treating provider as part of routine clinical care that we will use to determine study eligibility. It 
is possible that due to expected variation in SCr levels and measurements, the baseline SCr used 
to determine eligibility will differ from the reference SCr such that patients who meet inclusion 
criteria based on the screening SCr would not have been eligible based on the reference SCr. 
Such patients will not subsequently be excluded or withdrawn from the study. 


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B. 
Randomization procedures 
All patients meeting eligibility criteria and providing informed consent will be randomized to 
each of the two study interventions (IV isotonic bicarbonate versus IV isotonic saline and NAC 
versus placebo). The 2 x 2 factorial design will result in four discrete treatment combinations 
(bicarbonate/NAC, bicarbonate/placebo, saline/NAC and saline/placebo). Patients will be 
allocated in a 1:1:1:1 manner to each of these four treatment combinations. Randomization will 
be accomplished using a permuted block scheme with block size set to provide equal distribution 
into these four possible treatment combinations. Some offset or variability will be inserted to 
prevent anticipation of the next treatment. Randomization will be stratified by study site. 
Stratification by site is necessary to account for local variation in processes of care including the 
type and volume of iodinated contrast media administered during angiography and site-specific 
differences in peri-procedural provider practices such as discontinuation of angiotensin 
converting enzyme inhibitors, angiotensin receptor blockers, and diuretics. 
 
Study coordinators at each site will be responsible for obtaining a randomized treatment 
assignment for each eligible patient. A web-based randomization program will be provided to 
study sites for this purpose. This web-based program will be tested at each site prior to the start 
of the trial and will be reviewed, as per Center guidelines, by the CSP Clinical Research 
Pharmacy Coordinating Center (CSPCRPCC) and the MAVERIC CSPCC. At the time of subject 
enrollment, study coordinators will enter the Subject ID number and study site into the 
randomization program. The program will check that all eligibility criteria are met. If met, the 
program will select the first unused entry from the pre-specified list of random treatment 
assignments for the particular site. The lists are stored on a secure server at the CSPCRPCC. If 
the electronic system fails, the same process will be carried out by telephone and fax. In such 
instances, research personnel at the site will contact the CSPCRPCC for instructions on 
completing a manual randomization. The eligibility criteria will be verified by the CSPCRPCC. 
If eligible, the random treatment assignment will be provided to research personnel. 
 
C. 
Blinding 
Providers performing angiography, participating patients, personnel at the study  chairmen's 
office, and research personnel at each site will be blinded to treatment assignment. Study IV 


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fluids will be provided in coded bags without specific labeling on the bag regarding the 
composition of the fluid. The appearance of the sodium bicarbonate solutions and sodium 
chloride solutions will be identical. NAC will be provided as 300 mg capsules or matching 
placebo capsules prepared by the VA CSP Clinical Research Pharmacy Coordinating Center in 
Albuquerque, NM. The use of NAC powder as a capsule avoids the difficulty of masking the 
strong odor and unpleasant taste associated with the liquid formulation of NAC. 
 
D. 
Study interventions 
In each of the four study arms, patients will receive a combination of the two interventions: 
 IV isotonic sodium bicarbonate or IV isotonic saline 
 Oral NAC or oral placebo 
 
 
1. 
IV fluids 
We will administer ≥3 ml/kg of study IV fluid over ≥1 hour at an infusion rate of not less than 1 
mL/kg per hour and not more than 3 mL/kg per hour immediately prior to the angiographic 
procedure, 1-1.5ml/kg of study IV fluid per hour during angiography, and ≥6 ml/kg of study IV 
fluid over ≥ 2 hours following the procedure at an infusion rate of not less than 1 mL/kg per hour 
and not more than  3 mL/kg per hour. Providers will retain discretion to administer larger 
volumes of the randomly allocated study IV fluid (up to a maximum of 12 mL/kg) over durations 
of up to 12 hours pre and 12 hours post-procedure. The protocol will prohibit the delivery of 
smaller volumes of study IV fluid over shorter durations than the pre-specified minimums 
described above. In patients who are obese (BMI >30 kg/m2) and weigh more than 125 kg, 
calculated rates of fluid administration should be capped based on a weight of 125 kg. 
 
We chose this individualized approach rather than a strict protocol for IV fluid administration for 
two reasons. First, the optimal rate, duration, and volume of IV fluid for the prevention of CIAKI 
and other adverse outcomes have not been conclusively determined. Although there is a general 
belief that “more fluid” is superior to “less fluid,” this premise has not been rigorously tested. 
This uncertainty is underscored by published expert recommendations for the use of IV fluids 
that acknowledge the lack of evidence to support a specific IV fluid regimen.183 Second, requiring 
that IV fluids be administered at a specific rate for a precise period of time would likely be 
perceived as non-evidence based, could significantly limit provider willingness to have 


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their patients participate, and would reduce the generalizability of study findings. In clinical 
practice, the volume and duration of pre and post-procedure IV fluid often vary based on the 
clinical setting and individual patient circumstances. 
 
We do not believe that using this approach will compromise our ability to determine differences 
in study outcomes between the two isotonic IV fluids. The theoretical underpinning for the effect 
of bicarbonate relates to alkalinization of renal tubular fluid. Based on prior studies, which have 
used variable rates of fluid administration ranging from 3 mL/kg for 1 hour pre-procedure and 
1.5 mL/kg/hr for 4 hours post procedure to 1 mL/kg/hr for 12 hours pre and post-procedure, the 
rates of fluid administration that we propose to use should be more than sufficient to achieve 
urinary alkalinization among patients randomized to receive bicarbonate.103, 105 In addition, we 
anticipate that randomization will result in the delivery of equivalent volumes of study IV fluid 
across treatment groups. 
 
2. 
NAC and placebo 
NAC or placebo will be administered at a dose of 1200 mg orally to all patients approximately 1 
hour prior to angiography, approximately 1 hour following the procedure, and then twice daily 
for the next 4 days. Although initial studies using NAC utilized a dose of 600 mg per dose, 
subsequent studies have suggested greater benefit with higher doses of this agent.184 Therefore, 
we will provide 1200 mg per dose of oral NAC. Nearly all prior studies administered NAC for a 
total of 2 days. However, iodinated contrast may persist in the kidney tubules for a prolonged 
period of time, particularly in patients with decreased kidney function.185, 186 Although it is not 
known whether this residual contrast results in persistent renal damage, there may be benefit to 
more sustained therapy with NAC with little added cost or risk. Therefore, we will administer 
NAC capsules twice daily for 5 days. 
 
Although several prior trials investigated the benefit of NAC administered intravenously for the 
prevention of CIAKI, we chose to use oral administration for three reasons.23, 157, 162, 167 First, oral 
NAC is associated with minimal risk, while up to 15% of patients who receive IV NAC experience 
an adverse reaction, which rarely, includes anaphylaxis.187, 188 Second, IV NAC is considerably 
more expensive than the oral preparation.189 Finally, there is no clear evidence that 


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IV NAC offers greater protection against CIAKI or serious adverse outcomes compared to oral 
NAC. 
 
E. 
Additional peri-procedural management issues 
While all contrast agents may be a source of potential clinical complications, the osmolality of 
the contrast agent is believed to potentially impact the risk for CIAKI. Data conclusively 
demonstrate that high osmolality (>1200 mOsm/kg) agents pose a greater risk for CIAKI than 
low osmolality (500-860 mOsm/kg) agents in high-risk patients.12, 62 However, data on the 
comparative incidence of CIAKI with iso-osmolal and low-osmolal contrast are conflicting and 
inconclusive. To provide care that is consistent with prior guidelines issued by the American 
College of Cardiology/American Heart Association for the use of iodinated contrast in patients 
with CKD, all patients in this trial will receive either iso-osmolal contrast media (i.e., iodixanol) 
or non-ionic, low-osmolal contrast media with a recommendation to avoid using ioxaglate and 
iohexol.190 Selection of the specific contrast agent and the volume of contrast administered will 
be at the discretion of the treating provider as there is no current consensus on the least nephrotoxic 
contrast agent. Given the very large number of patients targeted for enrollment, we 
believe that the process of randomization will result in comparable distributions of patients who 
receive different contrast agents across study groups. 
 
We will recommend to the treating provider that selective and non-selective non-steroidal anti- 
inflammatory medications other than once daily aspirin be stopped at the time of the procedure 
and held for 4days following angiography, as the use of these medications is believed to increase 
the risk for CIAKI.183, 191 We will defer decisions on the discontinuation of angiotensin converting 
enzyme inhibitors, angiotensin receptor blockers, and diuretics to the treating provider(s) 
because there are no conclusive data on the optimal approach to the management of these 
medications in patients with CKD undergoing angiography. 
 
Finally, should the patient require bolus administration of IV fluid in excess of 250 ml during the 
angiogram, we will instruct providers performing the procedure that IV saline should be 
administered rather than study IV fluid since the bolus administration of large volumes of 
bicarbonate poses potential safety concerns due to abrupt systemic alkalemia. We do not believe 


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that such emergency boluses of saline are likely to affect our outcomes because only a minority 
of patients is likely to require such additional fluid boluses and the benefit of bicarbonate relates 
to its ability to alkalinize the urine. To assess urinary alkalinization in patients randomized to 
receive bicarbonate and evaluate differences in urine pH between IV fluid arms, we will obtain a 
urine specimen within approximately 4 hours following angiography for analysis of pH using  a 
digital pH analyzer. 
 
F. Post- procedure management issues 
Following angiography and prior to discharge from the hospital, study coordinators will provide 
the participant with instructions on how to take their study medication (i.e., NAC or placebo 
capsules) while at home. Participants will be given a study medication diary to record the dates 
and number of capsules taken. Participants will be instructed to notify study staff and bring 
their study medication with them in the event they require hospitalization. Prior to discharge, 
study coordinators will also arrange the participant’s blood specimen collection 4 days following 
their angiography. Options for this blood draw may include, but not be limited to: 1) returning 
to the study VA; 2) having a mobile phlebotomy service draw the blood; or 3) having the blood 
drawn at a non-study VA site such as a Community-Based Outpatient Clinic (CBOC) or another 
VA facility closer to the participant’s home. 
  
G. 
Study Outcomes 
1. 
Conceptual basis for study outcomes 
Nearly all clinical trials of IV fluid and NAC for the prevention of CIAKI utilized the surrogate 
endpoint of change in SCr within 2 to 5 days of contrast administration and were not designed or 
powered to test the hypothesis that these interventions prevent serious, adverse downstream 
outcomes. While there is a strong association between small changes in SCr within days of 
angiography and adverse downstream outcomes, not all episodes of CIAKI lead to serious 
downstream events (Figure 4). For this reason, the primary objective of this trial is to evaluate 
whether bicarbonate (as compared to saline) and NAC (as compared to placebo) reduce the 
incidence of serious, adverse patient-centered outcomes. We postulate that the beneficial effects 
of bicarbonate and NAC on adverse downstream outcomes will be mediated specifically by 
means of a reduction in the incidence of CIAKI. 


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2. 
Primary study outcome 
The primary outcome will be a composite 
of 
serious, 
adverse, 
patient-centered 
events, including death, need for acute 
dialysis, or persistent decline in kidney 
function 
within 
90 
days 
following 
angiography. These outcomes, which we 
refer to as major adverse kidney events and 
death (MAKE-D) will be defined as 
follows: 
 Death based on medical record 
and/or 
vital 
status 
registry 
documentation. 
 Need for acute dialysis defined as 
the initiation of any modality of 
renal         replacement         therapy 
Figure 4 - Conceptual basis for primary outcomes 
(intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy, or 
sustained low-efficiency dialysis) within 90 days of the index angiographic procedure. 
 Persistent decline in kidney function defined by an increase in SCr from the baseline 
value of at least 50% at 90 days following the index angiographic procedure. This 
outcome will be based on a comparison of the pre-angiography and 90-day SCr values 
analyzed at the central laboratory. 
 
3. 
Justification for components of the primary endpoint 
We selected the individual components of the primary endpoint based on the biologically and 
clinically plausible link between the development of CIAKI and these clinically-relevant 
downstream events. Each of the components of the primary outcome is a recognized 
complication of CIAKI and analyses of our database of over 25,000 Veterans with CKD who 
underwent coronary angiography demonstrate that patients who developed CIAKI following 
angiography were four times more likely than patients without CIAKI to experience one or more 
Development of CIAKI 
No serious, adverse
patient-centered
outcomes 
outcomes 
mortality 
dialysis 
- persistent renal injury 
- hospitalization with AKI 
Risk Factors 
- Chronic kidney disease 
- Diabetes 
- Heart failure 
 
Bicarbonate (v. saline) 
NAC (v. placebo) 


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of the events that comprise our primary endpoint. Prevention of CIAKI will likely decrease the 
incidence of each of these downstream outcomes. 
 
a. 
Justification for inclusion of death in primary endpoint 
Multiple prior studies (vide supra) have demonstrated an association of CIAKI with death.11, 16, 
19, 21, 192 While we anticipate that fewer patients will experience death compared to the other 
components of the primary endpoint, death is the most serious outcome and a competing event, 
and is therefore important to include in our composite endpoint. 
 
b. 
Justification for inclusion of acute dialysis in primary endpoint 
The need for dialysis as a component of our primary composite outcome refers to acute dialysis 
that may or may not lead to the chronic long-term requirement for renal replacement therapy. 
Given that we are proposing to enroll patients with Stage 3 and Stage 4 CKD (baseline eGFR 15- 
60 ml/min/1.73 m2), it would be unexpected for these patients to progress to ESRD and need 
chronic dialysis within the 90-day follow-up period without an acute change in the trajectory of 
their chronic kidney disease. For patients who require acute dialysis in the setting of AKI, failure 
to recover kidney function within 90 days is the conventionally accepted transition from acute 
dialysis to end-stage renal disease and "chronic" dialysis.193, 194 Thus, the need for dialysis within 
90 days of contrast administration as a component of the primary outcome in this study is, by 
definition, acute dialysis. Patients who require acute dialysis following an episode of CIAKI 
may: i) experience a full or partial recovery of kidney function obviating the need for continued 
dialysis therapy; ii) develop ESRD necessitating chronic renal replacement therapy; or iii) die 
within 90 days before meeting the definition of ESRD/chronic dialysis. While CIAKI resulting in 
death or the need for chronic dialysis (i.e., ESRD) is relatively uncommon, the clinical 
significance of such outcomes is unequivocal. Less well recognized are the important adverse 
short and long-term implications of AKI that requires acute transient dialysis. Acute temporary 
dialysis, either with intermittent hemodialysis or continuous renal replacement therapy, is 
associated with important short-term adverse outcomes, including bleeding and blood-borne 
infection related to dialysis catheter placement, hemodynamic instability due to fluid and solute 
shifts during the dialysis procedure, and financial costs that may exceed $500 to $1,000 per 
treatment. Two recently published large studies demonstrated the longer-term implications of 


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acute temporary dialysis following an episode of AKI. Wald et al. conducted a population-based 
cohort study comparing long-term outcomes of 3,769 patients who developed AKI that required 
temporary dialysis with 13,598 matched controls who were hospitalized, but did not develop 
AKI.195 At a median of 3 years of follow-up, the risk for ESRD was more than 3-fold higher 
among patients who required acute transient dialysis compared to severity of illness matched 
controls (adjusted HR 3.23; 95% CI: 2.70-3.86). Another study by Lo and colleagues examined 
the association of AKI that required transient dialysis with progression of CKD and mortality.196 
Among  562,799  hospitalized  patients  who  had  a  baseline  eGFR  ≥45  ml/min/1.73  m2,  703 
sustained dialysis-requiring AKI, of whom 295 (42%) died, 65 (9%) remained chronically dialysis 
dependent, and 343 (49%) recovered sufficient kidney function to be able to discontinue dialysis 
by the time of hospital discharge. In multivariate analyses, AKI requiring transient dialysis 
was associated with a 28-fold increased risk of developing progressive CKD, defined as a decline 
in kidney function to an eGFR ≤30 ml/min/1.73m2, and a 2-fold increase risk of death 
over 6 years of follow up.196 Thus, the need for acute transient dialysis following an episode of 
AKI has substantial short and long-term clinical implications and represents a clinically 
important component of our primary composite endpoint. 
 
c. 
Justification for inclusion of persistent decline in kidney function in primary endpoint 
A series of recent studies demonstrated robust associations of CIAKI with persistent renal injury 
and with an acceleration in the long-term rate of decline in kidney function.24, 30, 197 We propose 
to include persistent renal injury at 90 days following angiography, defined by an increase in SCr 
from baseline of ≥50%, in our primary composite endpoint. In preliminary analyses, we found 
that the development of CIAKI following angiography was associated with a prognostically 
meaningful, greater than 2-fold increase in the risk of developing a ≥50% increase in SCr at 90 
days (OR = 2.4, 95% CI 1.9-3.0) confirming the strong link between CIAKI and persistent renal 
injury    at    90 
days. 
However, 
in 
order 
to 
confirm 
the 
clinical 
  Table 7. Associations of Changes in SCr at 90 days with adverse 1 year outcomes   
25-50% ↑ SCr 
≥ 25% ↑ SCr 
≥ 50% ↑ SCr 
1-yr Outcome 
OR 
95% CI 
OR 
95% CI 
OR 
95% CI 
Death 
1.7 
1.3-2.3 
2.7 
2.2-3.3 
4.9 
3.7-6.3 
Need for dialysis 
1.8 
1.5-2.2 
2.8 
2.4-3.2 
5.2 
4.3-6.2 
Doubling in SCr 
4.8 
3.1-7.1 
6.5 
4.7-9.1 
7.9 
5.3-11.8 
Composite 
2.0 
1.7-2.3 
3.0 
2.7-3.4 
5.9 
4.9-7.0 


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significance of this level of persistent decline in kidney function at 90 days following 
angiography and justify its inclusion in our primary endpoint, we performed more long-term 
follow-up of over 25,000 Veterans with CKD who underwent coronary or non-coronary 
angiography within the VA Healthcare System. Using this VA database, we examined the 
associations of variable threshold increases in SCr at 90 days with adverse 1-year outcomes (i.e., 
death, need for dialysis, or doubling in SCr) (Table 7). While increases in SCr at 90 days of 25% 
to 50% and >25% were associated with increased risk for each of these adverse 1-year outcomes, 
the risk of these long-term events increased markedly among patients with a >50% increase in 
SCr at 90 days. Compared to patients who did not experience a ≥50% increase in SCr at 90 days 
following angiography, patients who developed a ≥50% increase in SCr at 90 days were nearly 6 
times more likely to die, develop the need for dialysis, and/or experience a doubling in SCr 
within one year (Table 7). Collectively, these data confirm the strong association between CIAKI 
and a ≥50% increase in SCr at 90 days following angiography, demonstrate the clinical 
importance and downstream implications of this threshold level of persistent renal injury at 90 
days, and provide robust evidence supporting the inclusion of this outcome as a component of 
our primary composite endpoint. 
 
d. 
Justification for 90-day time frame to assess the primary endpoint 
We chose to assess our primary endpoint at 90 days following angiography for two reasons. 
First, this represents a period of time during which adverse outcomes are more likely than not to 
be associated with the index angiographic procedure. Second, 90 days is commonly used in 
clinical practice and is proposed by the Kidney Disease: Improving Global Outcomes Foundation 
and the National Kidney Foundation to define the transition between acute and chronic 
impairment in kidney function. Therefore, persistent decline in kidney function measured at 90- 
days after the index angiographic procedure likely represents irreversible renal damage. 
 
4. 
Secondary study outcomes 
The secondary outcomes consist of: 
 CIAKI defined by an increase in SCr of ≥0.5 mg/dL and/or ≥25% from the pre-procedure 
value at 4 days following angiography. 
 Death within 90 days of the index angiographic procedure. 


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 The renal components of the primary endpoint: 
o Need for acute dialysis within 90 days of the index angiographic procedure 
o Persistent decline in kidney function at 90 days following the index angiographic 
procedure 
 Hospitalization with acute coronary syndrome, heart failure, or cerebrovascular accident 
within 90 days following the index angiographic procedure. These outcomes will be 
defined as a primary or secondary discharge diagnosis of acute coronary syndrome (i.e., 
STEMI, NSTEMI, unstable angina), heart failure, or cerebrovascular accident 
documented in the VA electronic medical record or the hospital discharge summary 
obtained for non-VA hospitalizations. (This will include the occurrence of any of these 
events during the index hospitalization). 
 All-cause re-hospitalization within 90 days of the index angiographic procedure assessed 
as episodes of re-hospitalization, days of hospitalization (inclusive of the index 
hospitalization), and hospital free days (alive and not in the hospital) through day 90. 
 
Because AKI can occur following angiography for reasons unrelated to the administration of 
iodinated contrast, in a sensitivity analyses, we will also evaluate the development of CIAKI 
using the same threshold change in SCr, but excluding patients who experienced hypotension 
and/or who underwent cardiac surgery or non-cardiac vascular surgery within the 4 days 
following angiography. 
 
5. 
Tertiary (exploratory) outcomes 
 Development of end-stage renal disease within one year following angiography defined 
by the requirement for chronic dialysis for ≥3 months based on documentation in the 
United States Renal Data System database. 
 Death within one year following angiography based on documentation in the VA 
Beneficiary Identification and Records Locator System, the National Center for Health 
Statistics National Death Index database, the Social Security Administration’s Death 
Master File and/or other similar databases. 


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H. 
Data collection 
1. 
Assessment of baseline demographic and clinical characteristics 
Following patient enrollment, research personnel will interview the subject and/or conduct a 
comprehensive review of the electronic medical record to abstract the following data elements: 
 Whether the subject was an inpatient or outpatient immediately prior to the angiography 
procedure 
 Demographic characteristics including date of birth, gender, race, and ethnicity 
 Contact information including home, work, and cell phone numbers; address; email; 
preferred contact times; as well as the same information for an alternate contact 
 Social security number 
 Military history 
 Pre-procedure laboratory parameters obtained as part of routine clinical care including 
date of test: 
o Hemoglobin level, serum glucose, serum bicarbonate, sodium, potassium and 
blood urea nitrogen most proximate to and within the 30 days preceding the index 
angiogram 
o If diabetic, most recent Hgb A1C within the past year 
 Comorbid medical conditions  including a history of : 
o Myocardial infarction, congestive heart failure, peripheral vascular disease, 
cerebrovascular disease, and chronic pulmonary disease. Standard procedures and 
definitions will be developed to systematically evaluate patients’ records for each 
of these conditions. 
 History of hypertension or being prescribed blood pressure medication 
 Smoking history 
 Administration of any non-study IV fluid including the type within the 12 hours prior to 
the initiation of study IV fluids 
 Weight in kilograms. The preferred method of obtaining the patient’s weight will be for 
research personnel to weigh them. In the event this is not possible, the most recent 
measurement found in the patient’s medical record will be recorded. Though not preferred, 
if there is no measurement in the medical record, this information will be collected 
via subject report. 


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 Blood pressure most proximate to and within 72 hours prior to the index angiogram 
including date of assessment 
 Names of all pre-procedure medications, including those prescribed by physicians outside 
the VA,  regularly taken by the subject 
 Whether the subject was instructed by their physician to discontinue any medications 
before their angiography procedure and if so, the name of the medication. 
 
2. 
Collection of baseline blood and urine specimens 
Prior to the initiation of study IV fluids, the subject will be asked to provide a blood sample 
for Scr testing at the designated Central Laboratory. We will collect the date of this blood draw 
and whether it was collected prior to the initiation of study IV fluids. 
In addition to the blood draw, subjects will be asked to provide a urine sample to measure 
urine albumin and creatinine. In the event the patient cannot provide urine prior to the angiogram, 
they will be asked to provide a urine specimen after the angiogram.  
3. 
Evaluation of procedure-related data 
Subsequent to the angiogram, research personnel will review the electronic medical record and 
angiogram procedure report to determine: 
 Date of index angiogram 
 Type of angiography 
 Indication for coronary angiography 
 Type and total volume of contrast administered. 
If ioxaglate (Hexabrix) or iohexol 
(Omnipaque) are noted, a reason must be given as to why that particular agent was used. 
 Site of the arterial puncture for the angiogram 
 Performance of percutaneous intervention 
 Left ventricular end-diastolic pressure if measured 
 Complications during the procedure including: 
o hypotension  necessitating  the  administration  of  additional  non-study  IV  fluid 
including the type of non-study IV fluid administered 
o hypotension necessitating the insertion of an intra-aortic balloon pump and/or the 
administration of vasopressor therapy 
o acute pulmonary edema necessitating the administration of IV diuretics


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Assessment of procedure-related complications will ensure that we capture all events that could 
impact the development of our primary and secondary outcomes. To clarify and confirm all of 
these procedure-related data, research personnel may also conduct a brief structured interview 
with the angiography nurse/technician. 
 
4. 
Evaluation of study IV fluid and NAC/placebo administration 
Research personnel will track and record from the electronic medical record the total volume and 
total duration of study IV fluid administered pre-procedure, intra-procedure, and post-procedure, 
and the administration of NAC or placebo capsules while the patient is in the hospital. NAC or 
placebo capsule administration outside the hospital will be captured during a follow up 
assessment 5-8 days following the angiography procedure (See Section VII.H.8.). 
 
5. 
Evaluation of post-procedure course (within 12 hours post procedure) 
Research personnel will review the electronic record and collect the following data elements: 
 Use of any IV fluids other than those specified as study IV fluids within the 12 hours 
following angiography including the type 
 Use of IV inotropes, vasodilators, and/or vasopressors 
 Episodes of hypotension defined as systolic blood pressure <90 mmHg and/or MAP <55 
mmHg 
 Performance of additional radiology procedures including coronary or non-coronary 
angiography or computed tomography with intravascular iodinated contrast including 
whether the procedure was planned and the type and volume of contrast administered 
 
Within approximately four hours of the angiography, research personnel will obtain a urine 
sample from the patient and record the date of collection, whether study IV fluids were being 
administered at the time of collection and the urine pH value. The collection of this urine sample 
outside the range of 12 hours pre- and 12 hours post-angiography will constitute a reportable 
protocol deviation. 
 
6. 
Evaluation of post-procedure hospitalization course (12 hours – 4 days post procedure) 
Research personnel will review the electronic record on a daily basis for patients who remain in 
the hospital following their angiography procedure or for patients who are readmitted to the 


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hospital within 4 days of their angiography procedure to assess a series of events/procedures that 
could impact the risk for our primary and secondary outcomes. These include: 
 Episodes of hypotension defined as systolic blood pressure <90 mmHg and/or MAP <55 
mmHg 
 Use of IV inotropes, vasodilators, and/or vasopressors 
 Performance of additional radiology procedures including coronary or non-coronary 
angiography or computed tomography with intravascular iodinated contrast including the 
date of procedure, whether the procedure was planned and the type and volume of 
contrast administered. If ioxaglate (Hexabrix) or iohexol (Omnipaque) are noted, a 
reason must be given as to why that particular agent was used. 
 Performance of surgical procedures requiring general or epidural anesthesia including the 
date and type 
 Use of renal replacement therapy 
 Occurrence of MI including the date and if it was an ST elevation MI 
 Duration of hospital stay beginning at the time of angiography 
 In-hospital death 
 Date of hospital discharge 
 
 
To capture these data in patients discharged from the hospital within the first 4 days following 
the index angiogram, we will provide patients with a study card at the time of their discharge 
with instructions to call research personnel if they visit an emergency room and/or are 
hospitalized within the 96-hour time frame following the index angiogram. For patients who visit 
a VA emergency room and/or are hospitalized within the VA, research personnel will review the 
electronic medical record to abstract the aforementioned data elements. For patients who visit a 
non-VA emergency room and/or are hospitalized outside the VA, research personnel will obtain 
the requisite release of information form(s) from the patient. Once the completed form(s) are 
received, research personnel will request the emergency room and/or hospital records to assess 
the aforementioned data elements. 
 
7. 
4 day blood collection 
Participants discharged from the hospital within four days following angiography will be asked 


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to provide a blood sample 4 (±1) days following the angiogram.  Options for this blood draw may 
include, but not be limited to: 1) returning to the study VA; 2) having a mobile phlebotomy 
service draw the blood; or 3) having the blood drawn at a non-study VA site such as a 
Community-Based Outpatient Clinic (CBOC) or another VA facility closer to the participant’s 
home.  
 
We chose this time frame to assess post-procedure renal function as almost all patients who 
develop CIAKI have an elevated SCr within 4 days. One aliquot of this sample will be sent to 
the central study laboratory to assess the development of CIAKI. A second aliquot from this 
sample will be delivered to the nearest VA laboratory in order for the practitioner who performed 
the angiogram to ascertain whether the patient experienced a rise in SCr. This approach will 
obviate the need for the patient to have more than one blood draw to assess for the development 
of CIAKI for study and clinical purposes. For patients who remain hospitalized for at least 4 (±1) 
days following angiography, a blood sample will be drawn at 4 (±1) days post-procedure. One 
aliquot of this sample will be sent to the central study laboratory for subsequent analysis for the 
development of CIAKI, while a second aliquot will be delivered to the hospital laboratory for the 
primary provider to review whether the patient experienced a post-procedure rise in SCr. 
 
To ensure patient safety and assist providers, research personnel will notify the provider who 
performed the angiography that a 4 (±1) days SCr will be processed in the VA laboratory as part 
of the study and will send an encrypted email to the patients’ primary provider describing the 
results of this 4 (±1) days post-procedure SCr within 2 days of the completion of this test. 
 
Since this creatinine determination is part of the secondary end-point, it is very important that the 
blood collection be done at 4 (±1) days after angiography. We recognize that unforeseen 
circumstances may preclude collection within this window. Under such circumstances the blood 
should be collected as soon as possible and most proximate to 5 calendar days after the date of 
angiography. In the event the blood is obtained before 3 or after 5 days following angiography, a 
protocol deviation should be completed. 
 


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8. 
Day 5 post procedure assessment 
 (5 days post angiography, allowable range 5-8 days post angiography) 
Five days post-angiography, research personnel will review the electronic medical record and 
perform a structured telephone interview with the patient.  For patients who remain hospitalized 
at this time point, research personnel will speak with them in-person. Beginning on the day of the 
patient’s angiography, the date and number of NAC/placebo capsules taken will be documented. 
Reasons for non-compliance will be collected. Research personnel will also review the EMR to 
verify that NAC/placebo was administered appropriately (at least one hour prior to the procedure 
and then again at least one hour following the procedure) on the day of the angiography procedure. 
 
During the EMR review and follow-up call (or visit to the patient in the hospital), research 
personnel will inquire about any adverse events the patient experienced, including any 
hospitalizations or the need to begin dialysis. To assess the adequacy of patient blinding to the 
interventions, research personnel will also ask participants to guess which IV fluid arm of the 
study they were assigned to and whether they received NAC or placebo capsules. 
 
Finally, research personnel will verify that the patient had their 4-day blood sample collected. 
 
 
We recommend that this contact should be made 5 days after angiography, with an allowable 
range of 5-8 days post angiography. We recognize that sometimes it may be difficult to contact a 
patient within this window. However, it is important to collect the required data, which should 
be done even if done after the recommended time frame has elapsed. It will not be considered a 
protocol deviation as long as the required data are collected and there is progress note 
documenting the attempt to schedule the data collection during the recommended time frame. 
 
 
 
 
 
 
 
 
 
 
 
 


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9. 
Day 35 post procedure assessment 
(35 days post angiography, allowable range 35-49 days post angiography) 
Thirty five days following the angiography, research personnel will review the electronic medical 
record and perform a structured telephone interview with the patient to inquire about any adverse 
events they experienced related to study participation. 
 
We recommend that this contact should be made at 35 days after angiography, with an allowable 
range of 35-49 days. We recognize that sometimes it may be difficult to schedule a patient 
within this window.  However, it is important to collect the required data, which should be done 
even if done after the recommended time frame has elapsed. It will not be considered a protocol 
deviation as long as the required data are collected and there is progress note documenting the 
attempt to schedule the data collection during the recommended time frame. 
 
10. 
Day 90 post procedure assessment 
(90 days post angiography, allowable range 90-104 days post angiography) 
a. 90 day blood collection 
In advance of the patient’s 90 day assessment, they will be contacted by research personnel 
regarding their 90 day blood collection. The blood sample obtained will be sent to the Central 
Laboratory for Scr measurement. Patients who are willing and able will return to the study VA 
at which their angiogram took place 90 days (allowable range of 90-104 days) following their 
index angiogram to provide this blood sample. Other options for this blood draw may include, 
but not be limited to: 1) having a mobile phlebotomy service draw the blood; or 2) having the 
blood drawn at a non-study VA site such as a Community-Based Outpatient Clinic (CBOC) or 
another VA facility closer to the participant’s home.  
 
If a participant initiates renal replacement therapy (intermittent hemodialysis, peritoneal dialysis, 
continuous renal replacement therapy [CRRT], or prolonged intermittent renal replacement 
therapy [PIRRT]) within 90 days of the index procedure , the study coordinator will collect the 
90-day blood draw based on the following criteria: 
 
 
 
 


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• If the participant initiates renal replacement therapy within 90 days of the index 
angiography procedure and continues to require renal replacement therapy on or after 
day 90, the 90-day blood draw will not need to be collected 
• If the participant initiates renal replacement therapy within 90 days of the index 
angiography procedure but recovers kidney function and renal replacement therapy is 
discontinued prior to day 90, the participant should have his/her 90-day blood drawn 
 
Since this creatinine determination is part of the primary end-point, it is very important that the 
blood collection be done 90 days after angiography, with a target range of 90-104 days, and 
with an allowable range of 90-180 days. We recognize that unforeseen circumstances, such as 
patient hospitalization outside the VA system, may preclude collection within the 90-104 day 
range. Under such circumstances the blood should be collected as soon as possible and most 
proximate to 90 days within 180 days and a protocol deviation should be noted if outside the 
target range of 90-104 days. 
 
This 90-day SCr value will be used to assess for evidence of persistent decline in kidney 
function. In subjects with a ≥50% increase in SCr between their baseline and 90 day 
measurements, a confirmatory SCr measurement will be obtained. Options for this blood draw 
may include, but not be limited to: 1) returning to the study VA; 2) having a mobile phlebotomy 
service draw the blood; or 3) having the blood drawn at a non-study VA site such as a 
Community-Based Outpatient Clinic (CBOC) or another VA facility closer to the participant’s 
home.  For purposes of determining whether the endpoint of a ≥50% increase in SCr at 90 days 
(persistent decline in kidney function) has been met, both SCr values will need to be ≥50% 
higher than baseline and mean of these two SCr will be used. If the 50% increase is confirmed, 
research personnel will notify the patient’s primary care provider using an institutionally 
approved notification method. 
 
Reimbursement will be provided for travel expenses to have study-related blood draws if these are 
not done by the mobile specimen collection agency. This payment will be dispersed by the local 
site according to their procedures. Other than travel reimbursement, patients will not receive 
any payment for their participation in this study. 
 
 
 


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b. 90 day assessment 
Ninety days following the index angiogram, research personnel will review the electronic medical 
record and perform a structured telephone interview with the patient. The electronic medical 
record review will specifically focus on assessing the development of any of the following primary 
and/or secondary end-points within the VA Healthcare System: 
 death including date based on medical record documentation 
 need for renal replacement therapy including date of initiation and duration of therapy 
 hospitalization including date and primary and secondary hospital discharge diagnoses (to 
assess for ACS, HF, and/or CVA) 
The 90-day structured telephone interview with the patient will complement the electronic 
medical record review. This telephone interview will verify data that was abstracted from the 
electronic medical record and enable research personnel to inquire about hospitalizations at non- 
VA facilities that would not have been captured in the VA electronic medical record. For any 
patients who were hospitalized outside the VA, the research personnel will obtain the requisite 
release of information form(s) from the patient. Once the completed form(s) is received, research 
personnel will acquire the pertinent medical records to assess for the development of any of these 
outcomes. In addition, death within this 90-day time period will be ascertained by linking our 
study database with the VA Beneficiary Identification and Records Locator System, National 
Center for Health Statistics National Death Index database, Social Security Administration’s 
Death Master File, and/or other similar databases. 
 
We recommend that the telephone contact be performed 90 days after the initial angiography, 
with an allowable range of 90-104 days. We recognize that sometimes it may be difficult to 
schedule a patient within this window. However, it is important to collect the required data, 
which should be done even if done after the recommended time frame has elapsed. It will not be 
considered a protocol deviation as long as the required data are collected and there is progress 
note documenting the attempt to schedule the data collection during the recommended time 
frame. 
 
 
 
 


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11. 
1-year assessment 
We will link our database with the United States Renal Data System to ascertain the 
development of ESRD and the date of initiation of renal replacement therapy within one year of 
the index angiographic procedure. Finally, death within this 1-year period will be ascertained by 
linking our database with the VA Beneficiary Identification and Records Locator System, 
National Center for Health Statistics National Death Index database, Social Security 
Administration’s Death Master File and/or other similar databases. Timing the performance of 
these linkages will depend upon the availability of data from the USRDS and the vital status 
registries, which may lag by 12-18 months after the end of each calendar year. 


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VIII. 
POTENTIAL PITFALLS OF THE PROPOSED STUDY DESIGN AND 
ALTERNATIVE STUDY DESIGN CONSIDERATIONS 
A. 
Study Hypotheses 
1. 
Relationship between CIAKI and patient-centered outcomes 
Our study design is based on a conceptual model in which CIAKI is not only associated with, but 
is the proximate event in a direct causal pathway leading to serious, adverse downstream 
outcomes. While we postulate that CIAKI mediates serious, adverse downstream events, we 
recognize that it is possible that the small changes in kidney function that define CIAKI may 
simply represent a marker of underlying cardiac and/or vascular disease and reflect pre- 
procedure risk for morbidity and mortality. Thus, it is possible that the proposed interventions 
may reduce the incidence of CIAKI, defined by change in SCr, but not affect the incidence of 
serious, adverse, patient-centered outcomes. While this outcome might be viewed as 
disappointing, we believe that such a finding would be extremely significant and would have a 
substantial impact on clinical care and resource allocation. 
 
Similarly, we recognize that post-angiography AKI has etiologies other than iodinated contrast, 
most notably hypotension and atheroembolic disease. Our interventions are unlikely to impact 
the development of AKI in such cases. To address this possibility, we will conduct sensitivity 
analyses in which we will evaluate the development of CIAKI using the same threshold change 
in SCr, but exclude patients who experienced hypotension, underwent cardiac or non-cardiac 
vascular surgery within the 4 days following angiography, and/or had a documented cause for 
acute kidney injury in the primary or secondary discharge diagnoses, other than contrast 
associated AKI. 
 
2. 
Effectiveness of Bicarbonate and NAC 
Our hypotheses that bicarbonate (compared to saline) and NAC (compared to placebo) will 
decrease the incidence of serious, adverse 90-day outcomes are based on the purported 
effectiveness of these interventions in preventing the short-term changes in SCr that define 
CIAKI. We recognize that if bicarbonate (compared to saline) and NAC (compared to placebo) 
are not effective for the prevention of CIAKI, we are unlikely to observe an effect of these 


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interventions on the events that comprise our primary study endpoint. For this reason, we have 
included prevention of CIAKI as a key secondary outcome. 
 
B. 
Study Population 
1. 
Inclusion of patient undergoing coronary or non-coronary angiography 
Most past studies of CIAKI have focused on patients undergoing coronary angiography. We 
propose enrolling patients undergoing either coronary or non-coronary angiography. While 
including patients undergoing non-coronary angiography will increase the heterogeneity of the 
study population, data from our prospective cohort study suggest that CIAKI and serious adverse 
events are even more common following non-coronary angiography than coronary 
angiography.198 Moreover, non-coronary angiograms make up approximately one-third of 
angiographic procedures performed within the VA. Therefore, we believe that despite the effect 
on patient heterogeneity, inclusion of patients undergoing non-coronary angiography will enrich 
the study population with high-risk patients, significantly increase the number of patients 
available for recruitment, and broaden the generalizability of the study findings. 
 
2. 
Exclusion of patients undergoing contrast-enhance computed tomography 
There are past trials of interventions for the prevention of CIAKI that included and/or were 
focused exclusively on patients undergoing contrast-enhanced computed tomography.142, 199 
Although inclusion of patients undergoing contrast-enhanced computed tomography in our 
proposed trial would substantially increase the pool of eligible patients, our prior observational 
cohort study of Veterans undergoing contrast-enhanced procedures found that CIAKI was less 
common following computed tomography than after angiography.8, 198 Inclusion of these lower 
risk patients would decrease the anticipated event rate and result in the need for a considerably 
larger study than we have proposed. Nevertheless, interventions to decrease the risk of CIAKI 
and serious, adverse, patient-centered outcomes following angiographic procedures will likely be 
applicable to high-risk patients undergoing contrast-enhanced computed tomography. 
 
3. 
Criteria for selection of high-risk patients 
Our study targets patients who are at high risk for CIAKI and serious, adverse events following 
angiography. While the inclusion of lower risk patients would broaden the study population, it 


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would result in the need to recruit a considerably larger number of participants and would likely 
add complexity to and decrease the feasibility of the study. We chose to define our patient 
population as being at high-risk based on the presence of underlying chronic kidney disease, with 
diabetes serving as an amplifier of risk in the setting of impaired renal function. We chose this 
approach because chronic kidney disease is commonly cited as the primary risk factor for 
CIAKI,  is  easily  assessed,  and  is  present  in  a  large  proportion  of  patients  undergoing 
angiographic procedures.21, 183  We recognize that other clinical conditions (e.g., heart failure, 
intravascular volume depletion) are also associated with an increased risk for CIAKI  and adverse, 
downstream outcomes and could be used to define a study population as high-risk. However, 
assessment of the presence and severity of heart failure and intravascular volume depletion 
is somewhat subjective and therefore more difficult to protocolize. 
 
C. 
Study interventions 
1. 
Fluid administration 
There is no consensus among experts on the optimal rate and duration of IV fluid administration 
for the prevention of CIAKI or single protocol for the administration of IV fluid that has been 
shown to be the most effective. Individual patient circumstances and provider preferences 
commonly dictate the volume and duration of IV fluids administered. We anticipate that some 
providers might be unwilling to have their patients participate in this trial if they have no control 
over the rate or duration of IV fluid administration in their patients. For these reasons, rather than 
adopting one of the multitude of fluid administration protocols employed in prior clinical trials 
for the prevention of CIAKI, the planning committee decided that a more flexible approach that 
specified a minimum volume and duration of administration of IV fluids would be more 
acceptable to providers without deviating from what would be considered appropriate preventive 
care. While we believe that this approach will provide a volume of IV fluid that is comparable to 
that used in most recent trials comparing bicarbonate and saline, it is possible that this strategy 
could result in systematic differences in the rate and duration of fluid administration in patients 
randomized to bicarbonate and saline. While this is very unlikely given the large trial size and 
blinding of fluid composition, we will closely monitor duration and volumes of fluid 
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2. 
Complications of fluid administration 
We anticipate that some patients will develop volume overload/pulmonary edema and/or 
elevated left ventricular end-diastolic pressure during angiography. In such instances, providers 
performing angiography may discontinue post-procedure IV fluids resulting in patients failing to 
receive study IV fluid following the angiogram. It is likely that this event will occur in a small 
proportion of patients and be equally distributed across treatment arms. While the volume of 
study IV fluid administered pre, during and post-procedure will be carefully recorded for all 
patients, given the importance of patient safety, we believe it would be inappropriate to require 
the administration of post-procedure study IV fluid in such instances. Since all analyses will be 
based on the intent-to-treat principle, these patients will not be excluded from the study analyses. 
 
3. 
Route and dose of NAC administration 
There is currently no universally accepted protocol for the route of administration of NAC for 
the prevention of CIAKI. While most prior studies used oral NAC, a small number of studies 
administered NAC intravenously.23, 153, 157, 162, 164, 167 The primary putative advantage of IV 
administration is a reduction in first-pass inactivation of NAC by the liver after enteric 
absorption, thereby increasing delivery to the kidneys. Notwithstanding this theoretical benefit of 
IV NAC, we selected the oral route of administration for three reasons. First, there are inadequate 
clinical data to demonstrate that the theoretical benefits of IV NAC translate into greater 
clinical effectiveness than oral NAC. Second, IV administration of NAC is associated 
with a considerably higher risk for adverse reactions, including anaphylaxis, than the oral 
formulation. Finally, the IV preparation of NAC is considerably more expensive than the oral 
preparation. 
 
Although the optimal dose of NAC for the prevention of CIAKI has not been clearly established, 
we have chosen to administer 1200 mg twice daily for four reasons. First, clinical trials that 
assessed the impact of dose on the incidence of CIAKI and serious, adverse outcomes 
demonstrated a benefit to higher dose NAC.23, 184 Second, data from experimental models suggests 
a dose-dependent effect of NAC with higher doses associated with less renal tubular damage.169 
Third, there is little safety risk with higher doses of NAC compared to lower doses of 


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NAC. Finally, current opinion-based recommendations for the prevention of CIAKI advocate the 
use of 1200 mg of NAC twice daily.183, 200 
 
4. 
Duration of study interventions 
The optimal duration of strategies for prevention of CIAKI is not known. As discussed in section 
VII.D.2, there are preliminary data indicating that iodinated contrast may persist in the kidney 
for several days following contrast-enhanced procedures. While it is not known whether this 
persistent contrast contributes to, or is a marker of renal injury, the planning committee felt that 
extending the administration of oral NAC to 5 days could be beneficial with little to no safety 
risk. Unlike the safety of longer duration NAC, extending the duration of IV fluids poses a risk 
for volume overload/pulmonary edema, would require prolonged hospitalization, and could be 
viewed unfavorably by both patients and providers. There was consideration given to providing 
oral sodium bicarbonate and oral sodium chloride tablets for 5 days. However, to match the 
amount of bicarbonate or saline given intravenously, nearly 7 grams of oral sodium bicarbonate 
and 5 grams of oral sodium chloride would have to be given daily, which would pose safety 
concerns regarding exacerbation of heart failure and/or worsening of hypertension. While lower 
doses of oral sodium bicarbonate and sodium chloride could be used, there are no preliminary 
clinical data to support this approach for the prevention of CIAKI or serious, adverse 
downstream outcomes. Therefore, although we extended the use of NAC to 5 days, our 
bicarbonate/saline intervention will be limited to IV fluid administration in the immediate peri- 
procedural period. 
 
5. 
Potential for interaction between bicarbonate and NAC 
Implicit in our use of a 2 x 2 factorial design is the a priori assumption that there is minimal to 
no interaction between the two study interventions. That is to say, the relative effect of 
bicarbonate in patients receiving NAC is the same as in patients receiving placebo, and the 
benefit of NAC is the same in patients receiving bicarbonate or saline. We acknowledge, however, 
that there are only limited data evaluating this interaction, and that these data are restricted 
to the prevention of CIAKI rather than prevention of serious, adverse outcomes. For example, 
in a recent systematic review and meta-analysis of IV sodium bicarbonate for the prevention 
of CIAKI, Zoungas et al. observed no difference in the incidence of CIAKI following 


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sodium bicarbonate administration with or without concomitant administration of NAC (p for 
heterogeneity = 0.73) in four studies which included data on 983 patients.118 Similarly, Brown 
and colleagues found that combination treatment of NAC with IV sodium bicarbonate reduced 
CIAKI by 35% compared to NAC with saline in a meta-analysis of 10 randomized controlled 
trials.119 In an experimental model, Romano et al. found no interaction between bicarbonate and 
NAC in the prevention of renal tubular cell apoptosis following exposure to iodinated contrast 
media.169 Nonetheless, these data are insufficient to definitively exclude the possibility of an 
attenuation of benefit associated with combined therapy. We have taken this into consideration in 
our statistical analysis (vide infra); as designed, the study will retain greater than 80% statistical 
power even in the presence of a 50% attenuation in effect with combined therapy. 
 
D. 
Selection of the primary study outcome 
We recognize that there are potential pitfalls to the use of composite endpoints in clinical trials 
generally, and drawbacks to the specific components of our proposed primary composite 
outcome.201 First, we selected the renal components of the endpoint as being representative of 
accepted, clinically meaningful decrements in kidney function, and included death as it 
represents a competing risk for the renal outcomes. However, we acknowledge that no prior 
studies have specifically examined the impact of interventions to prevent CIAKI on one 
component of this outcome: persistent decline in kidney function. Second, there may be 
disproportionate event rates for the individual components of the primary endpoint, although our 
preliminary analyses of existing data suggest that the incidence of each of the three components 
of the primary composite outcome occur with reasonably similar frequency. Third, we do not 
include major adverse cardiovascular events (e.g., acute coronary syndrome, heart failure, 
cerebrovascular accident) in the primary endpoint. Although these outcomes are of great clinical 
importance, they may primarily occur independent of the development of CIAKI in our study 
population. Moreover, we were concerned that any reduction in these events as a result of our 
study interventions would be masked by a high rate of these events that occurred independent of 
the interventions. Thus, we decided not to include these cardiovascular events in the primary 
study endpoint, but will assess them as a secondary outcome. 


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E. 
Ascertainment of baseline kidney function 
In order to ascertain a change in kidney function, it is critical to standardize the definition of 
baseline kidney function. SCr often fluctuates over time because of variations in volume status, 
protein and salt intake, and drift in the calibration of laboratory instruments. The specific timing 
of the SCr used to screen patients is less critical than the value used to define the baseline SCr 
for endpoint ascertainment. For practical purposes, we propose to screen patients based on a SCr 
obtained as part of routine clinical care performed by the patient’s provider within the 30 days 
prior to angiography. This will not be the same pre-angiography study SCr (reference SCr) that 
will be used to assess the development of persistent decline in kidney function (component of the 
primary endpoint) or to assess the development of CIAKI (a secondary endpoint). As a result, 
some patients who are found to be eligible and enrolled in the study based on the eGFR 
calculated from the SCr performed as part of routine clinical care will subsequently have an 
eGFR calculated from the pre-angiography study (reference) SCr measured at the central 
laboratory that is >60 mL/min/1.73 m2 (diabetic patients) or >45 mL/min/1.73 m2 (non-diabetic 
patients). While we do not anticipate that there will be many cases in which this discrepancy 
occurs, patients with such differences between the screening and pre-angiography study eGFR 
will not be excluded as the risk of CIAKI with progressive CKD is continuous and does not 
increase in a step-wise fashion as transitions between CKD stages occur. For example, the risk of 
CIAKI  for  a  diabetic  patient  with  an  eGFR  of  61  ml/min/1.73  m2   (i.e.,  stage  2  CKD)  is 
comparable to that of a diabetic patient with an eGFR of 59 ml/min/1.73 m2 (i.e., stage 3 CKD). 
Thus, we anticipate that including the small number of study patients who are deemed eligible 
based on their screening eGFR but whose baseline study SCr corresponds to an eGFR greater 
than the inclusion criteria will have minimal impact on our event rate estimates. We believe that 
it is critical to use a central laboratory to ascertain the reference and endpoint SCr values to 
minimize variation related to drift in instrument calibration. Samples for reference and endpoint 
ascertainment on a single patient will be run sequentially on the same analyzer to minimize 
issues related to drift in calibration. While this introduces issues related to sample storage, SCr is 
known to be stable over time in samples stored at -20 oC.202 


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F. 
Assessment of secondary outcomes 
1. 
Assessment of CIAKI 
Most patients who develop CIAKI manifest an initial increase in SCr within 2 to 4 days following 
contrast administration. However, past studies demonstrate that some patients who develop 
CIAKI may not be identified by a single SCr assessment at 48 hours.68 The optimal timing of 
assessment of SCr following the index angiogram to assess for the development of CIAKI in 
our trial was carefully considered by the planning committee. While it was agreed that multiple 
SCr assessments (e.g., at 2 days and 4 days) would ensure the identification of all patients 
who developed CIAKI, we ultimately determined that a single assessment at 4 days following 
angiography was optimal for several reasons. First, almost all patients who develop 
CIAKI will manifest an increase in SCr at 4 days following angiography. Second, an increase in 
SCr at 4 days following angiography is more likely to represent clinically significant CIAKI than 
an increase in SCr at 48 hours, as early changes in SCr are more likely to reflect transient 
hemodynamically-mediated perturbations in SCr rather than clinically consequential renal injury. 
Finally, the planning committee did not feel that measuring SCr at multiple time points in order 
to identify a small number of additional patients who meet criteria for this secondary outcome 
justified the added cost of more than $350,000 for each additional SCr assessment. 
 
1.        Assessment of cardiovascular outcomes 
We acknowledge the potential limitations of using administrative data/medical records for the 
assessment of cardiovascular outcomes, including heart failure, acute MI and stroke. We will 
assess these outcomes by reviewing the hospital discharge summary for documentation of any of 
the events that comprise the secondary cardiovascular outcomes. We considered the possibility 
of adjudicating the secondary outcomes using more comprehensive medical record review. 
However, we believe that while this would be a more robust approach, the additional time, effort 
and cost required to adjudicate these secondary outcomes using a comprehensive review of the 
medical record was not justified. 
 
G. 
Inclusion of a cost-effectiveness analysis and return on the investment to the VA 
While the inclusion of an economic analysis as part of this trial was strongly considered, we 
ultimately decided that the addition of economic data collection would detract from the primary 


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conduct of the study. Given the reasonably low expense of our interventions and the considerable 
effort and cost of tracking patients’ health resource utilization both within and outside the VA for 
an extended period of time (90 days), it was felt that including an economic analysis as part of 
this proposal was not advisable. If bicarbonate and/or NAC reduce the incidence of serious 
downstream outcomes following angiography as we hypothesize, there will likely be little reason 
to question their cost-effectiveness considering their low cost. That is, the effectiveness of the 
interventions will dominate the associated costs. 
 
While the cost of this trial is substantial, there will be a clear return on the investment to the VA 
whether the trial results are positive or negative. After consulting with a series of pharmacists, 
we conservatively assume an incremental cost of preparing bicarbonate and NAC of $20 
compared to the use of saline and non-use of NAC. Using conservative estimates of the number 
of angiograms performed in patients at high-risk for CIAKI, published costs of a single episode 
of CIAKI, and the incidence of this condition, demonstrating an absolute reduction in the 
incidence of CIAKI by 3% with bicarbonate or NAC will result in the study paying for itself 
within 1.3 years considering the costs to the VA and within 1 month considering the costs for all 
US health care (Table 8). 
 
Table 8 – Return on the investment to VA Healthcare System and across all US health care 
VA Healthcare 
System 
US Health care 
Assumptions 
# high risk patients undergoing angiography yearly 
50,000 
750,000 
Incremental cost of NAC and bicarbonate, per patient 
$20 
$20 
Cost per episode of CIAKI 26 
$11,800 
$11,800 
Cost of study 
$23,400,000 
$23,400,000 
If  either NAC or bicarbonate decreases CIAKI by 3% 
# patients at risk 
50,000 
750,000 
# patients/ year in whom CIAKI is averted by intervention 
1,500 
22,500 
Projected cost benefit if study is positive, per year 
$17,700,000 
$265,500,000 
Time to pay off cost of study 
1.3 years 
1 month 
If both interventions are ineffective 
# patients/ year not treated with NAC and bicarbonate 
50,000 
750,000 
Savings per patient 
$20 
$20 
Annual savings of not implementing interventions 
$1,000,000 
$15,000,000 
Time to pay off cost of study 
23.4 years 
1.6 years 


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While the return on the investment to the VA will take considerably longer in the event that 
bicarbonate and NAC are ineffective, a negative study also has important clinical as well as cost 
implications. First, it will prevent the widespread use of ineffective measures (i.e., bicarbonate 
and NAC) in perpetuity without an evidence basis to support their use. Second, it will prevent 
needless delays in the performance of angiographic procedures in urgent and emergent cases 
while awaiting bicarbonate and NAC preparation and administration. It is also important to note 
that these estimates of the return on the investment do not take into account the impact our 
findings are likely to have on preventive care provided to the large number of high-risk patients 
undergoing contrast-enhanced computed tomography both within and outside the VA Healthcare 
System. As our findings are highly likely to be translated to this large population of patients, the 
return on the investment to the VA and US health care overall is surely to be even greater than 
projected in Table 8. 
 
H. 
Secular trends in the prevention and incidence of CIAKI 
We acknowledge that it is possible that there will be new knowledge gained and changes in 
practice patterns related to the prevention of CIAKI and serious adverse outcomes following 
angiography during the conduct of the proposed trial. A comparison of the incidence of CIAKI 
reported in studies conducted in the 1980s to the incidence described in recent studies reveals a 
trend toward fewer patients experiencing this iatrogenic complication. However, much of this 
trend is likely related to the transition from the more nephrotoxic high-osmolal contrast agents to 
low and iso-osmolal contrast agents. Over the past decade, there is no evidence of a continued 
decline in the incidence of CKAKI or attenuation in the relationship between CIAKI and serious, 
adverse outcomes. This is best illustrated by a recent study of over 1,100 hospitalized subjects 
who underwent contrast-enhanced procedures that demonstrated that CIAKI developed in over 
40% of patients and was associated with a 2-fold increase in hospital duration and a 10-fold 
increase in mortality.22 
 
I. 
Alternative study design considerations 
We acknowledge that the proposed study, which uses a 2 x 2 factorial design, does not include a 
comparison of NAC to placebo in the absence of IV fluids. While assessing the benefit of NAC 
in the absence of IV fluids would be an interesting question, there are two reasons we did not 


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consider this approach. First, it is widely viewed that the primary intervention with documented 
effectiveness for the prevention of CIAKI is IV administration of isotonic crystalloid. A 
randomized clinical trial by Trivedi et al. demonstrated that high-risk patients who received IV 
isotonic saline at the time of angiography were at markedly lower risk of developing CIAKI than 
patients who received unrestricted oral fluids only (RR=0.11, 95% CI: 0.02-0.8).88 As a result, 
IV isotonic fluid is currently considered the standard of care for the prevention of CIAKI and 
withholding such treatment in a clinical trial is unlikely to be approved by existing Institutional 
Review Boards (IRB). Second, all but one of the published trials investigating NAC for the 
prevention of CIAKI were performed in conjunction with the administration of IV fluids.23, 142, 
144, 146-151, 153-158, 160-167   The single trial that did not use concomitant IV fluids enrolled a low risk 
patient population and failed to demonstrate a benefit of NAC.152 Therefore, evidence of the 
efficacy of NAC in the absence of IV fluids is lacking. Thus, we believe that including a study 
arm that received NAC or placebo without any concomitant IV fluids would be inconsistent with 
the current standard of care, would lead to refusal of practitioners to allow their patients to 
participate in the study, and would likely be viewed as unethical by IRBs. 


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IX. 
FEASIBILITY OF RECRUITMENT 
While our projected sample size is substantial, there are multiple important factors that support 
the feasibility of recruiting this large number of patients. First, the proportion of potentially 
eligible patients we will need to recruit in order to meet enrollment targets is relatively small. 
Approximately 47,000 Veterans who would meet eligibility criteria for our study undergo 
coronary or non-coronary angiography each year within the VA Healthcare System, of whom 
27,000 (57%) undergo these procedures at the 33 busiest VA Medical Centers. The number of 
angiographic procedures performed on an annual basis in potentially eligible patients at these 33 
centers ranges from a minimum of 519 to a maximum of 1,504. Assuming the need to enroll an 
average of 2 patients per week (100/year), successful recruitment of 6.7% of patients from the 
busiest center and 19% of patients from the 33rd  busiest center would ensure the attainment of 
our target recruitment goal. Even if our estimate of the number of potentially eligible subjects 
was 25% lower than projected, we would need to recruit no more than 26% of subjects from the 
33rd busiest hospital. In the event that not all of these 33 centers were able to participate in the 
study and certain of the 14 VA Medical Centers (sites 34-47) with the next highest volume of 
angiographic procedures were selected as sites, we would need to recruit no more than 25% of 
potentially eligible patients from the 47th busiest VA Medical Center to meet the target of 100 
participants yearly. Second, patients undergoing coronary and non-coronary angiography are 
easily identifiable. Nearly all of these procedures are non-emergent and scheduled in advance, 
which greatly facilitates identification and screening of potential study subjects. Third, unlike 
trials that recruit from a diverse array of patient settings (e.g., primary care offices, hospital 
wards, specialty clinics), our trial will recruit patients from just two hospital venues: cardiac 
catheterization laboratories and interventional radiology suites. This greatly simplifies the 
process of identifying and locating potentials participants. Fourth, at most VA Medical Centers, 
coronary and non-coronary angiograms are performed by a small number of medical 
practitioners. Unlike trials that require the assistance of many providers to identify potential 
patients, our study staff will only need to engage a small number of interventional cardiologists 
and radiologists at each study site. Fifth, many patients undergoing angiograms would be 
receiving one or both of our interventions (IV fluids and NAC) independent of study 
participation. Therefore, few patients or providers are likely to view the interventions as 
experimental or unsafe. Sixth, patient burden in this study is quite limited since there is no need 


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to return to the hospital for study visits. Follow up data collection will be performed using 
telephone calls, while multiple options are provided for the required blood draws including use of 
a mobile phlebotomy service if the patient is unable to return to the VA or the option of having 
the blood drawn at  non-study VA site such as a Community-Based Outpatient Clinic (CBOC) or 
another VA facility closer to the participant’s home. Therefore, patients are unlikely to view 
participation as unduly burdensome. 
 
It is also essential to note that the VA cohort study that we conducted in 2005-2006 provided us 
with highly valuable experience recruiting patients undergoing coronary and non-coronary 
angiography and demonstrates our past success in enrolling Veterans undergoing angiographic 
procedures. In that prospective study that required patients to return to the VA following 
angiography for a follow-up blood draw, we successfully recruited 63% of eligible patients. This 
recruitment rate is more than 3-fold higher than the most conservatively estimated recruitment 
rate that will be required for the successful attainment of the target population in the proposed 
clinical trial. We are highly confident in our capacity to successfully recruit the number of 
patients needed to meet our enrollment targets. 


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X. 
ANTICIPATED BARRIERS TO RECRUITMENT AND STRATEGIES TO 
ADDRESS POTENTIAL UNDER-ENROLLMENT 
A. 
Development of multi-disciplinary study teams 
Despite the feasibility of recruitment as outlined above, successful enrollment of the large 
number of patients we hope to enroll will depend in large part on the interest and willingness of 
interventional cardiologists and radiologists to have their patients enrolled. We recognize that 
these practitioners may not be focused on or necessarily prioritize the prevention of CIAKI and 
its associated outcomes, especially since they are often not involved in the longitudinal care of 
patients and may not be notified of delayed complications of angiography. We believe that 
establishing multi-disciplinary study teams at each site, including nephrologists, interventional 
cardiologists, and interventional radiologists will optimize the potential for successful subject 
enrollment. Just as we had a multi-disciplinary planning committee, we will include 
interventional cardiologists and interventional radiologists as site Principal Investigators. We 
will have a pre-study meeting with providers who perform angiograms at each study site to 
discuss the protocol and address questions and concerns they have regarding the study. We 
believe that the flexibility built into the protocol for study IV fluid administration rates, volumes, 
and durations will be attractive to providers performing angiography and will increase their 
interest in and willingness to have their patients participate in the study. 
 
B. 
Exclusion of patients enrolled in other clinical trials 
Given the significant number of large, clinical trials targeting patients undergoing coronary 
angiography, it is possible that patients who are eligible for inclusion in our study could be 
enrolled in or eligible for other interventional trials. Current CSP policy, while discouraging dual 
enrollment, does allow it if certain conditions are met. We will follow CSP policy, as per the 
following paragraph, in this regard: 
 
It is CSP policy that a participant be enrolled in only one drug or device intervention, 
randomized clinical study at any one time. It is permissible for participants to be in 
other non-interventional studies while participating in a CSP study (e.g., surveys, long- 
term follow-up cohort studies). Exemptions to this CSP policy will be allowed for 
individual participants on a case-by-case. Exemptions on the basis of an entire study are 


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rare. Exemption requests will require the agreement in writing of all of the following 
individuals or groups: (1) the Site Investigators of both studies; (2) the Study Chair of 
the involved studies; and (3) the appropriate CSP Center Director(s).  Exemptions sought 
on a per study basis are obtained using a similar process with the exception that letters 
from individual SIs would not be required. The Director, CSR&D makes the final 
decision. Only after the Director, CSR&D has given final approval, will the participant 
be allowed to participate in both studies. Approvals for exemption are primarily based 
on what is best for the participant and to protect the integrity of the involved studies. 
 
C. 
Strategies to address under-recruitment of study subjects 
Given the large size of our study and the critical importance of adequate patient recruitment, we 
anticipate using a number of strategies to address under-recruitment should it occur. First, in 
addition to the 33 VA study sites that we will include at the outset of the study, we will identify 
at least five additional VA centers as alternative study sites. We will closely monitor screening 
and enrollment at each site on an ongoing basis. Sites that fail to meet pre-specified milestones 
for recruitment may be placed on probationary status (See Section XIV.E.). If a participating site 
continues to fail to meet enrollment targets at pre-specified time points, we will exercise the 
option of replacing the site with one of the pre-identified alternative VA centers. Alternatively, 
we may choose to reduce funding to underenrolling sites (e.g., eliminating payment for 
the Research Associate or reducing funding for the Study Coordinator to less than full-
time status) and utilize those funds to increase support to high enrolling sites, or within 
budgetary constraints, to activate one or more additional study sites.   One advantage of 
the short follow-up (90 days) is that it will allow us to re-allocate resources in a relatively 
short period of time.  
 
Second, based on current eligibility criteria, we will exclude patients with baseline eGFR values 
of 45-60 ml/min/1.73 m2 who do not have diabetes because they are at slightly lower risk for 
CIAKI and serious, adverse, downstream outcomes. However, if we encounter difficulty 
meeting recruitment targets, we will reconsider the option of broadening our eligibility criteria to 
include patients with baseline eGFR 45-60 ml/min/1.73 m2 without diabetes,  
 
 


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but who have a documented history of heart failure in their medical record, which is another 
known risk factor for CIAKI. This approach, which would require us to operationalize a definition 
of non-decompensated CHF (e.g., NY Heart Association Functional class III-IV and/or a history 
of pulmonary edema due to cardiac disease), would only be utilized if all other efforts to boost 
enrollment were unsuccessful.203 We believe that having these two strategies to address potential 
under-enrollment will help ensure the attainment of the target sample size without 
compromising the scientific integrity of the study. 
 
D. 
Inclusion of non-VA study sites in Australia, New Zealand, and Malaysia 
As part of the planning process for this trial, we engaged with investigators from The George 
Institute for Global Health (TGI) in Sydney, Australia. The George Institute has an impressive 
track record in the conduct of large clinical trials and has collaborated with the Australia/New 
Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) in prior trials of acute 
kidney injury. While collaboration with The George Institute is not necessary to execute the trial 
based on our estimates of the numbers of procedures performed within the VA, collaboration 
will allow for the inclusion of non-VA study sites, increase the number of potential participants, 
and enhance the generalizability of the study to non-Veterans and women. The investigators 
from TGI are being sponsored by the National Health and Research Council of Australia for 
funding of approximately 10 sites and will enroll a total of 1,000 patients. 
 
 
XI. 
FUTURE ANCILLARY STUDIES 
In addition to the primary study, we may in the future perform additional ancillary studies related 
to the primary study, including following patients for a longer time to track renal and 
cardiovascular outcomes and mortality. In addition we may collect blood and urine specimens 
for biomarker testing to develop diagnostic and prognostic tests. These future ancillary studies 
will have separate protocols, consent documents and funding but will enroll participants from the 
parent study. 


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XII. 
HUMAN SUBJECTS 
A. 
Informed consent 
Potentially eligible patients will be identified by research personnel at each site. After the study 
is introduced to the patient by an individual participating in their care, research personnel will 
contact potentially eligible subjects to describe the study and present him/her with the detailed 
informed consent form and supplementary material to read and review. 
 
The general purpose of the study will be delineated and the treatment comparisons will be clearly 
described. The process of randomization will be discussed and a clear explanation of what will 
be expected of the patient will also be described. The risks associated with treatments and 
procedures will also be addressed. The importance of patient confidentiality will be stressed, 
including a description of the process for maintaining patient confidentiality. Research personnel 
will ensure that the patient understands every aspect of the trial, including its risks and benefits, 
prior to signing the informed consent. 
 
If the patient agrees, his/her consent to participate in the study will be documented on the 
Agreement to Participate in Research form (VA form 10-1086). The original will be placed in 
the patient's medical record.  Copies of the consent form will be provided to the patient, placed in 
the patient's study file, and faxed to the MAVERIC CSPCC at the time of enrollment in the 
study. A copy of the consent will also be posted in the patient’s electronic medical record. If the 
site is unable to scan the consent into the patient’s electronic medical record, a CPRS template or 
Word document that contains the currently approved consent language can be included in the 
enrollment note in CPRS. The note should contain information that indicates that the Veteran 
signed a paper copy of the consent and should list the ICF version number and date of signature. 
The note should also state that the copy is located in the investigators study file. 
 
 
 
 
 
 
 
 
 
 


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Informed consent requires that the patient understand the details of the study and agree, without 
coercion, to participate in the study. To obtain informed consent, the following information shall 
be provided to each subject: 
 Name of the study 
 Name of the Principal or Site Investigator(s) 
 Explanation that the study involves research 
 Explanation of the purpose of the study 
 Explanation of the treatment procedures 
 Description of randomization 
 Description of the risks and benefits of participation in the study 
 Description of alternatives to participation in the study 
 Explanation that all records will be kept confidential, but that records may be examined 
by representatives of the VA and/or the FDA 
 Whom to contact for questions about the research and about subjects' rights 
 Whom to contact in the event of a research-related injury 
 A statement that participation in the study is voluntary and that a decision not to participate 
or to withdraw from the study after initially agreeing involves no penalty, loss of benefits, 
or reduction in access to medical care 
 A statement that the treatments provided as part of this study are free 
 
Merely obtaining signed consent from the patient does not constitute informed consent. 
However, the use of a standardized consent form aids in assuring that subjects receive adequate 
and consistent information about the trial and that they have consented to participate. 
In conjunction with the informed consent procedure, patients will review and be asked to sign the 
Authorization for Release of Protected Health Information Form as required by HIPAA. 
 
B. 
Risks and benefits 
Any procedure/intervention has potential risks. The interventions used in this study may cause 
all, some, or none of the risks and side effects listed. There is also the potential for rare or 
unknown risks to occur. Active study participants will be informed of any information that 
becomes known during the course of the study regarding risks of the interventions that might 
affect their willingness to continue to participate. 


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1. 
Side effects associated with infusion of intravenous fluids 
Reactions due to solution or technique of administration: febrile response, infection at the site of 
injection, venous thrombosis or phlebitis extending from the site of injection, and extravasation 
of fluids 
 
2. 
Side effects associated with infusion of sodium chloride 
Cardiovascular:  heart failure (aggravated), edema 
Endocrine and metabolic: hypernatremia, hyperosmolarity, hypokalemia, metabolic acidosis 
Respiratory: pulmonary edema 
 
3. 
Side effects associated with infusion of sodium bicarbonate 
Cardiovascular: heart failure (aggravated), edema 
Central nervous system: hyper-irritability or tetany may occur due to rapid shifts of free ionized 
calcium or serum protein alterations arising from changes in pH 
Endocrine and metabolic: hypernatremia, hyperosmolarity, hypocalcemia, hypokalemia, 
increased affinity of hemoglobin for oxygen, reduced pH in myocardial tissue, necrosis when 
extravasated, intracranial acidosis, metabolic alkalosis 
Respiratory: pulmonary edema 
 
 
4. 
Side effects of NAC 
Cardiovascular: flushing, tachycardia, edema 
Dermatologic: urticaria, rash, pruritus 
Gastrointestinal: diarrhea, nausea, vomiting 
Respiratory: pharyngitis, rhinorrhea, rhonchi, throat tightness 
Central nervous system: dizziness 
<1%, postmarketing, and/or case reports (limited to important or life-threatening): 
anaphylaxis, bronchospasm, chest tightness, cough, dyspnea, hypotension, respiratory distress, 
stridor, wheezing 
 
Possible benefits of this study include a reduced risk of serious adverse outcomes, including 
death, need for acute dialysis, and persistent decline in kidney function among subjects receiving 
bicarbonate and/or NAC. 


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XIII. DATA MANAGEMENT 
Source documents may include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. Paper source document worksheets 
will be provided to study coordinators to facilitate data collection. If a paper source document 
worksheet is used as a primary means of collecting data (the data elements are newly created and 
not transcribed from other sources) then it will be considered a source document and must be 
maintained. The MAVERIC CSPCC will manage the trial data using a web-based Electronic 
Data Capture (EDC) system. The EDC system will allow study coordinators to enter the source 
data into a web-based study database and manage their patients, handle data clarifications, and 
correct patient data. Accordingly, the electronic system will be used to create, modify, maintain 
and retrieve clinical data for CSP#578 during each step of the data collection process. 
 
After the study is approved, the Study Chairmen and Study Director will prepare an Operations 
Manual for site staff to guide them through the operation and management of the study and data 
collection tools. A training session will occur at the study kick-off meeting for all investigators 
and coordinators to assure uniformity in patient management, data collection, and study 
procedures. At this training, coordinators will be provided with reference materials on the software 
tool and tasks. Once formal training is completed, user accounts utilizing a URL specific 
to the study to access and use the system and enter patient data will be activated. Accounts 
will be password protected and unique to the users' functional study group (i.e., those for a study 
coordinator would differ from those of the coordinating center or site monitors). Formal 
training on the use of the EDC system for clinical study management will also be provided. 
Systems training may also be held at annual meetings and on an as-needed basis for new 
research personnel. 
 
The MAVERIC CSPCC will utilize an EDC tool that is fully compliant with U.S. Federal 
regulations regarding electronic web-based data capture systems established by the FDA under 


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21 CFR 11. This system is designed to make the process of patient data management easier, 
timelier, and more efficient. Accessing the system requires a VA intranet connection and a web- 
browser. The paper source documents from which data will be entered into the electronic data 
capture tool’s case report forms provide the official clinical record for data collection. All paper- 
based study records will be kept under lock and key. The EDC system will be validated by the 
MAVERIC CSPCC Validation Team to ensure the integrity of the data capture software. 
Validation documentation and all system dependability documentation (i.e., software and 
hardware versions, etc.) will be maintained as study documentation, but will not be detailed in 
this protocol. 
 
For this trial, EDC designers will create a study-specific database that includes case report forms, 
interview schedules, and data queries using customized code imbedded directly into electronic 
case report forms. Data clarifications forms (DCFs) or data queries will be managed in two ways. 
Certain queries will be programmed into the forms that are designed to activate upon data entry. 
Additional DCFs will be programmed using other data analysis tools such as SQL and will be 
uploaded into the system for study coordinators to address. Furthermore, the system will allow 
manual DCFs to be entered into the EDC system by the coordinating center as needed. Updates 
to the electronic forms and database can be generated during the study without impacting collected 
data. Study reports can be generated from exported data in order to track the study progress 
and to monitor adverse events, in particular Serious Adverse Events. Study reports will be 
circulated to appropriate members, including the site investigators, the study chairmen, and the 
Data Monitoring Committee (DMC). 
 
The servers housing the study databases will be located at secure VA facilities that support 
round-the-clock web services and monitoring within a secure VA environment in order  to provide 
an optimal infrastructure for the protection of sensitive information. The clinical database with 
all research data will be housed behind the VA firewall on VA owned and maintained 
servers. Accordingly, the information housed within the EDC system will be afforded the same 
level of security as all forms of VA protected and/or highly sensitive information. Additionally, 
the system will be monitored by the MAVERIC CSPCC Quality Assurance and Information 
Technology teams to ensure that all applicable VA regulations and directives are 
strictly followed. 


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Backup copies of the database will be transferred behind the VA firewall to the MAVERIC 
CSPCC on a frequent basis depending on the study need (at least once per day). These backup 
copies will be transferred and stored across secure connections according to VA regulations and 
MAVERIC CSPCC operating procedures. Periodic off-site back-ups will be made as part of a 
comprehensive disaster recovery plan. The Director of Information Technology will ensure that 
backup media are stored in compliance with all federal and VA regulations on the storage of 
potentially sensitive information. The Director of Information Technology will also ensure that 
all backup media are encrypted in compliance with the current best practices established and 
approved by the Center Director(s). Encrypted backup media will be stored in a physically 
secure location with access restricted to essential personnel. Access to back-ups may be at the 
discretion of the Center Director(s) and/or the Director of Information Technology. 
 
Access to the study data is heavily restricted to individuals with CSP approval. Individuals must 
be properly credentialed research staff and must be compliant with VA security trainings (i.e., 
Research Data Security, HIPAA and VA Privacy Training, Information Security Awareness, and 
Good Clinical Practices). In addition, research data will be stored on VA secure servers with 
restricted permissions for copying and exporting data. Only properly approved Coordinating 
Center personnel will have the ability to copy and export data. These individuals have received 
training on the local SOP governing their permissions and will not access or export data without 
written approval from the MAVERIC CSPCC Center Director. Furthermore, the permissions of 
the electronic systems are structured such that individual sites can only see the data for their 
study participants. They cannot see or access the data for another clinical site or for another 
participant. 
 
Access to protected health information (PHI) will be restricted to individuals approved by CSP to 
have access to the data. Once an individual is no longer an active member of the research team, 
their access to research data will be removed. 
 
 
 


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At the Local Clinical Sites, individuals in these positions will be able to access PHI: 
 Site Investigator 
 Co-Site Investigator 
 Study Coordinator 
 Project Support Staff 
 
 
At the MAVERIC CSPCC, individuals in these positions will be able to access PHI: 
 Center Director 
 Study Director 
 Project Manager 
 Project Coordinator 
 Research Assistant 
 Data Manager 
 Database Coordinator 
 Biostatistician 
 Junior Biostatistician 
 Quality Assurance Officer 
 SAS Programmer 
 
 
At the CSPCRPCC, individuals in these positions will be able to access de-identified forms of 
PHI: 
 Clinical Monitors 
 Study Pharmacist 
 Adverse Event Specialist (Regulatory Affairs and Safety Officer) 
 Pharmacy Project Manager 
 
 
Research data will only be stored on secure VA servers within the VA firewall. Data will not be 
stored on desktops or on University affiliate servers. Study data will be coded with a unique 
study identifier for each participant and stored in a de-identified manner. Identifiable information 
will be collected for patient tracking and safety purposes. All private information will be kept on 
an encrypted, password protected server to which a small number of people will have access. 
Access to the cross-walk file linking the participant's identifiers and their study data will be 


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restricted to the clinical site and to the approved personnel at the coordinating center. This file 
will be destroyed according to CSP policy. 
 
When the study is on-going, the electronic data capture systems will utilize state-of-the-art 
technologies in order to protect the data during transmission. All of these technologies exceed 
the current VA standards for transport. In brief, electronic systems will employ secure socket 
layer technology and FIPS 140-2 compliant encryption algorithms to ensure that data is not 
vulnerable during transport. In addition, all data will be stored within the VA firewall and will be 
password protected at all times. Hard copy data will be sent via a traceable mail system (i.e., 
UPS), via a courier, or via secure fax. Faxes are electronically routed to document management 
systems housed on VA protected servers located at the Regional Data Center in Philadelphia, 
PA. Access to these secure fax servers is restricted to the Coordinating Center personnel with 
approved access to the system. All secure fax servers are compliant with VA directive 1605.1 
and 6500. All data security incidents will be reported in accordance with VA policy within one 
hour of discovering the incident to the District (local) Information Security Officer (ISO) and the 
MAVERIC CSPCC Data Security Officer. Data security incidents will be reported to the VA 
Central IRB within 5 days of becoming aware of the event. 
 
Quality control checks and clinical monitoring will enable the Coordinating Center to survey the 
study database and the clinical sites to ensure that the data have not been improperly used or 
accessed. 21 CFR part 11 compliant audit trails and access logs will be checked routinely. In 
addition, the clinical monitors (SMART) will provide continuing education on good clinical 
practices and will check clinical site operations for compliance with data security policies and 
best practices. 
 
The clinical data for CSP 578 are considered property of the Cooperative Studies Program and 
shall not be sent off-site (i.e., outside of the VA) without the expressed, written permission from 
the MAVERIC CSPCC Center Director and CSP Central Office. All data transfer and data 
security policies of the VA, the Cooperative Studies Program, the MAVERIC CSPCC, and the 
local healthcare system will be closely followed. The MAVERIC CSPCC Quality Assurance 
team will work closely with the local research compliance officer, the information security 


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officer, and the VA privacy officer as needed to ensure that data security and data transfers are 
handled appropriately. 
 
Retention and destruction of data will be conducted according to CSP operating procedures and 
federal and local VA regulations. This will include paper and electronic data stored at the local 
sites, the MAVERIC CSPCC, and at the VA facility housing our servers. Identifiable data will be 
kept according to CSP policy as outlined in the "CSP Guidelines for the Planning and Conduct of 
Cooperative Studies." 
 
At the completion of the study, a data set from the study will be banked at the MAVERIC CSP 
Coordinating Center in a data repository that will be established for research purposes under the 
oversight of  the VA Boston Institutional Review Board. The Data Repository will be established 
and used in accordance with the Repository Protocol, relevant Standard Operating Procedures, 
and existing regulations. Data will be made available to appropriately credentialed researchers 
conducting studies related to the topics explored in this protocol or other health questions in 
accordance with the Standard Operating Procedures of the Data Repository.  
 
Regarding our collaboration with The George Institute in Australia, as described in Section X.D., 
study data from the VA and The George Institute will be submitted to MAVERIC CSPCC and 
analyzed as one combined dataset. 


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XIV. QUALITY CONTROL PROCEDURES 
A. 
Standardization/validation of measurements 
Prior to the initiation of the study, all investigators from the clinical sites as well as study 
coordinators will meet to review study procedures and receive training on collecting data for the 
study. Much of this training will take place during the study kickoff meeting. The protocol and 
source document worksheets will be sent to site investigators and coordinators to review prior to 
the meeting. During the meeting, study coordinators will receive training on obtaining and 
maintaining source documents and completing study assessments and electronic case report 
forms. Verbal feedback and discussion will follow to ensure that each coordinator comprehends 
the proper methodology for assessment. The meeting will also cover an in-depth review of the 
study operations manual. Such a review will serve to reinforce the training described above and 
will orient the research personnel to the reference guides for the study. 
 
Prior to the start of any study using the MAVERIC CSPCC electronic data capture tool, extensive 
study specific validation will be performed. This process will be documented and placed on 
file at the MAVERIC CSPCC. 
 
B. 
Patient management 
For CSP 578, the site investigator at each site will be responsible for the management of his/her 
patients. If the patient is unable to return to the VA facility at which their angiogram was 
performed for specimen required blood collection other o ptions for this blood draw may include, 
but not be limited to: 1) having a mobile phlebotomy service draw the blood; or 2) having the 
blood drawn at a non-study VA site such as a Community-Based Outpatient Clinic (CBOC) or 
another VA facility closer to the participant’s home. Every effort will be made to accommodate 
the patient’s schedule and safety concerns. 
 
C. 
Protocol deviations 
Documentation of any protocol deviations will be required. A Protocol Deviation form has been 
created by the MAVERIC CSPCC to ensure the proper tracking of events. Protocol deviations 
will be evaluated by the Study Chair’s office and the MAVERIC CSPCC, and a determination 
made regarding the validity of any justification for the deviation. Any medical center or subject  


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with repeated protocol deviations in the absence of valid justification, and after remedial protocol 
training, will be recommended for termination to the DMC. If any member of the DMC or the 
monitoring bodies for CSP 578 feel that adherence to the protocol will be detrimental to a 
participant's health or well-being, the interest of the participant will take precedence and the 
subject will be withdrawn after consultation with the Executive Committee. Protocol deviations 
will be reported to the VA Central IRB as required. 
 
D. 
Unblinding the study treatment 
This CSP clinical trial is a double-blinded study in which neither the patient nor the site 
investigator knows to which of the four study arms the patient has been assigned. The 
CSPCRPCC will not provide Emergency Code Envelopes to the sites’ Pharmacy Service. 
Emergency unblindings will be managed through the 24-hour emergency call service (505-248-
3203). This number is also listed on the patient ID cards given to each patient participating in CSP 
#578. The system managed by the CSPCRPCC will electronically capture up-to-date study drug 
assignment information gathered from the PRESERVE IWRS. 
Under unusual circumstances, chiefly related to participant safety, unblinding may be necessary. 
This is usually done after consultation with the Study Chair, Steven Weisbord MD, MSc or Study 
Co-Chair, Paul Palevsky MD. If Dr. Weisbord and Dr. Palevsky are unavailable, the CSPCRPCC 
Clinical Research Pharmacist (Todd Conner, PharmD) or the Study Director (James Kaufman, MD) 
should be contacted. Current telephone numbers are listed in the study personnel directory on the 
CSP578 Main SharePoint Site.  
If unblinding is required in an emergency, the Local Site Investigator (LSI) or Study Coordinator 
(SC) must contact the CSPCRPCC through the 24-hour emergency call service to obtain study drug 
assignment information. The CSPCRPCC will notify the Study Chair’s Office and the MAVERIC 
CSPCC by telephone as soon as possible after an unblinding has occurred.  If the CSPCRPCC 
receives a request for unblinding information from anyone other than the LSI or SC, the 
CSPCRPCC will refer the requester to the LSI or SC or, in his or her absence, the CSPCRPCC will 
confer with the parties above. 
 
 
 
 


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E. 
Probation/termination of participating centers 
The recruitment rate and operational aspects of this study will be monitored continuously by the 
Study Chairmen and MAVERIC CSPCC. Medical centers may only continue participation if the 
performance measures described below are met. Termination of a center will only be taken in 
accordance with Cooperative Studies policies and procedures. 
 
The following performance measures will be used to determine whether sites are at risk for or 
should be placed on probation. Other reasons for probation include, but are not limited to, 
noncompliance with the protocol, ICH, or applicable federal regulations. 
 
1. Recruitment rate. Recruitment rate will be calculated by dividing the number of randomized 
patients by the number of expected patients. This measure will be continuously monitored and 
sites between 75% and 90% of expected recruitment will be subject to remediation such as action 
plans or mentoring. Sites under 75% cumulative recruitment after a 3-month ramp-up period may 
be placed on probation. Assessment for probation will occur on a monthly basis. 
 
2. Follow-up rate. Follow-up rate will be calculated by dividing the number of patients with any 
90-day follow-up forms completed by the expected number of patients with 90-day visits due. 
Both the numerator and denominator will be subject to a 4-week delay in order to allow for 
scheduling of the 90 day visit and completion of forms. Sites with cumulative follow-up rates 
below 90% may be placed on probation. Assessment for probation will occur on a monthly basis. 
 
3. Forms Completion rate. Forms completion rate will be calculated by dividing the number of 
completed forms by the number of expected forms, where the number of expected will exclude 
forms marked not collected. Forms completion rates will be calculated both by patient and by 
form. Sites with cumulative forms completion rates under 90% may be placed on probation. 
Assessment for probation will occur on a monthly basis. 


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Once a site is placed on probation, failure to meet the requirements specified by the end of the 
probation period will result in a recommendation for termination. Additionally, sites that fail to 
meet two or more of the above performance measures, and sites that habitually under-perform by 
any of these measures, will be at risk of termination. After careful monitoring of site performance 
by study leadership, a site may be terminated without being put on formal probation if deemed 
appropriate.


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XV. 
GOOD CLINICAL PRACTICES 
1. Role of GCP  
This trial will be conducted in compliance with Good Clinical Practice (GCP) regulations.  The 
intent of these regulations is to safeguard subjects’ welfare and assure the validity of data resulting 
from the clinical research. The VA Cooperative Studies Program will assist Local Site 
Investigators (LSIs) in complying with GCP requirements through its Site Monitoring, Auditing 
and Resource Team (SMART) based in Albuquerque, NM.  SMART serves as the Quality 
Assurance arm of CSP for GCP compliance.  Study site personnel will receive a GCP overview at 
the study organizational meeting. 
.SMART will provide training, manuals and materials to assist study personnel in organizing 
study files and will be available throughout the trial to advise and assist LSIs regarding GCP issues.  
2. Summary of Monitoring and Auditing Plans 
a. Monitoring Visits – 
(1) Initiation visits at each site soon after study start-up 
(2) Subsequent monitoring will be conducted yearly thereafter 
(3) Final monitoring visit to each site during last year of study 
(4) Additional monitoring visits may be conducted as deemed necessary by study 
leadership or SMART. 
b. Audits 
 
(1) Routine audits – independent site visits to one or more sites per year as 
determined by SMART.  
(2) For-Cause audits –independent audit of a site as requested by study leadership or 
CSP Central Office.  
(3) Audits may be scheduled or unannounced. 
 


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XVI. 
STUDY MONITORING AND AUDITING PLANS 
Protection of the rights and welfare of patients is a primary concern of CSP. In addition to the 
International Conference on Harmonisation (ICH) Good Clinical Practice Guidelines, this trial 
will be conducted in compliance with VA guidelines, the Declaration of Helsinki, and the 
applicable parts of the United States Code of Federal Regulations or local laws governing the 
conduct of good clinical studies. 
 
A. 
Monitoring bodies 
Four external bodies will oversee the ongoing scientific and ethical conduct of the study including 
the Data Monitoring Committee, the CSPCC Human Rights Committee (HRC), the VA Central 
IRB and Clinical Monitors (SMART). In addition, at the mid-point of the study, the Cooperative 
Studies Scientific Evaluation Committee (CSSEC) will review the study. 
 
By agreeing to participate in the study, the medical center delegates responsibility for global 
monitoring of the ongoing study to these four bodies. However, the Research and Development 
(R&D) and the Human Studies Committee of the local medical center may require the 
investigators to submit additional reports concerning the status of the study. Internal operational 
oversight (described in Section XVIII) will be conducted by the MAVERIC CSPCC, the 
CSPCRPCC and the Study Chairmen’s Office. 
 
1. 
Data Monitoring Committee 
The Data Monitoring Committee (DMC) will review the progress of the study and monitor 
adherence to the protocol, participant intake, outcomes, complications, and other issues related 
to participant safety. They will also monitor the assumptions underlying sample size 
calculations for the study and alert the investigators if they see substantial departures as the data 
accumulate. The DMC will be composed of experts in nephrology, cardiology, and clinical 
trials. The Study Chairmen will make nominations to the Director, Cooperative Studies 
Program, who will make the final selection for the Committee. The DMC will make 
recommendations to the Director of the Cooperative Studies Program as to whether the study 
should continue or be terminated. The DMC can consider participant safety or other 
circumstances as grounds for early termination, including either compelling internal or external 


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evidence of treatment differences or feasibility of addressing the study hypotheses (e.g. poor 
participant enrollment, poor adherence). The DMC will conduct an in depth assessment of 
safety and efficacy data every six months at which time the study biostatistician will provide the 
DMC with an interim summary report on the study status and on safety data for monitoring 
purposes. 
 
2. 
Human Rights Committee 
The Human Rights Committee (HRC) at the Coordinating Center may review the study at the 
request of the Coordinating Center Director in order to provide suggestions regarding study 
participants' protection. 
 
3. 
VA Central IRB 
The VA Central IRB provides expert ethical and scientific review of multi-site projects while 
ensuring local issues are addressed. The VA Central IRB performs full, expedited, exempt, and 
continuing review and provides waivers of HIPAA authorization as necessary and appropriate. 
The VA Central IRB meets monthly in person and/or by video or teleconference. The Study 
Chairmen will initially submit a principal investigator (PI) application which will include model 
documents such as the informed consent form and any waiver requests. Once approved, this 
application package will be sent to all potential participating sites who will be responsible for 
submitting their own local site investigator (LSI) applications. Once both the PI and LSI 
applications have been approved, the study is reviewed in accordance with local R&D 
Committee policies and the VA Central IRB is provided a copy of the site approval document for 
the study to begin at that site. Continuing reviews are done annually. 
 
4. 
CSP Site Monitoring, Auditing and Resource Team (SMART) 
The CSP Site Monitoring, Auditing and Resource Team (SMART), located in the CSPCRPCC in 
Albuquerque, will monitor the trial for compliance with Good Clinical Practices.  GCP monitors 
from SMART will visit participating sites shortly after enrollment is initiated and subsequent 
monitoring will be conducted yearly thereafter to monitor investigator regulatory and protocol 
compliance and to evaluate research practices.  SMART will provide an orientation to GCP at the 
study kick-off meeting and provide GCP tools to enhance compliance.  Additionally, SMART will  


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conduct periodic routine audits throughout the course of the study and for-cause audits as requested 
by study leadership or CSP VACO 
 
B. 
Monitoring adverse events (AEs) and serious adverse events (SAEs) 
Timely and complete reporting of safety information assists study management in identifying 
any untoward medical occurrence, thereby allowing: 1) protection of study patients’ safety; 2) a 
greater understanding of the overall safety profile of the study interventions and therapeutic 
modalities; 3) appropriate modification of the study protocol; 4) improvements in study design or 
procedures; and 5) compliance with regulatory requirements. 
 
The local Site Investigator will be responsible for the AE and SAE reporting requirements as 
described in this protocol and outlined below: 
 Closely monitoring research subjects during the study for the development of new AEs 
and SAEs. 
 Reviewing the accuracy and completeness of all AEs and SAEs reported. 
 Reporting all  SAEs  to the CSPCRPCC and MAVERIC CSPCC within 72 hours of 
becoming aware of the event. 
 Complying with VA Central IRB policies for reporting adverse events 
 Implementing plans the Study Group and Executive Committee may develop in response 
to safety concerns. 
 
1. 
Adverse events 
Adverse events (AEs) are defined by the VHA Handbook 1058.01, paragraph 4 (a) as "An AE is 
any untoward physical or psychological occurrence in a human subject participating in research. 
An AE can be an unfavorable and unintended event, including an abnormal laboratory finding, 
symptom, or disease associated with the research or the use of a medical investigational test 
article. An AE does not necessarily have to have a causal relationship with the research. " 
 
For the purpose of CSP 578, the study interventions are study IV fluids and oral NAC/placebo. 
Related events involve an assessment of the degree of causality (attribution) between the study 
interventions and the event. Site investigators will be asked to provide an assessment of  
 


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relatedness. All AEs with a reasonable causal relationship to the investigative treatment will be 
considered "related." A definite relationship does not need to be established. 
 
Local site investigators, with assistance from their study coordinator, are responsible for 
collecting AE information regarding the subjects at their sites. During the study, data on adverse 
events will be collected spontaneously through patient reports, actively elicited during the 
angiography visit through open-ended questioning and examination, and gathered at the time of 
telephone contact and medical record reviews during the follow-up period. Related adverse event 
data will be collected from the time of consent to 35 days post angiography. If a patient receives 
care at a non-VA facility for an adverse event they experience, research personnel will obtain 
the requisite release of information form(s) from the patient and once received, acquire the 
pertinent medical records from the facility. 
 
AEs related to the study intervention that are reported to research personnel will be recorded on 
an adverse event form and documented in source records (e.g., the electronic VA medical record 
and/or the subject's study record). In this way, the site creates a permanent record that provides 
information on the subject's clinical course while in the study. 
 
Adverse events which develop into Serious Adverse Events, as defined below, will be reported 
as such and followed to resolution or stabilization. 
 
2. 
Serious adverse events 
Serious adverse events (SAEs) are a subset of adverse events defined in VHA Handbook 1058.01, 
paragraph 4(r) and 21 CFR 312.32(a), as follows: 
 
Definition of SAE from CFR 312.32 (a): Serious adverse event. An adverse event or suspected 
adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening,  
 


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or require hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
Definition of SAE according to VA Handbook 1058.01: An SAE is an untoward occurrence 
in human research that results in death, a life-threatening experience, inpatient hospitalization, 
prolongation of hospitalization, persistent or significant disability or incapacity, congenital 
anomaly, or birth 
defect, or that requires medical, surgical, behavioral, social, or other 
intervention to prevent such an outcome. 
 
All SAEs, as defined in VHA Handbook 1058.01, paragraph 4(r) and 21 CFR 312.32(a), will be 
collected, regardless of whether or not they are considered related to the study interventions. 
SAEs with a reasonable causal relationship to the study interventions and associated medications 
will be reported as "related." A definite causal relationship does not need to be established. 
 
Local site investigators, with assistance from their study coordinator, are responsible for 
collecting SAE information regarding the subjects at their sites. SAEs will be collected from the 
time of consent through day 90 following the patient’s index angiography procedure or the time 
of patient termination if before day 90. During the study, data on SAEs  will  be  collected  
spontaneously  through  patient  reports,  actively  elicited  during  the angiography visit through 
open-ended questioning and examination, and gathered at the time of telephone contact and 
medical record reviews during the follow-up period. If a patient receives care at a non-VA 
facility for a serious adverse event they experience, research personnel will obtain the requisite 
release of information form(s) from the patient and once received, acquire the pertinent medical 
records from the facility. 
 
SAEs that are reported to research personnel will be documented in source records (e.g., the 
electronic VA medical record and/or the subject's study record). In this way, the site creates a 
permanent record that provides information on the subject's clinical course while in the study. 
Research personnel at the site will ask follow-up questions to determine the exact nature of the 
SAE and obtain appropriate medical records, if needed. Each SAE will be followed to resolution 
or stabilization or until the end of study participation. 
 


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a. 
Expedited reporting of serious adverse events 
All SAEs must be reported to CSPCRPCC and MAVERIC CSPCC and entered into the EDC 
system within 72 hours of the local site staff becoming aware of the event. The site must notify 
MAVERIC CSPCC, Chair’s Office, and CSPCRPCC of the event by email upon entering the SAE 
into the EDC system. The SAE will also be documented in source records (e.g., the electronic VA 
medical record and/or the subject’s study record). 
 
SAEs that are BOTH unanticipated AND related to the study interventions (administration study 
fluids or NAC/Placebo) will be reported, in writing, to the VA Central IRB within 5 business days 
of the local staff becoming aware of the event. In addition, any research deaths that are BOTH 
unanticipated AND related to the study interventions will be reported by telephone to the VA 
Central IRB immediately upon the local staff becoming aware of the death. Written notification 
to the VA Central IRB must follow within 5 business days of becoming aware of the death.   
 
All other SAEs (i.e., SAEs that are either anticipated or unrelated to the study interventions), 
including deaths that are either anticipated or unrelated to the study interventions, will only be 
reported to the VA Central IRB at the time of Continuing Review (CR).  Sites should maintain the 
individual participant CSP #578 AE Tracking Logs provided by SMART to facilitate this reporting. 
 
If an event meets FDA reporting criteria, meaning it is serious, unexpected and deemed possibly 
related to the study drug it will be reported by the CSPCRPCC to the CRADO after review by the 
Study Pharmacist, Study Chairs, MAVERIC CSPCC Director, and CSPCRPCC Director. 
If needed, as required under the Food and Drug Administration Investigational New Drug (IND) 
protocol, CSPCRPCC will report SAEs that are both related to study intervention and unexpected 
to the FDA no later than 15 days from when they are notified. If the SAE is a death or a life-
threatening event, this notification will happen within 7 days. 
 
 
 
 
 
 
 
 
 
 
 
b. 
Monitoring of serious adverse events 


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SAEs will be monitored throughout the study by the Data Monitoring Committee. The study 
pharmacist and study biostatistician will generate tabulations of AEs and SAEs and present a 
summary of all AEs and SAEs to the DMC on a schedule set by the DMC. The DMC will also 
determine when they should be unblinded to treatment assignment for the reviewing of adverse 
event data. The DMC will recommend to the CSRD Director whether the study should continue 
or be stopped for safety reasons. The DMC will also monitor the primary endpoint at pre- 
determined intervals and recommend to the CSRD Director whether the trial should be stopped 
for efficacy or futility. Summary reports from the DMC will be provided to the VA Central IRB. 
We believe that the independent DMC can effectively monitor the trial for safety, since it will 
regularly review all outcomes according to treatment assignment, and will also have access to 
statistical support to determine the significance of any observed differences. 


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XVII. BIOSTATISTICAL CONSIDERATIONS 
A. 
Overview of design 
1. 
The analytic model 
There are two primary hypotheses that will be tested: 1) peri-procedure infusion of sodium 
bicarbonate is superior to infusion of sodium chloride for the prevention of serious, adverse 
clinical events within 90 day of angiography and; 2) peri-procedure administration of oral N- 
acetylcysteine (NAC) is superior to placebo for the prevention of serious, adverse clinical events 
within 90 day of angiography. The study will enroll 7,680 subjects over 2.5 years and evaluate 
each subject 90 days after the intervention. Within each site, subjects will be randomly assigned 
to one of four combinations of study interventions: 1) bicarbonate and NAC placebo, 2) saline 
and NAC placebo, 3) bicarbonate and NAC and 4) saline and NAC. 
 
The study design for the primary hypothesis is a 2 x 2 factorial design with a binary outcome - 
any of a selected list of important clinical events occurring within 90 days of study treatment 
including death, need for acute dialysis, and persistent change in SCr at 90 days of at least 50% 
from the baseline SCr. We denote the 90-day binary outcome as ‘MAKE-D’ (major adverse 
kidney events and death). The binary predictors are the interventions bicarbonate and NAC. The 
interaction term, bicarbonate*NAC, represents the combination of these two interventions. The 
primary analysis starts with  a logistic regression analysis with three binary predictors. 
 
For the primary hypothesis, the model equation for the analysis is: 
 
 
MAKE-D =  β1* Bicarbonate + β2* NAC + β12* Bicarbonate*NAC 
Model Equation 
 
 
where, β1 , β2, and β12 are the logistic regression beta coefficients. 
 
 
The two main questions of interest that we will test for the primary hypothesis are: 
1) Does bicarbonate reduce the incidence of MAKE-D? 
2) Does NAC reduce the incidence of MAKE-D? 


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owever, we 
recognize the 
 
 
 
The power calculation for determining the total sample size depends only on these two main 
effect hypotheses. This means that the exploratory analyses do not have any associated power 
analyses. The primary analysis will -firstly test the significance of the interaction term, 
bicarbonate*NAC.  In the event of a non-significant interaction term at p=0.05 level, the regression model 
will be refitted without the interaction term. Otherwise, a stratified analysis will ensue where logistic models 
with single binary predictors for different levels of bicarbonate and NAC will be refitted. We will carry 
out the primary analysis by means of multivariable logistic regression without adjustment for 
any additional covariates. 
 
2. 
Incidence of the 90-day endpoint and effects of our interventions 
The events included in MAKE-D are death, need for acute dialysis, and persistent decline in 
kidney function. These events overlap. As previously discussed and summarized in Tables 4 and 
5, most published randomized trials that investigated the proposed interventions did not report on 
these outcomes. However, for those that did track these events, acute dialysis was necessary in 0- 
7%, death occurred in 0-6%, and persistent decline in kidney function occurred in up to 19% of 
patients. Using the VA Austin database, we identified 25,909 Veterans who recently underwent 
coronary or non-coronary angiography who met our study entry criteria. Examining event rates 
at 90 days following angiography, we found that 1% died, 5% initiated dialysis, and 4% had a 
persistent increase in SCr of at least 50% (only about one-half of the patients had a measurement 
of SCr at 90 days). Overall, 8.7% had at least one of these events within 90 days. We therefore 
believe that the baseline incidence of MAKE-D in this patient population is 8.7%. Assuming an 
equal distribution of use of NAC versus no use of NAC and saline versus bicarbonate in this 
population with an overall event rate of 8.7%, a 25% reduction in the incidence of the composite 
primary outcome with bicarbonate (vs. saline) and with NAC (vs. placebo) would lead to the 
distribution of events with each treatment combination shown in Model 1. Using this approach, 
the overall sample size estimate, assuming a type 1 error of 0.025, 90% power, and 3% loss to 
follow-up, would be 6,500 subjects. 
 
 
 
Model 1 
Bicarbonate 
Saline 
NAC 
6.4% 
8.5% 
7.5% 
Placebo 
8.5% 
11.3% 
9.9% 
7.5% 
9.9% 
Overall event rate 
8.7% 


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The  specific 
details of 
Overall event rate 
7.6% 
 
 
 
Our proposed sample size of 7,680 patients, based on the rates summarized in Model 2 (see 
below), arises from more conservative assumptions. The 8.7% overall event rate derived from 
the VA Austin database represents the incidence of this composite outcome in a patient 
population in which the specific use of preventive care for CIAKI is unknown. Recognizing that 
these patients may or may not have received the interventions we propose to study, we have 
taken a more conservative approach to estimating the necessary sample size by assuming that 
this 8.7% event rate represents the rate in each of the control arms (i.e., placebo with saline or 
bicarbonate and saline with or without NAC) as shown in Model 2. In this proposed model, the 
overall event rate in the entire population is 7.6%, which is 13% lower than the event rate (8.7%) 
which is suggested by our analyses of the VA Austin database. Using this more conservative 
estimate of the overall event rate resulted in our proposed sample size of 7,680 patients. We 
believe that this approach will help ensure that our study is not underpowered and is grounded on 
conservative, yet clinically reasonable event rate estimates. 
Model 2 
Bicarbonate 
Saline 
NAC 
5.59% 
7.46% 
6.52% 
Placebo 
7.46% 
9.95% 
8.70% 
6.52% 
8.70% 
 
Most trials have reported effect sizes for the outcome of CIAKI rather than for our defined 90 
day primary composite outcome. For CIAKI, a recent meta-analysis reported a pooled relative 
risk of 0.62 (95% CI: 0.45-0.86) favoring bicarbonate when compared to saline, with the 
individual study effect sizes ranging from 2% to 92%. There were too few studies that 
systematically tracked other clinical outcomes to reliably analyze the risks for dialysis (RR=0.51, 
95% CI: 0.17-1.51) or death (RR=0.83, 95% CI: 0.32-2.19). Similar results have been reported 
for NAC. The Planning Committee felt that a 25% effect size would be clinically meaningful and 
within the range of what might be expected from previous studies, since the reduction in 90 day 
clinical outcomes is likely mediated by a reduction in CIAKI, which available literature suggests 
is reduced by as much as 92%. 


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Therefore, considering Model 2, we postulate that: 
 Under control conditions, the 90-day event rate for our primary outcome (MAKE-D) is 
8.7% 
 Each of the two interventions will prevent 25% of these events 
 Under each intervention condition, the 90-day event rate is 6.52% 
 The absolute effect of each intervention will be a 2.18% reduction in 90-day events 
 
 
We have two primary hypotheses, one for each main effect in the model. We will therefore 
allocate the type I error of 5% equally across the two interventions, assigning a type I error of 
2.5% to each. Including a third test for the interaction term from the set of primary hypotheses 
would slightly decrease the statistical power. We discuss the potential impact of the interaction 
on the power of the study later in this section. One interim analysis using an O’Brien-Fleming 
rule will be carried out when half the expected number of MAKE-D events have occurred. 
 
B. 
Primary end-points 
The two main interventions will be analyzed in the same way. Hence, we fully describe the 
bicarbonate versus saline intervention and the MAKE-D outcome. The analyses for the other 
intervention, NAC versus placebo, are analogous. 
 
The null hypothesis is that the two treatment groups (bicarbonate and saline) do not differ in 
terms of the proportion of subjects who experience MAKE-D events. The alternative hypothesis 
is that the absolute difference in the incidence of MAKE-D between the bicarbonate intervention 
group and the saline group is 2.18% or more. 
 
Formal statement of the null hypothesis 
Under the null hypothesis: 
 The  proportion  of  90-day  MAKE-D  events  for  patients  administered  bicarbonate  is 
8.70% 
 Under the alternative hypothesis, the proportion of 90-day MAKE-D events for patients 
administered saline is 8.70% 


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The formal hypothesis test is two-sided allowing for bicarbonate to be either more or less 
effective than saline. However, the study of bicarbonate will only be viewed as more successful 
if subjects treated with bicarbonate have a significantly lower proportion of 90-day MAKE-D 
events than patients who receive saline. We will test this hypothesis using the strategy described in 
section A. 
 
C. 
Secondary end-points 
Our secondary objectives, as previously outlined, will be tested using a logistic regression 
analysis similar to the primary objective. These objectives are: 
1. To assess the effectiveness of the interventions to prevent CIAKI, defined by  an increase 
in SCr of ≥ 0.5 mg/dL and/or ≥ 25% at 96 hrs following angiography compared to 
baseline values. 
2. To assess the effectiveness of the interventions for the prevention of the following 
outcomes within 90 days of coronary or non-coronary angiography: 
a) death 
b) major adverse kidney endpoints (MAKE) including need for acute dialysis or 
persistent decline in kidney function defined by an increase in SCr of at least 
50% at 90 days 
c) hospitalization with acute coronary syndrome, heart failure, or cerebrovascular 
accident defined by primary or secondary ICD-9 discharge diagnosis codes of 
acute coronary syndrome (i.e., STEMI, NSTEMI, unstable angina), heart 
failure, or cerebrovascular accident and/or by documentation of any of these 
three events in the hospital discharge summary. 
d) all-cause hospitalization 
 
 
D. 
Tertiary (exploratory) end-points 
We also wish to explore whether the interventions prevent adverse outcomes occurring within 
the first year after angiography. To that end, using logistic regression analysis, we will determine 
whether the interventions prevent: 


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1. Development of end-stage renal disease within one year following angiography 
defined by the requirement for chronic dialysis for ≥ 3 months based on documentation in 
the United States Renal Data System 
2. Death within one year following angiography based on documentation in the VA 
Beneficiary Identification and Records Locator System, the National Center for Health 
Statistics National Death Index database, or the Social Security Administration’s Death 
Master File 
 
E. 
Additional exploratory analyses 
We will explore several other hypotheses related to the binary 90 day MAKE-D outcome: 
1. The combination of bicarbonate and NAC (interaction term) is more effective than 
bicarbonate or NAC alone. 
2. (Per Protocol analysis) Bicarbonate, NAC, and their combination reduce the 
incidence of the primary outcome, MAKE-D, among subjects who received the full 
dose of bicarbonate. 
3. (Per Protocol analysis) Bicarbonate, NAC, and their combination reduce the 
incidence of the primary outcome, MAKE-D, among subjects who received the full 
course of NAC. 
4. Bicarbonate, NAC, and their combination reduce the incidence of the individual 
components of MAKE-D, each treated as a separate outcome: death, need for acute 
dialysis, and persistent decline in kidney function. 
5. Bicarbonate, NAC, and their combination reduce the incidence of each of the 
individual cardiovascular components of the secondary outcome; namely acute 
coronary syndrome, heart failure, and cerebrovascular accident. 
6. Bicarbonate, NAC, and their combination result in a greater reduction in the 
incidence of MAKE-D outcomes in subjects who develop CIAKI compared to those 
who do not develop CIAKI. 
7. Bicarbonate, NAC, and their combination increase the mean number of days that 
participants are alive and hospitalization free (hospital free days) in the 90 days after 
angiography. 


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8. The benefits of bicarbonate, NAC, and their combination on MAKE-D outcomes are 
independent of the volume and rate of fluid administration above the minimum values 
prescribed in the protocol. 
 
This brief list entails a large number of analyses. However, the sample size is large and the 
implicit hypotheses are highly inter-correlated. Thus, we anticipate that we can use a significance 
level of 1% (p = 0.01) to detect associations of potential clinical importance in these exploratory 
analyses. 
 
Analyses of the association of CIAKI with MAKE-D events 
Most previous studies of outcomes following procedures that utilized iodinated contrast have 
focused on acute increases in SCr within days of contrast administration (CIAKI). Compared to 
the events that comprise our 90-day primary outcome (MAKE-D), CIAKI occurs more 
frequently. While some episodes of CIAKI foreshadow MAKE-D events, some do not. Our 
analysis of data from the VA Austin databases demonstrated that compared to patients who do 
not develop CIAKI following angiography, patients who develop CIAKI have a nearly four-fold 
increased risk of experiencing a MAKE-D event. We propose to explore this relationship by 
stratifying the study participants into two groups: those who do and those who do not develop 
CIAKI. We will then run the logistic regression model for each stratum. This analysis may reveal 
different levels of effectiveness of the interventions based on whether CIAKI developed. We will 
carry out a more global analysis using log-linear models to address the same question by adding 
many interaction terms without explicit stratification. We chose a sensitive definition of CIAKI 
based on an increase in SCr of ≥0.5 mg/dL and/or ≥25%. This definition has been used in most 
prior trials and will permit us to compare our findings with prior studies on CIAKI. Nonetheless, 
we will also examine the incidence of CIAKI defined by more stringent criteria (AKIN 
definition), evaluate the effectiveness of our interventions on the prevention of larger changes in 
SCr, and assess the association of CIAKI defined by greater increases in SCr with MAKE-D 
outcomes. 
 
Our protocol involves administering treatment before we assess the occurrence  of  CIAKI. Hence, 
the occurrence of CIAKI cannot be viewed as a simple treatment confounder. In fact, we 


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hypothesize that CIAKI lies on a causal pathway leading to MAKE-D events. Therefore, the 
exploratory analysis based on strata defined by the development of CIAKI is the first step in 
confirming the presence of such a causal pathway. 
 
The above list is not exhaustive and the study team may choose to perform additional analyses on 
the PRESERVE cohort within the scope of the study population, diseases of interest, and data 
points collected. 
 
F. 
Sample size and statistical power considerations for the primary hypotheses 
The results for the primary outcome measure, occurrence of a 90-day MAKE-D event, will be 
analyzed by means of the two-sided logistic regression model analysis specified by the Model 
Equation above. Removing all independent terms from the model equation except the 
bicarbonate term, the analysis is equivalent to a comparison of two proportions by means of the 
Chi-square test of association for a 2 x 2 contingency table. 
 
The following table shows the sample size that would be needed for a range of powers, event 
rates, and effect sizes. The calculations are based on the assumptions of a type I error of 2.5% 
and equal allocation to each treatment arm. 
 
Table 10 - Sample size for selected response rates 
 
 
 
 
 
 
 
 
 
 
 
 
 
a  rates and sample size for proposed model (with adjustment for losses to follow-up) 
b  adjusted for an O'Brien-Fleming stopping rule with one interim and one final test of hypothesis and 
considering a two-sided type I error = 0.025. 
 
Thus, based on a 90 day event rate of 8.70% in the control group (i.e., saline or placebo) and 
Rate in control 
(C) group 
Rate in treatment 
(T) group 
% reduction 
(C -T)/C 
Total sample size 
80% power b 
Total sample size 
90% power b 
7.0 
4.90 
30% 
5,030 
6,562 
7.0 
5.25 
25% 
7,432 
9,688 
7.0 
5.6 
20% 
11,924 
15,546 
8.7 
6.1 
30% 
3,995 
5,196 
8.7a 
6.52a 
25%a 
5,900 a 
7,680 a 
8.7 
7.0 
20% 
9,440 
12,317 
10.4 
7.3 
30% 
3,271 
4,285 
10.4 
7.8 
25% 
4,844 
6,314 
10.4 
8.3 
20% 
7,763 
10,123 


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6.52% in the treatment group (i.e., bicarbonate or NAC), an absolute difference of 2.18% and a 
relative difference of 25%, we would need 7,450 patients to test the primary hypotheses with 
90% power, assuming a type I error of 2.5% (splitting the alpha equally between the two primary 
hypotheses) without accounting for loss to follow up. Accounting for 3% lost to follow up, we 


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would need 7,680 patients. For the NAC intervention, the description above is entirely 
analogous. 
 
Adjustment for Lost to Follow-Up 
Because follow-up does not require a return to the VA medical center after the index angiogram 
and can be accomplished through electronic medical record review, telephone contact of patients, 
and mobile blood draws, we expect losses to follow-up to be uncommon and have estimated 
them to be 3%. Accounting for this estimated loss to follow up rate, our adjusted sample size will 
be 7,680. The study will permit secondary analysis of any SCr values assayed at a local laboratory 
that fit specimen collection timeframes for those blood specimens that were unable to be collected 
for analysis by the central laboratory. 
 
Impact of Potential Interaction between Treatments on Sample Size and Statistical Power 
The prior discussion of sample size and statistical power is predicated on the assumption that the 
effects of bicarbonate and NAC are independent. Stated in other terms, we have assumed that the 
relative reduction in the rate of MAKE-D events in patients assigned to bicarbonate/NAC 
compared to saline/NAC will be the same as that in patients assigned to bicarbonate/placebo 
compared to saline/placebo. Similarly, we have assumed that the relative reduction in the rate of 
MAKE-D events in patients assigned to bicarbonate/NAC compared to bicarbonate/placebo will 
be the same as that in patients assigned to saline/NAC compared to saline/placebo. The event 
rates under these assumptions are summarized in the following model. 
 
 
Model 2 in the Absence of Interaction 
Bicarbonate 
Saline 
NAC 
5.59% 
7.46% 
6.52% 
Placebo 
7.46% 
9.95% 
8.70% 
6.52% 
8.70% 
 
The rate of 5.59% for the combination of bicarbonate and NAC is lower than the rate of 7.46% 
for NAC with saline because, some patients who do not respond to NAC will, at random, 
respond to bicarbonate. This is what is meant by ‘the absence of interaction.’ In contrast, an 
interaction between NAC and bicarbonate could result in an absence of further benefit from 
combined treatment as compared to treatment with either agent alone. 


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Model 2 with Interaction Resulting in 
Complete Attenuation 
Bicarbonate 
Saline 
NAC 
7.45% 
7.45% 
7.45% 
Placebo 
7.45% 
9.95% 
8.7% 
7.45% 
8.7% 
 
In this scenario, the overall effect at the margins would be reduced from a 25% reduction in 
MAKE-D events with each treatment to slightly more than a 14% relative reduction in events as 
demonstrated in the model above. This decrease in effect size would result in a reduction in the 
statistical power of the study to 40% with the proposed sample size of 7,680 patients; the total 
sample size would need to be increased to over 18,900 subjects to restore statistical power to 
80% under these conditions. Fortunately, such an attenuation of effect of our interventions has 
not been observed in trials that have utilized both agents for the prevention of CIAKI. 103, 108, 118, 
119 However, the possibility of a smaller attenuation of benefit cannot be excluded as the result of 
an interaction between bicarbonate and NAC. The impact of lesser degrees of interaction between 
the two interventions is illustrated in Table 11 below. These calculations are based on 
assumptions of a 25% reduction in MAKE-D events with bicarbonate (compared to saline) and 
NAC (compared to placebo); a baseline rate of events in the patients treated with both 
bicarbonate and NAC of 5.6% assuming no interaction/attenuation of effect; an overall sample 
size of 7,680 individuals equally allocated to each treatment arm; an estimated loss to follow-up 
rate of 3%; and a type I error of 2.5%. 
 
 
Table 11 - Impact of Interaction between Bicarbonate and NAC on Statistical Power 
% attenuation from 
interaction between 
Bicarbonate & NAC 
Rate in subjects 
assigned to 
Bicarbonate/NAC 
Rate in 
treatment (T) 
group 
Rate in 
control (C) 
group 
% reduction 
(C-T)/C 
Power 
No interaction 
5.60 % 
6.52% 
8.7% 
25% 
90% 
10% attenuation 
5.78% 
6.62% 
8.7% 
23.9% 
87.5% 
20% attenuation 
5.97% 
6.71% 
8.7% 
22.9% 
84% 
30% attenuation 
6.15% 
6.81% 
8.7% 
21.7% 
79.3% 
50% attenuation 
6.53% 
6.99% 
8.7% 
19.7% 
69.4% 


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Thus, the study will retain nearly 80% statistical power with the proposed sample size of 7,680 
patients even if an interaction between bicarbonate and NAC leads to a 30% attenuation of their 
combined effect. 
 
G. 
Interim analysis 
Using the O’Brien-Fleming procedure, we will carry out an interim analysis after half the 
expected number of events (292 events) has occurred, roughly after 18 months, to determine if 
either intervention shows a substantial beneficial effect. We will compare the proportion of 
subjects with a MAKE-D event with and without the use of bicarbonate and will compare the 
proportion of subjects with a MAKE-D event with and without the use of NAC. The respective 
absolute differences are dBicarbonate and dNAC.  At the interim analysis, a z-value of 
3.18 will be needed to reject the null hypothesis with Type I error of 2.5%. At the final analysis a 
z-value of 2.25 will be needed to reject the null hypothesis with Type I error of 2.5%. 
 
H. 
Data analysis plan 
The primary analysis will be based on intention to treat principles. Since treatment is given for a 
very short duration (five days), we expect very few drop outs or crossovers. 
 
Analytic reports 
Analytic reports will provide the proportions, the differences among proportions, the odds ratios, 
and the 95% confidence intervals for each of the summary statistics. This will be followed by a 
report of the results of confirmatory analyses. The confirmatory exploratory analyses will add to 
the basic model, factors related to disease severity, demographic and anthropomorphic measures, 
and structural factors such as medical site. The regression modeling we shall employ will include 
a model with treatment by covariate terms to explore the possibility of treatment by covariate 
effects (that is, exploration of potential subgroup effects). We will test that results vary or do not 
vary significantly by medical site. Finally we will explore the effect of including site as a random 
effect by extending logistic regression to generalized linear models that treat site as a random 
effect. 


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Losses to follow up and missing data 
We conservatively estimate that up to 3% of subjects may be lost to follow up before 90 days. 
The site coordinators will make every effort to locate such subjects including at least three 
telephone contact attempts and one registered letter. Research staff are permitted to mail a letter 
to the participant for the purpose of appointment scheduling/reminders or follow-up contact. If 
such efforts fail and we have no information indicating the outcome for these subjects, then 
we will exclude them from the primary analysis and then carry out a worst case analysis to 
confirm the result of the primary analysis. 


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XVIII. STUDY ORGANIZATION AND ADMINISTRATION 
The Cooperative Studies Program Central Office in Washington, D.C. will oversee the CSP#578 
Study Group, which is responsible for all aspects of operational oversight of this trial including 
monitoring protocol adherence. The Study Group includes the following components: the 
MAVERIC CSPCC, Boston, MA; the Study Chairmen's Office at the VA Pittsburgh Healthcare 
System; the Cooperative Studies Program Clinical Research Pharmacy Coordinating Center 
(CSPCRPCC) at the Albuquerque VA Medical Center; and the participating VA medical centers. 
The Study Group will meet face-to-face prior to study initiation and at least annually thereafter 
and in addition, will communicate at least quarterly via conference call. In addition to the Study 
Group, an Executive Committee headed by the Study Chairmen and including selected site 
investigators, selected members of the Planning Committee, and members of the Study Group 
from the MAVERIC CSPCC, will be responsible for internal operational oversight of the study. 
The study management structure is depicted in Figure 5. 
 
 
 


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A. 
Cooperative Studies Program Central Office 
The Cooperative Studies Program Central Office in Washington, D.C. establishes overall policies 
and procedures that are applied to all VA cooperative studies through the Study Chairmen's 
Office, the MAVERIC CSPCC, and the CSPCRPCC. 
 
B. 
Study Chairmen’s Office and MAVERIC CSPCC 
The Study Chairmen's Office and the MAVERIC CSPCC will jointly perform the day-to-day 
scientific and administrative coordination of the study. This includes developing the study 
protocol, preparing the Operations Manual and source document worksheets, ensuring that 
appropriate support for the participating centers is provided, scheduling of meetings and 
conference calls, answering questions about the protocol, publication of newsletters, preparing 
interim and final progress reports, and archiving of study data at the end of the study. Patient 
accrual and data quality will be monitored closely to ensure that the study is progressing 
satisfactorily. 
 
C. 
CSP Clinical Research Pharmacy Coordinating Center 
The CSP Clinical Research Pharmacy Coordinating Center acts as a liaison in all VA cooperative 
studies between the study participants and the manufacturer of the study drug. This center will 
take the lead in developing a drug information report and drug handling procedures, obtaining 
and distributing the study medications, and providing advice and consultation about drug-related 
matters during the course of the study. 
 
D. 
Executive Committee 
The Executive Committee will oversee study operations, the performance of participating 
medical centers, and the quality of data collected. This Committee will also monitor adherence 
to the protocol. The Executive Committee formulates plans for publications and oversees the 
publication and presentation of all data from the study. Permission must be granted by the 
Executive Committee before data from the study may be used for presentation or publication. 
The members of the Executive Committee will be selected by the Study Chairmen from members 
of the Planning Committee and Participating Investigators. The Executive Committee may meet 
quarterly by conference call and in-person as necessary. 


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XIX. PUBLICATIONS 
A. 
Publication policy 
It is the policy of the CSP that outcome data will not be revealed to the participating investigators 
until the data collection phase of the study is completed. This policy safeguards against possible 
biases affecting the data collection. The regular and ex-officio members of the DMC will be 
monitoring the outcome results to ensure that the study is stopped if a definitive answer is 
reached earlier than the scheduled end of the study. 
 
All presentations and publications from this study will be done in accordance with current CSP 
guidelines. The presentation or publication of any or all data collected by participating 
investigators on patients entered into the VA Cooperative Study is under the direct control of the 
study's Executive Committee. This policy is applicable whether the publication or presentation is 
concerned with the results of the principal undertaking or is associated with the study in some 
other way. No individual participating investigator has any inherent right to perform analyses or 
interpretations or to make public presentations or seek publication of any or all of the data other 
than under the auspices and approval of the Executive Committee. 
 
The Executive Committee has the authority to establish one or more publication committees, 
usually made up of sub-groups of participating investigators and some members of the Executive 
Committee, for the purpose of producing manuscripts for presentation and publication. Any 
presentation or publication, when formulated by the Executive Committee or its authorized 
representatives, should be circulated to all investigators participating in manuscript preparation for 
their review, comments, and suggestions at least four weeks prior to submission of the 
manuscript to the presenting or publication body. All publications must give proper recognition 
to the study's funding source, including the Department of Veterans Affairs, and should list all 
investigators in the study. If an investigator's major salary support and/or commitment is from 
the VA, it is obligatory for the investigator to list the VA as his/her primary institutional 
affiliation. Submission of manuscripts or abstracts must follow the current VA policy. Since all 
publications should state that it is a publication from a VA Cooperative Study, ideally, a sub-title 
is used stating, "A VA Cooperative Study." The DVA contributions to the research project 


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should be acknowledged in all written and oral presentations of the research results, including 
scientific articles, news releases, news conferences, public lectures, and media interviews. 
 
All clinical study reports and journal manuscripts must be reviewed and approved by the 
MAVERIC CSPCC Director prior to submission for publication. After approval for submission 
is granted by the MAVERIC CSPCC Director, the MAVERIC CSPCC Associate Center Director 
for Administrative Operations must be notified as it is their responsibility for sending all scientific 
publications from CSP related studies to VA Central Office upon acceptance. This includes 
minor publications such as abstracts and poster presentations. 
 
B. 
Planned publications 
A plan outlining intended study publications is provided in Table 12. 
 
 
Table 12 – Planned study manuscripts 
Manuscript 
Projected Time of Submission 
Design paper 
1 year following study initiation 
90-day outcomes (primary) 
6-12 months after end of primary 
outcome data collection 
1-year outcomes 
6-12 months after primary manuscript 
Comparison of prediction scores for the 
development of CIAKI 
12-24 months after primary manuscript 
Assessment of risk factors for serious, adverse 
outcomes at 90 days post-angiography 
12-24 months after primary manuscript 
 
 
 
 
 
 
The above list is not exhaustive and the study team may choose to perform additional analyses on 
the PRESERVE cohort within the scope of the study population, diseases of interest, and data 
points collected. 


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contrast-induced nephropathy: a case study of the pitfalls in the evolution of evidence. Arch 
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171. 
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for contrast-induced acute kidney injury. J Gen Intern Med 2009;24(3):289-98. 
172. 
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knowledge of contrast-induced acute kidney injury. Am J Med Sci 2009;338(4):280-6. 
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of renal function in the intensive care unit. Expert opinion of the Working Group for 
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Personal communication with primary authors Dr. John Kellum and Dr. Norbert Lameire. 
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isoosmolar contrast medium. Nephrol Dial Transplant 2004;19(6):1654-5. 
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computed tomography nephrogram: its significance in the diagnosis of contrast-associated 
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Kanter MZ. Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen 
poisoning. Am J Health Syst Pharm 2006;63(19):1821-7. 
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Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: a 
prospective case controlled study. Accident and emergency nursing 2004;12(1):10-5. 
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Culley CM, Krenzelok EP. A clinical and pharmacoeconomic justification  for intravenous 
acetylcysteine: a US perspective. Toxicological reviews 2005;24(2):131-43. 
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for the management of patients with ST-elevation myocardial infarction (updating the 2004 
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injury in the rat. J Clin Invest 1988;82(2):401-12. 
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James MT, Ghali WA, Tonelli M, et al. Acute kidney injury following coronary 
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advocacy to consensus and validation of the RIFLE criteria. Intensive care medicine 
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Hoste EA, Kellum JA. Acute kidney injury: epidemiology and diagnostic criteria. Curr 
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Lo LJ, Go AS, Chertow GM, et al. Dialysis-requiring acute renal failure increases the risk 
of progressive chronic kidney disease. Kidney Int 2009;76(8):893-9. 
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Weisbord SD, Mor MK, Resnick AL, Hartwig KC, Palevsky PM, Fine MJ. Incidence and 
outcomes of contrast-induced AKI following computed tomography. Clin J Am Soc Nephrol 
2008;3(5):1274-81. 
199. 
Barrett BJ, Katzberg RW, Thomsen HS, et al. Contrast-induced nephropathy in patients 
with chronic kidney disease undergoing computed tomography: a double-blind comparison of 
iodixanol and iopamidol. Invest Radiol 2006;41(11):815-21. 
200. 
Dauerman HL. In search of an algorithm to prevent acute kidney injury. Jacc 
2009;2(11):1125-7. 
201. 
Tomlinson G, Detsky AS. Composite end points in randomized trials: there is no free 
lunch. Jama 2010;303(3):267-8. 
202. 
Donnelly JG, Soldin SJ, Nealon DA, Hicks JM. Stability of twenty-five analytes in 
human serum at 22 degrees C, 4 degrees C, and -20 degrees C. Pediatr Pathol Lab Med 
1995;15(6):869-74. 
203. 
Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast- 
induced nephropathy after percutaneous coronary 
intervention: development and initial 
validation. J Am Coll Cardiol 2004;44(7):1393-9. 

SAP_001.pdf: 
Weisbord SD, Palevsky PM: CSP#578 “Prevention of Serious Adverse Events Following Angiography” 
VA COOPERATIVE STUDY # 578 
PREVENTION OF SERIOUS 
ADVERSE EVENTS FOLLOWING 
ANGIOGRAPHY (PRESERVE)
Statistical Analysis Plan v2.0
Effective 08/26/2016
NCT01467466
A DEPARTMENT OF VETERANS AFFAIRS COOPERATIVE STUDY 


MAVERIC Study 
Specific Documents
DATE OF ISSUE 
DOCUMENT DESCRIPTION   
This document describes the statistical analysis plan for 
the CSP578 randomized clinical trial.   
AUTHOR:  Soe Soe Thwin, MS, PhD                                                   
   SUBMITTED BY:   Soe Soe Thwin, MS, PhD   
DOCUMENT/RECORD HISTORY:  
DATE 
              VERSION 
              RECORD HISTORY  
 09/13/2013 
           1.0 
                        Initial Version  
08/26/2016 
     
       2.0                         Revised Version  (Summary of revisions included)      
AUTHORIZATION SIGNATURES 
NAME 
FUNCTION TITLE 
SIGNATURE 
DATE 
Steven Weisbord MD, MSc 
Study Chairman  
8/30/16 
Paul Palevsky, MD 
Study Chairman  
8/30/2016 
James Kaufman, MD, MPH 
Study Director   
Soe Soe Thwin, MS, PhD 
Study Biostatistician   
Ryan Ferguson , MPH, ScD 
Acting Center Director   




 
Page 1 of 21 
 
List of Revisions 
 
 
(1) Section 3.4 - Algorithm to compute adherence for oral medication 
 
% Adherence for oral medication is based on total #capsules only, and therefore 
removed section using #dose 
 
 
(2) Section 3.4 - Algorithm to compute adherence for IV medication 
 
% Adherence will be based on recommended ranges of 
Pre -   Volume of 3 to 12 ml/kg 
Intra-  Rate of 1 to 1.5 ml/kg/hour 
Post-   Volume of 6-12 ml/kg  
 
% Adherence will be computed as a range from % of lower limit to % of upper limit. 
 
Per protocol subject if 80-120% for pre- procedure and intra-procedure at minimum. 
Pre-Procedure 
Intra-procedure 
Post-procedure 
Volume (mL/kg) 
% Dose Given Rate (mL/kg/Hr) 
% Dose Given 
Volume (ml/kg) 
% Dose Given 
1 
33.3% 
0.5 
1 
16.7% 
2 
66.7% 
0.6 
2 
33.3% 
3 
100% 
0.7 
3 
50% 
4 
100% 
0.8 
4 
66.7% 
5 
100% 
0.9 
5 
83.3% 
6 
100% 
1.0 
100% 
6 
100% 
7 
100% 
1.1 
100% 
7 
100% 
8 
100% 
1.2 
100% 
8 
100% 
9 
100% 
1.3 
100% 
9 
100% 
10 
100% 
1.4 
100% 
10 
100% 
11 
100% 
1.5 
100% 
11 
100% 


 
Page 2 of 21 
 
12 
100% 
1.6 
107% 
12 
100% 
13 
108.3% 
1.7 
13 
108.3% 
14 
116.7% 
1.8 
14 
116.7% 
15 
125% 
1.9 
15 
125% 
 
(3) Day-90 blood sample now allowed to be collected within Angio+90+6month 
window. 
 
(4) Day-90 blood sample not necessary if pt is already on dialysis at day-90. 
 
(5) DMC Shell tables are updated often, and therefore reside on Sharepoint 
independent of the Statistical Analysis Plan, link provided. 


 
Page 3 of 21 
 
Abbreviations 
CRF 
 
Case Report Forms 
SAP 
 
Statistical Analysis Plan 
CSP 
 
Cooperative Studies Programs 
Bicarb  
IV isotonic sodium bicarbonate  
Saline  
IV isotonic saline 
NAC 
 
N-acetylcysteine 
VHA 
 
Veterans Health Administration 
MAKE-D 
major adverse kidney events and death 
CIAKI  
contrast induced acute kidney injury  
ESRD  
end stage renal disease 
CKD 
 
chronic kidney disease 
eGFR  
estimated glomerular filtration rate 
SCr 
 
Serum Creatinine 
DMC  
Data Monitoring Committee 
CDW   
VHA Corporate Data Warehouse 
 
 
1. Introduction 
This document outlines the statistical methods for the analysis of data collected in the 
Department of Veterans Affairs Cooperative Studies Programs (CSP) study #578 entitled 
“Prevention of Serious Adverse Events Following Angiography”.  The purpose of this document 
is to provide guidelines from which the analysis will proceed.  Deviations from these guidelines 
will be documented and filed electronically in the study central file Sharepoint site. 
The following documents were used in preparation of this statistical analysis plan (SAP): 
 
Clinical Study Protocol CSP #578 
 
Case Report Forms (CRF) from above entitled Protocol 
 
Global CSP SOP 2.9: “Developing and Conducting Statistical Analyses 
 
Local Work Instruction WI 201Statistical Analysis Plan and Biostatistical Research Data 
Processing Plan Creation and Amendment 
 
Local Job Aid No. 5: Guide to Writing Statistical Analysis Plans 
 
 
2. Overview of the Study Design and Objectives 
This is a double-blind, randomized clinical trial that will use a 2 x 2 factorial design to assess the 
effectiveness of IV isotonic Sodium Bicarbonate (Bicarb) compared to IV isotonic saline (Saline) 
and the efficacy of orally administered N-acetylcysteine (NAC) compared to placebo for the 
prevention of serious, adverse, patient-centered outcomes in high-risk patients undergoing 
coronary or non-coronary angiography.    


 
Page 4 of 21 
 
A total of 7680 subjects recruited from the 33 Veterans Health Administration (VHA) centers are 
expected to be randomized equally to each of the 4 groups as shown in Table 1 below.  An 
additional 1000 subjects are expected to be enrolled in the 12 non-VHA sites in Australia to 
augment the data collected in the US. 
Table 1. Intervention Groups 
 
Bicarb 
Saline 
 
NAC 
Group1: NAC+Bicarb 
Group2: NAC+Saline 
Compare 
NAC vs. Placebo 
(Groups 1+2 vs. 3+4) 
Placebo 
Group3:Placebo+Bicarb 
Group4:Placebo+Saline 
 
 
Compare Bicarb vs. Saline 
(Groups 1+3 vs. 2+4) 
 
The primary objective: 
As the primary objective, the trial will test two hypotheses:  
 
(#1) IV isotonic bicarbonate is more effective than saline, and  
 
(#2) NAC is more effective than placebo 
in prevention of major adverse kidney events (need for acute dialysis or 50% increase in serum 
creatinine at 90 days after angiography) and death (MAKE-D) following coronary and non-
coronary angiography.  This will be accomplished by comparing the incidence of MAKE-D in 
groups 1 and 3 combined to groups 2 and 4 combined for hypothesis (#1), and by comparing 
groups 1 and 2 combined to groups 3 and 4 combined for hypothesis (#2). See 3.5.1. 
 
Secondary Objective:  
The trial will also evaluate the effectiveness of the study interventions for the prevention of 5 
individual secondary endpoints (section 3.5.2) by comparing the treatment groups as in the 
primary objective.  The secondary endpoints are:   
 
1)contrast induced acute kidney injury (CIAKI) at day5 after angiography 
 
2)death  
 
3)major adverse kidney endpoints (MAKE) 
 
4)hospitalization with acute coronary syndrome, heart failure, or cerebrovascular 
 
accident 
 
5)all-cause hospitalization. 
 
Tertiary Objective: 
The trial will explore the effectiveness of the study interventions for the prevention of the 
following outcomes (see 3.5.3), within one year following coronary or non-coronary angiography 
by comparing the treatment groups as in the primary objective.  The tertiary endpoints are:  
1) development of end stage renal disease (ESRD), and 
2) death. 
 
 


 
Page 5 of 21 
 
3. Investigational Plan 
 
3.1. Description of the Study Population 
 
Inclusion Criteria: Patients are eligible if, at the time of index angiography, they have 
underlying chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) 
values calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) formula 
as described on page 33 of the protocol: 
 
(1) eGFR <60 ml/min/1.73 m2 and a diagnosis of diabetes mellitus, or  
(2) eGFR <45 ml/min/1.73 m2 regardless of whether or not they have diabetes mellitus.  
 
Table 2. Exclusion Criteria. Patients are excluded if they satisfy any of these 13 conditions.  
 
3.2. Description of the Intervention Strategy 
 
Eligible patients who consent to participate will be randomized prior to angiography to 
receive one of 4 regimens: 1) NAC and Bicarb, 2) NAC and Saline, 3) Placebo and Bicarb, 
or 4)Placebo and Saline.  Study drug administration schedule is outlined in Table 3. 
 
(1) <18 years of age 
(8) have de-compensated heart failure 
(2) pregnant 
(9)  having an emergent angiogram 
(3) unwilling to comply with 4 and 90 day 
outcome assessment 
(10) received iodinated contrast within past 7 
days 
(4) participating in a clinical trial 
(11) received NAC within past 48 hours 
(5) received dialysis 
(12) have known allergy to NAC 
(6) have stage 5 CKD 
(13) have known allergy to iodinated contrast 
(7) have unstable baseline Serum 
Creatinine (SCr) 
 


 
Page 6 of 21 
 
Table 3. Study Drug Administration Schedule. 
 
 
3.3. Definition of Intention to Treat Sample 
 
All consented and randomized subjects will be accounted for and reported in the CONSORT 
diagram for the study, however, only those randomized subjects who initiated either IV or 
oral intervention (i.e., did not drop out or withdraw prior to start of the allocated intervention), 
will be considered as an intention to treat (ITT) subject to be included in the Data Monitoring 
Committee (DMC) reports and primary efficacy analysis. 
 
An analytic sample file consisting of only the “ITT” subjects as defined above will be created 
and maintained throughout the study.  This file will be called the “CSP578_ITT” file. 
 
3.4. Definition of per-Protocol sample 
 
Adherence to allocated intervention according to the protocol, as outlined in Table 3, will be 
ascertained for randomized subjects for identification of “per-Protocol” sub-group.  Percent 
adherence will be determined for IV fluid and oral interventions separately.  
 
Oral medication adherence will be computed by capsule count only as follows: 
Time 
IV 
ORAL 
Immediately prior 
to the angiographic 
procedure 
 
3 to12 ml/kg of the IV isotonic study crystalloid 
solution (Bicarb or saline) infused over a minimum 
of 1 hour and maximum of 12 hours at an infusion 
rate of not less than 1 mL/kg per hour and not 
more than 3 mL/kg per hour 
NAC or Placebo in an 
oral dose of 1200 mg 
(4 capsules) 
administered within 1 
hour preceding the 
procedure 
During the 
procedure 
IV isotonic study crystalloid solution infused at a 
rate of 1 to 1.5mL/kg per hour 
None 
Following the 
procedure 
6 to 12 mL/kg of the IV isotonic study crystalloid 
solution infused over a minimum of 4 hours and 
maximum of 12 hours at an infusion rate of not 
less than 1 mL/kg per hour and not more than 1.5 
mL/kg per hour 
NAC or Placebo in an 
oral dose of 1200 mg  
(4 capsules) 
administered within 1 
hour following the 
procedure 
Day 1 through 4 
post procedure 
None 
NAC or Placebo 
administered in an oral 
dose of 1200 mg       
(4 capsules) twice 
daily 


 
Page 7 of 21 
 
% adherence = 
%
100
40
#

ken
capsulesTa
Total
 
 
 
 Those who had (>=80% and <=120%) adherence by the capsule count will be considered 
as adherent to the protocol.   
 
IV fluid adherence will be based on the recommended ranges for each period (pre-
procedure, intra-procedure, and post-procedure) described in Table 3. 
 
Pre – procedure:    
Volume of 3 to 12 ml/kg 
Intra – procedure:    
Rate of 1 to 1.5 ml/kg/hour 
Post – procedure:    
Volume of 6 to12 ml/kg  
 
% adherence will be computed as a range from % of lower limit to % of upper limit outlined 
in Table 4. 
 
Table 4. IV fluid adherence table 
Pre-Procedure 
Intra-procedure 
Post-procedure 
Volume (mL/kg) 
% Dose Given Rate (mL/kg/Hr) 
% Dose Given 
Volume (ml/kg) 
% Dose Given 
1 
33.3% 
0.5 
50% 
1 
16.7% 
2 
66.7% 
0.6 
60% 
2 
33.3% 
3 
100% 
0.7 
70% 
3 
50% 
4 
100% 
0.8 
80% 
4 
66.7% 
5 
100% 
0.9 
90% 
5 
83.3% 
6 
100% 
1.0 
100% 
6 
100% 
7 
100% 
1.1 
100% 
7 
100% 
8 
100% 
1.2 
100% 
8 
100% 
9 
100% 
1.3 
100% 
9 
100% 
10 
100% 
1.4 
100% 
10 
100% 
11 
100% 
1.5 
100% 
11 
100% 


 
Page 8 of 21 
 
12 
100% 
1.6 
106.7% 
12 
100% 
13 
108.3% 
1.7 
113.3% 
13 
108.3% 
14 
116.7% 
1.8 
120% 
14 
116.7% 
15 
125% 
1.9 
126.7% 
15 
125% 
 
Those who had (>=80% and <=120%) adherence for, at minimum, the pre-procedure and 
intra procedure periods will be considered as adherent to the protocol. 
 
Those who are adherent to the protocol for both oral study medication and IV study fluid will 
be included in the “per-Protocol” analytic sub-sample.   
 
3.5. Description of the Efficacy Endpoints 
 
3.5.1. 
 Primary Endpoints 
 
The primary endpoint for the study is the composite end-point assessed at 90 days post 
index angiographic procedure and is comprised of the 3 events described below. Those 
subjects with at least one of these 3 events will be considered to have the primary study 
endpoint. 
 
(1) Death from all causes to be verified by medical record and/or vital status registry 
documentation such as the VA Beneficiary Identification and Records Locator System, the 
National Center for Health Statistics National Death Index database, the Social Security 
Administration’s Death Master File. 
  
(2) Acute dialysis defined as the initiation of any modality of renal replacement therapy, 
which includes intermittent hemodialysis, peritoneal dialysis, continuous renal replacement 
therapy, or prolonged intermittent renal replacement therapy.  
 
(3) Persistent decline in kidney function defined as ≥50% increase in SCr at 90 days post 
procedure relative to baseline SCr collected pre-Angiography procedure, and derived as 
follows. 
 
 
 (SCrday90 / Scr pre-procedure)*100% ≥150% 
 
Both the initial 90 day specimen and the confirmatory sample processed at the Central Lab 
must establish a ≥50% increase in SCr to qualify as an endpoint event. 
 
Please note: 
 


 
Page 9 of 21 
 
1. 90 day blood sample is allowed to be collected within 6month window 
starting 90 days post index angiographic procedure. 
2. 90 day blood sample is not necessary if pt is already on dialysis at day 90 
post index angiographic procedure. 
 
 
3.5.2. 
Secondary Endpoints 
 
The secondary endpoints except for CIAKI for the study are assessed at 90 days post index 
procedure and they include the following individual outcomes: 
 
(1) CIAKI defined by an increase in SCr of ≥0.5 mg/dL and/or ≥25% increase at 96 hours 
following contrast administration, derived as follows. 
 
(SCr96Hours / Scr pre-procedure)*100% ≥125% 
 
(2)  Death from all causes to be verified by medical record and/or vital status registry 
documentation such as the VA Beneficiary Identification and Records Locator System, the 
National Center for Health Statistics National Death Index database, the Social Security 
Administration’s Death master File. 
 
(3) MAKE defined by (a) initiation of any modality of renal replacement therapy, which 
include intermittent hemodialysis, peritoneal dialysis, continuous renal replacement therapy, 
or prolonged intermittent renal replacement therapy, or (b) persistent decline in kidney 
function as defined in 3.5.1. 
 
(4) Hospitalization with acute coronary syndrome, heart failure, or cerebrovascular accident 
within 90 days following the index angiographic procedure. These outcomes will be defined 
as a primary or secondary discharge diagnosis of acute coronary syndrome (i.e., STEMI, 
NSTEMI, unstable angina), heart failure, or cerebrovascular accident documented in the VA 
electronic medical record or the hospital discharge summary obtained for non-VA 
hospitalizations. Note: This will include the occurrence of any of these events during the 
index hospitalization. 
 
(5) All-cause re-hospitalization within 90 days of the index angiographic procedure assessed 
as episodes of re-hospitalization, days of hospitalization (inclusive of the index 
hospitalization), and hospital free days (alive and not in the hospital) through day 90. 
 
3.5.3. 
Tertiary Endpoints 
 
The tertiary endpoints for the study are assessed at one year post index procedure.  The 
following endpoints will be obtained from study data and from registry documentation 
specified below. 


 
Page 10 of 21 
 
 
1) Development of ESRD defined by the requirement for chronic dialysis for >3 months 
based on documentation in the United States Renal Data System database, 
 
2) Death from all causes to be verified by medical record and/or vital status registry 
documentation such as the VA Beneficiary Identification and Records Locator System, the 
National Center for Health Statistics National Death Index database, the Social Security 
Administration’s Death Master File. 


 
Page 11 of 21 
 
 
3.6. Description of Baseline Data  
 
Demographic details (e.g., age, sex, race, ethnicity, marital status, military service), medical 
history (e.g., co-morbidities, smoking history), and baseline labs will be evaluated overall, by 
intervention group, by country (Australia or USA), and by enrollment site. 
 
3.7. Description of Procedure Related Data 
 
Angiographic procedure related details (e.g., type of procedure, inpatient/outpatient status, 
type and volume of dye administered), study interventions received prior to and during 
procedure, and information on additional therapy, if any, required during the procedure will 
be evaluated overall and by intervention group. 
 
3.8. Description of Follow-up Assessment Data 
 
Details on additional angiography procedure, therapies other than angiography, if any, 
clinical events such as hospital re-admissions, initiation of dialysis, and death within 90 days 
post index procedure will be evaluated overall and by intervention group. 
 
3.9. Safety Data 
 
The safety information to be collected for this study include the description of the event, 
distinction between serious and non-serious adverse event, severity and expectedness of 
the event, relatedness to the study intervention, and outcome of the event.  In addition, data 
on all events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) (Version 9.0) coding dictionary. 
 
Safety data will be collected for all consented subjects from the date the consent was signed 
up to 35 days post index angiography procedure for non-serious adverse events, and up to 
90 days post index angiography procedure for serious adverse events.  If the subject 
terminates from the study prior to 90 days post index procedure, collection of safety data will 
cease on termination date.  
 
For reporting to the DMC and inclusion in the final report safety data will be aggregated for 
the ITT sample only as described in 3.3.  Data will be summarized as follows. 
 
 
Frequency and percentages of all non-serious and serious adverse events overall 
and by intervention group 
 
Frequency and percentages of all unique subjects with non-serious and serious 
adverse events overall and by intervention group 
 
Rates of non-serious and serious adverse events overall, by intervention group, and 
by center, calculated as # events/ person-time in years 


 
Page 12 of 21 
 
 
Tabulation of event type, MEDRA classification, severity, expectedness, relatedness 
and outcome of all events overall and by intervention group 
 
Overall hospitalization, dialysis, and mortality rate at 90 days and 1year overall and 
by intervention group 
 
 
4. Sample Size and Power 
 
With a total sample of 7680 subjects equally allocated to each of 4 treatment arms, CSP 587 
is powered to detect at least a 25% reduction in the 90-day incidence of MAKE-D for each 
intervention. Expected event rates used in sample size estimation to achieve 90% statistical 
power for hypothesis testing are given in Table 4 below. Justification for selecting these 
rates to estimate sample size and power are provided in the protocol. 
 
Table 4. Expected 90-day Incidence of MAKE-D Endpoint  
 
 
 
 
 
 
 
These estimations assume no interaction between the two active interventions, are adjusted 
for an O'Brien-Fleming stopping rule with one interim and one final test of hypothesis, and 
allow for an overall two-sided type I error of 2.5% for each hypothesis being tested.  Hence, 
each of the interim hypothesis for main effect will be tested at p=0.001 level (allowing for 
0.1% Type I error), and each of the final hypothesis for main effect will be tested at p=0.024 
level (allowing for 2.4% Type I error). 
 
If an attenuation of effect is present due to interaction between Sodium Bicarbonate and 
NAC, adjustment to the statistical power for 10% to 50% attenuation are given as follows. 
 
Table 5. Statistical Power in the Presence of Effect Attenuation.  
 
% attenuation from 
interaction between 
Bicarbonate & NAC 
Rate in 
Bicarbon
ate/NAC 
Rate in 
treatment 
(T) group 
Rate in 
control 
(C) group 
% 
reduction 
(C-T)/C 
Power 
No interaction 
5.60 % 
6.52% 
8.7% 
25% 
90% 
10% attenuation 
5.78% 
6.62% 
8.7% 
23.9% 
87.5% 
20% attenuation 
5.97% 
6.71% 
8.7% 
22.9% 
84% 
 
Bicarbonate 
Saline 
 
NAC 
5.59% 
7.46% 
6.52%     
Placebo 
7.46% 
9.95% 
8.70% 
 
6.52% 
8.70% 
 
Overall event rate  
7.6% 


 
Page 13 of 21 
 
30% attenuation 
6.15% 
6.81% 
8.7% 
21.7% 
79.3% 
50% attenuation 
6.53% 
6.99% 
8.7% 
19.7% 
69.4% 
 
Sample recruitment and subsequent event rates will be summarized and presented to the 
DMC bi-annually as outlined in section 7 below.  These reports will be used for monitoring 
the progress of the study and any modification to the recruitment schedule or the statistical 
analysis plan will be at the recommendation of the DMC.  
 
 
5. Statistical Methods 
 
5.1. Handling of Missing Data in Analysis 
 
Up to 3% of subjects have been estimated to drop out prior to end of follow-up before 90 
days. Distribution of subjects lost to follow-up and missing data on key variables across the 
treatment groups will be monitored throughout the study. 
 
Missing endpoint data will not be imputed.  All those with missing endpoint data either due to 
attrition or active withdrawal of consent will be excluded from primary analysis.  Those who 
completed 90 days of follow-up and have initial 90 day blood-draw demonstrating a >50% 
increase in serum creatinine but are missing the confirmatory blood draw will not be 
included in the primary analysis as having met the primary endpoint, however, they will be 
included in the sensitivity analysis as having met this endpoint data. See section 5.3.5. 
 
5.2. Univariate and Bivariate Distributions of Baseline, Procedure Related, Safety and 
Follow-up data 
 
 
In general, the number of observations, mean, median, standard deviation, minimum, 
and maximum will be calculated for continuous variables. The number of decimals 
places will be to plus two decimal places. 
 
Frequencies and percentages will be calculated for categorical data. 
 
Distribution of continuous variables and proportions of categorical variables will be 
tabulated by intervention group, and t-test and chi-square tests will be performed to 
evaluate if these variables are balanced across 4 intervention groups. 
 
Baseline is defined as the randomization visit. 
 
5.3. Primary Efficacy Analysis 
 
Primary efficacy analysis will include the intention to treat sample as defined in 3.3 and 
further specified in 5.1 above. 
 


 
Page 14 of 21 
 
The primary hypotheses will be tested by modeling the binary outcome of presence or 
absence of MAKE-D event within 90 days post angioplasty procedure.  All the proposed 
tests for the primary analysis are tests of superiority and will be set up as two-sided tests, 
i.e., study intervention can be better or worse than the control. 
 
Our analytic strategy is to use generalized linear model regression, specifically the 
GENMOD procedure in the SAS statistical package with a logit link, to model the binary 
outcome data to estimate the odds of a MAKE-D event at 90 days post angioplasty among 
those allocated to IV isotonic sodium bicarbonate therapy compared to those allocated to IV 
isotonic saline, and among those allocated to NAC compared to those allocated to Placebo.  
Sample SAS code is provided in section 6. 
 
Analytic reports will provide the proportions, the differences among proportions, the odds 
ratios, and the 95% confidence interval, Wald chi-square p-value, followed by a report of the 
results. 
 
5.3.1. 
Testing for Interaction 
 
A multivariable logistic regression model to be fitted includes two binary predictors with an 
interaction term, and can be expressed as: 
 
 
Log (Odds (MAKE-D)) = α + β1 X1+ β2 X2 + β3 X1X2                      (Model 1) 
 
Where X1 is the indicator for IV intervention (1=Bicarb, 0=Saline), X2 is the indicator variable 
for oral intervention (1=NAC, 0=Placebo), and X1X2 is the interaction of the two interventions 
(1=Bicarb and NAC, 0=otherwise). 
 
The parameter β1 will estimate the independent effect of Bicarb compared to Saline, the 
parameter β2 will estimate the independent effect of NAC compared to Placebo, and the 
parameter β3 will estimate the additional effect of both Bicarb and NAC. 
 
Presence of significant interaction between Bicarb and NAC (either beneficial or detrimental) 
will be tested as follows. 
 
Null  
 
H0: β3 = 0 
 
Alternative  
Ha: β3 <> 0 
 
If the Wald Chi-square test has p > 0.05, then the null hypothesis for interaction cannot be 
rejected and we will conclude that there is no evidence of significant modification of effect 
from receiving both Bicarb and NAC. 
 
If the Wald Chi-square test has p <0.05, then the null hypothesis for interaction will be 
rejected and alternative hypothesis accepted to conclude that a significant modification of 


 
Page 15 of 21 
 
effect exists from receiving both Bicarb and NAC.   Primary analysis will proceed as 
described in section 5.3.3. 
 
5.3.2. 
Absence of Interaction 
 
In the event of a non-significant interaction term at p=0.05 level, the regression model will be 
refitted without the interaction term.  This multivariable logistic regression model will include 
two binary predictors, and can be expressed as: 
 
 
Log (Odds (MAKE-D)) = α + β1 X1+ β2 X2                       
(Model 2) 
 
Where X1 is the indicator for IV intervention (1=Bicarb, 0=Saline), and X2 is the indicator 
variable for oral intervention (1=NAC, 0=Placebo). 
 
The parameter β1 will estimate the independent effect of Bicarb compared to Saline, and the 
parameter β2 will estimate the independent effect of NAC compared to Placebo. 
 
Efficacy of Bicarb relative to Saline will be tested as follows. 
 
 
Null  
 
H0: β1 = 0 
 
Alternative  
Ha: β1 <> 0 
 
If the Wald Chi-square test has p < 0.024, then the null hypothesis will be rejected and 
alternative hypothesis accepted.  If the 95% Confidence Interval of the Odds Ratio does not 
include 1 and β1 < 0, we can conclude that Bicarb is superior to Saline, after adjusting for 
NAC and Placebo.  Conversely, if the 95% Confidence Interval of the Odds Ratio does not 
include 1 and β1 > 0, we can conclude that Bicarb is not superior to Saline, after adjusting 
for NAC and Placebo. 
 
Similarly, efficacy of NAC relative to Placebo will be tested as follows. 
 
 
Null  
 
H0: β2 = 0 
 
Alternative  
Ha: β2 <> 0 
 
If the Wald Chi-square test has p < 0.024, then the null hypothesis will be rejected and 
alternative hypothesis accepted.  If the 95% Confidence Interval of the Odds Ratio does not 
include 1 and β2 < 0, we can conclude that NAC is superior to Placebo, after adjusting for 
Bicarb and Saline.  Conversely, if the 95% Confidence Interval of the Odds Ratio does not 
include 1 and β2 > 0, we can conclude that NAC is not superior to Saline, after adjusting for 
Bicarb and Saline. 


 
Page 16 of 21 
 
 
5.3.3. 
Presence of Interaction 
 
In the event of a significant interaction at p=.05 level, a stratified analysis will ensue where 
logistic models with single binary predictors for different levels of X1 and X2 will be refitted as 
follows 
 
 
In NAC subgroup: 
 
Log (Odds (MAKE-D)) = α + β1a X1                     (Model 3) 
 
In Placebo subgroup : 
Log (Odds (MAKE-D)) = α + β1b X1                     (Model 4) 
 
In Bicarb subgroup: 
 
Log (Odds (MAKE-D)) = α + β2a X2                     (Model 5) 
 
In Saline subgroup: 
 
Log (Odds (MAKE-D)) = α + β2b X2                     (Model 6) 
 
Where X1 is the indicator for the IV intervention (1=Bicarb, 0=Saline), and X2 is the indicator 
variable for the oral intervention (1=NAC, 0=Placebo). 
 
The parameter β1a will estimate the independent effect of Bicarb compared to Saline among 
those allocated to NAC, β1b will estimate the independent effect of Bicarb compared to 
Saline among those allocated to Placebo, β2a will estimate the independent effect of NAC 
compared to Saline among those allocated to Bicarb, and β2b will estimate the independent 
effect of NAC compared to Placebo among those allocated to Saline. 
 
The efficacy of Bicarb relative to Saline and NAC relative to Placebo will be tested in each of 
the 4 subgroups at p=0.048 overall. 
 
Based on the parameter estimates, the magnitude and direction of any interaction will be 
evaluated. 
 
5.3.4. 
Evaluating Covariate Effects 
 
To explore the possibility of treatment by covariate effects, we will refit the model with a 
vector of covariates included in the model, expressed as 
 
 
Log (Odds (MAKE-D)) = α + β1X1+ β2X2+r[Z]                        
 
(Model 7) 
 
Where, [Z] is the vector of factors indicating disease severity, demographic and 
anthropomorphic measures, and structural factors such as medical site.  Factors identified 
not to be balanced between the intervention groups in section 5.2 will be evaluated. 
 
 Additionally, we will explore the effect of including site as a random effect by extending 
logistic regression to generalized linear models that treat site as a random effect. 


 
Page 17 of 21 
 
 
5.3.5. 
Sensitivity Analysis 
 
We will refit Models 1 and 2 to evaluate the odds of the event of interest at 90 days post 
angioplasty among those allocated to IV isotonic sodium bicarbonate therapy compared to 
those allocated to IV isotonic saline, and among those allocated to NAC compared to those 
allocated to Placebo. The primary analysis will be repeated under 5 different scenarios as 
follows and the results will be displayed in a Forest plot. 
 
 (1) On the first “per-Protocol” sample with 80-120% adherence as defined in 3.4 to evaluate 
efficacy among those adherent to the protocol. Subjects who are over-adherent (>=120%) or 
have had a non-protocol administration of study medication, particularly IV sodium 
bicarbonate, will be excluded. 
 
(2) On the second “per-Protocol” sample with >=80% adherence as defined in 3.4 including 
those subjects who are over-adherent or have had a non-protocol administration of study 
medication, particularly IV sodium bicarbonate. 
 
(3) On the “ITT” cohort that includes those with the initial 90-day blood sample but are 
missing the confirmatory sample.  
 
(4) On the “ITT” cohort assuming all those with missing endpoint data had events before 90 
days (the worst case scenario), and 
 
(5) On the “ITT” cohort assuming all those with missing endpoint data had no events before 
90 days (the best case scenario) 
 
5.4. Secondary Analysis 
 
For each of the five secondary endpoint events listed in 3.5.2 we will follow the same 
analytic strategy as the primary analysis described in 5.3, where the odds of having an 
outcome will be estimated by modeling the outcome as a binary indicator of presence or 
absence of an event. 
 
We will derive the Odds Ratios (i.e., the odds of the event of interest at 90 days post 
angioplasty among those allocated to IV isotonic sodium bicarbonate therapy compared to 
those allocated to IV isotonic saline, and among those allocated to NAC compared to those 
allocated to Placebo), and test for statistical significance of these odds ratios at p=0.025 
level. 


 
Page 18 of 21 
 
 
5.5. Tertiary Analysis 
 
Data for this exploratory tertiary objective will be accrued from the US Renal Data System 
Warehouse, NDI database, SSDI database, and the VHA Corporate Data Warehouse 
(CDW). 
 
For each of the 2 tertiary endpoint events listed in 3.5.3 we will follow the same analytic 
strategy as the primary and secondary analyses described in 5.4 above. 
 
5.6. Interim Analysis 
 
This study is expected to enroll 7680 subjects over a 2.5 years (or 30 month) recruitment 
period. At 18 months, i.e., after 15 months of recruitment plus 3 months of follow-up, 
approximately half or 3840 subjects are expected to be enrolled with primary endpoint 
events occurring in roughly 292 subjects (7.6%).  Using the O'Brien-Fleming procedure, we 
will carry out an interim analysis to determine if either intervention shows a substantial 
beneficial effect.  
 
We will compare the proportion of subjects with a MAKE-D event among those with and 
without the use of bicarbonate and among those with and without the use of NAC.  
 
We will follow the same analytic strategy as described in 5.3 for primary analysis, where the 
odds of having an outcome will be estimated by modeling the outcome as a binary indicator 
of presence or absence of the MAKE-D event. 
 
We will derive the Odds Ratios (i.e., the odds of the event of interest at 90 days post 
angioplasty among those allocated to IV isotonic sodium bicarbonate therapy compared to 
those allocated to IV isotonic saline, and among those allocated to NAC compared to those 
allocated to Placebo), and test for statistical significance of these odds ratios at p=0.001 
level, assuming no interaction between the active interventions. 
 
If the Wald Chi-square test has p < 0.001 for regression coefficient β1 in Model 2, then the 
null hypothesis of H0: β1 = 0 will be rejected and alternative hypothesis of Ha: β1 <> 0 
accepted.  If the 95% Confidence Interval of the Odds Ratio does not include 1 and β1 < 0, 
we can conclude that Bicarb is superior to Saline.  Conversely, if the 95% Confidence 
Interval of the Odds Ratio does not include 1 and β1 > 0, we can conclude that Bicarb is not 
superior to Saline. 
 
Similarly, if the Wald Chi-square p < 0.001 for regression coefficient β2 in Model 2, then the 
null hypothesis of H0: β2 = 0 will be rejected and alternative hypothesis Ha: β2 <> 0 accepted.  
If the 95% Confidence Interval of the Odds Ratio does not include 1 and β2 < 0, we can 
conclude that NAC is superior to Placebo.  Conversely, if 95% Confidence Interval of the 


 
Page 19 of 21 
 
Odds Ratio does not include 1 and β2 > 0, we can conclude that NAC is not superior to 
Saline. 
 
5.6.1. 
Futility Analysis 
 
If requested by the DMC, a futility analysis that includes conditional power estimation will be 
conducted to determine the probability of observing a significant result assuming the 
distribution of future event rates from additional data from the second half of the study follow 
3 scenarios.  These assumptions are: 
 
no-change scenario – future event rates are same as currently observed,  
expected scenario – future event rates are as proposed in the protocol, and  
extreme scenario – all new events at the currently observed rate are in the control group. 
 
 
6. Sample SAS Code 
 
proc genmod; 
class outcome Bicarb NAC; 
model outcome = Bicarb  NAC/ error=bin link=logit type3; 
make 'parmest' out=parmest; 
run; 
 
/*to get estimated odds ratios*/ 
data parmest; 
set parmest; 
if df gt 0; 
OR=exp(estimate); 
low_OR=exp(estimate-1.96*stderr); 
hi_OR=exp(estimate+1.96*stderr); 
run; 
 
proc print data=parmest label noobs; 
title 'Estimated Odds Ratios and 95% CIs'; 
var parm level1 estimate stderr or low_OR hi_OR; 
format estimate stderr OR low_OR hi_OR 6.3; 
label 
parm='Parameter' 
level1='Level' 
estimate='Beta estimate' 
stderr='Standard Error' 
OR='Estimated OR' 
low_OR='Lower limit 95% CI' 


 
Page 20 of 21 
 
hi_OR='Upper limit 95% CI'; 
run; 
 
 
7. Data Monitoring Committee Reports 
 
Data and study progress will be monitored by the study executive committee and by the 
Data Monitoring Committee.  The DMC will review the study progress and safety 
semiannually with additional meetings and communications as needed.  
 
All reports will be generated in conjunction with the Data Management department using 
SQL and SAS. 
 
Updated Shell tables can be found on Sharepoint using the following link 
 
https://vaww.ord.research.va.gov/CSP/Boston/csp578/centralfile/Data%20Monitoring%20Co
mmittee/Forms/AllItems.aspx?RootFolder=%2fCSP%2fBoston%2fcsp578%2fcentralfile%2f
Data%20Monitoring%20Committee%2f6%2e%20DMC%20Reports%20Shell%20Tables&Fo
lderCTID=&View=%7b2F07C9DC%2d37B3%2d456C%2dAFDC%2d7F19514038EE%7d 
 
7.1. Analytic Sample for DMC Reports 
 
All subjects randomized more than six weeks prior to the DMC meeting date will be included 
in the analytic cohort for the upcoming DMC report, and all data collected up to four weeks 
prior to the DMC meeting date will be analyzed. This allows for two weeks lag time for 
submission of data from sites. 
 
7.2. Outline of DMC Reports 
   
Shell tables with algorithm annotated for creating the table content are provided in section 8 
below.  The report is divided into four sections to cover subject disposition, baseline 
assessment, follow-up assessment, and safety assessment.  Following is the list of tables to 
be included within each of these 4 sections.  Revision to this list, if any, will be discussed at 
the first DMC meeting to be held within six months of the initiation of subject enrollment in 
the VA sites.  
 
7.2.1. 
Section A: Subject Disposition 
 
Figure A1. CONSORT Diagram for CSP578 
Figure A2. Overall Study Enrollment 
Figure A3. Enrollment by Site 
Table A4. Protocol Deviations 
Table A5. Terminations 


 
Page 21 of 21 
 
Table A6. Form Completion, by Form Type 
Table A7. Form Completion, by Site 
 
7.2.2. 
Section B: Baseline Assessment 
 
Table B1. Patient Characteristics 
Table B2. Military Service, VA sites only  
Table B3. Medical History and Baseline Assessments 
Table B4. Baseline Labs 
Table B5. Study Procedure - Part I 
Table B6. Study Procedure – Part II 
Table B7. Study Medication Capsule Administration 
Table B8. Study IV Fluid Administration 
Table B9. Non-Study Drugs Pre- and Post- Procedure 
 
Table B10. Sample Specimens Collected 
 
7.2.3. 
Section C: Follow-up Assessment 
 
Table C1. Post Procedure Assessment , Part I 
Table C2. Post Procedure Assessment, Part II 
Table C3. Study Outcome Events 
 
7.2.4. 
Section D: Safety Assessment 
 
Table D1. Rates of Non-Serious Adverse Events (NAEs) and Serious Adverse Events 
(SAEs), by Site   
Table D2. Summary of Non-Serious Adverse Events 
Table D3. Summary of Serious Adverse Events   
Table D4. Non-Serious Adverse Events by System Organ Class and Preferred Term   
Table D5. Serious Adverse Events by System Organ Class and Preferred Term  
 
 
8. References 
 
Proschan MA, Lan KKG, Wittes JT (2006) Statistical Monitoring of Clinical  
Trials: A Unified Approach. 1st edn. Springer: USA  
 
Jitlal M, Khan I, Lee SM, Hackshaw A (2012) Stopping clinical trials early for futility: 
retrospective analysis of several randomised clinical studies. British Journal of Cancer 
(2012) 107, 910–917