Clinical trial NCT02285920
Conditions: End-Stage Renal Disease
Keywords: hemodialysis spironolactone cardiac fibrosis diastolic function
Sponsor: University of Pennsylvania
Start date: 2014-11-01; Completion date: 2017-07-30
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The SPin-D Trial is a phase II randomized, double-blind, placebo-controlled, multi-center study of spironolactone (SPL) for patients with hemodialysis-dependent end-stage renal disease.

Detailed description:
The primary objective of this study is to characterize the safety and tolerability of multiple doses of chronic SPL therapy compared with placebo in maintenance hemodialysis patients and to assess the feasibility of conducting a full-scale, mortality-powered trial of SPL. The effects of SPL compared with placebo on multiple cardiovascular efficacy parameters will also be analyzed. The primary efficacy parameter will be the change in the E' measurement on tissue Doppler echocardiography (TDI) as an index of diastolic function and a surrogate for myocardial fibrosis. Secondary cardiac parameters of interest that will be studied in the overall population or in sub-studies include heart rate variability, circulating markers of fibrosis, and coronary flow reserve (CFR) as an index of microvascular function. These parameters are designed to broaden insight into the potential effects of SPL on cardiac structure and function in individuals with dialysis-dependent ESRD and to assess the feasibility of conducting a full-scale, mortality-powered trial.

Arms: arm 1: Participants will initiate treatment at 12.5 mg daily and continue at this dose for 36 weeks. arm 2: Participants will initiate treatment at 12.5 mg daily for 2 weeks at which time the dose will be increased to 25 mg daily for a total treatment time of 36 weeks. arm 3: Participants will initiate treatment at 12.5 mg daily for 2 weeks at which time the dose will be increased to 25 mg daily for 2 weeks, and increased to 50 mg daily for a total treatment time of 36 weeks. arm 4: Participants will be treated with placebo for 36 weeks.
Interventions: intervention 1: Spironolactone
Intervention descriptions: intervention 1: The trial will be conducted in 2 phases - a dose escalation phase (6 weeks) and a treatment phase (30 weeks). At the end of the dose escalation phase, participants will continue treatment based on the randomized dose assignment for an additional 30 weeks (treatment phase) such that the total duration of study medication is 36 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
Hemodialysis Novel Therapies Consortium 
Clinical Research Protocol 
Page i 
Version 5.0, May 9, 2016 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
Safety and Cardiovascular Efficacy of Spironolactone 
in Dialysis-Dependent ESRD (SPin-D) Trial  
A phase II randomized, double-blind, placebo-controlled,  
multi-center study of the safety and effects on cardiac structure and 
function of spironolactone in patients with hemodialysis-dependent 
ESRD 
Funding Sponsor: 
National Institutes of Diabetes and Digestive 
and Kidney Diseases 
National Institutes of Health 
2 Democracy Plaza 
6707 Democracy Boulevard 
Bethesda, MD  20892-5458 
 
Study Product: 
Spironolactone (Spironolactone) 
Protocol Number: 
NA 
IND Number: 
 
NCT Identifier: 
NA 
 
NCT02285920 
 
 
Initial version:  V1.0, September 29, 2014 
Amended: 
V2.0, February 3, 2015 
Amended: 
V3.0, October 7, 2015 
Amended:  
V4.0, February 18, 2016 
Amended: 
V5.0,  May 9, 2016 


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Clinical Research Protocol 
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CONFIDENTIAL 
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INVESTIGATOR AGREEMENT:  
 
 
I agree to conduct this study entitled, Safety and Cardiovascular Efficacy of Spironolactone in 
Dialysis-Dependent ESRD (SPin-D) Trial, according to protocol version 5.0 dated May 9, 2016.  
I also agree to conduct this study in compliance with: applicable federal, state and local 
regulations, Good Clinical Practices, and the requirements of my Institutional Review Board 
(IRB).   
 
I understand that I may not implement this protocol or amendment without reading this 
document and receiving written IRB approval.  I understand that I am not to make any changes 
to this protocol or amendment without the prior approval of the Steering Committee of the 
Hemodialysis Novel Therapies Consortium and the IRB. 
 
I will provide copies of the protocol and amendment, any subsequent protocol amendments, and 
access to all pertinent information furnished by the Steering Committee of the Hemodialysis 
Novel Therapies Consortium to study personnel under my supervision.  I will discuss this 
material with them to ensure that they are fully informed about the study protocol. 
 
 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
 
Name (Please Print) 
 
Institution 
 
Once signed, this original shall be maintained in the Regulatory Binder at the clinical center, 
with a copy emailed or faxed to the DCC Project Manager (215-573-6262). 
 


Hemodialysis Novel Therapies Consortium 
Clinical Research Protocol 
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Version 5.0, May 9, 2016 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
Table of Contents 
STUDY SUMMARY ...................................................................................................................................... 1 
1. 
INTRODUCTION .................................................................................................................................. 2 
1.1. 
BACKGROUND ................................................................................................................................ 2 
1.2. 
INVESTIGATIONAL AGENT ................................................................................................................ 4 
1.3. 
CLINICAL DATA TO DATE................................................................................................................. 6 
1.4. 
DOSE RATIONALE AND RISK/BENEFITS .......................................................................................... 11 
1.4.1. 
Risks ................................................................................................................................. 11 
1.4.2. 
Benefits ............................................................................................................................. 12 
2. 
STUDY OBJECTIVES ....................................................................................................................... 12 
2.1. 
PRIMARY OBJECTIVES .................................................................................................................. 13 
2.2. 
SECONDARY OBJECTIVES ............................................................................................................. 14 
3. 
STUDY DESIGN ................................................................................................................................. 14 
3.1. 
GENERAL DESIGN ........................................................................................................................ 14 
3.2. 
STUDY ENDPOINTS....................................................................................................................... 15 
3.2.1. 
Primary Endpoints ............................................................................................................. 15 
3.2.2. 
Secondary Endpoints ........................................................................................................ 16 
4. 
PARTICIPANT SELECTION AND WITHDRAWAL .......................................................................... 17 
4.1. 
INCLUSION CRITERIA .................................................................................................................... 17 
4.2. 
EXCLUSION CRITERIA ................................................................................................................... 18 
4.3. 
PARTICIPANT RECRUITMENT AND SCREENING................................................................................ 18 
4.3.1. 
Women of Childbearing Potential ..................................................................................... 19 
4.4. 
EARLY WITHDRAWAL OF PARTICIPANTS AND EARLY TERMINATION OF STUDY MEDICATION .............. 19 
4.4.1. 
Early Withdrawal of Participants ....................................................................................... 19 
4.4.2. 
Early Termination of Study Medication ............................................................................. 19 
5. 
STUDY DRUG .................................................................................................................................... 20 
5.1. 
DESCRIPTION ............................................................................................................................... 20 
5.2. 
TREATMENT REGIMEN .................................................................................................................. 20 
5.3. 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ................................................. 21 
5.4. 
PREPARATION AND ADMINISTRATION OF STUDY DRUG AND MAINTENANCE OF BLIND ....................... 21 
5.5. 
PARTICIPANT ADHERENCE MONITORING ........................................................................................ 23 
5.6. 
CONCOMITANT THERAPY .............................................................................................................. 23 
5.7. 
PACKAGING ................................................................................................................................. 23 
5.8. 
BLINDING OF STUDY DRUG ........................................................................................................... 23 
5.9. 
RECEIVING, STORING, DISPENSING AND RETURNING STUDY DRUG ................................................ 23 
5.9.1. 
Receiving Study Drug Supplies ........................................................................................ 23 
5.9.2. 
Study Drug Storage........................................................................................................... 24 
5.9.3. 
Dispensing Study Drug ..................................................................................................... 24 
5.9.4. 
Return or Destruction of Study Drug ................................................................................. 24 
6. 
STUDY PROCEDURES ..................................................................................................................... 24 
6.1. 
PRE-SCREENING ACTIVITIES ......................................................................................................... 24 
6.2. 
SCREENING VISIT (DAY ‒30 TO DAY 0) ......................................................................................... 24 
6.3. 
BASELINE/RANDOMIZATION VISIT (DAY 0) ..................................................................................... 25 
6.4. 
WEEK 1, WEEK 2, WEEK 3, WEEK 4, WEEK 5, AND WEEK 6 VISITS (WINDOW FOR EACH: -4 TO +3 
DAYS) ......................................................................................................................................... 26 
6.5. 
WEEK 8 (-4 TO +3 DAYS), WEEK 12, WEEK 16, WEEK 20, WEEK 24, WEEK 28, AND WEEK 32 VISITS 
(-7 TO +7 DAYS FOR ALL EXCEPT WEEK 8) .................................................................................... 26 
6.6. 
WEEK 36 VISIT (END OF TREATMENT) (-7 TO +7 DAYS) .................................................................. 27 
6.6.1. 
Early Withdrawal Visit ....................................................................................................... 27 
6.7. 
WEEK 40 VISIT (-7 TO +7 DAYS) .................................................................................................... 27 
6.8. 
HYPOTENSION MANAGEMENT ....................................................................................................... 27 


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6.9. 
HYPERKALEMIA MANAGEMENT ...................................................................................................... 28 
6.10. 
GYNECOMASTIA, GASTROINTESTINAL SYMPTOMS OR RASH ........................................................... 31 
7. 
STATISTICAL PLAN ......................................................................................................................... 31 
7.1. 
SAMPLE SIZE DETERMINATION ...................................................................................................... 31 
7.2. 
RANDOMIZATION AND STRATIFICATION .......................................................................................... 31 
7.3. 
INTENT-TO-TREAT ANALYSIS AND MISSING DATA ........................................................................... 32 
7.4. 
STATISTICAL METHODS ................................................................................................................ 33 
7.4.1. 
Descriptive Analyses and Primary Efficacy and Safety Analyses .................................... 33 
7.4.2. 
Secondary Analyses ......................................................................................................... 34 
7.4.3. 
Interim Analysis ................................................................................................................. 34 
8. 
SAFETY AND ADVERSE EVENTS ................................................................................................... 34 
8.1. 
DEFINITIONS ................................................................................................................................ 34 
8.1.1. 
Adverse Event ................................................................................................................... 34 
8.1.2. 
Serious Adverse Event ..................................................................................................... 34 
8.1.3. 
Unanticipated Problems Involving Risk to Participants or Others .................................... 35 
8.1.4. 
Pre-Existing Condition ...................................................................................................... 35 
8.1.5. 
General Physical Examination Findings ........................................................................... 35 
8.2. 
ADVERSE EVENT TRACKING PERIOD ............................................................................................. 35 
8.2.1. 
Post-study Adverse Event ................................................................................................. 35 
8.3. 
RECORDING OF ADVERSE EVENTS ................................................................................................ 35 
8.3.1. 
Adverse Events of Interest ................................................................................................ 36 
8.3.2. 
Trial-Defined Events.......................................................................................................... 36 
8.3.3. 
Abnormal Laboratory Values ............................................................................................ 36 
8.3.4. 
Anticipated Adverse Events .............................................................................................. 37 
8.4. 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 37 
8.4.1. 
Investigator Reporting to the IRB ...................................................................................... 38 
8.4.2. 
DCC Notification to Participating Investigators ................................................................. 39 
8.5. 
UNBLINDING PROCEDURES ........................................................................................................... 39 
8.6. 
STOPPING RULES ......................................................................................................................... 40 
8.7. 
MEDICAL MONITORING ................................................................................................................. 40 
8.7.1. 
Independent Data and Safety Monitoring Board (DSMB) ................................................. 40 
9. 
DATA MANAGEMENT ...................................................................................................................... 41 
9.1. 
DATA QUALITY ............................................................................................................................. 41 
9.1.1. 
Quality Control Activities ................................................................................................... 41 
9.1.2. 
Routine reports .................................................................................................................. 41 
9.2. 
DATA SECURITY ........................................................................................................................... 42 
9.2.1. 
Confidentiality .................................................................................................................... 42 
9.2.2. 
Data Linkage ..................................................................................................................... 42 
9.3. 
SOURCE DOCUMENTS .................................................................................................................. 43 
9.3.1. 
Case Report Forms ........................................................................................................... 43 
9.3.2. 
Maintaining Anonymity of Submitted Medical Records ..................................................... 43 
9.3.3. 
Data and Biosample Sharing ............................................................................................ 43 
9.3.4. 
Records Retention ............................................................................................................ 44 
10. STUDY COMPLIANCE ...................................................................................................................... 44 
10.1. 
PROTOCOL DEVIATIONS  AND EXCEPTIONS .................................................................................... 44 
10.2. 
STUDY MONITORING PLAN ............................................................................................................ 45 
10.3. 
AUDITING AND INSPECTING ........................................................................................................... 45 
11. ETHICAL CONSIDERATIONS .......................................................................................................... 45 
12. STUDY FINANCES ............................................................................................................................ 46 
12.1. 
FUNDING SOURCE ........................................................................................................................ 46 
12.2. 
CONFLICT OF INTEREST ................................................................................................................ 46 
12.3. 
PARTICIPANT STIPENDS OR PAYMENTS ......................................................................................... 46 


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13. PUBLICATION PLAN ........................................................................................................................ 46 
14. REFERENCES ................................................................................................................................... 47 
15. ATTACHMENTS ................................................................................................................................ 53 
15.1. 
STUDY PROCEDURES ................................................................................................................... 54 
15.2. 
NIDDK DSMB CHARTER ............................................................................................................. 55 
 


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List of Abbreviations 
ACE 
angiotensin converting enzyme inhibitor 
AE 
adverse event 
ARB 
angiotensin receptor blocker 
ALDO 
aldosterone 
ANCOVA 
analysis of covariance 
ARB 
angiotensin receptor blocker 
BID 
twice daily 
CFR 
coronary flow reserve 
CKD 
chronic kidney disease 
CM 
centimeter 
CRF 
case report form 
CRP 
C-reactive protein 
CVD 
cardiovascular disease 
CVR 
coronary vascular resistance 
DCC 
Data Coordinating Center 
DSMB 
Data and Safety Monitoring Board 
ESRD 
end stage renal disease 
FTP 
file transfer protocol 
GFR 
glomerular filtration rate 
HD 
hemodialysis 
Hg 
mercury 
HIPAA 
Health Insurance Portability and Accounting Act 
IDS 
Investigational Drug Service 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intention to treat 
K 
potassium 
L 
liter 
LVMI 
left ventricular mass index 
mEq 
milliequivalent 
MM 
millimeter 
MG 
milligram 
MOP 
Manual of Procedures 
MRI 
magnetic resonance imaging 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
OHRP 
Office of Human Research Protections 
PET 
positron emission tomography 
PHI 
protected health information 
PICP 
procollagen type I carboxy-terminal peptide 
PTH 
parathyroid hormone 
QD 
daily 
RCT 
randomized controlled trial 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SPL 
spironolactone 
TDI 
tissue Doppler index  
UAE 
unanticipated adverse event 
 
 


SPin-D Trial 
 
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Version 5.0, May 9, 2016 
Introduction 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
Study Summary 
Title 
Safety and Cardiovascular Efficacy of Spironolactone in  
Dialysis-Dependent ESRD Trial  
Short Title 
SPin-D Trial 
NCT Identifier 
 NCT02285920 
Phase 
Phase II 
Methodology 
Randomized, double-blind, placebo-controlled 
4-arm  
Study Duration 
2 years 
Study Center(s) 
Brigham and Women’s Hospital 
George Washington University 
University of Washington 
Vanderbilt  University / Nashville VA Medical Center  
University of Pennsylvania (Data Coordinating Center) 
Objectives 
• To generate pilot data on the safety and tolerability of spironolactone (SPL) 
in patients with dialysis-dependent ESRD.   
• To generate pilot estimates of the effect of SPL compared with placebo on 
cardiovascular efficacy parameters in patients with dialysis-dependent 
ESRD.  
Number of Participants 
125 
Diagnosis and Main 
Inclusion Criteria 
Dialysis-dependent ESRD  
Study Product, Dose, 
Route, Regimen 
Spironolactone 12.5, 25, or 50 mg, orally daily 
Duration of 
administration 
36 weeks 
Reference therapy 
Placebo 
Major Outcomes 
• 
Safety:  hyperkalemia, hypotension 
• 
Tolerability:  treatment adherence 
• 
Efficacy:  change in mitral annular E′ velocity 
• 
Feasibility:  recruitment  
Statistical 
Methodology 
Mixed effects linear regression models will be used to assess the direction and 
time averaged magnitude of change in efficacy parameters, with and without 
controlling for baseline covariates, to compare the effects of therapy.   
 
These mixed effects models will also be utilized to investigate the potential 
shift in overall potassium levels.  The incidence of safety events, especially 
serious hyperkalemia, in treatment and placebo groups will be compared with 
Chi-square test or Fisher’s exact test. 
 


SPin-D Trial 
 
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Introduction 
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1. Introduction 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 
and International Conference on Harmonization guidelines), applicable government regulations 
and Institutional research policies and procedures.  
1.1. 
Background 
End stage renal disease (ESRD) is characterized by cardiovascular disease (CVD) with a 
unique pathogenesis, the absence of effective therapies, and an extremely high rate of 
cardiovascular (CV) death1-8.  Given the predicted growth in the dialysis-dependent ESRD 
population9, the lack of effective therapy represents a critical public health challenge.  New 
strategies for treating CVD in this setting are desperately needed.   
The majority of CV deaths in dialysis-dependent ESRD result from sudden cardiac death rather 
than overt myocardial infarction.  Only 5.3% of deaths in ESRD are due to myocardial infarction 
compared with 26.1% from arrhythmia and cardiac arrest10.  Although an increase in the risk of 
sudden cardiac death is detectable in early stages of CKD, the risk is particularly marked in 
individuals with ESRD.  For example, in a study of individuals with documented coronary artery 
disease, the relative risk of sudden cardiac death was 1.9 for those with stage 3-4 CKD 
compared to those with preserved renal function and 4.7 for those with stage 5 CKD.  In 
dialysis-dependent ESRD the sudden cardiac death incidence was increased to 24 cases per 
1000-patient years versus only 3.8 per 1000-patient years among individuals with preserved 
GFR11.  This association between renal function and sudden cardiac death was independent of 
angiographic findings as well as standard CVD risk factors, suggesting a direct effect of 
impaired renal function on the risk of sudden cardiac death. 
The disproportionate risk of sudden cardiac death relative to myocardial infarction suggests that 
neither faster progression of epicardial coronary artery disease nor an increased likelihood of 
plaque rupture and subsequent myocardial infarction fully explains the high incidence of sudden 
cardiac death in ESRD.  Instead, the risk appears to be related to changes in the myocardium 
itself ‒ specifically, an increase in the extent of myocardial fibrosis and a decrease in the supply 
of myocardial capillaries in the uremic myocardium.   
Experimental models of CKD are characterized by greater microvascular loss in the heart than 
other organs12, decreased myocardial capillary density, reduced ischemia tolerance, and 
increased infarct size after coronary artery ligation12-17.  These changes are accompanied by 
hypertension-independent increases in left ventricular hypertrophy interstitial collagen, and 
myocardial fibrosis 12-14, 18.  Similar changes have been observed in patients with ESRD.  In an 
autopsy study, ESRD patients with left ventricular hypertrophy but without coronary artery 
disease had fewer myocardial capillaries and more interstitial fibrosis than patients with 
preserved renal function19.  Myocardial coronary flow reserve – a measure of microvascular 
supply and function – also declines in parallel with glomerular filtration rate20-23 while coronary 
collateral vessels – the presence of which reduces the risk of death in CAD24, 25 – are 41% less 
abundant in individuals with mild-moderate CKD than in those without CKD26.  Left ventricular 


SPin-D Trial 
 
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Introduction 
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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
mass, diastolic function and late gadolinium enhancement (a marker of myocardial scar and 
fibrosis) also increase dramatically as GFR declines and predict an increased risk of death 27-34.  
The combination of left ventricular hypertrophy, increased interstitial collagen content, and 
microvascular rarefaction increases the distance between capillaries and cardiomyocytes14, 19 
and impairs myocardial oxygen delivery even when overt coronary obstruction is absent, 
thereby increasing the likelihood of myocyte necrosis with even minor reductions in coronary 
flow.  The resultant hypoxia in combination with disruption of myocardial electrical circuits by 
both interstitial fibrosis and frank scar in areas of prior necrosis lowers the threshold for the 
generation of fatal arrhythmias and creates a favorable substrate for their propagation.  
Alterations in myocardial structure are appear to be a key factor underlying the high incidence of 
sudden cardiac death in patients with ESRD,35, 36 and thus, inhibiting these changes may 
provide a potent, disease-specific strategy for improving CV outcomes in the setting of ESRD.  
Role of Aldosterone.  Aldosterone plays a key role in the development of myocardial fibrosis and 
capillary rarefaction.  In the L-NAME model of hypertensive cardiomyopathy, for example, 
aldosterone blockade with spironolactone (SPL) largely reverses left ventricular hypertrophy37.  
SPL as well as a second aldosterone blocker, eplerenone, prevent both angiotensin-2 and  
L-NAME-induced myocardial necrosis, inflammation and fibrosis via sodium- and potassium-
independent mechanisms38-40, and both adrenalectomy and eplerenone inhibit myocardial 
fibrosis via blood pressure-independent mechanisms41.  In models of CKD, SPL attenuates 
diastolic dysfunction and eliminates left ventricular fibrosis while strongly inhibiting collagen 
production in cultured cardiac fibroblasts42.  These experimental findings are consistent with 
data from a placebo-controlled trial in humans in which SPL decreased collagen production, 
reduced left ventricular mass and improved left ventricular relaxation (diastolic function) in 
individuals with stage 2-3 CKD 43, 44, and with studies showing that aldosterone concentrations 
are elevated and associated with left ventricular hypertrophy in individuals with ESRD45, 46. 
Aldosterone plays a similarly important role in microvascular homeostasis.  Aldosterone 
blockade exerts beneficial effects on the renal microvasculature41, 47, and eplerenone 
dramatically increases microvascular density and tissue perfusion following induction of  
hind-limb ischemia in a murine model48.  Finally, an ability of aldosterone blockade to preserve 
myocardial vessels has been demonstrated in experimental models showing that both 
adrenalectomy and eplerenone reduce L-NAME-induced fibrinoid necrosis of intra-myocardial 
vessels41.  
Potential Benefits of Aldosterone Antagonism.  In patients with congestive heart failure, 
aldosterone blockade with SPL or eplerenone dramatically reduces overall and CV mortality49, 
50.  This effect appears to be associated with reduced myocardial collagen synthesis as 
evidenced by reduced circulating concentrations of serum procollagen type I carboxy-terminal 
peptide (PICP) and other collagen fragments, suggesting that beneficial effects of SPL and 
eplerenone are at least partly mediated via the inhibition of myocardial fibrosis and adverse 
cardiac remodeling 51, 52.  Similar effects have been observed in a randomized trial of stage 2-3 
CKD patients in which SPL (25 mg per day for 40 weeks) reduced left ventricular mass index by 
11.4% and the amino terminal peptide of procollagen 3 by 5%43, and by a recent, open-label 


SPin-D Trial 
 
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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
trial in which the administration of 25 mg of SPL daily to chronic dialysis patients was associated 
with a 60% reduction in death or cardiovascular hospitalizations53.  Analogous changes in 
capillary supply are suggested by the 20% improvement in coronary flow reserve observed 
following just 4 weeks of SPL therapy in a study of diabetic patients54.  
Summary.  Both experimental and clinical data strongly implicate aldosterone homeostasis in 
ESRD-associated CVD, providing a compelling rationale for assessing the safety, tolerability 
and therapeutic potential of aldosterone blockade using SPL to improve cardiovascular 
outcomes and overall mortality in the setting of dialysis-dependent ESRD.  Although the cardiac 
effects of aldosterone blockade in ESRD have not been broadly assessed, preliminary studies 
in patients treated with maintenance dialysis suggest that SPL administered as a daily dose of 
25 mg is effective for reducing blood pressure and has a good safety profile with a rate of 
serious hyperkalemia of less than 3% 53, 55-63.  Furthermore, as noted above, in a recently 
completed open-label trial comparing SPL and standard therapy in maintenance hemodialysis 
patients, SPL dramatically reduced overall mortality and the combined endpoint of mortality and 
cardiovascular hospitalization53.  Lastly, two additional trials comparing SPL with placebo have 
been recently initiated in Europe64, 65.  In light of the established body of evidence and emerging 
interest in the use of SPL in dialysis-dependent ESRD, the current protocol is a randomized, 
pilot trial designed to assess the safety and tolerability of SPL in maintenance hemodialysis 
patients and to generate pilot estimates of the effect of SPL compared with placebo on 
cardiovascular efficacy parameters in maintenance hemodialysis by assessing diastolic 
function, heart rate variability, and circulating markers of fibrosis.  The trial will build on existing 
and emerging data about the use and therapeutic potential of SPL in dialysis-dependent ESRD.  
In particular, the study will generate important information about the feasibility of recruiting 
participants for a mortality-powered SPL trial in the United States and about the safety of SPL 
therapy US dialysis population under standard of care hemodialysis practices.  In addition, to 
our knowledge, the proposed trial will be the first in the dialysis-dependent ESRD population to 
prospectively compare the safety and efficacy of multiple doses of SPL and placebo, and it will 
thereby provide critical preliminary data needed to choose an optimal dose of SPL in the dialysis 
population and to design large-scale trials testing whether SPL can effectively improve the poor 
cardiovascular outcomes in dialysis-dependent ESRD. 
1.2. 
Investigational Agent  
(Information obtained from the FDA Package Insert66) 
Aldactone (spironolactone) oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone 
antagonist spironolactone,17-hydroxy-7α-mercapto-3-oxo-17α-
pregn-4-ene-21-carboxylic acid γ-lactone acetate, which has the 
following formula: 
SPL is practically insoluble in water, soluble in alcohol, and freely 
soluble in benzene and in chloroform. Inactive ingredients include 
calcium sulfate, corn starch, flavor, hypromellose, iron oxide, 
magnesium stearate, polyethylene glycol, povidone, and titanium 
dioxide. 


SPin-D Trial 
 
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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
Mechanism of action: SPL is a specific pharmacologic antagonist of aldosterone, acting 
primarily through competitive binding of receptors at the aldosterone dependent sodium-
potassium exchange site in the distal convoluted renal tubule.  SPL causes increased amounts 
of sodium and water to be excreted, while potassium is retained.  SPL acts both as a diuretic 
and as an antihypertensive drug by this mechanism.  It may be given alone or with other diuretic 
agents which act more proximally in the renal tubule. 
Aldosterone antagonist activity:  Increased levels of the mineralocorticoid, aldosterone, are 
present in primary and secondary hyperaldosteronism.  Edematous states in which secondary 
aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and the 
nephrotic syndrome.  By competing with aldosterone for receptor sites, SPL provides effective 
therapy for the edema and ascites in those conditions.   
SPL is effective in lowering the systolic and diastolic blood pressure in patients with primary 
hyperaldosteronism.  It is also effective in essential hypertension, even though aldosterone 
secretion may be within normal limits in essential hypertension. 
Through its action in antagonizing the effect of aldosterone, SPL inhibits the exchange of 
sodium for potassium in the distal renal tubule and helps to prevent potassium loss. 
Pharmacokinetics:  SPL is rapidly and extensively metabolized.  Sulfur-containing products are 
the predominant metabolites and are thought, together with SPL, to be primarily responsible for 
the therapeutic effects of the drug.  The following pharmacokinetic data were obtained from 12 
healthy volunteers following the administration of 100 mg of SPL (Spironolactone film-coated 
tablets) daily for 15 days.  On the 15th day, spironolactone was given immediately after a low-fat 
breakfast and blood was drawn thereafter. 
 
Accumulation Factor: 
AUC (0-24 hr, day 15) 
/AUC (0-24 hr, day 1) 
Mean Peak Serum 
Concentration 
Mean (SD)  
Post-Steady  
State Half-life 
7-α-(thiomethyl)  
spirolactone (TMS) 
1.25 
391 ng/mL at 3.2 hr 
13.8 hr (6.4) (terminal) 
6-β-hydroxy-7-α-(thiomethyl) 
spirolactone (HTMS) 
1.50 
125 ng/mL at 5.1 hr 
15.0 hr (4.0) (terminal) 
Canrenone (C) 
1.41 
181 ng/mL at 4.3 hr 
16.5 hr (6.3) (terminal) 
Spironolactone 
1.30 
80 ng/mL at 2.6 hr 
Approximately 1.4 hr 
(0.5) (β half-life) 
 
The pharmacological activity of SPL metabolites in man is not known.  However, in a study of 
adrenalectomized rats, the anti-mineralocorticoid activities of the metabolites C, TMS, and 
HTMS, relative to SPL, were 1.10, 1.28, and 0.32, respectively.  Relative to SPL, the binding 
affinities of these metabolites to the aldosterone receptors in rat kidney slices were 0.19, 0.86, 
and 0.06, respectively.  In humans the potencies of TMS and 7-α-thiospirolactone in reversing 
the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition 
were 0.33 and 0.26, respectively, relative to SPL.  However, since the serum concentrations of 


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these steroids were not determined, their incomplete absorption and/or first-pass metabolism 
could not be ruled out as a reason for their reduced in vivo activities.  SPL and its metabolites 
are more than 90% bound to plasma proteins. The metabolites are excreted primarily in the 
urine and secondarily in bile.  The effect of food on spironolactone absorption (two 100 mg SPL 
tablets) was assessed in a single-dose study of 9 healthy, drug-free volunteers. Food increased 
the bioavailability of un-metabolized spironolactone by almost 100%. The clinical importance of 
this finding is not known. 
1.3. 
Clinical Data to Date 
Heart Failure:  The RALES trial was a multi-national trial that enrolled 1663 patients with NYHA 
class 4 heart failure and a median creatinine clearance of 57 mL/min to SPL 25 mg daily or 
placebo.  The primary endpoint was time to all-cause mortality.  RALES was terminated early 
because of a significant mortality benefit.  Spironolactone reduced the risk of death by 30% 
compared to placebo (p<0.001; 95% confidence interval 18% to 40%).  Spironolactone reduced 
the risk of cardiac death, primarily sudden death and death from progressive heart failure by 
31% compared to placebo (p <0.001; 95% confidence interval 18% to 42%.50 
Stage 2-3 CKD:  Edwards et al randomized 112 patients with stage 2-3 CKD and controlled 
blood pressure on ACEI or ARB therapy to SPL 25 mg daily or placebo for 36 weeks.  The  
co-primary endpoints of the study were change in LV mass and arterial stiffness measured by 
pulse wave velocity.  No patients died during follow-up.  LV mass increased by 3 gram in the 
placebo group but decreased by 13 gram in the SPL group (P<0.01).  Similarly, pulse wave 
velocity decreased by 0.2 meter/second in the placebo group compared with a decrease of  
0.8 meter/second in the SPL group (P<0.01).44 
ESRD:  Trials including 332 hemodialysis patients treated with SPL and 78 peritoneal dialysis 
patients suggest that it is associated with minimal changes in serum potassium and a serious 
hyperkalemia incidence of <3%53, 55-63.   
Gross et al conducted a randomized, crossover trial of 2 weeks of SPL 50 mg twice daily 
compared with placebo in 8 hemodialysis patients.  Patients on ACEI or ARB were excluded. 
The mean change in systolic blood pressure was 11 mm Hg (P<0.05).  Changes in potassium 
were not significantly different in placebo (4.7 ± 0.4 mEq/L to 4.7 ± 0.5 mEq/L) and SPL group 
4.6 ± 0.7 to 5.0 ± 0.8, P>0.05)55. 
Hussain treated 15 hemodialysis patients with SPL 25 mg daily for 28 days56.  Pre-enrollment 
ACE or ARB was continued throughout the treatment period in 6 of 15 patients.  Mean serum 
potassium levels were 4.6 ± 0.6mEq/L at baseline and 4.7±0.6 mEq/L at study completion 
(P=0.19). Nine patients completed the trial with all serum potassium levels <5.6 mEq/L and 13 
completed therapy with all potassium levels < 6.0 mEq/L.  Of the remaining 2 patients, the peak 
potassium level was detected following a missed dialysis session.  
Michea treated 9 hemodialysis patients with SPL 50 mg 3x/week for 2 weeks followed by 2 
weeks of placebo therapy.  During each study period participants were challenged with an oral 
potassium load.  Individuals using ACEI or ARB were excluded from enrollment.  In this study, 
there was no significant effect of SPL therapy on the rise in potassium concentration following 


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the potassium load.  No patient developed hyperkalemia during the study period61. 
Saudan studied a low dose of SPL (12.5 mg 3x/weekly for 2 weeks, followed by 25 mg 
3x/weekly for 2 weeks) in 14 hemodialysis patients57.  ACEI or ARB was continued in 8 of 14 
participants.  SPL therapy resulted in a decrease of potassium from 5.0 ± 0.4 to 4.9 ± 0.4 mEq/L 
compared with a change from 4.8 ± 0.8 to 4.6 ± 0.7 mEq/L in a non-randomized concurrent 
control group.  In a multi-variable, analysis adjusting for baseline potassium concentration, SPL 
therapy was associated with a decrease in serum potassium compared with placebo. 
Taheri conducted a small, randomized trial of 16 hemodialysis patients with an ejection fraction 
<45%58.  The treatment group received SPL 25 mg daily for 6 months and the control group was 
treated with placebo therapy.  All patients were treated with ACEI and/or ARB. 
SPL therapy was associated with a significant increase in ejection fraction compared with 
placebo therapy (6.2 ± 1.64% vs. 0.83 ± 0.49%, P=0.046) as well as a decrease in left 
ventricular mass compared with a small increase in the placebo group (P=0.02).  Potassium 
concentrations increased by a mean of 1.02 ± 0.34 mEq/L in the SPL group compared with 0.08 
± 0.45, (P=0.004).  However, only 1 patient developed frank hyperkalemia.   
A larger randomized trial of 66 patients was conducted by Vukusich59.  This study enrolled 
prevalent hemodialysis patients not taking ACEI or ARB and randomized patients to 50 mg of 
SPL 3x/week or placebo for 24 months.  Carotid ultrasound was performed before and at the 
end of therapy.  No patients died during therapy and there were no hyperkalemic events.  In this 
study, SPL did not have a significant effect on blood pressure at 24 months (systolic blood 
pressure change of -2 mm Hg in the SPL group).  Calculated carotid intimal-medial thickness 
progression rate for left and right segments in the placebo group were 0.06  ± 0.07 mm/year in 
the common carotid artery versus 0.01 ± 0.04 mm/year in the SPL group (P=0.003).  These 
effects were consistent across other carotid artery segments.  Plasma potassium concentration 
increased by 0.012 mEq/L per month during treatment (P = 0.001) in the SPL group, but did not 
change significantly in the placebo group.  
Matsumoto administered SPL 25 mg daily for 6 months to 61 oligo-anuric prevalent, 
hemodialysis patients60.  ACEI or ARB was used by 66% of patients during the study period.  No 
patient discontinued therapy due to hyperkalemia or required ion-exhange therapy, although 3 
patients discontinued therapy due to gynecomastia, and 3 additional patients discontinued 
therapy due to possible side-effects.  Serum potassium rose from 4.96 ± 0.72 to 5.18 ± 0.72 
during therapy.  A serum potassium >6.8 mEq/L was not observed in any of the patients.   
Flevari62 conducted a sequential, non-randomized crossover trial of 14 stable dialysis patients 
without heart failure.  Placebo was administered for 4 months followed by 4 months of  
SPL 25 mg post-dialysis 3 times per week.  ACEI and ARB were continued if previously used.  
Pre-dialysis potassium levels increased from 4.4 ± 0.2 to 5.5 ± 0.3 meq/L during SPL therapy 
(P<0.05) and 2 patients required administration of potassium binding resins.  Treatment with 
SPL was not associated with changes in left ventricular mass, systolic function, or the E/A ratio.  
However, there were significant decrements in systolic blood pressure from 145 ± 4.2 to 121 ± 
2.3, and significant improvements in flow-mediated reactive forearm vasodilatation, and heart 


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rate variability. 
McGill63 studied 30 prevalent dialysis patients (mean time on dialysis 6 years).  Thirteen 
individuals completed 9 months of SPL 25 mg daily.  ACE inhibitor therapy was continued in 
7/13 participants.  The remaining 17 patients failed to complete the trial protocol.  Reasons for 
non-completion were varied.  Although only limited data on reasons for non-completion were 
presented, drug side-effects were not implicated in the published report.  No potassium 
measurements of >6.0 mEq/L were observed.  Hemodialysis prescriptions were adjusted on 2 
occasions ‒ for measurements of 5.7 and 5.9 mEq/L, respectively.  There was no detectable 
pattern of change in serum potassium levels during the study.  MRI measurements of LV mass 
did not decrease between baseline and follow-up in the small subset of individuals completing 
baseline and follow-up scans.  However, there were non-significant decreases in relative wall 
thickness (from 0.60 ± 0.20% to 0.56 ± 0.20%) and end diastolic volume index (from 99 ± 27 
mL/m2 to 92 ± 33 mL/m2) and a non-significant increase in ejection fraction (from 59 ± 10% to 60 
± 10%). 
Masumoto53 randomized 309 Japanese maintenance hemodialysis patients to 25 mg SPL daily 
or placebo.  During a 3-year, open-label trial, 5.7% of patients in the SPL group reached the 
primary endpoint of combined death or CV hospitalization compared with 12.5% of patients in 
the  control group (HR 0.40; 95% CI: 0.20 to 0.81).  There was also a significant effect on the 
secondary outcome of all-cause mortality with 10 deaths (6.4%) in the treatment group and 30 
(19.7%) in the control group (HR 0.36; 95% CI: 0.19 to 0.66).  Serious hyperkalemia requiring 
drug discontinuation was rare and occurred in only 3 (1.9%) participants during the trial.  
Finally, Ito randomized 158 peritoneal dialysis patients on concurrent ACEI or ARB therapy to 
open-label SPL or standard therapy67.  LVMI assessed by echocardiography improved 
significantly at 6 months (P=0.03) and 2 years (P=0.01) in individuals taking SPL compared with 
control therapy.  There was no detectable impact of SPL therapy on rate of change in residual 
renal function.  Hyperkalemia (K>6.0 mEq/L) occurred in only 2 of 78 patients (2.6%) in the SPL 
group and 1 of 80 patients (1.3%) in the control group, P=0.62.  None of the SPL participants 
experienced a K>6.0 mEq/L.  Gynecomastia affected 11 of 78 (14.1%) SPL participants 
compared with 2 of 80 (2.5%) control patients (P=0.01), but drug discontinuation was required in 
only 2 participants.  
Based on available experience in the ESRD population the incidence of hyperkalemia with SPL 
therapy appears to be low.  Available data are summarized in Table 1.  In addition to the studies 
described above, the ALCHEMIST trial, which randomizes participants to SPL or placebo, was 
recently initiated in France.64  Despite some overlap, there are important differences between 
ALCHEMIST and the current trial.  In particular, ALCHEMIST will enroll a more selective, less 
generalizable population as participants are required to have diabetes, left ventricular 
hypertrophy, history of cardiovascular disease, or low ejection fraction.  The ALCHEMIST study 
will enroll patients exclusively in France and will therefore not provide data on the safety and 
efficacy of SPL within the context of standard of care dialysis practices in the United States or 
within the U.S. dialysis population.  Thirdly, the ALCHEMIST study focuses on clinical endpoints 
comparing a single dose of SPL with placebo with only limited physiologic studies planned.  


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Thus, in contrast to the current study, ALCHEMIST is not expected to improve understanding of 
the biological and physiological effects of SPL, nor will it provide the comparative safety and 
efficacy data needed to define the optimal dose of SPL.  
Because ALCHEMIST is not powered for the detection of differences in mortality, larger trials 
will be necessary to change the standard of care following its completion.  Results of the current 
trial will contribute important information for the planning of definitive trials and for determining 
the optimal dose of SPL for patients treated with chronic hemodialysis.  Nevertheless, all newly 
available data from ALCHEMIST or other SPL studies will be reviewed on an ongoing basis 
during conduct of the current trial.  New data with the potential to alter the risks and benefits of 
participation in the current trial will be shared with the Data and Safety Monitoring Board which 
will be asked to make recommendations for continuing the study unchanged, modifying the 
protocol, or discontinuing the study.  
 


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Table 1.  Hyperkalemia in Dialysis Studies of Spironolactone 
Author 
Design 
Number of 
Participants 
Hyperkalemia 
Definition 
Hyperkalemia 
Incidence in 
SPL Group 
Notes 
Gross55 
RCT, crossover design, placebo 
vs SPL 50 mg BID x 2 weeks 
8 
NA 
NA 
Non-significant change in potassium (P>0.05) 
a) placebo 4.7 ± 0.4 to 4.7± 0.5 mEq/L  
b) SPL 4.6 ± 0.7 to 5.0 ± 0.8. 
Hussain56 
Single arm study, SPL 25 mg QD 
x 28 days 
15 
≥6.0 mEq/L 
2/15 (13.3%) 
Hyperkalemia detected post missed dialysis session 
in both cases. Concurrent ACEI/ARB in 6/15 
participants. 
 
Michea61 
Crossover, non-randomized, 
placebo or SPL 50 mg 3x/wk x 2 
wks. Challenge with high 
potassium diet. 
9 
Undefined 
0/9 (0.0%) 
Mean potassium values during SPL therapy 4.56 ± 
1.13 mEq/L. 
Saudan57 
Single arm study, SPL 12.5 mg 
3x/week x  2 weeks to SPL 25 mg 
3x/week x 2 weeks 
14 
NA 
NA 
SPL therapy resulted in a decrease in potassium 
from 5.0 ± 0.4 to 4.9 ± 0.4 mEq/L. ACEI/ARB 
continued in 8/14 participants. 
Taheri58 
RCT.  Placebo vs. SPL 25 mg QD 
x 6 months 
16 
Undefined 
0/8 
ACEI/ARB in all participants. 
Vukusich59 
RCT.  SPL 50 mg 3x/week vs. 
placebo x 24 months 
66 
Undefined 
0/33 
No concurrent ACEI/ARB. 
Matsumoto60 
Single arm study, SPL 25 mg QD 
x 6 months 
61 
>6.5 mEq/L 
8/61(13.1%) 
Concurrent ACEI/ARB  use in 66%.  All serum 
potassium measurements ≤6.8 mEq/L. Resin use 
not required in any participants. 
Flevari62 
Non-randomized crossover. 
Placebo vs. SPL 25 mg 3x/week 
x 4 months. 
14 
>6.0 mEq/L 
2/14 (14.2%) 
Concurrent ACEI/ARB allowed. 2 participants 
required potassium binding resins for K>6.0 mEq/L. 
McGill63 
Single arm study, SPL 25 mg QD 
x 9 months. 
13 
>6.0m mEq/L 
0/13 (0.0%) 
Concurrent ACEI in 7/13 participants.  Additional 17 
participants enrolled but did not complete study for 
reasons other than hyperkalemia. 
Masumoto53 
RCT.  SPL 25 mg QD vs. placebo 
x 3 years. 
309 
Discontinuation due 
to hyperkalemia 
(criteria not specified) 
3/157 (1.9%) 
Non-blinded. Inclusion criteria required mean K<6.5 
mEq/L in 2 months prior to randomization. 
Concurrent ACEI/ARB allowed.  
Ito67 
RCT. SPL 25 mg QD vs. standard 
therapy x 2 years. 
158 
≥6.0 mEq/L 
2/78 (2.6%) 
Non-blinded. Concurrent ARB in 100%. 


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1.4. 
Dose Rationale and Risk/Benefits 
An SPL oral dose of 25 mg daily has been associated with improvement in mortality and 
ventricular function in a large, heart failure trial50, and a 25 mg daily dose has also been 
associated with improvement in ventricular structure and function in mild to moderate CKD.  
Doses tested in ESRD have ranged from 25 mg 3x/week to 50 mg 2x/day.  Although, a 25 mg 
daily dose has been the most frequently tested, and appears to be well-tolerated and associated 
with a minimal incidence of serious hyperkalemia as detailed in Section 1.3 and Table 1, the 
optimal dose in terms of safety and efficacy in the ESRD population remains uncertain.  To our 
knowledge, no  study to date has compared the relative safety, efficacy, or tolerability of multiple 
doses with each other or with placebo within the structure of a single trial. Thus, in order to 
generate comparative information on safety, efficacy and tolerability, the current study will 
compare 3 doses of SPL, representing a low dose (12.5 mg/day), a medium dose (25 mg/day) 
and a high dose (50 mg/day), with placebo therapy.  Spironolactone will be administered once 
per day.  On days in which dialysis is performed the drug will be taken post-dialysis to minimize 
effects of dialysis on drug metabolism.  In addition to spanning a range from low to medium to 
high dose, the targeted doses of SPL are consistent with available tablet sizes and standard 
clinically utilized/approved doses for the FDA-labeled indications.  Although additional doses 
could be tested, it is uncertain whether significantly greater knowledge would be generated 
through the addition of medium-high dose (e.g. 37.5 mg/day) compared with the current plan to 
test low, medium and high dosing strategies.  Conversely, addition of an ultra-high dose group 
(e.g. >50 mg/day) is more likely to be associated with a high rate of adverse events 
necessitating drug discontinuation.  Additional dosing arms also have the disadvantage of 
increased logistical complexity.  Furthermore, in the absence of an increase in overall sample 
size, a smaller cohort size in each dose group could have the undesired effect of limiting power 
to detect differences in safety or efficacy across doses.  The increase in the overall sample size 
required to increase power across 4 or more active dose groups would increase the costs, 
recruitment challenges, and probably the duration of the trial.  
1.4.1. 
Risks 
Risks of SPL include hyperkalemia, hypotension and intra-dialytic hypotensive symptoms.  
Other potential side effects include gynecomastia and gastrointestinal symptoms.  Of particular 
concern in trials of SPL in patients with CKD is the risk of hyperkalemia and the potential for 
hyperkalemia-associated arrhythmias.  Although the effects of SPL on potassium excretion are 
important, it is noteworthy that extracorporeal (dialytic) clearance, rather than renal or colonic 
clearance, provides the majority of potassium excretion in dialysis-dependent ESRD.  This 
extracorporeal clearance should not be impaired by SPL therapy.   
In the current trial, risks of hyperkalemia will be reduced through close monitoring of serum 
potassium concentrations through scheduled study-specific safety labs, and through standard 
clinical practice at the treating dialysis unit (monthly to bi-monthly in individuals with normal 
serum potassium, more frequently in individuals with hyperkalemia or hypokalemia).  
Manipulation of dietary intake of potassium, eliminating, when medically acceptable, 
concomitant use of medications with hyperkalemic effects, and adjustment of dialysate 


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potassium will also be used as additional safety measures (see Section 6.8).  The use of low 
potassium dialysate is currently considered by many clinicians to be an appropriate approach 
for treating hyperkalemia, and dialysate potassium concentration may be altered according to 
standard practice of the treating clinicians throughout the course of the study.  However, the 
study protocol will not mandate or recommend prophylactic changes to the dialysate 
prescription and calls for lowering dialysate potassium only as a second-line response to 
significant hyperkalemia after other measures fail to resolve hyperkalemia.  The relative risks of 
arrhythmic death from hypokalemia, hyperkalemia and low dialysate potassium levels in 
hemodialysis patients is an active area of inquiry and uncertainty and further research into the 
best approach is warranted68-70.  In the absence of definitive data on the optimal approach to 
dialytic management of serum potassium concentration, evaluation of the relative risks and 
benefits of SPL therapy within the context of standard clinical approaches to dialysate 
potassium prescription will increase the understanding of the true risks and benefits of SPL 
therapy within the context of standard clinical approaches to hemodialysis in the United States.    
Given these uncertainties and equipoise regarding the ideal serum potassium concentration and 
ideal dialysate potassium in chronic hemodialysis patients, changes in dialysate potassium 
concentration will be recommended only as a secondary means of controlling serum potassium 
to be utilized only in the context of significant hyperkalemia.  Use of 1 mEq/L potassium 
dialysate will be recommended only as a temporizing measure of last resort.  The proportion of 
treatments requiring use of 1 mEq/L dialysate will be monitored as a secondary safety endpoint 
and compared across treatment groups. 
1.4.2. Benefits 
Benefits of SPL therapy in the dialysis population remain unproven at this time.  Hypothesized 
benefits of SPL therapy include improved blood pressure control, improvement in cardiovascular 
function and structure, and a decrease in arrhythmias.  
 
2. Study Objectives 
The primary objective of this study is to characterize the safety and tolerability of multiple doses 
of chronic SPL therapy compared with placebo in maintenance hemodialysis patients and to 
assess the feasibility of conducting a full-scale, mortality-powered trial of SPL.  The effects of 
SPL compared with placebo on multiple cardiovascular efficacy parameters will also be 
analyzed.  The primary efficacy parameter will be the change in the E′ measurement on tissue 
Doppler echocardiography (TDI) as an index of diastolic function and a surrogate for myocardial 
fibrosis.  Secondary cardiac parameters of interest that will be studied in the overall population 
or in sub-studies include heart rate variability, circulating markers of fibrosis, and coronary flow 
reserve (CFR) as an index of microvascular function.   These parameters are designed to 
broaden insight into the potential effects of SPL on cardiac structure and function in individuals 
with dialysis-dependent ESRD and to assess the feasibility of conducting a full-scale, mortality-
powered trial. 
 


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2.1. 
Primary Objectives 
Safety 
• 
To evaluate the safety of chronic spironolactone therapy in individuals with ESRD 
on HD. 
o Safety events will include the following:  
 
Potassium level >6.5 mEq/L  
 
Serious hypotension is defined as hypotension requiring hospitalization or 
treatment in an emergency room and not attributable to overt sepsis, acute 
myocardial infarction, or other cardiovascular event (e.g. aortic dissection) 
 
Serious hyperkalemia defined as hyperkalemia requiring hospitalization, 
emergency/unscheduled dialysis, or emergency/unscheduled resin therapy 
 
The combined incidence of potassium level >6.5 mEq/L or serious 
hyperkalemia defined as hyperkalemia requiring hospitalization, 
emergency/unscheduled dialysis, or emergency/unscheduled resin therapy 
 
Treatment-emergent events defined as the combined incidence of death, 
myocardial infarction, stroke, hospitalizations, potassium level >6.5 mEq/L, 
serious hyperkalemia defined as hyperkalemia requiring hospitalization, 
emergency/unscheduled dialysis, or emergency/unscheduled resin therapy, 
and serious hypotension defined as hypotension requiring hospitalization or 
treatment in an emergency room and not attributable to overt sepsis, acute 
myocardial infarction, or other cardiovascular event 
 
The individual components of the treatment-emergent endpoint 
 
Cardiovascular death 
 
Hyperkalemia requiring adjustment in dialysate potassium concentration, or 
discontinuation of study medication 
 
Proportion of dialysis sessions utilizing 1 mEq/L potassium dialysis solution bath 
 
Within-patient variability in serum potassium concentration 
 
Symptomatic inter- or intra-dialytic hypotension 
Tolerability 
• 
To evaluate the tolerability of chronic spironolactone therapy in individuals with ESRD 
treated with hemodialysis 
o Tolerability events will include reduction in dose of study medication during the 
course of the treatment period or discontinuation of study drug  
Efficacy 
• 
To test the hypothesis that chronic blockade of aldosterone with SPL improves diastolic 
function in individuals with ESRD on HD.  The change in E′ on TDI echocardiography of 
the left ventricle from baseline to end of study will be used in the primary endpoint 
assessment of diastolic function. 


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Feasibility  
• 
To assess feasibility of conducting a full-scale mortality-powered trial. 
o Feasibility will be assessed based on recruitment rate and dropout rates. 
 
2.2. 
Secondary Objectives 
Secondary objectives are designed to expand understanding of cardiovascular structure and 
function and their association with SPL therapy in ESRD by analysis of the following 
parameters:  
• 
Change between baseline and 36 weeks in left ventricular mass index (LVMI)  
• 
Change between baseline and 36 weeks in ejection fraction  
• 
Change between baseline and 36 weeks in myocardial strain and strain rate 
• 
Change between baseline and 36 weeks in circulating indices of tissue fibrosis such as 
procollagen type I carboxy-terminal peptide (PICP), galectin-3, soluble ST2, GDF-15 
• 
Change between baseline and 36 weeks in circulating indices of systemic inflammation  
such as CRP, IL-1, IL-2, IL-6, IL-10, IL-18, TNF-alpha, albumin, sVCAM-1, leptin, 
adiponectin 
• 
Change between baseline and 36 weeks in circulating indices of oxidative stress such as 
F2 isoprostanes and isofurans 
• 
Change between baseline and 36 weeks in coronary flow reserve  
• 
Association between change in coronary flow reserve (CFR) and change in E′ 
• 
Heart rate variability 
• 
Arrhythmia 
 
3. Study Design 
3.1. 
General Design 
This is a randomized, placebo-controlled 4-arm trial that will compare placebo with 3 doses of 
SPL.  Participants will be randomized in a 2:1:1:1 fashion to placebo or SPL, with equal 
proportions randomized to each of 3 SPL doses: 12.5, 25 or 50 mg once daily.  As shown in 
Figure 1, the study will be conducted in 2 phases ‒ a dose escalation phase and a treatment 
phase.   
All participants randomized to SPL will initiate treatment at 12.5 mg daily.  Participants will be 
evaluated weekly for tolerability, hypotension and hyperkalemia.  At 2 weeks, if the initial dose 
has been tolerated, participants randomized to the 25 or 50 mg SPL arm will increase the dose 
to 25 mg for 2 weeks with weekly evaluation for tolerability, hypotension and hyperkalemia.  
Participants randomized to 12.5 mg SPL or placebo arm will continue on the same dose with 
weekly evaluation for tolerability, hypotension and hyperkalemia. 
At 4 weeks, participants randomized to the 50 mg SPL arm will increase the dose to 50 mg if the 
25 mg dose was tolerated with weekly evaluations for tolerability, hypotension and hyperkalemia 


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until 6 weeks.  Participants randomized to 12.5 mg, 25 mg, or placebo will continue on the same 
dose with weekly evaluation for tolerability, hypotension and hyperkalemia until 6 weeks. 
In order to maintain the blind, during the dose escalation phase all study participants, regardless 
of randomized assignment, will receive new study drug kits every 2 weeks and will be evaluated 
weekly.   
At the end of the dose escalation phase, participants will continue treatment based on the 
randomized dose assignment for an additional 30 weeks (treatment phase) such that the total 
duration of study medication is 36 weeks.  As described in Sections 6.8 and 6.9, the dose of 
SPL or placebo will be decreased during the dose-escalation and follow-up phases for 
hypotension, hyperkalemia or other dose limiting side-effects.   
Figure 1.  Study Design 
 
 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
Safety 
The primary safety endpoints are: 
1) The incidence of serum potassium >6.5 mEq/L  
2) The incidence of serious hypotension defined as hypotension requiring hospitalization or 
treatment in an emergency room and not attributable to overt sepsis, acute myocardial 
infarction, or other cardiovascular event (e.g. aortic dissection). 
Tolerability 
Tolerability will be assessed on the basis of whether participants can continue the assigned 
dose throughout the entire treatment period.  Any reduction in dose of study medication will be 
considered a failure of primary tolerability.  
Efficacy 
The primary efficacy parameters will be measured between baseline and 36 weeks:  
Change in mitral annular E′ velocity will be measured using Tissue Doppler Index (TDI) 
echocardiography of the left ventricle as a measure of diastolic function and as surrogate 
measure of left ventricular fibrosis. 
 


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E′ has been chosen to be the primary echocardiographic endpoint because the intra-observer 
coefficient of variation is low71 and multiple studies demonstrate a high correlation with 
myocardial fibrosis72-74, a primary biologic endpoint of interest.  E′, for example, parallels the 
accumulation of myocardial collagen and fibrosis in the senescence prone mouse75,  and 
correlates with endomyocardial fibrosis after human cardiac transplant76 as well as the presence 
of late gadolinium enhancement77 ‒ a highly-validated measure of myocardial scar ‒ across 
multiple disease states.  Furthermore, abnormalities in TDI have been strongly linked to 
mortality in multiple disease states78-80 demonstrating that TDI is a clinically relevant measure.  
In addition, ESRD-specific studies show that E′ is highly correlated with LV mass and other 
indices of diastolic function, and that changes in E′ predict mortality34, 81.  
In contrast to other echocardiographic measures, E′ (or the ratio of E/E′) is minimally affected by 
intravascular volume status82-84 ‒ a critical consideration in ESRD where volume status can vary 
widely.  The adjunctive information on diastolic and systolic function and filling pressures 
generated by echocardiography provide additional advantages to the use of TDI while the 
measurement of strain rate and strain may allow detection of subtle changes in myocardial 
function due to fibrotic processes85.  Finally, these measures are known to respond to 
therapeutic interventions that exert anti-fibrotic effects86.  Alternative approaches for assessing 
fibrosis include myocardial biopsy which is considered the gold standard, and cardiac magnetic 
resonance imaging with gadolinium.  However, both of these have risks of serious complications 
and thus are not suitable for a research study.  
Feasibility  
An objective of this study is to assess the feasibility of conducting a full-scale mortality-powered 
trial.  Feasibility will be assessed based on recruitment, dropout and loss to follow-up rates. 
3.2.2. 
Secondary Endpoints 
Safety  
• Serious hyperkalemia defined as hyperkalemia requiring hospitalization, 
emergency/unscheduled dialysis, or emergency/unscheduled resin therapy 
 The combined incidence of potassium level >6.5 mEq/L or serious hyperkalemia defined 
as hyperkalemia requiring hospitalization, emergency/unscheduled dialysis, or 
emergency/unscheduled resin therapy 
• Treatment-emergent events defined as the combined incidence of death, myocardial 
infarction, stroke hospitalization, potassium level >6.5 mEq/L, serious hyperkalemia, and 
serious hypotension 
• The individual components of the treatment-emergent endpoint 
• Cardiovascular death 
• Hyperkalemia requiring adjustment in dialysate potassium or discontinuation of study 
medication 
• Potassium ≥6.0 mEq/L 
• Mean serum potassium during follow-up 
• Proportion of dialysis sessions utilizing 1 mEq/L potassium dialysis solution bath 
• Within-patient variability in serum potassium concentration 


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• Mean pre-dialysis blood pressure during follow-up 
• Symptomatic inter- or recurrent intra-dialytic hypotension 
o Symptomatic inter-dialytic hypotension is defined as systolic blood pressure <90 mm 
Hg or hypotension requiring adjustment in blood pressure medications or treatment 
in an emergency or hospitalized setting 
o Recurrent intra-dialytic hypotension is defined as systolic blood pressure <80 mm Hg 
during ≥3 dialysis sessions per 30-day period or treatment for either hypotension or 
symptoms of hypotension during ≥3 dialysis sessions per 30-day period.  Treatment 
includes saline infusion, lowering of the ultrafiltration rate or other interventions 
directed at hypotension such as vasopressor agents. Symptoms include but are not 
limited to muscle cramping, lightheadedness, and nausea.  
Efficacy 
Secondary outcome measures include other echocardiographic markers of systolic and diastolic 
function, circulating markers of fibrosis,heart rate variability and arrhythmias (sub-study), and 
coronary flow reserve (CFR) as assessed by myocardial positron emission tomography 
(PET)(sub-study).   
• Change in left ventricular mass index (LVMI) between 0 and 36 weeks 
• Change in ejection fraction between 0 and  36 weeks 
• Change in myocardial strain and strain rate between 0 and 36 weeks 
• Change in cardiac fibrosis markers between baseline and 36 weeks 
• Change in inflammatory markers between baseline and 36 weeks 
• Change in oxidative stress markers between baseline and 36 weeks 
• Change in CFR between baseline and 36 weeks (sub-study) 
• Association between change in CFR and change in E′ (sub-study) 
• Heart rate variability assessed by Medtronic SEEQ monitor (sub-study) 
• Arrhythmias assessed by Medtronic SEEQ monitor (sub-study) 
 
4. Participant Selection and Withdrawal 
4.1. 
Inclusion Criteria 
a) Maintenance hemodialysis therapy for end-stage renal disease 
b) Age 18-85 years 
c) ≥3 calendar months since dialysis initiation  
If a patient has been on dialysis for ≥3 but less than 6 calendar months, there must be:  
i)  no hospitalizations during the 6 weeks prior to screening and  
ii) no change in EDW within 2 weeks of the screening date. 
d) For women of childbearing potential, willingness to use a highly effective method of birth 
control for up to 4 weeks after the last dose to study drug.  See Section 4.3.1 for 
definition of childbearing potential and acceptable methods of birth control. 
e) Ability to provide informed consent 
 


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4.2. 
Exclusion Criteria 
a) Serum potassium ≥6.5 mEq/L within the 3 months prior to screening 
b) Serum potassium level ≥6.0 mEq/L within 2 weeks prior to the baseline visit. If a 
potassium value is not available through routine clinical care during this 2-week period a 
potassium measurement will be performed as a research test. 
c) Unscheduled dialysis for hyperkalemia within the 3 months prior to screening 
d) Pre-dialysis systolic blood pressure <100 mm Hg within 2 weeks prior to screening or at 
the baseline visit 
e) 2 or more dialysis sessions within the month prior to screening with either 2 
intra-dialytic measurements of systolic blood pressure <80 mm Hg  
f) Current dual use of ACEI and ARB  
g) Current use of digoxin 
h) Current use of spironolactone or epleronone 
i) Allergy to spironolactone 
j) Inability to maintain dialysis machine blood flow ≥300 mL/min during any of the most 
recent 3 dialysis sessions prior to the screening visit as an indicator of vascular access 
dysfunction 
k) Mitral valve repair or replacement 
l) Severe mitral valve disease by echocardiography, coronary angiography or cardiac 
magnetic resonance imaging 
m) Anticipated kidney transplant, change to peritoneal dialysis, or transfer to another 
dialysis unit within 9 months 
n) Expected survival <9 months 
o) Pregnancy, anticipated pregnancy, or breastfeeding 
p) Incarceration 
q) Participation in another intervention study 
4.2.1. Exclusion Criteria for SEEQ Heart Rhythm Monitoring Sub-study Only 
a) symptomatic arrhythmias for which heart rhythm monitoring is clinically indicated 
4.3. 
Participant Recruitment and Screening 
Participants at dialysis units affiliated with investigator and co-investigator practices will be 
screened for eligibility.  In addition to active screening of dialysis unit patient rosters by study 
personnel, informational handouts and brochures may be disseminated at affiliated dialysis units 
in order to allow potential participants to learn about the study and to contact investigators if 
interested.  All study material must be approved by local IRBs before dissemination to potential 
study participants.   
Dialysis unit labs, medical records at the investigator’s institution, and treatment or history 
records at local dialysis units will be reviewed to assess eligibility for enrollment.  Prior to 
enrollment, each participant’s treating nephrologist will be contacted to assess suitability for 
enrollment. 
Once preliminary eligibility is confirmed, informed consent will be obtained by a qualified, 
investigator or study site designee during an in-person visit.  This visit may take place either at 


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the local dialysis unit or at the investigator’s institution (referred to hereafter as the Clinical 
Center), according to investigator and participant preferences. No study-specific testing is 
required to confirm eligibility, except a serum pregnancy test for women of childbearing potential 
(see Section 4.3.1), and serum potassium if a measurement is not available through clinical 
measurements within the specified time window.  A Baseline/Randomization visit will be 
scheduled within 30 days of the screening visit. 
4.3.1. 
Women of Childbearing Potential 
Women of childbearing potential include any female who has experienced menarche and who 
has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or is not postmenopausal.  Postmenopausal is defined as:  
• Amenorrhea for ≥12 consecutive months without another cause or 
• Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL or 
• Women on hormone replacement therapy (HRT) 
 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, 
skin patches, or implanted or injectable products), or mechanical products such as an 
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent 
pregnancy, or who are practicing abstinence, or have a partner who is sterile (e.g., vasectomy) 
should be considered to be of childbearing potential. 
Acceptable methods of highly effective birth control include: 
o Condom with spermicide 
o Diaphragm and spermicide 
o Cervical cap and spermicide 
o Hormonal contraception 
4.4. 
Early Withdrawal of Participants and Early Termination of Study Medication 
4.4.1. 
Early Withdrawal of Participants 
Early withdrawals will be discouraged and participants who are not willing or able to continue 
study medication will be encouraged to remain in the study and continue study evaluations.  In 
the case of withdrawal of consent, every attempt will be made to obtain consent to continue 
monitoring for the occurrence of mortality, hospitalizations and other safety signals via 
telephone or in-person contact with participants, relatives, and dialysis unit staff and records.  
As a last resort, the Social Security Death Index will be queried for mortality events on 
individuals otherwise lost to follow-up.  If a patient becomes pregnant, she will be withdrawn 
from the study but will be followed for specific pregnancy outcomes.   
4.4.2. 
Early Termination of Study Medication 
Study medication will be discontinued by the research team in the following circumstances 
because of the potential for compromising patient safety:   


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• 
Allergy to or documented intolerance of study medications  
• 
Poor adherence with dialysis schedule compromising ability to follow serum potassium 
on a monthly basis 
• 
Organ transplantation 
• 
Change to a different dialysis modality 
• 
Initiation of digoxin therapy 
• 
Transfer to a non-participating dialysis unit  
 
If study medication is discontinued study visits and procedures will continue unless the 
participant withdraws consent for follow-up.   
 
5. Study Drug  
5.1. 
Description 
Study drug will be administered as matched, gel-encapsulated capsules containing 12.5 mg,  
25 mg or 50 mg of  spironolactone (Spironolactone,17-hydroxy-7α-mercapto-3-oxo-17α-pregn-
4-ene-21-carboxylic acid γ-lactone acetate) or placebo (methylcellulose powder).  
5.2. 
Treatment Regimen   
As depicted in Figure 1, 125 participants will be randomized in a 2:1:1:1 fashion to either 
placebo or SPL (12.5, 25, or 50 mg), with an equal proportion in each SPL group. SPL will be 
matched with placebo and administered orally, once daily, post-dialysis.  Participants will be 
instructed that, on days of dialysis treatment, the dose should be taken after the dialysis 
session.  All patients will be started on SPL 12.5 mg once daily or matched placebo.  Potassium 
levels will be checked 3-5 days and 2 weeks after initiation of study drug.  Dialysis run-sheets 
will be evaluated weekly for the occurrence of adverse events such as hypotension and 
gastrointestinal symptoms.  Adjustment to dosage of concomitant medications, the dialysis 
prescription, or study drug for hypotension or hyperkalemia will be made as described in 
Section 6.8 and Section 6.9.   
At 2 weeks, in the absence of dose-limiting hyperkalemia or hypotension, subjects randomized 
to the 25 or 50 mg SPL arm will increase the dose to 25 mg and those randomized to 12.5 mg 
will continue that dose.  At 4 weeks, in the absence of dose-limiting hyperkalemia or 
hypotension, participants randomized to 50 mg SPL will increase the dose to 50 mg SPL, and 
participants randomized to 12.5 mg or 25 mg will continue the same dose. 
In order to maintain the blind, all study participants, regardless of randomized assignment, will 
receive a new study drug supply every 2 weeks during the dose escalation phase.  For all 
participants, serum potassium levels will be checked at 3-5 days and at 2 weeks after the new 
study drug supply is dispensed, and weekly evaluations will be performed for tolerability, 
hypotension and hyperkalemia.   
At the end of the dose escalation phase, participants will continue treatment based on the 


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randomized dose assignment for an additional 30 weeks (treatment phase) such that the total 
duration of study medication is 36 weeks.  As described in Sections 6.8 and 6.9, the dose of 
SPL or placebo will be decreased or discontinued during the dose-escalation and treatment 
phases for hypotension, hyperkalemia or other dose limiting side-effects.  
5.3. 
Method for Assigning Participants to Treatment Groups 
The DCC will generate randomization schedules stratified by 1) participating recruitment site; 
2) dialysis vintage (≥ 1 vs. < 1 year on dialysis) and 3) angiotensin converting enzyme inhibitor 
(ACEI) or angiotensin receptor blocker (ARB) use.  Randomly permuted blocks of random sizes 
will be used to control the balance of participants assigned to each treatment regimen within 
each stratum.  This method guarantees that at no time during randomization will the number of 
participants in any arm be grossly imbalanced, and ensures that the sites will be unable to 
predict assignments.  Both longer dialysis vintage and use of ACEI or ARB increase the 
likelihood of hyperkalemia through loss of residual renal function and drug effects, respectively, 
and thus, are potential confounders that should be balanced across treatment groups.  
All randomization schedules will remain confidential, and known only to authorized members of 
the DCC staff and the central pharmacy. 
All relevant screening and eligibility confirmation data will be entered into the centralized data 
management system in advance of randomization in order for an eligible participant to be 
randomized.  When the study team agrees that the patient should be randomized, and the 
“Ready to Randomize Report” confirms that all eligibility criteria have been met, the Study 
Coordinator will implement the web-based randomization assignment managed centrally at the 
DCC.  This centralized randomization process will provide a randomized treatment assignment 
for that participant within the relevant stratum, linked with a specific study drug kit prepared at 
the central pharmacy.  This kit will be provided to the local investigative team for distribution at 
the randomization/baseline visit. 
5.4. 
Preparation and Administration of Study Drug and Maintenance of Blind 
Study drug and matching placebo will be prepared by the University of Pennsylvania 
Investigational Drug Service (IDS) which will be the Central Pharmacy for this study.  Study drug 
kits will contain 2-week supplies during the dose escalation phase, a 6-week supply for weeks 
6-12, and 12-week supplies for weeks 13-24 and weeks 25-36.   
Study drug will be prepared using gelatin encapsulation or equivalent methods such that all 
study drug, regardless of type (SPL or placebo) and dose are identical in appearance.  During 
encapsulation, SPL tablets will remain intact and will not be altered.  All dose levels will be 
administered as a single capsule.  IDS personnel will have access to the randomization scheme 
and code in order to prepare study drug kits containing the correct dose of SPL or placebo. IDS 
personnel responsible for preparation of study drug will not have access to study data or results 
and will not participate in analyses of study data or publications.  Randomized treatment 
assignments and the dosages provided in study drug kits will not be known by the Clinical 
Center research teams or the Clinical Center Research Pharmacy staff.  Only the Investigational 
Drug Service personnel and the database programmer at the DCC will be unblinded.  


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During the 6-week dose escalation phase, a study drug request form signed by a Clinical Center 
investigator will be entered into the data management system at each 2-week interval to request 
the next supply of study drug.  Unless there is a contraindication to a dose increase (e.g. 
hypotension or hyperkalemia), the investigator will indicate on the request form approval for 
dose escalation.  The Data Management System will generate a unique kit number based on 
the randomized treatment assignment and the prior dose.  If up-titration to the next dose is 
contraindicated, the Clinical Center investigator will indicate this on the study drug request form 
and a kit number corresponding to the current dose of SPL (or placebo) will be generated.  At 
the end of the dose titration period, participants will be provided with a 6 week supply of study 
medication at the indicated dose.  At the 12-week and 24-week visits, study drug request forms 
signed by the Clinical Center investigator will be submitted through the Data Management 
System to request 12 week supplies of study medication.   
If down-titration of the study drug dose is required during the dose escalation phase or during 
the treatment phase, the Clinical Center investigator will request a dose reduction on the 
study drug request form.  In this case, a supply of blinded study medication using the next 
lower dose of SPL (or placebo) will be provided.  In the event that a participant is already 
receiving the lowest dose of SPL, placebo will be substituted for the first two down-titrations.  
As only 3 doses of SPL (12.5, 25 and 50 mg/day) are specified, study medication will be 
discontinued in the event that a 3rd down titration of dose is required (see Table 1).  For 
participants already on placebo, a new supply of placebo will be provided in order to maintain 
blinding. Un-blinding to preserve patient safety will be considered via a formal request to the 
DCC.   
If the dose escalation schedule is interrupted (e.g., if a participant is hospitalized at the 
scheduled time of dose escalation and did not take study drug during the hospitalization), 
dose escalation will be delayed until the participant has had access to the current dose of 
study drug for a total of two weeks.  If, due to considerable delays in dose escalation, a 
participant has not reached the final dose assignment by their Week 12 visit, the participant 
will remain at the current dose of study drug for the remainder of the study and the treatment 
phase (i.e., the 30-week post-escalation period) will be shortened accordingly such that the 
total duration of study participation is not increased as a result of the delay. For example, if 
dose escalation is not completed until week 10, the treatment phase will be 26 weeks rather 
than 30 weeks.    
 
Table 1.  Study Drug Down-Titration Scheme 
 
Masked  
Study Drug 
Masked  
Study Drug 
Masked  
Study Drug 
Masked  
Study Drug 
Randomized Assignment 
Placebo 
12.5 mg 
25 mg 
50 mg 
1st Down Titration 
Placebo 
Placebo 
12.5 mg 
25 mg 
2nd Down Titration 
Placebo 
Placebo 
Placebo 
12.5 mg 
3rd Down Titration 
Discontinue 
Discontinue 
Discontinue 
Discontinue 


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5.5. 
Participant Adherence Monitoring 
Study drug containers will be returned to site investigators at the conclusion of each 2-week 
period during dose escalation (weeks 2, 4 and 6), and at the Week 12, 24 and 36 visits. Pill 
counts will be performed to assess participant adherence with prescribed study medication.   
5.6. 
Concomitant Therapy 
Medication use (both oral and intravenous) will be collected at baseline and throughout the 
course of the study.  Digoxin use, dual ACE inhibitor/ARB therapy and non-selective beta 
blocker use are exclusion criteria.  If these medications are initiated during follow-up the treating 
clinician will be contacted by the research team.  For digoxin or dual ACEI/ARB use, if the 
prohibited drug cannot be discontinued, study medication will be withdrawn and participants will 
continue to be followed.  For non-selective beta blocker use, it is anticipated that the treating 
clinician will be comfortable substituting a selective beta blocker but if not, study drug will be 
discontinued and the participant will continue to be followed.    
5.7. 
Packaging 
Study drug will be distributed in patient-specific containers with 17 capsules for every 2-week 
period during the dose escalation phase, 49 capsules for the weeks 6-12, and 91 capsules for 
weeks 12-24 and weeks 24-36.  The extra capsules allow for continued dosing in the event of a 
short delay in dispensing the subsequent study drug supply.  Labeling will include patient name, 
patient ID, protocol number, study-center, expiration date, and prescribing physician (study 
investigator).  
5.8. 
Blinding of Study Drug 
Generic SPL will be purchased, and matching placebos will be prepared by the University of 
Pennsylvania IDS.  The IDS will send study drug to the Clinical Center research pharmacies 
and the identity SPL and matched placebo will be concealed from both investigators and 
participants. Only the IDS and the database programmer will be unblinded.  See Section 8.5 for 
information on unblinding procedures, if needed. 
5.9. 
Receiving, Storing, Dispensing and Returning Study Drug 
5.9.1. 
Receiving Study Drug Supplies 
The University of Pennsylvania IDS will ship study drug to the Clinical Center research 
pharmacies and will maintain inventory at the pharmacies based on study drug utilization.  Each 
Clinical Center research pharmacy will be responsible for maintaining detailed records regarding 
the receipt of study drug.  General Study Product Accountability, Patient Specific Study Product 
Accountability, and if necessary, Shipment Tracking Accountability Logs will be maintained by 
the site pharmacist to document study drug use.  Documentation includes study product receipt, 
storage, dispensing, and final disposition.  Study product will be inventoried at least once per 
month within 30 days of the count for the previous month. 


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5.9.2. 
Study Drug Storage 
SPL and matched placebo will be stored at <25ºC.  Study supplies will be stored in the central 
IDS pharmacy at the University of Pennsylvania until shipment to the Clinical Center research 
pharmacy.  Study drug will be stored at the Clinical Center’s research pharmacy until distribution 
to the participant.     
5.9.3. 
Dispensing Study Drug 
The Clinical Center pharmacist or trained site designee will dispense study drug to the 
participant and complete a dispensing/accountability log for each participant.  Designated site 
personnel with responsibility for dispensing and reconciling study drug will have appropriate 
training and documentation of this training will be maintained in the site′s regulatory binder. 
5.9.4. 
Return or Destruction of Study Drug 
Study drug containers will be returned by participants at the end of each 2-week, 6-week, or  
12-week period and remaining pills will be counted to assess adherence.  Unused supplies of 
study drug will be destroyed by the Clinical Center research pharmacy once the pill count is 
completed and documented.  In the event that a participant does not return study drug 
containers he/she will be instructed to stop taking any study drug from the non-returned 
container.  
 
6. Study Procedures 
A schedule of study visits and procedures is provided in the Study Procedures Table in  
Section 15.1 (Attachments). 
6.1. 
Pre-screening Activities 
Dialysis unit records and study center medical records will be reviewed by Clinical Center study 
personnel to assess eligibility.  The treating nephrologist for a potentially eligible patient will be 
contacted to further assess eligibility and obtain permission to contact the patient.  Patients 
remaining eligible after these procedures will be approached in person at the dialysis unit to 
confirm eligibility for and interest in participation.  Participants signing IRB-approved 
informational flyers that indicate willingness to be called by study personnel may be  
pre-screened by telephone.   
6.2. 
Screening Visit (Day ‒30 to Day 0) 
Potential participants expressing interest in enrolling in the study will be scheduled for a 
Screening visit.  This visit may take place at the local dialysis unit or at the Clinical Center and 
may take place over more than 1 visit.  Screening activities must be completed within 30 days 
prior to the baseline visit.   
Informed consent will be obtained and documented before any study procedures are performed. 
Demographic data (age, sex, race), medical history (hypertension, coronary artery disease, 
coronary revascularization, diabetes, hypercholesterolemia, cerebral or peripheral vascular 
disease, peptic ulcer disease, cancer, smoking, arrhythmia, cause of ESRD, dialysis vintage, 


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prior transplant), dialysis unit labs (chemistries, intact parathyroid hormone, complete blood 
count), and dialysis prescription will be collected during Screening.  Blood will be drawn for 
serum pregnancy testing in women of childbearing potential. Participants will perform an inter-
dialytic urine collection prior to or within seven days following the baseline visit, for assessment 
of residual renal function.  The urine collection will begin immediately after dialysis and continue 
until the start of the next dialysis session, and will be performed during one of the 44-hour 
(approximately) inter-dialytic periods rather than during the 68-hour (approximately) inter-dialytic 
period.   
Potential participants will be excluded if there is any serum potassium value of ≥6.5 mEq/L 
within 3 months prior to the Baseline/Randomization visit or if there is any serum potassium 
value ≥6 mEq/L within 2 weeks prior to the Baseline/Randomization visit.  It is required that 
there be at least one serum potassium value obtained within 2 weeks prior to Baseline.  The 
potassium measurement can be obtained either through routine clinical testing or as a research 
test.  Participants who do not meet eligibility can be rescreened one additional time.     
If the participant has agreed to participate in the heart rhythm monitoring sub-study, the first 
monitoring will be performed between the screening and baseline/randomization visits.  The 
participant will wear the Medtronic SEEQ heart monitor for 7 consecutive days.  Participants will 
receive the monitor kit from the research team and will return the kit after the monitoring period. 
The heart rhythm data will be transmitted in batches to the DCC and will not be analyzed until a 
participant has completed participation in the study.  Reports will not be generated for clinical 
use by the investigators, treating physicians, or participants.  Participants will be informed of this 
at the time of enrollment and will be instructed to report to the research team or their treating 
physician any concerning symptoms they have while wearing the heart rhythm monitor.  The 
same approach will be used for heart rhythm monitoring that takes place at 6 weeks and 32-36 
weeks. 
6.3. 
Baseline/Randomization Visit (Day 0) 
The Baseline/Randomization visit will take place on a non-dialysis day during the short 
(approximately 44-hour) inter-dialytic interval.  At this visit, medication use, vital signs, a brief 
physical examination and adverse events will be recorded, and eligibility will be confirmed. Once 
eligibility has been confirmed, randomization to treatment group will be performed through the 
centralized Data Management System.    
Serum and plasma will be collected, aliquoted, and shipped for batched measurement of 
cardiac and inflammatory markers and for long-term storage.  Whole blood will be collected for 
DNA extraction.  Blood will also be drawn for local measurement of chemistries and complete 
blood count.  If blood cannot be collected on the day of the Baseline/Randomization visit (Day 
0), it should be collected the following day prior to the dialysis session and before the initiation 
of study drug.  If blood for batched analyses, long-term storage, and DNA extraction cannot be 
obtained on the day of randomization or the following day, it is acceptable to obtain the blood 
within the 10 days prior to the Baseline/Randomization visit, and, if on a dialysis day, prior to 
initiation of the dialysis session.  However, the blood for local measurement of chemistries and 


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complete blood count will be obtained on the day of or the day after the Baseline/Randomization 
visit rather than within 10 days prior.   
Tissue Doppler Index echocardiography (TDI echo) will be performed on the day of the 
Baseline/Randomization visit.  If the TDI echo cannot be performed at that visit (Day 0), it 
should be completed as soon as possible thereafter and within 7 days after the 
Baseline/Randomization visit.  The echo must be performed on a non-dialysis day during the 
short (approximately 44 hour) inter-dialytic interval.  A subset of participants will have positron 
emission tomography (PET scan) (after exclusion of pregnancy). 
A 2-week supply of study drug will be dispensed and the participant will be instructed to start the 
study drug the following day, after dialysis. 
6.4. 
Week 1, Week 2, Week 3, Week 4, Week 5, and Week 6 Visits (window for 
each: -4 to +3 days) 
Blood will be obtained for measurement of serum potassium at 3-5 days and 2 weeks after the 
initiation of each new study drug kit during the dose escalation phase.  Participants will be 
interviewed weekly in person or by telephone for the occurrence of serious adverse events and 
adverse events of interest.  Adverse events of interest include hypotension, gastrointestinal 
symptoms, gynecomastia/breast tenderness, hyperkalemia and rash (see Section 8.3.1).  
Dialysis unit records will be reviewed for inter-current laboratory values, the occurrence of 
hypotension, and changes to the dialysis prescription.  The dose of study drug may be reduced 
if a participant experiences dose-limiting adverse events, as outlined in Section 6.8 and 6.9.   
A new supply of study drug will be dispensed and used pill containers returned at the week 2, 
week 4, and week 6 visits as described in sections 5.9.3 and 5.9.4.  Pill counts will be 
performed to assess participant adherence with study medication, and unused study drug will 
be destroyed by the Clinical Center research pharmacies once the pill count has been 
documented.   
At the end of the dose escalation phase, participants in the heart rhythm monitoring sub-study 
will undergo heart rhythm monitoring using the Medtronic SEEQ device.  The participant will 
wear the Medtronic SEEQ heart monitor for 7 consecutive days.  Participants will receive the 
monitor kit from the research team and will return the kit after the monitoring period. 
6.5. 
Week 8 (-4 to +3 days), Week 12, Week 16, Week 20, Week 24, Week 28, and 
Week 32 Visits (-7 to +7 days for all except Week 8) 
Participants will be contacted at weeks 8, 12, 16, 20, 24, 28 and 32 either in person or by 
telephone to review the occurrence of serious adverse events and adverse events of interest as 
described in Section 6.4.  Dialysis unit records will be reviewed for inter-current laboratory 
values, the occurrence of hypotension, and changes to the dialysis prescription.  If a serum 
potassium value is not available in the participant’s dialysis unit record, corresponding to the 
date of the monthly study visit (plus window), blood will be obtained from the participant for 
measurement of serum potassium.  The dose of study drug will be reduced for participants 
experiencing dose-limiting adverse events as outlined in Sections 6.8 and 6.9.   


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
New study drug will be dispensed and used pill containers returned at the week 12 and week 24 
visits as described in Sections 5.9.3 and 5.9.4.  Pill counts will be performed to assess 
participant adherence with study medication, and unused study drug will be destroyed once the 
pill count has been documented.   
Participants in the heart rhythm monitoring sub-study will undergo heart rhythm monitoring using 
the Medtronic SEEQ device for a continuous 7 day period between Weeks 32 and 36.  
Participants will receive the monitor kit from the research team and will return the kit after the 
monitoring period. 
6.6. 
Week 36 Visit (End of Treatment) (-7 to +7 days) 
At the Week 36 visit, participants will be interviewed in person to review the occurrence of 
adverse events as described in Section 6.4.  Dialysis unit records will be reviewed for  
inter-current laboratory values, the occurrence of hypotension, and changes to the dialysis 
prescription.  Pill containers will be returned and unused pills counted and destroyed.  Serum 
and plasma will be collected, aliquoted, and shipped for batched measurement of cardiac and 
inflammatory markers and for long-term storage.  Blood will also be drawn for local 
measurement of chemistries, complete blood count and, for women of childbearing potential, 
serum pregnancy testing.  If the blood collection is performed on a dialysis day, the collection 
should take place prior to the dialysis session.  End-of- study TDI echo will be performed and a 
subset of participants will have a PET scan performed (following exclusion of pregnancy).   
6.6.1. 
Early Withdrawal Visit 
If a patient withdraws from the trial before the Week 36 milestone or if it becomes known that a 
participant will not be available for an in-person visit at Week 36 (e.g., due to relocation), an 
Early Withdrawal visit will be scheduled to conduct the final comprehensive assessments that 
otherwise would be performed at Week 36.  For participants in the heart rhythm monitoring sub-
study, the assessments will include heart rhythm monitoring using the Medtronic SEEQ device 
for 7 continuous days at the time of early withdrawal, if possible.  Patients who stop taking study 
medication are not considered early withdrawals and will be asked to continue to provide follow-
up data on the study schedule and to participate in the final comprehensive assessment at 
Week 36.  
6.7. 
Week 40 Visit (-7 to +7 days) 
At the Week 40 visit (4 weeks after end of treatment), patients will be interviewed in person or 
by telephone to review the occurrence of adverse events as described in Section 6.4.  Dialysis 
unit records will be reviewed for inter-current laboratory values, the occurrence of hypotension, 
and changes to the dialysis prescription. 
6.8. 
Hypotension Management 
In the event of recurrent intra-dialytic hypotension or serious hypotension not attributable to 
acute events (see Section 3.2.2 for definitions of intra-dialytic hypotension and serious 
hypotension), study investigators will review the participant’s non-study anti-hypertensive 
medications, dry weight, and volume status.  The participant’s clinician will be contacted to 


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consider the following interventions listed in the preferred order of implementation: 
1) Decrease non-study anti-hypertensive medication(s)  
2) Increase dry weight if there is no evidence of peripheral or pulmonary edema  
3) Reduce ultrafiltration rate by increasing dialysis session duration 
4) Reduce dose of study drug if: 
a. Peripheral or pulmonary edema is present  
 
 
AND 
b. There are no other anti-hypertensive medications prescribed OR other  
anti-hypertensive medications should not be discontinued (e.g., beta blocker 
following myocardial infarction) 
5) Discontinue study medication at the 3rd dose reduction 
Treating clinicians will be free to manage hypotension according to standard clinical practices 
and are not obligated to follow the study guidelines with respect to non-study medication, fluid 
removal rate, or dry weight.  In contrast, dose reduction or discontinuation of study drug will be 
directly managed by study staff in accordance with the guideline.   
6.9. 
Hyperkalemia Management 
Serum potassium will be measured at 3-5 days and 2 weeks after study drug initiation or dose 
increase as well as monthly throughout the duration of treatment.  In order to minimize the risks 
of hyperkalemia, all participants will be provided with standardized, routine printed dietary 
information about dietary sources of potassium at the Baseline/Randomization visit.  Treating 
clinicians will continue to manage the dialysate potassium concentration according to local 
standards.  A hyperkalemia management guideline will be provided to treating clinicians.  Study 
staff will monitor potassium values and contact treating clinicians in the event of hyperkalemia to 
review the management guidelines and ensure that hyperkalemia is being actively managed.  
Treating clinicians will be free to manage hyperkalemia according to local standards.  However, 
study drug dose reductions or discontinuation will be directly managed by study investigators in 
accordance with the Hyperkalemia Management algorithm (see Figure 2).    
As shown in Figure 2, study drug will be discontinued if serum potassium is ≥7.0 mEq/L.  Study 
drug will also be discontinued if a 3rd study drug dose reduction is required.  Study drug dose will 
be reduced if serum potassium is 6.0 – 6.9 mEq/L and either a) remains ≥6.5 mEq/L on repeat 
measurement or b) remains ≥6 mEq/L on repeat measurement despite a dialysate potassium bath 
concentration of ≤2.0 mEq/L.  Reversible causes of hyperkalemia should be considered and 
addressed when serum potassium is ≥6.0 mEq/L even if there are changes to study drug dosing.  
Reversible causes of hyperkalemia include vascular access dysfunction, missed dialysis sessions, 
shortened or technically compromised dialysis sessions, dietary indiscretion and ACEI or ARB 
use.  In general, these reversible causes should be addressed prior to reducing the dialysate 
potassium concentration.  Use of 1.0 mEq/L dialysate potassium is not recommended.  However, 
treating clinicians are not prohibited from using low potassium dialysate solutions in accordance 
with local practices.  Serum potassium will be rechecked within one week when potassium is ≥6.0 
mEq/L.  Results of serum potassium and recommendations for change in dialysis orders will be 
conveyed to treating clinicians and the dialysis unit nursing staff. 


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Figure 2.  Management of Hyperkalemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-dialysis 
K ≥6.0 mEq/L  
Potential Corrective 
Actions 
• Discontinue or reduce ACEI 
or ARB 
• Dietary Counseling 
• Address vascular access 
dysfunction 
• Investigate compliance 
with dialysis regimen 
• *Reduce dialysate 
potassium to 2.0 mEq/L 
 
1. Study team to contact primary 
nephrologist within 24 hours to confirm 
active clinical responses to  hyperkalemia 
2. Repeat measurement of potassium within 
1 week  
**Reduce dose of 
study drug 
Pre-dialysis K ≥7.0 mEq/L 
Pre-dialysis K <7.0 mEq/L 
**Discontinue study drug 
and consider additional 
Potential Corrective Actions: 
• Schedule additional dialysis 
session 
• Resin Therapy 
• Discontinue /reduce ACEI or 
ARB 
• Reduce dialysate potassium 
to 2.0 mEq/L   
• Address vascular access 
dysfunction 
• Investigate compliance with 
prescribed dialysis regimen 
Repeat K ≥6.5  
OR  
Repeat K≥6.0 and K dialysate ≤2.0 mEq/L 
**Discontinue study drug if: 
• K≥7.0 mEq/L  
        OR 
• Study drug dose has already 
been reduced 2 times  
               KEY 
**Required by protocol 
  *Suggested when either:  
a) K ≥6.5 mEq/L or  
b) K ≥6.0 mEq/L following 
dietary intervention 
and/or adjustment in dose 


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6.10. Gynecomastia, Gastrointestinal Symptoms or Rash 
In the event of persistent gynecomastia/breast tenderness, nausea, vomiting, diarrhea, or 
anorexia without alternative cause, the dose of study medication may be reduced.  Study drug 
should be discontinued if there is a rash that is not attributable to another cause. 
 
7. Statistical Plan 
7.1. 
Sample Size Determination 
Sample size considerations were framed using standard study design parameters to ensure 
80% power to detect pre-specified effect sizes utilizing intermediate outcomes.  However, for 
this early phase pilot study, the primary focus is directed at assessing safety and feasibility, with 
no attempt to create critical test result regions for standard hypothesis testing.  
From preliminary studies, we assumed estimated baseline parameters of E′ to be 5.8 ± 1.8 
cm/s.34, 43, 87, 88  Assuming a correlation ≥ 0.2 between pre and post-therapy E′, and a 10% 
dropout rate of study participants by the end of the study, a sample size of 125 (2:3; 50 patients 
for the placebo arm and 25 per SPL dose x 3 active treatment arms) will provide 80% power to 
detect effect size of 0.7SD (1.3 cm/sec) difference in change from baseline to 9 month endpoint 
in E′, equivalent to a 22% average reduction across the 3 active SPL treatment arms.  Short-
term studies with SPL in diabetes were consistent with an effect of this magnitude54.   
For the safety endpoint of hyperkalemia incidence, we assumed a 5% incidence in the placebo 
arm.  With a sample size of 125, derived under the effect size considerations noted previously, 
this design provides 80% power to detect an average incidence of 22% across the 3 SPL dose 
arms.  Moreover, this same sample size also provides 80% power to detect a small difference of 
0.1 mEq/L in time-averaged serum potassium concentration, treated as a continuous variable, 
between placebo and treatment arms.  
7.2. 
Randomization and Stratification 
To ensure balance in treatment assignments within potential confounders, a stratified 
randomization procedure, blocking on four (4) strata formed by the 2 x 2 cross-classification of 
1) dialysis vintage (≥ 1 vs. < 1 year on dialysis) by 2) ACEI or ARB use (yes, no), within Clinical 
Centers will be implemented within a web-based randomization module deployed centrally 
within the DCC.  Within each of these strata, participants will be randomly allocated to the 
placebo and the three SPL dose arms with the ratio of 2:1:1:1.  
The treatment assignment code, corresponding to each treatment identifier number, will be 
known only to the person serving as the DCC Quality Assurance Director and the IDS, until the 
completion of treatment and data collection on all participants.  At the end of a patient’s study 
phase, the participants and the treating physicians will be asked to guess their treatment 
groups, and provide the basis for their judgments for analysis later, to determine whether the 
blinding has been broken.  However, except in the case of emergency unmasking, the treatment 
codes will not be identified until the DSMB has approved unblinding in preparation for the public 
dissemination of results. 


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7.3. 
Intent-to-treat Analysis and Missing Data 
An intent-to-treat analysis, in which all available data on all randomized participants are 
included, will be used for the primary comparison of treatments.  All attempts will be made to 
keep missing data to a minimum, and participants who withdraw from treatment will be 
encouraged to continue on study in order to provide complete follow-up information.  Thus, 
irrespective of withdrawal from treatment, all participants should continue to be followed with all 
scheduled outcome evaluations until the end of the study.  However, it is expected that up to 
10% of the randomized participants may withdraw prior to the final assessment of response at 
36 weeks.  These participants will be included in the denominator for evaluation of the response 
rates defined for the primary endpoint. 
The characteristics at the time of randomization for those participants without complete  
follow-up will be examined; however, there will be limited statistical power to detect any but 
major differences between these participants and those with complete follow-up.  In addition, in 
order to assess the potential biases introduced by differential withdrawal among treatment arms, 
a comparison of withdrawal rates and/or time to withdrawal will be included as an ancillary 
analysis to the primary endpoint comparison. 
Secondary analyses will examine the all-treated, as-treated, and per-protocol populations as 
defined below: 
• 
All-randomized population/intention-to-treat (ITT):  Any participant randomized into the 
study, regardless of whether they received study drug. 
• 
As-treated population:  Any participant randomized into the study regardless of whether 
they received study drug.  As-treated participants will be analyzed according to the dose 
of study drug actually received. 
• 
All-treated population:  Any participant randomized into the study that received at least 
one dose of study drug. 
• 
Per-protocol population:  Any participant who was appropriately randomized, and 
received the protocol-dictated study drug exposure (≥75% of prescribed doses) and 
endpoint assessments through 36 ± 2 weeks.   
Because dose-related efficacy and safety are primary questions of interest in this study, the ITT 
analysis will be supplemented with an analysis of the as-treated population.  Although ITT 
approaches provide the least-biased analysis of treatment efficacy and safety, as-treated 
analyses provide important complementary information on  biological effectiveness of therapy 
(e.g. theoretical efficacy if drug were tolerated by all participants) and on the effects of actual 
doses used that is not captured by ITT analyses in which the unit of analysis is a randomized 
therapy that may not have been used by individual participants89.  For this reason, as-treated 
approaches provide important complementary information to ITT analyses and are typically 
mandated as an important secondary analyses of clinical trials by the FDA89.  Given a treatment 
protocol that allows for dose reduction of study medications, the as-treated analysis will provide 
critical information in this trial for assessing dose-related efficacy and the incidence of adverse 
events such as hyperkalemia.  As-treated analyses will assign treatment dose according to the 
dose used at the time of an adverse event (safety analyses) or according to the mean dose 
received during the trial (efficacy analysis). 


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In general, missing data will not be imputed.  Every effort will be made to use statistical methods 
that are robust to missingness, and the number of participants included with each analysis will 
be given with the results. 
7.4. 
Statistical Methods 
In addition to the analyses described subsequently, descriptive statistics will be used during the 
course of the study as part of data management procedures for monitoring data quality.  A brief 
overview of some of the statistical methods that may be used at the time of analysis, both for 
descriptive purposes and in more comprehensive analysis of the primary research questions, is 
summarized in the following sections.  It is recognized that these methods may be revised and 
additional ones considered as the details of the specific analyses are developed.  
7.4.1. 
Descriptive Analyses and Primary Efficacy and Safety Analyses 
Standard descriptive statistics will be used to summarize baseline characteristics and study 
outcome measures at each follow-up visit, both overall, and within each treatment group.  
Examination of baseline characteristics will include estimates of the distribution of age, race, 
and other demographic characteristics, lab measures and study center.  Summary statistics 
theresuch as means, medians, and ranges will be produced for all measured variables.  
Frequencies will be computed for all categorical and ordinal variables.  Graphical methods 
including stem-and-leaf diagrams and boxplots will be used to examine distributions, identify 
potential influential points, and guide in the choice of transformations, if warranted.  The balance 
of baseline measures across the three treatment groups will be compared using appropriate k-
sample tests, including Kruskal-Wallis tests and Fisher’s exact tests. 
Analysis of Primary Efficacy and Safety Outcomes Mean (± standard deviation) or median 
(interquartile values) of baseline and end of study measurement in the primary endpoint E′ will 
be presented.  Change in E′ velocity at 36 weeks will be assessed and reported quantitatively, 
and descriptive statistics for absolute and % change will be provided.  Mixed effects linear 
regression models with baseline covariate adjustments will be used for assessment of treatment 
effects.  Model assumptions regarding homoscedasticity and normality will be examined using 
standard techniques.   
For the primary safety endpoint, tables with percent incidence and incidence rate (for events 
that can occur more than once during follow-up) will be prepared.  Differences in incidence and 
incidence-rate will be assessed using logistic regression or Poisson regression with factors for 
assigned treatment and the stratification variable.  In particular, for safety endpoints, we will 
investigate the potential change in potassium level in placebo and treatment groups with 
monthly measure of potassium. Mixed effects linear regression models will be used to assess 
the direction and time averaged magnitude of change in potassium, with and without controlling 
for baseline covariates.  The proportion of serious hyperkalemia in treatment and placebo 
groups will be compared with Chi-square test or Fisher’s exact test.  
The primary analysis will examine the intention to treat population.  All analyses will be repeated 
in the as-treated, all-treated and per-protocol populations (see Section 7.3).  Secondary 
endpoint analyses will be presented using analogous techniques.  P<0.05 will be considered 


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significant in all analyses. 
7.4.2. 
Secondary Analyses 
A number of secondary analyses will be conducted to evaluate the secondary efficacy 
outcomes.  Secondary efficacy parameters include cytokine concentration/markers of 
inflammation, circulating markers of fibrosis, aldosterone concentration, heart rate variability 
(sub-study), arrhythmias (sub-study), additional echocardiographic parameters including change 
in resting and hyperemic myocardial blood flows between baseline and 36 weeks and change in 
LVMI between 0 and 36 weeks, and coronary flow reserve (CFR) on myocardial PET (sub-
study). Analysis for these secondary outcomes will be similar to that for the primary outcome. 
Distribution of the secondary parameters will be examined and appropriate transformation will 
be applied. 
7.4.3. 
Interim Analysis 
No interim efficacy analysis is planned. 
 
8. Safety and Adverse Events 
8.1. 
Definitions 
Definitions are per the January 2007 Guidance on Reviewing and Reporting Unanticipated 
Problems Involving Risks to Participants or Others and Adverse Events, Office on Human 
Research Protection (OHRP) Guidance. http://www.hhs.gov/ohrp/policy/advevntguid.html  
8.1.1. 
Adverse Event 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human study 
participant, including any abnormal sign (for example, abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with the participant’s involvement in the 
research, whether or not considered related to the participant’s participation in the research. 
8.1.2. 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that is:  
• 
fatal or results in death 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
results in congenital anomalies or birth defects 
• 
an important medical event* 
*Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. 
 


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8.1.3. 
Unanticipated Problems Involving Risk to Participants or Others  
(See also Section 8.3.4) 
An Unanticipated Problem is any incident, experience, or outcome that meets all of the following 
criteria: 
• 
unexpected (in terms of nature, severity, or frequency) given the research procedures 
that are described in the IRB-approved research protocol and informed consent 
document and the characteristics of the participant population being studied; 
• 
related or possibly related to participation in the research; possibly related means that 
there is a reasonable possibility that the incident, experience or outcome may have been 
caused by the procedures involved in the research, and 
• 
suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) related to the research than 
was previously known or recognized. 
8.1.4. 
Pre-Existing Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
will be recorded as an adverse event if the frequency, intensity, or the character of the condition 
worsens during the study period. 
8.1.5. 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting condition.  At 
the end of the study, any new clinically significant findings/abnormalities that meet the definition 
of an adverse event will also be recorded and documented as an adverse event. 
8.2. 
Adverse Event Tracking Period 
The study period during which adverse events must be tracked and reported is normally defined 
as the period from the initiation of study procedures to the end of the study treatment follow-up.  
For this study, the study treatment follow-up is 4 weeks following the last dose of study drug. 
8.2.1. 
Post-study Adverse Event 
All unresolved adverse events will be followed by the investigator until the events are resolved, 
the participant is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the investigator will instruct each participant to report any subsequent event(s) 
that the participant, or the participant’s personal physician, believes might reasonably be related 
to participation in this study.  The investigator will notify the DCC of any death or adverse event 
occurring at any time after a participant has discontinued or terminated study participation that 
may reasonably be related to the study.  The sponsor (NIDDK) will also be notified if the 
investigator should become aware of the development of cancer or of a congenital anomaly in a 
subsequently conceived offspring of a participant that has participated in this study.  
8.3. 
Recording of Adverse Events 
At each contact with the participant, the investigator or site designee will seek information on 
adverse events by specific questioning and, as appropriate, by examination.  Information on 
adverse events will be recorded in the source document, and also on the adverse event log 


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case report form (CRF).  All signs, symptoms, and abnormal diagnostic procedure results 
relating to the same event will be recorded under one diagnosis name. 
8.3.1. 
Adverse Events of Interest 
The following adverse events are anticipated in patients treated with spironolactone and will be 
recorded on the appropriate Adverse Event of Interest CRF. 
• 
Hyperkalemia 
• 
Hypotension 
• 
Gynecomastia 
• 
Breast tenderness 
• 
Gastrointestinal symptoms including: diarrhea, constipation, and nausea 
• 
Rash 
 
If the event meets the definition of serious as defined in Section 8.1.2, it will be recorded on an 
SAE form in addition to the appropriate adverse event of special interest CRF.   
Participants will be contacted weekly during dose escalation and monthly while on treatment to 
assess for the occurrence of Adverse Events of Interest.  The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study treatment 
or participation is not the cause.   
8.3.2. 
Trial-Defined Events 
The hemodialysis population undergoes frequent laboratory testing and has a high rate of  
peri-dialytic hypotensive events requiring changes in the dialysis prescription, adjustment of dry 
weight, or change in dialysis-related medications.  Due to the unique nature of this population, 
the following events are considered routine aspects of chronic dialysis therapy and will not be 
recorded as an adverse event except as noted: 
• 
Anemia – will be reported when hemoglobin  is <8.0 mg/dL 
• 
Hyperkalemia – will be reported when potassium level ≥6.0 mEq/L   
• 
Hyperphosphatemia – will be reported when phosphorous >9.5 mg/dL 
• 
Hypocalcemia – will be reported when serum calcium <7.0 mg/dL 
• 
Hypercalcemia – will be reported when serum calcium >11.0 mg/dL 
• 
Hyperparathyroidism – will be reported when PTH >1000 pg/mL 
• 
Hypotension – will be reported when it meets the criteria for recurrent or symptomatic 
intra- or inter-dialytic hypotension as defined in Section 3.2.2.  
 
8.3.3. 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if:  
• The laboratory abnormality is not otherwise refuted by a repeat test that was performed 
specifically to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 


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• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
• The abnormality meets the criteria in Section 8.3.2. 
8.3.4. 
Anticipated Adverse Events 
The following adverse events are anticipated in the hemodialysis population and will not be 
considered to be Unanticipated Problems.  Note that the designation as “Anticipated” does not 
imply that the event is not an SAE but relates to the regulatory definition of Unanticipated 
Problems as provided in Section 8.1.3. 
• 
Death 
• 
Coronary Ischemia including: 
o Unstable angina 
o Acute MI 
o Coronary revascularization 
• 
Heart failure hospitalization or exacerbation 
• 
Cardiac arrest 
• 
Cardiac arrhythmia (ventricular or atrial) 
• 
Peripheral vascular revascularization 
• 
Amputation 
• 
Vascular Access Events Including: 
o Catheter exchange, removal or declotting 
o Arteriovenous graft or fistula complications 
 
Clotting 
 
Stenosis 
 
Revascularization 
 
Infection 
• 
Infections Including: 
o Pneumonia 
o Vascular access infection 
o Bacteremia 
o Clostridium difficile infection 
 
8.4. 
Reporting of Serious Adverse Events and Unanticipated Problems 
Study sites are required to report SAEs and Unanticipated Problems to the DCC within 24 hours 
of first knowledge of the event.  To report such events, an SAE form or an Unanticipated 
Problem form will be completed by the investigator and faxed to the DCC.  The DCC will 
facilitate the timely medical review and reporting of the event to the NIDDK, the DSMB, and the 
study sites in accordance with DSMB-approved study policies and IRB requirements. 
The investigator will keep a copy of the SAE form / Unanticipated Problem form on file at the 
study site.  At the time of the initial report, the following information should be provided: 


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 
Study identifier 
 
Study Center 
 
Participant number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as 
serious 
 
Investigator assessment of the association 
between the event and study treatment 
 
Within the following 7 days, the investigator will provide further information on the SAE or the 
unanticipated problem in the form of a written narrative.  This should include a copy of the 
completed SAE form or Unanticipated Problem Form, and any other diagnostic information that 
will assist the understanding of the event.  Significant new information on ongoing serious 
adverse events should be provided promptly to the DCC. 
SAEs that are still ongoing at the end of the study period must be followed up to determine the 
final outcome.  Any SAE that occurs after the study period and is considered to be possibly 
related to the study treatment or study participation should be recorded and reported 
immediately. 
If a patient becomes pregnant while participating in the trial it will be reported as an adverse 
event and will trigger the collection of additional information about the pregnancy on the 
Pregnancy Report Form.  Pregnancy outcomes will be collected, including the outcome of the 
infant and if the pregnancy was terminated.  Study Staff should complete the Pregnancy Report 
form when they learn about a pregnancy, and follow-up with the participant and update the form 
when additional information is available about the baby.  The Pregnancy Report form will be 
submitted to the University of Pennsylvania IRB, and to the local site IRB as required. 
8.4.1. 
Investigator Reporting to the IRB 
Site investigators will report SAEs and Unanticipated problems to their IRB in accordance with 
the reporting requirements of the local IRB or with the Office of Human Research Protections 
(OHRP) guidelines, whichever is sooner.  OHRP recommends that: 
1) Unanticipated problems that are serious adverse events should be reported to the IRB 
within 1 week of the investigator becoming aware of the event; and   
2) Any other unanticipated problem should be reported to the IRB within 2 weeks of the 
investigator becoming aware of the problem.  
Reporting Process 
Unanticipated problems posing risks to participants or others as noted above will be reported 
using the appropriate IRB-designated form or as a written report of the event (including a 
description of the event with information regarding its fulfillment of the above criteria, follow-
up/resolution and need for revision to consent form and/or other study documentation). 
Copies of each report and documentation of IRB notification and receipt will be maintained in 
the Clinical Center Investigator’s study file. 


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Other Reportable events: 
• Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 
• Any adverse event that would cause the sponsor to modify the investigators brochure, 
protocol or informed consent form, or would prompt other action by the IRB to assure 
protection of human participants. 
• Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency.  
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
• Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the participant to 
remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the 
complaint cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB 
approved protocol) that in the opinion of the investigator placed one or more participants 
at increased risk, or affects the rights or welfare of participants. 
8.4.2. 
DCC Notification to Participating Investigators 
The DCC will notify all Clinical Center principal investigators, in a written safety report, of 
any adverse event that meets the criteria for an unanticipated problem as described in 
Section 8.1.3.   
8.5. 
Unblinding Procedures 
Unblinding of study drug may be considered when necessary for safety purposes.  Examples of 
these circumstances may include, but are not limited to, serious allergic reactions such as 
Stevens-Johnson syndrome, or overdose of study drug.  In the event that un-blinding of study 
drug is viewed by the Clinical Center Principal Investigator, or an appropriate designee, as 
necessary for safety purposes, the investigator will contact the DCC.  The circumstances of the 
event and rationale for unblinding will be described to the DCC Principal Investigator, or an 
appropriate designee, who may authorize unblinding if deemed necessary to preserve 
participant safety.  Following this, an SAE report will be submitted within 24 hours to the DCC 
and to the local IRB as described in Sections 8.4 and 8.4.1.  The circumstances and need for 
unblinding should also be appropriately documented in the source documents. 


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
8.6. 
Stopping Rules  
Given that the primary focus of this pilot trial is on safety, tolerability and feasibility, there are no 
pre-specified stopping rules for efficacy outcomes.  However, the Consortium investigators will 
monitor all safety endpoints for evidence of differential safety effects, and routinely update the 
NIDDK and the DSMB.  The DSMB may recommend study termination on the basis of 
unacceptable increases in adverse events or external data. 
8.7. 
Medical Monitoring 
Each Clinical Center Principal Investigator will be responsible for overseeing the safety of the 
study at his/her site.  This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and implementation of a 
site data and safety-monitoring plan (See Section 9).  Medical monitoring will include a regular 
assessment of the number and type of serious adverse events. 
8.7.1. 
Independent Data and Safety Monitoring Board (DSMB) 
The information provided in this section of the protocol is a general description of the DSMB 
responsibilities and processes.  The DSMB charter for the Hemodialysis Novel Therapies 
Consortium is provided as an attachment in Section 15.2.   
A DSMB has been established by the NIDDK and provides input to the Institute.  The DSMB is 
comprised of individuals with expertise in clinical trials design and methodology, biostatistics, 
clinical nephrology and other relevant medical specialties.  The DSMB members are not 
affiliated with the study and are appointed by the NIDDK.  DSMB members will be free of 
conflicts of interest that could be affected by the outcomes of the study.  During the study, 
DSMB members who develop real or perceived conflicts of interest that impact objectivity will 
disclose them to NIDDK project officers, who will arrange for replacement of the member, if 
indicated.  
The DSMB will review the protocol prior to initiation of the study. After initial approval during the 
course of the study, the primary responsibilities of the DSMB will be to: 
• Review safety data and provide input to protect the safety of the study participants; 
• Provide input on major changes to the research protocol and plans for data and safety 
monitoring;  
• Provide input on the progress of the study, including periodic assessments of data quality 
and timeliness, participant recruitment, accrual and retention, participant risk versus 
benefit, performance of the study sites, and other factors that may affect study outcomes;  
• Consider factors external to the study when relevant information becomes available, such 
as scientific or therapeutic developments that may have an impact on the need for 
continuation of the study, safety of the participants or the ethics of the study;  
• Provide input on modification of the study protocol or possible early termination of the 
study because of attainment of study objectives, safety concerns, or inadequate 
performance (such as enrollment and retention problems). 
 
 


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Data management 
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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
9. Data management 
An internet-based registration system designed by the DCC will be used for all of the pilot and 
feasibility studies of the Hemodialysis Novel Therapies Consortium in order to promote 
uniformity across studies. The central registration system will include a randomization module 
for each study that will confirm eligibility.  Central participant registration will also allow the DCC 
to generate recruitment reports across concurrent studies. 
An Oracle Clinical data management system designed by the DCC will be used for the 
collection, storage and management of data.  Site personnel will enter data directly using Oracle 
Clinical Remote Data Capture.  Electronic case report forms (eCRFs) will incorporate range and 
logical edit checks, both within and across forms.  Data entry will be followed daily with manual 
and programmed checks and edits for errors and omissions.  
9.1. 
Data Quality 
The DCC will collaborate with the Clinical Center investigators to establish parameters for 
primary and secondary outcomes, safety, and descriptive values. The data management team 
will use a data validation plan, rule set specifications, and programming logic to implement data 
validation rules. The DCC staff will interact with Clinical Center study staff to verify queried data 
and track all queries to resolution.   
9.1.1. 
Quality Control Activities 
The Quality Control Committee and the DCC will develop a quality assurance and control plan 
that ensures that study data are as precise and reliable as possible.  
Manual of Procedures (MOP) – The MOP will describe the sequence of study conduct and 
provide detailed instruction for the performance of screening, baseline, enrollment, treatment 
allocation and follow-up procedures.  The MOP will provide instruction in case report form 
completion, use of the electronic data management system, and collection, documentation and 
transfer of specimens and tests to laboratories and reading centers.  
Training and certification procedures – The DCC will conduct a training session before the study 
starts to train and certify personnel in the performance of study procedures.  
Site visits – Site visits will be conducted as outlined in the Study Monitoring Plan.  Findings from 
site visits will be used to resolve problems and develop corrective action plans.  
External data sources – The DCC will monitor quality control of data received from study 
laboratories and reading centers.   
Internal quality control procedures – A data validation plan, rule set specifications, and 
programming logic to implement data validation rules will be implemented.  
9.1.2. 
Routine reports 
The DCC will develop a set of standard enrollment, tracking, quality review, and safety 
monitoring reports.  Adverse event reports, DSMB reports and reports for statistical analysis will 
be developed and produced on an appropriate schedule.  


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
9.2. 
Data Security 
The data management system will be designed to prevent unauthorized access to trial data and 
to prevent data loss due to equipment failure or catastrophic events. The procedures to do so 
encompass user account management, user privilege assignment, data loss prevention 
(database backup), and DMS change management.  User access will be controlled by 
assignment of confidential usernames and passwords. 
Study data collected at the Clinical Centers will be entered into Oracle Clinical.  This data 
management system uses a secure connection between the client browser at the Clinical 
Center and the web server at the DCC.  Data transmitted over this connection is authenticated 
by the use of digital certificates and is encrypted as it travels the Internet to the DCC. 
Where applicable, electronic files containing data from hand held devices, central laboratories, 
or central reading centers will be transferred to the DCC using secure FTP technology.  The 
DCC team will maintain a secure FTP server.  The files transmitted using this method will be 
encrypted during the exchange. 
The DCC project team will collaborate with the IDS and the biostatistics team to protect the 
blinding of treatment assignments and electronic access to information that could indirectly or 
directly lead to unblinding treatment assignment or codes.  Internal access to such information 
is stored in password-protected files.  Documentation is stored in the locked files of the IDS at 
the University of Pennsylvania.  Within the DCC this information is locked in files to which only 
department managers have access. 
9.2.1. 
Confidentiality 
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed participant authorization informing the participant of the following:  
• What protected health information (PHI) will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI.  
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of participant 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the participant is 
alive) at the end of their scheduled study period. 
9.2.2. 
Data Linkage 
Participants will be asked to consent to provide their Social Security Number (SSN) to facilitate 
access to long term clinical outcomes after study participation has ended, in national databases 
at the Social Security Administration, the Center for Medicare and Medicaid Services (CMS) and 
the United States Renal Data Systems (USRDS).  Providing the SSN and access to national 
databases is optional, and is not required for participation in the study. 


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
9.3. 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data 
records include: dialysis unit records, hospital records, clinical and office charts, laboratory 
reports, memoranda, participant 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, participant files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
9.3.1. 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF will be recorded.  All missing data will be explained.  “N/D” will be 
used to indicate on the CRF that a procedure was not done or a question was not asked rather 
than leaving a space blank.  “N/A” will be used to indicate that an item is not applicable to the 
individual case.  All entries will be printed legibly in black ink.  If any entry error has been made, 
to correct such an error, a single straight line will be drawn through the incorrect entry and the 
correct data will be entered above it.  All such changes will be initialed and dated.  Erasing or 
white-out will not be used for errors.  For clarification of illegible or uncertain entries, the 
clarification will be printed above the item, and the clarification will be initialed and dated. 
9.3.2. 
Maintaining Anonymity of Submitted Medical Records 
Clinical site personnel will de-identify all medical records before sending them to the DCC by 
obliterating any Protected Health Information (PHI).  Upon receipt, DCC personnel will review 
the records to ensure that no PHI is visible. 
If a SSN is provided by the participant during the informed consent process, it will be maintained 
in a restricted-access section of the data management system, and only DCC personnel who 
are directly involved in the collection of long term clinical outcomes data from national 
databases will be granted access.  Once the necessary outcome data are obtained, the data will 
be linked to the participant’s study ID number.  The SSN will be excluded from any shared data. 
9.3.3. 
Data and Biosample Sharing 
Research results will be made available to the scientific community and public in a timely 
manner.  The primary method by which data will be shared with the scientific community will be 
through peer-reviewed publications and presentation at scientific and professional society 
meetings.  In addition, data and results will be submitted to the NIH in the annual progress 
reports required under the terms and conditions of the funding award.  This study will also be 
registered with clinicaltrials.gov prior to initiation. 
Data from the study will be submitted to the NIDDK Data Repository in accordance with the 
NIDDK Data Sharing policy.  The policy requires that data sets be transferred no later than 2 
years after study completion or 1 year after publication of the primary results, whichever comes 
first.  Through the repository, the study data will be made available to external investigators.   


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
A portion of the serum and plasma collected at Baseline and Week 36, as well as extracted 
DNA, will be submitted to the NIDDK Biosample Repository for future investigations.  The NIH 
Data and Biosample Repositories will meet all NIH standards, and will provide data and/or 
specimens to researchers in accordance with IRB, HIPAA, and NIH procedures that protect the 
confidentiality of participants. 
9.3.4. 
Records Retention 
The site investigators will retain study documents, including participant files and Regulatory 
Binders, for at least 5 years after the close of the study, or longer depending on site institutional 
requirements. 
 
10. Study Compliance 
10.1. Protocol Deviations  and Exceptions 
A protocol deviation is any change or alteration to the IRB-approved protocol without 
prospective IRB approval.   A protocol exception is a one time, intentional change or alteration 
to the IRB-approved protocol that is approved by the IRB prior to implementation.  
Major Deviation:   Any change/alteration that has or has the potential to: 1) adversely affect the 
rights, welfare or safety of the subjects, 2) adversely affect the integrity of the research data, or 
3) affect the subject’s willingness to participate.  
Examples of Major Deviations  
• 
Failure to obtain informed consent ( i.e., no documentation of informed consent or 
informed consent was obtained after initiation of study procedures)  
• 
Informed consent obtained by someone not approved to obtain consent for the 
protocol  
• 
Use of invalid consent form (i.e., consent form without IRB approval stamp, or 
outdated/expired consent form)  
• 
Enrollment of a participant who is ineligible for the study  
• 
Performing a research procedure not in the approved protocol  
• 
Failure to report serious adverse event to sponsor/DCC  
• 
Study medication dispensing or dosing error  
• 
Failure to follow the approved study protocol that affects participant safety or data 
integrity (e.g., failure to properly schedule study visits or failure to perform laboratory 
tests)  
• 
Continuing research activities after IRB approval has expired  
• 
Use of recruitment procedures that have not been approved by the IRB  
• 
Participant giving study medication to a third-party  
• 
Enrolling significantly more participants than approved in the IRB protocol  
 


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
Minor Deviation:   Any change/alteration that has not or does not have the potential to:  
1) adversely affect the rights, welfare or safety of the subjects, 2) adversely affect the integrity of 
the research data, or 3) affect the subject’s willingness to participate. 
Examples of Minor Deviations 
• 
Delay in a study visit beyond the protocol-defined window  
• 
Failure to obtain a blood sample for laboratory measurements that are not related to 
safety monitoring 
10.2. Study Monitoring Plan 
A monitoring plan that includes formal visits to the Clinical Centers by members of the 
Consortium (DCC, Clinical Center investigators and study coordinators, and NIDDK 
representatives) will be developed by the Consortium Executive Committee.  Clinical Center 
investigators will allocate adequate time for such monitoring activities.  The Principal 
Investigator will also ensure that the monitor and other compliance or quality assurance 
reviewers are given access to study-related documents and study related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.), and have adequate space to conduct the monitoring visit. 
10.3. Auditing and Inspecting 
The DCC and Clinical Center investigators will permit study-related monitoring, audits, and 
inspections by the EC/IRB, the NIH, government regulatory bodies, and University compliance 
and quality assurance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The DCC and Clinical Center 
investigators will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
11. Ethical Considerations 
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study.  The decision of the EC/IRB concerning the 
conduct of the study will be made in writing to the Clinical Center investigator and a copy of this 
decision will be provided to the sponsor before commencement of the study at the site. 
All study participants will be provided a consent form describing the study and providing 
sufficient information to make an informed decision about participating in the study.  The 
consent form will be submitted with the protocol for review and approval by the EC/IRB.  The 


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Publication Plan 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
formal consent of a participant, using the EC/IRB-approved consent form, must be obtained 
before that participant undergoes any study procedure.  The consent form must be signed by 
the participant or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent.  
 
12. Study Finances 
12.1. Funding Source 
This study is financed through grants from the National Institute of Diabetes and Digestive and 
Kidney Diseases of the U.S. National Institutes of Health. 
12.2. Conflict of Interest 
All investigators will follow the conflict of interest policies of the National Institutes of Health as 
well as their home institution.  Any investigator who has a potential conflict of interest with this 
study (patent ownership, royalties, or financial gain greater than the minimum allowable by their 
institution, etc.) must have the conflict reviewed by a properly constituted Conflict of Interest 
Committee with a Committee-sanctioned conflict management plan that has been reviewed and 
approved by the study sponsor prior to participation in this study. 
12.3. Participant Stipends or Payments 
Participants may be compensated for parking and time and effort required to participate in 
the study.  Compensation approaches will be determined by the Clinical Centers and approved 
the local EC/IRB. 
 
13. Publication Plan 
Neither the complete, nor any part of, the results of the study carried out under this protocol, nor 
any of the information provided by the Hemodialysis Novel Therapies Consortium for the 
purposes of performing the study, will be published or passed on to any third party without the 
consent of the Consortium Executive Committee.  Any investigator involved with this study is 
obligated to provide the Data Coordinating Center with complete test results and all data derived 
from the study. 


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References 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
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Acta Physiol (Oxf). 2008;194:45-55 
38. Martinez DV, Rocha R, Matsumura M, Oestreicher E, Ochoa-Maya M, Roubsanthisuk W, 
Williams GH, Adler GK. Cardiac damage prevention by eplerenone: Comparison with low 
sodium diet or potassium loading. Hypertension. 2002;39:614-618 
39. Oestreicher EM, Martinez-Vasquez D, Stone JR, Jonasson L, Roubsanthisuk W, Mukasa 
K, Adler GK. Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of 
early angiotensin ii/ng-nitro-l-arginine methyl ester-induced myocardial injury. Circulation. 
2003;108:2517-2523 
40. Simko F, Matuskova J, Luptak I, Pincikova T, Krajcirovicova K, Stvrtina S, Pomsar J, 
Pelouch V, Paulis L, Pechanova O. Spironolactone differently influences remodeling of the 
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41. Rocha R, Stier CT, Jr., Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler GK. 
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42. Tian J, Shidyak A, Periyasamy SM, Haller S, Taleb M, El-Okdi N, Elkareh J, Gupta S, 
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Spironolactone attenuates experimental uremic cardiomyopathy by antagonizing 
marinobufagenin. Hypertension. 2009;54:1313-1320 
43. Edwards NC, Ferro CJ, Kirkwood H, Chue CD, Young AA, Stewart PM, Steeds RP, 
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46. Steigerwalt S, Zafar A, Mesiha N, Gardin J, Provenzano R. Role of aldosterone in left 
ventricular hypertrophy among african-american patients with end-stage renal disease on 
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47. Ikeda H, Tsuruya K, Toyonaga J, Masutani K, Hayashida H, Hirakata H, Iida M. 
Spironolactone suppresses inflammation and prevents l-name-induced renal injury in rats. 
Kidney Int. 2009;75:147-155 
48. Kobayashi N, Fukushima H, Takeshima H, Koguchi W, Mamada Y, Hirata H, Machida Y, 
Suzuki N, Yokotsuka F, Tabei K, Kobayashi E, Fukuda N, Ishimitsu T. Effect of eplerenone 
on endothelial progenitor cells and oxidative stress in ischemic hindlimb. Am J Hypertens. 
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49. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, 
Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left 
ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321 
50. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The 
effect of spironolactone on morbidity and mortality in patients with severe heart failure. 
Randomized aldactone evaluation study investigators. N Engl J Med. 1999;341:709-717 
51. Iraqi W, Rossignol P, Angioi M, Fay R, Nuee J, Ketelslegers JM, Vincent J, Pitt B, Zannad 
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complicated by left ventricular dysfunction and heart failure: Insights from the eplerenone 
post-acute myocardial infarction heart failure efficacy and survival study (ephesus) study. 
Circulation. 2009;119:2471-2479 
52. Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix 
turnover may contribute to survival benefit of spironolactone therapy in patients with 
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Rales investigators. Circulation. 2000;102:2700-2706 
53. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, Yakushigawa T, 
Sugiyama H, Shimada Y, Nojima Y, Shio N. Spironolactone reduces cardio- and 
cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 
2014;63:528-536 
54. Joffe HV, Kwong RY, Gerhard-Herman MD, Rice C, Feldman K, Adler GK. Beneficial 
effects of eplerenone versus hydrochlorothiazide on coronary circulatory function in 
patients with diabetes mellitus. J Clin Endocrinol Metab. 2007;92:2552-2558 
55. Gross E, Rothstein M, Dombek S, Juknis HI. Effect of spironolactone on blood pressure 
and the renin-angiotensin-aldosterone system in oligo-anuric hemodialysis patients. Am J 
Kidney Dis. 2005;46:94-101 
56. Hussain S, Dreyfus DE, Marcus RJ, Biederman RW, McGill RL. Is spironolactone safe for 
dialysis patients? Nephrol Dial Transplant. 2003;18:2364-2368 
57. Saudan P, Mach F, Perneger T, Schnetzler B, Stoermann C, Fumeaux Z, Rossier M, 
Martin PY. Safety of low-dose spironolactone administration in chronic haemodialysis 
patients. Nephrol Dial Transplant. 2003;18:2359-2363 
58. Taheri S, Mortazavi M, Shahidi S, Pourmoghadas A, Garakyaraghi M, Seirafian S, 
Eshaghian A, Ghassami M. Spironolactone in chronic hemodialysis patients improves 
cardiac function. Saudi J Kidney Dis Transpl. 2009;20:392-397 
59. Vukusich A, Kunstmann S, Varela C, Gainza D, Bravo S, Sepulveda D, Cavada G, Michea 
L, Marusic ET. A randomized, double-blind, placebo-controlled trial of spironolactone on 
carotid intima-media thickness in nondiabetic hemodialysis patients. Clin J Am Soc 
Nephrol. 2010;5:1380-1387 
60. Matsumoto Y, Kageyama S, Yakushigawa T, Arihara K, Sugiyama T, Mori Y, Sugiyama H, 
Ohmura H, Shio N. Long-term low-dose spironolactone therapy is safe in oligoanuric 
hemodialysis patients. Cardiology. 2009;114:32-38 


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61. Michea L, Vukusich A, Gonzalez M, Zehnder C, Marusic ET. Effect of spironolactone on 
k(+) homeostasis and enac expression in lymphocytes from chronic hemodialysis patients. 
Kidney Int. 2004;66:1647-1653 
62. Flevari P, Kalogeropoulou S, Drakou A, Leftheriotis D, Panou F, Lekakis J, Kremastinos D, 
Vlahakos DV. Spironolactone improves endothelial and cardiac autonomic function in non 
heart failure hemodialysis patients. J Hypertens. 2013;31:1239-1244 
63. McGill RL, Biederman RW, Getts RT, Hazlett SM, Sharma SB, Duran J, Brandys DE, 
Sysak JC, Sureshkumar KK, Sandroni SE, Marcus RJ. Cardiac magnetic resonance 
imaging in hemodialysis patients. J Nephrol. 2009;22:367-372 
64. Pitt B, Rossignol P. Mineralocorticoid receptor antagonists in patients with end stage renal 
disease (ESRD) on chronic hemodialysis. J Am Coll Cardiol. 2014;63:537-538 
65. Hammer F, Krane V, Stork S, Roser C, Hofmann K, Pollak N, Allolio B, Wanner C. 
Rationale and design of the mineralocorticoid receptor antagonists in end-stage renal 
disease study (MiREnDa). Nephrol Dial Transplant. 2013;29:400-405 
66. Inc GS. Spironolactone package insert. 2008 
67. Ito Y, Mizuno M, Suzuki Y, Tamai H, Hiramatsu T, Ohashi H, Ito I, Kasuga H, Horie M, 
Maruyama S, Yuzawa Y, Matsubara T, Matsuo S, on behalf of the Nagoya Spiro Study G. 
Long-term effects of spironolactone in peritoneal dialysis patients. J Am Soc Nephrol. 
2014;25:1094-1102 
68. Adam WR. Plasma and dialysate potassium concentrations and haemodialysis associated 
mortality. Nephrology (Carlton). 2013;18:655-656 
69. Jadoul M, Thumma J, Fuller DS, Tentori F, Li Y, Morgenstern H, Mendelssohn D, Tomo T, 
Ethier J, Port F, Robinson BM. Modifiable practices associated with sudden death among 
hemodialysis patients in the dialysis outcomes and practice patterns study. Clin J Am Soc 
Nephrol. 2012;7:765-774 
70. Spiegel DM. Avoiding harm and achieving optimal dialysis outcomes--the dialysate 
component. Adv Chronic Kidney Dis. 2012;19:166-170 
71. Olsen NT, Jons C, Fritz-Hansen T, Mogelvang R, Sogaard P. Pulsed-wave tissue doppler 
and color tissue doppler echocardiography: Calibration with m-mode, agreement, and 
reproducibility in a clinical setting. Echocardiography. 2009;26:638-644 
72. Shan K, Bick RJ, Poindexter BJ, Shimoni S, Letsou GV, Reardon MJ, Howell JF, Zoghbi 
WA, Nagueh SF. Relation of tissue doppler derived myocardial velocities to myocardial 
structure and beta-adrenergic receptor density in humans. J Am Coll Cardiol. 2000;36:891-
896 
73. Shimoni S, Frangogiannis NG, Aggeli CJ, Shan K, Quinones MA, Espada R, Letsou GV, 
Lawrie GM, Winters WL, Reardon MJ, Zoghbi WA. Microvascular structural correlates of 
myocardial contrast echocardiography in patients with coronary artery disease and left 
ventricular dysfunction: Implications for the assessment of myocardial hibernation. 
Circulation. 2002;106:950-956 
74. Weidemann F, Herrmann S, Stork S, Niemann M, Frantz S, Lange V, Beer M, Gattenlohner 
S, Voelker W, Ertl G, Strotmann JM. Impact of myocardial fibrosis in patients with 
symptomatic severe aortic stenosis. Circulation. 2009;120:577-584 
75. Reed AL, Tanaka A, Sorescu D, Liu H, Jeong EM, Sturdy M, Walp ER, Dudley SC, Sutliff 
RL. Diastolic dysfunction is associated with cardiac fibrosis in the senescence-accelerated 
mouse. Am J Physiol Heart Circ Physiol 2011;301:H824–H831 
76. Goland S, Siegel RJ, Burton K, De Robertis MA, Rafique A, Schwarz E, Zivari K, Mirocha J, 
Trento A, Czer LS. Changes in left and right ventricular function of donor hearts during the 
first year after heart transplantation. Heart. 2011;97:1681-1686 
77. Moreo A, Ambrosio G, De Chiara B, Pu M, Tran T, Mauri F, Raman SV. Influence of 
myocardial fibrosis on left ventricular diastolic function: Noninvasive assessment by cardiac 
magnetic resonance and echo. Circ Cardiovasc Imaging. 2009;2:437-443 


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78. Ho SJ, Feng AN, Lee LN, Chen JW, Lin SJ. Predictive value of predischarge spectral tissue 
doppler echocardiography and n-terminal pro-b-type natriuretic peptide in patients 
hospitalized with acute heart failure. Echocardiography. 2011;28:303-310 
79. Park SJ, Lee SC, Jang SY, Chang SA, Choi JO, Park SW, Oh JK. E/E′ ratio is a strong 
prognostic predictor of mortality in patients with non-valvular atrial fibrillation with preserved 
left ventricular systolic function. Circ J. 2011;75:2350-2356 
80. Snopek G, Drewniak W, Borys M, Dabrowski M. Prognostic value of tissue doppler 
echocardiographic imaging in elderly patients with acute myocardial infarction. 
Echocardiography. 2011;28:298-302 
81. Kimura H, Takeda K, Tsuruya K, Mukai H, Muto Y, Okuda H, Furusho M, Ueno T, 
Nakashita S, Miura S, Maeda A, Kondo H. Left ventricular mass index is an independent 
determinant of diastolic dysfunction in patients on chronic hemodialysis: A tissue doppler 
imaging study. Nephron Clin Pract. 2011;117:c67-73 
82. Vignon P, Allot V, Lesage J, Martaille JF, Aldigier JC, Francois B, Gastinne H. Diagnosis of 
left ventricular diastolic dysfunction in the setting of acute changes in loading conditions. 
Crit Care. 2007;11:R43 
83. Agmon Y, Oh JK, McCarthy JT, Khandheria BK, Bailey KR, Seward JB. Effect of volume 
reduction on mitral annular diastolic velocities in hemodialysis patients. Am J Cardiol. 
2000;85:665-668, A611 
84. Oguzhan A, Arinc H, Abaci A, Topsakal R, Kemal Eryol N, Ozdogru I, Basar E, Ergin A. 
Preload dependence of doppler tissue imaging derived indexes of left ventricular diastolic 
function. Echocardiography. 2005;22:320-325 
85. Jellis C, Martin J, Narula J, Marwick TH. Assessment of nonischemic myocardial fibrosis. J 
Am Coll Cardiol. 2010;56:89-97 
86. Mottram PM, Haluska B, Leano R, Cowley D, Stowasser M, Marwick TH. Effect of 
aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic 
heart failure. Circulation. 2004;110:558-565 
87. Hayashi SY, Rohani M, Lindholm B, Brodin LA, Lind B, Barany P, Alvestrand A, Seeberger 
A. Left ventricular function in patients with chronic kidney disease evaluated by colour 
tissue doppler velocity imaging. Nephrol Dial Transplant. 2006;21:125-132 
88. Mendes L, Ribeiras R, Adragao T, Lima S, Horta E, Reis C, Amaral T, Aguiar C, Gouveia 
R, Silva A. Load-independent parameters of diastolic and systolic function by speckle 
tracking and tissue doppler in hemodialysis patients. Rev Port Cardiol. 2008;27:1011-1025 
89. Armijo-Olivo S, Warren S, Magee D. Intention to treat analysis, compliance, drop-outs and 
how to deal with missing data in clinical research: A review. Phyical Therapy Reviews. 
2009;14:36-49 
 


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CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
15. Attachments 
 
 
 


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
15.1. Study Procedures 
SCREENING 
BASELINE  
DOSE ESCALATION PHASE WEEKS 1 – 6 
TREATMENT PHASE WEEKS 7 – 36 
FOLLOW-
UP 
PRN 
Location 
Facility or Study Center Study Center 
In person or phone 
In person or phone 
In person Phone 
as 
needed 
Procedure 
Prescreening 
Activities 
Screening 
Visit 
Baseline/Rand 
Week 0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
prn 
Visit Window (days) 
 
Day  
-30 to 0 
Day 0 
Day 
 -4 to +3 
Day 
 -4 to +3 
Day 
 -4 to +3 
Day 
 -4 to +3 
Day 
 -4 to +3 
Day 
 -4 to +3 
Day  
-4 to 
+3  
Day  
-7 to 
+7 
Day  
-7 to 
+7 
Day  
-7 to 
+7 
Day  
-7 to 
+7 
Day  
-7 to 
+7 
Day-7 to 
+7  
Day  
-7 to +7 
Day  
-7 to +7 
 
Preliminary eligibility assessment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Confirm eligibility 
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographic info & medical history 
  
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Concomitant medications 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 X 
Serum pregnancy 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
 X 
Vital signs 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X  
  
  
Focused physical exam  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inter-dialytic urine 
  
  
X1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Chemistries, CBC, LFTs 
  
  
X 
  
  
  
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
Serum Potassium2 
  
 X 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
X  
Dispense study medication 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
  
  
  
X 
Reconcile study medication 
  
  
  
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
  
X 
  
X 
TDI Echocardiography 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
Review adverse events 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review facility clinical info & lab results 
  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Collect serum/plasma for storage3 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
Dose adjustment (prn) 
  
  
  
X 
 X 
  
X 
PET Scan (substudy) 
  
  
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
X4 
  
  
SEEQ Heart Monitor 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X5 
X5 
 
 
1Inter-dialytic urine collection is performed before or within 7 days after the Baseline/Randomization visit. 
2Serum potassium value that is obtained for clinical purposes can be used if the collection date falls within the visit window.   
3At Baseline, blood will also be collected for DNA extraction. 
4Serum pregnancy test performed prior to PET scan at Baseline/Randomization and Week 36. 
5 SEEQ Heart Monitoring should occur between the Week 32 and Week 36 Visits.


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Attachments 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
15.2. NIDDK DSMB Charter 
 
Data and Safety Monitoring Board (DSMB) Charter 
HD Novel Therapies Consortium 
 
The Data and Safety Monitoring Board (DSMB) will act in an advisory capacity to the National 
Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) to monitor patient safety and 
evaluate the efficacy of the interventions.  The HD Novel Therapies Consortium – Spin-D 
Protocol/Trial is funded by the NIDDK. 
 
DSMB RESPONSIBILITIES 
 
The initial responsibility of the DSMB will be to review the study protocols, consent documents 
and plans for data safety monitoring, and approve the initiation of these clinical trials. After this 
approval, and at periodic intervals during the course of the trials, the DSMB responsibilities are 
to:  
• 
review and approve major changes in the research protocol, informed consent documents 
and plans for data safety and monitoring, including all proposed revisions; 
• 
evaluate the progress of the trial, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus benefit, 
performance of the trial sites, and other factors that may affect study outcome;  
• 
consider factors external to the study when relevant information becomes available, such 
as scientific or therapeutic developments that may have an impact on the safety of the 
participants or the ethics of the trial;  
• 
protect the safety of the study participants;  
• 
report on the safety and progress of the trial;  
• 
make recommendations to the NIDDK, the Steering Committee and, if required, to the 
Food and Drug Administration (FDA) and the Institution Review Boards (IRBs) concerning 
continuation, termination or other modifications of the trial based on the observed 
beneficial or adverse effects of the treatment under study;  
• 
if appropriate, conduct interim analysis of efficacy in accordance with stopping rules which 
are clearly defined in advance of data analysis and have the approval of the DSMB;  
• 
ensure the confidentiality of the trial data and the results of monitoring;  
• 
assist the NIDDK by commenting on any problems related to study conduct, enrollment, 
sample size, and/or data collection.  
 
MEMBERSHIP  
 
The DSMB will consist of at least eight members. Five participating members will constitute a 
quorum. The members have been appointed by the NIDDK. Members of the DSMB shall have 
no financial, scientific, or other conflict of interest with the studies. Collaborators or associates of 
the investigators in this trial are not eligible to serve on the DSMB. Written documentation 
attesting to absence of conflict of interest is required.  
  
Dr. Paul Palevsky of University of Pittsburgh School of Medicine has been selected by the 
NIDDK to serve as the DSMB Chairperson for the remainder of the study. He is responsible for 
overseeing the meetings and developing the agenda in consultation with the NIDDK Program 
Directors, Dr. Paul Kimmel and Dr. John Kusek.  Dr. Kimmel will serve as the DSMB Executive 
Secretary.  The Chairperson is the contact person for the DSMB.  Other NIDDK official (s) or 


SPin-D Trial 
 
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CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
NIDDK appointee (s) may serve as an ex-officio member (s) of the DSMB.  The DCC, University 
of Pennsylvania, shall provide the logistical management for the DSMB, in coordination with 
NIDDK (Dr. Yining Xie, as point of contact). Whenever possible, Dr. Robert Star, Director of the 
Division of Kidney, Urology and Hematology of NIDDK will also attend meetings.  
 
BOARD PROCESS  
 
The DSMB will meet a minimum of once a year at the call of the Chair, with advance approval of 
the NIDDK Program Director.  An NIDDK representative will be present at every meeting.  
 
Meetings shall be closed to the public because discussions may address confidential patient 
data. Meetings are attended, when appropriate, by the principal investigator and members of 
his/her staff.  Meetings may be convened as conference calls/webinars as well as in person. An 
emergency meeting of the DSMB may be called at any time by the Chairperson or by the NIDDK 
Program Director should questions of patient safety arise. The DSMB Chairperson should 
contact the NIDDK Program Director prior to convening the meeting. 
 
MEETING FORMAT  
 
An appropriate format for DSMB meetings consists of open, closed and executive sessions. This 
format may be modified as needed. A brief closed and/or an executive session will usually be 
held before the open session.  
 
Open Session: 
 
The members of the DSMB, the NIDDK staff, the steering committee, including the study 
biostatistician will attend the open session.  Issues discussed will include the conduct and 
progress of the study, including patient recruitment, data quality, general adherence and toxicity 
issues, compliance with protocol, and any other logistical matters that may affect either the 
conduct or outcome of the study.  Protocol amendments may also be presented in this session. 
 
Closed Session: 
 
The closed session will be attended by voting DSMB members, representatives from the NIDDK, 
or its appointees, and the study biostatistician. The discussion at the closed session is 
completely confidential. 
 
Analyses of blinded outcome data are reviewed by masked intervention groups, including 
baseline characteristics, primary and secondary outcomes, adverse events, adherence and 
dropouts, and examination of any relevant subgroups. However, the DSMB may request 
unmasking of the data for either safety or efficacy concerns.   
 
Executive Session: 
 
The executive session will be attended by voting DSMB members, and the NIDDK Staff, or its 
appointees. 
 
The DSMB will discuss information presented to it during the closed and open sessions and 
decide whether to recommend continuation or termination, protocol modification or other 
changes to the conduct of the study in the Executive Session.  The DSMB can become 
unblinded if trends develop either for benefit or harm to the participants.  


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CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
 
Should the DSMB decide to issue a termination recommendation, a full vote of the DSMB will be 
required. In the event of a split vote, majority vote will rule and a minority report should be 
appended.  Reasons for early termination may include: 
• 
Serious adverse effects in the entire intervention group or in a dominating subgroup; 
• 
Greater than expected beneficial effects; 
• 
A statistically significant difference by the end of the study is improbable; 
• 
Logistical or data quality problems so severe that correction is not feasible. 
 
Final Open Session (optional): 
 
The final session may be attended by voting DSMB members, steering committee members, the 
study biostatistician or other study members, and the NIDDK staff. 
 
The Chairperson of the DSMB or the NIDDK Staff shall report on the recommendations of the 
DSMB regarding study continuation and concerns regarding the conduct of the study.  Requests 
regarding data presentation for subsequent meetings will be made.  Scheduling of the next 
DSMB meeting may be discussed. 
 
REPORTS  
 
Interim Reports: Interim reports will be prepared by the Data Coordinating Center, located at 
the University of Pennsylvania.  The reports will be distributed to the DSMB and the NIDDK 
Program Director at least 7 days prior to a scheduled meeting. These interim reports are 
numbered and provided in sealed envelopes within an express mailing package or by secure 
email as the DSMB prefers. The contents of the report are determined by the DSMB. Additions 
and other modifications to these reports may be directed by the DSMB on a one-time or 
continuing basis. Interim data reports generally consist of two parts: 
 
Part 1 (Open Session Report) provides information on study aspects such as accrual, baseline 
characteristics, and other general information on study status.  This report is generally shared 
with all investigators involved with the clinical trial.  The reports contained in this section may 
include: 
o Comparison of Target Enrollment to Actual Enrollment by Month 
o Comparison of Target Enrollment to Actual Enrollment by Site 
o Overall Subject Status by Site, including: Subjects Screened, Enrolled, Active, 
Completed and Terminated 
o Demographic and Key Baseline Characteristics by Group 
o Treatment Duration for Subjects who Discontinue Therapy 
o Adverse Events/Serious Adverse Events by Site and Subject 
 
Part 2 (Closed Session Report) may contain data on study outcomes, including safety data, 
including serious adverse events or termination.  Data will be presented by blinded treatment 
groups; however, the DSMB may request that the treatment groups be unblinded to ensure that 
there are no untoward treatment effects. This report should not be viewed by any members of 
the clinical trial except the designated study statistician. 
 
Reports from the DSMB: A formal report containing the recommendations for continuation or 
modifications of the study, prepared by the Executive Secretary with concurrence of the DSMB, 
will be sent to the Chair of the Steering Committee and the DCC PI. This report will also contain 
any recommendations of the NIDDK in reference to the DSMB recommendations.  It is the 


SPin-D Trial 
 
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Version 5.0, May 9, 2016 
Attachments 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
responsibility of the DCC PI to distribute this report to all other PIs and to assure that copies are 
submitted to all the IRBs associated with the study. 
 
Each report should conclude with a recommendation to continue or to terminate the study. This 
recommendation should be made by formal majority vote. A termination recommendation may 
be made by the DSMB at any time by majority vote. The NIDDK is responsible for notifying the 
Chair of the Steering Committee of a decision to terminate the study. In the event of a split vote 
in favor of continuation, a minority report should be contained within the regular DSMB report. 
The report should not include unblinded data, discussion of the unblinded data, or any other 
confidential data.  
 
Mailings to the DSMB: On a scheduled basis, (as agreed upon by the DSMB) blinded safety 
data should be communicated to all DSMB members and the NIDDK Program Director. Any 
concerns noted by the DSMB should be brought to the attention of the NIDDK Program Director.  
 
Access to Interim Data: Access to the accumulating endpoint data should be limited to as small 
a group as possible. Limiting the access to interim data to the DSMB members relieves the 
investigator of the burden of deciding whether it is ethical to continue to randomize patients and 
helps protect the study from bias in patient entry and/or evaluation.  
 
CONFIDENTIALITY  
 
All materials, discussions and proceedings of the DSMB are completely confidential. Members 
and other participants in DSMB meetings are expected to maintain confidentiality.