Conditions: End-Stage Renal Disease
Keywords: ESRD End-Stage Kidney Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
Anti-Cytokine Therapy for Hemodialysis InflammatION (ACTION) is a phase II multi-center study to evaluate the safety and tolerability of anakinra, an IL-1 receptor antagonist, for patients treated with maintenance hemodialysis.

Detailed description:
The ACTION Trial will enroll 80 participants being treated with maintenance hemodialysis for end-stage renal disease. Participants will be randomized to receive Anakinra, 100 mg administered intravenously 3 times per week at the end of the hemodialysis session, or matched placebo. The duration of study drug administration is 24 weeks. There will be an additional 24 weeks of follow-up after study drug administration has been completed.

Arms:
arm 1: Anakinra (Kineret®) is a therapeutic agent that blocks the effects of IL-1 alpha and IL-1 beta by competitively binding to the interleukin-1 type I receptor (IL-1RI). Anakinra is a recombinant, non-glycosylated form of the naturally occurring human interleukin-1 receptor antagonist (IL-1Ra).

Anakinra will be supplied in pre-filled syringes as a sterile, clear, colorless-to-white, preservative free solution. Each syringe will contain 100 mg in 0.67 ml solution (pH 6.5) containing disodium EDTA (0.12 mg), sodium chloride (5.48 mg), sodium citrate (1.29 mg), and polysorbate 80 (0.70 mg) in Water for Injection, USP. arm 2: Saline (0.9%) will be used as the placebo, supplied in pre-filled syringes as a sterile, clear, colorless-to-white, preservative free solution.

Interventions: intervention 1: Anakinra intervention 2: Placebo
Intervention descriptions: intervention 1: Anakinra (Kineret®) is a therapeutic agent that blocks the effects of IL-1α and IL-1β by competitively binding to the interleukin-1 type I receptor (IL-1RI). It is a recombinant, non-glycosylated form of the naturally occurring human interleukin-1 receptor antagonist (IL-1Ra) but differs from human IL-1Ra in that it has the addition of a single methionine residue at the amino terminus. It is supplied commercially in single use 1 ml prefilled glass syringes as a sterile, clear, colorless-to-white, preservative free solution. Each syringe contains: 0.67 ml (100 mg) of anakinra in a solution (pH 6.5) containing sodium citrate (1.29 mg), sodium chloride (5.48 mg), disodium EDTA (0.12 mg) and polysorbate 80 (0.70 mg) in Water for Injection, USP. intervention 2: Saline (0.9%) will be used as the placebo, in single use 1 ml prefilled glass syringes as a sterile, clear, colorless-to-white, preservative free solution.

Protocol document:
Prot_SAP_000.pdf: 
Hemodialysis Novel Therapies Consortium 
Clinical Research Protocol 
CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
 
 
Anti-Cytokine Therapy for Hemodialysis InflammatION 
(ACTION) 
 
A phase II multi-center study to evaluate the safety and tolerability of anakinra, 
an IL-1 receptor antagonist, for patients treated with maintenance hemodialysis 
 
 
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: 
Anakinra 
 
Protocol Number:        826900  
 
IND Number:  
       134008 - Exempt  
 
 
 
Initial version: 
V. 1January 6, 2017 
Amended: 
V1.1 June 6, 2017 
Amended: 
V1.2 August 8, 2017 
Amended: 
V1.3  May 8, 2018 
 


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Table of Contents 
 
LIST OF ABBREVIATIONS ................................................................................................................... IV 
STUDY SUMMARY ............................................................................................................................. V 
1 
INTRODUCTION .........................................................................................................................1 
1.1 
INFLAMMATION AS A TARGET TO IMPROVE OUTCOMES IN ESRD ............................................................. 1 
1.2 
IL-1 AS A SPECIFIC TARGET TO IMPROVE OUTCOMES IN ESRD ................................................................. 2 
1.3 
ANTI-INFLAMMATORY INTERVENTIONS IN ESRD ................................................................................... 2 
1.3.1 
IL-1Ra as an anti-inflammatory agent in ESRD ....................................................................... 2 
1.4 
STUDY AGENT .................................................................................................................................. 3 
1.4.1 
Information obtained from FDA product label ........................................................................ 3 
1.4.2 
Intravenous administration of anakinra ................................................................................. 3 
1.4.3 
Dosing of Anakinra in Renal Impairment ................................................................................ 4 
1.4.4 
Dose Rationale for ACTION Trial ............................................................................................. 4 
1.5 
CLINICAL EFFICACY EVALUATIONS OF ANAKINRA .................................................................................... 5 
1.6 
RISKS ............................................................................................................................................. 5 
1.7 
BENEFITS ........................................................................................................................................ 6 
2 
STUDY OBJECTIVES .....................................................................................................................6 
2.1 
PRIMARY OBJECTIVES ....................................................................................................................... 6 
2.2 
SECONDARY OBJECTIVES ................................................................................................................... 6 
3 
STUDY DESIGN ...........................................................................................................................6 
3.1 
GENERAL DESIGN (FIGURE 2) ............................................................................................................. 6 
3.2 
STUDY ENDPOINTS ........................................................................................................................... 7 
3.2.1 
Safety Endpoints ...................................................................................................................... 7 
3.2.2 
Tolerability Endpoint ............................................................................................................... 7 
3.2.3 
Feasibility Endpoints ................................................................................................................ 7 
3.2.4 
Efficacy Endpoints ................................................................................................................... 8 
4 
PARTICIPANT SELECTION AND WITHDRAWAL .............................................................................8 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 8 
4.1.1 
CRP Eligibility Threshold .......................................................................................................... 9 
4.2 
EXCLUSION CRITERIA......................................................................................................................... 9 
4.2.1 
Women of Childbearing Potential ........................................................................................... 9 
4.3 
RECRUITMENT ............................................................................................................................... 10 
5 
STUDY DRUG ........................................................................................................................... 10 
5.1 
DESCRIPTION ................................................................................................................................. 10 
5.2 
ADMINISTRATION OF STUDY DRUG ................................................................................................... 10 
5.3 
RECEIVING, STORING, DISPENSING AND RETURNING STUDY DRUG ......................................................... 11 
5.3.1 
Receiving Study Drug ............................................................................................................. 11 
5.3.2 
Return or Destruction of Study Drug ..................................................................................... 11 
5.4 
CONCOMITANT THERAPY ................................................................................................................. 11 
6 
STUDY PROCEDURES ................................................................................................................ 11 
6.1 
STUDY VISITS AND ACTIVITIES ........................................................................................................... 11 
6.1.1 
Pre-screening Activities ......................................................................................................... 11 


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6.1.2 
First Screening Visit (Day –30 to Day –14) ............................................................................ 12 
6.1.3 
Second Screening Visit (Day –10 to Day –1) .......................................................................... 12 
6.1.4 
Baseline/Randomization Visit (Day 0) ................................................................................... 13 
6.1.5 
Initiation of Study Drug Administration ................................................................................ 13 
6.1.6 
Weeks 1, 2, and 3 .................................................................................................................. 13 
6.1.7 
Weeks 4, 8, 16, and 20 .......................................................................................................... 13 
6.1.8 
Weeks 12 and 24 (End of Treatment Visit) ............................................................................ 13 
6.1.9 
Early Withdrawal Visit ........................................................................................................... 14 
6.1.10 
Post-Treatment Period:  Weeks 28 through 48................................................................. 14 
6.1.11 
Patient Reported Outcomes (PROs) Questionnaire Administration ................................. 14 
6.1.12 
Pharmacokinetic and Pharmacodynamic Studies ............................................................. 15 
6.2 
TEMPORARY DISCONTINUATION OF STUDY DRUG (SEE ALSO SECTION 6.4) .............................................. 15 
6.3 
PERMANENT DISCONTINUATION OF STUDY DRUG................................................................................ 15 
6.4 
MANAGEMENT OF CLINICAL EVENTS ................................................................................................. 16 
6.4.1 
Infection................................................................................................................................. 16 
6.4.2 
Neutropenia .......................................................................................................................... 16 
6.4.3 
Thrombocytopenia ................................................................................................................ 16 
6.4.4 
Immunizations ....................................................................................................................... 16 
6.4.5 
Allergic / Acute Hypersensitivity Reactions to Anakinra ....................................................... 17 
6.4.6 
Management of Active Suicidal Intent .................................................................................. 17 
6.5 
EARLY WITHDRAWAL OF PARTICIPANTS ............................................................................................. 18 
7 
STATISTICAL PLAN .................................................................................................................... 18 
7.1 
SAMPLE SIZE DETERMINATION ......................................................................................................... 18 
7.2 
RANDOMIZATION AND STRATIFICATION ............................................................................................. 19 
7.3 
ANALYSIS POPULATIONS AND MISSING DATA ...................................................................................... 19 
7.4 
STATISTICAL METHODS ................................................................................................................... 20 
7.4.1 
Descriptive Analyses and Primary Efficacy and Safety Analyses ........................................... 20 
7.4.2 
Secondary Analyses ............................................................................................................... 21 
7.4.3 
Interim Analysis ..................................................................................................................... 21 
7.4.4 
Missing Data ......................................................................................................................... 21 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................. 22 
8.1 
DEFINITIONS .................................................................................................................................. 22 
8.1.1 
Adverse Event ........................................................................................................................ 22 
8.1.2 
Serious Adverse Event ........................................................................................................... 22 
8.1.3 
Unanticipated Problem Involving Risk to Participants or Others .......................................... 22 
8.1.4 
Pre-Existing Condition ........................................................................................................... 22 
8.2 
ADVERSE EVENT REPORTING PERIOD ................................................................................................. 23 
8.2.1 
Post-study Adverse Events .................................................................................................... 23 
8.3 
RECORDING OF ADVERSE EVENTS ...................................................................................................... 23 
8.3.1 
Anticipated Adverse Events ................................................................................................... 23 
8.3.2 
Non-Reportable Events .......................................................................................................... 24 
8.4 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................ 24 
8.4.1 
Investigator Reporting to the IRB .......................................................................................... 25 
8.4.2 
DCC Notification to Participating Investigators .................................................................... 26 
8.5 
MEDICAL MONITORING .................................................................................................................. 26 
8.5.1 
Independent Data and Safety Monitoring Board (DSMB) ..................................................... 26 


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9 
DATA MANAGEMENT ............................................................................................................... 27 
9.1 
DATA QUALITY .............................................................................................................................. 27 
9.1.1 
Quality Control Activities ....................................................................................................... 27 
9.1.2 
Routine reports ...................................................................................................................... 28 
9.2 
DATA SECURITY ............................................................................................................................. 28 
9.2.1 
Confidentiality ....................................................................................................................... 28 
9.3 
SOURCE DOCUMENTS ..................................................................................................................... 29 
9.3.1 
Case Report Forms ................................................................................................................ 29 
9.3.2 
Maintaining Anonymity of Submitted Medical Records ....................................................... 29 
9.3.3 
Data Sharing .......................................................................................................................... 29 
9.3.4 
Records Retention ................................................................................................................. 30 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 30 
10.1 
STUDY MONITORING PLAN .............................................................................................................. 30 
10.2 
AUDITING AND INSPECTING .............................................................................................................. 30 
11 
ETHICAL CONSIDERATIONS ....................................................................................................... 30 
12 
STUDY FINANCES ..................................................................................................................... 31 
12.1 
FUNDING SOURCE .......................................................................................................................... 31 
12.2 
CONFLICT OF INTEREST .................................................................................................................... 31 
12.3 
PARTICIPANT STIPENDS OR PAYMENTS ............................................................................................... 31 
13 
PUBLICATION PLAN .................................................................................................................. 31 
14 
REFERENCES ............................................................................................................................ 32 
15 
ATTACHMENTS ........................................................................................................................ 34 
15.1 
STUDY PROCEDURES ....................................................................................................................... 35 
15.2 
DSMB CHARTER ............................................................................................................................ 37 
 


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List of Abbreviations 
AE 
adverse event 
ANC 
absolute neutrophil count 
BDI-II 
Beck Depression Index II 
CBC 
complete blood count 
CKD 
chronic kidney disease 
CRF 
case report form 
CRP 
C-reactive protein 
CVD 
cardiovascular disease 
DCC 
Data Coordinating Center 
DMS 
data management system 
DSMB 
Data and Safety Monitoring Board 
ESRD 
end stage renal disease 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FTP 
File Transfer Protocol 
HD 
hemodialysis 
HIPAA 
Health Insurance Portability and Accounting Act 
hsCRP 
high-sensitivity C-reactive protein  
IDS 
Investigational Drug Service 
IL 
Interleukin 
IL-1ra 
Interleukin 1 receptor antagonist 
IRB 
Institutional Review Board 
IV 
Intravenous 
KDQOL SF12 
Kidney Disease Quality of Life Short Form 12 
MOP 
Manual of Procedures 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NIH 
National Institutes of Health 
OHRP 
Office of Human Research Protections 
PHI 
protected health information 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TNF-α 
tumor necrosis factor-alpha 
UAE 
unanticipated adverse event 
 


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Study Summary 
Title 
Anti-Cytokine Therapy for Hemodialysis Inflammation (ACTION) 
Short Title 
ACTION 
Protocol Number 
  
Phase 
Phase II 
Methodology 
Randomized, double-blind, placebo-controlled trial 
Study Duration 
3 years 
Study Centers 
Brigham and Women’s Hospital 
George Washington University 
University of Washington 
Vanderbilt  University  
University of Pennsylvania (Data Coordinating Center) 
Objectives 
1. To evaluate the safety and tolerability of the interleukin-1 receptor antagonist, 
anakinra, for patients receiving maintenance hemodialysis during a 24- week 
treatment period and a 24-week post-treatment period during which participants 
will not be enrolled in any other interventional research study 
2. To assess the efficacy of anakinra for reducing CRP during 24 weeks of treatment for 
patients receiving maintenance hemodialysis 
3. To explore the effects of anakinra on markers of inflammation, cardiovascular risk, 
nutrition and metabolism, and patient reported outcomes for patients receiving 
maintenance hemodialysis 
Number of Participants 
80 
Condition / Main Inclusion Criteria 
End-stage renal disease /  treatment with maintenance hemodialysis  
Study Product, Dose, Route 
Anakinra; 100 mg administered intravenously 3X per week at the end of hemodialysis 
Duration of administration 
24 weeks 
Reference therapy 
Placebo 
Major Outcomes 
Safety Outcomes   
• Adverse events 
• Infections 
• Cytopenias 
Feasibility Outcomes 
• Recruitment rate, retention, dosing completeness 
Efficacy Outcomes 
• Reduction in CRP over 24 weeks 
• Change in markers of inflammation, cardiovascular disease, nutrition, and 
metabolism 
• Change in patient reported indicators of fatigue, depression, symptoms, and quality 
of life 
• Change in hand grip strength 


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Statistical Methodology 
Efficacy:  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.  
 
Safety:  Generalized linear mixed effects models (logistic and/or Poisson regression) will 
be used to compare incidence and incidence rate of safety parameters, adjusting for 
stratification factors and baseline covariates. 


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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, applicable government regulations, and the 
research policies and procedures in effect at the institutions where the study is implemented.  
1.1 
Inflammation as a Target to Improve Outcomes in ESRD 
The mortality of patients undergoing maintenance hemodialysis in the United States is unacceptably 
high1.  A majority of the deaths are due to cardiovascular diseases, followed by infectious complications 
and protein-energy wasting2.  Strategies to reduce the mortality of these patients, including those 
directed at traditional cardiovascular risk factors such as statins, have largely been ineffective3-5.  
Biomarkers of the inflammatory state, such as C-reactive protein (CRP), interleukin-1 (IL-1), and 
interleukin-6 (IL-6), are elevated in maintenance hemodialysis patients and are also robust predictors of 
cardiovascular disease and mortality in this patient population6,7,8.  In addition to its predictive ability, 
inflammation has been implicated in the pathogenesis of atherosclerotic cardiovascular disease and 
protein-energy wasting.  There is ample evidence showing that atherosclerosis is an inflammatory 
process and pro-inflammatory cytokines play a crucial role in its development9.  There are also data 
supporting an intimate link between systemic inflammation and vascular calcification, another 
important component of cardiovascular disease in end stage renal disease (ESRD) 10.  Pro-inflammatory 
cytokines also cause anorexia and skeletal muscle breakdown, leading to protein-energy wasting, a 
condition with significant morbidity and mortality risk in ESRD11.  Elevations in IL-6 and TNF-alpha have 
been associated with increased symptom burden and reduced quality of life in chronic kidney disease 
(CKD)12.  Taken together, the available data indicate a causal relationship between inflammation and 
morbidity in ESRD patients rendering inflammation a critically important target to improve outcomes in 
this high risk patient population (Figure 1).   
 
Co-Morbid Conditions 
(Diabetes, CVD) 
(+) 
(-) 
Figure 1: Conceptual model for etiology of systemic inflammation and its adverse effects in advanced 
kidney disease. HPT: Hyperparathyroidism; GH: Growth hormone; CVD: Cardiovascular Disease 
Dietary Nutrient 
Intake 
(-) 
Dialyzer Membrane 
Bio-incompatibility 
(-) 
(+) 
(+) 
(+) 
Metabolic Derangements 
(HPT, Metabolic Acidosis, 
GH Resistance) 
Uremic 
Wasting 
Loss of Kidney Function  
Uremic Toxins 
 
INFLAMMATION 
(+) 
Cardiovascular 
Disease 
Frailty, 
Depression 


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1.2 
IL-1 as a Specific Target to Improve Outcomes in ESRD 
IL-1 plays a key role in the development and progression of atherosclerosis.  Elevated levels of IL-1 result 
in secretion of chemokines and other cytokines (eg, IL-6)13, increased levels of CRP14, increased 
expression of adhesion molecules, activation of endothelial and smooth muscle cell proliferation, 
macrophage activation, and increased vascular permeability.  IL-1 stimulates release of endothelin-115, a 
potent  vasoconstrictor, and also stimulates inducible nitric oxide synthase, which increases the 
formation of reactive oxygen species and reactive nitrogen species which leads to oxidative stress and 
endothelial dysfunction16.  IL-1 is also implicated in the proposed link between vascular calcification and 
systemic inflammation.  TNF-α induces mineralization of calcifying vascular cells in vitro, and co-culture 
of these cells with monocyte⁄macrophages accelerates mineralization17.  IL-1 down-regulates the 
synthesis and release of fetuin-A, a circulating inhibitor of calcification.  Vascular calcification, via the 
deposition of basic calcium-phosphate crystals in the arterial intima, activates human monocyte-derived 
macrophages, inducing a pro-inflammatory state18. 
 
These observations, together with the strong relationship between pro-inflammatory cytokine levels 
and risk of cardiovascular events and death in ESRD, have motivated the current protocol which 
evaluates the safety, feasibility, and efficacy of treatment with anakinra, an IL-1 receptor antagonist 
(IL1ra), in patients with ESRD receiving maintenance hemodialysis, through a 24-week single dose, 
placebo-controlled, double blind trial. 
 
1.3 
Anti-Inflammatory Interventions in ESRD 
While anti-inflammatory interventions, especially specific anti-cytokine therapies, have been used 
successfully to treat patients with inflammatory bowel disease19, psoriasis, rheumatoid arthritis20, and 
auto-inflammatory syndromes21, and while encouraging results such as improvement in glycemic control 
and beta cell function have been reported with their use in type 2 diabetes mellitus22, there are only 
limited studies using these interventions in patients undergoing maintenance hemodialysis.  Etanercept, 
a TNF-receptor antagonist, was tested in a small number of maintenance hemodialysis patients over a 
44-week period 23.   Although there were encouraging positive effects on serum albumin and prealbumin 
levels compared to the placebo group and no adverse events, etanercept treatment did not result in 
significant reductions in serum CRP or IL-6 concentrations.    
1.3.1 
 IL-1Ra as an anti-inflammatory agent in ESRD 
In comparison with other specific anti-cytokine agents, there is more precedence for the use of IL-1ra as 
anti-cytokine therapy.  In addition to significant amelioration of the systemic inflammatory response in 
multiple chronic disease states such as rheumatologic diseases and diabetes mellitus, short-term 
inhibition of IL-1 with the IL-1ra anakinra has been shown to reduce circulating markers of oxidative 
stress and improve brachial artery flow-mediated dilation (an indicator of endothelial function) in 
patients with rheumatoid arthritis24.  There are also intriguing preliminary data for IL-1 blockade in 
patients with ESRD.  In a placebo-controlled pilot study that evaluated IL-1 inhibition in 22 maintenance 
hemodialysis patients, 14 of whom completed the trial, the active treatment group had a 53% reduction 


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in mean hsCRP compared with 1% in the placebo arm (P = 0.008), and a 40% reduction in mean IL-6 
levels compared with a 20% increase in the placebo arm (P = 0.03) 25.  In a subgroup of these patients 
who underwent metabolic studies using stable isotopes, anakinra resulted in a significant decrease in 
skeletal muscle breakdown compared to placebo (Hung et al, ASN abstract presentation 2014).  These 
improvements were associated with an increase in serum adiponectin concentrations, suggesting 
significant metabolic and nutritional benefit in response to IL1-ra administration in maintenance 
hemodialysis patients. 
 
In addition to studies in ESRD patients, IL-1 antagonism has been studied in non-dialysis dependent 
chronic kidney disease.  A recently completed two-site pilot randomized clinical trial evaluated 
rilonacept, an interleukin-1 (IL-1) trap, for 12 weeks in 42 patients with stage 3-4 chronic kidney disease.  
This study found significant improvements in markers of inflammation (hsCRP, IL-6) and vascular health 
(brachial artery flow-mediated dilation) in the active drug group compared with the placebo group.  The 
medication was very well tolerated without any significant side-effects. (Novak et al and Hung et al ASN 
2015, Oral Presentation, Late-Breaking Clinical Trials session). 
1.4 
Study Agent 
1.4.1 
Information obtained from FDA product label 
Anakinra (Kineret®) is a therapeutic agent that blocks the effects of IL-1α and IL-1β by competitively 
binding to the interleukin-1 type I receptor (IL-1RI).  Anakinra is a recombinant, non-glycosylated form of 
the naturally occurring human interleukin-1 receptor antagonist (IL-1Ra).  It differs from native human 
IL-1Ra in that it has the addition of a single methionine residue at the amino terminus.  Anakinra is 
produced using recombinant technology in an E. coli bacterial expression system.  Anakinra is supplied 
commercially in single use 1 ml prefilled glass syringes as a sterile, clear, colorless-to-white, preservative 
free solution.  Each 1 ml prefilled glass syringe contains: 0.67 ml (100 mg) of anakinra in a solution (pH 
6.5) containing sodium citrate (1.29 mg), sodium chloride (5.48 mg), disodium EDTA (0.12 mg) and 
polysorbate 80 (0.70 mg) in Water for Injection, USP.   
 
1.4.2 
Intravenous administration of anakinra 
Anakinra has FDA marketing approval for subcutaneous administration but was initially developed for 
intravenous administration for patients with sepsis, and can be administered intravenously.  The 
formulation used for intravenous administration is identical to that used for subcutaneous 
administration, and, with the exception of injection site reactions that can occur with subcutaneous but 
not with intravenous administration, the adverse event profiles do not differ based on administration 
route.  The ACTION trial will use intravenous administration of anakinra at a dose of 100 mg three times 
per week administered over 1 minute at the end of hemodialysis sessions.  The rationale for using 
intravenous rather than subcutaneous administration is as follows:   
 
1) Intravenous administration eliminates a) the risk of injection site reactions, the most common 
adverse event with anakinra, and b) the risk of injection-associated pain.  Because these events are 


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caused by the vehicle (which would be used for the placebo to maintain blinding), the elimination of risk 
through the use of intravenous administration is relevant not only for participants receiving active drug 
but also for those randomized to placebo.  Injection site reactions are often mild but can result in 
abscess formation and can necessitate discontinuation of study drug.  Injection-associated pain is 
anticipated to be a deterrent to study participation.  Thus, the use of intravenous rather than 
subcutaneous administration of anakinra for the ACTION trial is expected to decrease risk of important 
adverse events, increase enrollment rates, and increase participant retention. 
 
2) Because anakinra can be administered through the hemodialysis extracorporeal blood circuit during 
regularly scheduled hemodialysis sessions, intravenous administration of anakinra does not require 
placement of venous access and should be highly feasible in the research setting and, if found to be 
beneficial, in the clinical setting.   
 
1.4.3 
Dosing of Anakinra in Renal Impairment 
Renal excretion accounts for a substantial proportion of the elimination of anakinra.  The half-life with 
subcutaneous administration is 4-6 hours in patients with rheumatoid arthritis.  As reported in the FDA 
product label, in mild renal impairment (creatinine clearance 50-80 ml/min) and moderate renal 
impairment (creatinine clearance 30-49 ml/min), the mean plasma clearance was reduced by 16% and 
50%, respectively.  For patients with severe renal impairment (creatinine clearance less than 30 ml/min) 
and end-stage renal disease, the mean plasma clearance was decreased by 70% and 75%, respectively.  
The recommended dose of anakinra for patients receiving maintenance hemodialysis is 100 mg 
subcutaneous every other day (from FDA product label).   
 
The pharmacokinetics of anakinra with intravenous administration have been studied in individuals with 
normal kidney function and various degrees of renal impairment26.  Among individuals receiving 
maintenance hemodialysis, the mean plasma clearance of anakinra was 18.2 ±3.2 ml/min compared 
with 137±21 ml/min in individuals with normal kidney function.  The mean half-life of anakinra 
administered intravenously at a dose of 1 mg/kg was 7.15 hours in hemodialysis patients compared with 
2.64 hours in those with normal kidney function.  The plasma concentrations of anakinra at 24, 48, and 
72 hours after drug administration were similar with intravenous and subcutaneous administration. 
 
1.4.4 
Dose Rationale for ACTION Trial 
The recommended dose of anakinra for patients with rheumatoid arthritis is 100 mg per day 
administered subcutaneously.  The recommended dose of anakinra for Cryopyrin-Associated Periodic 
Syndromes  (CAPS) is 1 -2 mg/kg daily with a maximum dose of 8 mg/kg.  For patients with severe renal 
impairment (creatinine clearance less than 30 ml/min) or ESRD, it is recommended that the prescribed 
dose be administered every other day.  In the previous published trial of anakinra in hemodialysis 
patients, the dosing schedule was 100 mg three times per week.  This is the schedule that will be used in 
the ACTION trial25.  With dialysis schedules of Monday, Wednesday, and Friday or Tuesday, Thursday, 


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and Saturday, participants will receive anakinra every other day for 2 of the 3 doses each week, and 
every 3rd day for one of the 3 doses each week.  As described in Section 1.4.3, pharmacokinetic studies 
suggest that for patients receiving hemodialysis, the same dosing schedule can be used for intravenous 
and subcutaneous administration of anakinra26.  
1.5 
Clinical Efficacy Evaluations of Anakinra 
Anakinra was approved by the US Food and Drug Administration for the treatment of rheumatoid 
arthritis in 2002, and for (CAPS) in 2013.  At the time of regulatory approval the efficacy of anakinra for 
rheumatoid arthritis had been evaluated in three randomized, double-blind, placebo-controlled clinical 
trials that enrolled a total of 1392 patients.  In two of these studies, anakinra was administered in 
combination with other disease-modifying anti-rheumatic drugs other than TNF blocking agents27,28, and 
in one study anakinra was used as monotherapy29.  Efficacy was evaluated using the American College of 
Rheumatology (ACR) response criteria (ACR20, ACR50, and ACR70).   Patients receiving active treatment 
were more likely to achieve an ACR20 or higher magnitude of response than patients treated with 
placebo.  Most of the responses occurred within 12 weeks.  An additional fourth randomized, placebo-
controlled trial in 1414 patients with rheumatoid arthritis was conducted to assess safety30.  In this trial, 
patients received a variety of concurrent medications, other than TNF blocking agents, including 
methotrexate, sulfasalazine, hydrochloroquine, gold, penicillamine, leflunomide, and azathioprine, and 
the trial enrolled patients predisposed to infection based on comorbid conditions.   
The FDA approval of anakinra for Cryopyrin-Associated Periodic Syndromes was based on a long-term, 
open label, uncontrolled study of 43 patients of 0.7 to 46 years of age with Neonatal-Onset Multisystem 
Inflammatory Disease (NOMID).  Treatment was administered for up to 60 months31.  Efficacy 
assessment was based on a disease specific Diary Symptom Sum score that included fever, rash, joint 
pain, vomiting and headache.  Improvements occurred in all the individual symptoms as well as in 
circulating inflammatory markers.  Among patients who underwent a treatment withdrawal phase, 
symptoms and inflammatory markers worsened after withdrawal and responded promptly to 
resumption of the treatment.   
1.6 
Risks  
The following adverse events have been reported with the use of anakinra in non-ESRD populations: 
1. Serious infections (2%) vs. placebo (<1%).  In studies of rheumatoid arthritis the incidence of serious 
infections over 6 months was 2% in anakinra-treated patients and 1% in placebo-treated patients. 
Most of the infections were bacterial and included cellulitis, pneumonia and bone and joint 
infections. Opportunistic infections from fungal, mycobacterial and bacterial pathogens have 
occurred in clinical studies and post-marketing experience.    
2. Neutropenia, particularly when used in combination with TNF blocking agents (8%) vs placebo (2%). 
3. Injection-site reactions with subcutaneous administration are the most common adverse events. 
These are generally mild, typically last 14-28 days, and are characterized by erythema, ecchymosis, 
inflammation, and pain. In some studies, 71% of the subjects treated with anakinra experienced an 
injection-site reaction, compared to 28% of individuals receiving saline placebo.  Injection site 
reactions are not a risk with intravenous administration as will be used in the ACTION study. 


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4. Other adverse events, with incidence compared to placebo, have included headache (12% vs. 9%), 
nausea (8% vs. 6%), diarrhea (7% vs. 5%), sinusitis (7% vs. 6%), influenza-like symptoms (6% vs. 5%), 
and abdominal pain (5% vs. 4%). 
5. Hypersensitivity reactions including anaphylactic reactions and angioedema have been reported 
with anakinra. 
1.7 
Benefits 
There are no established benefits of anakinra in the dialysis population.  It is hypothesized that anakinra 
will reduce inflammation and, as a result, have benefits on cardiovascular disease, protein-energy 
wasting, anemia, fatigue, quality of life, and, possibly, survival. 
2 Study Objectives 
The goals of this study are to evaluate the safety and tolerability of anakinra for patients receiving 
maintenance hemodialysis, and to explore in this patient population the efficacy of anakinra on a broad 
array of parameters.  The findings from this early phase study will be used to assess the feasibility and 
inform the design of a subsequent efficacy trial.  
2.1 
Primary Objectives 
• 
To evaluate the safety and tolerability of the interleukin-1b receptor antagonist, 
anakinra, for patients receiving maintenance hemodialysis during a 24-week treatment 
period and a 24-week post-treatment period during which participants will not be 
enrolled in any other interventional study 
• 
To evaluate the efficacy of anakinra on reducing CRP after 24 weeks of treatment for 
patients receiving maintenance hemodialysis 
2.2 
Secondary Objectives 
• 
To explore the efficacy of anakinra on improving markers of inflammation and 
cardiovascular disease risk after 24 weeks of treatment for patients receiving 
maintenance hemodialysis 
• 
To explore the efficacy of anakinra on improving nutritional and metabolic markers after 
24 weeks of treatment for patients receiving maintenance hemodialysis 
• 
To explore the efficacy of anakinra on patient reported indicators of fatigue, depression, 
symptoms, and quality of life after 24 weeks of treatment for patients receiving 
maintenance hemodialysis 
3 Study Design 
3.1 
General Design (Figure 2) 
This is a randomized, placebo-controlled 2-arm trial that will compare anakinra 100 mg IV three times 
per week to placebo.  Treatment assignment will be masked to participants and researchers.  Treatment 


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duration will be 24 weeks and participants will be followed for safety assessment for an additional 24 
weeks after treatment is completed.  
 
Figure 2.  Trial Design 
 
3.2 
Study Endpoints 
3.2.1 
Safety Endpoints 
The safety endpoints are: 
1) adverse events  
2) adverse events that preclude further treatment with the study agent 
3) infections 
a. All infections – any infection regardless of severity, treatment, or distribution (i.e., 
localized versus systemic) 
b. Serious infections - defined as documented bacteremia, systemic fungal infection, 
central nervous system infection, pneumonia, infection-associated sepsis, infection 
requiring hospitalization for more than 2 calendar days, or infection-associated 
death 
4) neutropenia defined as absolute neutrophil count <1000 cells/mm3 (1.0 x 109 cells/L) 
5) thrombocytopenia defined as platelets <75,000/mm3 (75 x 109/L) 
6) systemic hypersensitivity reactions 
3.2.2 
Tolerability Endpoint 
The tolerability endpoint is:  
1) the proportion of participants able to complete the full 24 weeks of treatment 
3.2.3 
Feasibility Endpoints 
An objective of this study is to assess the feasibility of conducting a large-scale trial powered for clinical 
outcomes.  Feasibility will be assessed based on rates of recruitment, withdrawal, and loss-to-follow-up, 
reasons for ineligibility, and adherence to the study drug administration schedule. 


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3.2.4 
Efficacy Endpoints 
1) The primary efficacy endpoint is the change in log-transformed circulating CRP concentration 
over the 24-week treatment period.  The pre-treatment CRP will be the mean of the values from 
the two Screening and the Baseline CRP measurements, all performed at the same central 
laboratory as the CRPs obtained during the treatment period and Week 28 visit (see Sections 
6.1.2 and 6.1.3 for procedure for obtaining screening CRP measurements)     
2) Secondary efficacy endpoints include: 
a. Change in circulating markers of inflammation and oxidative stress between baseline 
and end of treatment   
i. pro- and anti-inflammatory  cytokines (e.g.,  IL-6, TNF-α, IL-10) 
ii. serum albumin concentration 
iii. F2-isoprostane/isofuran, sICAM, sVCAM levels 
b. Change in circulating markers of cardiac disease risk between baseline and end of 
treatment.  Markers of cardiomyocyte injury, myocardial stretch, and cardiac fibrosis 
include troponin T, NT-pro-BNP, and galectin-3, respective 
c. Change in circulating nutritional and metabolic markers between baseline and end of 
treatment (e.g., adiponectin, insulin, leptin, resistin, cholesterol, and prealbumin levels) 
d. Change in patient reported outcomes using indicators of fatigue (FACIT), depression 
(Beck Depression Index II), symptoms (Dialysis Symptom Index, Illness Effects 
Questionnaire), and quality of life (KDQOL™ SF-12) 
e. Change in muscle strength (hand grip) 
4 Participant Selection and Withdrawal 
4.1 
Inclusion Criteria 
a) Maintenance hemodialysis therapy 3 times per week for end-stage renal disease  
b) Age 18 – 85 years 
c) ≥6 months since hemodialysis initiation 
d) C-reactive protein measured by high sensitivity assay (hsCRP) ≥2.0 mg/L at screening and within 
10 days prior to randomization (see Section 4.1.1 for explanation of pre-specified plan for 
changing the hsCRP threshold while enrollment is underway, if necessary) 
e) Most recent single pool Kt/V ≥ 1.2 within 30 days prior to first screening visit  
f) Negative tuberculosis interferon gamma release assay (e.g. Quantiferon-TB Gold) for 
tuberculosis unless documented treatment for a) positive PPD, b) positive interferon gamma 
release assay, or c) tuberculosis. 
g) Negative human immunodeficiency virus (HIV) antibody test, negative hepatitis C Ab test unless 
viral clearance following direct antiviral therapy is documented, and negative hepatitis B surface 
antigen positivity. 
h)  For women of childbearing potential, willingness to use a highly effective method of birth 
control for up to 4 weeks after the last dose of anakinra.  See Section 4.2.1 for definition of 
childbearing potential and acceptable methods of birth control. 
i) 
Ability to provide informed consent 


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4.1.1 
Change to CRP Eligibility Threshold 
  Version 1.0 of the protocol used a CRP threshold of >3 mg/L with the stipulation that the threshold 
could be decreased to ≥2.0 mg/L if needed to facilitate enrollment.  In accordance with that stipulation, 
Version 1.3 of the protocol incorporates the new threshold of ≥2.0 mg/L.  In addition to enhancing 
enrollment, using the lower threshold will increase the generalizability of the findings, both in terms of 
safety and efficacy. 
4.2 
Exclusion Criteria 
a) Current or anticipated use of a hemodialysis central venous catheter 
b) Acute bacterial infection, including vascular access infection, within 60 days prior to screening 
unless treated with antibiotics and resolved.  Any chronic bacterial infection (e.g.,  osteomyelitis 
or bronchiectasis) 
c) Hospitalization within 30 days unless for vascular access procedure 
d) Cirrhosis 
e) Malignancy within the past 5 years with exception of basal or squamous cell carcinoma 
f) Use of an immunosuppressive drug within the past 3 months except low doses of oral 
corticosteroids (total daily dose ≤10 mg/day of prednisone or equivalent)  
g) Receipt of live vaccine within the past 3 months.  Live vaccines include Varicella zoster, measles, 
oral polio, rotavirus, yellow fever, and the nasal spray influenza vaccine  
h) Absolute neutrophil count (ANC) <2,500 cells/mm3 (2.5 x 109 cells/L)  
i) 
Platelet count <100,000/mm3 (100 x 109/L) 
j) 
Known allergy to anakinra  
k) Anticipated kidney transplantation, change to peritoneal dialysis, or transfer to another dialysis 
unit within 9 months  
l) 
Expected survival less than 9 months 
m) Pregnancy, anticipated pregnancy, or breastfeeding 
n) Incarceration 
o) Receipt of an investigational drug within the past 30 days 
p) Current or anticipated participation in another intervention study 
4.2.1 
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 receiving 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 


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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: 
• 
Condom with spermicide 
• 
Diaphragm and spermicide 
• 
Cervical cap and spermicide 
• 
Hormonal contraception 
 
A serum pregnancy test will be done at the local laboratory for women of childbearing potential at the 
second screening visit, and at weeks 4, 8, 12, 16, 20, 24, and 28.    
4.3 
Recruitment  
Participants at dialysis units affiliated with the practices of a Clinical Center 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 laboratory studies, medical records at Clinical Centers, 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, written 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 the 
dialysis unit or at the Clinical Center according to investigator and participant preferences.   
Participants may be compensated for study participation.  Each Clinical Center is responsible for 
developing a compensation plan and schedule, and distributing payment.  
5 Study Drug 
5.1 
Description 
Anakinra will be supplied in pre-filled syringes as a sterile, clear, colorless-to-white, preservative free 
solution.  Each syringe will contain 100 mg in 0.67 ml solution (pH 6.5) containing disodium EDTA (0.12 
mg), sodium chloride (5.48 mg), sodium citrate (1.29 mg), and polysorbate 80 (0.70 mg) in Water for 
Injection, USP.  There will be no modification to the formulation of the manufacturer-supplied anakinra.  
Saline (0.9%) will be used as the placebo. The study drug will be refrigerated at 2 °C – 8 °C and will be 
kept away from light.   
5.2 
Administration of Study Drug 
Study drug (100 mg) will be administered via a medication port in the extracorporeal dialysis blood 
circuit three times per week during the last 30 minutes of the hemodialysis session.  The study drug will 


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be administered by a dialysis unit nurse over 1 minute.   There must be at least one calendar day 
between successive doses, meaning that the drug will not be administered on consecutive days even if 
dialysis occurs on both days.  The duration of treatment is 24 weeks.  Participant-specific study drug 
administration logs documenting each dose administration as well as scheduled doses that are not 
administered, with the reason for non-administration, will be completed by the dialysis unit nurse 
administering drug, and provided to  the Clinical Center research teams upon resupply visits. Receiving, 
Storing, Dispensing and Returning Study Drug 
5.2.1 
Receiving Study Drug 
Study drug and placebo will be distributed by Sobi, the manufacturer of study drug, to the research 
pharmacy at each Clinical Center.  Each Clinical Center research pharmacy will be responsible for 
maintaining detailed records regarding the receipt of study drug.  General study drug accountability, 
participant-specific study drug accountability and, if necessary, Shipment Tracking Accountability logs 
will be maintained by the Clinical Center pharmacists.  Documentation includes study drug receipt, 
storage, dispensing, and final disposition.   
5.2.2 
Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of study agent shipped, study agent 
consumed, and study agent remaining.  This reconciliation will be logged on the study agent 
reconciliation form, signed and dated.  Any discrepancies noted will be investigated, resolved, and 
documented before the return or destruction of unused study agent.  Study agent destroyed on site will 
be documented in the study files. 
5.3 
Concomitant Therapy 
Information about medication use will be collected at baseline and throughout the course of the study.  
Appropriate sources for obtaining this information include the participant, the medical/dialysis unit 
record, and treating clinicians.   
6 Study Procedures 
6.1 
Study Visits and Activities 
A schedule of study visits and procedures is provided in the Study Procedures Table in Section 15.1. 
All blood collections will be performed either on a non-dialysis day, or before the initiation of dialysis on 
a dialysis day.  Post-randomization study visits can take place in the dialysis unit or via phone.  
6.1.1 
Pre-screening Activities 
Patients at participating dialysis units will be screened for eligibility.  Clinical Center study personnel will 
review dialysis unit records and other medical records 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.     


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6.1.2 
First Screening Visit (Day –30 to Day –14) 
Patients who appear eligible based on pre-screening will be approached in person to determine interest 
in participation and confirm eligibility.  Study personnel will discuss the study goals and procedures with 
the potential participant in detail.  If the patient agrees to participate in the study, study personnel will 
review and assess understanding of the entire informed consent form before obtaining written informed 
consent from the participant.  The consenting process will be performed by a qualified investigator or 
study site designee.  Informed consent will be obtained and documented before any study procedures 
are performed.  
The screening activities may take place over a single visit or multiple visits.   
Screening Activities 
• 
Obtain informed consent 
• 
Collect baseline data including demographics, medical history, and medication use 
• 
Obtain blood for hsCRP (local Clinical Center laboratory and central laboratory), and CBC with 
differential (local laboratory).  The hsCRP result from the local laboratory will be used for 
eligibility determination and a batched measurement made by the central laboratory on a 
stored sample will be used for determining the pre-treatment hsCRP value used in efficacy 
assessments.  The blood obtained for the central laboratory measurement will be processed, 
aliquoted and stored at -80 °C for future batched shipping.  If blood is obtained on a dialysis day, 
blood should be drawn before dialysis. 
• 
Testing for tuberculosis, hepatitis B, hepatitis C, and HIV if clinical results are not available (at 
research team’s discretion, can occur at Screening Visit 1 or 2). 
• 
Review eligibility criteria  
6.1.3 
Second Screening Visit (Day –10 to Day –1) 
The second screening visit should be performed within 10 days prior to the baseline/randomization visit 
and far enough in advance of the baseline/randomization visit to be sure that the results of the hsCRP 
(performed at the local laboratory), CBC with differential, and, if applicable, serum pregnancy test, will 
be available prior to baseline.   
• 
Obtain blood for hsCRP (local Clinical Center laboratory and central laboratory), and CBC with 
differential (local laboratory).  The hsCRP result from the local laboratory will be used for 
eligibility determination and a batched measurement made by the central laboratory on a 
stored sample will be used for determining the pre-treatment hsCRP value used in efficacy 
assessments.  The blood obtained for the central laboratory measurement will be processed, 
aliquoted and stored at -80 °C for future batched shipping.  If blood is obtained on a dialysis day, 
blood should be drawn before dialysis. 
• 
Testing for tuberculosis, hepatitis B, hepatitis C, and HIV if clinical results are not available (at 
research team’s discretion, can occur at Screening Visit 1 or 2). 
• 
Obtain blood for serum pregnancy test for women of childbearing potential (local laboratory) 
• 
Review eligibility criteria  


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6.1.4 
Baseline/Randomization Visit (Day 0) 
At the baseline visit medication use, vital signs, physical examination and adverse events will be 
recorded, and eligibility will be confirmed.  After eligibility has been confirmed, a call will be scheduled 
for the participant to complete five telephone questionnaires (see section 6.1.13).  Hand grip strength 
will be measured using a dynamometer. 
Blood will be collected for serum, plasma, and buffy coat isolation for future DNA extraction.  Samples 
will be aliquoted and stored at -80 °C for future batched shipping.  Blood collection will be performed 
prior to dialysis initiation if performed on a dialysis day.  If blood is not collected on the day of the 
Baseline/Randomization visit (Day 0), it will be collected pre-dialysis at the next dialysis session and prior 
to initiation of the study drug.  The batched samples will include blood for hsCRP. 
Randomization to treatment group will be performed through the centralized Data Management 
System. 
6.1.5 
Initiation of Study Drug Administration 
Study drug administration will begin at a dialysis session within 1 week after the 
Baseline/Randomization Visit and continue through Week 24 at a frequency of 3 times per week.  The 
study drug administration log will be completed after each administration to document the 
administration and any symptoms or adverse events that occur during the dialysis session.   
6.1.6 
Weeks 1, 2, and 3  
Week 1 begins on the day of the first drug administration.  During Weeks 1, 2, and 3 there will be an in-
person or telephone contact to perform the following:  
• 
Review clinical events  
6.1.7 
Weeks 4, 8, 16, and 20 
The following will be performed at in-person visits which may take place at the dialysis unit: 
• 
Blood collection for CBC with differential that will be performed at the local Clinical Center 
laboratory 
• 
Blood collection for hsCRP that will be performed at the central laboratory 
• 
Obtain blood for serum pregnancy test for women of childbearing potential (local laboratory)  
• 
Recording of concomitant medications, and adverse events 
6.1.8 
Weeks 12 and 24 (End of Treatment Visit) 
The following will be performed at in-person visits which may take place at the dialysis unit: 
• 
Blood collection for serum and plasma.  Samples will be aliquoted and stored at -80 °C for future 
batched shipping.  The batched samples will include blood for hsCRP. 
• 
Blood collection for CBC with differential that will be performed at the local Clinical Center 
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• 
Obtain blood for serum pregnancy test for women of childbearing potential (local laboratory)  
• 
Recording of dialysis unit laboratory studies, concomitant medications, and adverse events 
• 
Hand grip strength measurement using a dynomometer 
6.1.9 
Early Withdrawal Visit 
If a participant withdraws from the trial before the Week 24 end of treatment visit an Early Withdrawal 
visit will be scheduled to conduct the assessments that otherwise would be performed at Week 24.  
Participants who stop taking study drug 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 assessment at Week 
24. 
6.1.10 Post-Treatment Period:  Weeks 28 through 48 
After the study drug treatment period, participants will be followed for an additional 24 weeks to collect 
additional information about safety.  Visits will occur every 4 weeks.   Participants who stop taking study 
drug before Week 24 will be followed for an additional 24 weeks following study drug discontinuation.  
Participants will be instructed that enrolling in another interventional study during this post-treatment 
period is not permitted.   
Week 28 
The following will be performed at in-person visits which may take place at the dialysis unit: 
• 
Blood collection for serum and plasma.  Samples will be aliquoted and stored at -80 °C for future 
batched shipping.  The batched samples will include blood for hsCRP. 
• 
Blood collection for CBC with differential that will be performed at the local Clinical Center 
laboratory 
• 
Obtain blood for serum pregnancy test for women of childbearing potential (local laboratory)  
• 
Recording of concomitant medications and adverse events 
• 
Hand grip strength measurement using a dynomometer 
 
Weeks 32, 36, 40, 44, and 48 
Adverse events will be recorded.   
6.1.11 Patient Reported Outcomes (PROs) Questionnaire Administration 
The University of New Mexico Health Sciences Center Computer Assisted Telephone Interviewing (CATI) 
team will contact study participants at Baseline and Weeks 12, 24, and 28 to administer the following 
questionnaires via telephone: 
• 
Beck Depression Index (BDI) II 
• 
FACIT Fatigue Scale 
• 
Illness Effects Questionnaire 
• 
Dialysis Symptom Index 
• 
KDQOL™ SF-12 


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The questionnaires will be administered on non-dialysis days.  It is expected that completion of the 
questionnaires will take approximately 45 minutes.  If participants are unable to complete the full 
battery of questionnaires at one time, they will be permitted to continue the interview on a subsequent 
day.   
6.1.12 Pharmacokinetic and Pharmacodynamic Studies 
Pharmacokinetic and pharmacodynamic studies will be performed on 12 participants.  Blood will be 
collected for measurement of anakinra concentration and hsCRP assay according to the following 
schedule starting on the first day of study drug administration: 
1. Sampling Day 1 (the first day of study drug administration and prior to a 48-hour interval 
between dialysis sessions): prior to dialysis initiation and at the end of the dialysis session  
2. Sampling Day 2 (the non-dialysis day following the first day of study drug administration): at 
the same time as the Sampling Day 1 end-of-dialysis collection 
3. Sampling Day 3 (the dialysis session approximately 48 hours after the Sampling Day 1 pre-
dialysis blood draw): prior to dialysis initiation and at the end of the dialysis session 
4. Sampling Day 4 (dialysis day, 4 weeks after the first day of study drug administration, and 
prior to a 48-hour interval between dialysis sessions): prior to dialysis initiation and at the end 
of the dialysis session 
5. Sampling Day 5 (the non-dialysis day immediately following Sampling Day 4): at the same time 
as the Sampling Day 4 end-of-dialysis collection 
6. Sampling Day 6 (the dialysis session approximately 48 hours after the Sampling Day 4 pre-
dialysis blood draw): prior to dialysis initiation and at the end of the dialysis session 
6.2 
Temporary Discontinuation of Study Drug (see also Section 6.4) 
Study drug will be temporarily discontinued by the research team for the following events but can be 
resumed after event: 
• 
Non-serious Infection (see Section 6.4.1) 
• 
Neutropenia with absolute neutrophil count (ANC) <1000/mm3 but ≥500/mm3 
• 
Thrombocytopenia with platelet count <75,000/mm3 but ≥25,000/mm3 
• 
Use of a tunneled or non-tunneled central venous dialysis catheter.  If a central venous catheter 
is placed after trial enrollment, study drug will be discontinued until the catheter is removed. 
 
Resumption of study drug must be approved by a Study Drug Management Committee comprised of 
Clinical Center and DCC investigators. 
6.3 
Permanent Discontinuation of Study Drug 
Study drug will be permanently discontinued by the research team for the following events because of 
the potential for compromising patient safety:   
• 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that treatment with anakinra is not in the best interest of 
the subject 
• 
Serious infection (see Section 6.4.1) 


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• 
Allergy to or documented intolerance of study drug 
• 
New malignancy 
• 
Initiation of immunosuppressive therapy 
• 
Neutropenia with ANC <500/mm3  
• 
Thrombocytopenia with platelet count  <25,000/mm3 
• 
Organ transplantation 
• 
Change to a different dialysis modality 
• 
Transfer to a non-participating dialysis unit  
 
If study drug is discontinued study visits and procedures will continue to the extent possible unless the 
participant withdraws consent for follow-up.   
6.4 
Management of Clinical Events  
6.4.1 
Infection 
Participants with clinically significant infections should be treated according to standard of care and the 
adverse event should be recorded.  Study drug should be temporarily discontinued for non-serious 
infections until it is clear that the infection has resolved.  Study drug should be permanently 
discontinued if there is a serious infection.  Serious infections include documented bacteremia, systemic 
fungal infection, central nervous system infection, pneumonia, infection-associated sepsis, infection 
requiring hospitalization for more than 2 calendar days, or infection-associated death. 
The Study Drug Management Committee must approve resumption of study drug after discontinuation 
for infection. 
6.4.2 
Neutropenia  
Study drug will be temporarily discontinued if the ANC is <1000/mm3 and ≥500/mm3, and can be 
resumed once the ANC is ≥2000/mm3.  Study drug will be permanently discontinued if the ANC is 
<500/mm3.  A complete blood count will be obtained at least once per week until the ANC is 
≥2000/mm3. 
6.4.3 
Thrombocytopenia 
Study drug will be temporarily discontinued if the platelet count is <75,000/mm3 and ≥25,000/mm3, and 
can be resumed once the platelet count is >120,000/mm3.   A complete blood count will be obtained at 
least once per week until the platelet count is >120,000/mm3.    Study drug will be permanently 
discontinued if the platelet count is <25,000/mm3.  A complete blood count will be obtained at least 
once per week until the platelet count is ≥75,000/mm3. 
6.4.4 
Immunizations 
Live vaccines should not be administered to subjects during the study (including the screening period).  
Live vaccines include Varicella zoster, measles, oral polio, rotavirus, yellow fever, and nasal spray (live 


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attenuated) influenza vaccine.  Inactivated vaccines (e.g., influenza injection) are allowed; however, the 
efficacy may be attenuated.  
6.4.5 
Allergic / Acute Hypersensitivity Reactions to Anakinra  
Signs of potential acute hypersensitivity reactions include hypotension; dyspnea; wheezing; acute pain 
in the chest, back, or extremities; chills, fever, or urticaria; or generalized erythema.  These events 
should be recorded on the appropriate Case Report Form.  In the case of discontinuation of study drug 
due to potential acute hypersensitivity reactions, the participant should not be rechallenged with the 
study drug.  Management of potential acute hypersensitivity reaction should be determined by the 
investigator or clinician and might include intravenous fluid, epinephrine, glucocorticoids, 
antihistamines, and/or pressor agents.   
Allergic / acute hypersensitivity reactions will be graded using the Common Terminology Toxicity Scale 
Version 4.0 shown in the Table below. 
 
Grade 
Toxicity 
1 
2 
3 
4 
5 
Allergic reaction 
Transient 
flushing or 
rash, drug 
fever <39° C 
(<100.4° F); 
intervention 
not indicated  
Intervention or 
infusion interruption 
indicated; responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics); 
prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (e.g., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for clinical 
sequelae 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Anaphylaxis 
 
 
Symptomatic 
bronchospasm with or 
without urticaria; 
parenteral 
intervention indicated; 
allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
CTC Toxicity Scale, Version 4.0, http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
6.4.6 
Management of Active Suicidal Intent 
This trial is not specifically enrolling individuals who are at high risk for suicide. However, it is possible 
that suicidal ideation will be evident from responses to the Beck Depression Inventory-II (BDI-II) which is 
one of several patient reported outcome instruments used in this study. Participants will be considered 


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to have active suicidal intent if the answer to Question 9 of the BDI-II is either “I would like to kill 
myself” or “I would kill myself if I had the chance”.  
 
The personnel at the central PRO administration center (CATI Center) administering the BDI-II will have 
emergency telephone numbers for 3 members of the research team at each Clinical Center. If a 
participant indicates active suicidal intent by answering either “I would like to kill myself” or “I would kill 
myself if I had the chance” to question 9 on the BDI-II, the person administering the BDI-II will 
immediately stop administering that questionnaire.  The CATI team member will inform the participant 
that the research team will follow up with them to provide follow-up and resources, and end the call.  
The CATI team will immediately contact the research team at the participant’s Clinical Center to inform 
them of the participant’s possible suicidal intent.  A designated member of the Clinical Center research 
team will immediately contact the participant and provide appropriate support and resources, including 
arrangement for emergency care and/or referral to mental health specialists as needed.    
 The CATI team member will also notify the DCC electronically using the participant’s study ID.  
 
If a participant indicates active suicidal intent requiring follow up by the clinical center, the 
administration of the remaining ACTION questionnaires will be deferred until a later date after the 
management of suicidal intent protocol has been completed.  
 
6.5 
Early Withdrawal of Participants  
Early withdrawals will be discouraged and participants who are not willing or able to continue study 
drug 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.   
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 mean CRP at baseline to be 9.5 ± 4 mg/L and log-
transformed mean CRP at baseline to be 2.14 ± 0.55 log(mg/L) 25.  Assuming a correlation of 0.6 between 
pre- and post-treatment CRP in the placebo group, and a 10% dropout rate of study participants by the 
end of the study, a sample size of 80 (40 patients for the placebo arm and 40 patients for the active 


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treatment arm) will provide 80% power to detect an effect size of 0.6SD (0.33 log(mg/L)) difference 
between treatment arms in the change from baseline to 24-week endpoint in log-transformed CRP.  
7.2 
Randomization and Stratification 
A stratified randomization procedure, blocking on two strata (diabetes or no diabetes) 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 anakinra or placebo in a 1:1 
distribution. 
The treatment assignment code, corresponding to each treatment identifier number, will be known only 
to a single member of the DCC data management group and to the research pharmacist at the relevant 
Clinical Center, until the completion of treatment and data collection on all participants.  At the end of a 
treatment, the participant and the treating physician will be asked to guess the assigned treatment 
group, 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. 
7.3 
Analysis Populations and Missing Data 
The analysis populations are defined as follows:  
• 
All-randomized / intention-to-treat (ITT) population:  Any participant randomized into the study, 
regardless of whether study drug was received. 
• 
As-treated population:  The as-treated population is the same as the ITT population (i.e., any 
participant randomized into the study regardless of whether study drug was received).  However 
for the as-treated analysis, patients in the active drug group who did not receive at least one 
dose of study drug will be classified into the placebo arm. 
• 
All-treated population:  Any participant randomized into the study who 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 24 ± 2 weeks.   
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 24 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  


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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 as-treated, per-protocol, and all-treated populations.  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 are not captured by ITT analyses in which the 
unit of analysis is a randomized therapy that may not have been used by individual participants32.  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 FDA32.   
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 such as means, medians, and 
interquartile ranges will be produced for all measured variables.  Frequencies and percentages will be 
computed for all categorical and ordinal variables.  Graphical methods including quantile-quantile plots 
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 2-sample tests, including Mann-Whitney tests and Fisher’s 
exact tests. 
For the analyses of the primary efficacy outcome, mean (± standard deviation) or median (interquartile 
ranges) of baseline and each of subsequent measurements in the primary endpoint, log-transformed 
CRP, will be presented.  Change in log-transformed CRP at 24 weeks will be assessed and reported 
quantitatively, and descriptive statistics for absolute and % change will be provided. Linear mixed effects 
regression models with adjustment for stratification factors and baseline covariates will be used for 
assessment of treatment effects on repeated measurements of CRP.  Model assumptions regarding 


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homoscedasticity and normality will be examined using standard techniques.  With repeated 
measurements of CRP, the area under the time-log-transformed CRP curve33 can be estimated from the 
linear mixed effects models and used to compare an aggregate efficacy between treatment and placebo 
arms over the 24-week period of the study.  
For the safety endpoints, tables with percent incidence and incidence rate (for both adverse events and 
infections which can occur more than once throughout the course of study) will be prepared.  
Differences in incidence and incidence rate between arms will be assessed using generalized linear 
mixed effects models (logistic and/or Poisson regression) adjusting for stratification factors and baseline 
covariates.  
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 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 outcomes include change in markers of inflammation and oxidative stress (including 
pro- and anti-inflammatory cytokine, serum albumin, F2-isoprostane/isofuran levels, etc.), in circulating 
markers of cardiac disease risk, in nutritional and metabolic markers, and in patient reported outcomes 
(including indicators of fatigue, depression, symptoms, muscle strength, and quality of life) between 
baseline and 24 weeks.  For markers measured repeatedly, (generalized) linear mixed effects models will 
be used to assess the effect of treatment.  Analytical approaches for these secondary outcomes will be 
similar to that used for the primary outcome.  Distribution of the secondary outcome parameters will be 
examined and appropriate transformation will be applied.  For this early phase study, analyses of the 
secondary efficacy outcomes will be viewed as exploratory, and correction for multiple comparisons will 
not be performed. 
7.4.3 
Interim Analysis 
The pharmacokinetic and pharmacodynamic data will be analyzed after 12 participants have completed 
the assessments in order to allow modification of dosing if indicated based on anakinra concentrations 
or CRP concentrations. 
7.4.4 
Missing Data 
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. 


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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 examination 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. 
8.1.3 
Unanticipated Problem Involving Risk to Participants or Others  
An Unanticipated Problem is any incident, experience, or outcome that meets all of the following 
criteria: 
• 
it is 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; 
• 
it is 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 
• 
it 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. 


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8.2 
Adverse Event Reporting Period 
The study period during which adverse events must be tracked and reported is defined as the period 
from the initiation of study procedures to study completion.  Participants who fail screening will no 
longer be followed for adverse events or serious adverse events.  If a participant is rescreened in the 
future, he or she will once again be followed for those events once screening procedures resume. 
8.2.1 
Post-study Adverse Events 
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 Data Coordinating Center (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.   
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 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 
Anticipated Adverse Events 
The following adverse events are anticipated in the hemodialysis population and are not considered 
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 
• 
Hypotension 
• 
Vomiting 
• 
Vascular Access Events Including: 
o Catheter exchange, removal or declotting 
o Arteriovenous graft or fistula complications 


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 
Clotting 
 
Stenosis 
 
Revascularization 
 
Infection 
• 
Infections Including: 
o Pneumonia 
o Bacteremia 
o Hemodialysis vascular access infection  
8.3.2 
Non-Reportable Events 
The hemodialysis population is characterized by frequent laboratory testing and a high rate of peri-
dialytic hypotensive events requiring change 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 they will not be considered to 
meet the criteria of SAE in this study except as noted: 
• 
Anemia—will be reported only when hemoglobin <8.0 mg/dL 
• 
Hyperphosphatemia—will be reported only when phosphate >9.5 mg/dL 
• 
Hypocalcemia—will be reported only when serum calcium <7.0 mg/dL 
• 
Hypercalcemia—will be reported only when serum calcium >11.0 mg/dL 
• 
Hyperparathyroidism—will be reported only when PTH>1000 pg/mL 
• 
Hypotension—will be reported only when requiring emergency room visit or  hospitalization 
8.4 
Reporting of Serious Adverse Events and Unanticipated Problems 
Study sites are required to report SAEs to the DCC within 24 hours of first knowledge of the event.  To 
report such events, an SAE form will be completed by the investigator and faxed or emailed to the 
DCC.  The DCC will facilitate the timely medical review and reporting of the event, and provide reports to 
the NIDDK and the Data and Safety Monitoring Board (DSMB) in accordance with DSMB-approved study 
policies and regulatory requirements (see Section 8.5.1 for details of the DSMB). 
The investigator will keep a copy of the SAE form on file at the study site.  At the time of the initial 
report, the following information should be provided: 
 
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 participation 
 


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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, and any other diagnostic information that will assist in the understanding of the event.  
Significant new information on ongoing serious adverse events should be provided promptly to the DCC. 
If a participant becomes pregnant while participating in the study it will be reported as an adverse event 
and will trigger the collection of additional documentation about the pregnancy.  Pregnancy outcomes 
will be collected, including the outcome of the infant and if the pregnancy was terminated.  This 
information will be submitted to the University of Pennsylvania IRB, and to the local site IRB as required. 
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. 
The DCC will report SAEs for any participant identified to be on active drug to Sobi at the end of the trial 
once unblinding has occurred.   
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. 
Other Reportable Events: 
• 
Any adverse event that would cause the study’s Steering Committee to modify the 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.  
• 
Breach of confidentiality 


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• 
Change to the protocol made 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 45 CFR 
part 46 subpart C and the investigator believes it is in the best interest of the participant to 
remain in 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 of an unanticipated and related event as described in Section 8.1.3.   
8.5 
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.  Medical monitoring will include a regular assessment of the number and type of 
serious adverse events. 
8.5.1 
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.  A DSMB charter for the Hemodialysis Novel Therapies Consortium 
includes additional detail.  The NIDDK DSMB charter is provided as an attachment in Section 15.   
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 before 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;  


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• 
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). 
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 (DMS) 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 (CRF) completion, use of the 
electronic DMS, and collection, documentation and transfer of specimens and tests to central 
laboratories.  
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.  Personnel who join the study after 


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its initiation will be trained and certified in study procedures before being allowed to complete tasks 
associated with their role. 
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 central laboratories.   
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.  
9.2 
Data Security 
The DMS will be designed to prevent unauthorized access to study 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 DMS 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 and central laboratories will 
be transferred to the DCC using secure File Transfer Protocol (FTP) technology.  The DCC team will 
maintain a secure FTP server.  The files transmitted using this method will be encrypted during the 
exchange. 
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 authorization for use of his or her 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 before the revocation of participant 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts should 


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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 9CMS) 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. 
9.3 
Source Documents 
Source data are all information, original records of clinical findings, observations, or other activities in a 
research study necessary for the reconstruction and evaluation of the study.  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 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 removing 
any PHI.  Upon receipt, DCC personnel will review the records to ensure that no PHI is visible. 
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 before 
initiation. 


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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.   
A portion of the serum and plasma collected at Baseline and Weeks 12, 24, and 28, 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 Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
A monitoring plan that may include 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. 
10.2 Auditing and Inspecting 
The DCC and Clinical Center investigators will permit study-related monitoring, audits, and inspections 
by the 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 institution compliance and quality assurance offices. 
11 Ethical Considerations 
This study will be conducted according to US and international standards of Good Clinical Practice, all 
applicable government regulations, and all local institutional research policies and procedures. . 
This protocol and any amendments will be submitted to properly constituted IRBs, in agreement with 
local legal prescriptions, for formal approval of the study.  The decision of the IRB concerning the 


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Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
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 DCC 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 IRB.  The formal consent of a participant, 
using the 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.  Anakinra and placebo and financial support for 
centralized ascertainment of patient-reported outcomes is provided by Sobi (Stockholm, Sweden). 
12.2 Conflict of Interest 
All investigators will follow the conflict of interest policies of the NIDDK and 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 before participation in this study. 
12.3 Participant Stipends or Payments 
Participants will be compensated for participating in the study.  Compensation approaches will be 
determined by the Clinical Centers and approved by the local 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 and Steering Committee.  Any investigator involved with this study is 
obligated to provide the DCC with results of all study-related testing and all data derived from the study. 


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14 References 
1. 
Himmelfarb J, Ikizler TA. Hemodialysis. N Engl J Med 2010;363:1833-45. 
2. 
Collins AJ, Foley RN, Chavers B, et al. United States Renal Data System 2011 Annual Data Report: Atlas 
of chronic kidney disease & end-stage renal disease in the United States. Am J Kidney Dis 2012;59:A7, 
e1-420. 
3. 
Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus 
ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised 
placebo-controlled trial. Lancet 2011;377:2181-92. 
4. 
Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients 
undergoing hemodialysis. N Engl J Med 2009;360:1395-407. 
5. 
Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing 
hemodialysis. N Engl J Med 2005;353:238-48. 
6. 
Kimmel PL, Phillips TM, Simmens SJ, et al. Immunologic function and survival in hemodialysis patients. 
Kidney Int 1998;54:236-44. 
7. 
Stenvinkel P, Barany P, Heimburger O, Pecoits-Filho R, Lindholm B. Mortality, malnutrition, and 
atherosclerosis in ESRD: what is the role of interleukin-6? Kidney Int Suppl 2002:103-8. 
8. 
Stenvinkel P, Heimburger O, Jogestrand T. Elevated interleukin-6 predicts progressive carotid artery 
atherosclerosis in dialysis patients: association with Chlamydia pneumoniae seropositivity. Am J Kidney 
Dis 2002;39:274-82. 
9. 
Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med 1999;340:115-26. 
10. Moe SM, Chen NX. Inflammation and vascular calcification. Blood Purif 2005;23:64-71. 
11. Ikizler TA. Nutrition, inflammation and chronic kidney disease. Curr Opin Nephrol Hypertens 
2008;17:162-7. 
12. Farag YM, Keithi-Reddy SR, Mittal BV, et al. Anemia, inflammation and health-related quality of life in 
chronic kidney disease patients. Clin Nephrol 2011;75:524-33. 
13. Sironi M, Breviario F, Proserpio P, et al. IL-1 stimulates IL-6 production in endothelial cells. J Immunol 
1989;142:549-53. 
14. Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood 1991;77:1627-52. 
15. Corder R, Carrier M, Khan N, Klemm P, Vane JR. Cytokine regulation of endothelin-1 release from 
bovine aortic endothelial cells. J Cardiovasc Pharmacol 1995;26 Suppl 3:S56-8. 
16. Peluffo G, Radi R. Biochemistry of protein tyrosine nitration in cardiovascular pathology. Cardiovasc Res 
2007;75:291-302. 
17. Demer LL, Tintut Y, Parhami F. Novel mechanisms in accelerated vascular calcification in renal disease 
patients. Curr Opin Nephrol Hypertens 2002;11:437-43. 
18. Nadra I, Mason JC, Philippidis P, et al. Proinflammatory activation of macrophages by basic calcium 
phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and 
arterial calcification? Circ Res 2005;96:1248-56. 
19. Silva LC, Ortigosa LC, Benard G. Anti-TNF-alpha agents in the treatment of immune-mediated 
inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy 2010;2:817-33. 
20. Miller AV, Ranatunga SK. Immunotherapies in rheumatologic disorders. Med Clin North Am 
2012;96:475-96, ix-x. 
21. Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells 
syndrome. N Engl J Med 2003;348:2583-4. 
22. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. 
N Engl J Med 2007;356:1517-26. 
23. Don BR, Kim K, Li J, Dwyer T, Alexander F, Kaysen GA. The effect of etanercept on suppression of the 
systemic inflammatory response in chronic hemodialysis patients. Clin Nephrol 2010;73:431-8. 


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CONFIDENTIAL 
Do not disclose or use except as authorized by the Hemodialysis Novel Therapies Consortium. 
24. Ikonomidis I, Lekakis JP, Nikolaou M, et al. Inhibition of interleukin-1 by anakinra improves vascular and 
left ventricular function in patients with rheumatoid arthritis. Circulation 2008;117:2662-9. 
25. Hung AM, Ellis CD, Shintani A, Booker C, Ikizler TA. IL-1beta receptor antagonist reduces inflammation 
in hemodialysis patients. J Am Soc Nephrol 2011;22:437-42. 
26. Yang BB, Baughman S, Sullivan JT. Pharmacokinetics of anakinra in subjects with different levels of 
renal function. Clin Pharmacol Ther 2003;74:85-94. 
27. Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human 
interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, 
multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:614-24. 
28. Cohen SB, Moreland LW, Cush JJ, et al. A multicentre, double blind, randomised, placebo controlled 
trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid 
arthritis treated with background methotrexate. Ann Rheum Dis 2004;63:1062-8. 
29. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant 
human interleukin-1 receptor antagonist. Arthritis Rheum 1998;41:2196-204. 
30. Fleischmann RM, Schechtman J, Bennett R, et al. Anakinra, a recombinant human interleukin-1 
receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, 
multicenter, placebo-controlled trial. Arthritis Rheum 2003;48:927-34. 
31. Sibley CH, Plass N, Snow J, et al. Sustained response and prevention of damage progression in patients 
with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to 
determine three- and five-year outcomes. Arthritis Rheum 2012;64:2375-86. 
32. 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. 
33. Pruessner JC, Kirschbaum C, Meinlschmid G, Hellhammer DH. Two formulas for computation of the 
area under the curve represent measures of total hormone concentration versus time-dependent 
change. Psychoneuroendocrinology 2003;28:916-31. 
 
 
 
 


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15 Attachments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15.1 Study Procedures 
 
SCREENING 
BASELINE / 
RANDOM- 
IZATION 
STUDY DRUG TREATMENT 
Post-Treatment Follow-Up 
Procedure 
Pre 
screening 
1st  
Screening 
Visit 
Day -30 to 
Day -14 
2nd 
Screening 
Visit 
Day -10 to 
Day -1 
Baseline Visit 
Day 0 
 
Weeks 
1-3 
Week 4 Week 8 Week 
12 
Week 
16 
Week 
20 
Week 
24 
Week 
28 
Week 
32 
Week 
36 
Week 
40 
Week 
44 
Week 
48 
Preliminary eligibility  
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm eligibility 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics & medical 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
CRP 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
CBC with differential 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Serum pregnancy (WOCBP)1 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Testing for TB, Hep B/C, HIV 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood collection for batched 
assays 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Physical Exam, Vital Signs 
Assessment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACIT-Fatigue 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
BDI-II 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Dialysis Symptom Index 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Illness Effects Questionnaire 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
KDQOL-SF12 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Hand Grip 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
 
 
 
Study Drug Administration 
 
 
 
 
3X / week at hemodialysis 
 
 
 
 
 
 
Drug Tolerability 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 


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1Woman of childbearing potential includes 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.   


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15.2 DSMB Charter 
 
Data and Safety Monitoring Board (DSMB) Charter 
Hemodialysis 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 Hemodialysis Novel Therapies Consortium – ACTION 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 Institutional 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 analyses 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. Kusek will serve as the DSMB Executive Secretary.  The Chairperson is the contact person 
for the DSMB.  Other NIDDK official (s) or NIDDK appointee (s) may serve as an ex-officio member (s) of 


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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(s) of the DCC and members of 
his/her staff, and by Clinical Center investigators, as needed.  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 


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conduct of the study in the Executive Session.  The DSMB can become unblinded if trends develop either 
for benefit or harm to the participants.  
 
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 masked treatment groups; however, 
the DSMB may request that the treatment groups be unmasked 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. 
 


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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 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 include 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.