Table 1: Erythrocyte Stimulating Agents

Compound	Drug Names	Manufacturer	Production Site	Supplier	Distribution Sites
Erythropoietin- α	Epogen	Amgen	USA	Amgen	USA
Erythropoietin-α	Procrit	Amgen	USA	Ortho Biotech	USA
Erythropoietin-α (citrate buffer)	Erykine-cancer Epofit-kidney	Intas	India	---	---
Erythropoietin-α (w/o serum albumin)	Eprex Epypo Epopen Epoxitin Globuren	J&J subsidiary (Ortho Biologics)	Puerto Rico	Cilag Janssen	Europe, Canada (Some of these no longer distributed)
Erythropoietin-α Otherwise unspecified	Abseamed Binocrit HEXAL	Rentschler Biotechnologie GmbH	---	---	---
Erythropoietin-α Otherwise unspecified	Wepox	Wockhardt-India.	---	---	---
Erythropoietin-β	(Neo)Recormon	Roche	Germany	Roche	Europe Recormon no longer marketed
Erythropoietin-β	Erantin	---	---	Boehringer Mannheim (Spain), Roche (Spain)	Discontinued or no longer marketed
Erythropoietin-β	Epoch	Chugai	Japan	---	Under development
Erythropoietin-β	Betapoietin	CinnaGen Zahravi	---	---	---
Erythropoietin-δ In human cell lines	Dynepo Gene Activated Erythropoietin	Aventis Transkaryotic Therapies	---	Shire	Europe (not yet launched) Patent issues
Erythropoietin-Ω	Epomax Hemax Hemax-Eritron	Baxter	---	Cryopharma (Mexico) Lek (Czech) Sidus (Argentina) Bio Sidus (Thailand) Biosintetica (Brazil)	Countries outside USA
Erythropoietin-Ω	Hemax EPOMAX HP-Epo	Elanex with Hindustan Antibiotics	---	---	---
Erythropoietin-ζ	Retacrit Silapo	Norbitec GmbH BIOCEUTICALS Arzneimittel AG	Germany?	Hospira STADA	European Union Germany
Erythropoietin-Unspecified	Ceriton	Ranbaxy	India	---	---
Erythropoietin-Unspecified	Epofer-cancer Vintor-kidney	Emcure	India	---	---
Erythropoietin-Unspecified	Epotin	Gulf /Julphar	UAE	---	---
Erythropoietin-Unspecified	Espogen	LG Life Sciences (India)	Korea	LG Life Sciences	Asia, Africa, Middle East
Erythropoietin-Unspecified	ReliPoietin	Reliance Life Sciences with Reliance Gene-Medix Plc	Ireland India	---	---
Erythropoietin-Unspecified	Shanpoietin	Shantha (Sanofi-Aventis)	India	Shantha	India Developing Countries
Erythropoietin-Unspecified	Zyrop	Zydus Cadila	India	---	---
Modified erythropoietin-α Darbepoietin	Aranesp	Amgen	USA	Amgen	USA, Europe
Modified erythropoietin-α Darbepoietin	Nespo	Amgen	---	Dompé Biotec S.p.A.	Europe
Modified Erythropoietin-β Continuous Erythropoietin Receptor Activator (Pegylation)	Mircera	Roche	---	Roche	USA, Europe (Patent issues affect distribution)

?= possibly

Table 2: Mortality and Anemia: Observational Data from USRDS

Mortality Rates (Deaths/1000 tx-yrs)	Hematocrit (Vol%)
Groups & Causes of Death	<27	27 to <30	30 to <33	33 to <36
Non-diabetic—All Cause	214.7	192.0	170.6	161.4
Cardiac	80.1	77.8	71.8	69.0
Diabetic—All Cause	342.7	298.2	258.3	234.6
Cardiac	147.9	135.9	119.7	112.7

Table 3A: FDA Registration studies-Erythropoietin alpha*

Study	Population	Blind	Size	Duration	Entry Criteria	Exclusion Criteria
8601 Eschbach 1989 x2, 1991 Adamson 1989 Lundin 1991 FDA 1989 USA 9 sites	Hemo Adults	No control Open-label	426 or 412 or 333 or 309	Not stated 12+ mos	Hct <30% Adequate Fe	Dx impairing EPO result Uncontrolled HTN
86-004 Canadian Group 1990 Keown 1991 Laupacis 1991 FDA 1989 Canada 13 sites	Hemo Adults	Double	118	26 wks	Hb <9	Non-epo deficiency anemia Unable to do walk test bc of disorders such as type 1 diabetes (Keown 1991)
8701 FDA 1989 Unpublished USA 3 sites	Hemo Adults	Double to Open-label	101 or 62, 82 or 106	12 wk control to 12 wk extension	---	---
8904 FDA 1989 Unpublished	Peritoneal Adults	Double to Open-label	152	12 wk control to 12 wk extension	---	---
FDA 1989 Unpublished Canada 1 site	Hemo	Double	18	9 wks	---	---
US Study Group-Teehan 1990, 1991 Abels 1990 G88-011 Lim 1989 n=10 ?Stone 1988 FDA 1989 USA 15 sites	Pre-dialysis	Double to Open-label	117	8 wks to 6 mos extension	Hct ≤ 38 ♂ ≤ 32♀ Serum Cr used No GFR stated Good nutrition	Recent infection Major clinical dx Uncontrolled HTN Recent androgen use Recent transfusions
FDA 1989 Kleinman 1989 n=14 ?Watson 1990 Complete trial unpublished USA ? sites	Pre-dialysis	Double to ?Open & > dose	93	12 wks ?12 wk extension	Anemia undefined Serum Cr 3 to11 mg/dl	Dx impairing EPO result Recent infection Major clinical dx, seizure Uncontrolled HTN Fe or vitamin deficiency GI/urinary blood loss Recent androgen use Obesity
FDA 1989 Unpublished Europe ? sites	Pre-dialysis	Open-label	24	8 wks	---	---

? = possibly or unknown
Cr = creatinine
Dx = diagnosis
EPO = erythropoietin
FDA = Food and Drug Administration
Fe = iron
GFR = glomerular filtration rate
Hb = hemoglobin
Hct = hematocrit
Hemo = hemodialysis
HTN = hypertension

Table 3B: FDA Registration studies-Erythropoietin alpha (continued)*

Study	Dose	Target Hb(Hct)	Transfusion Criteria	Stratification by
Study	Dose	Target Hb(Hct)	Transfusion Criteria	Hb (Hct)	Dose	Dialysis Adequacy or Renal Clearance
8601 Eschbach 1989 x2, 1991 Adamson 1989 FDA 1989 USA 9 sites	IV 300 to 150 to 75 U/kg	32 to 38%	None	No	No	No
86-004 Canadian Group 1990 Keown 1991 Laupacis 1991 FDA 1989	IV 100 U/kg to variable	9.5 to 11 vs 11.5 to 13 vs No EPO	None	Not entry QOL by target	No	No
8701 FDA 1989 <Unpublished <USA 3 sites >	? Route 0 or 150 U/kg	35%	---	---	---	---
8904 FDA 1989 <Unpublished	---	---	---	---	---	---
FDA 1989 <Unpublished <Canada 1 site >	IV 0, 50, 100, or 200 U/kg	---	---	---	---	---
US Study Group-Teehan 1990, 1991 Abels 1990 G88-011 Lim 1989 ?Stone 1988 FDA 1989 <USA 15 sites>	IV 0, 50, 100, or 150 U/kg To IV or SQ & variable dose	---	None	No	No	No
FDA 1989 Kleinman 1989 ? Watson 1990 <USA ? sites >	SQ 0 or 100 U/kg (?150 U/kg extension)	---	None	---	---	---
FDA 1989 Unpublished Europe ? sites	IV 50, 100, or 150 U/kg	---	---	---	---	---

IV = intravenous
QOL = quality-of-life
SQ = subcutaneous

Table 3C: FDA Registration studies-Erythropoietin alpha (continued)*

Study	Results
8601 Eschbach 1989 x2, 1991 Adamson 1989 FDA 1989 USA 9 sites	T=0 hct data available for 304. Mean t=0 hct 22%. T=6 mos & 10 mos hct data available for n = 33 & 104. QOL testing limited to n = 130 assessed at variable times. Reportedly transfusion need ↓, but no accounting for drop-out. Some kinds of transfusions, e.g., for dialysis blood loss not included in analysis. Non-responsive patients identified. Bone marrow bx not in protocol. HTN ↑ & perhaps associated with seizures. Vascular access clotting reported.
Canadian Group 1990 Keown 1991 Laupacis 1991 FDA 1989 Canada 13 sites	Mean t = 0 hb 7 g/dl. Hb increased; mean dosing higher for higher targets. 41.5% had >6U packed red blood cells in prior yr. ↓ transfusions in Epo groups. QOL reportedly better with Epo for Sickness Impact Profile, but > rigorous Time Trade-off ,score. Also not better. with higher vs lower Hb Epo tx levels. Kidney Diseae questionairre Exercise stress test better, walking tolerance not better Diastolic HTN & vascular access clotting ↑. Bone marrow bx not in protocol.
8701 FDA 1989 Unpublished USA 3 sites	62/101 evaluable for efficacy Patients also evaluated after X-over in extension study Hct%: NA Transfusion: NA QOL: Karnofsky by patient; Nottingham Health Profile; National Kidney Dialysis & Kidney Transplantation Study; Single item patient-reported outcome: Per FDA meeting
8904 FDA 1989 Unpublished	Patients also evaluated after X-over in extension study Hct%: NA Transfusion: NA QOL : Karnofsky by patient; Nottingham Health Profile; National Kidney Dialysis & Kidney Transplantation Study; Single-item patient-reported outcome: Per FDA meeting
FDA 1989 Unpublished Canada 1 site	Hct increased per dose response: NA
US Study Group-Teehan 1990, 1991 Abels 1990 G88-011 Lim 1989 ?Stone 1988 FDA 1989 USA 15 sites	Mean t=0 hct 28.8%. Hct increased per dose response. Doses 75-150 U/kg TIW corrected hct. 106/117 completed 8 wks; 11 DC for AEs No transfusion data in FDA summary. No information on QOL instrument in methods. HTN adverse event data limited by lack of definition. Bone marrow bx done in 6 of Stone subset n = 12 @8 wks. Concerns about doses ≥100 U/kg. (Stone) Pharmacokinetic data from 8 (Lim) Exercise data from 8 (1 placebo) (Lim)
FDA 1989 Kleinman 1989 ? Watson 1990 Complete trial unpublished USA ? sites	Hct corrected in 58% of Epo treated vs 4% of placebo No transfusion data in FDA summary. Bone marrow bx not in protocol. No complete publication. Kleinman subset n = 14. ?Watson subset n = 11.
FDA 1989 Unpublished Europe ? sites	Hct increased per dose response: NA No transfusion data in FDA summary. Bone marrow bx not in protocol.

*Non-randomized studies not used for FDA approval such as Bommer 1987, Casati 1987, Eschbach 1987, Graf 1987, Moia 1987, Schaefer 1988, Strutz 1987, Winearls 1986 were not included.
? = unknown
↑ = increased
↓ = decreased
>= more (than)
Bx = biopsy
NA = not available for review
T = 0 = value at baseline or time zero
TIW = three time weekly

Table 4: Anemia and Transfusion in the Canadian Group Study: Hemodialysis
6 Month Study (Mean Age Mid 40s)

Blood Parameter	Placebo	Hct target 9.5-11% vol Variable IV dose 3x/wk	Hct target 11.5-13% vol Variable IV dose 3x/wk
Baseline Hct	7.1±0.9 n=40	6.9±1.0 n=40	7.1±1.2 n=38
Hct at 6 mo (completers)	7.4±1.2 n=32	10.2±1.0 n=34	11.7±1.4 n=33
Hct at end (ITT)	----------	-----------	----------
Transfusion—patient number	23	1	1
Transfusion—number of blood units	----------	-----------	----------
Transfusion—number of units/person transfused	----------	-----------	----------
Transfusion—number of transfusions by a priori protocol established criteria	----------	-----------	----------
Transfusions—number of transfusions for hct <10	----------	----------- (GI bleed)	---------- (During surgery)
Transfusions—number of transfusions for hct <7	----------	-----------	----------
Transfused in prior year	7.3±8.3	6.6±6.8	5.6±6.4
Transfusion dependent (≥ 6 transfusions/year; >2 transfusions in 3 months if dialysis just started)	19	19	11
Anemia evaluation	Fe tests at t=0 & during study; Fe given prn	Fe tests at t=0 & during study; Fe given prn	Fe tests at t=0 & during study; Fe given prn

Fe+ = iron
Hct = hematocrit
ITT = intent-to-treat analysis
IV = intravenous
PRN = as needed
T = 0 = value at baseline or time zero

Table 5: Anemia and Transfusion in US Human Recombinant Erythropoietin Pre-dialysis Study Group (Teehan 1991) 8 Week Study (Mean Age 57.1 yrs)

Blood Parameter	Placebo	50 u/kg 3x/wk IV	100 u/kg 3x/wk IV	150 u/kg 3x/wk IV
Baseline Hct	M 29.9±4.1 n = 17 F 28.4±3.1 n = 12	M 29.7±3.8 n = 18 F 28.4±2.6 n = 10	M 29.4±4.7 n = 17 F 27.0±2.1 n = 11	M 28.2±5.6 n = 17 F 29.7±3.3 n = 13
Hct at 6 mo (completers)	----------	----------	----------	----------
Hct at end (ITT)	----------	----------	----------	----------
Hct ↑ of 6% vol during 8 wks	N=3	N=16	N=22	N=27
Discontinuation	N=4	N=1	N=3	N=3
Transfusion—patient number	N=0	N=0	N=0	N=0
Transfusion—number of blood units	----------	----------	----------	----------
Transfusion—number of units/person transfused	----------	----------	----------	----------
Transfusion—number of transfusions by a priori protocol established criteria	----------	----------	----------	----------
Transfusions—number of transfusions for hct < 10	----------	----------	----------	----------
Transfusions—number of transfusions for hct < 7	----------	----------	----------	----------
Transfused in prior year	----------	----------	----------	----------
Transfusion dependent (≥ 6 transfusions/year; > 2 transfusions in 3 months if dialysis just started)	----------	----------	----------	----------
Anemia evaluation	Fe, B-12, Folate tests at t = 0. Folate given.	Fe, B-12, Folate at t = 0. Folate given.	Fe, B-12, Folate at t = 0. Folate given.	Fe, B-12, Folate at t = 0. Folate given. Multiple Myeloma incidentally found later

F = female
Fe = iron
Hct = hematocrit
ITT = intent-to-treat analysis
IV = intravenous
M = male
T = 0 = value at baseline or time zero

Table 6A: FDA Registration studies-darbepoetin alpha

Study	Population	Blind	Size	Duration	Entry Criteria	Exclusion Criteria
Study 117 Nissenson 2002 (IND) US sites 35 Canadian sites 5 (Amgen)	HD Adult (57.9 yrs; range 20-90)	Double Blind Active Control	507(504) (1D:2 E) 361 PP	28 wk randomized tx 4 wk screening	Hb 9.5-12.5 g/dl (Actual hb 11.2 g/dl; range 9.6-12.6 g/dl) Stable IV Epo dose	Infection, inflammation Congestive heart failure Seizures Uncontrolled HTN Fe deficiency Recent transfusion
Study 970200 or 200 Varenterghem 2002 (Non-IND) European sites 27 Australian sites 4 (Amgen)	HD, PD Adult (60.4 yrs; range 18-88)	Open-label Active Control	522(519) (2D:1E) 366 PP	32 wk randomized tx 4 wk screening +20 wk maintenance	Hb 9.5-12.5 g/dl Stable Epo dose	Infection, inflammation CHF, Seizures Uncontrolled HTN Fe deficiency Recent transfusion

Study

Population

Blind

Size

Duration

Entry Criteria

Exclusion Criteria

Study 117
Nissenson
2002
(IND)
US sites 35
Canadian sites 5
(Amgen)

HD
Adult
(57.9 yrs;
range 20-90)

Double Blind
Active Control

507(504)
(1D:2 E)
361 PP

28 wk randomized tx
4 wk screening

Hb 9.5-12.5 g/dl
(Actual hb 11.2 g/dl;
range 9.6-12.6 g/dl)
Stable IV Epo dose

Infection, inflammation
Congestive heart failure
Seizures
Uncontrolled HTN
Fe deficiency
Recent transfusion

Study 970200 or 200
Varenterghem 2002
(Non-IND)
European sites 27
Australian sites 4
(Amgen)

HD, PD
Adult
(60.4 yrs;
range 18-88)

Open-label
Active Control

522(519)
(2D:1E)
366 PP

32 wk randomized tx 4 wk screening
+20 wk maintenance

Hb 9.5-12.5 g/dl

Stable Epo dose

Infection, inflammation
CHF,
Seizures
Uncontrolled HTN
Fe deficiency
Recent transfusion

CHF = congestive heart failure
D = darbe = darbepoetin
E = Epo = erythropoietin
Fe = iron
Hb = hemoglobin
HD = hemodialysis
HTN = hypertension
IND = Study performed as an investigational new drug under the purview of the FDA
IV = intravenous
PD = peritoneal dialysis
PP = per protocol

Table 6B: FDA Registration studies-darbepoetin alpha (continued)

Study	Dose	Target Hb(Hct)	Transfusion Criteria	Stratification by
Study	Dose	Target Hb(Hct)	Transfusion Criteria	Hb (Hct)	Dose	Dialysis Adequacy or Renal Clearance
Study 117 Nissenson 2002 (IND) US sites 35 Canadian sites 5 (Amgen)	IV Initial dose based on prior Epo dose Epo 3x/wk vs Darbe 1x/wk + 2x/wk placebo Doses titrated	Hb within -1 & 1.5 g/dl of t=0 Hb 9-13 g/dl	---	--- (Actual hb 11.2 g/dl; range 9.6-12.6 g/dl)	--- (Actual t=Epo dose 13,776;1.2-120 x10³U/wk)	---
Study 970200 or 200 Varenterghem 2002 (Non-IND) European sites 27 Australian sites 4 (Amgen)	IV or SQ Initial dose based on prior Epo dose Epo same route & regimen vs Darbe q2 wk (if prior Epo 1x/wk) or 1x/wk (if prior Epo 2-3x/wk) by prior route Doses titrated	Hb within -1 & 1.5 g/dl of t=0 Hb 9-13 g/dl	---	--- (Actual hb 11.2 g/dl; range 9.5-12.5 g/dl)	--- (Actual t=median Epo dose 6000; quartiles 4-9 x10³U/wk)	---

Hct = hematocrit
SQ = subcutaneous

Table 6C: FDA Registration studies-Darbepoetin alpha (continued)

Study	Endpoint/Results
Study 117 Nissenson 2002 (IND) US sites 35 Canadian sites 5 (Amgen)	Non-inferiority (Per-protocol)(~71-2% patients n = 361)(drop-outs: 85; other non-per-protocol 68[71]) Endpoint Hb change t = 0 to t = wk 21-28; also by regimen & route % hb values within target range (-1 & 1.5 g/dl of t = 0; hb 9-13 g/dl) % dose change for out of range hb values Intra-patient hb variability Drug dose
Study 970200 or 200 Varenterghem 2002 (Non-IND) European sites 27 Australian sites 4 (Amgen)	Non-inferiority (Per-protocol)(~64% patients n=336)(drop-outs: ~76; other non-per-protocol ~110) Endpoint Hb change t = 0 to wk 25-32 % hb values within target range (-1 & 1.5 g/dl of t=0; hb 9-13 g/dl) Intra-patient hb variability Transfusion level (not reported in paper; indicated in FDA review)

Study

Endpoint/Results

Study 117
Nissenson 2002
(IND)
US sites 35
Canadian sites 5
(Amgen)

Non-inferiority (Per-protocol)(~71-2% patients n = 361)(drop-outs: 85; other non-per-protocol 68[71])
Endpoint Hb change t = 0 to t = wk 21-28; also by regimen & route
% hb values within target range (-1 & 1.5 g/dl of t = 0; hb 9-13 g/dl)
% dose change for out of range hb values
Intra-patient hb variability
Drug dose

Study 970200 or 200
Varenterghem 2002
(Non-IND)
European sites 27
Australian sites 4
(Amgen)

Non-inferiority (Per-protocol)(~64% patients n=336)(drop-outs: ~76; other non-per-protocol ~110)

Endpoint Hb change t = 0 to wk 25-32
% hb values within target range (-1 & 1.5 g/dl of t=0; hb 9-13 g/dl)
Intra-patient hb variability
Transfusion level (not reported in paper; indicated in FDA review)

Table 7A: FDA Registration studies-Pegylated erythropoietin-beta

Study	Population	Blind	Size	Duration	Entry Criteria	Exclusion Criteria
Canaud (STRIATA) 2008 (Hoffmann La Roche)	HD, PD On IV darbe Adult	Open Active Control	313	36 wk randomized tx +16 wk safety period	Hb 10.5-13 g/dl HD Kt/V ≥1.2; URR ≥ 65% PD Kt/V >1.8 Adequate Fe	“Non-renal” anemia CRP ↑↑ Life expectancy <12 mo
Klinger (AMICUS) 2007 (Hoffmann-LaRoche)	HD, PD Adult	Open Active Control	181 (C3:E1)	24 wk randomized tx (Part 1 ESA type)	Hb 8-11 g/dl HD Kt/V ≥ 1.2;URR > 65% PD Kt/V ≥ 1.8 Adequate Fe	Recent ESA use “Non-renal” anemia CRP ↑↑ Uncontrolled HTN No severe disease No recent transfusion
Levin (MAXIMA) 2007 (Hoffmann La Roche)	HD, PD On IV epo 1-3x/wk Adult	Open Active Control	673	36 wk randomized tx +16 wk safety period	Hb 10.5-13 g/dl Adequate Fe	“Non-renal” anemia CRP ↑↑ No recent transfusion Life expectancy <12 mo
Macdougall (ARCTOS) 2008 (See Kessler 2010 extension with regimen change) (Hoffmann-LaRoche)	CRI Stage 3-4 Adult	Open Active Control	324	28 wk randomized tx + 24 wk re-randomi-zation in CERA	Hb 8-11 g/dl Adequate Fe	Stated ESA naïve, but really no recent ESA “Non-renal” anemia CRP ↑ PLTs ↑↑ Uncontrolled HTN Immuno-suppression Expected need for dialysis <6 mo No severe disease Life expectancy <12 mo No recent transfusion
Spinowitz (RUBRA) 2008 (Hoffmann La Roche) (See regimen)	HD, PD On Epo IV SQ Adult	Open Active Control	336(333)	36 wk randomized tx 4 wk baseline	Hb 10.5-13 g/dl HD (Kt/V ≥ 1.2; URR ≥ 65%) PD (Kt/V ≥1.8) Adequate Fe	“Non-renal” anemia CRP ↑↑ Life expectancy < 12 mo No recent transfusion
Sulowicz (PROTOS) 2007 (Hoffman-LaRoche)	HD, PD On SQ Epo Adult	Open Active Control	572	36 wk randomized tx +16 wk safety period	Hb 10.5-13 g/dl HD Kt/V ≥ 1.2;URR > 65% PD Kt/V ≥ 1.2 Adequate Fe	“Non-renal” anemia CRP ↑↑ PLTs ↑↑ Uncontrolled HTN No severe disease No recent transfusion

↑↑ = markedly increased
C = CERA= continuous erythropoiesis receptor activator=methoxy polyethylene glycol epoetin beta=pegylated erythropoietin-beta
CRI = chronic renal insufficiency; stage 3 & 4 are pre-dialysis
CRP = C-reactive protein
Darbe = darbepoietin
E = Epo = erythropoietin
Fe = iron
Hb = hemoglobin
HD = hemodialysis
HTN = hypertension
IV = intravenous
Kt/V = dialyzer clearance of urea x dialysis time/ volume of urea distribution in the body (measure of dialysis adequacy)
PD = peritoneal dialysis
PLTs = platelets
SQ = subcutaneous
URR = urea reduction ratio (measure of dialysis adequacy)

Table 7B: FDA Registration studies-Pegylated erythropoietin-beta (continued)

Study	Dose	Target Hb(Hct)	Transfusion Criteria	Stratification by
Study	Dose	Target Hb(Hct)	Transfusion Criteria	Hb (Hct)	Dose	Dialysis Adequacy or Renal Clearance
Canaud (STRIATA) 2008 (Hoffmann La Roche)	CERA IV q2 wks based on prior Darbe doses. Could be as high as Darbe >80 ug/wk, CERA 180 ug q 2wks.	Hb 10-13.5 g/dl Hb ±1 g/dl of baseline Doses titrated	---	---	---	---
Klinger (AMICUS) 2007 (Hoffmann-LaRoche)	CERA IV q2 wks. Start 0.40 ug/kg/2 wks Epo [alpha, beta] IV 3x/wk at approved tx doses	Hb ≥11 g/dl Hb ↑ of ≥1 g/dl Doses titrated	---	---	---	---
Levin (MAXIMA) 2007 (Hoffmann La Roche)	CERA SQ q2 wks & q 4 wks based on prior Epo [alpha, beta] doses. Could be as high as Epo > 16,000 U/wk, CERA 180 ug q 2 wks & 360 ug q4 wks.	Hb 10-13.5 g/dl Hb ±1 g/dl of baseline Doses titrated	---	---	---	---
Macdougall (ARCTOS) 2008 (See Kessler 2010 extension with regimen change) (Hoffmann-LaRoche)	CERA SQ started at 0.6 ug/kg/2 wks. Darbe SQ started at 0.45 ug/kg/wk	Hb ≥11 g/dl Hb ↑ of ≥1 g/dl Doses titrated	---	---	---	---
Spinowitz (RUBRA) 2008 (Hoffmann La Roche) (See regimen)	CERA SQ, IV q2 wks & q 4 wks based on prior Epo [alpha, beta] doses & prior route. Could be as high as Epo > 16,000 U/wk, CERA 180 ug q 2 wks.	Hb 10-13.5 g/dl Hb ±1 g/dl of baseline Doses titrated	---	---	---	---
Sulowicz (PROTOS) 2007 (Hoffman-LaRoche)	CERA SQ q2 wks & q 4 wks based on prior Epo [alpha, beta] doses. Could be as high as Epo > 16,000 U/wk, CERA 180 ug q 2 wks & 360 ug q4 wks.	Hb 10-13.5 g/dl Hb ±1 g/dl of baseline Doses titrated	---	---	---	---

D = Darbe = darbepoetin

Table 7C: FDA Registration studies-Pegylated erythropoietin-beta (continued)

Study	Results
Canaud (STRIATA) 2008 (Hoffmann La Roche)	Efficacy response rate=Change in Hb level t=0 & wks 29-36. Non-inferiority in the per-protocol population. (D -0.12 g/dl vs C 0.06 g/dl) Hb level (D 11.8 g/dl vs C 12.1g/dl) Hb + 1 g/dl of baseline (ITT population) (D 65.5% vs C q2wk 71.8%) Hb variability (mean within pt SD) (D 0.5 g/dl vs C 0.6 g/dl) Transfusions (D 10.3% vs C q2wk 12.4%)(Hb prior to transfusion recorded) Death rate (D 7.7%, C q2wk 8.5%)
Klinger (AMICUS) 2007 (Hoffmann-LaRoche)	Efficacy response rate = Hb >11 g/dl & Hb ↑ of ≥ 1 g/dl during 24 wks; Per-protocol (C 98.3% vs E 97.2%) ITT (C 93.3% vs E 91.3%); Post hoc non-inferiority. Doses to achieve response rate QOL-short SF 36 Transfusions Fe supplementation requirements Cardiovascular disease imbalance at baseline E > C
Levin (MAXIMA) 2007 (Hoffmann La Roche)	Efficacy response rate=Change in Hb level t = 0 & wks 29-36. Non-inferiority in the per-protocol population. (E -0.75 g/dl vs C q2wk -0.71 g/dl, C qmo -0.25 g/dl) Hb + 1 g/dl of baseline (during wks 29-36) (E 67% vs C q2 wks 68%, C q1 mo 68%) Hb variability (mean within pt SD)(post hoc) (E 0.6 vs C q2wk 0.6, C qmo 0.6 during wks 29-36) Transfusion incidence (E 8%, C q2wk 10% C qmo 7%) Death rate (E 8%, C q2wk 9% , C qmo 7%)
Macdougall (ARCTOS) 2008 (See Kessler 2010 extension with regimen change) (Hoffmann-LaRoche)	Efficacy response rate = Hb >11 g/dl & Hb ↑ of ≥1 g/dl during 28 wks. Per-protocol (D 99.3% vs C 99.3%) Hb level over time (D 12.0 g/dl vs 12.2 g/dl at 28 wks) Time to hb target (Median D 29 days vs C 43 days) Transfusion incidence (6.8% vs C 2.5%) QOL Short SF-36 (not clear if any differences were significant [biologically, statistically]; only reported improved from baseline) Deaths (D 6% vs C 5%)
Spinowitz (RUBRA) 2008 (Hoffmann La Roche)	Change in Hb level t = 0 & wks 29-36. Non-inferiority in the per-protocol population. (E -0.01 g/dl vs C 0.14 g/dl) Effect of route on primary endpoint No difference Hb + 1 g/dl of baseline (ITT population) Transfusions (ITT population) (E 11.3% vs C 9.7%) Doses (Median E 7,310 IU/wk [IQR: 4,000–13,800] vs C 60 ug/2 wks [IQR: 36–94]) Death rate (E = 10 vs C = 7)
Sulowicz (PROTOS) 2007 (Hoffman-LaRoche)	Efficacy response rate = Change in Hb level t = 0 & wks 29-36. Non-inferiority in the per-protocol population. (E -0.11 g/dl vs C q2 wks 0.03 g/dl, C q1 mo -0.13 g/dl) Hb level (E 11.5 g/dl vs C q2wk 11.7 g/dl, C qmo 11.5 g/dl) (PP) Hb + 1 g/dl of baseline (ITT population) (E 72.2% vs C q2wk 75.6%, C qmo 66.1%) Hb variability (mean within pt SD)(post hoc) E 0.6 g/dl vs C q2 wks 0.5 g/dl, C q mo 6 g/dl) Transfusion incidence (E 9.9% vs C q2wk 6.3%, C qmo 10.5%) Death rate (E 1-3x/wk 6.3%, C q2wk 6.8%, C qmo 9.5%)

Fe = iron
ITT = intent-to-treat
Q = each
QOL = quality-of-life
SD = standard deviation
SF-36 = Short Form Health Survey

Table 8A: FDA Registration studies-Peginesatide

Study	Population	Blind	Size	Duration	Entry Criteria	Exclusion Criteria
Study AFX-01-012 Emerald 1 (unpublished) (Affymax/Takeda)	HD Adult (median ~54; 49-67)	Open-label Active Control	803 (2:1 P:E)	36 wk randomized tx 4 wk screening	Hb 10-12 g/dl	Bleeding disorders Non-renal anemia Cancer Uncontrolled HTN
Study AFX-01-014 Emerald 2 (unpublished) (Affymax/Takeda)	HD Adult (median 59; 50-69)	Open-label Active Control	823 (2:1 P:E)	36 wk randomized tx 4 wk screening	Hb 10-12 g/dl	Bleeding disorders Non-renal anemia Cancer Uncontrolled HTN

www.clinicaltrials.gov/ct2/show/NCT00597753?term=affymax&rank=10
www.clinicaltrials.gov/ct2/show/NCT00597584?term=affymax&rank=13
E = erythropoietin
Hb = hemoglobin
HD = hemodialysis
HTN = hypertension
P = peginesatide

Table 8B: FDA Registration studies-Peginesatide (continued)

Study	Dose	Target Hb(Hct)	Transfusion Criteria	Stratification by
Study	Dose	Target Hb(Hct)	Transfusion Criteria	Hb (Hct)	Dose	Dialysis Adequacy or Renal Clearance
Study AFX-01-012 Emerald 1 (Affymax/Takeda)	IV Doses titrated	Hb 10-12 g/dl	---	---	---	---
Study AFX-01-014 Emerald 2 (Affymax/Takeda)	IV Doses titrated	Hb 10-12 g/dl	---	---	---	---

Table 8C: FDA Registration studies-Peginesatide (continued)

Study	Endpoint/Results
Study AFX-01-012 Emerald 1 (Affymax/Takeda)	Non-inferiority Hb change t = 0 to wk 36 % patients with mean hb values between 10-12 g/dl t = 0 and 8 wks % patients transfused t=0 to 36 wks
Study AFX-01-014 Emerald 2 (Affymax/Takeda)	Non-inferiority Hb change t = 0 to wk 36 % patients with mean hb values between 10-12 g/dl t = 0 and 8 wks % patients transfused t=0 to 36 wks

Table 9: Anemia and Transfusion in ESA Analogue/Receptor Activator Pivotal Trials

Study	Randomized	Completed	Per-protocol	Hb (g/dl)	Dose (weekly) By wt*	Transfusion	Deaths
Nissenson 2002 Study 117	507 (D1:E2)	423	361	PP Wk 28 Mean from graph E 3x/wk ~ 11.2 D 1x/wk ~ 11.2	PP Wks 21-28 IV Mean(SD) E 3x/wk 13639 (12805) D 1x/wk 54.2 (47.6) Median (range) E 3x/wk 9900 (0-78,750) D 1x/wk 38.0 (0-309.0)	? E 3x/wk 11% D 1x/wk 10% Transfusion > 1 unit PP Wks 11-28 (endpoint) E 3x/wk 21(8.8%) D 1x/wk 7(5.8%)	Safety T+ 28 d f/u E 3x/wk 23(6.9%) D 1x/wk 9(5.3%)
Varenterghem 2002 Study 970200 or 200	522	389	336	?Wk 24-32 Mean from graph E 1-3x/wk ~10.8 D q1or2/wks ~10.8	IV SQ Mean from graph for 4 wk period immediately after wk 24-32 evaluation period E 1-3x/wk IV ~ 7000 SQ 5000 D q1 or 2/wks IV ~ 27 SQ ~ 28	E 1-3x/wk D q1 or 2/wks	E 1-3x/wk11/173(6%) D q1 or 2/wks 41/346(12%)
Canaud 2008 (STRIATA)	313	249	249	PP Mean(SD) Wks 29-36 D q1-2 wks 11.8 + 1.0 C q2 wks 12.1 + 1.0	?PP Median(range)* Wks 29-36 D q1-2 wks 28.1(17.6-52.0) C q2 wks 24.1(13.1-37.2)	? over 16 wks D q1-2 wks 10.3% C q2 wks 12.4%	ITT (unclear if 36 or 52 wks) Patient#(%) D q1-2 wks 10 (6.4%) C q2 wks 12(7.6%)
Klinger 2007 (AMICUS)	181 (C3:E1)	164	155(148)	PP Mean(SD) Wk 24 IV E 3x/wk 12.0 + 1.1 C q2 wks 12.1 + 1.4 No recent ESA	ITT Median(range)* Wk 24 IV E 3x/wk 5484 (2939-10186) C q2 wks 20.4 (8.1-31.2)	ITT Patient#(%) E 3x/wk 2(4.3%) or 3(6.5%) conflict C q2 wks 7(5.2%)	ITT Patient#(%) E 3x/wk 0(0%) C q2 wks 2(1.5%) (1 requested dialysis DC)
Levin 2007 (MAXIMA)	673	566	540	PP Mean(SD) Wks 29-36 E 1-3x/wk 11.9 + 0.8 C q2 wks 11.9 + 1.1 C q4 wks 11.9 + 1.0	Safety Median(range)* Wks 29-36 IV E 1-3x/wk 10800(6-18000) C q2 wks 28.5(14-50) C q4 wks 43.8(28.8-73)	Unclear if data collection limited to wks 28-36 or entire 36 wks E 1-3x/wk 17(8%) C q2 wks 21(10%) C q4 wks 16	ITT Patient#(%) [+ 16 wk f/u] [bf study end + after study completion or withdrawal] E 1-3x/wk 15(6.6%) 21(9.3%) 17(8%) C q2 wks 11(4.9%) 17(7.6%) 19(9%) C q4 wks 12(5.4%) 13(5.8%) 15(7%)
Macdougall 2008 (ARCTOS)	324	297	283	?ITT Mean(noSD) Wk 28 D 1x/wk 12.0+?? C q2 wks 12. 2+ ?? No recent ESA	?Median (no range) Wk 28 SQ D 1x/wk 15.3 +?? C q2 wks 13.1 +??	Patient#(%) D 1x/wk 11(6.8%) C q2 wks 4(2.5%)	Safety Patient#(%) D 1x/wk 4(2.5) C q2 wks 4(2.5%)
Spinowitz 2008 (RUBRA)	336(333)	282	256	PP Mean(SD) Wk 29-36 E 1-3x/wk 11.9 + 1.0 C q2 wks 11.9 + 1.0	Safety Median(range)* Wks 29-36 IV SQ E 1-3x/wk 7310 (4-13800) C q2 wks 30 (18-47)	Safety Transfusion#(Event#) E 1-3x/wk 59(23) C q2 wks 34(21)	Safety+F/U period Patient#(%) E 1-3x/wk 9+1(6.0%) C q2 wks 7 (4.2%)
Sulowicz 2007 (PROTOS)	572	499	474	PP Mean(SD) Wks 29-36 E 1-3x/wk 11.5 + 1.1 C q2 wks 11.7 + 1.0 C q4 wks 11.5 + 1.0	Safety Median(range)* Wks 29-36 SQ E 1-3x/wk 5500 (3-9000) C q2 wks 28 (13.5-42) C q4 wks 37.5(22.8-62.5)	Safety Patient#(%) E 1-3x/wk 19(9.9%) C q2 wks 12(6.3%) C q4 wks 20(10.5%)	Safety F/U period Patient#(%) E 1-3x/wk 11 + 1(6.3%) C q2 wks 12 + 2(6.8%) C q4 wks 18(9.5%)

? = unknown if
C = CERA= continuous erythropoiesis receptor activator=methoxy polyethylene glycol epoetin beta=pegylated erythropoietin-beta
d = day
D = darbepoetin
DC = discontinued
E = erythropoietin
F/U = follow-up
ITT = intent-to-treat
IV = intravenous
PP = per protocol
SD = standard deviation
SQ = subcutaneous
T = study duration

Table 10: Exercise Studies

Study	Size	Duration	Blind	Hb(Hct)	Dose	Results
Canadian Group 1990 Laupacis 1990, 1991 Orthobiotech/ J&J	118 99 completers HD	6 mos	DB	11.5-13 vs 9.5 to 11 vs No EPO	Variable	Mean hb ∆ 7.1 à 11.7 g/dl (↑ hgb) arm vs 6.9 à 10.2 g/dl (usual hb) vs 7.1 à 7.4 g/dl (placebo) (at 6 mo) Exercise stress test (time walked) better: 16.1à19.7 min (↑ hgb) vs 11.2à14.8 min (usual hb) vs 11.4à13.2 min (placebo)(at 6 mo) but imbalance at baseline Exercise tolerance (distance walked) not different: 470à 521 m (↑ hgb) vs 418à451 m (usual hb) vs 421à440 m (placebo) (at 6 mo) Post hoc analysis with limited correlation between treadmill time and hb ∆
Clyne 1992 Swedish National Federation of Kidney Patients, Swedish Society of Nephrology, Karolinska Inst.	12 tx; 8 control CRI	3 mos	Open	30 vs No EPO	Variable	Mean hb ∆ 8.6à11.7 g/dl (Epo arm) vs 9.3à9.4 g/dl (placebo) T=0 imbalance favored tx arm/determinationprocess/downloads/ ∆ in maximal exercise capacity (bike) better 128à145 W (Epo arm) vs 98à101 W (placebo) Perceived exertion & leg fatigue did not differ by group
Furuland 2003 Janssen-Cilag	Adult 416 210 completers (33 withdrawn bc of Besarab study) CRI, HD, PD	48-76 wks Length ↑ because of slow hb ∆	Open	13.5 -15 F & 14.5 -16 M vs 9-12	Variable	Mean hb ∆ (48 wks) Pre-dialysis 10.6à14.3 g/dl (↑ hgb) vs 10.9à11.7 g/dl (usual hb) vs PD 11.2à13.4 g/dl (↑ hb) vs 11.2à11.5 g/dl (usual hb) vs HD 11à13.5 g/dl (↑ hb) vs 11à11.3 g/dl (usual hb) Powered for exercise tests. Exercise component not completed bc many patients could not perform test.
McMahon 1999, 2000 Janssen-Cilag, Australian Kidney Fdn, Thailand	Adult 30 sedentary 14 completers HD (X-over)	4-8 mo titration; 4 wk maintenance	DB	14 vs 10	Variable	Mean hb ∆ ~8.6à ~ 14 g/dl (↑ hb) vs ~ 8.4à ~ 10.3 g/dl (usual hb) (in completers) Leg fatigue was the reason for exercise stoppage Peak work rate better (bike) at study end 145 (↑ hgb) vs 134 (usual hb) W (in completers); no t=0 Peak VO₂ better (bike) at study end 19.9 (↑ hgb) vs 19.1 (usual hb) L/min (in completers); no t=0
Morris 1993 BM	Children 14 7 completers HD, PD (X-over)	2-24 wk tx arms	SB	10.5-12 g/dl vs placebo	Variable	Mean hb ∆ 7.3à11.2 gdl 2 minute walk test (only 7 old enough to do) approached, but did not reach statistical significance with n = 7 in each arm Treadmill test (only 6 old enough to do; Bruce n=3; modified Bruce n = 3) approached, but did not reach statistical significance with n = 5 in each arm No means presented; individual patient results presented graphically
Painter 2002 Amgen	Adult 65 HD 55 completers	5 mos	DB	40-42 vs 30-33 ± exercise training	Variable	Mean hb ∆ 10.5à13.1 g/dl (↑ hb) vs 10.5à13.7 g/dl (↑ hb+exercise) vs 10.6à10.7 g/dl (usual hb) vs 10.4à10.4 (usual+exercise) Peak VO₂ minimally better (& not normal) with exercise training, but not ↑ Hct (Hb) Mean peak VO₂ 18.8à18.7 ml/kg/min (↑ hb) vs 18.5à20.8 ml/kg/min (↑ hb+exercise) vs 19.8à19.9 ml/kg/min (usual hb) vs 19.5à22.1 ml/kg/min (usual hb+exercise) Analysis on completers
Parfrey 2005 J&J	Adult 596 Incident HD 324 completers No cardiac sx	24 wk titration; 72 wk maintenance	DB treating MDs not blinded	13.5-14.5 vs 9.5-11.5		Mean hb ∆ 11à13.1 g/dl (↑ hb) vs 11à10.8 g/dl (usual hb) 6 minute walk test not different 277à143 m (completers) or 242 m (ITT) (↑ hb) vs 284à142 m (completers) or 254 m (ITT) (usual hb) Left ventricular volume not different (1^o endpoint). (See cardiac section.)
Palazzuoli 2006 Roche, NDRC & CKF salary support	Adult 40 CHF w CRI 38 completers (2 placebo pts re-ceived transfu-sions for hb < 8 g/dl despite GI work-up) Hb < 11 g/dl	3 mos 1 year follow-up (open-label)	DB	11.5-12 (Epo+Fe) vs Only Fe	6000 U 2x/wk	Mean hb ∆ 10.4à12.4 g/dl (Epo+Fe) vs 10.6à10.5 g/dl (Fe) 3 non-responders to Epo (2 polycystic kidney disease; 1 monoclonal gammopathy) Exercise tolerance (modified Naughton) better. Mean distance walked: 278à356 M (Epo+Fe) vs 285à266 m (Fe). Mean time: 5.8à7.8 min (Epo+Fe) vs 5.8à6.0 min (Fe) (completers) Peak VO₂ better. VO₂ 12.8 to 115.1 ml/kg/min (Epo+Fe) vs 12.5 to 12.0 ml/kg/min (Fe)(completers) Correlation ∆ peak VO₂& ∆ Hb: r²= 0.036 (Epo + Fe only); Hb & NYHA class: r²= -0.41 (Epo + Fe only n = ?16)

1--Non-randomized studies were not included. (Akiba 1995, Baraldi 1990, Barany 1991, 1993, Bocker 1988, Braumann 1991, Bonzel 1991, Davenport 1992, Delano 1989, Grunze 1990, Guthrie 1993, Harris 1991, Hase 1993, Juric 1995, Leikis 2006, Lewis 1993, Lim 1989, Lundin 1991. Macdougall 1990 a,b, Marrades 1996, Martin 1993, Mayer 1988, Metra 1991, Montini 1990, Robertson 1990, Rosenlof 1989, Suzuki 1995, Teehan 1990, Topuzovic 1999, Tsutsui 1989, Warandy 1991, Wizemann 1992)
2—Abstracts were not included (Stray-Gunderson 1997)
3—Studies with patient-reported physical function were not included. (Abu-Alfa 2008, Alexander 2007, Benz 2007, Beusterian 1996, Drueke 2006, Foley 2000, Fukuhara 2008, Gandra 2010, Islam 2005, Johansen 2010, Levin 1993; MacDougall 2008, McMahon 1992 a, b, Moreno 1996, 2000, Muirhead 1992, Provenzano 2004, 2005, Revicki 1995, Roger 2004, Rossert 2006, Singh 2006.)
4--Studies with physician-reported physical function were not included. Both were open-label. (Delano 1989, Evans 1990)
∆ = delta = change
1^o= primary
BM = Boehringer Mannheim
Bruce & McNaughton = cardiac/exercise test protocols
CHF = congestive heart failure
CRI = chronic renal insufficiency, but not on dialysis
DB = double blind
Epo = erythropoietin
F = female
Fe = iron
Fdn = foundation
GI = gastrointestinal
Hb = hemoglobin
HD = hemodialysis
ITT = intent-to-treat
J&J = Johnson and Johnson
M = male
MD = physician
NYHA = New York Heatt Association
PD = peritoneal dialysis
SB = single blind
Sx = symptoms
T = 0 = value at baseline or time zero
VO₂= oxygen consumption
X-over = cross-over

Table 11: Intermediate Cardiac Surrogate Studies

Study	Size	Duration	Blind	Hb(Hct)	Dose	Results
Conlon (part of NCHT) 2000	31 HD w CHF, ischemia	28 wks	Open	42 vs 30	Variable	Silent ischemia (Holter) not different
Cianciaruso 2008	95 CRI	24 mos (∆ 12 mos)	Open	12-14 vs No EPO unless <9	Variable	LV mass index not different
Levin 2005	172 (152) CRI	24 mos	Open	12-14 vs No EPO unless <9	Variable	LV mass index not different
McMahon 1999 & 2000	30 enrolled 14 completed Dialysis	18 mos	DB X-over	14 vs 10	Variable	LV-end diastolic volume decreased and correlated with plasma and blood volumes, but not hemoglobin mass
Palazzuoli 2007	51 CRI w CHF	4 mos	DB	12-12.5 vs No EPO	6000 U 2x/wk	LV function & geometry better
Pappas 2007	31 CRI	1 yr	Not stated	>13 vs No EPO	Variable	LV function & geometry better
Parfrey 2005 Foley 2008,9	596 HD	96 wks	DB	13-14.5 vs 9.5-11.5	Variable	LV cavity volume not different
Ritz 2007	172 CRI Stage 1-3 DM; mild anemia	15 mo	Open	13-15 vs. 10.5-11.5	Variable	LV mass index not different
Roger 2004	155 CRI	2 yrs or dialysis	Open	12-13 vs 9-10	Variable	LV mass index not different
Sikole 1993	40 (38) HD	12 mo for controlled segment	Not stated	30-35 vs No EPO	Variable	LV mass & morphology better LV function not different

1—The open-label randomized study by MacDougall et al. was not included because only 20- pre-dialysis CKD patients in each hemoglobin target treatment arm (of a total of 197 randomized patients) completed 3 years before the sponsor stopped the study. Left ventricular mass did not differ by treatment group. (MacDougall 2007)
2-Non-randomized studies were not included. (Abdulhadi 1990, Ayus 2005, Bedani 2001, Chen 2008, Furuland 2005a,b [subset of 2003], Frank 2004, Grutzmacher 1988, MacDougall 1990, Pascual 1991, 1992, Schwartz 1991, Silberberg 1990, Tagawa 1991, Thanakitcharu 2007)
∆ = delta = change
CHF = congestive heart failure
CRI = chronic renal insufficiency, but not on dialysis
DB = double blind
DO = dropout
EPO = erythropoietin
HD = hemodialysis
LV = left ventricular
Rx = medication
X-over = cross-over

Table 12: Studies of Progression to Dialysis

	Hgb (g/dl) Target	Tx	N =	Entry GFR Criteria (ml/min/1.73 m2)	Baseline GFR (ml/min/1.73 m2) High vs Low Target	Progression to RRT High vs Low Target
CHOIR Singh 2006	13.0-13.5 (∆ to 13.5) vs 10.5-11.0 (∆ to 11.3)	Epo α	1432	15-50 (MDRD)	27.0 vs 27.3	155 (21.7%) 134 (18.7%)
CREATE Drueke 2006	13.0-15.0 vs 10.5-11.5	Epo β	605 (603)	15-50 (CG)	24.9 vs 24.2	127 vs 111 p=0.03
TREAT Pfeffer 2009	~13 vs ESA rescue if <9 g/dl	Darbe α	4047 (4038) DM	20-60 (MDRD)	34 vs 33	338 (16.8%) 330 (16.3%)

∆ = delta = change
CG = Cockcroft-Gault formula for estimating GFR using serum creatinine
Darbe = darbepoetin
DM = patients with Type 2 diabetes
Epo = erythropoietin
GFR = glomerular filtration rate
MDRD = Modification of Diet in Renal Disease formula for estimating GFR using serum creatinine
RRT = Renal Replacement Therapy (need for dialysis or renal transplant)
Tx = treatment

Table 13: Quality of Life (QoL) Studies

	Population	Duration	Treatment	Instruments/Results	Correlation with Patient Level
	Population	Duration	Treatment	Instruments/Results	Hb(hct) Level/ Change	Exercise Tests	Cardiac Tests
Canadian Group EP-86-004 1990 Laupacis 1991 Keown 2010 (Muirhead 1992 for uncontrolled 12 mo extension) Post hoc Muirhead 2011	Adult 118 HD	26 wks	Hb target x2 +placebo	KDQ SIP TTO QOL reportedly did not differ between 2 hb targets (Keown 2010 is a post hoc analysis of ITT population using imputation [vs completer population in initial publications])	NR Post hoc limited correlation with SIP and KDQ with hb ∆	NR	NA
McMahon 1992	Adult 12 HD	4 month arms X-over	Hb target x2	SIP-reported improvement in both treatment arms compared to baseline, but the results did not differ by hemoglobin target. Most improvement was reported in the physical dimension (ambulation and mobility, but not body care and movement) and the total composite score. Improved work status did not result in increased employment.	NR	NA	NA
McMahon 2000	Adult 30(14) HD	2-6 wk arms X-over	Hb target x2	SIP-reported improvement in total, psychosocial, and work categories, but not physical dimension categories.	NR	NA	NR
Morris 1993 SB	Children 11 1-CRI, 1 HD, 9 PD	2-24 wks arms X-over Single-blind	ESA vs placebo	25 element questionnaire for parents modified from instrument used Bacon 1981 for barbiturate study. Post hoc clustering of elements.Global score not different. Reportedly better “general health” and “physical function”.	NR	NR	NA
Parfrey 2005 Foley 2009	Adult 596 Incident HD	96 wks	Hb target x2	FACIT-limited to fatigue question-not improved KDQoL-a-Improvement in ∆ energy/ fatigue question score at interval time-points, but not at endpoint. Final absolute score not > for ↑ hb target bc of >t = 0 score for ↓ hb target arm. Estimated mean difference over study period not >10% of baseline score. KDQoL-b-Social interaction question score not improved. KDQoL-c- Reportedly ↑ baseline ESA predicted deterioration in scores; ↑ age predicted deterioration in KDQoL physical function scores. SF-36 Vitality question score improved at some interval time points and endpoint, but interpolated data were used. Mean difference at endpoint: 3.5 not >7% of baseline score.	NR	NR	NR
Pfeffer 2009	Adult 4038 CRI	Max 4 yrs Mean 29 mos	Hb target x2	FACT-fatigue:1.4 (of 50) change; SF-36: No difference	NR	NA	NA
US Recombinant Human Erythro-poietin Predialysis Study Group Teehan 1991	Adult 117 CRI	8 wks	ESA vs placebo	Weekly questionnaire to rate energy level & ability to do work on 5 point scale. “More energy” reported in 60% (ESA) vs 42% (placebo) 0.97 point more “work capacity” reported in ESA vs placebo treated patients	NR	NA	NA
Kleinman 1989 Possible subset of a larger study	Adult 14 CRI	12 wks	ESA vs placebo	Weekly questionnaire of 3 questions for energy, work capacity, and general QoL expressed using unlabeled 10 cm VAS. Instrument reference Gough 1983 for QoL in cancer. Results converted to a 100 point scale. Reportedly general QoL improved.	NR	NA	NA
Lillevang 1990 Subset of a larger study (Danish)	Adult 19 HD	8 wks	ESA vs placebo	Structured interview	NR	NA	NA
8701 Not published*	Adult 82 HD	12 wks (partial X-over to 12 wk open-label extension)	ESA vs placebo	_________	NR	NA	NA
8904 Not published*	Adult 68 PD	12 wks (partial X-over to 12 wk open-label extension)	ESA vs placebo	_________	NR	NA	NA

1—Non-randomized studies were not included. (Abu-Alfa 2008, Alexander 2007, Benz 2007 Beusterian 1996, Delano 1989, Deniston 1990, Eschbach 1989 (Study 8601), Evans 1990, Finkelstein 2009, Fukuhara 2008, Harris 1991, Islam 2005, Levin 1993, Matuszkiewicz 1996, Mujais 2009, Provenzano 2004, 2005)
2—Open-label studies were not included. (Bahlmann 1991, Besarab 1998, Drueke 2006, Foley 2000, Furuland 2003, Klinger 2007, Levin 2005, MacDougall 2008, Muirhead 1992a [uncontrolled extension segment of the Canadian study], Painter 2002, Provenzano 2004, Revicki 1995, Ritz 2007, Roger 2004, Rossert 2006, Singh 2006) (N.B. Bahlmann 1991 was double-blinded for only 4 weeks of a 3 or 6 month long study.)
* Information from FDA 2007 CRAC briefing documents www.fda.gov/ohrms/dockets/ac/cder07.htm#CardiovascularRenal. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4315b1-04-AMGEN.pdf and slide set www.fda.gov/ohrms/dockets/ac/07/slides/2007-4315s1-09-FDA-Trentacosti_files/slide0086.htm. (Accessed July 19, 2010)
CRI = chronic renal insufficiency, but not on dialysis
FACT = Functional Assessment of Cancer Therapy
FACIT = Functional Assessment of Chronic Illness Therapy
Hb = hemoglobin
HD = hemodialysis
KDQ = Kidney Disease Questionnaire (Laupacis 1992)
KDQoL = Kidney Disease Quality of Life
NA = not applicable
NR = not-reported
PAIS = Psychosocial Adjustment to Illness Scale
PD = peritoneal dialysis
QOL = quality oflife
SF-36 = Short Form 36 Health Survey
SIP = Sickness Impact Profile
TTO = Time Trade Off
X-over = cross-over
VAS = Visual Analogue Scale

Table 14: One Year Unadjusted Mortality (per 1,000 USRDS patients) by Hematocrit and Erythropoietin Dose Cohort (Zhang 2004)

	Hematocrit (Vol%)
Epo Dose Quartile	< 30	30-32.9	33-35.9	36-38.9	≥ 39
Q1-lowest dose	215	198	172	176	181
Q2	302	242	221	195	193
Q3	348	303	246	231	230
Q4-highest dose	486	395	327	295	279

Table 15: Case-Mix Adjusted Mortality Hazard Ratio by Hemoglobin Level (Regidor 2006)

	Hemoglobin Level (g/dl)
Death	< 9	9 to < 9.5	9.5 to < 10	10 to < 10.5	10.5 to < 11	11 to < 11.5	11.5 to < 12	12 to < 12.5	12.5 to < 13	13 to < 13.5	13.5 to < 14	≥14
All Cause	3.1	2.5	2.2	2.0	1.7	1.2	1.0	0.9	0.9	1.0	1.2	1.2
Cardiovascular	2.5	2.4	1.9	2.0	1.6	1.3	1.0	0.9	1.0	1.1	1.2	1.2

Table 16: Mortality and Erythropoietin Dose (Regidor 2006)

Epo Dose (U/wk)	Baseline Hb (g/dl)	All Cause Death N (%)	Cardiovascular Death N (%)	Cohort Size N (%)
None	12.3	833 (22%)	315 (8%)	4,087 (7%)
1 to < 6,000	12.4	1,335 (20%)	640 (10%)	6,539 (11%)
6,000 to < 12,000	12.2	2,523 (21%)	1,097 (9%)	12,033 (21%)
12,000 to < 18,000	12.1	2,533 (24%)	1,122 (11%)	10,751 (19%)
≥18,000	11.6	7,258 (29%)	3,069 (13%)	24,671 (43%)

Table 17: Mortality Hazard Ratio (based on quarterly USRDS data) (Messana 2009)

	Mean Hematocrit (Vol%)
Epo Dose (U/wk)	< 30	30-32.9	33-35.9	36-38.9	39-41.9	> 42
0	2.84	1.68	1.12	1.32	1.67	1.96
1-5999	2.52	1.56	0.92	0.87	1.23	1.70
6000-11,999	2.82	1.63	1.00 reference	0.91	1.12	1.55
12,000-17,999	3.32	1.85	1.24	1.13	1.32	1.77
>18,000	3.83	2.41	1.71	1.71	1.92	2.52

Table 18: Scandinavian Study

	Total		Pre-dialysis		Hemodialysis		Peritoneal Dialysis
	N-Hb	S-Hb	N-Hb	S-Hb	N-Hb	S-Hb	N-Hb	S-Hb
	N = 216	N = 200	N = 36	N = 36	N = 157	N = 136	N = 23	N = 28
Death due to All Causes	29	27	4	1	21	20	3	6
Cardiovascular Death	24	16	3	1	18	10	3	5
Non-Cardiovascular Death	5	11	1	0	3	10	0	1
Mean Achieved Hb (g/dl) Wk 48	---	---	14.3 ±1.1	11.7 ±1.3	13.5 ±1.4	11.3 ±1.3	13.4 ±1.5	11.5 + 1.2
Mean Epo Dose (U/kg/wk) Wk 48	---	---	107 ±117	39 ±5 3	236 ±148	140 ±182	168 ±118	58 ±86

Epo = erythropoietin
N-Hb = Normal Hb target 13.5 -15 g/dl for women, 14.5-16 g/dl for men
S-Hb = Subnormal Hb target 9-12 g/dl

Table 19: Randomized Active Control Studies: Route of Administration

Study	Population	Blind	Size	Duration	Treatment Arms	Endpoints/Comments
Aarup 2006 (Amgen)	HD on ESA Adult No sig dx	Open	71	20 wk each arm 3 wk run-in on titrated darbe SQ	Cross-over Darbe SQ vs IV 1x/wk Doses titrated	Dose requirement (mean) Hb AUC
Bommer 2008	HD On SQ darbe Adult No sig dx	Open	126	48 randomized tx 4 wk screening+baseline	Darbe IV vs SQ on prior schedule Doses titrated (Transfusions per MD)	Dose requirement Hb level Relationship between t = 0 dose & hb level Epo resistance index = darbe dose x200/weight x hb
Boran 1993	HD Hb < 9g/dl No ↑↑ HTN	Not stated	36	Presumably 12 wks	Epo 25-40 U/kg SQ vs 50-90 U/kg IV; both 3x/wk	Hb response (≥ in SQ arm) AEs (4/18 with accelerated HTN in IV arm)
Cervelli 2005 (Amgen)	HD on ESA Fe replete Adult No sig dx	Not stated	53	6 mo arms 4 mo dose titrationà 2 mo dose observation	Cross-over Darbe SQ vs IV 1x/wk Doses titrated	Dose requirement mos 5-6 Hb level mos 5-6 (24 in analysis)
Chazot 2009 (Amgen) (See route)	HD on Epo SQ Adult	Open	154	6 mo randomized tx 3 mo screening	Equivalence Non-randomized: Epo IVà Darbe IV Randomized: Darbe SQ x2 moàDarbe IV vs Darbe IV converted directly	% w stable Hb at 6 mo Dose requirement Hb stability at 3 mo
De Schoenmakere 1998 (Janssen-Cilag author)	HD on SQ epo Adult Hct 28-36% Inflammation PKD	Not stated	30	12 mos 6 mo SQà6 mo IV vs 12 mo SQ	Epo SQ vs IV 6 mo SQà6 mo IV vs 12 mo SQ Doses titrated	Dose requirement by route Hct level Fe studies
Jensen 1996 (Danish Medical Research Council)	D Adult Transfusion need &/or hb < 5.8 mmol/l No sig dx	Open	50	>10 mos 1 mo fixed dose à Time to titrated to targetà 4 mo maintenanceà cross-over	Cross-over Epo-beta SQ vs IV	Dose requirement by route Hb level Dialysis adequacy Fe studies BP & HTN rx
Kaufman(Veterans’ Adm) 1998 (Amgen, Schwartz Pharma, Schein)	HD Fe replete	Open	208	Period for dose ↓ Hct < 30% Dose ↑ to hct 30-33% for 26 wks	SQ vs IV Doses titrated for both phases	Dose Requirement Pain
Kim 2009 (Korea Health, Ministry of Commerce, Industry, Energy)	HD On SQ Epo Adult Hb 8-11 g/dl No sig dx	Open	65	24 wk randomized tx 8 wk baseline 4 wk screening	Equivalence Darbe IV 1x/wk or SQ 1x/wk Dose titrated	Dose requirement wks 20-24 Hb level wks 20-24
Lai 1991 (Liu Re-search Fund)	PD Hb < 9g/dl No ↑↑ HTN	Not stated	20	16 wks	Epo α SQ vs IP Doses titrated	Hb level (less response with IP-dose info not provided) BP (6/10 in IP arm vs 2/10 in SQ arm required anti-HTN rx change; dose relationship not provided) Labs: ANP, endothelin, plasma renin activity
Lee 2009	HD On SQ Epo Adult No sig dx	Open	78	4-77 mo	Epo SQ 2-3x/wk vs Epo IV 2-3 x/wk Doses titrated hb 9-12 g/dl Stratified by access type & diabetes status	Time to vascular access failure (shorter w SQ) CV events Dose requirement Hb level
Leikis 2004 (Janssen-Cilag)	HD URR ≥65% On Epo SQ Hb 10.5-30 g/dl Fe replete No ↑ CRP, Al toxicity, thrombosis	Not stated	88(81)	6 mo randomized tx Fe adequacy maintained	Superiority Cross-over Eprex SQ vs IV (with re-randomization to subgroups 1x, 2x, or 3x/wk Constant dose	Hb level Change in hb Effect of dose frequency
Lui 1990 (L.C. Research Fund & Cilag)	CAPD No other anemia cause (Hb < 9 g/dl) No ↑↑ HTN	Not stated	20	16 wks	SQ vs IP Doses titrated	% in target 10-12 g/dl Dose requirement by route PK parameters AEs
Muirhead 1992 (R W Johnson Pharmaceutical Research Institute)	HD w co-morbid disease Adult Hb < 9.5 g/dl	Not stated	128	4 wk randomized tx with dose titrations 4 wk single-blind placebo run-in ?24 wk follow-up period	Epo SQ vs IV Doses titrated	Dose requirement by route Hb level Dialysis need by route QoL KDQ Thrombosis by route Dose requirement by co-morbid disease (? post hoc) (Large drop-out)
Ostrvica 2010 (See ESA type) (See regimen)	HD on Epo β Adult Hb 9-11 g/dl No cancer	Not stated	60	6 mo randomized tx	Epo α IV vs Epo β IV vs Epo β SQ 3x/wk	Hb level Dose requirement
Paganini 1995 (Amgen) (See ESA type) (See regimen)	HD on IV Epo in prior studies	Open	108	12 wk randomized tx 12-24 wk run-in Epo SQ 3x/wk Extension study	Diluted Epo α 3x/wk vs undiluted Epo 3x wk vs Epo 1x wk Doses titrated	Dose requirement by route Change in Hb level t = 0 to either wks 13-16 or 12-24 Pain
Ruedin 1992 (French)	HD	---	50	8 mo 2 mo IV administration 3 mo SQ administration in some & 6 mo in others	Cross-over Epo SQ vs IV	Dose requirement Hb level Pain level
Schaller 1994 (Boehringer Mannheim) (See ESA type)	D Fe replete No sig dx	DB	90	8 wk randomized tx Unspecified length open extension	Production site (1 in U.S; 1 in Germany) Epo β SQ vs IV Doses titrated	Dose requirement by route Change in Hct level (packed cell volume) Antibodies AEs
Sohmiya 1998 Ministries of Education-Culture & Health-Welfare-Japan, Fdn for Renal Disorders	CRI Type 2 diabetes & malnutrition	Not stated	5	8 wk randomized tx arms Intervening 4 wk washout	Cross-over Epo β SQ injection (6000 U) 1x wk vs continuous SQ infusion (36 U/0.24 ml/hr) Fixed doses	Plasma epo level Retic count Hb change
Spinowitz (RUBRA) 2008 (Hoffmann La Roche) (See ESA type)	HD (Kt/V ≥1.2; URR ≥65%) PD (Kt/V ≥1.8) On Epo IV SQ Fe replete Adult Hb 10.5-13 g/dl No sig dx	Open	366	36 wk randomized tx 4 wk run-in on prior dose & route	Non-inferiority Epo SQ or IV 1-3x/wk vs SQ or IV CERA q2wks (using prior route) Doses titrated	Hb change t = 0 & wks 29-36 Effect of route on Hb change # pts with stable hb # transfusions (but no tx algorithm)
Stockenhuber 1991	HD, PD	Not stated	42	3 mo	Epo SQ vs IV HD-7 SQ dose; 7 IV dose PD-7 SQ dose Fixed dose	Change on hb
Taylor 1994	HD No sig dx	Not stated	16	14 wk randomized tx 4 wk no rx 6 wk dose adjustment 8 wk maintenance	Cross-over w washout Epo SQ vs IV Doses titrated	Dose requirement by route Change in Hb level Retic count
Virot 1996	HD on IV epo No sig dx	Not stated	49	4 mo randomized tx	Epo SQ vs IV Stratified by prior epo needs	Dose requirement by route & epo need strata at 120 d Hb level

1—Serial switch studies were not included. (Salmonson 2000, Zehnder 1989, 1990)
↑ = increased
ANP = Atrial natriuretic peptide, endothelin, plasma renin activity
AUC = area-under-the-curve
CERA = C = continuous erythropoiesis receptor activator=methoxy polyethylene glycol epoetin beta=pegylated erythropoietin-beta
CRI = chronic renal insufficiency, but not on dialysis
CRP = C-reactive protein
CV = cardiovascular
Dx = diagnosis
Epo = erythropoietin
Fe = iron
Hb = hemoglobin
Hct = hematocrit
HD = hemodialysis
IP = intraperitoneal
IV = intravenous
Kt/V = dialyzer clearance of urea x dialysis time/ volume of urea distribution in the body (measure of dialysis adequacy)
MD = physician
PD = peritoneal dialysis
SQ = subcutaneous
Tx = treatment
URR = urea reduction ratio (measure of dialysis adequacy)

Table 20: Randomized Active Control Studies: ESA Type

Study	Population	Blind	Size	Duration	Treatment Arms	Endpoints/Comments
Berthoux 2008 (Hoffmann La Roche)	Normals Adult No sig dx	SB	40	Single injections w 1 wk washout	Superiority design Placebo then randomization to Epo-beta SQ vs Darbe SQ	Pain level Pain duration
Canaud (STRIATA) 2008 (Hoffmann La Roche)	HD (Kt/V ≥ 1.2; URR ≥ 65%) PD (Kt/V ≥ 1.8) On IV darbe Adult Hb 10.5-13 g/dl Fe replete, no other anemia No ↑ CRP	Open	313	36 wk randomized tx 4 wk run-in 28 wk dose adjustment 8 wk evaluation + 16 wk randomized safety observation after endpoint using new target range	Non-inferiority CERA IV q2wks vs Darbe IV q 1 or 2 wks Doses titrated	Hb change t = 0 & wks 29-36 % pts maintaining stable hb Hb variability # needing dose adjustments Transfusions (no algorithm) AEs (Consideration of #s on ACE inhibitors & angiotensin II receptor antagonists)
Chazot 2009 (Amgen) (See route)	HD on Epo SQ Adult	Open	154	6 mo randomized tx 3 mo screening	Equivalence Non-randomized: Epo IVà Darbe IV Randomized: Darbe SQ x2 moàDarbe IV vs Darbe IV converted directly	% w stable Hb at 6 mo Dose requirement Hb stability at 3 mo
Frenken 1991	HD On SQ Epo Adult	DB	32	1 day; injections separated by 1 hour	Cross-over Epo α albumin citrate vs Epo β lyophilisate (freeze dried under vacuum)	Pain level Pain duration
Goh (Biogeneric Study Group) 2007 (NCPC GeneTech Biotechnology)	HD On IV Eprex Adult Hb ≥ 9 g/dl Fe replete No sig dx	Open	186(188)	12 wk randomized tx	Non-inferiority Exprex IV vs generic Epo IV Dose changes not recom-mended	Change in Hb t = 0 to wk 12
Granolleras 1991	HD On SQ Epo Adult No ↑↑ HTN	DB	18	2 wks 2 of 3 tx given during each period	3 period cross-over Epo α albumin citrate vs Epo β lyophilisate vs placebo	Pain level
Haag-Weber (INJ-9) 2009 (Sandoz/Hexal)	HD on IV Epo Adult Hb 10-13 g/dl No ↑CRP	DB	479 2:1 Rand	28 wk randomized tx 28 wk open extension	Equivalence Eprex/Erypo IV vs Epo α HX575-Sandoz/Hexal Doses titrated	Hb change t=0 & wks 25-28 Dose requirement Antibodies AEs
Jensen 1994 (Danish)	HD	DB	22	Two 4 wk arms	Cross-over Epo albumin Epo lyophilisate	Pain level & duration Local reaction
Klinger (AMICUS) 2007 (Hoffmann-LaRoche) (See regimen)	HD (Kt/V ≥ 1.2; URR ≥ 65%) PD (Kt/V ≥ 1.8) No recent ESA Adult No other anemia No sig dx (but baseline CVD imbalance)	Open	181 3:1 rand Then 1:1	24 wks-part 1 ESA type 28 wks-part 2 Regimen	Post hoc non-inferiority Epo (α, β) IV 3x/wk vs CERA IV q2 wks Then if CERA responseà CERA IV q2 wks vs 4wks (Epo control retained) Doses titrated	Change in Hb ≥1 g/dl Hb ≥ 11 g/dl anytime during study Antibodies QoL short SF-36
Krivoshiev (Epoetin Zeta Study Group) 2008 (STADA)	HD ±ESA Adult Hb < 9 g/dl No sig dx	DB	609	24 wk randomized tx 6 wk run-in for anemia dx & Fe correction 28 wk open extension	Equivalence Epo α IV 1-3x/wk vs Epo-zeta IV 1-3x/wk Doses titrated	Mean dose during last 4 wks Mean Hb during last 4 wks Antibodies
Krivoshiev (Epoetin Zeta Study Group) 2010 (STADA)	HD on Epo (see run-in) Adult No sig dx	Dose adjuster blind	462	28 wk randomized tx 12-16 wks pre-randomization dose titration Epo-zeta (N = 679) 54 wk open extension	Equivalence Epo α SQ vs Epo-zeta SQ Doses titrated	Mean Hb during last 4 wks (Equivalence ±0.5 g/dl) Mean dose during last 4 wks (Equivalence ±45 U/kg/wk) Antibodies AEs (11 deaths on Epo-zeta during run-in & 16 deaths/ 37 SAEs on Epo-zeta vs 7 deaths/9 SAEs on Epo α
Levin (MAXIMA) 2007 (Hoffmann La Roche)	HD, PD On IV Epo 1-3x/wk Adult Hb 10.5-13 g/dl Fe replete No ↑↑ CRP	Open	673	36 wk randomized tx 4 wk run-in 28 wk titration 8 wk assessment +16 wk randomized extension	Non-inferiority Epo IV 1-3x/wk vs CERA q2 wks vs CERA q4 wks Doses titrated	Change in Hb t = 0 & wks 28-36 Patient number with hb within 1 g/dl of t = 0 Transfusions
Li 2008 (Kirin Pharmaceu-tical)	PD On SQ Epo Adult Hb 8-12 g/dl No sig dx	Open	46(45)	24 wks randomized tx	Epo (~3x/wk) vs Darbe (1x/mo) Doses titrated	Hb change t = 0 & wks 17-22 or wks 23-24 Dose requirement Dosing frequency AEs
Locatelli (NESP 980202 Study Group) 2001 (Non-IND) (Amgen) Long-term extension not complete at time of FDA review	CRI No recent ESA Hb < 11 g/dl No sig dx	Open	166 D3:E1 rand	24 wk randomized tx	Darbe 1x wk vs Epo 2x/wk Doses titrated	Hb change > 1 & level > 11 g/dl Antibodies AEs
Locatelli 2008 (Hoffmann La Roche) (See regimen)	HD	Open	289	28 wks	Equivalence Epo α IV qwk vs Darbe qwk vs Epo 2-3x/wk	Hb change t = 0 & wks 16-28 Dose requirement
Locatelli 2010 8 pooled studies (Hoffmann La Roche)	CRI & dialysis	Not stated	2737	Variable duration	Variable design CERA vs other ESAs (Epo α, Epo β, Darbe)	Adverse events
Macdougall (ARCTOS) 2008 (See Kessler 2010 extension with regimen change) (Hoffmann-LaRoche)	CRI Stage 3-4 Stated ESA naïve, but really no recent ESA Adult Hb 8-11 g/dl Fe replete, no other anemia No sig dx	Open	324	28 wk randomized tx 18 wk dose adjustment 10 wk evaluation + 24 wk randomized extension (See Kessler 2010)	Non-inferiority CERA IV q 2wk vs darbe q1wk Extension with in-group randomization if on CERA to q2wk or q1mo; if on Darb given choice of q1 or 2 wks Doses titrated	Change in Hb ≥ 1 g/dl & Hb ≥ 11 g/dl t = 0 & wks 19-28 (% response) Change in Hb Transfusions Antibodies QoL Short SF-36
Martin (Delta 3001 Study Group) 2007 (Shire/Hoechst Marion Roussel) (See below)	HD On Epo α Adult Hb 9.6-12.4 g/dl Fe replete No ↑↑ HTN	DB	752 D3:A1 rand	24 wk randomized tx (28 wk extension)	Equivalent hb level IV Epo α vs Epo-delta Doses titrated	Hb level during wks 12-24 Antibodies
Martin (Delta 3001 Study Group) 2007 (Shire/Hoechst Marion Roussel) (See above)	HD On Epo α Adult Hb 9.6-12.4 g/dl Fe replete No ↑↑ HTN	Open	583	28 wk extension study	All patients on Epo-delta Doses titrated	Hb level during wks 25-52 Antibodies
Milutinovic 2006 (See below)	HD Adult Hb <9.5 g/dl Fe replete No sig dx	SB	77	12 wk randomized tx 4 wk safety follow-up	Epo α SQ vs Epo-omega SQ 2x/wk Doses titrated	Dose requirement Change in Hb level (Consideration of #s on ACE inhibitors)
Milutinovic 2006 (See above)	HD Adult Hb <9.5 g/dl Fe replete No sig dx Completed above study	SB	54	12 wk cross-over with completers from above 4 wk safety follow-up Duration between studies 5-16 mos	Cross-over from above Epo α SQ vs Epo-omega SQ 2x/wk Doses titrated	Dose requirement Change in Hb level (Consideration of #s on ACE inhibitors)
Nissenson 2002 ?FDA approval	HD	DB	507 504 D1:E2 rand	20 wk titration 8 wk evaluation	Non-inferiority Darbe 1x wk vs Epo 3x/wk Doses titrated	Hb change t = 0 to wks 21-28
Ostrvica 2010 (See route) (See regimen)	HD on epo β Adult Hb 9-11 g/dl No cancer	Not stated	60	6 mo randomized tx	Epo α IV vs Epo β IV vs Epo β SQ 3x/wk	Hb level Dose requirement
Paganini 1995 (Amgen) (See regimen) (See route)	HD on IV Epo in prior studies	Open	108	12 wk randomized tx 12-24 wk run-in Epo SQ 3x/wk Extension study	Diluted Epo α 3x wk vs undiluted Epo 3x wk vs Epo 1x wk Doses titrated	Dose requirement by route Change in Hb level t=0 to either wks 13-16 or 12-24 Pain
Roger (COMFORT) 2008 (Hoffmann La Roche)	CRI Stage 3-4, PD, Transplant Adult Hb 10-13 g/dl	SB	48	2 wk arms 2 injections/arm	Cross-over Epo β SQ 1x/wk vs Darbe SQ 1x/wk Fixed doses	Pain Patient preference
St Peter 1998 (Amgen)	HD	TB	28	2- arms; 1 day for each formulation Separated by 1 wk	Cross-over SQ Epo α single dose formulation vs Epo α multi-dose formulation-benzyl alcohol SQ placebo in opposite arm	Pain level & duration
Schaller 1994 (Boehringer Mannheim) (See regimen)	D Fe replete No sig dx	DB	90	8 wk randomized tx Unspecified length open extension	Production site (1 in U.S; 1 in Germany) Epo β SQ vs IV Doses titrated	Dose requirement by route Change in Hct level (packed cell volume) Antibodies AEs
Schmitt 2006 (Hoffmann- LaRoche)	HD, PD On ESA Pediatric	DB	13	12 wks Initial injection Epo β Then randomization	Darb SQ vs Epo β SQ q 4 weeks x2	Pain Pain duration
Spinowitz (RUBRA) 2008 (Hoffmann La Roche) (See regimen)	HD (Kt/V ≥ 1.2; URR ≥65%) PD (Kt/V ≥ 1.8) On Epo IV,SQ Fe replete; no other anemia Adult Hb 10.5-13 g/dl No sig dx	Open	366	36 wk randomized tx 4 wk run-in on prior dose & route 28 wk titration 8 wk evaluation	Non-inferiority Epo SQ or IV 1-3x/wk vs SQ or IV CERA q2wks (using prior route) Doses titrated	Hb change t = 0 & wks 29-36 Effect of route on Hb change # pts with stable hb # transfusions (but no tx algorithm) during titration & evaluation
Sulowicz (PROTOS) 2007 (Hoffman-LaRoche)	HD Kt/V ≥ 1.2 &/or URR ≥ 65% PD Kt/V ≥1.2 On SQ Epo Adult Hb 10.5-13 g/dl Fe replete, no other anemia No sig dx	Open	572	36 wk randomized tx 4 wk baseline +16 wks randomized extension	Non-inferiority Epo SQ1-3x/wk vs CERA SQ 1x/2 wks vs CERA SQ 1x/4 wks Doses titrated	Change in Hb level t = 0 & wks 29-36 Hb level Hb variability (post hoc) Death rate Epo 1-3x 6.3%, q2wk 6.8%, qmo 9.5%
Ter Wee 2009	CRI stage 4, PD On SQ ESA	DB	42	1 day-4 injections 4 sites	Placebo x2 (0.3 or 0.5 ml) vs Darbe SQ vs Epo β SQ	Pain
Tolman 2005 (Yorkshire Kidney Research Fund)	HD On 3x/wk SQ Epo Adult No ↑↑ HTN	Open	217	9 mo randomized tx	Darbe SQ 1x/wk vs Epo β SQ 1x/wk Dosing via algorithm	Doses requirement Hb level Iron required Transfusions for hb <8 g/dl & sx (only PP D 22 in 8, E 32 in 11)
Vanrenterghem NESP 970200 Study Group) 2002 For FDA approval (Amgen)	HD/PD On SQ/IV epo Adult Hb 9.5-12.5 g/dl No inflammatory or hematologic conditions	Open	522 D2:E1 rand	Up to 52 weeks 4 wk baseline 32 wk randomized tx 20 wk extension	Non-inferiority SQ vs IV dosing If Epo 1x/wk, then Darbe 1x/2wks If Epo 2-3x/wk, then Darbe 1x/wk Doses titrated	Hb change t = 0 to wks 25-32 Hb variability Pain Antibodies AEs (death D 12% vs E 6%; p=0.06)
Veys 1992 (see below)	HD on SQ epo α	SB	10	4 wk trial ESA type randomized by individual dose	Sequential random admini-stration SQ Epo α albumin ci-trate vs Epo β lyophili-sate	Pain level
Veys 1992 (part of above)	HD on SQ/IV epo β	SB	40	1 day Simultaneous random administration of ESA types to different thighs	Simultaneous random administration SQ Epo α albumin ci-trate vs Epo β lyophili-sate	Pain level Pain by prior route
Veys 1992 (part of above)	HD on SQ/IV Epo β	DB	6 Subset of above	1 day Simultaneous random administration of ESA types to different thighs	Simultaneous random administration SQ Epo α albumin ci-trate vs Epo β lyophili-sate	Pain level
Wizeman (Epoetin Zeta Study Group) 2008 (STADA)	HD on Epo Adult No sig dx	DB	313	2-12 wk randomized tx arms 12-18 wk run-in w Epo α 28 wk open extension	Equivalence Cross-over Epo α IV 1-3x/wk vs Epo-zeta IV 1-3x/wk	Intra-patient Hb differences (Equivalence ±0.6 g/dl) Intra-patient dose differences (Equivalence ±45 U/kg/wk) # transfusions (but no tx algorithm) Antibodies AEs
Yu 1998	HD, PD	SB	40	2 injections for each formulation; 1 in each arm. Repeat dosing separated by 1 wk	Epo α citrate buffer vs Epo α phosphate buffer Fixed doses	Pain level and duration
Unpublished 211 FDA-IND study (Amgen)	HD epo naïve (no epo in last 12 wks) Adult Hb < 10 g/dl Fe, B12, folate replete No sig dx	Open	160 D3:1E	20 wk randomized tx	Supportive equivalence Darbe 0.45 μg/kg QW vs Epo 50 U/kg 3x/wk IV or SQ initially Doses titrated	% with Hb ↑≥1.0 g/dL &H b ≥11.0 g/dL during study (Designating 50% response rate as clinically meaning-ful; Not accepted by FDA) Hb & change in Hb q4 wks Time to target Dose Antibodies
Unpublished EMERALD 1 AFX01-12 (Affymax-Takeda)	HD on epo IV Adult Hb 10-12 g/dl No other anemia No sig dx	Open	803 vs 793 P2:E1	36 wk randomized tx	Non-inferiority P QW vs Epo 1-3x/wk Doses titrated	Hb change t = 0 & wks 29-36 % target range t = 0 & wk 8 Transfusions t = 0 & 36 wks
Unpublished EMERALD 2 AFX-01-014 (Affymax-Takeda)	HD on epo IV Adult Hb 10-12 g/dl No other anemia No sig dx	Open	823 vs 815 P2:E1	36 wk randomized tx (?52 + wk tx)	Non-inferiority P QW vs Epo 1-3x/wk Doses titrated	Hb change t = 0 & wks 29-36 % target range t = 0 & wk 8 Transfusions t = 0 & 36 wks
Unpublished PEARL 1 AFX01-11 (Affymax-Takeda)	CRI GFR < 60 ml/ min/1.73m² Adult Hb 8-11 g/dl No other anemia No sig dx	Open	490 P₁1:P₂:1D₁:1	36 wk randomized tx (?52 + wk tx) 4 wk screening	Non-inferiority P 0.025 mg/kg QW vs P 0.04 mg/kg QW vs Darbe 0.75 μg/kg Q2W Doses titrated	Hb change t = 0 & wks 29-36 % target range over 36 wks Transfusions over 36 wks
Unpublished PEARL 2 AFX01-013 (Affymax-Takeda)	CRI GFR <60 ml/ min/1.73m² Adult Hb 8-11 g/dl No other anemia No sig dx	Open	493 P₁1:P₂:1D₁:1	36 wk randomized tx (?52+ wk tx) 4 wk screening	Non-inferiority P 0.025 mg/kg QW vs P 0.04 mg/kg QW vs Darbe 0.75 μg/kg Q2W Doses titrated	Hb change t = 0 & wks 29-36 % target range over 36 wks Transfusions over 36 wks
Unpublished AFX-01-15 (Affymax-Takeda)	HD Not on epo Adult Hb 8-11 g/dl No other anemia No sig dx	Open	114 P₁1:P₂:1D₁:1	7+ mo tx 4 wk screening (Russian sites)	2 Peginesatide doses Q4 wks vs 1 Epo 3x/wk Doses titrated	Hb change t = 0 & wk 8 Hb response over 28 wks Transfusions over 28 wks

1—Abstracts were not included (Choukroun G 2005 cited by Roger 2008)
2—Uncontrolled and switch studies were not included. (Akizawa 2007, Amar 1994, Thanakitcharu 2007, Thitiachkul 2007)
↑ = increased
? = possibly
AE = adverse event
C = CERA = continuous erythropoiesis receptor activator = methoxy polyethylene glycol epoetin beta = pegylated erythropoietin-beta
CRI = chronic renal insufficiency, but not on dialysis
CRP = C-reactive protein
CVD = cardiovascular disease
D = darbe = darbepoetin
DB = double blind
Dx = diagnosis
E = epo = erythropoietin
Fe = Iron
GFR = glomerular filtration rate
Hb = hemoglobin
HD = hemodialysis
HTN = hypertension
Kt/V = dialyzer clearance of urea x dialysis time/ volume of urea distribution in the body (measure of dialysis adequacy)
Q = each
QoL = quality of life
P = peginesitide
PD = peritoneal dialysis
SF-36 = Short Form 36 Health Survey
Sig=significant
TB = triple blind
Tx = treatment
URR = urea reduction ratio (measure of dialysis adequacy)

Table 21: Randomized Active Control Studies: Different Treatment Regimens

Study	Population	Blind	Size	Duration	Treatment Arms	Endpoints/Comments
Buemi 1993	HD	Open	26	Not stated a priori	Daytime vs nighttime dialysis & Epo dosing Doses titrated	Dose & time required to reach hct 32%
Frifelt 1996 (Ercopharm)	PD Completed epo stabilization Adult No sig dx	Not stated	33	3 mo stabilization 3 mo randomized tx	Epo β SQ 3x/wks vs 1x/wk Doses titrated in a limited way	Hb change at 3 mo Dose requirement by route Fe need (7/73 died during 3 mo stabilization)
Kessler (ARCTOS-extension) 2010 (See Regimen Macdougall 2008) (Hoffman La Roche)	CRI (responder on CERA in 28 wk ACTOS) Adult No rapid renal decline No ↑ CRP	Open	296	24 wk extension period (See Macdougall 2008)	If responded in earlier 28 wk study, randomized to remain on CERA SQ q2wks vs CERA SQ q4 wks. Darbe pts given option of qwk or q2wk dosing	Hb level Dose requirement Hb variability at wk 36 Death: Cq2wk 2/73, Cq4wk 1/72, D6/161
Klinger (AMICUS) 2007 (Hoffmann-LaRoche) (See ESA type)	HD (Kt/V ≥1.2; URR ≥65%) PD (Kt/V ≥ 1.8) No recent ESA Adult No sig dx (but baseline CVD imbalance)	Open	181 3:1 rand Then 1:1	24 wks-part 1 ESA type 28 wks-part 2 Regimen	Post hoc non-inferiority Epo (α,β) IV 3x/wk vs CERA IV q2 wks Then if CERA responseà CERA IV q2 wks vs 4wks (Epo control retained) Doses titrated	Change in Hb ≥1 g/dl Hb ≥ 11 g/dl Antibodies QoL SF-36
Koch 1995 (Boehringer Mannheim author)	CRI Hct < 30% No sig dx	Open	275 (266) (2 study combo)	Variable	Epo β SQ 3x wk vs 1x wk Doses titrated	Dose requirement Hct change Serum creatinine change
Lee 2008	HD on Epo Hb 9-12 g/dl	Open	83	(Pre-study 4 wk dose adjustment period) 12 wks: 10 wk maintenance + 2 wk evaluation period	Espogen (epo-α) SQ 1x/wk vs 2-3x/wk Stratified by prior Epo dose	Dose requirement Hb level
Locatelli (Study Group) 2002 (Hoffmann La Roche)	HD (Kt/V ≥ 1.2 On Epo β Adult Hct 28-38% Fe replete No sig dx	Open	173	24 wk randomized tx 4 wk pre—study period with Epo SQ 3x/wk	Equivalence Epo β SQ 3w/wk vs 1x/wk Doses titrated	Hct AUC wks 13-24 Dose requirement wks 13-24 Hb & hct change Transfusion (no algorithm)
Locatelli 2008 (Hoffmann La Roche) (See regimen)	HD	Open	289	28 wks	Equivalence Epo α IV qwk vs Darbe qwk vs Epo 2-3x/wk	Hb change t=0 & wks 16-28 Dose requirement
Lui 1991 (Cilag)	CAPD No other anemia cause (Hb <8 g/dl) No ↑↑ HTN	Not stated	20	16 wks	Equivalence Epo 1x q wk vs 2x q wk Doses titrated	Hb change t=0 & wk 16 Dose requirement Fe metabolism AEs
Lui 1992 (Cilag)	HD No ↑↑ HTN (Hb <6 g/dl)	Not stated	20	12 wks	Equivalence Epo 1x q wk vs 2x q wk Doses titrated	Hb change t=0 & wk 12 Dose requirement Fe metabolism AEs
Macdougall (NESP 960245/46 Group) 2003 (Amgen) (See below)	HD No recent Epo Hb <10 g/dl Adult Fe replete No sig dx	Not stated	75	4 wks if no hb ↑ ≥ 1g/dl 52 wks if hb ↑ (non-responders could re-enroll at a higher dose)	Serial dose escalation with randomization by regimen Darbe IV 3x/wk vs 1x/wk Doses titrated after 16 wks	Hb change ≥ 1g/dl at 4 wks Hb at 16 wks Antibodies AEs
Macdougall (NESP 960245/46 Group) 2003 (Amgen) (See above)	PD No recent Epo Hb < 10 g/dl Adult Fe replete No sig dx	Not stated	47	4 wks if no hb ↑ ≥ 1g/dl 52 wks if hb ↑ (non-responders could re-enroll at a higher dose)	Serial dose escalation with randomization by regimen Darbe SQ 3x/wk vs 1x/wk Doses titrated after 16 wks	Hb change ≥ 1g/dl at 4 wks Hb at 16 wks Antibodies AEs
Mircescu 2006 (Hoffmann-LaRoche)	HD Hb > 10 g/dl (w baseline Epo tx) Replete Fe Adult No DM; sig dx	Open	207	24 wk randomized tx 8 wk baseline with Epo q 1x/wk	Epo β SQ 1x/wk vs q2 wks Doses titrated	Mean hb level wks 13-24 Dose requirement AEs (Systolic BP 8.7 mm Hb higher in q2/wk arm)
Nagaya 2010 (Japan Dialysis Outcome Group)	HD on IV darbe (see run-in) Adult No sig dx	Not stated	48(39)	8 wks pre-randomization for dose stabilization on darbe Presumably 24 wk randomized tx	Darbe IV q1wk vs q2wks Doses titrated	Mean dose requirement at wk 24 (dose requirement higher with longer interval) Hb level AEs (BP higher with longer interval & perhaps higher doses)
Ostrvica 2010 (See ESA type) (See route)	HD on Epo β Adult Hb 9-11 g/dl No cancer	Not stated	60	6 mo randomized tx	Epo α IV vs Epo β IV vs Epo β SQ 3x/wk	Hb level Dose requirement
Paganini 1995 (Amgen) (See ESA type) (See route)	HD on IV Epo in prior studies	Open	108	12 wk randomized tx 12-24 wk run-in Epo SQ 3x/wk Extension study	Diluted Epo α 3x wk vs undiluted Epo 3x wk vs Epo 1x wk Doses titrated	Dose requirement by route Change in Hb level t = 0 to either wks 13-16 or 12-24 Pain
Pergola 2009 (Epo-AKD-3001) (J&J)	CRI (Stage 3-4) Adult No recent ESA Hb < 11 g/dl* No sig dx	Open	375	44 wks of tx, but at 22 wks 3x/wk cohort à 1x/wk 4 wk post tx period	Non-inferiority Epo α 3x/wk vs 1x/wk vs q2wks Doses titrated	Hb change t = 0 to mean wk 14-wk 22 Hb change ≥ 1g/dl AEs (although suggestion transfusion, progression, CHF may be worse)
Pergola 2010 (Epo-AKD-3002) (J&J)	CRI stage 3-4 On Epo 1x/wk Hb 10-11.9 g/dl No sig dx	Open	430 1:1:2 rand	36 wks	Non-inferiority Epo α 1x/wk vs q2wks vs q4 wks Doses titrated	Change in Hb level t=0 to last 12 wks AEs
Rocha 1998	HD on IV epo No sig dx	Not stated	20	12 week arms	Cross-over Continuous IV vs bolus IV Dose fixed	Hct level Urea kinetics PTH
Weiss (Swedish Study Group) 2000	HD (Kt/V > 1) No ↑↑ HTN Replete Fe Hb 10-12.5 g/dl (w 8 wk Epo tx) Adult	Open	158	24 wk randomized tx 8 wk baseline	Original SQ injection 2 or 3x/wk vs SQ 1x wk Doses titrated	Dose requirement Hb level AEs (Pain, BP) (High drop-out)

1—Serial switch studies were not included. (Akizawa 2007, Grezsczak, 2005, Nomoto 1994)
2—Economic analyses were not included. (Piccoli 1995 was an economic analysis of Nomoto 1994)
↑ = increased
AE = adverse event
AUC = area-under-the-curve
BP = elevated blood pressure
C = CERA = continuous erythropoiesis receptor activator = methoxy polyethylene glycol epoetin beta = pegylated erythropoietin-beta
CHF = congestive heart failure
CRI = chronic renal insufficiency, but not on dialysis
CVD = cardiovascular disease
D = darbe = darbepoetin
DM = diabetes mellitus
Dx = diagnosis
E = epo = erythropoietin
Fe = iron
Hb = hemoglobin
Hct = hematocrit
HD = hemodialysis
HTN = hypertension
IV = intravenous
Kt/V = dialyzer clearance of urea x dialysis time/ volume of urea distribution in the body (measure of dialysis adequacy)
QoL = quality of life
PD = peritoneal dialysis
Sig = significant
SQ = subcutaneous
PTH = parathyroid hormone
Tx = treatment
URR = urea reduction ratio (measure of dialysis adequacy)

Table 22: Randomized Active Control Studies: Other Study Types

Study	Population	Blind	Size	Duration	Treatment Arms	Endpoints/Comments
Brandt 1999	CRI, D Hb <-2 SD age < 21 yrs Fe replete No ↑↑ HTN, seizure	Not stated	44	~ 12 wks; until hb target	Fixed doses Epo 150 vs 450 U/kg/wk Doses titrated after 12 wks	Hb change t = 0 to 12 wks Time to target Dose requirement Changes in renal function/ dialysis adequacy Panel reactive antibodies Transfusion (no algorithm)
Morris 1994	HD	DB	48	2 comparisons made on each of 2 days	SQ epo alpha vs SQ Epo beta +/- EMLA anaesthetic cream	Pain

↑ = increased
CRI = chronic renal insufficiency, not requiring dialysis
DB = double-blind
Epo = erythropoietin
Fe = iron
Hb = hemoglobin
HD = hemodialysis
HTN = hypertension
SD = standard deviation
SQ = subcutaneous

Table 23A: Studies Designed to Assess Survival and/or Cardiovascular Outcomes

Study	Population	Blind	Size	Duration	Entry Criteria	Exclusion Criteria
NCHT Besarab 1998 epo α USA 51 sites Amgen	Hemo	Open-label	1253	3+ yrs (planned)	CHF Ischemic HD Hct 27-33 on ESA	Recent cardiac events Diastolic HTN ↓ life expectancy Fe deficiency Androgen use
CREATE Drueke 2006 epo β 22 nations 94 sites	Pre-dialysis	Open-label	603	>2 yrs Max 4.25 yrs Mean 3 yrs	Hb 11-12.5 GFR calculated (CG)* 15-35	Non-renal anemia Prior ESA use Inflammation Serious CVD Transplant need
CHOIR Singh 2006 epo α USA 130 sites Ortho Biotech/J&J	Pre-dialysis	Open-label	1432	Max 3 yrs	Hb <11 GFR calculated (MDRD)** 15-50	Prior ESA Uncontrolled HTN Angina CA GI bleed Frequent transfusion
TREAT Pfeffer 2009 darbe α 24 nations 623 sites Amgen	Pre-dialysis	Double	4038	-------- Max 4 yrs Mean 29 mo	Hb <11 Transferrin > 15% Type 2 DM Stratified by CVD & spot urine protein	Recent ESA Antibiotics Uncontrolled HTN Recent CV event HIV, CA, or CA tx Bleeding, Hematologic disease Recent seizure Fe insufficiency Transplant need

1- Underpowered studies were not included (Bahlmann 1991, Furuland 2003, 2005 a and b.)
↓= decreased
↑ = increased
CA = cancer
CG = Cockcroft-Gault formula for estimating GFR using serum creatinine
CHF = congestive heart failure
CV(D) = cardiovascular (disease)
DM = diabetes mellitus
Fe = iron
GFR = glomerular filtration
GI = gastrointestinal
Hb = hemoglobin
Hct = hematocrit
HD = Hemo = hemodialysis
HTN = hypertension
MDRD = Modification of Diet in Renal Disease formula for estimating GFR using serum creatinine
Tx = treatment

Table 23B: Studies Designed to Assess Survival and/or Cardiovascular Outcomes (continued)

Study	Dose	Target Hb (g/dl) or Hct (%)	Transfusion Criteria	Stratification by
Study	Dose	Target Hb (g/dl) or Hct (%)	Transfusion Criteria	Hb (Hct)	Dose	Dialysis Adequacy or Renal Clearance
NCHT Besarab 1998 epo α USA 51 sites Amgen	↑ by 1.5x, then 25% of t=0 q 2 wks vs 10-25 U/kg q2 wks until target*. Actual use: Mean ~460 U/kg/wk vs ~120 U/kg/wk. IV or SQ	Hct 39-45 vs 27-33	No	No	No	No
CREATE Drueke 2006 epo β 22 nations 94 sites Hoffman-La Roche	Initial dose of 2000 U/wk with an increase of 25-50% q 4 wks Actual use: Median 5000 U/wk (range 3000-8000) vs 2000 U/wk (range 1000-3000)	Hb 13-15 vs 10.5-11.5 (ESA if <10.5)	No	No	No	No
CHOIR Singh 2006 epo α USA 130 sites Ortho Biotech/J&J	10,000 U/wk 20,000 U/wk max (in appendix) SQ	Hb 13-13.5 vs 10.5-11 (13.5 vs 11.3)	No	No	No	No
TREAT Pfeffer 2009 darbe α 24 nations 623 sites Amgen	Initial dose 0.75 ug/kg with increases by algorithm to a maximum of 6000 ug/mo 104-305 ug/mo (in appendix) SQ	Hb ~13 (ESA if <9)	No	No	No	Spot urinary protein-to-creatinine ratio <1, ≥1

IV = intravenous
SQ = subcutaneous

Table 23C: Studies Designed to Assess Survival and/or Cardiovascular Outcomes (continued)

Study	Results (high vs low target)
NCHT Besarab 1998 epo α USA 51 sites Amgen	1^o endpoint: time to death or 1^st non-fatal myocardial infarction Study stopped at 29 mo Withdrawal rates not indicated 183 deaths + 19 non-fatal myocardial infarctions vs 150 deaths + 14 non-fatal myocardial infarctions Venous access thrombosis: 243 vs 176; p=0.001 Transfusion: 129 vs 192 persons (many for surgical or GI bleeding) Kt/V: ↓ in high target arm 1.38 vs ↑ in low 1.44; p<0.001 Hospitalization: 445 vs 425 Quality of life: Global SF-36: No difference. Reported improvement in physical function domain. Dose: Not reported in 1^opaper Post hoc analysis (Kilpatrick 2008): ↑ mortality with ↓ ESA responsiveness
CREATE Drueke 2006 epo β 22 nations 94 sites	1^o Endpoint : time to death & CV composite Cardiac event rate lower than expected based on prior calculations Withdrawal: 25% experimental group; 17% control group 1^st cardiovascular event 58 vs 47 (including stroke and transient ischemic attack 13 vs 7) Mortality: 31 vs 21 Left ventricular mass: no difference. Thrombosis of fistula: 12/127 vs 8/111 Transfusion: 26 vs 33 persons Progression to RRT: 127 vs 111; p=0.03 Hospitalization: 61% vs 59% (unclear if limited to cardiac-related admissions) Quality of life (SF-36): Reported improvements at 1 year, but maximal differences in subunit scores apparently converted to 100 scale were <8 units. These differences were not sustained beyond the first year. Dose: Not reported
CHOIR Singh 2006 epo α USA 130 sites Ortho Biotech/J&J	1^o endpoint: (time to) mortality & CV composite Study stopped because ability to show efficacy unlikely Withdrawal 38% with imbalance in those not à transplant Composite events: 125 vs 97. (Death 52 vs 36, CHF 64 vs 47, MI 18 vs 20, CVA 12 vs 12) Progression to renal replacement: 155 vs 134 Thrombovascular: 126 vs 120 Transfusion: Not reported Progression to RRT: 155 vs 134 Hospitalization: 369 vs 334 Quality-of- life: (LASA, KDQ, SF-36): No difference Dose: 11,215 U/wk (10,694 if achieved; 12,884 if did not ) vs 6276 U/wk (6057 if achieved; 11,098 if did not)
TREAT Pfeffer 2009 darbe α 24 nations 623 sites Amgen	1^o endpoint: time to death or cardiovascular composite endpoint & time to death or renal failure Imbalance at baseline for placebo and congestive heart failure Withdrawal: Treatment stopped, but followed 20% + Discontinued without follow-up except +/- death status 13% Mortality and/or cardiovascular endpoint (includes stroke): 632 vs 602. Stroke: 101 adjudicated (161, ischemic 150, hemorrhagic 89) vs 53 adjudicated (102, ischemic 96, hemorrhagic 49) Cancer death: 39 vs 25 Venous thromboembolic events: 41 vs 23; p=0.02 Arterio thromboembolic events 178 vs 144; p=0.04 Transfusion: 297 vs 496 persons Progression to RRT: 338 vs 330 (mean GFR information not reported) Hospitalization: Not reported Quality-of-life: FACT-fatigue: 1.4 (of 50) change; SF-36: No difference Dose: Not reported

1^o = primary
CHF = congestive heart failure
CV = cardiovascular
CVA = stroke
FACT-fatigue = Functional Assessment of Cancer Therapy-Fatigue subscale
GI = gastrointestinal
KDQ = Kidney Disease Questionnaire
LASA = Linear Analogue Self Assessment
MI = myocardial infarction
RRT = renal replacement therapy (dialysis ot transplantation)
SF-36 = Short Form 36 Health Survey

Table 24: Secular Trends in Blood Usage in the United Kingdom

HSE	1999-2000	2000-2001	2001-2002	2002-2003	2003-2004	2004-2005	2005-2006	2006-2007	2007-2008	2008-2009
RBC	2,737,572	2,706,307	2,679,925	2,678,098	2,607,410	2,428,934	2,316,152	2,235,638	2,174,256	2,209,153
Cry, FFP, PLT, RBC	3,446,855	3,426,782	3,404,865	3,399,988	3,340,221	3,103,200	3,002,797	2,914,228	2,845,459	2,903,760

Cry = Cryoprecipitate
FFP = Fresh frozen plasma
PLT = Platelet
RBC = Red blood cell

Table 25: Adverse Events with Blood Usage in the United Kingdom

Adverse Event	IBCT	I&U	HSE	AntiD*	ATR	HTR	TRALI	TACO	TAD	PTP	TA- GvHD	TTI	Autologous	Total
Death: Transfusion reaction causal contributory	27	4	0	0	19	11	42	5	0	2	13	15	0	138
Major morbidity: Probably/definitely attributed to transfusion	116	3	0	25	58	48	165	18	1	13	0	48	0	495
Minor/no Morbi-dity: with trans-fusion reaction/error	3439	161	335	361	1154	383	50	29	4	34	0	6	42	5998
Unknown	11	0	0	0	3	1	0	0	0	0	0	0	0	15
Total	3593	168	335	386	1234	443	257	52	5	49	13	69	42	6646

AntiD = Anti-D antigen related events. There were also 127 cases of potential major morbidity where anti-D had been omitted or given more than 72 hours after the event.
ATR = Acute transfusion reaction
Autologous = Autologous transfusion
HSE = Handling & storage errors
HTR = Hemolytic transfusion reaction
IBCT = Incorrect blood component transfused
I&U = Inappropriate & unnecessary transfusion
PTP = Post transfusion purpura
TACO = Transfusion related circulatory overload
TAD = Transfusion associated dyspnea
TA-GvHD = Transfusion associated graft vs host disease
TRALI = Transfusion related acute lung injury
TTI = Transfusion transmitted infection

Table 26: Transfusion Guidance and Evidence Rating

Hemoglobin (g/dl)	Compensatory Capacity Risk Factor(s)	RBC Transfusion	Evidence Rating
≤ 6 g/dl	---	Yes	1C+ No randomised, controlled studies, but unambiguous data available
>6-8 g/dl	Symptomic Decompensation (ECG ischemia, hypotension, lactic acidosis, tachycardia)	Yes	1C+ No randomised, controlled studies, but unambiguous data available
	Limited Compensation Risk factors such as cardiovascular disease & cardiac insufficiency	Yes	1C+ No randomised, controlled studies, but unambiguous data available
	Adequate Compensation No risk factors	No	1C+ No randomised, controlled studies, but unambiguous data available
> 8-10 g/dl	Symptomic Decompensation (ECG ischemia, hypotension, lactic acidosis, tachycardia)	Yes	2C Very Weak recommendation, depending on the individual case, a different course of action may be indicated
> 10 g/dl	---	No	1A Strong recommendation. Valid for most patients.

Table 27: NCCCC Anemia Management Guidelines for Patients with Renal Disease

Conclusion	Source	Evidence Quality	Overall Quality
Iron should be given to anemic CKD patients with serum ferritin <100 ng/ml or TSAT <20 percent or CHr <29 pg/cell	National Kidney Foundation, 2007 Panesar & Agarwal, 2002; Silverberg et al., 1996; Stoves, Inglis, Newstead, 2001;	At least 1 properly ran-domized controlled trial	Good High grade evidence (I or II-1) directly linked to health outcome
Insufficient evidence regarding the lower threshold of ESA	Levin et al., 2005; Locatelli et al., 2004; National Kidney Foundation, 2007; Roger et al., 2004	At least 1 properly ran-domized controlled trial	Fair High grade evidence (I or II-1) linked to intermediate outcome or Moderate grade evidence (II-2 or II-3) directly linked to health outcome
Hemoglobin >13 g/dL are associated with increased mortality and frequency of cardiovascular events.	Drueke et al. 2006; Singh et al., 2006; National Kidney Foundation, 2007	At least 1 properly ran-domized controlled trial	Fair High grade evidence (I or II-1) linked to intermediate outcome or Moderate grade evidence (II-2 or II-3) directly linked to health outcome
Vitamin C, androgens, or carnitine should not be administered.	National Kidney Foundation, 2007	At least 1 properly ran-domized controlled trial	Fair High grade evidence (I or II-1) linked to intermediate outcome or Moderate grade evidence (II-2 or II-3) directly linked to health outcome

Table 28: Mortality and Cardiovascular Events in Major Trials

Study	Composite Events	Death	Cardiovascular Other	Other	DC Early	Withdrawal
NCHT Dialysis Epo α	High target 202 Low target 164	High target 183 Low target 150	1st non-fatal MI High target 19 Low target 14	--- ---	Yes Safety	Not indicated
CHOIR Pre-dialysis Epo α	High target 125 Low target 97	High target 52 Low target 36	CHF+MI+CVA High target 64+18+12 Low target 47+20+12	--- ---	Yes Ability to show + results unlikely Safety	38%
CREATE Pre-dialysis Epo β	High target 58 Low target 47	High target 31 Low target 21	LV mass ∆ yr 1, yr 2 (g/m²) High target −4.6, −6.4 Low target −3.3,−7.8	--- ---	No	High target 25% Low target 17%
TREAT Pre-dialysis Darbe α	High target 632 Low target 607	High target 31 Low target 21	Stroke High target Low target	Cancer Death High target 39 Low target 25	No	Tx DC but followed 20% DC & followed only for death status 13%

DC = discontinued
Tx = treatment

Table 29: Hemoglobin Level and Erythropoietin Dose in the 2003 ESAM Cross-sectional Survey on Anaemia Management (Jacob 2005)

Location	Mean Epo Dose (U/wk)	Hb <11 g/dl (%)	Mean Epo Dose (U/wk)	Hb >11 g/dl (%)	Ratio Epo Dose Hb<11 g/dl/>11g/dl	Mean Epo Dose (U/wk)
Belgium	16,477	23.6	10,023	76.4	1.6	11,546
Israel	15,310	28.7	9,358	71.3	1.6	11,064
Sweden	15,649	23.8	9,744	76.2	1.6	11,147
Austria	14,049	28.6	7,653	71.4	1.8	9,483
Finland	12,095	27.1	6,835	72.9	1.8	8,261
Switzerland	11,943	21.1	7,923	78.9	1.5	8,771
Netherlands	11,623	32.1	7,038	67.9	1.65	8,511
United Kingdom	11,196	34.6	7,503	65.4	1.5	8,782
Greece	10,335	42.4	7,109	57.6	1.45	8,476
Slovenia	9,940	32.3	6,245	67.7	1.6	7,437
Germany	8,628	34.6	5,532	65.4	1.6	6,603
Poland	4,420	62.9	2,583	37.1	1.7	3,738
Overall Mean	9,836	33.9	6,781	66.1	1.45	7,817

N = 8100, 284 centers 12 countries

Table 30: Hemoglobin Level and Erythropoietin Dose in the 2002-3 DOPPS Cross-sectional Survey in Hemodialysis Patients (Pisoni 2004)

Location	Mean Epo Dose (U/wk)	Weekly Epo Dose 1K-18 K (%)	Mean Hb (g/dl)	Hb >11 g/dl (%)	Epo Use b/f Dialysis (%)*	Mean Hb b/f Dialysis (g/dl)*
United States	17360	69	11.7	76	27	10.4
Belgium	12312	85	11.5	68	33	10.3
Sweden	12202	78	11.8	74	65	10.7
Canada	10808	86	11.4	66	43	10.1
Australia/New Zealand	8725	91	11.5	63	50	10.1
Italy	8118	95	11.1	56	59	10.2
United Kingdom	8010	96	11.2	58	44	10.2
Spain	7607	96	11.5	67	56	10.6
France	7401	96	11.0	51	43	10.1
Germany	6846	99	11.3	61	46	10.5
Japan	4875	98	10.2	19	62	8.3
Overall Mean	N=11,041				N=1886

Table 31: Hemoglobin Level and Erythropoietin Dose in the UK Renal Registry Surveys in 1997 and 2007 (Burton 2000, Richardson 2009)

Type Dialysis/ Time Survey	ESA Dose (U/wk)	ESA Use (%)	No ESA+Hb >10g/dl (%)	Hb (g/dl)	Hb >10 g/dl (%)	Hb >11 g/dl (%)
Hemodialysis-2007	9299	92	7	11.6 mean	86	68
Peritoneal Dialysis-2007	6101	75	20	11.9 mean	91	76
Hemodialysis-1997	---	73	18	10.5 median	62	---
Peritoneal Dialysis-1997	---	48	39	11.0 median	76	---

Table 32: Erythropoietin Resistance and Mortality (NCHT)

	Least Responsive Quartile 1	Quartile 2	Quartile 3	Most Responsive Quartile 4
Mortality %	34	28	25	14