1. title page - vfa 20101236 - observational... · date: 23 may 2013 page 8 of 48 methoxy...

Product: Darbepoetin alfa Observational Research Study Report (redacted for DE): 20101236 Date: 23 May 2013 of 48

1. TITLE PAGE

Study Title: AFFIRM: Aranesp Efficiency Relative to Mircera

Investigational Product: None

Indication: Chronic kidney disease (CKD) and anaemia

Brief Description: This retrospective, multi-centre, observational, descriptive study enrolled CKD subjects who were receiving haemodialysis (HD) and switched from darbepoetin alfa to methoxy polyethylene glycol-epoetin beta (peg-EPO [Mircera]) for the treatment of anaemia. No investigational product was used.

Study Sponsor: Amgen Ltd 240 Science Park, Milton Road Cambridge CB4 0WD, United Kingdom

Study No.: 20101236

Study Phase: 4

Study Initiation Date: 01 June 2011

Early Study Termination Date:

Not applicable.

Study Completion Date: 03 November 2011

Principal Investigators: Investigators are listed in Appendix 2 (on request)

Contact Person: Janet Addison Phone: +44 1223 437367 Fax: +44 1223 4436805

Good Clinical Practice: This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents will be retained in accordance with ICH GCP.

Report Date: 23 May 2013


2. TABLE OF CONTENTS

1. TITLE PAGE ........................................................................................................... 1

2. TABLE OF CONTENTS .......................................................................................... 2

2.1 List of Tables ............................................................................................... 3

2.2 List of Figures ............................................................................................. 4

3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................. 5

4. INTRODUCTION .................................................................................................... 7

5. METHODOLOGY ................................................................................................... 9

5.1 Study Outcomes........................................................................................ 10

5.1.1 Primary Outcome ...................................................................... 10

5.1.2 Secondary Outcome Measures ................................................. 10

5.1.3 Other Outcomes Measures ........................................................ 10

5.2 Statistical Methods .................................................................................... 11

5.2.1 Analysis Sets ............................................................................. 11

5.2.2 Sample Size .............................................................................. 12

5.2.3 Methods of Analyses ................................................................. 12

5.2.4 Notable Changes to Pre-Specified Analyses ............................. 14

6. RESULTS ............................................................................................................. 17

6.1 Enrolment and Patient Disposition ............................................................ 17

6.2 Demographics and Baseline Characteristics at the Time of Switch ....................................................................................................... 17

6.3 Primary Outcome ...................................................................................... 21

6.3.1 Population Mean Maintenance Dose Conversion Ratio of Peg-EPO Dose in the Post-Switch EP to Darbepoetin alfa Dose in the Pre-Switch EP ............................. 21

6.3.2 Subgroup Analyses for Primary Outcome Measure ................... 21

6.4 Secondary Outcomes ................................................................................ 24

6.4.1 Dose Only Ratios Over Time for Peg-EPO Post-switch EP Dose to Darbepoetin Alfa Pre-switch EP Dose .................... 24

6.4.2 Average Weekly Darbepoetin Alfa and Peg-EPO Doses During the Pre-Switch and Post-Switch Observation Periods .................................................................. 25

6.4.3 Percentage Dose Changes from Darbepoetin Alfa Dose at Switch to Peg-EPO Dose Post-Switch .......................... 27

6.4.4 ESA Dose, Frequency, and Route of Administration during the Pre-Switch and Post-Switch Observation Periods ...................................................................................... 27

6.4.5 Number of Dose and/or Dose Frequency Changes During the Pre-Switch and Post-Switch Periods ........................ 29

6.4.6 Monthly Haemoglobin Concentrations During Pre-Switch and Post-Switch Periods ................................................ 29


6.4.7 Relationship Between Average Weekly Darbepoetin Alfa Dose During Pre-switch EP and Average Weekly Peg-EPO Dose During Post-switch EP...................................... 31

6.5 Other Outcomes ........................................................................................ 32

6.5.1 Monthly Haemoglobin Concentration by Categories during the Pre- and Post-switch Observation Period ................. 32

6.5.2 Subject Specific Changes in Haemoglobin Concentrations .......................................................................... 35

6.5.3 Markers of Health Status ........................................................... 35

6.5.3.1 Severe Acute Exacerbation of Inflammatory Conditions .......................................... 35

6.5.3.2 Severe Acute Infections .......................................... 35

6.5.3.3 Laboratory Parameters ............................................ 36

6.5.3.4 Iron Status and Supplemental Iron Use ................... 37

6.5.3.5 Transfusions ........................................................... 38

6.5.3.6 Hospitalisations and Surgical Procedures ............... 38

6.5.3.7 Haemodialysis Parameters ...................................... 39

6.5.3.8 Co-morbid Conditions .............................................. 40

6.5.3.9 Concomitant Medications ........................................ 41

6.6 Safety Results ........................................................................................... 41

6.6.1 Deaths ....................................................................................... 42

6.6.2 Adverse Drug Reactions ............................................................ 42

7. BIAS/LIMITATIONS .............................................................................................. 43

8. CONCLUSIONS ................................................................................................... 44

9. REFERENCES ..................................................................................................... 46

10. SUMMARY TABLES AND FIGURES .................................................................... 48

2.1 List of Tables

Table 4-1. Peg-EPO Starting Dose based on Previous Darbepoetin Alfa Dose Prior to Switch. ................................................................................ 8

Table 5-1. Expected Precision of the DCR Estimate for the PAS .................................. 12

Table 6-1. Summary of Subject Characteristics at the Time of Switch (Full Analysis Set [FAS] and Primary Analysis Set [PAS]) .............................. 19

Table 6-2. Population Mean Maintenance Dose Conversion Ratios for the PAS by Predefined Subgroups .............................................................. 22

Table 6-3. Summary of Dose and Dose Ratio at Switch and at 2-Month Post-switch Intervals from the Pre-switch EP (Primary Analysis Set) ......................................................................................................... 25

Table 6-4. Summary of Average Weekly Darbepoetin Alfa Dose by Month during the Pre-Switch Observation Period (Primary Analysis Set) ......................................................................................................... 26


Table 6-5. Summary of Average Weekly Peg-EPO Dose by Month during the Post-Switch Observation Period (Primary Analysis Set) ......................... 26

Table 6-6. Summary of Peg-EPO Weekly Dose Percent Change by Month during the Post-Switch Observation Period (Primary Analysis Set) ......................................................................................................... 27

Table 6-7. Summary of Frequency of Administration of Intravenous Darbepoetin Alfa at Monthly Intervals during the Pre-Switch Observation Period (Primary Analysis Set) ............................................ 28

Table 6-8 Summary of Frequency of Administration of Intravenous Pegylated Erythropoietin Beta at Monthly Intervals during the Post-Conversion Observation Period (Primary Analysis Set) .......................... 29

Table 6-9. Summary of Haemoglobin Concentrations by Month during the Pre-Switch Observation Period (Primary Analysis Set) ........................... 30

Table 6-10. Summary of Haemoglobin Concentrations by Month during the Post-Switch Observation Period (Primary Analysis Set) ......................... 30

Table 6-11. Summary of Haemoglobin by Study Month According to Broad Categories and Site Specific Target Ranges - Pre-Switch Observation Period (Primary Analysis Set) ............................................ 34

Table 6-12. Summary of Haemoglobin by Study Month According to Broad Categories and Site Specific Target Ranges - Post-Switch Observation Period (Primary Analysis Set) ............................................. 34

2.2 List of Figures

Figure 6-1. Scatter Plot With Relationship Between Pre-Switch EP Weekly Darbepoetin Alfa Dose and Post-Switch EP Weekly Peg-EPO Dose (Primary Analysis Set) .................................................................. 31

Figure 6-2. Bland and Altman Presentation of Subjects Dosing at EPs (Primary Analysis Set) ............................................................................ 32


3. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

Abbreviation or Term Definition/Explanation

ADR adverse drug reaction

CI confidence interval

CKD chronic kidney disease

CRP C-reactive protein

Dose conversion ratio

(DCR)

ratio of pegylated erythropoietin beta to darbepoetin alfa dose to

achieve the same Hb concentration

Dose only ratio ratio of pegylated erythropoietin beta dose to darbepoetin alfa dose

EOS end of study

EP evaluation period

EPAR European Public Assessment Report

EPO erythropoietin

ESA erythropoiesis-stimulating agents

EU European Union

FAS Full Analysis Set

GCP Good Clinical Practice

Hb haemoglobin

HD haemodialysis

ICH International Conference on Harmonisation

IV Intravenous(ly)

kDa kiloDalton

Kt/V a measure of haemodialysis adequacy

Observation period 14-month period comprising the 7 months prior to switch from

darbepoetin alfa to peg-EPO and the 7 months post-switch

ORSR observational research study report

PAS Primary Analysis Set

Peg polyethylene glycol

Peg-EPO methoxy polyethylene glycol-epoetin beta (Mircera)

PI principal investigator

Post-switch evaluation

period

months 6 and 7

Post-switch observation

period

months 1 to 7

Page 1 of 2


Abbreviation or Term Definition/Explanation

Pre-switch evaluation

period

months -1 and -2

Pre-switch observation

period

months -7 to -1

PTH parathyroid hormone

QM once a month

QW once a week or more frequently

QW once a week

Q2W once every 2 weeks





Q6W once every 6 weeks or less often

RBC red blood cell

rHuEPO recombinant human EPO

RPP research project plan

SAS Status Analysis Set

SC subcutaneous(ly)

SD standard deviation

SE standard error

SmPC Summary of Product Characteristics

SOC system organ class

TSAT transferrin saturation

UK United Kingdom

Page 2 of 2


4. INTRODUCTION

Anaemia is a frequent complication of chronic kidney disease (CKD), occurring in over

90% of subjects undergoing dialysis (Rao and Pereira, 2005). The pathogenesis of

anaemia of CKD is multi-factorial, but the predominant and most consistent cause is the

failure of adequate production of endogenous erythropoietin (EPO) by the kidneys. The

fundamental impact of anaemia on organ function is reduced oxygen delivery to tissues

(Horina et al, 1993; Braumann et al, 1991; Robertson et al, 1990). Fatigue and effort

intolerance are the cardinal symptoms, but anaemia can be associated with other

consequences, such as impaired cognitive function and concentration or sleep disorders

(Furuland et al, 2003; Foley et al, 2000; Bárány et al, 1993; Muirhead et al, 1992;

Bahlmann et al, 1991; Marsh et al, 1991; Canadian Erythropoietin Study Group, 1990;

Evans et al, 1990). Treatment of anaemia with erythropoiesis-stimulating agents (ESAs)

effectively increases haemoglobin (Hb) concentration and reduces the need for red

blood cell (RBC) transfusions (Provenzano et al, 2004; Valderrábano et al, 2003;

Besarab et al, 1998; Eschbach, 1994; Canadian Erythropoietin Study Group, 1990).

Darbepoetin alfa is a glycoprotein analogue of erythropoietin that was created by

introducing 5 amino acid changes into the primary sequence of erythropoietin to create

2 extra consensus N-linked carbohydrate addition sites and thus increasing the potential

maximum number of sialic acid residues to 22 as opposed to 14 residues in rHuEPO

(Elliott et al, 2003, Macdougall, 2002a). Darbepoetin alfa stimulates erythropoiesis by

the same mechanism as both endogenous EPO and recombinant human EPO

(rHuEPO). Due to the additional carbohydrate chains, darbepoetin alfa has an

approximately 3-fold longer serum half-life and longer in vivo biological activity than

rHuEPO (Macdougall, 2002b, Egrie et al, 2003), allowing darbepoetin alfa to be

administered at extended intervals compared with rHuEPO.

In Europe, darbepoetin alfa is approved for the treatment of symptomatic anaemia in

patients with chronic kidney disease (CKD). Darbepoetin alfa is given as a

subcutaneous (SC) or intravenous (IV) injection at a dosing frequency of once-weekly or

once every 2 weeks (Q2W), in patients receiving or not receiving dialysis, or monthly

(QM) for maintenance of Hb in patients not on dialysis. The starting dose is either

weight-based for patients previously not receiving an ESA or calculated from the short-

acting ESA dose immediately prior to switching to darbepoetin alfa (Aranesp®

[darbepoetin alfa] Summary of Product Characteristics [SmPC], 2011).


Methoxy polyethylene glycol-epoetin beta (peg-EPO [Mircera®]) is another long-acting

erythropoietic agent, which differs from erythropoietin through formation of a chemical

bond between an amino group present in the short acting ESA epoetin beta and

methoxy polyethylene glycol (Peg) butanoic acid. Peg-EPO has an approximate

molecular weight of 60 kiloDalton (kDa) and as compared to epoetin beta, exhibits

slower association with and faster dissociation from the receptor, a reduced specific

activity in vitro with an increased activity in vivo, as well as an increased half-life

(Mircera® European Public Assessment Report [EPAR]).

Peg-EPO is approved for the treatment of symptomatic anaemia associated with CKD,

also administered either IV or SC, but with a dose frequency option of Q2W or QM in

patients receiving or not receiving dialysis. The starting dose is either weight-based for

patients previously not receiving an ESA or calculated from the previous weekly ESA

dose. The starting doses recommended for peg-EPO based on the previous weekly

darbepoetin alfa dose are shown in Table 4-1 (Mircera® SmPC, 2012):

Table 4-1. Peg-EPO Starting Dose based on Previous Darbepoetin Alfa Dose Prior to Switch.

Previous Weekly Darbepoetin Alfa

Intravenous or Subcutaneous Dose

(ug/Week)

Monthly peg-EPO Intravenous or

Subcutaneous Dose (ug/Month)

<40 120

40-80 200

>80 360

However, there is little information available on switching from darbepoetin alfa to peg-

EPO in a non-experimental setting. AFFIRM is a retrospective, multi-site, observational,

descriptive study designed to examine haemodialysis (HD) patients whose treatment

was switched from darbepoetin alfa to peg-EPO QM outside the protocol of an

interventional clinical study.

This was a 14-month study comprising a 7-month pre-switch period on darbepoetin alfa

and a 7-month post-switch period on peg-EPO. The primary objective was to estimate a

population mean maintenance Dose Conversion Ratio (DCR) of peg-EPO to darbepoetin

alfa. Secondary objectives were to investigate parameters of clinical management of

anaemia, including Hb concentrations, Hb excursions, ESA dose changes, and RBC

transfusions.


5. METHODOLOGY

This was a non-interventional, retrospective, multi-site, observational, descriptive study

and was not intended to alter clinical management of subjects. The population studied

included subjects with CKD, on HD, who were dialysed at European dialysis centres and

whose anaemia therapy had been switched from darbepoetin alfa to QM peg-EPO for

the treatment of anaemia. The individual subject observation period was 14 months

(7 month pre-switch to 7 month post-switch).

Number of Subjects Planned: 400

Diagnosis and Main Criteria for Eligibility: Eligible subjects were at least 18 years of

age and were receiving HD and switched from darbepoetin alfa to QM peg-EPO for the

treatment of anaemia. Subjects were required to have:

received HD for at least 12 months prior to switching from treatment with darbepoetin alfa to treatment with peg-EPO QM,

received darbepoetin alfa treatment IV for at least 7 months immediately prior to switching to QM peg-EPO IV treatment (breaks due to treatment being intentionally withheld were permitted),

switched from darbepoetin alfa to QM peg-EPO at least 7 months prior to enrolment,

received at least 1 dose of peg-EPO after switching from darbepoetin alfa treatment,

provided informed consent, if applicable, according to local requirements.

Subjects were not eligible for enrolment if they:

enrolled in an investigational device or drug study at any time during the 14-month data observation period or within 30 days prior to commencement of the data observation period,

received treatment with an ESA other than darbepoetin alfa during the 7 months prior to switch to peg-EPO (with the exception of short-acting ESAs, which may have been used for a cumulative period of up to 2 weeks only, and not within the pre-switch evaluation period [EP]).

Investigational Product, Dose and Mode of Administration, Manufacturing Lot

Number: Not applicable: No investigational product was administered in this

observational study.

Duration of Treatment: Not applicable: No investigational product was administered in

this observational study.

Reference Therapy, Dose and Mode of Administration, Manufacturing Lot Number:

Not applicable: No investigational product was administered in this observational study.


5.1 Study Outcomes

5.1.1 Primary Outcome

The primary outcome was the ratio of the peg-EPO dose during the post-switch EP

(months 6 and 7) relative to the darbepoetin alfa dose during the pre-switch EP (the

2 months prior to switch [months -2 and -1]). The primary outcome was to be calculated

for the primary analysis set only if the population-level mean change in Hb from the pre-

switch EP to the post-switch EP was within 0.5 g/dL. See Section 5.2.1 for a definition

of this analysis set.

5.1.2 Secondary Outcome Measures

Dose only ratio (ie, ratio of weekly doses only, differing from DCR by ESA doses being dissociated from achieved Hb concentrations) of peg-EPO average weekly dose to the darbepoetin alfa average weekly dose during the pre-switch EP:

at the time of switch from darbepoetin alfa to peg-EPO

during months 2 and 3 post-switch

during months 4 and 5 post-switch

ESA use during the study characterized by:

Weekly doses of darbepoetin alfa and peg-EPO dose during the pre- and post-switch periods

ESA type, dose, frequency, and route

Number of dose and/or dose frequency changes, for the pre- and post-switch periods separately

Percentage dose change from darbepoetin alfa dose at switch to peg-EPO dose at each month post-switch

Hb concentration in each month pre- and post-switch

5.1.3 Other Outcomes Measures

Incidence of Hb concentrations by category in each month pre- and post-switch

Hb within the site’s Hb target each month pre- and post-switch

Hb within 1 g/dL difference between month -7 and switch, and post-switch to month 7.

Clinical management parameters, including laboratory assessments (serum calcium, serum phosphate, parathyroid hormone [PTH], albumin, and C-reactive protein [CRP]), Kt/v, iron status; new or worsening co-morbid conditions; transfusions (number of transfusions and units); kidney transplants; changes in vascular access type; hospitalisations and surgeries over the 14-month study period.


5.2 Statistical Methods

5.2.1 Analysis Sets

Three analysis sets were defined:

The Full Analysis Set (FAS) was defined as all subjects who switched to peg-EPO from darbepoetin alfa, received at least 1 dose of peg-EPO, met all of the study inclusion criteria, and none of the exclusion criteria.

The Primary Analysis Set (PAS) was changed from the definition provided in the research project plan (RPP) (see Section 5.2.4) and was ultimately defined as all subjects in the FAS with the exception of the following groups of subjects:

Subjects who died during the post-switch observation period

Subjects who were lost to follow-up during the post-switch observation period

Subjects who received ESAs other than peg-EPO within 1 month prior to or during the post-switch EP

Subjects with Hb data not available for either/both EPs

The Status Analysis Set (SAS) was defined as all subjects in the PAS who:

Had mean Hb values in the 2 EPs that differed by no more than

0.5 g/dL at the individual subject level

Had stable darbepoetin alfa dose prior to switch (defined as a dose change of

25% in the 3 months prior to switch)

Subgroups that were explored within this final analysis include:

Site Conversion Pattern Categories

PAS 100% switching subgroup - those subjects from sites that switched all subjects receiving darbepoetin alfa to receive peg-EPO

PAS < 100% switching subgroup - those subjects from sites that did not switch all subjects receiving darbepoetin alfa to receive peg-EPO

Country (France, Germany, United Kingdom [UK], Spain)

Age at switch ( 65 years, > 65 to 75 years, > 75 years)

Sex (male, female)

Primary CKD etiology (diabetes, hypertension, other)

Hb concentration category at switch ( 9, > 9 to 10, > 10 to 11, > 11 to 12,

> 12 to 13, > 13 g/dL)

Dose frequency category immediately prior to switch

Subject stability status at switch (stable, unstable)

Subject stability was defined in the RPP as Hb fluctuation less than 2 g/dL and dose changes less than 25% in the 12 weeks prior to switching


5.2.2 Sample Size

Based on feasibility assessments, it was estimated that approximately 400 subjects

could be enrolled into the study and would be included in the FAS. It was assumed that

60% to 85% of subjects in the FAS would qualify for inclusion in the PAS, giving a

sample size of between 240 and 340 in the PAS. In addition, it was expected that

approximately 40% to 60% of subjects would be in the ―PAS 100% switching subgroup‖,

ie, between 96 and 204 subjects. Sample size calculations assumed that the standard

deviation (SD) of the peg-EPO/darbepoetin alfa dose ratio in the study population would

be approximately 1.20. This assumption was derived from Amgen Studies 20040104

and 20050210. In these studies, the SD for the dose ratio between the evaluation period

and baseline was 0.60 and 0.86 (and up to 1.07 in some subgroup analyses)

respectively. Given the observational nature of this study and the broader subject

population, a higher SD of 1.20 was used for the sample size calculations. Table 5-1

below shows the expected precision of the DCR estimate if the entire PAS is used.

Sample sizes in the table range from 240 to 340 (the feasible range for the number of

patients in the PAS).

Table 5-1. Expected Precision of the DCR Estimate for the PAS

Number of Patients in the PAS Full Width of 95% CI for the DCR Estimate

240 0.30

290 0.28

340 0.26

CI = confidence interval, DCR = dose conversion ratio, PAS = primary analysis set

5.2.3 Methods of Analyses

The primary objective of the study was to estimate the population mean maintenance

DCR for subjects who switched from darbepoetin alfa to peg-EPO. If the population

mean Hb levels were similar (i.e. within ± 0.5 g/dL), then the analysis of the primary

endpoint was to be performed. If the population mean Hb levels were not similar, the

analysis of the primary endpoint would not be performed and only the secondary

endpoints for the study would be analysed.

Geometric mean weekly doses of ESA were calculated per subject for each monthly

interval (including the first dose of peg-EPO), by first calculating a mean daily dose for

the interval (by dividing each dose evenly between the days bounded by its date of

administration and the day before the next dose, then taking a mean of these partial


doses for the days in the interval) and multiplying by 7 to convert to a weekly dose. The

DCR for each subject was then calculated as the geometric mean weekly dose of peg-

EPO during the post-switch EP divided by the geometric mean weekly dose of

darbepoetin alfa during the pre-switch EP. The mean population DCR was then

calculated by taking the mean of all individual DCRs and presented as both a continuous

(mean, median, SD, standard error [SE], minimum, and maximum) and a categorical

variable (number of subjects in each of the following categories: [< 0.5:1], [ 0.5 :1 and

< 0.75:1], [ 0.75:1 and < 1:1], [ 1:1 and < 1.25:1], [ 1.25:1 and < 1.5:1], [ 1. 5:1 and

< 2:1], [ 2:1]. To compensate for skewing in the dose data, geometric means were

calculated. Where geometric means have been reported they are noted as such in this

observational research study report (ORSR); all other ―mean‖ values are arithmetic.

The dose only ratio (the dose ratio calculated without reference to Hb concentration)

compared to the pre-switch EP was summarised as both a continuous and a categorical

variable.

The ESA type, weekly dose, route, and frequency of administration were summarised for

each month before and after the switch to peg-EPO. ESA type, route, and frequency

assigned to a subject at the beginning of the month were reported. The analyses of

average weekly dose used all dose data during the particular month. The number of

dose and/or frequency changes of ESA was summarised over the study duration. The

percentage dose change from the dose at commencement of peg-EPO to the dose at

each month post commencement was also summarised.

A Bland and Altman plot of the average weekly dose (darbepoetin alfa average weekly

dose plus peg-EPO average weekly dose divided by 2) compared to the difference

between each individual’s weekly dose of darbepoetin alfa and peg-EPO (peg-EPO

average weekly dose minus darbepoetin alfa average weekly dose) during the two EPs

was done to assess the concordance between the darbepoetin alfa and peg-EPO doses.

Hb concentrations for each study month and during each EP were summarised using the

mean, 95% confidence interval (CI) for the mean, median, 25th and 75th percentiles, and

minimum and maximum. Change in Hb from pre-switch EP to post-switch EP was also

summarised. Hb concentrations were summarised by category for each study month

and during each EP. The number and percentage of subjects with Hb in the following

categories were summarised: ( 9 g/dL, > 9 and 10 g/dL, >10 and ≤11 g/dL, >11 and

≤12 g/dL, >12 and ≤13 g/dL, >13 and ≤14g/dL, >14 g/dL and ≥10 and ≤12 g/dL). The


percentage of subjects with Hb concentrations within the particular site’s Hb target range

at each month was also summarised using counts and percentages. A summary is also

provided of the percentage of subjects whose individual mean Hb concentrations at the

first and last month pre-switch (months -1 and -7) and at the first and last month post-

switch (months 1 and 7) respectively differed by no more than 1.0 g/dL.

Patient demographics and characteristics at the time of switching from darbepoetin alfa

to pegylated erythropoietin beta were summarised. These included age, sex, diabetic

status, etiology of disease, co-morbidities, kidney transplant history and access type.

Summaries over the duration of the observation period were produced for the following:

HD parameters (vascular access type and HD duration and efficiency)

Laboratory parameters (PTH, CRP, albumin, serum calcium, and serum phosphate)

Iron status (assessed as serum ferritin and/or TSAT)

New occurrences or worsening of inflammatory conditions, infections or bleeding

episodes

New co-morbidities or worsening of existing co-morbidities (cardiovascular disease,

diabetic status, and malignancies)

The incidence of red blood cell transfusions (number of transfusions and number of

units)

Kidney transplants, hospitalisations, and surgeries

The primary and secondary analyses were performed using the PAS and using the FAS

and SAS as sensitivity analyses. Analyses of transfusions, iron status, markers of

clinical management, and co-morbid conditions, were performed on the FAS. In the

FAS, data were censored at the point of renal transplantation, subject death,

discontinuation of haemodialysis, or loss to follow-up (censoring level 1) and at

discontinuation of peg-EPO (censoring level 2).

5.2.4 Notable Changes to Pre-Specified Analyses

Changes to Analysis Sets

Due to lower than expected enrolment (~75% of planned enrolment) and fewer than

expected subjects meeting the criteria for inclusion in the PAS, the definition of the PAS


population was broadened from the definition in the RPP to include all eligible patients

who:

Had Hb data in both EPs

Had not received an ESA other than darbepoetin alfa during the pre-switch EP or peg-EPO within one month of or during the post-switch EP

Did not die or were not lost-to-follow up during the observation period

The following inclusion criteria for the original PAS were no longer applied to the

redefined PAS:

Remained on peg-EPO IV QM for 7 months post-switch (breaks due to treatment being intentionally withheld were permitted), remained on HD and received no other ESA treatment during the 7-month period (with the exception of short-acting ESAs, which may have been used for a cumulative period of up to 2 weeks only, and not within the post-switch period)

Had adequate iron levels during each period (transferrin saturation [TSAT] 20%;

serum ferritin 100 μg/L)

Had none of the following: severe intercurrent events within 90 days of the start of or during either EP; bleeding episodes or RBC transfusion; major surgery (investigator clinical opinion); long-term hospitalisation (> 10 days in-patient admission); severe acute infection (investigator clinical opinion); severe acute inflammatory episode (investigator clinical opinion)

Had none of the following during the 14-month period: malignancy (excluding localized basal cell or squamous cell carcinoma of the skin); renal transplant; new diagnosis or worsening of diabetes; new diagnosis or worsening of cardiovascular disease.

The above change was implemented prior to database lock.

Changes to Analyses of Study Outcomes

In the RPP, a sequential procedure was defined whereby the DCR was to be calculated

firstly within the PAS 100% switching subgroup, secondly within the PAS < 100%

switching subgroup and finally the total PAS. The derivation of the DCRs at each step

was dependent upon the EP population mean Hb values being within 0.5g/dL, and the

DCRs for the subgroup analyses being within 10% of each other. Due to a smaller

than expected PAS and a lower than expected number of subjects being enrolled at

sites that switched 100% of subjects, and to the location of the 100% switching sites

being limited to Spain and France, the analysis was changed to calculate the population

mean maintenance DCR within the entire PAS.

The RPP also pre-defined that the outcomes would be explored for the FAS and the

SAS. Due to low sample size, a reduced set of analyses were performed for the SAS


and these are provided in this ORSR (see Section 10) but are not discussed within the

text.

Changes to Subgroups

Subgroups not explored in the final analyses due to the limited number of subjects

available for analysis across these subgroups:

Dose conversion ratio used at the time of conversion from darbepoetin alfa to

peg-EPO, categorized as [< 0.5:1], [ 0. 5 :1 and < 0.75:1], [ 0.75:1 and < 1:1],

[ 1:1 and < 1.25:1], [ 1.25:1 and < 1.5:1], [ 1. 5:1 and < 2:1], [ 2:1]

Dose route of darbepoetin alfa immediately prior to conversion to peg-EPO (no subjects received SC darbepoetin alfa)


6. RESULTS

6.1 Enrolment and Patient Disposition

Planned enrolment was 400 subjects. Informed consent was obtained for 325 subjects,

and 302 subjects (93%) were included in the FAS. Twenty-three subjects (7%) were

considered ineligible and were excluded from the FAS.

In the FAS, data were censored in two ways. Censoring level 1 censored 24 subjects

(8%) during the post-switch period: 15 (5%) subjects died, 7 (2%) subjects were lost to

follow-up, and 2 (1%) subjects were censored at the point of transplant; data after

discontinuation of peg-EPO was retained in the analyses. Censoring level 2 censored

66 subjects (22%) during the post-switch period: 43 (14%) subjects at the point of

discontinuing peg-EPO, 15 (5%) subjects died, 7 (2%) subjects were lost to follow-up

and 1 (< 1%) subject was censored at the point of transplant.

Of the 302 subjects in the FAS, 206 subjects (68% of the FAS) were included in the

PAS. The reasons for exclusion from the PAS, which were not mutually exclusive,

included: Hb values not available for either EP (59 subjects, 20%); use of an ESA other

than peg-EPO within 1 month prior to the post-switch period (43 subjects, 14%); died

during the post-switch observation period (15 subjects, 5%); and lost to follow-up

(5 subjects, 2%) during the post-switch observation period.

A total of 58 subjects (19% of subjects from the FAS) were included in the SAS.

6.2 Demographics and Baseline Characteristics at the Time of Switch

Subjects in the PAS were enrolled from 4 countries in the European Union (EU): France

(73%), Germany (11%), UK (9%), and Spain (7%). The majority of subjects in the PAS

were male (62%) and the mean (SD) age at switch was 65.3 (15.0) years (46% of

subjects were 65 years of age, 22% were > 65 to 75 years of age, and 32% > 75

years of age).

The most common primary etiologies of CKD included diabetes (21%),

glomerulonephritis (18%), hypertension (14%), and other/unknown (31%). Twenty one

(10%) subjects had a renal transplant prior to inclusion in the study. The median (Q1,

Q3) time from transplantation to switching was 13.2 (7.9, 23.1) years and at switch 9

subjects (4%) had a graft in situ. The median (Q1, Q3) HD vintage at switch was 42.0

(24.8, 72.1) months. Vascular access immediately prior to switching was arteriovenous


fistula (86%), permanent venous catheter (8%), arteriovenous graft (5%), and other

(1%).

Approximately one-third of all subjects had diabetes mellitus (33%) and about two-thirds

of subjects had a history of cardiovascular disease (68%), most commonly coronary

artery disease (28%), peripheral artery disease (15%), heart failure (11%) and other

(33%). Approximately 9% of the subjects in the PAS had a malignancy or history of a

malignancy, the most common of which were prostate (3%), bladder (2%), and breast,

and kidney (1% each).

The median (Q1, Q3) duration of darbepoetin alfa treatment prior to switching was 25.3

(14.6, 37.0) months. The most common dosing frequencies were ≤QW (dosing every

1 to 10 days) (59%) and Q2W (dosing every 11 to 17 days) (21%). Four percent of

subjects were dosed once every 3 weeks (Q3W) and the remaining 16% dosed Q4W or

less frequently. The geometric mean (95% CI) average weekly darbepoetin alfa dose

during the pre-switch EP was 24.1 (21.3, 27.1) µg/week. The mean (SD) average Hb

concentration during the pre-switch EP was 11.5 (1.1) g/dL. Approximately 15% of

subjects were considered to be stable, defined as Hb fluctuations less than 2 g/dL and

dose changes less than 25% in the 12 weeks prior to switching.

A summary of baseline characteristics of the FAS and the PAS is provided in Table 6-1.


Table 6-1. Summary of Subject Characteristics at the Time of Switch (Full Analysis Set [FAS] and Primary Analysis Set [PAS])

FAS

(N = 302)

PAS

(N = 206)

Patient demographics:

Age (years)

Mean (SD) 65.31 (15.12) 65.25 (14.97)

Sex – n (%)

Male 184 (60.9) 127 (61.7)

Female 118 (39.1) 79 (38.3)

Country – n (%)

Germany 25 (8.3) 23 (11.2)

Spain 54 (17.9) 15 (7.3)

France 172 (57.0) 150 (72.8)

United Kingdom 51 (16.9) 18 (8.7)

Clinical characteristics:

Prior history – n (%)

Diabetes mellitus 105 (34.8) 67 (32.5)

Cardiovascular disease 199 (65.9) 139 (67.5)

Stroke 23 (7.6) 11 (5.3)

Malignancy 29 (9.6) 19 (9.2)

Kidney transplant 29 (9.6) 21 (10.2)

Primary aetiology of chronic kidney disease – n (%)

Diabetes 70 (23.2) 44 (21.4)

Glomerulonephritis 44 (14.6) 38 (18.4)

Hypertension 39 (12.9) 28 (13.6)

Interstitial nephropathy 30 (9.9) 18 (8.7)

Polycystic kidney disease 14 (4.6) 12 (5.8)

Tumour 4 (1.3) 2 (1.0)

Other 53 (17.5) 39 (18.9)

Unknown 48 (15.9) 25 (12.1)

Haemodialysis vintage at switch (monthsa)

Median (Q1, Q3) 41.99 (24.34, 73.07) 42.02 (24.80, 72.05)

Kt/V single pool

Mean (95% CI) 1.548 (1.489, 1.607) 1.463 (1.394, 1.532)

Haemodialysis access immediately prior to switchb – n (%)

Arteriovenous fistula 236 (78.1) 178 (86.4)

Arteriovenous graft 12 (4.0) 10 (4.9)

Temporary venous catheter 1 (0.3) 0 (0.0)

Permanent venous catheter 51 (16.9) 16 (7.8)

Other 2 (0.7) 2 (1.0)

Footnotes on last page Page 1 of 2


Table 6-1. Summary of Subject Characteristics at the Time of Switch (Full Analysis Set [FAS] and Primary Analysis Set [PAS])

FAS

(N = 302)

PAS

(N = 206)

Haematological characteristics:

Frequency of administration of darbepoetin alfa immediately prior to switchb, c

categories – n (%)

QW 192 (63.6) 122 (59.2)

Q2W 67 (22.2) 44 (21.4)

Q3W 9 (3.0) 8 (3.9)

Q4W 16 (5.3) 15 (7.3)

Q5W 3 (1.0) 3 (1.5)

Q6W 15 (5.0) 14 (6.8)

Duration of darbepoetin alfa treatment prior to switch (monthsa)

Median (Q1, Q3) 28.11 (16.33, 39.20) 25.33 (14.59, 36.96)

Subject-specific mean darbepoetin alfa dose for the pre-switch evaluation periodd

(μg/week)

Geometric Mean (95% CI) 27.71 (25.15, 30.53) 24.05 (21.32, 27.13)

Subject-specific mean haemoglobin concentration for the pre-switch evaluation periodd

(g/dL)

Mean (SD) 11.54 (1.12) 11.53 (1.06)

Laboratory variables

Transferrin saturation –

mean (95% CI)

N = 224

27.76 (25.84, 29.68)

N = 168

26.69 (24.67, 28.71)

Ferritin (µg/L) –

mean (95% CI)

N = 281

437.45 (404.32, 470.59)

N = 195

410.37 (371.29, 449.44)

CRP (mg/L) –

median (Q1, Q3)

N = 276

5.05 (3.00, 12.50)

N = 190

5.00 (3.00, 10.10)

Serum albumin (g/L) –

mean (95% CI)

N = 252

36.12 (35.52, 36.72)

N = 166

36.65 (35.92, 37.37)

PTH (pmol/L) –

median (Q1, Q3)

N = 197

28.70 (16.60, 49.77)

N = 136

25.07 (13.58, 43.93)

Page 2 of 2 CI = confidence interval; CRP = c-reactive protein, FAS = Full Analysis Set; Kt/V = A measure of

haemodialysis adequacy; N = Number of subjects in analysis set; PAS = Primary Analysis Set; PTH = parathyroid hormone; QW = once a week; Q2W = once every 2 weeks; Q3W = once every 3 weeks; Q4W = once every 4 weeks; Q5W = once every 5 weeks; Q6W = once every 6 weeks, SD = standard deviation.

a One month is defined as (365.25/12) days.

b Immediately prior to switch is defined as the day prior to the date of switch.

c Frequency of administration is calculated as the duration of the dose interval overlapping the specified

time point; the QW category is assigned for dose intervals from 1 to 10 days in length, Q2W 14 3

days (ie 11 to 17 days) in length, Q3W 21 3 days, etc., Q6W 39 days or more in length. d The weekly dose for pre-switch evaluation period (months -2 and -1), calculated per subject as the arithmetic mean daily dose from all days in the interval, multiplying by 7.


6.3 Primary Outcome

6.3.1 Population Mean Maintenance Dose Conversion Ratio of Peg-EPO Dose in the Post-Switch EP to Darbepoetin alfa Dose in the Pre-Switch EP

The primary outcome was the ratio of the peg-EPO dose during the post-switch EP to

the darbepoetin alfa dose during the pre-switch EP, expressed as the population mean

maintenance DCR for the PAS.

In order to calculate the population mean maintenance DCR, the mean of the individual

subject-specific Hb concentrations in the pre- and post-switch EPs was to be within

0.5 g/dL; this prerequisite was met since the mean difference in Hb was -0.09 g/dL

(Section 6.5.2). The population mean maintenance (95% CI) DCR was 1.17 (1.05,

1.29); which is consistent with the fact that the geometric mean (95% CI) of the average

weekly darbepoetin alfa dose was lower at the pre-switch EP (24.1 [21.3, 27.1] µg/week)

than the average weekly peg-EPO dose in the post-switch EP (28.6 [26.0,

31.5] µg/week. Approximately 42% of subjects had a subject-specific DCR < 1.0 and

58% had a subject-specific DCR 1.0.

Sensitivity analyses were performed to explore the robustness of the primary analysis.

In an analysis which removed from the PAS 15 subjects who had a transfusion within 90

days prior to or during either EP, the population mean maintenance DCR was 1.21 (95%

CI: [1.09, 1.35]).

In the sensitivity analysis using subjects from the FAS who had Hb and dose data in

both EPs (N = 265), the population mean maintenance (95% CI) DCR was 1.12 (1.03,

1.22).

In the SAS analysis (N = 58), the population mean maintenance (95% CI) DCR in the

SAS population was 1.14 (0.98, 1.32).

6.3.2 Subgroup Analyses for Primary Outcome Measure

The DCR was estimated for the PAS split into subgroups defined by country, age, sex,

primary CKD etiology, Hb concentration category, dose frequency category, and subject

stability status at switching. A summary of population mean maintenance DCR

estimates for each of these subgroups is provided in Table 6-2. Small numerical

differences existed between the population mean maintenance DCRs across certain

subgroups.


Table 6-2. Population Mean Maintenance Dose Conversion Ratios for the PAS by Predefined Subgroups

Subgroup

Parameter

Dose Conversion Ratio

(Months 6 and 7 to Months -2 and -1 )

N

Geometric Mean

a 95% CI of Geometric Mean

a

Country

France 147 1.18 1.03, 1.34

Germany 23 1.29 0.98, 1.70

Spain 15 0.93 0.70, 1.24

United Kingdom 18 1.15 0.99, 1.34

Age

65 95 1.15 0.98, 1.34

65 to 75 45 1.15 0.95, 1.39

> 75 63 1.20 0.98, 1.47

Sex

Male 125 1.18 1.04, 1.34

Female 78 1.14 0.95, 1.36

Primary CKD etiology

Diabetes 44 1.24 1.01, 1.52

Hypertension 27 1.14 0.87, 1.50

Other 132 1.15 1.00, 1.31

Hb concentration category

9 g/dL 3 0.75 0.07, 8.03

> 9 to 10 g/dL 10 1.16 0.68, 1.97

> 10 to 11 g/dL 51 1.12 0.92, 1.36

> 11 to 12 g/dL 71 1.33 1.11, 1.59

> 12 to 13 g/dL 51 1.16 0.92, 1.47

13 g/dL 17 0.83 0.64, 1.07

Page 1 of 2

CI = confidence interval; CKD = chronic kidney disease; EPO = erythropoietin, Hb = haemoglobin; N = Number of subjects that remain under observation at the start of the specified interval; PAS = Primary Analysis Set; QW = once a week; Q2W = once every 2 weeks.

a Mean weekly doses were calculated per subject for all the intervals (including the first dose of peg-EPO), by first calculating a mean daily dose for the interval (by dividing each dose evenly between the days bounded by its date of administration and the day before the next dose, then taking a mean of these partial doses for the days in the interval) and multiplying by 7 to convert to a weekly dose.


Table 6-2. Population Mean Maintenance Dose Conversion Ratios for the PAS by Predefined Subgroups

Subgroup

Parameter

Dose Conversion Ratio

(Months 6 and 7 to Months -2 and -1 )

N Geometric Mean 95% CI of Geometric Mean

Dose frequency category

QW 121 1.02 0.90, 1.14

Q2W 43 1.12 0.92, 1.35

Other 39 1.87 1.37, 2.54

Subject stability status at switch

Stable 29 1.00 0.81, 1.23

Unstable 174 1.20 1.07, 1.34

Page 2 of 2

CI = confidence interval; CKD = chronic kidney disease; EPO = erythropoietin, Hb = haemoglobin; N = Number of subjects that remain under observation at the start of the specified interval; PAS = Primary Analysis Set; QW = once a week; Q2W = once every 2 weeks.

a Mean weekly doses were calculated per subject for all the intervals (including the first dose of peg-EPO), by first calculating a mean daily dose for the interval (by dividing each dose evenly between the days bounded by its date of administration and the day before the next dose, then taking a mean of these partial doses for the days in the interval) and multiplying by 7 to convert to a weekly dose.


6.4 Secondary Outcomes

6.4.1 Dose Only Ratios Over Time for Peg-EPO Post-switch EP Dose to Darbepoetin Alfa Pre-switch EP Dose

In the PAS, the geometric mean (95% CI) of the average weekly darbepoetin alfa dose

during the pre-switch EP was 24.1 (21.3, 27.1) while the geometric mean (95% CI) of the

average weekly dose of peg-EPO at switch was 26.9 (24.5, 29.5). The geometric mean

(95% CI) dose ratio at switch was 1.12 (1.01, 1.24). After a slight decrease at months 2

and 3, (geometric mean [95% CI] dose ratio = 1.03 [0.93, 1.14]), the geometric mean

dose ratios increased by the end of the observation period, to values that were similar to

the dose ratio at the time of switch (geometric mean [95% CI] = 1.13 [1.02, 1.25] at

months 4 and 5 and 1.17 [1.05, 1.29], at months 6 and 7 respectively. Results were

similar when 15 subjects who had a transfusion within 90-days prior to, or during, either

EP were removed from the analysis.


Table 6-3. Summary of Dose and Dose Ratio at Switch and at 2-Month Post-switch Intervals from the Pre-switch EP (Primary Analysis Set)

Darbepoetin

alfa Pegylated erythropoietin betaa

Months -2 and

-1 First Dose

Months 2

and 3

Months 4

and 5

Months 6

and 7

PAS population

Dose (µg/week)

N 206 206 206 205 203

Geometric mean 24.05 26.93 24.77 27.16 28.64

95% CI geometric mean 21.32, 27.13 24.54, 29.54 22.52, 27.24 24.65, 29.93 26.00, 31.54

Dose ratio to months -2 and -1 (µg peg-EPO per 1 µg darbepoetin alfa)

Geometric mean - 1.12 1.03 1.13 1.17

95% CI geometric mean - 1.01, 1.24 0.93, 1.14 1.02, 1.25 1.05, 1.29

PAS excluding subjects with RBC transfusions within 90 days prior to or during either EP

Dose (µg/week)

N 191 191 191 190 188

Geometric mean 22.27 26.38 24.33 26.20 27.65

95% CI geometric mean 19.78, 25.08 24.03, 28.96 22.15, 26.74 23.74, 28.92 25.06, 30.50

Dose ratio to months -2 and -1 (µg peg-EPO per 1 µg darbepoetin alfa)

Geometric mean - 1.18 1.09 1.17 1.21

95% CI geometric mean - 1.07, 1.31 0.98, 1.21 1.06, 1.31 1.09, 1.35

CI = confidence interval; EP = evaluation period; EPO = erythropoietin, N = Number of subjects that remain under observation at the start of the specified interval; PAS = Primary Analysis Set; RBC = red blood cell. a Mean weekly doses were calculated per subject for all the intervals (including the first dose of peg-EPO), by

first calculating a mean daily dose for the interval (by dividing each dose evenly between the days bounded by its date of administration and the day before the next dose, then taking a mean of these partial doses for the days in the interval) and multiplying by 7 to convert to a weekly dose

The results for the PAS population are similar to those for the FAS population.

6.4.2 Average Weekly Darbepoetin Alfa and Peg-EPO Doses During the Pre-Switch and Post-Switch Observation Periods

The geometric mean of the average weekly dose of darbepoetin alfa during the pre-

switch observation period is summarised by month for the PAS population in Table 6-4.

The geometric mean of the average weekly dose of peg-EPO during the post-switch

observation period is summarised by month for the PAS population in Table 6-5.


Table 6-4. Summary of Average Weekly Darbepoetin Alfa Dose by Month during the Pre-Switch Observation Period (Primary Analysis Set)

Darbepoetin Alfa Weekly Dose by Month

Month -7 Month -6 Month -5 Month -4 Month -3 Month -2 Month -1

PAS population- Mean dose (µg/week) a

N 182 203 205 206 206 206 206

Geometric Mean 26.09 25.08 23.85 24.24 24.49 23.65 23.24

95% CI

Geometric Mean

23.16,

29.38

22.31,

28.18

21.01,

27.06

21.52,

27.29

21.59,

27.77

20.75,

26.96

20.56,

26.27

CI = confidence interval; N = Number of subjects in analysis set and each subgroup; PAS = Primary Analysis Set.

a Mean weekly doses were calculated per subject by first calculating a mean daily dose for the interval (by dividing each dose evenly between the days bounded by its date of administration and the day before the next dose, then taking a mean of these partial doses for the days in the interval) and multiplying by 7 to convert to a weekly dose.

Table 6-5. Summary of Average Weekly Peg-EPO Dose by Month during the Post-Switch Observation Period (Primary Analysis Set)

Pegylated Erythropoietin Weekly Dose by Month

Month 1 Month 2 Month 3 Month 4 Month 5) Month 6 Month 7

PAS population- Mean dose (µg/week) a

N 206 206 206 205 205 203 199

Geometric Mean 26.71 24.52 24.49 26.69 26.92 27.58 29.04

95% CI Geometric Mean

24.38, 29.26

22.28, 26.98

22.18, 27.05

24.18, 29.46

24.34, 29.78

24.99, 30.44

26.17, 32.23

CI = confidence interval; EPO = erythropoietin, N = Number of subjects in analysis set and each subgroup; PAS = Primary Analysis Set.

a Mean weekly doses were calculated per subject by first calculating a mean daily dose for the interval (by dividing each dose evenly between the days bounded by its date of administration and the day before the next dose, then taking a mean of these partial doses for the days in the interval) and multiplying by 7 to convert to a weekly dose.

The geometric mean (95% CI) of the average weekly darbepoetin alfa dose by month

fluctuated during the pre-switch observation period, but generally decreased slightly from

the beginning of the pre-switch observation period (month -7: 26.09 [23.16,

29.38] µg/week) to the month before switching (month -1: 23.24 [20.56, 26.27]

µg/week).

During the post-switch period, the geometric mean (95% CI) of weekly peg-EPO dose

fluctuated with a small decrease at month 2 (24.52 [22.28, 26.98]) and month 3 (24.49

[22.18, 27.05]), but generally slightly increased from month 1 (26.71 [24.38,

29.26] µg/week) to the end of the study (month 7: 29.04 [26.17, 32.23] µg /week).

The results noted in the PAS population are similar to those for the FAS population.


6.4.3 Percentage Dose Changes from Darbepoetin Alfa Dose at Switch to Peg-EPO Dose Post-Switch

The mean (SE) percent difference in mean weekly peg-EPO dose from Month 1 is

summarised by time point for the PAS population in Table 6-6.

Table 6-6. Summary of Peg-EPO Weekly Dose Percent Change by Month during the Post-Switch Observation Period (Primary Analysis Set)

Peg-EPO Weekly Dose Percent Change

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7

PAS population- percent difference in arithmetic mean dose from month 1 (%)

N - 206 206 205 205 203 199

Mean - -3.79 -0.48 12.53 18.56 22.10 33.01

SE - 1.88 3.05 4.60 5.67 5.70 7.32

N = Number of subjects in analysis set and each subgroup; PAS = Primary Analysis Set. The difference is the subject-specific mean dose for each month less the month 1 value.

The arithmetic mean (SE) weekly dose percent difference from Month 1 of peg-EPO

trended upward after Month 4 of the post-switch observation period resulting in a 33%

(7.3) dose change by the end of the post-switch observation period.

6.4.4 ESA Dose, Frequency, and Route of Administration during the Pre-Switch and Post-Switch Observation Periods

During the pre-switch observation period, all 206 subjects in the PAS population

received darbepoetin alfa IV. At the beginning of the pre-switch observation period,

approximately 68% of subjects were dosed at QW or more frequently, 30% of subjects

were dosed Q2W, and 2% of subjects were dosed less frequently (ie, once every 3

weeks [Q3W]). At the end of the pre-switch observation period, 59% of subjects were

dosed QW or more frequently, 21% were dosed Q2W and approximately 19% of

subjects were dosed less frequently (Table 6-7).

During the post-switch observation period, all 206 subjects in the PAS population

received peg-EPO intravenously. At the beginning of the post-switch observation period,

approximately 70% of subjects were dosed once every 4 weeks (Q4W) and 17% of

subjects were dosed once every 5 weeks (Q5W) or less frequently, while approximately

13% of subjects were dosed more frequently than Q4W. By the end of the post-switch

observation period, 76% of subjects were dosed Q4W and approximately 11% of

subjects were dosed Q5W or less frequently while approximately 7% of subjects were

dosed more frequently than Q4W (Table 6-8).


Table 6-7. Summary of Frequency of Administration of Intravenous Darbepoetin Alfa at Monthly Intervals during the Pre-Switch Observation Period

(Primary Analysis Set)

Frequency of

Administra-

tion

First day

of

month -7

(N = 206)

n (%)

First day

of

month -6

(N = 206)

n (%)

First day

of

month -5

(N = 206)

n (%)

First day

of

month -4

(N = 206)

n (%)

First day

of

month -3

(N = 206)

n (%)

First day

of

month -2

(N = 206)

n (%)

First day

of

month -1

(N = 206)

n (%)

Last day

of

month -1

(N = 206)

n (%)

Darbepoetin

alfa (IV)

206

(100.0)

206

(100.0)

206

(100.0)

206

(100.0)

206

(100.0)

206

(100.0)

206

(100.0)

206

(100.0)

QW 140 (68.0) 129 (62.6) 127 (61.7) 121 (58.7) 118 (57.3) 121 (58.7) 120 (58.3) 122 (59.2)

Q2W 61 (29.6) 57 (27.7) 49 (23.8) 58 (28.2) 56 (27.2) 53 (25.7) 52 (25.2) 44 (21.4)

Q3W 1 (0.5) 2 (1.0) 3 (1.5) 4 (1.9) 5 (2.4) 6 (2.9) 2 (1.0) 8 (3.9)

Q4W 2 (1.0) 10 (4.9) 11 (5.3) 8 (3.9) 14 (6.8) 7 (3.4) 5 (2.4) 15 (7.3)

Q5W 0 (0.0) 1 (0.5) 3 (1.5) 1 (0.5) 0 (0.0) 2 (1.0) 5 (2.4) 3 (1.5)

Q6W 1 (0.5) 6 (2.9) 13 (6.3) 14 (6.8) 13 (6.3) 17 (8.3) 22 (10.7) 14 (6.8)

IV = intravenous(ly); N = Number of subjects in analysis set; QW = once a week; Q2W = once every 2 weeks; Q3W = once every 3 weeks; Q4W = once every 4 weeks; Q5W = once every 5 weeks; Q6W = once every 6 weeks. Note: the frequency presented for the first day of study month -7 is the reported intended frequency of darbepoetin alfa at 7 months prior to switch, with QM responses coded as Q4W; for the remaining time

points the frequency was calculated as the duration of the overlapping dose interval. The QW category is

assigned for dose intervals from 1 to 10 days in length, Q2W = 14 3 days (11 to 17 days), Q3W = 21 3

days (18 to 24 days), Q4W = 28 3 days (25 to 31 days), Q5W = 35 3 days (32 to 38 days); Q6W = 39 days or more in length.


Table 6-8 Summary of Frequency of Administration of Intravenous Pegylated Erythropoietin Beta at Monthly Intervals during the Post-Conversion Observation

Period (Primary Analysis Set)

Frequency of

Administra-

tion

First day

of month

1

(N = 206)

n (%)

First day

of month

2

(N = 206)

n (%)

First day

of month

3

(N = 206)

n (%)

First day

of month

4

(N = 206)

n (%)

First day

of month

5

(N = 206)

n (%)

First day

of month

6

(N = 206)

n (%)

First day

of month

7

(N = 206)

n (%)

Last day

of month

7

(N = 206)

n (%)

Pegylated

erythropoietin

beta (IV)

206

(100.0)

206

(100.0)

206

(100.0)

205

(99.5)

205

(99.5)

203

(98.5)

199

(96.6)

193

(93.7)

QW 8 (3.9) 0 (0.0) 1 (0.5) 1 (0.5) 2 (1.0) 1 (0.5) 3 (1.5) 4 (1.9)

Q2W 15 (7.3) 10 (4.9) 9 (4.4) 9 (4.4) 7 (3.4) 11 (5.3) 6 (2.9) 6 (2.9)

Q3W 4 (1.9) 3 (1.5) 1 (0.5) 3 (1.5) 5 (2.4) 3 (1.5) 7 (3.4) 4 (1.9)

Q4W 145

(70.4)

128

(62.1)

126

(61.2)

139

(67.5)

138

(67.0)

128

(62.1)

146

(70.9)

157

(76.2)

Q5W 24 (11.7) 43 (20.9) 45 (21.8) 31 (15.0) 31 (15.0) 32 (15.5) 14 (6.8) 13 (6.3)

Q6W 10 (4.9) 22 (10.7) 24 (11.7) 22 (10.7) 22 (10.7) 28 (13.6) 23 (11.2) 9 (4.4)

No ESA

treatmenta

0 (0.0) 0 (0.0) 0 (0.0) 1 (0.5) 1 (0.5) 3 (1.5) 7 (3.4) 13 (6.3)

ESA = erythropoiesis-stimulating agents; EOS = end of study, IV = intravenous(ly); N = Number of subjects receiving haemodialysis and (first course of) peg-EPO that remain under observation at the specified time point; QW = once a week; Q2W = once every 2 weeks; Q3W = once every 3 weeks; Q4W = once every 4 weeks; Q5W = once every 5 weeks; Q6W once every 6 weeks. Note: the frequency presented for the last day of study month 7 is the reported dose interval that applied to the last ESA/biosimilar dose administered at the end of the observation period; for the remaining time points the frequency was calculated as the duration of the overlapping dose interval. The ≤QW category is assigned for dose intervals from 1 to 10 days in length, Q2W 14 ± 3 days (i.e. 11 to 17 days) in length, Q3W 21 ± 3 days, etc., ≥Q6W 39 days or more in length.

a Defined as no ESA treatment on the given day after extrapolation from last dose to the lesser of EOS dosing interval (assumed 30 days if 0 or missing days reported) or date of death.

6.4.5 Number of Dose and/or Dose Frequency Changes During the Pre-Switch and Post-Switch Periods

Approximately 13% of subjects in the pre-switch period had changes in darbepoetin

dose only and 18% of subjects had changes in only the frequency of administration of

darbepoetin alfa during the pre-switch period; 53% of subjects had changes in both

darbepoetin dose and frequency during the pre-switch period. During the post-switch

period, 18% of subjects had changes in peg-EPO dose only and 14% of subjects had

changes in only the frequency of administration of peg-EPO; 52% of subjects had

changes in both peg-EPO dose and frequency during the post-switch period.

Approximately 16% of subjects in each period experienced no ESA dose changes.

6.4.6 Monthly Haemoglobin Concentrations During Pre-Switch and Post-Switch Periods

The mean (SE) of the monthly Hb concentrations during the pre-switch observation

period is summarised by month for the PAS population, and the PAS population


excluding Hb values within 90 days of a RBC transfusion, in Table 6-9. The mean (SE)

of the monthly Hb concentrations during the post-switch observation period is

summarised by month for the PAS population, and the PAS population excluding Hb

values within 90 days of a RBC transfusion in Table 6-10.

Table 6-9. Summary of Haemoglobin Concentrations by Month during the Pre-Switch Observation Period (Primary Analysis Set)

Monthly Haemoglobin Concentration

Month -7 Month -6 Month -5 Month -4 Month -3 Month -2 Month -1

PAS population - haemoglobin concentration (g/dL)

N 168 179 196 185 181 184 180

Mean 11.57 11.52 11.54 11.42 11.52 11.60 11.48

SE 0.09 0.09 0.08 0.09 0.09 0.09 0.08

PAS, excluding Hb values within 90 days of RBC transfusion - Haemoglobin concentration (g/dL)

N 168 179 195 183 177 179 174

Mean 11.57 11.52 11.55 11.43 11.53 11.64 11.51

SE 0.09 0.09 0.08 0.09 0.09 0.09 0.08

N = Number of subjects in analysis set; PAS = Primary Analysis Set. Note: when multiple assessments were available for a subject, the single assessment closest to centre of interval was used.

Table 6-10. Summary of Haemoglobin Concentrations by Month during the Post-Switch Observation Period (Primary Analysis Set)

Monthly Haemoglobin Concentration

Month 1 Month 2 Month 3 Month 4 Month 5 Month 6 Month 7

PAS population- Haemoglobin concentration (g/dL)

N 198 196 190 197 191 175 181

Mean 11.67 11.43 11.32 11.26 11.31 11.36 11.44

SE 0.09 0.09 0.09 0.10 0.10 0.10 0.09

PAS, Excluding Hb values within 90 days of RBC transfusion - Haemoglobin concentration (g/dL)

N 195 193 185 192 188 171 175

Mean 11.66 11.48 11.36 11.29 11.29 11.39 11.47

SE 0.09 0.09 0.09 0.10 0.10 0.09 0.10

N = Number of subjects in analysis set; PAS = Primary Analysis Set; RBC = red blood cell. Note: when multiple assessments were available for a subject, the single assessment closest to centre of interval was used.

For the PAS, the mean (SE) of the monthly Hb concentration generally remained stable

during the pre-switch observation period with mean values ranging from 11.4 (0.09) g/dL

(month –4) to 11.6 (0.09) g/dL (month -2). During the post-switch observation period,

the mean (SE) Hb concentrations remained stable and mean values ranged from 11.3

(0.10) g/dL (Month 3) to 11.7 (0.09) g/dL (Month 1). Similar results for mean Hb

concentrations were noted in the FAS population during the pre-switch and post-switch


observation periods. Furthermore, in a sensitivity analysis which excludes Hb

measurements within 90 days of a RBC transfusion at any time during the study, the

results were similar to those for the analysis which includes all Hb values, regardless of

transfusions (Table 6-9 and Table 6-10).

6.4.7 Relationship Between Average Weekly Darbepoetin Alfa Dose During Pre-switch EP and Average Weekly Peg-EPO Dose During Post-switch EP

The relationship between darbepoetin alfa average weekly dose during the pre-switch

EP and peg-EPO average weekly dose during the post-switch EP is presented for the

PAS graphically in Figure 6-1.

Figure 6-1. Scatter Plot With Relationship Between Pre-Switch EP Weekly Darbepoetin Alfa Dose and Post-Switch EP Weekly Peg-EPO Dose


A non-linear relationship exists between the average weekly darbepoetin alfa dose

during the pre-switch EP and average weekly peg-EPO dose during the post-switch EP.

A fixed ratio of weekly darbepoetin alfa dose in the pre-switch EP to weekly peg-EPO

dose in the post-switch EP does not hold true for the whole PAS. A Bland and Altman

plot of the average weekly dose (darbepoetin alfa average weekly dose plus peg-EPO

average weekly dose divided by 2) compared to the difference between each individual’s

weekly dose of darbepoetin alfa and peg-EPO (peg-EPO average weekly dose minus

darbepoetin alfa average weekly dose) during the two EPs is presented in Figure 6-


2. This plot illustrates that with increasing dose there is less concordance between the

darbepoetin alfa and peg-EPO doses.

Figure 6-2. Bland and Altman Presentation of Subjects Dosing at EPs (Primary Analysis Set)

6.5 Other Outcomes

6.5.1 Monthly Haemoglobin Concentration by Categories during the Pre- and Post-switch Observation Period

Monthly Hb concentrations were summarised by broad categories defined as < 10 g/dL;

10 and 12 g/dL; and > 12 g/dL. Monthly Hb categories were also summarised by

site-specific target ranges. These summaries can be found for the PAS in


Table 6-11 for the pre-switch observation period and Table 6-12 for the post-switch

observation period.

During the pre-switch observation period, the majority of subjects in the PAS started with

Hb concentrations in either the 10 and 12 g/dL category (44%) or the > 12 g/dL

(30%) categories. By the end of the pre-switch observation period, the percentage of

subjects in the 10 and 12 g/dL category increased to 54% while the percentage of

subjects in the > 12 g/dL category decreased to 26%. The proportion of subjects with

Hb < 10 g/dL was 8% at month -7 and increased to 11% at month -4 before decreasing

to 7% at month -1. Similar trends were noted in the FAS population during the pre-

switch observation period.

During the post-switch observation period, the percentages of subjects in the PAS with

Hb concentrations 10 and 12 g/dL was approximately 50% and remained stable from

the beginning (49% at month 1) to the end (48% at month 7) of the post-switch

observation period. The proportion of subjects with mean Hb concentrations in the

> 12 g/dL category decreased from 37% at month 1 to 30% at month 7. The proportion

of subjects with Hb < 10 g/dL was 10% at month 1 and increased to 16% at month 4

before decreasing to 10% at month 7. Similar trends were noted in the FAS population

during post-switch observation period.

When Hb values were evaluated according to the site’s specific target range for the

PAS, the proportion of subjects with Hb values within range was higher during the pre-

switch EP (month -1 = 51%) compared to the post-switch EP (month 7 = 41%).


Table 6-11. Summary of Haemoglobin by Study Month According to Broad Categories and Site Specific Target Ranges - Pre-Switch Observation Period


Category

Month -7

(N = 206)

n (%)

Month -6

(N = 206)

n (%)

Month -5

(N = 206)

n (%)

Month -4

(N = 206)

n (%)

Month -3

(N = 206)

n (%)

Month -2

(N = 206)

n (%)

Month -1

(N = 206)

n (%)

Broad categories

N = 206 N = 206 N = 206 N = 206 N = 206 N = 206 N = 206

< 10 g/dL 16 (7.8) 16 (7.8) 14 (6.8) 23 (11.2) 21 (10.2) 19 (9.2) 15 (7.3)

10 to 12 g/dL 91 (44.2) 97 (47.1) 116 (56.3) 106 (51.5) 95 (46.1) 100 (48.5) 112 (54.4)

> 12 g/dL 61 (29.6) 66 (32.0) 66 (32.0) 56 (27.2) 65 (31.6) 65 (31.6) 53 (25.7)

Missing 38 (18.4) 27 (13.1) 10 (4.9) 21 (10.2) 25 (12.1) 22 (10.7) 26 (12.6)

Site specific target range

N = 206 N = 206 N = 206 N = 206 N = 206 N = 206 N = 206

Below range 25 (12.1) 28 (13.6) 32 (15.5) 33 (16.0) 30 (14.6) 29 (14.1) 27 (13.1)

Within range 89 (43.2) 90 (43.7) 103 (50.0) 96 (46.6) 88 (42.7) 94 (45.6) 106 (51.5)

Above range 54 (26.2) 61 (29.6) 61 (29.6) 56 (27.2) 63 (30.6) 61 (29.6) 47 (22.8)

Missing 38 (18.4) 27 (13.1) 10 (4.9) 21 (10.2) 25 (12.1) 22 (10.7) 26 (12.6)

N = Number of subjects in analysis set. Note: when multiple assessments were available for a subject, the single assessment closest to centre of interval was used.

Table 6-12. Summary of Haemoglobin by Study Month According to Broad Categories and Site Specific Target Ranges - Post-Switch Observation Period


Category

Month 1

(N = 206)

n (%)

Month 2

(N = 206)

n (%)

Month 3

(N = 206)

n (%)

Month 4

(N = 206)

n (%)

Month 5

(N = 206)

n (%)

Month 6

(N = 206)

n (%)

Month 7

(N = 206)

n (%)

Broad categories

N = 206 N = 206 N = 206 N = 206 N = 206 N = 206 N = 206

< 10 g/dL 21 (10.2) 29 (14.1) 29 (14.1) 32 (15.5) 28 (13.6) 20 (9.7) 20 (9.7)

10 to 12 g/dL 100 (48.5) 103 (50.0) 106 (51.5) 111 (53.9) 109 (52.9) 102 (49.5) 99 (48.1)

> 12 g/dL 77 (37.4) 64 (31.1) 55 (26.7) 54 (26.2) 54 (26.2) 53 (25.7) 62 (30.1)

Missing 8 (3.9) 10 (4.9) 16 (7.8) 9 (4.4) 15 (7.3) 31 (15.0) 25 (12.1)

Site specific range

N = 206 N = 206 N = 206 N = 206 N = 206 N = 206 N = 206

Below range 28 (13.6) 41 (19.9) 44 (21.4) 47 (22.8) 40 (19.4) 32 (15.5) 37 (18.0)

Within range 100 (48.5) 96 (46.6) 95 (46.1) 100 (48.5) 102 (49.5) 95 (46.1) 84 (40.8)

Above range 70 (34.0) 59 (28.6) 51 (24.8) 50 (24.3) 49 (23.8) 48 (23.3) 60 (29.1)

Missing 8 (3.9) 10 (4.9) 16 (7.8) 9 (4.4) 15 (7.3) 31 (15.0) 25 (12.1)

N = Number of subjects in analysis set. Note: when multiple assessments were available for a subject, the single assessment closest to centre of interval was used.


6.5.2 Subject Specific Changes in Haemoglobin Concentrations

The mean (SE) Hb concentration was 11.5 (0.07) g/dL at months -2 and -1. After

switching, the mean (SE) differences from months -2 and -1 ranged from -0.28

(0.10) g/dL at months 4 and 5 to -0.09 (0.10) g/dL at months 6 and 7. Analyses which

excluded Hb measurements within 90 days of a RBC transfusion at any time during the

study showed similar results.

6.5.3 Markers of Health Status

6.5.3.1 Severe Acute Exacerbation of Inflammatory Conditions

During the pre-switch observation period, a total of 8 subjects reported 8 acute

inflammatory events for an exposure adjusted subject incidence rate of 4.7 per 100

subject-years. These conditions, which were reported in 1 subject each, consisted of

pericarditis, endocarditis, herpes zoster, infected skin ulcer, transplant failure, osteitis,

femoral arterial stenosis, and thrombophlebitis. The exposure-adjusted subject

incidence rate per 100 subject years for each of these events was 0.6.

During the post-switch observation period, a total of 6 subjects reported 6 acute

inflammatory events for an exposure adjusted subject incidence rate of 3.7 per 100

subject-years. These conditions, which were reported in 1 subject each, consisted of

dermo-hypodermitis, mastitis, vascular graft complication, rheumatoid arthritis, sciatica,

and skin ulcer. The exposure-adjusted subject incidence rate per 100 subject years for

each of the preferred terms was 0.6.

6.5.3.2 Severe Acute Infections

During the pre-switch observation period, 24 subjects reported 27 infections for an

exposure adjusted subject incidence rates of 14.4 per 100 subject-years. The most

frequent types of infections reported were respiratory infections (lung infection,

bronchitis, pneumonia, respiratory tract infection, and tuberculosis), abscess, and

device-related infections. The exposure-adjusted subject incidence rate per 100 subject

years ranged from 0.6 (1 subject/event) to 2.3 (4 subjects/event).

During the post-switch observation period, 24 subjects reported 34 infections for an

exposure adjusted subject incidence rate of 15.1 per 100 subject-years. The most

frequent types of infections were respiratory infections (respiratory tract and lung

infection), device-related infection and sepsis, diverticulitis, endocarditis, infected skin

ulcer and sepsis. The exposure-adjusted subject incidence rate per 100 subject years

was similar to the pre-switch period for most events and ranged from 0.6

(1 subject/event) to 2.4 (4 subjects/event).


6.5.3.3 Laboratory Parameters

All laboratory parameters are reported for the FAS population, using censoring level 1

analyses.

6.5.3.3.1 Transferrin Saturation

Mean TSAT remained relatively stable over the study duration. The mean (SE) TSAT

was 29.6 (1.1) % at the beginning of the observation period (months -7 and -6) (N = 172)

and 29.7 (0.9) % at the end of the observation period (months 6 and 7) (N = 203).

The percentage of subjects with TSAT values 20% was 45% at months -7 and -6, and

increased over the study duration; at months 6 and 7, 58% of subject had TSAT values

20%.

6.5.3.3.2 Serum Ferritin

Mean serum ferritin concentrations fluctuated over the observation period. The mean

(SE) serum ferritin was 461.6 (16.8) µg/L at the beginning of the observation period

(months -7 and -6) (N = 231) and 417.6 (17.0) µg/L at the end of the observation period

(months 6 and 7) (N = 245).

The percentage of subjects with serum ferritin values 100 µg/L was 74% at months -7

and -6, and increased to 83% by months 6 and 7.

6.5.3.3.3 Serum Albumin

Mean serum albumin concentrations remained relatively stable over the observation

period. The mean (SE) serum albumin was 36.7 (0.4) g/L at the beginning of the

observation period (months -7 and -6) (N = 176) and 36.0 (0.4) g/L at the end of the

observation period (months 6 and 7) (N = 213).

6.5.3.3.4 C - reactive protein

Median CRP concentrations remained relatively stable over the study duration. The

median (Q1, Q3) CRP concentration was 5.0 (3.2, 11.9) mg/L at the beginning of the

observation period (Months -7 and -6) (N = 227) and 6.0 (4.0, 12.0) mg/L at the end of

the observation period (Months 6 and 7) (N = 237).

6.5.3.3.5 Serum Calcium

Mean serum calcium concentrations remained relatively stable over the study duration.

The mean (SE) serum calcium concentration was 2.23 (0.02) mmol/L at the beginning of

the observation period (months -7 and -6) (N = 239) and 2.22 (0.01) mmol/L at the end

of the observation period (months 6 and 7) (N = 251).


6.5.3.3.6 Serum Phosphate

Mean serum phosphate concentrations remained relatively stable over the study

duration. The mean (SE) serum phosphate concentration was 1.62 (0.04) mmol/L at the

beginning of the observation period (months -7 and -6) (N = 218) and 1.61 (0.04) mmol/L

at the end of the observation period (months 6 and 7) (N = 231).

6.5.3.3.7 Parathyroid Hormone

Median PTH concentrations remained relatively stable over the observation period. The

median (Q1, Q3) PTH concentration was 29.6 (14.3, 52.8) pmol/L at the beginning of the

observation period (months -7 and -6) (N = 178) and 30.1 (17.4, 49.1) pmol/L at the end

of the observation period (months 6 and 7) (N = 166).

6.5.3.4 Iron Status and Supplemental Iron Use

Iron status was assessed using TSAT and serum ferritin levels. At the beginning of the

observation period (months -7 and -6), TSAT data were available for 172 subjects and

serum ferritin data were available for 231 subjects. At the end of the observation period

(months 6 and 7), TSAT data were available for 203 subjects and serum ferritin data

were available for 245 subjects.

Adequate iron status was defined as either having TSAT 20% or serum ferritin levels

100 µg/L (see Section 6.5.3.3.1 and Section 6.5.3.3.2). Approximately 9% more

subjects had adequate iron status at the end of the study (74%) compared to the

beginning of the study (65%). The percentage of subjects with adequate iron status at

the time of switching (month -1 and 1) was 72%.

For the FAS during the pre-switch observation period, the use of supplemental iron

remained relatively stable (monthly proportion of subjects range: 72% to 75%). With the

exception of 1 subject who received oral iron, all supplemental iron was administered

intravenously. During the pre-switch observation period, the monthly proportion of

subjects with supplemental iron use by dose ranged from 25% to 27% for doses 100

mg supplemental iron, 7% to 11% for doses > 100 mg and 200 mg iron, 16% to 20%

for doses > 200 mg and 400 mg iron, and 21% to 22% for doses > 400 mg iron.

During the post-switch observation period, the use of supplemental iron remained

relatively stable (monthly subject incidence range: 75% to 77%). Compared with the

pre-switch observation period, a higher proportion of subjects in the post-switch

observation period received supplemental iron doses 100 mg (monthly proportions of

subjects ranged from 29% to 32%). The monthly proportions of subjects receiving other


doses of iron were similar to the pre-switch observation period and ranged from 7% to

10% for doses > 100 mg and 200 mg iron, 15% to 18% for doses > 200 mg and 400

mg iron, and 18% to 21% for doses > 400 mg iron.

6.5.3.5 Transfusions

Fewer subjects had transfusions during the pre-switch observation period compared with

the post-switch observation period (11 vs 29 subjects); the exposure adjusted subject

incidence rate was 6.4 per 100 subject years during the pre-switch observation period

and 18.5 per 100 subject years during the post-switch observation period.

Also, a lower overall number of RBC units were transfused during the pre-switch

observation period compared with the post-switch observation period (34 vs 95 units);

the exposure adjusted subject incidence rate was 19.6 per 100 subject years during the

pre-switch observation period and 57.5 per 100 subject years during the post-switch

observation period.

A summary of the Hb concentrations within 14 days prior to transfusion indicate that the

majority of subjects who were transfused during the pre- and post-switch observation

periods had Hb concentrations in the 9 g/dL or > 9 and 10 g/dL categories; 1 subject

during each period had a Hb in the > 11 and 12 g/dL category prior to transfusion.

6.5.3.6 Hospitalisations and Surgical Procedures

For the pre-switch period, 75 hospitalisations were reported, for an exposure-adjusted

subject incidence rate of 43.8 per 100 subject years while during the post-switch

observation period, 108 hospitalisations were reported, for an exposure-adjusted subject

incidence rate of 66.5 per 100 subject years. The most common reasons for

hospitalisation (reason provided for 75 subjects) during the pre-switch period (n;

exposure-adjusted subject incidence rate per 100 subject years) included:

cardiovascular (n = 12; 6.9), and surgery (n = 9; 5.2). The most common reasons for

hospitalisation (reason provided for 107 subjects) during the post-switch period (n;

exposure-adjusted subject rate per 100 subject years) were cardiovascular (n = 9; 5.4),

inflammatory (n = 9; 5.4), and surgery (n = 7; 4.2).

The number of subjects hospitalised by month in the pre-switch period ranged from 6

subjects (24.4 subjects per 100 subject years) at Month -1 to 15 subjects (62.0 subjects

per 100 subject years) at Month -5. The number of subjects hospitalized by month

during the post-switch period ranged from 11 subjects (48.9 subjects per 100 subject

years) in Month 7 to 18 subjects (77.4 subjects per 100 subject years) at Month 3. The


overall duration of hospitalisation was 875 days or 504 days per 100 subject years in the

pre-switch period and 1067 days or 645 days per 100 subject years in the post-switch

period.

The final hospital diagnosis preferred terms (n; exposure-adjusted subject incidence rate

per 100 subject years) reported more than twice during the pre-switch observation

period included arteriovenous fistula site complications (n = 5; 2.9), respiratory tract

infection (n = 3; 1.7), and catheter placement (n = 3; 1.7). The final hospital diagnosis

preferred terms (n; exposure-adjusted subject incidence rate per 100 subject years)

reported more than twice during the post-switch observation period included pancreatitis

(n = 4; 2.4), venous stenosis (n = 4; 2.4), respiratory tract infection (n = 3; 1.8), sepsis (n

= 3; 1.8), arteriovenous fistula thrombosis (n = 3; 1.8), and arteriovenous fistula

operation (n = 3, 1.8).

No surgical procedures were reported more than once during the pre-switch observation

period while the following surgical procedures were reported more than once during the

post-switch observation period (n; exposure-adjusted subject incidence rate per 100

subject years): arteriovenous fistula operation (n = 2; 1.2), and cholecystectomy (n = 2;

1.2).

6.5.3.7 Haemodialysis Parameters

At the beginning of the pre-switch observation period, most subjects (78%) had an

arteriovenous fistula; the remaining subjects had a permanent venous catheter (17%),

an arteriovenous graft (4%), a temporary venous catheter (1%) or other access (0.7%).

By the end of the post-switch observation period, the percentage of subjects with an

arteriovenous fistula (80%) was similar to the pre-switch observation period; the

remaining subjects had a permanent venous catheter (15%), an arteriovenous graft

(5%), a temporary venous catheter (0.4%), or other access (0.7%).

At the beginning of the pre-switch observation period, 48% of subjects in the FAS had an

average duration of HD > 700 and 800 minutes/week, 28% of subjects had an average

duration of HD 700 minutes/week, 22% of subjects had HD > 800 and

900 minutes/week, and 2% of subjects had HD > 900 and 1000 minutes/week. With

the exception of 1 subject who increased to > 1000 minutes/week of HD after month -6,

the duration of HD remained stable during the pre-switch observation period.

At the end of the post-switch observation period, the time required for dialysis was

distributed similar to the beginning of the observation period: 48% of subjects had an


average duration of HD > 700 and 800 minutes/week, 26% of subjects had HD lasting

700 minutes/week, 24% of subjects had HD lasting > 800 and 900 minutes/week,

2% of subjects had HD > 900 and 1000 minutes/week, and 1 subject had HD lasting

> 1000 minutes/week.

Haemodialysis efficiency (Kt/V), for both the single pool and double pool methods also

remained stable during the pre-switch and post-switch observations periods. The mean

(SE) single pool Kt/V was 1.53 (0.03) at the beginning of the pre-switch observation

period (months -7 and -6) (N = 110) and 1.50 (0.03) at the end of the post-switch

observation period (months 6 and 7) (N = 96). The mean (SE) double pool Kt/V was

1.33 (0.05) at the beginning of the pre-switch observation period (months -7 and -6)

(N = 13) and 1.37 (0.06) at the end of the post-switch observation period (months 6 and

7) (N = 24).

6.5.3.8 Co-morbid Conditions

Co-morbidities present at the time of switching are presented in Section 6.2. This

section reports new co-morbidities or worsening of existing co-morbidities during the pre-

and post-switch observation periods.

No new events of either type 1 or type 2 diabetes were diagnosed in the pre- or the post-

switch observation period. During the pre-switch observation period, 2 new events of

worsening diabetes were reported, for an exposure-adjusted subject incidence rate of

1.2 per 100 subject years. During the post-switch observation period, 4 new events of

worsening diabetes were reported for an exposure-adjusted subject incidence rate of 2.4

per 100 subject years.

One new malignancy (prostate) was reported during both the pre-switch and post-switch

observation periods; the exposure-adjusted subject incidence rate during each period

was 0.6 per 100 subject years. One case of progression of malignancy was reported in

the pre-switch observation period, for an exposure-adjusted subject incidence rate of 0.6

per 100 subject years.

Five new events of cardiovascular disease were reported in the pre-switch observation

period and 11 new events were reported in the post-switch observation period. The

overall exposure-adjusted subject incidence rate per 100 subject years during the pre-

switch period was 2.9 and was 6.8 during the post-switch period. During the pre-switch

and post-switch observation periods, 8 cases of worsening cardiovascular disease were

reported in each period, resulting in an exposure-adjusted subject incidence rate of 4.7


per 100 subject years in the pre-switch period and 4.9 per 100 subject years during the

post-switch period.

Specific cardiovascular events reported during the pre-switch observation period

included (1 event each): coronary artery disease; heart failure; peripheral arterial

disease; transient ischaemic attack; and ventricular tachycardia/fibrillation.

Cardiovascular events reported during the post-switch observation period included the

same number of events that were reported during the pre-switch period (coronary artery

disease, heart failure). In addition, 1 additional event of peripheral arterial disease

(n = 2) and transient ischaemic attack (n = 2) along with new events of arterial

revascularization (n = 2), stroke (n = 1), and other new events that were not specified

(n = 2) were reported in the post-switch observation period.

A total of 2 subjects (0.7%) had a renal transplantation during the post-switch

observation period.

6.5.3.9 Concomitant Medications

For the FAS, relevant concomitant medication use (defined as therapies associated with

the management of CKD-mineral and bone disorder, ie, phosphate

binders/calcimimetics/vitamin D; oral and/or IV antibiotics; angiotensin converting

enzyme inhibitors; angiotensin II receptor blockers) was summarised for the pre- and

post-switch observation periods. During the pre-switch observation period, 44% of

subjects were reported as using a relevant concomitant medication; the most common

( 5%) included alfacalcidol and calcium carbonate (6% each) and cinacalcet (5%).

During the post-switch observation period, 41% of subjects were reported as using a

relevant concomitant medication, of which alfacalcidol (6%) and cinacalcet (7%) were

reported in 5% of subjects.

6.6 Safety Results

Safety results are reported for the FAS. In the FAS, safety data from the post-switch

observation period were censored at the point of renal transplantation, death,

discontinuation of haemodialysis, or when subjects were lost to follow-up; data collected

after discontinuation of peg-EPO are included in these analyses (censoring level 1). In

addition, summaries of safety data which additionally exclude data after withdrawal of

peg-EPO (censoring level 2) are provided in Section 10.


6.6.1 Deaths

Fifteen subjects were recorded as not completing the observation period due to death;

none were reported as resulting from an adverse drug reaction (ADR). Further details

are not available for these subjects as death data were not required to be captured in the

eCRF unless death was an outcome of an adverse drug reaction (ADR).

6.6.2 Adverse Drug Reactions

An ADR was defined as any adverse event reported by the site that was considered

related to either medicinal product. No ADRs or serious ADRs were reported for this

study.


7. BIAS/LIMITATIONS

The limitations to extrapolating the findings of this study to the broader HD population

include the following:

The relatively small PAS sample size of 203 subjects;

The study population was drawn largely from a single country (France), which

contributed over 70% of the subjects and 10 of the 14 study sites while the remaining

enrolment was at 4 sites divided between 3 other countries;

The population mean maintenance DCR was calculated only on the 203 PAS

subjects who continued to receive peg-EPO into the 7th month after switch, who

represent a selected cohort. Of the subjects enrolled in the study, 32% did not

complete the 7-month post-switch period analyses.

The study findings show that the relationship between darbepoetin alfa dose and

peg-EPO dose is non-linear, suggesting that a single population mean DCR may not

extrapolate to all HD populations.


8. CONCLUSIONS

The primary objective of this retrospective, multi-centre, observational study was to

estimate the mean maintenance DCR at the population level, in HD subjects

switched from darbepoetin alfa to peg-EPO QM for treatment of anaemia. The

observation period (7 months both pre- and post-switch) was chosen to allow time for

completion of titration post-switch and to obtain a fair estimate of dose requirement

for the calculation of the DCR. The secondary objectives included parameters of

clinical management of anaemia.

A total of 302 subjects were included in the Full Analysis Set (FAS), and 206

subjects were included in the Primary Analysis Set (PAS). The population mean

maintenance (95% CI) DCR calculated on the PAS was 1.17 (1.05, 1.29). The

population mean maintenance (95% CI) DCR calculated on the FAS was similar to

the PAS (1.12 [1.03, 1.22]). A total of 15 PAS subjects had a transfusion within 90

days of or within the evaluation periods. A sensitivity analysis which excluded these

subjects from the PAS indicated a DCR (95% CI) of 1.21 (1.09, 1.35) in the non-

transfused population.

Exploration of dose requirements in the PAS demonstrated that the relationship

between the average weekly darbepoetin alfa dose during the pre-switch EP and

average weekly peg-EPO dose during the post-switch EP was non-linear. A fixed

dose ratio of pre-switch EP to post-switch EP weekly ESA doses does not hold true

for the whole PAS.

During the month prior to switching, 54% of subjects had Hb >10 to <12 g/dL and

50% had Hb within the site specific range. Seven months after switching, 48% of

subjects had Hb >10 to <12 g/dL and 41% of subjects had Hb within the site-specific

range. The percentage of subjects with Hb below 10g/dL was 7% at 1 month prior to

switching and 10% at 7 months post-switch. Hb > 12g/dL was observed in 26% of

subjects at 1 month prior to switching and 30% of subjects at 7 months post-switch.


Eleven subjects had an RBC transfusion in the pre-switch period, receiving a total of

34 units of blood. Twenty-nine subjects were transfused in the post-switch period,

receiving a total of 95 units of blood. There were 75 hospitalisations in the pre-

switch period for an exposure adjusted rate of 43.8 per 100 subject years while there

were 108 hospitalisations during the post-switch period for an exposure-adjusted

subject rate of 66.5 per 100 subject years.

In conclusion, the population mean maintenance DCR (of peg-EPO to darbepoetin

alfa) was 1.17 (1.05, 1.29), rising to 1.21 (1.09, 1.35) when excluding subjects who

had a transfusion within 90 days of or within the EPs. While the concluded DCR may

anticipate the overall change in dose requirements in a population of HD patients

switched from darbepoetin alfa to peg-EPO, the non-linearity of the DCR indicates

that on the individual patient level, a fixed DCR cannot be used to predict weekly

peg-EPO dose based on the previous darbepoetin alfa dose.


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10. SUMMARY TABLES AND FIGURES

For consistency across programs, Amgen has a uniform numbering system for the data

displays presented in this section. Tables and figures are categorized and numbered in

accordance with ICH E3 guidelines. The number sequence may have gaps and

tables/figures do not necessarily appear in the order in which they are cited in the text.

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