Clinical trial NCT03552393
Conditions: Anemia Renal Insufficiency, Chronic
Sponsor: Hoffmann-La Roche
Start date: 2018-08-03; Completion date: 2021-07-19
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Ascertain the starting dose of Mircera given subcutaneously for the maintenance treatment of anemia in pediatric participants with chronic kidney disease (CKD) on dialysis or not yet on dialysis when switching from stable subcutaneous (SC) maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin alfa.

Detailed description:

Arms: arm 1: Mircera will be administered subcutaneously once every 4 weeks
Interventions: intervention 1: Mircera
Intervention descriptions: intervention 1: The initial dose of Mircera will be one of nine starting doses corresponding to the prefilled syringe strengths based on the total weekly erythropoiesis-stimulating agent (ESA) dose during the screening period.

Protocol documents:
Prot_000.pdf: 
 
Official Title: An Open-Label, Single-Arm, Multicenter Study to Ascertain the 
Optimal Starting Dose of Mircera® Given Subcutaneously for the 
Maintenance Treatment of Anemia in Pediatric Patients With Chronic 
Kidney Disease on Dialysis or not yet on Dialysis 
NCT Number: NCT03552393 
Document Date: Protocol Version 4: 07-December-2018 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Mircera—F. Hoffmann-La Roche Ltd
Protocol NH19708, Version 4
PROTOCOL
TITLE:
AN OPEN-LABEL, SINGLE-ARM, MULTICENTER 
STUDY TO ASCERTAIN THE OPTIMAL STARTING
DOSE OF MIRCERA® GIVEN SUBCUTANEOUSLY 
FOR THE MAINTENANCE TREATMENT OF ANEMIA 
IN PEDIATRIC PATIENTS WITH CHRONIC KIDNEY 
DISEASE ON DIALYSIS OR NOT YET ON DIALYSIS
PROTOCOL NUMBER: NH19708
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-004779-39
IND NUMBER:
10158
TEST PRODUCT:
Mircera(RO0503821)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  19 October 2017
DATES AMENDED:
Version 2:  19 January 2018
Version 3:  11 July 2018
Version 4:  See electronic date stamp below.
 
07-Dec-2018 17:01:54
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Mircera—F. Hoffmann-La Roche Ltd
2/Protocol NH19708, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol NH19708 has been amended to add an exclusion criterion and provide 
additional clarification of procedures.  The changes made are as follows:

Requirements for scheduling the screening visits and the approximate length of the 
screening period have been clarified (Sections 3.1, 4.5, and 4.5.1, and Appendix 1).

Exclusion Criteria have been amended to exclude patients who have undergone a 
kidney transplant with use of immunosuppressive therapies known to exacerbate 
anemia, as inclusion of these patients would add a bias to the studied patient 
population (Section 4.1.2).

An explanatory note has been added to the exclusion criterion related to pregnancy 
testing for patients of childbearing potential (Section 4.1.2).

Table 3, Mircera Dose Adjustments, has been amended to clarify the dose 
adjustment rules for Mircera (Section 4.3.2.1.1).

Language has been added to indicate that assessment of body weight should be 
performed after dialysis for patients on hemodialysis (Section 4.5.4, Appendix 1, and 
Appendix 2).

Section 4.5.6 has been updated with information regarding sample storage and the 
use of samples after withdrawal of patient consent.

Text has been modified to account for the fact that special situations (i.e., accidental 
overdoses and medication errors) are not required to be reported within 24 hours
(Sections 5.4 and 5.4.4). Note that serious adverse events associated with special 
situations are still required to be reported within 24 hours.

Language has been updated to indicate that therapeutic or elective abortions are not 
considered adverse events unless performed because of an underlying maternal or 
embryofetal toxicity.  In such cases, the underlying toxicity should be reported as a 
serious adverse event.  Language has also been added to clarify that all abortions 
are to be reported on the paper Clinical Trial Pregnancy Reporting Form
(Section 5.4.3.2).

Language has been added for consistency with Roche's current data retention policy 
and to accommodate more stringent local requirements (if applicable)
(Section 7.5).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

Language has been revised to clarify that redacted CSRs are provided only if 
requirements of Roche's global policy on data sharing have been met (Section 9.5). 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Mircera—F. Hoffmann-La Roche Ltd
3/Protocol NH19708, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9
PROTOCOL SYNOPSIS .................................................................................... 10
1.
BACKGROUND .......................................................................................... 17
1.1
Background on Chronic Kidney Disease ............................... 17
1.2
Background on Mircera.......................................................... 18
1.3
Study Rationale and BenefitRisk Assessment..................... 20
2.
OBJECTIVES AND ENDPOINTS ............................................................... 21
3.
STUDY DESIGN......................................................................................... 22
3.1
Description of the Study......................................................... 22
3.2
End of Study and Length of Study......................................... 23
3.3
Rationale for Study Design.................................................... 23
3.3.1
Rationale for Mircera Dose and Schedule ............................. 24
4.
MATERIALS AND METHODS .................................................................... 24
4.1
Patients.................................................................................. 24
4.1.1
Inclusion Criteria.................................................................... 25
4.1.2
Exclusion Criteria................................................................... 26
4.2
Method of Treatment Assignment and Blinding..................... 27
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 27
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 27
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 27
4.3.2.1
Rationale for Starting Dose Selection.................................... 28
4.3.3
Investigational Medicinal Product Accountability ................... 30
4.3.4
Continued Access to Mircera................................................. 30
4.4
Concomitant Therapy ............................................................ 30
4.4.1
Permitted Therapy................................................................. 30
4.4.2
Iron Supplementation ............................................................ 30
4.4.3
Red Blood Cell Transfusions ................................................. 31
4.4.4
Dialysis .................................................................................. 32


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4.4.5
Prohibited Therapy ................................................................ 32
4.5
Study Assessments ............................................................... 33
4.5.1
Informed Consent Forms and Screening Log........................ 33
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 34
4.5.3
Physical Examinations........................................................... 34
4.5.4
Height and Body Weight........................................................ 35
4.5.5
Vital Signs.............................................................................. 35
4.5.6
Laboratory Assessments ....................................................... 35
4.5.6.1
Safety Assessments .............................................................. 35
4.5.6.2
Pharmacokinetic Assessments.............................................. 36
4.5.7
Patient-Reported, Observer-Reported, and 
Clinician-Reported Outcomes................................................ 37
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 38
4.6.1
Study Treatment Discontinuation........................................... 38
4.6.2
Patient Discontinuation from Study........................................ 38
4.6.3
Study Discontinuation............................................................ 39
4.6.4
Site Discontinuation............................................................... 39
5.
ASSESSMENT OF SAFETY....................................................................... 39
5.1
Safety Plan ............................................................................ 39
5.1.1
Risks Associated with Mircera............................................... 40
5.1.1.1
Hypertension and Hypertensive Encephalopathy.................. 40
5.1.1.2
Anti-Erythropoietin Antibody-Mediated Pure Red 
Cell Aplasia............................................................................ 40
5.1.1.3
Low Platelet Count ................................................................ 41
5.1.1.4
Vascular Access Thrombosis ................................................ 41
5.1.1.5
Stevens-Johnson Syndrome and Toxic 
Epidermal Necrolysis............................................................. 41
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 41
5.1.2.1
Anti-Erythropoietin Antibody-Mediated Pure Red 
Cell Aplasia............................................................................ 41
5.2
Safety Parameters and Definitions ........................................ 42
5.2.1
Adverse Events ..................................................................... 42


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5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 43
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 44
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 44
5.3.1
Adverse Event Reporting Period ........................................... 44
5.3.2
Eliciting Adverse Event Information....................................... 45
5.3.3
Assessment of Severity of Adverse Events ........................... 45
5.3.4
Assessment of Causality of Adverse Events ......................... 45
5.3.5
Procedures for Recording Adverse Events............................ 46
5.3.5.1
Injection Reactions ................................................................ 46
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 46
5.3.5.3
Adverse Events That are Secondary to Other 
Events.................................................................................... 47
5.3.5.4
Persistent or Recurrent Adverse Events................................ 47
5.3.5.5
Abnormal Laboratory Values ................................................. 48
5.3.5.6
Abnormal Vital Sign Values ................................................... 48
5.3.5.7
Abnormal Liver Function Tests.............................................. 49
5.3.5.8
Deaths ................................................................................... 49
5.3.5.9
Preexisting Medical Conditions.............................................. 50
5.3.5.10
Loss of Effect......................................................................... 50
5.3.5.11
Progression of Kidney Disease.............................................. 51
5.3.5.12
Hospitalization or Prolonged Hospitalization.......................... 51
5.3.5.13
Patient-Reported or Observer-Reported Outcome 
Data....................................................................................... 51
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 52
5.4.1
Emergency Medical Contacts................................................ 52
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 53
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 53
5.4.2.2
Events That Occur after Study Drug Initiation........................ 53
5.4.3
Reporting Requirements for Pregnancies.............................. 53
5.4.3.1
Pregnancies in Female Patients............................................ 53


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5.4.3.2
Abortions ............................................................................... 54
5.4.3.3
Congenital Anomalies/Birth Defects ...................................... 54
5.4.4
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 54
5.4.5
Reporting Requirements for Medical Device 
Complaints............................................................................. 55
5.5
Follow-Up of Patients after Adverse Events .......................... 56
5.5.1
Investigator Follow-Up........................................................... 56
5.5.2
Sponsor Follow-Up ................................................................ 56
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 56
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 56
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 57
6.1
Determination of Sample Size ............................................... 57
6.2
Summaries of Conduct of Study............................................ 58
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 58
6.4
Efficacy Analyses .................................................................. 58
6.4.1
Primary Efficacy Endpoint...................................................... 58
6.4.2
Secondary Efficacy Endpoints............................................... 59
6.4.3
Exploratory Analyses............................................................. 59
6.5
Safety Analyses..................................................................... 59
6.6
Pharmacokinetic Analyses..................................................... 60
6.7
Pharmacodynamic analysis................................................... 60
6.8
Immunogenicity Analyses...................................................... 60
6.9
Planned Interim Analysis ....................................................... 61
7.
DATA COLLECTION AND MANAGEMENT ............................................... 61
7.1
Data Quality Assurance......................................................... 61
7.2
Electronic Case Report Forms............................................... 62
7.3
Source Data Documentation.................................................. 62
7.4
Use of Computerized Systems .............................................. 63
7.5
Retention of Records............................................................. 63


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8.
ETHICAL CONSIDERATIONS.................................................................... 63
8.1
Compliance with Laws and Regulations ................................ 63
8.2
Informed Consent.................................................................. 64
8.3
Institutional Review Board or Ethics Committee.................... 65
8.4
Confidentiality........................................................................ 65
8.5
Financial Disclosure .............................................................. 66
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 66
9.1
Study Documentation ............................................................ 66
9.2
Protocol Deviations................................................................ 66
9.3
Site Inspections ..................................................................... 66
9.4
Administrative Structure......................................................... 67
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 67
9.6
Protocol Amendments ........................................................... 68
10. REFERENCES ........................................................................................... 69
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 21
Table 2
Mircera Starting Dose ................................................................. 28
Table 3
Mircera Dose Adjustments.......................................................... 29
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 45
Table 5
Causal Attribution Guidance ....................................................... 46
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 23


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LIST OF APPENDICES
Appendix 1
Schedule of Activities Core Period (Week 3 to Week 21) ......... 73
Appendix 2
Schedule of Activities for Optional Safety Extension Period 
(Week 21 to Week 45) ................................................................ 76
Appendix 3
Formula Guidelines for Calculation of Dialysis Adequacy, 
Transferrin Saturation, and eGFR............................................... 78
Appendix 4
Educational Program for Anti-Erythropoietin 
AntibodyMediated Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents............................................... 80
Appendix 5
Blood Pressure Measurements in Children................................. 91
Appendix 6
Blood Pressure Levels According to Age and Height.................. 92
Appendix 7
WHO Toxicity Grading Scale for Determining the Severity of 
Adverse Events........................................................................... 95


Mircera—F. Hoffmann-La Roche Ltd
9/Protocol NH19708, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
AN OPEN-LABEL, SINGLE-ARM, MULTICENTER 
STUDY TO ASCERTAIN THE OPTIMAL STARTING
DOSE OF MIRCERA® GIVEN SUBCUTANEOUSLY 
FOR THE MAINTENANCE TREATMENT OF 
ANEMIA IN PEDIATRIC PATIENTS WITH CHRONIC 
KIDNEY DISEASE ON DIALYSIS OR NOT YET ON
DIALYSIS
PROTOCOL NUMBER:
NH19708
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-004779-39
IND NUMBER:
10158
TEST PRODUCT:
Mircera(RO0503821)
MEDICAL MONITOR:
, Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to the Sponsor or their designee.  


Mircera—F. Hoffmann-La Roche Ltd
10/Protocol NH19708, Version 4
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL, SINGLE-ARM, MULTICENTER STUDY TO 
ASCERTAIN THE OPTIMAL STARTING DOSE OF MIRCERA®
GIVEN SUBCUTANEOUSLY FOR THE MAINTENANCE
TREATMENT OF ANEMIA IN PEDIATRIC PATIENTS WITH 
CHRONIC KIDNEY DISEASE ON DIALYSIS OR NOT YET ON 
DIALYSIS
PROTOCOL NUMBER:
NH19708
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-004779-39
IND NUMBER:
10158
TEST PRODUCT:
Mircera(RO0503821)
PHASE:
Phase II
INDICATION:
Chronic renal anemia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will ascertain the starting dose of Mirceragiven subcutaneously for the maintenance 
treatment of anemia in pediatric patients with chronic kidney disease (CKD) on dialysis or not 
yet on dialysis when switching from stable subcutaneous (SC) maintenance treatment with 
epoetin alfa, epoetin beta, or darbepoetin alfa.  Specific objectives and corresponding endpoints 
for the study are outlined below.
Table 1 Objectives and Corresponding Endpoints
Efficacy Objective
Corresponding Endpoints
To ascertain the starting dose of 
Mircera given subcutaneously in 
pediatric patients with CKD on dialysis 
or not yet on dialysis when switching 
from stable SC maintenance treatment 
with epoetin alfa, epoetin beta, or 
darbepoetin alfa 
Primary endpoint:
Change in Hb concentration (g/dL) between the 
baseline and the evaluation period for each patient
Secondary endpoints:
Number of patients with an average Hb concentration 
during the evaluation period within 1 g/dL of their 
baseline Hb or above, within or below the range of 
1012 g/dL
Change in Mircera dose over time, including the 
change between the starting dose and the evaluation 
period
Safety Objective
Corresponding Endpoints
To assess the safety and tolerability of 
multiple doses of Mircera given 
subcutaneously in pediatric patients
Occurrence and severity of adverse events
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory 
test results


Mircera—F. Hoffmann-La Roche Ltd
11/Protocol NH19708, Version 4
Pharmacokinetic and 
Pharmacodynamic Objective
Corresponding Endpoints
To evaluate the pharmacokinetics and 
the pharmacodynamics of Mircera in 
patients on dialysis or not yet on 
dialysis who receive the study 
medication by the SC route of 
administration
Serum concentrations of Mircera and Hb will be used 
to evaluate the pharmacokinetics and the 
pharmacodynamics of Mircera through PK and PK/PD 
models. 
CKDchronic kidney disease; Hbhemoglobin; PDperitoneal dialysis; PKpharmacokinetic; 
PK/PDpharmacokinetic/pharmacodynamic.
Study Design
Description of Study
This study is an open-label, single-arm, multicenter study to ascertain the optimal starting dose 
of Mircera given subcutaneously for the maintenance treatment of anemia in pediatric patients 
with CKD on dialysis or not yet on dialysis.
Following written informed consent from a parent or legal guardian and, if appropriate, assent 
from the child, the patient will be screened for eligibility during a screening period of 
approximately 3 weeks.  During this period, patients will continue to receive epoetin alfa, 
epoetin beta, or darbepoetin alfa at the same weekly dose, route (SC), and interval as before 
screening.  The total weekly doses 4 weeks before the first Mircera administration should not 
change 25% (increase or decrease).  Provided that all eligibility criteria are met, including 
those for hemoglobin (Hb) levels and iron status, the patients will start Mircera administered 
subcutaneously. 
At least 40 pediatric patients 3 months17 years of age will be enrolled.  Approximately 1015 
of these patients will be 12 years old, with a goal to include as many patients 5 years old as 
possible (with a minimum of 3 patients).  Approximately 1015 patients, irrespective of age, will 
not be on dialysis.  
Available hemodialysis (HD) patients receiving their erythropoiesis-stimulating agent (ESA) 
subcutaneously are eligible for enrollment.  No more than 10 patients on HD should be enrolled.
Mircera will be administered subcutaneously once every 4 weeks for the duration of the study.  
Dose adjustments may be performed every 4 weeks according to dose adjustment rules.
The core study will last for 23 weeks and consists of three periods:  screening (3 weeks), dose 
titration (16 weeks), and evaluation (4 weeks). 
Patients completing the 20 weeks of treatment with Hb within 1 g/dL of their baseline Hb and 
within the target range of 1012 g/dL, will be eligible to enter an optional 24-week safety 
extension period.  Those patients not eligible or not consenting to enter the long-term safety 
extension should be treated according to clinical practice.  All patients must complete the 
Week 21 visit (Visit 10), regardless of whether they continue in the safety extension period.  
Visit 10 will serve as the final visit of the core study and the first visit of the safety extension 
period for patients eligible and willing to continue in the study.
Once 12 patients have completed 20 weeks of treatment (dose titration and evaluation periods), 
an interim analysis to assess the pharmacokinetics, efficacy, and safety of Mircera will be 
performed.
Number of Patients
Approximately 40 pediatric patients (3 months17 years of age), who are evaluable for 
intent-to-treat (ITT) and safety analyses, who have clinically stable chronic renal anemia on 
dialysis or not yet on dialysis, and who are receiving maintenance SC treatment with an ESA, 
will be enrolled in this study.


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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent from parent/legal guardian and willingness of parent/legal 
guardian to abide by the requirements of the study  

Written informed consent or assent from child where appropriate  
If required by national legislation, patients 18 years of age at screening who are 
legally considered to be adults according to national legislation must consent in their 
own right. 

Pediatric patients 3 months17 years of age with clinically stable chronic renal anemia

CKD with estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2 (determined by 
the Bedside Schwartz formula) or dialysis treatment for at least 8 weeks before the first 
dose of Mircera

For patients on peritoneal dialysis (PD):  a weekly Kt/V 1.8

For patients on HD:  adequate HD, urea reduction ratio (URR) 65% or Kt/V 1.2 for 
patients on HD three times per week.  
Patients with fewer than or more than three HD sessions per week should have a 
weekly Kt/V 3.6.

Baseline Hb concentration 10.012.0 g/dL determined from the mean of two Hb values 
measured at Visit 1 (Week 3) and Visit 2 (Week 1)

Stable SC maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin alfa with 
the same dosing interval for at least 6 weeks before the first dose of Mircera

Stable dose of epoetin alfa, epoetin beta, or darbepoetin alfa treatment with no weekly dose 
change 25% (increase or decrease) for at least 4 weeks before the first dose of Mircera

Adequate iron status defined as ferritin 100 ng/mL or transferrin saturation (TSAT) 20% 
(or percentage of hypochromic red cells 10%); mean of two values measured during 
screening

For post-pubertal female patients of childbearing potential:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or to use acceptable contraceptive methods during 
the study and for 90 days after the final dose of Mircera
A female patient is considered to be of childbearing potential if she is postmenarcheal.
The following are acceptable contraceptive methods:  hormonal contraceptives; 
hormone-releasing intrauterine devices; copper intrauterine devices; male or female 
condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.

The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Overt gastrointestinal bleeding within 8 weeks before screening or during the screening 
period

RBC transfusions within 8 weeks before screening or during the screening period

Hemoglobinopathies (e.g., homozygous sickle-cell disease, thalassemia of all types)

Hemolytic anemia

Active malignant disease

PD subjects with an episode of peritonitis within the past 30 days prior to screening and/or 
during the screening period 

Uncontrolled or symptomatic inflammatory disease (e.g., systemic lupus erythematosus)




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The average Hb value for each individual during the evaluation period will be calculated using 
the same method as for the baseline period.  The evaluation period is defined as all 
assessments between Visit 8 (Week 17) and Visit 10 (Week 21) inclusive.  Subtracting the 
baseline period value from the evaluation period value gives the change in Hb concentration 
(g/dL) between the baseline and evaluation period.
For patients with no recorded Hb during the evaluation period, the primary endpoint will be 
missing.  Values missing in between non-missing assessments will not be replaced, as these 
will be interpolated by the trapezoidal rule.  To correct for any increase in Hb caused by RBC 
transfusions, the Hb values measured within 3 weeks after an RBC transfusion will be deleted.
The individual change from baseline will be reported using summary statistics (including mean, 
standard deviation, and 90% CI of mean change).  No formal statistical testing will be performed.  
Additional analysis will be performed by age category (5, 511, 12 years), dialysis type (not 
yet on dialysis, PD, HD) and previous ESA (epoetin alfa, epoetin beta, and darbepoetin alfa), if 
numbers allow.
Determination of Sample Size  
This is an exploratory study without a powered statistical group comparison.  Therefore, no 
formal sample size estimation will be performed; however, the calculations below indicate the 
approximate precision that could be achieved.  
Assuming a 30% withdrawal rate (based on the withdrawal rate for the NH19707 study), of the 
40 patients evaluable for ITT and safety analysis, more than 26 patients will have data for the 
evaluation period.  Twenty-six patients will be sufficient to provide approximately 90% power 
that the 90% CI for the Hb change from baseline to the evaluation period is between 1 and 
1 g/dL, provided the standard deviation is smaller than 1.5 and the optimum dose conversion is 
able to maintain the Hb at the baseline level.
Approximately 1015 of the patients will be 12 years old, with the objective to include as many 
patients 5 years old (minimum 3 patients) as possible.  Approximately 1015 patients, 
irrespective of their age, will not be on dialysis.  Available HD patients receiving their ESA 
subcutaneously are eligible for enrollment.  No more than 10 patients on HD should be enrolled.
To achieve the recruitment of the intended number of patients and in case of excessive dropout 
rate, additional patients may be enrolled to replace patients not treated for a minimum duration 
of 18 weeks.
Interim Analyses
Once 12 patients have completed 20 weeks of treatment, an interim analysis to assess efficacy, 
safety, and pharmacokinetics will be performed.  The analysis will be reviewed by a Roche 
Internal Monitoring Committee (IMC) with the primary objective of assessing the safety and 
efficacy of the CFs for starting treatment with SC Mircera.  This will be assessed using Hb (the 
pharmacodynamic marker), changes in dose, and assessment of the pharmacokinetic (PK) data 
to compare to the available pediatric PK data under IV dosing.  The variability of Hb will also be 
assessed at this time, with regard to protocol assumptions, and the sample size will be revised if 
necessary. 
An individual’s Hb response will be based on the mean Hb during the evaluation period 
(Weeks 1721) and is defined as a mean Hb change from baseline within 1g/dL.  The 90% CI 
for the average Hb change from baseline will be calculated.  
Interim PK and pharmacokinetic/pharmacodynamic (PK/PD) analyses will be conducted, as 
follows:

External validation of the existing PK and PK/PD models against preliminary 
Study NH19708 data to highlight any deviation from the current knowledge of Mircera PK 
and pharmacodynamic properties; the bioavailability in pediatric patients will be carefully 
regarded. 

A Bayesian feedback approach will also be used on Mircera serum concentration-time data 
to get a first assessment of the individual PK parameters in pediatric patients receiving 
Mircera subcutaneously, especially bioavailability.
The full details of the interim analysis, and any decision criteria, will be specified in separate 
IMC documents.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AEAB
anti-erythropoietin antibody
AEAB-mediated PRCA
anti-erythropoietin antibody-mediated pure red cell 
aplasia
CF
conversion factor
CKD
chronic kidney disease
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
EPO
erythropoietin
ESA
erythropoiesis-stimulating agent
ESRD
end stage renal disease
FDA
Food and Drug Administration
Hb
hemoglobin
HD
hemodialysis
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ITT
intent-to-treat
IxRS
interactive voice or web-based response system
KDOQI
Kidney Disease Outcomes Quality Initiative
LPLV
last patient, last visit
NAPRTCS
North American Pediatric Renal Trials and 
Collaborative Studies
ObsRO
observer-reported outcome
PD
peritoneal dialysis
PFS
prefilled syringe
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic
PRCA
pure red cell aplasia
PRO
patient-reported outcome
PTH
parathyroid hormone
SJS
Stevens-Johnson Syndrome


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Abbreviation
Definition
TEN
toxic epidermal necrolysis
TSAT
transferrin saturation
ULN
upper limit of normal
URR
urea reduction ratio
USRDS
United States Renal Data System
VAS
visual analogue scale
VAT
vascular access thrombosis


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1.
BACKGROUND
1.1
BACKGROUND ON CHRONIC KIDNEY DISEASE
Chronic kidney disease (CKD) is characterized by a progressive decline in renal function. 
As CKD progresses, inadequate levels of erythropoietin (EPO)mainly synthesized in 
the kidneys and stimulating the production of red blood cells in the bone marroware 
produced (Caro et al. 1979) and the resulting anemia becomes progressively more 
severe (Astor et al. 2002; McClellan et al. 2004).  If left untreated, anemia impairs quality 
of life (Klang et al. 1996; Gerson et al. 2004) and may lead to cardiovascular dysfunction 
(Mitsnefes et al. 2000; Chavers and Herzog 2004), impaired cognition 
(Pickett et al. 1999), and reduced physical activity (Sietsema et al. 2002; 
Pattaragarn et al. 2004). The anemia of CKD is also associated with increased 
hospitalization and mortality rates in both adults and children (Ma et al. 1999; 
Xia et al. 1999; Warady and Ho 2003).
The mechanism of anemia due to CKD in children is identical to that in adults. 
Treatment modalities are also identical (KDIGO 2012). Exogenous replacement of EPO 
by erythropoiesis-stimulating agents (ESAs) is an established method for anemia 
treatment in CKD in conjunction with iron supplementation (Locatelli et al. 2004). The 
currently available treatment options include short-acting human recombinant EPOs 
(epoetin alfa and epoetin beta), requiring several injections per week due to their short 
half-life, and longer-acting ESAs (hyperglycosylated [darbepoetin alfa] and pegylated 
[Mircera]), which need less frequent dosing due to their prolonged half-life. Epoetin 
alfa/beta and darbepoetin alfa are approved treatments for anemia associated with CKD 
in pediatric patients.  Several studies in pediatric patients with CKD have demonstrated 
that the safety profile of epoetin alfa/beta or darbepoetin alfa in pediatric patients is 
similar to that in adults (Gagnadoux et al. 1994; Van Damme-Lombaerts et al. 1994; 
Burke 1995; Sieniawska and Roszkowska 1997; Brandt et al. 1999; Greenbaum et al.
2000; Morgan et al. 2001; Seeherunvong et al. 2001; Geary et al. 2005; 
Warady et al. 2006; Warady 2015). The long-term safety and efficacy of darbepoetin 
alfa were assessed in a prospective registry study of 319 patients treated for up to 
2 years (Schaefer et al. 2016). No new safety signals were found for darbepoetin alfa 
treatment, and anemia was effectively managed in these patients.
Similar to adults with CKD, many children with CKD undergoing hemodialysis (HD) or 
peritoneal dialysis (PD) require continuous long-term treatment with ESAs to maintain 
anemia correction. In addition, a significant number of children with reduced kidney 
function not yet on dialysis (CKD Stage 3b) develop anemia and may need therapy 
with ESAs to raise hemoglobin (Hb) values (Koshy and Geary 2008).  
Data on the epidemiology of CKD in children who are on dialysis are available from the 
North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS 2014) and 
the United States Renal Data System (USRDS 2016). Information regarding pediatric 
patients who receive maintenance HD or PD has been captured since 1992. Children 


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with CKD represent a very small percentage of the total CKD population (NAPRTCS 
2014 and USRDS 2016).
The 2014 NAPRTCS registry spans more than 25 years and has collected information 
on the transplants of over 11,186 children. As of 1 January 2014 (database closure for 
the 2014 report), 12,189 renal transplants had been reported for 11,186 pediatric 
patients. This represents 586 new transplants and 554 patients with their first registry 
transplant since the 2010 annual report.
In 2014, the total number of children in the United States who had not yet received a 
primary kidney transplant and were on maintenance dialysis was 7,045 (NAPRTCS 
2014). However, 25% of the primary transplants were preemptive, as these patients had 
never received maintenance dialysis.
Epidemiology data from the latest USRDS annual report (2016) show that the incidence 
of end stage renal disease (ESRD) in children has decreased annually between 2008 
and 2014 in the United States. In 2014, a total of 1,398 children had a new onset of 
ESRD, which was 6% less than in 2013. By age, the number of incident cases ranged 
from a low of 152 in children 59 years of age to 555 in young adults 1821 years of 
age. Children 1821 years of age account for 40% of the incident pediatric 
ESRD population. In terms of rates, incidence ranges from 6.8 per million for children
59 years of age to 30.6 per million in children 1821 years of age. Similarly, as of 
31 December 2014, the point prevalence of children with ESRD was 9,721, which 
represents a 1.6% decrease from the previous year. Prevalence counts do not account 
for the large number of pediatric patients who have aged into adulthood.
Of the 9,721 children, adolescents, and young adults between the ages of 0 and 
21 years with prevalent ESRD as of 31 December 2014, kidney transplant was the most 
common treatment modality (6,825 [70.2%]), followed by HD (1,745 [18.0%]) and PD
(1,122 [11.5%]). Over 80% of prevalent children 513 years of age have a kidney 
transplant. This equates to a point prevalence per million population of 18.5 for HD, 
11.7 for PD, and 69.8 for transplant.
1.2
BACKGROUND ON MIRCERA
Methoxy polyethylene glycol-epoetin beta (Mircera) is a chemically synthesized 
continuous EPO receptor activator.  Mircera differs from EPO through integration of 
amide bonds between amino groups and methoxy polyethylene glycol butanoic acid.  
This results in a calculated molecular weight of approximately 60 kDa. 
The available toxicology data suggest excellent safety and tolerability.  Single- and 
multiple-ascending dose studies in healthy volunteers show potent dose-dependent 
stimulation of erythropoiesis after both IV and SC administration.  Mircera has a long 
elimination half-life (approximately 130 hours after single-dose SC administration and 


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approximately 90 hours after single-dose IV administration) (Locatelli and Reigner, 2007).  
The serum concentrations of Mircera are not affected by standard HD or hemofiltration.
In contrast with EPO, Mircera shows a different activity at the receptor level,
characterized by a slower association to the receptor, reduced specific activity in vitro 
with an increased activity in vivo, as well as an increased half-life (Jarsch et al. 2008).  
These pharmacological properties are relevant in achieving a monthly dosing regimen 
with Mircera. 
The global clinical development program for Mircera included 13 Phase I clinical 
pharmacology studies and 10 therapeutic studies comprising 4 Phase II and 6 Phase III 
studies in patients with CKD, including patients on dialysis and not on dialysis
(Del Vecchio et al. 2008). Administration of Mircera for the treatment of anemia 
associated with CKD was generally well tolerated, with no difference in the safety profile 
in comparison to reference ESAs. 
Mircera was efficacious in correcting anemia associated with CKD in patients who were 
on dialysis or not on dialysis and who were not currently treated with an ESA, regardless 
of route of administration (IV or SC).  Mircera, with its effect on erythropoiesis and its 
long elimination half-life requiring infrequent administration, offers potential benefits
compared to other ESAs (Mircera Summary of Product Characteristics and Mircera 
Prescribing Information)
Data are available on the efficacy and safety of Mircera administered once every
4 weeks by IV application in pediatric patients (64 children, ages 617 years old).  The 
completed Phase II Study NH19707 showed that pediatric patients with CKD on HD can 
be switched from maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin 
alfa to Mircera using defined conversion factors (CFs) (Fischbach et al. 2018) 
(see Section 1.3).
In addition to Study NH19707, Mircera has been studied in children in two independent 
investigator-initiated trials.  Cano et al. [2011] evaluated the efficacy and safety of 
Mircera in the management of anemia in 16 pediatric patients (ages 214 years) on 
stable PD receiving EPO who converted to Mircera SC, scheduled every 2 weeks. 
Wedekin et al. [2011] conducted a study with Mircera administered intravenously every 
4 weeks in 12 pediatric patients (ages 617 years) in a post-transplant setting. In both 
studies, no adverse events attributable to Mircera were reported, and Hb levels were 
effectively controlled. In Study NH19707, the adverse event profile observed during the 
core study period and in the safety extension period did not reveal any unexpected 
safety concerns. 
Refer to the Mircera Investigator's Brochure for details on nonclinical and clinical studies.


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1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
Most patients with CKD (Stage 3b) not yet on dialysis or undergoing HD or PD require 
continuous long-term treatment with ESAs (e.g., epoetin alfa, epoetin beta, or 
darbepoetin alfa) to correct anemia and to maintain anemia correction.  The Phase II 
and III studies of Mircera in adult patients with CKD have shown that it is safe and 
effective in the treatment of anemia in patients not yet on dialysis and in those receiving 
HD or PD (Del Vecchio et al. 2008). Cumulative exposure to Mircera since it was first 
licensed in 2007 is estimated to be about 1.5 million patient-years in 2016.
Study NH19707 identified CFs of 4previous weekly darbepoetin alfa dose [g]/0.55 
and 4previous weekly epoetin alfa/beta dose [IU]/125 to switch from the previous 
maintenance treatment to once every 4 weeks Mircera IV treatment in HD patients 
(ages 517 years). By using these CFs, patients maintained Hb within target levels
during the core and the safety extension periods. The adverse event profile observed 
during the study did not reveal any unexpected safety concerns. 
State-of-the-art pharmacokinetic/pharmacodynamic (PK/PD) models have been 
developed on a pooled dataset of Phase II and Phase III data from adult patients with 
CKD and the NH19707 Phase II pediatric data. The analysis provided a good 
understanding of the pharmacokinetic (PK) properties of Mircera; age and body weight 
captured the differences between adult and pediatric patients. Similarly, the analysis 
also described the pharmacodynamic properties of Mircera in pediatric patients; it 
showed no difference in Mircera-specific PK/PD parameters in pediatric and adult 
patients, thus suggesting the same exposure/response relationship in both populations.
In adults, there was neither an impact of dialysis modality nor a difference between IV 
and SC routes of administration on PK and PK/PD parameters (Chanu et al. 2010). 
Model-based simulations of clinical outcomes of Mircera, when Mircera is administered 
subcutaneously once every 4 weeks for the maintenance treatment of anemia in 
pediatric patients with CKD, support the current dosing strategy.  Based on clinical 
experience in adults and model-based simulations in children, the same initial dose of 
Mircera can be used intravenously and subcutaneously when switching from epoetin alfa, 
epoetin beta, or darbepoetin alfa.
This study will address the following questions that remain open following 
Study NH19707: use of Mircera in younger children (6 years old), SC administration of 
Mircera, its use in patients on PD or not yet on dialysis, and confirmation of the results of 
the modeling and simulation studies. 
The same CFs as identified in the previous pediatric study (Study NH19707) will be 
tested for Mircera given subcutaneously to patients 3 months17 years of age who are 
on dialysis or not yet on dialysis and are switching from stable SC maintenance 
treatment with epoetin alfa, epoetin beta, or darbepoetin alfa.


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2.
OBJECTIVES AND ENDPOINTS
This study will ascertain the starting dose of Mircera given subcutaneously for the 
maintenance treatment of anemia in pediatric patients with CKD on dialysis or not yet on 
dialysis when switching from stable SC maintenance treatment with epoetin alfa, epoetin 
beta, or darbepoetin alfa.  Specific objectives and corresponding endpoints for the study 
are outlined below (Table 1).
Table 1
Objectives and Corresponding Endpoints
Efficacy Objective
Corresponding Endpoints
To ascertain the starting dose of 
Mircera given subcutaneously in 
pediatric patients with CKD on dialysis
or not yet on dialysis when switching 
from stable SC maintenance treatment 
with epoetin alfa, epoetin beta, or 
darbepoetin alfa 
Primary endpoint:
Change in Hb concentration (g/dL) between the 
baseline and the evaluation period for each patient
Secondary endpoints:
Number of patients with an average Hb concentration 
during the evaluation period within 1 g/dL of their 
baseline Hb or above, within or below the range of 
1012 g/dL
Change in Mircera dose over time, including the 
change between the starting dose and the evaluation 
period
Safety Objective:
Corresponding Endpoints
To assess the safety and tolerability of 
multiple doses of Mircera given 
subcutaneously in pediatric patients
Occurrence and severity of adverse events
Change from baseline in targeted vital signs
Change from baseline in targeted clinical laboratory 
test results
Pharmacokinetic and 
Pharmacodynamic Objective
Corresponding Endpoints
To evaluate the pharmacokinetics and 
the pharmacodynamics of Mircera in 
patients on dialysis or not yet on 
dialysis who receive the study 
medication by the SC route of 
administration
Serum concentrations of Mircera and Hb will be used 
to evaluate the pharmacokinetics and the 
pharmacodynamics of Mircera through PK and PK/PD 
models.
CKDchronic kidney disease; Hbhemoglobin; PDperitoneal dialysis; PKpharmacokinetic; 
PK/PDpharmacokinetic/pharmacodynamic.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This study is an open-label, single-arm, multicenter study to ascertain the optimal
starting dose of Mircera given subcutaneously for the maintenance treatment of anemia 
in pediatric patients with CKD on dialysis or not yet on dialysis.
Following written informed consent from a parent or legal guardian and, if appropriate, 
assent from the child, the patient will be screened for eligibility during a screening period 
of approximately 3 weeks.  During this period, patients will continue to receive epoetin 
alfa, epoetin beta, or darbepoetin alfa at the same weekly dose, route (SC), and interval 
as before screening. The total weekly doses 4 weeks before the first Mircera 
administration should not change 25% (increase or decrease).  Provided that all 
eligibility criteria are met, including those for Hb levels and iron status, the patients will 
start Mircera administered subcutaneously. 
At least 40 pediatric patients 3 months17 years of age will be enrolled.  Approximately 
1015 of these patients will be 12 years old, with a goal to include as many patients
5 years old as possible (with a minimum of 3 patients). Approximately 1015 patients, 
irrespective of age, will not be on dialysis.  
Available HD patients receiving their ESA subcutaneously are eligible for enrollment. 
No more than 10 patients on HD should be enrolled.
Mircera will be administered subcutaneously once every 4 weeks for the duration of the 
study.  Dose adjustments may be performed every 4 weeks according to dose 
adjustment rules defined in Section 4.3.2.1.1.
The core study will last for 23 weeks and consists of three periods: screening (3 weeks), 
dose titration (16 weeks), and evaluation (4 weeks). 
Patients completing the 20 weeks of treatment with Hb within 1 g/dL of their 
baseline Hb and within the target range of 1012 g/dL, will be eligible to enter an 
optional 24-week safety extension period. Those patients not eligible or not consenting 
to enter the long-term safety extension should be treated according to clinical practice.  
All patients must complete the Week 21 visit (Visit 10), regardless of whether they 
continue in the safety extension period.  Visit 10 will serve as the final visit of the core 
study and the first visit of the safety extension period for patients eligible and willing to 
continue in the study.
Once 12 patients have completed 20 weeks of treatment (dose titration and evaluation 
periods), an interim analysis to assess the pharmacokinetics, efficacy, and safety of 
Mircera will be performed (see Section 6.9).  




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treatment with IV epoetin alfa, epoetin beta, or darbepoetin alfa to Mircera IV using CFs
to define the starting dose.  The purpose of this study is to use the same CFs to 
ascertain the starting dose of Mircera given subcutaneously for the maintenance 
treatment of anemia with SC ESAs in pediatric patients with CKD on dialysis or not yet 
on dialysis.
The study design is based on the study design of NH19707 but with fewer visits, as 
patients on PD or not yet on dialysis visit the nephrology centers less frequently than 
patients on HD.  The similar study design will allow pooling of the data from the two
pediatric studies. 
3.3.1
Rationale for Mircera Dose and Schedule
The completed Phase III program of Mircera in adult patients with CKD included four 
studies to assess how to switch patients treated with epoetin alfa, epoetin beta, or 
darbepoetin alfa to Mircera, administered intravenously or subcutaneously.  The CFs 
that were tested in the Phase II Study NH19707 in pediatric patients were directly 
derived from the Sponsor’s experience in adults receiving Mircera intravenously and 
from the results of a published study of darbepoetin alfa conducted in pediatric patients 
(Warady et al. 2006).  This completed study identified CFs of 4 previous weekly 
darbepoetin alfa dose [g]/0.55 for darbepoetin alfa and 4previous weekly epoetin 
dose [IU]/125 for epoetin alfa and epoetin beta in order to switch from the previous 
weekly maintenance treatment dose to Mircera IV once every 4 weeks in HD patients.  
Model-based evaluation of the data from this pediatric study and subsequent simulations,
coupled with the data from the adult studies, suggest that these CFs will also be 
appropriate in the SC setting. Real-world data from independent registries (International 
Pediatric Dialysis Network) of pediatric patients (3 months and older) treated with 
Mircera SC and IV confirmed the model-based simulations and the conversion factor 
identified in Study NH19707. Therefore, the same CFs will be used to identify the 
starting dose of Mircera administered subcutaneously every 4 weeks.  
The patients included in this study are already on stable maintenance doses of SC ESA 
prior to conversion to Mircera and, assuming a linear relationship across dose ranges, 
the use of CFs will result in a Mircera dose that is proportional to the previous ESA dose, 
thus correcting for the higher weight-adjusted dose requirements in pediatric patients.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 40 pediatric patients, (3 months17 years of age), who are evaluable for 
intent-to-treat (ITT) and safety analyses (see Section 6.4 and Section 6.5, respectively),
who have clinically stable chronic renal anemia on dialysis or not yet on dialysis, and 
who are receiving maintenance SC treatment with an ESA, will be enrolled in this study.  


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Approximately 1015 of the patients will be 12 years old, with the objective to include 
as many patients as possible 5 years old (with a minimum of 3 patients).  
Approximately 1015 patients, irrespective of age, will not be on dialysis.  Available 
HD patients receiving their ESA subcutaneously are eligible for enrollment.  No more 
than 10 patients on HD should be enrolled.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent from parent/legal guardian and willingness of parent/legal
guardian to abide by the requirements of the study

Written informed consent or assent from child where appropriate
If required by national legislation, patients 18 years of age at screening who 
are legally considered to be adults according to national legislation must 
consent in their own right. 

Pediatric patients 3 months17 years of age with clinically stable chronic renal
anemia

CKD with estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2
(determined by the Bedside Schwartz formula [see Appendix 3]) or dialysis treatment
for at least 8 weeks before the first dose of Mircera

For patients on PD: a weekly Kt/V 1.8

For patients on HD: adequate HD, urea reduction ratio (URR) 65% or Kt/V 1.2 for
patients on HD three times per week.
Patients with fewer than or more than three HD sessions per week should have 
a weekly Kt/V 3.6.

Baseline Hb concentration 10.012.0 g/dL determined from the mean of two Hb
values measured at Visit 1 (Week 3) and Visit 2 (Week1)

Stable SC maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin alfa
with the same dosing interval for at least 6 weeks before the first dose of Mircera

Stable dose of epoetin alfa, epoetin beta, or darbepoetin alfa treatment with no
weekly dose change 25% (increase or decrease) for at least 4 weeks before the
first dose of Mircera

Adequate iron status defined as ferritin 100 ng/mL or transferrin saturation (TSAT)
20% (or percentage of hypochromic red cells 10%); mean of two values
measured during screening

For post-pubertal female patients of childbearing potential:  agreement to remain
abstinent (refrain from heterosexual intercourse) or to use acceptable contraceptive
methods during the study and for 90 days after the final dose of Mircera
A female patient is considered to be of childbearing potential if she is 
postmenarcheal.
The following are acceptable contraceptive methods:  hormonal contraceptives; 
hormone-releasing intrauterine devices; copper intrauterine devices; male or 
female condom with or without spermicide; and cap, diaphragm, or sponge with 
spermicide.




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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Patients will be enrolled to receive Mircera once every 4 weeks, and no randomization 
will be performed. An interactive voice or Web-based response system (IxRS) will be 
used to track the enrollment and to monitor the disposition of patients with respect to the 
different subgroups (age group and dialysis type).
Blinding is not applicable; this is an open-label, single-arm study.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is Mircera.
4.3.1
Study Treatment Formulation, Packaging, and Handling
Mircera will be provided by the Sponsor in sterile injectable solution in single-use,
prefilled syringes (PFS).  The Mircera solution is formulated in sodium phosphate, 
sodium sulfate, mannitol, methionine, and poloxamer 188, pH 6.2.  This formulation does 
not contain any preservative. 
The PFS is available in the following strengths:
30
50
75
100
120
150
200
250
g/0.3 mL
360
g/0.6 mL
The PFS should be stored in a refrigerator at 2C8C (35.6F46.4F) and protected 
from light. The investigational site is responsible for maintaining a daily temperature log 
of this refrigerator.
For information on the formulation and handling of Mircera, see the Mircera 
Investigator's Brochure and the local prescribing information for Mircera.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimen is summarized in Section 3.1.
The Mircera PFS should reach room temperature in its outer carton box before injecting.  
Mircera should be administered subcutaneously using a PFS, and each PFS should be 
used only once. 


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The empty PFS blisters/medication boxes with patient identification information must be 
retained and made available for the Roche Monitor to check at each visit. Once the 
Roche Monitor has checked the empty PFS blisters/medication boxes with the patient 
identification, they will be sent back to the Sponsor, or upon approval by the Sponsor, 
they may be destroyed at the site, either at the end of the study or as required by the site.
All doses administered need to be reported on the Study Drug Administration electronic 
Case Report Form (eCRF).  Any dose modification should be noted on the Study Drug 
Administration eCRF.  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.4.4.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.2.
4.3.2.1
Rationale for Starting Dose Selection
The starting dose will be based on CFs obtained from the dose-finding study 
(Study NH19707) (see Section 3.3.1). The initial dose of Mircera will be one of nine
starting doses corresponding to the PFS strengths based on the total weekly ESA dose 
during the screening period, as described in Table 2.
Table 2
Mircera Starting Dose 
Previous Weekly 
Epoetin Alfa or  
Epoetin Beta Dose 
[IU/Week]
Previous Weekly 
Darbepoetin Alfa Dose
[g/Week]
Every 4-week 
Mircera
Dose [g]
1300
6 
30
13002000
69
50
20002700
912
75
27003500
1215
100
35004200
1519
120
42005500
1924
150
55007000
2431
200
70009500
3142
250
9500
42
360
Once 12 patients have completed 20 weeks of treatment, an interim analysis to assess 
the pharmacokinetics, efficacy, and safety will be performed (see Section 6.9). If the 
results of this interim analysis indicate that the starting dose is not appropriate, then it 
may be changed (see Section 6.9).


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4.3.2.1.1
Dose Adjustments of Mircera
Dose adjustments may be performed during the entire study.  The dose of Mircera 
should be adjusted to maintain the individual patient’s Hb within a target range of 
1 g/dL of his or her baseline Hb and between 10.012.0 g/dL.  Baseline Hb is 
calculated as the mean of Hb values obtained at Visit 1 (Week 3) and Visit 2 (Week 1). 
Dose adjustments should be performed at the scheduled dosing days and should be 
based on the Hb value measured on that day.  They should not be performed more often 
than once every 4 weeks.
Dose adjustment rules for Mircera in response to Hb changes, including those required 
for safety reasons, are summarized in Table 3.
Table 3
Mircera Dose Adjustments 
Hemoglobin Assessment
Compared with the Previous Mircera Dose
Hb decreases by more than 1.0 g/dL 
compared with baseline Hb.
Increase dose by approximately 25% (or closest 
higher PFS strength).
Hb is less than 10 g/dL and greater than or 
equal to 9 g/dL (Hb 10.0 and 9.0 g/dL).
Increase dose by approximately 25% (or closest 
higher PFS strength).
Hb is less than 9 g/dL (Hb 9.0 g/dL).
Increase dose by approximately 50% (or closest 
to 50% increase PFS strength).
Hb increases by more than 1.0 g/dL 
compared with the baseline Hb.
Decrease dose by approximately 25% (or closest 
lower PFS strength).
Hb is increasing and is approaching 12 
g/dL or Hb is greater than or equal to 12 
g/dL (Hb 12 g/dL).
Decrease dose by approximately 25% (or closest 
lower PFS strength).
If Hb exceeds 12 g/dL and continues to 
increase following a dose reduction.
Stop doses until Hb is less than 12.0 g/dL.
Resume dose at approximately 25% below 
previous dose (or closest lower PFS strength) at 
next scheduled dosing day.
Hb hemoglobin; PFS prefilled syringe..
4.3.2.1.2
Dose Adjustments in Case of Red Blood Cell Transfusion
In case of an RBC transfusion due to worsening anemia secondary to inadequate doses 
or to poor response to Mircera, the dose (administered at the next scheduled dosing day, 
if possible) should be adjusted according to the guidelines in Table 3.
In case of an RBC transfusion to replace acute blood loss, the dose should not be 
changed, and the next dose should be administered as scheduled.


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4.3.3
Investigational Medicinal Product Accountability
All IMPs (Mircera) required for completion of this study will be provided by the Sponsor 
where required by local health authority regulations.  The study site will acknowledge 
receipt of IMPs supplied by the Sponsor, using the IxRS to confirm the shipment 
condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site’s method of destroying Sponsor-supplied 
IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Mircera
Currently, the Sponsor does not have any plans to provide the Roche IMP (Mircera) or 
any other study treatments or interventions to patients who have completed the study.  
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment within 
3 months before screening.  All such medications should be reported to the investigator 
and recorded on the Concomitant Medications eCRF.
4.4.1
Permitted Therapy 
All treatments (medications and medical procedures) are permitted before screening, 
during the screening period, and throughout the 20-week treatment period, except for 
those listed in Section 4.4.5.
4.4.2
Iron Supplementation
An adequate iron status is a prerequisite to achieve and maintain target Hb levels. Iron 
deficiency during treatment may cause a reduced erythropoietic response to epoetin 
therapy. In addition, epoetin therapy results in increased erythropoiesis that may lead to 
a depletion of iron stores. The iron status will be monitored throughout the study by 
assessing serum ferritin and TSAT. TSAT will be calculated as described in Appendix 3. 
The percentage of hypochromic red cells can be determined instead of TSAT.


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Adequate iron status is defined as follows:
Serum ferritin 100 ng/mL 
or 
TSAT20% (or percentage of hypochromic red cells 10%)
Patients must be iron-replete at baseline to be enrolled in this study and should maintain 
an adequate iron status throughout the treatment period. For baseline, iron status 
should be assessed using the mean of two values measured during screening 
(Weeks 3 and 1).
Supplemental iron will be administered to prevent iron deficiency during the screening 
period and during the study, and to maintain adequate iron status. Therefore, oral or IV
iron will be given during the entire study period (screening, dose titration, and evaluation 
periods) according to center practice. If iron treatment is ongoing at the start of the 
study, it should not be interrupted. 
To avoid iron toxicity, caution is suggested in patients with serum ferritin 500 ng/mL or 
TSAT 30%.
All oral and IV iron supplementations administered within 3 months before screening and 
started/stopped at any time during the screening and treatment periods should be 
documented in the iron supplementation section of the eCRF.
Iron Loading
In case of inadequate iron stores at the end of screening, the patient should receive iron 
loading according to center practice. After completion of the iron loading, the patient will 
be allowed to be re-screened.  New assessment of iron stores should be performed at 
least 1 week after iron loading.
4.4.3
Red Blood Cell Transfusions
RBC transfusions may be given during the treatment period in case of medical need, 
that is, in severely anemic patients with recognized symptoms or signs of anemia 
(e.g., in patients with acute blood loss or in patients whose Hb has declined to critical 
levels).  Every reasonable effort should be made to avoid RBC transfusions in patients 
with Hb concentrations above 8 g/dL. 
All RBC transfusions administered during the study should be documented 
(i.e., specified by type, number of units transfused, and total volume transfused) in the 
RBC transfusions section of the eCRF.  The pre-transfusion Hb level must be measured 
before each RBC transfusion and recorded on the appropriate page in the eCRF.


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The indication for the RBC transfusions (e.g., the etiology of the acute blood loss or 
worsening of anemia if no other etiology is known) should be recorded as an adverse 
event on the eCRF page and the RBC transfusions listed as treatment on the same 
eCRF page.
4.4.4
Dialysis
Dialysis modality at study start (HD, PD, or none), number of HD sessions per week, the 
type of vascular access for HD, PD type, time since first dialysis, and dialysis adequacy 
assessments should be documented in the dialysis section of the eCRF.  
In the event that a patient not previously on dialysis requires emergent or long-term 
dialysis treatment due to worsening of renal function, the patient should be kept in the 
study, whenever possible, until the final visit. The route of administration for Mircera 
should stay the same (SC). The start of dialysis and dialysis modality should be 
documented in the dialysis page of the eCRF.
Dialysis modality changes (i.e., switch from PD to HD) may be performed during the 
treatment period in case of medical need.  If a switch from PD to HD during the study 
becomes necessary, the patient can continue to participate in the study as long as the 
SC route of administration is maintained. The visits should occur on the day of the 
mid-week dialysis. The change of dialysis should be documented in the dialysis page of 
the eCRF. 
4.4.5
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Other IMPs (defined as any material [i.e., placebo or drug] dispensed under the 
provision of a protocol) within 4 weeks before screening, during screening, or during
the treatment periods.  
Participation in studies testing investigational devices or dialysis solutions 
should be reported to the Sponsor in advance and approved by the Sponsor.

Non-Food and Drug Administration (FDA) or European Medicines Agency-approved 
biosimilar ESAs within 12 weeks before screening or during screening

RBC transfusions within 8 weeks before screening or during screening (see also 
Section 4.4.3) 

Immunosuppressive therapies known to exacerbate anemia, such as 
cyclophosphamide, sirolimus, tacrolimus, azathioprine, and mycophenolate mofetil, 
administered the last 12 weeks before the first screening visit


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
Whenever possible, intermittent treatment (i.e., start or stop) or dose change of 
medications known to influence Hb concentration should be avoided.  
These medications include androgens (known to improve anemia), 
angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and 
immunosuppressive therapies, except for corticosteroids for a chronic condition, 
cyclosporine, and monoclonal /polyclonal antibodies
If drugs that are highly bound to RBCs (e.g., cyclosporine) are given during the study, 
blood levels of these drugs should be monitored and their dosage adjusted as the Hb 
rises. 
4.5
STUDY ASSESSMENTS 
The schedules of activities to be performed during the study are provided in Appendix 1
and Appendix 2.  All activities must be performed and documented for each patient.
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
Throughout the screening period and the 20-week treatment period (dose titration and 
evaluation periods), the study visits should be scheduled, if possible, on the same day of 
the week. For patients undergoing HD or patients converting to HD, the visits should 
occur on the day of the mid-week dialysis.
A follow-up visit will be performed for all patients at study end (Week 21) or at any time 
during the study in case of premature withdrawal. In case of premature withdrawal due 
to kidney transplantation, the follow-up visit must take place before the transplantation;
otherwise, there will be no follow-up visit.
Patients completing the 20 weeks of treatment with Hb within 1 g/dL of their baseline 
Hb and within the target range of 1012 g/dL will be eligible to enter an optional 24-week 
safety extension period.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent from the parent/legal guardian and willingness of the 
parent/legal guardian to abide by the requirements of the study, and written informed 
consent or assent from the child where appropriate, must be obtained before performing 
any study-related procedures (including screening evaluations).  If required by national 
legislation, patients 18 years of age at screening who are legally considered to be 
adults according to national legislation must consent in their own right. 
Informed Consent Forms for enrolled patients and for patients who are not subsequently 
enrolled will be maintained at the study site.


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Eligibility will be assessed during an initial screening period.  All screening evaluations 
must be completed and reviewed to confirm that patients meet all eligibility criteria 
before enrollment.  The investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Patients who fail screening may be re-screened if it is considered likely that they could 
later become eligible. Patients who are not eligible will be allowed to undergo a 
maximum of two new rounds of screening assessments. All eligibility criteria have to be 
reassessed during the new screenings.
Provided that the efficacy and safety profiles for the patient are acceptable, at least 
2 weeks prior to the follow-up visit (Visit 10, Week 21), the investigator should discuss 
with the parents/legal guardians and, if appropriate, with the patient, the possibility of 
continuing with an optional safety extension period. A new signature on the informed
consent (and, if indicated, on the assent) should be obtained at this time. The clinical 
and laboratory assessments at Week 21 (Visit 10, follow-up visit) of the core study 
period are also used as initial assessments for the optional safety extension period.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
The following information will be collected during the screening period:

Medical history includes etiology of CKD, dialysis modality (HD,PD or none), 
number of HD sessions per week, the type of vascular access for HD, anticoagulant 
treatment during HD, PD type, date of first dialysis treatment, dialysis adequacy 
assessments, previous ESA treatments, and iron supplementation. It also includes 
risk factors and dialysis-related events, as well as clinically significant diseases.

In addition, all medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient within 3 months prior to screening will be recorded.

Demographic data will include age, sex, and self-reported race/ethnicity (where 
permissible).

Reproductive status and smoking history will be collected.
4.5.3
Physical Examinations
A complete physical examination, performed at screening (Week 3, Visit 1),at the 
follow-up visit (Week 21, Visit 10), and at the final safety extension visit (Week 45), 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal,
genitourinary, and neurologic systems.  Any abnormality identified should be recorded 
on the corresponding page of the eCRF.


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4.5.4
Height and Body Weight
Height will be collected at Week 1, Visit 3, at the follow-up visit (Week 21, Visit 10), and 
at the final safety extension visit (Week 45).  Body weight will also be recorded 
throughout the study (after dialysis for patients on HD).
4.5.5
Vital Signs
Vital signs will be measured regularly throughout the study.  They include measurements 
of systolic and diastolic blood pressure and pulse rate while the patient is if possible in a 
seated position, and they will be measured before blood sampling (see Appendix 5). 
The blood pressure should be measured at least twice and the average of these 
measurements should be recorded. An appropriate-sized cuff should be used. Blood 
pressure should be determined before and after the dialysis session for HD patients.
4.5.6
Laboratory Assessments
For sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual.
Biological samples will be destroyed no later than the time of completion of the final Clinical 
Study Report, with the following exception:

Serum samples collected for PK or immunogenicity analysis may be needed for additional 
immunogenicity characterization and for PK or immunogenicity assay development and 
validation; therefore, these samples will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed.
When a patient withdraws from the study, samples collected prior to the date of withdrawal 
may still be analyzed, unless the patient specifically requests that the samples be destroyed or 
local laws require destruction of the samples. However, if samples have been tested prior to 
withdrawal, results from those tests will remain as part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards described in 
Section 8.4.
4.5.6.1
Safety Assessments
Normal ranges for the study laboratory parameters should be supplied to Roche before 
the study starts.  Blood sampling should always be performed before ESA administration
and for patients on HD before the dialysis.  The following laboratory assessments will be 
performed throughout the study at selected visits (see the schedules of activities in 
Appendix 1 and Appendix 2) and analyzed at the study site’s local laboratory:

Hematology:  Hb, RBC, absolute reticulocyte count  

Safety laboratory:  leukocytesplus differential, AST, ALT, serum albumin, ALP, 
C-reactive protein, potassium, phosphorus, calcium, and platelets

Serum creatinine:  measured only for patients not on dialysis
eGFR will be calculated using the Bedside Schwartz formula (see Appendix 3).


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
Iron parameters:  serum ferritin, serum iron, and TSAT. TSAT will be calculated as 
described in Appendix 3 with either serum transferrin or total iron-binding capacity. 
The percentage of hypochromic red blood cell may be determined instead of TSAT.

Serum pregnancy test for post-pubertal female patients of childbearing potential 

Kt/V for patients on PD  
Frequency will follow current Kidney Disease Outcomes Quality Initiative 
(KDOQI) guidelines (2006).

Kt/V or URR for patients on HD  
Frequency will follow current KDOQI guidelines (2006).
Per individual, the trial-related blood loss (including any losses in the maneuver) should 
not exceed 3% of the total blood volume during a period of four weeks and should not 
exceed 1% at any single time. The total volume of blood is estimated at 80 to 90 ml/kg 
body weight; 3% is 2.4 ml blood per kg body weight (DG SANTE 2008). Blood sampling 
to assess the different laboratory parameters should be done routinely at the site but 
should not exceed the recommended maximal volume of 2.4 ml per kg per four weeks.
Samples for the following laboratory tests will be sent to one or several bioanalytical 
laboratories for analysis:

Serum samples will be collected to evaluate the pharmacokinetics of Mircera 
administered subcutaneously (see Section 4.5.6.2).

Anti-EPO and anti-Mircera antibody will be determined at Week 1, Visit 3, at 
Week 9 (Visit 6), and follow-up visit (Week 21, Visit 10).  An additional sample 
will be collected at Week 45 (Visit 16) for the patients participating in the safety 
extension period.
For the patients participating in the optional safety extension period, laboratory 
assessments will be performed every 4 weeks (see the schedules of activities in 
Appendix 1 and Appendix 2).
4.5.6.2
Pharmacokinetic Assessments
PK sampling will be performed in all patients throughout the 20-week treatment period
(dose titration and evaluation periods).  Serum concentrations of Mircera will be used to 
evaluate the pharmacokinetics and the concentration-effect relationships in all patients.  
The timing of all PK and hematology samples needed for this study will coincide as 
much as possible with regularly scheduled visits.
Samples taken at the following timepoints will be sent to one or several bioanalytical
laboratories for analysis:

Week 1 (Visit 3) before the first Mircera dose administration

Week 3 (Visit 4)

Week 9 (Visit 6) before the Mircera dose administration


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
Week 17 (Visit 8) before the Mircera dose administration

Week 19 (Visit 9)

At the patient’s convenience, one additional sample between 24 hours and 5 days 
after any one Mircera dose administration should be collected.
A minimum of one PK sample after treatment initiation is requested in patients younger 
than 2 years old; the sample on Week 1 can be omitted in these patients.
The exact time of PK blood sampling must be recorded on the lab requisition form and 
the exact time of the preceding Mircera administration must be recorded on the 
appropriate page in the eCRF.  
PK samples must be handled according to the procedures described in a separate 
document.
The standard laboratory parameters should be measured locally at the study site. PK 
and antibody samples will be shipped to one or several bioanalytical laboratories for 
measurement.  
4.5.7
Patient-Reported, Observer-Reported, and Clinician-Reported 
Outcomes
Patients 4 years or older, along with their parent/guardian and nurse/site staff member, 
will assess pain from the ESA injection and the Mircera injection.  Patients who receive 
an ESA injection during either or both of the screening visits will assess injection pain. 
Assessments of the Mircera injection will occur at Week 1 (Visit 3) and Week 9 (Visit 6).
Patient-Reported Injection Pain
Patients 4 years old or older will be asked to assess their pain from the injection 
5 minutes after the injection takes place. Pain will be rated on a visual analogue scale 
(VAS) consisting of a 10-cm horizontal line ranging from did not hurt at allto as 
painful as it could be,as in Schmitt et al. (2006). Scores out of 10 will be determined by 
measuring the mark on the line. For young children (4 years old and 10 years old),
five cartoon faces ranging from neutralto very distressedwill be added as a guide. 
Children under the age of 4 will not be asked to rate their own pain, as reliability is 
questionable in very young patients.
Parent-Reported Injection Pain
Parents or guardians will be asked to rate observed pain. Pain will be rated on a VAS 
consisting of a 10-cm horizontal line ranging from did not hurt at allto as painful as it 
could be.Scores out of 10 will be determined by measuring the position of the mark on 
the line. As much as possible, the same parent/guardian should rate pain at every visit.


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Nurse-Reported Injection Pain
The nurse or site staff member administering the ESA or Mircera doses will be asked to 
rate observed pain. Pain will be rated on a VAS consisting of a 10-cm horizontal line 
ranging from did not hurt at allto as painful as it could be.Scores out of 10 will be
determined by measuring the position of the mark on the line. As much as possible, the 
same nurse/site staff member will rate each patient across all visits.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Pregnancy

Kidney transplantation

AEAB-mediated PRCA
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
In this study, if a patient discontinues study treatment for the reasons mentioned above,
he or she will be discontinued from the study.  See Section 4.6.2 for additional possible 
reasons for patient discontinuation from study.
4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
Reasons for withdrawal from the study may include, but are not limited to, the following:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.
In case of premature withdrawal, patients will return to the clinic for a follow-up visit (all 
assessments for Visit 10, see Appendix 1 for details).  In case of premature withdrawal 
due to a kidney transplantation, the follow-up visit must take place before the 
transplantation; otherwise, there will be no follow-up visit.


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The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF page.  If a patient requests to be withdrawn from the study, this 
request must be documented in the source documents and signed by the investigator.
Additional patients may be enrolled to replace patients who withdraw early, before the 
Week 17 (Visit 8).
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with Mircera in 
completed and ongoing studies.  The anticipated important safety risks for Mircera are 
outlined below.  Please refer to the Mircera Investigator's Brochure for a complete 
summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.


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5.1.1
Risks Associated with Mircera
5.1.1.1
Hypertension and Hypertensive Encephalopathy
Observational studies and registry data show that more than half of children with CKD 
have high blood pressure based upon a casual blood pressure reading. 
ESA treatment may increase blood pressure in patients with CKD, possibly due to 
effects on the vasoactive hormone axes. The role of blood viscosity remains uncertain. 
During development trials in adults, hypertension was reported as an adverse event in 
23.6% of patients receiving Mircera and 22.6% of patients receiving reference ESAs.
In Study NH19707, around 50% of patients had hypertension reported as a preexisting 
condition at baseline, and 58% of patients were receivingor had previously 
receivedantihypertensive and/or diuretic agents. During the core study, 13% of 
patients required an increase in antihypertensive treatment. Of 8 patients with 
hypertension reported as an adverse event during the core study, all had hypertension 
and/or had received antihypertensive therapy prior to enrollment.
Hypertensive encephalopathy describes a syndrome of neurological dysfunction induced 
by severe hypertension. Less than 1% of patients with hypertension experience a 
hypertensive crisis at any time. During clinical development studies in adults, 
hypertensive encephalopathy was reported in 0.3% of patients receiving Mircera and in 
0.1% of patients receiving reference ESAs. No patients in Study NH19707 experienced 
hypertensive encephalopathy.
Instructions for recording blood pressure values and adverse events of high blood 
pressure and hypertension are provided in Section 5.3.5.6.
5.1.1.2
Anti-Erythropoietin Antibody-Mediated Pure Red Cell Aplasia 
AEAB-mediated PRCA is a very rare adverse effect of ESA treatment, caused by the 
formation of AEABs that neutralize endogenous EPO. The condition is characterized by 
severe, progressive, refractory anemia, low reticulocyte count, and absent erythroid 
precursor cells in bone marrow. Patients typically develop ESA resistance following 
initial response to treatment, and become transfusion-dependent. No cases of 
AEAB-mediated PRCA have been observed in patients receiving Mircera during clinical 
trials. Cumulatively to 19 July 2016, there have been 8 cases of confirmed 
AEAB-mediated PRCA following exclusive use of Mircera in the postmarketing setting, 
all involving adult patients with CKD. Total cumulative exposure to Mircera is currently 
more than 1.5 million patient-years.
Detailed information on recognition and diagnosis of AEAB-mediated PRCA is provided 
in Appendix 4.


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5.1.1.3
Low Platelet Count
During development trials in adults, platelet values below 100109/L were observed in 
9.7% of patients treated with Mircera versus 6.7% of patients treated with reference 
ESAs. The incidence of thrombocytopenia reported as an adverse event was similar in 
both groups (approximately 0.22% vs. 0.32%, respectively).
In Study NH19707, platelet count at baseline ranged from 80518109/L. Median
platelet count decreased slightly during the core study period in both dose groups. No 
events of bleeding were reported in any patients in association with low platelet counts. 
Thrombocytopenia was reported as an adverse event in 2 patients, in both cases 
classified as mild.
Instructions for recording platelet count values and adverse events of low platelet count 
and thrombocytopenia are provided in Section 5.3.5.
5.1.1.4
Vascular Access Thrombosis
Vascular access thrombosis (VAT) is a frequent and potentially serious problem in HD
patients.  Arteriovenous grafts are at greater risk of VAT than fistulas.  Other possible 
risk factors include high hematocrit, hypercoagulability, and decreased blood flow 
(e.g., due to low cardiac output, hypovolemia, hypotension, or compression).  During 
development trials, events suggestive of VAT were reported in 13.2% of patients 
receiving Mircera and 11.6% of patients receiving reference ESAs.  In Study NH19707 
involving pediatric patients on HD, during the core period, 4 patients reported 5 events 
of VAT.
5.1.1.5
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
There has been only one case of Stevens-Johnson Syndrome (SJS)/toxic epidermal 
necrolysis (TEN) in which available information was suggestive of a possible causal role 
of Mircera, based primarily on temporal course and reappearance of typical symptoms 
after re-challenge. No cases suggestive of SJS/TEN or other severe cutaneous adverse 
reactions caused by Mircera were observed during clinical trials.
5.1.2
Management of Patients Who Experience Adverse Events
5.1.2.1
Anti-Erythropoietin Antibody-Mediated Pure Red Cell Aplasia 
ESAs should be discontinued in any patient with confirmed AEAB-mediated PRCA. The 
physician should investigate for the presence of anti-EPO and anti-Mircera antibodies 
and perform a bone marrow examination. An additional blood sample should also be 
stored for an anti-PEG antibody determination after the assay has been developed.
Patients must not be switched to another recombinant ESA because of the risk of 
cross-reactivity of antibodies with endogenous and all recombinant ESAs 
(see Appendix 4 for further detailed information on recognition and management of 
AEAB-mediated PRCA).


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.8 and 
Section 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., invasive procedures such as 
blood sampling, discontinuation of medications)
Kidney transplantation and routine diagnostic procedures/tests are not considered 
adverse events and should therefore not be recorded on an Adverse Event eCRF page.
The start of dialysis or the change in dialysis modality should not be considered an 
adverse event and should be recorded on a specific eCRF page (see Section 5.3.5.11).


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5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life-threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" (Section 5.3.3) and "serious" are not synonymous.  Severity refers to 
the intensity of an adverse event (e.g., rated as mild, moderate, or severe); the event 
itself may be of relatively minor medical significance (such as severe headache without 
any further findings).  Seriousness is a regulatory criterion for adverse event reporting.  It 
should be considered in determining whether a case needs to be reported as a serious  
adverse event or not (e.g., a headache may be severe in terms of interfering  
significantly with a patient’s usual function but would not be classified as serious, unless 
it met one of the criteria for seriousness described above).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the Adverse Event eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
As an exception, the following serious adverse events, which are common in the dialysis 
population, will not be reported in an expedited manner if unrelated to study drug, but will 
be recorded as serious adverse events on the Adverse Event pages of the eCRF:

Thrombosis of vascular access for HD

Peritonitis due to PD


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6. The 
investigator is also responsible for reporting medical device complaints (see
Section 5.4.5).
For each adverse event recorded on the Adverse Event page of the eCRF, the 
investigator will make an assessment of seriousness (see Section 5.2.2 for seriousness 
criteria), severity (see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as blood sampling, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The World Health Organization (WHO) toxicity grading scale (see Appendix 7) will be 
used for assessing adverse event severity.  Table 4 will be used for assessing severity 
for adverse events that are not specifically listed or are not appropriate (e.g., due to the 
disease under study or age of the patient) in the WHO toxicity grading scale.
Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale
Grade
Severity
1
Mild; transient or mild discomfort (48 hours); no medical intervention 
or therapy required
2
Moderate; mild to moderate limitation in activity; some assistance may 
be needed; no or minimal medical intervention or therapy required
3
Severe; marked limitation in activity; some assistance usually 
required; medical intervention or therapy required; hospitalization 
possible
4
Life-threatening; extreme limitation in activity; significant assistance 
required; significant medical intervention or therapy required, 
hospitalization or hospice care probable
Notes:  Developed by the Division of Microbiology and Infectious Diseases.
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition 
of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study


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
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event
Table 5
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Injection Reactions
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of injection reaction).
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than injection reactions (see Section 5.3.5.1), a diagnosis (if 
known) should be recorded on the Adverse Event eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases).  However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome at the time of reporting, 
each individual event should be recorded on the Adverse Event eCRF.  If a diagnosis is 
subsequently established, all previously reported adverse events based on signs and 
symptoms should be nullified and replaced by one adverse event report based on the 


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single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 upper limit of normal [ULN] associated with 
cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the Adverse 
Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of CKD.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").


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If the death is attributed to progression of CKD, the term "chronic kidney disease" should 
be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Loss of Effect
Hb values will be monitored regularly throughout the study, and dose adjustments to 
achieve target Hb will be made according to protocol guidance (see Section 4.3.2.1.1).
Loss of effect is defined as follows: a decline in Hb of at least 2.8 g/dL in a 4-week 
period without transfusion or requirement for transfusion of 1 blood unit or more per 
week for a minimum of 2 consecutive weeks in the absence of overt bleeding or blood 
loss, under uninterrupted treatment with study drug and with dose changes according to 
protocol guidance (Eckardt and Casadevall 2003). If loss of effect is suspected, the 
cause should be actively sought. Possible causes include the following: iron deficiency, 
infection, inflammation, occult blood loss, hyperparathyroidism, myelofibrosis, and 
malignancy. If a cause for loss of effect is not found, a hematologist should be consulted 
(possible bone marrow examination), and an unscheduled blood sample should be 
obtained for a reticulocyte count and an anti-EPO and anti-Mircera antibody
determination. An additional blood sample should also be stored for an anti-PEG 
antibody determination after the assay has been developed.
If a diagnosis of PRCA is not confirmed, the patient should be maintained on the IMP,
and other possible causes of loss of effect should be investigated. 
If a diagnosis of PRCA is confirmed, treatment with the IMP should be stopped. The 
patient should not receive another epoetin, and causes of PRCA should be investigated. 
Reticulocyte counts and anti-EPO, anti-Mircera, and anti-PEG antibody testing will be 
performed every 8 weeks until the end of the study (see Appendix 4 for further, detailed 
guidance).  


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5.3.5.11
Progression of Kidney Disease
Events that are clearly consistent with the expected pattern of progression of the 
patient’s underlying kidney disease should not be recorded as adverse events.  Kidney 
transplantation should not be recorded as an adverse event.  Start of dialysis or change 
of dialysis modality should not be considered an adverse event and should be reported 
on the dialysis eCRF. If the worsening of kidney function is faster than expected, the 
worsening of kidney function may be recorded as an adverse event term. Every effort 
should be made to document progression through use of objective criteria.  If there is 
any uncertainty as to whether an event is due to disease progression, it should be 
reported as an adverse event.
5.3.5.12
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.13
Patient-Reported or Observer-Reported Outcome Data
Adverse event reports will not be derived from patient-reported outcome (PRO) or 
observer-reported outcome (ObsRO) data by the Sponsor, and safety analyses will not 
be performed using PRO or ObsRO data. Sites are not expected to review the PRO or 
ObsRO data for adverse events.


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5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (as defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)

Medical device complaints (see Section 5.4.5 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board or Ethics Committee 
(IRB/EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, Ph.D. (Primary)
Telephone No.:
Medical Monitor/Roche Medical Responsible:
, M.D. (Secondary)
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 


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7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse events of special interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event Reporting Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 28 days after the final dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 90 days after the final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 


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pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal 
or embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug should be classified as a serious adverse event, recorded on the Adverse Event 
eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.4.4
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.


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Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For Mircera, 
adverse events associated with special situations should be recorded as described 
below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with Mircera, regardless of whether they 
result in an adverse event, should be recorded on the Adverse Event eCRF as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.4.5
Reporting Requirements for Medical Device Complaints
In this study, the single-use, prefilled syringe is considered a medical device.  The 
investigator must report all medical device complaints to the Sponsor.  The investigator 
should document as much information as possible on the IMP Deviation Form, including 
the product batch number, and forward the form to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event) (refer to the pharmacy manual for further 
details).  If the medical device results in an adverse event to the study patient, the event 


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must be reported on the Adverse Event eCRF and submitted through the EDC system.  
If the event is serious, the Adverse Event eCRF must be completed immediately (i.e., no 
more than 24 hours after learning of the event), as outlined in Section 5.4.2.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the final dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.


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To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Mircera Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and, if unrelated to study drug, will be 
excluded from expedited reporting.  These anticipated events include, but are not limited 
to, the following:

Peritonitis due to PD

Thrombosis of vascular access for HD patients
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
6.1
DETERMINATION OF SAMPLE SIZE
This is an exploratory study without a powered statistical group comparison.  Therefore,
no formal sample size estimation will be performed; however, the calculations below 
indicate the approximate precision that could be achieved. 
Assuming a 30% withdrawal rate (based on the withdrawal rate for the NH19707 study),
of the 40 patients evaluable for ITT and safety analysis, more than 26 patients will have 
data for the evaluation period.  Twenty-six patients will be sufficient to provide 
approximately 90% power that the 90% CI for the Hb change from baseline to the 
evaluation period is between 1 and 1 g/dL, provided the standard deviation is smaller 
than 1.5 and the optimum dose conversion is able to maintain the Hb at the baseline 
level.
Approximately 1015 of the patients will be 12 years old, with the objective to include 
as many patients 5 years old (minimum 3 patients) as possible.  Approximately 
1015 patients, irrespective of their age, will not be on dialysis.  Available HD patients 
receiving their ESA subcutaneously are eligible for enrollment.  No more than 
10 patients on HD should be enrolled.
To achieve the recruitment of the intended number of patients and in case of excessive 
dropout rate, additional patients may be enrolled to replace patients not treated for a 
minimum duration of 18 weeks.


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6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the core study and the 
safety extension period will be summarized.  Reasons for premature study withdrawal 
will be listed and summarized.  Enrollment and major protocol deviations will be listed 
and evaluated for their potential effects on the interpretation of study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, height, weight, laboratory 
parameters, and previous ESA therapy) will be summarized using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate.  Summaries will be presented overall, by age group, by 
dialysis type (on PD, HD or not yet on dialysis), and previous ESA therapy (EPO alfa 
and beta combined vs. darbepoetin alfa).
6.4
EFFICACY ANALYSES
All efficacy variables (original values and change from baseline) over time will be 
presented in summary tables and graphically. The estimates will be summarized 
descriptively using means, standard deviations, and percentiles.
The analysis population for the primary and secondary efficacy analyses will be the ITT 
population consisting of all enrolled patients.
An additional analysis will be performed based on the per-protocol population, which will 
be precisely defined in the statistical analysis plan, before database closure, as the 
subset of the ITT population without major protocol deviations.
6.4.1
Primary Efficacy Endpoint
The primary endpoint will be the change in Hb concentration (g/dL) between the baseline 
and the evaluation period for each patient. 
This is calculated on a per-patient basis, using an area under the curve approach to 
calculate an individual’s average for both the baseline and evaluation periods and taking 
the difference. 
The baseline period is defined as all assessments between the day of first study dose 
and the previous 35 days. If during the baseline period Hb measurements H0,…,Hn are 
taken at timepoints t0,…,tn, a time adjusted average baseline Hb value will be calculated
by 



1
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






i
i
i
i
i
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t
t
H
H
t
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y


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The value on the day of the first dose is included in the baseline calculation, as this 
assessment will be performed before the first dose is given. 
The average Hb value for each individual during the evaluation period will be calculated 
using the same method as for the baseline period. The evaluation period is defined as 
all assessments between Visit 8 (Week 17) and Visit 10 (Week 21) inclusive.  
Subtracting the baseline period value from the evaluation period value gives the change 
in Hb concentration (g/dL) between the baseline and evaluation period.
For patients with no recorded Hb during the evaluation period, the primary endpoint will 
be missing. Values missing in between non-missing assessments will not be replaced,
as these will be interpolated by the trapezoidal rule. To correct for any increase in Hb 
caused by RBC transfusions, the Hb values measured within 3 weeks after an RBC 
transfusion will be deleted.
The individual change from baseline will be reported using summary statistics (including 
mean, standard deviation, and 90% CI of mean change). No formal statistical testing will 
be performed. Additional analysis will be performed by age category (5, 511, 
12 years), dialysis type (not yet on dialysis, PD, HD) and previous ESA (epoetin alfa, 
epoetin beta, and darbepoetin alfa), if numbers allow.
6.4.2
Secondary Efficacy Endpoints
The number of patients with an average Hb concentration during the evaluation period 
within 1 g/dL of their baseline Hb or above, within, or below the range of 1012 g/dL 
will be summarized.
The change in Mircera dose over time, including the change between the starting dose
and the evaluation period, will be analyzed descriptively.
6.4.3
Exploratory Analyses
The patient if 4 years or older, the parent/guardian, and the nurse/site staff member who 
gives the injection will assess injection pain using a VAS scale 5 minutes following ESA 
administration, as appropriate. The assessments will take place during the screening 
period for all patients who received an ESA injection during either or both of the visits, 
and at Week 1 (Visit 3) and Week 9 (Visit 6). Injection pain data will be plotted by visit 
for each patient and analyzed in an exploratory manner.
6.5
SAFETY ANALYSES
Safety data for the whole study including the safety extension period will be presented. 
The safety analysis population will consist of all patients who received at least one dose 
of study drug regardless of whether they withdrew prematurely or not. 
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to a four-point scale (see Section 5.3.3).


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Tables with group summary statistics will be provided for all safety parameters (vital 
signs, adverse events, and safety laboratory parameters). Vital signs and safety 
laboratory parameters will be assessed for clinically significant abnormalities as well as 
shifts from baseline. For safety analyses, baseline is defined as the last value before 
first study medication.
Most safety endpoints will include data from the whole study period, including the 
optional safety extension period. Selected outputs may be prepared for the core and 
extension periods separately.
6.6
PHARMACOKINETIC ANALYSES
Mircera serum concentration-time data will be described using non-linear mixed effect 
modeling.  The previously developed model was a one-compartment model with first 
order absorption and elimination processes.  It will be updated with Study NH19708 data. 
The influence of covariates (e.g., age, body weight) on PK parameters will be studied.
PK analysis will be performed in two steps:

The existing PK model will be challenged against Study NH19708 data to check its 
predictive performance and to highlight any deviation from the current knowledge of 
Mircera pharmacokinetics.  The results of the interim PK analysis will guide the
change in bioavailability in pediatric versus adult patients. 

The PK model will be updated by pooling Study NH19708 data with historical adult 
and pediatric PK data; estimation of the bioavailability of the SC formulation in 
pediatric patients will be performed.
6.7
PHARMACODYNAMIC ANALYSIS
Hb concentration-time data will be described, using non-linear mixed effect modeling. 
The previously developed PK/PD model was a life-span type of longitudinal model
(Chanu et al. 2010). It will be updated with Study NH19708 data.  The influence of 
covariates (e.g., previous ESA dose) on pharmacodynamic parameters will be studied.
Pharmacodynamic analysis will be performed in two steps:

The existing pharmacodynamic model will be challenged against Study NH19708 
data to check its predictive performance and to highlight any deviation from the 
current knowledge of Mircera PD properties. 

The PK/PD model will be updated by pooling Study NH19708 data with historical 
adult and pediatric pharmacodynamic data. Sensitivity analysis will be performed by 
re-estimating the PK/PD model parameters on pediatric data only.
6.8
IMMUNOGENICITY ANALYSES
Anti-EPO and anti-Mircera antibodies will be measured at baseline, at Week 9 (Visit 6),
and at end of study. An additional sample will be collected at Week 45 (Visit 16) for the 
patients participating in the safety extension period.  Any non-negative findings will be 
documented. 


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6.9
PLANNED INTERIM ANALYSIS
Once 12 patients have completed 20 weeks of treatment, an interim analysis to assess 
efficacy, safety, and pharmacokinetics will be performed.  The analysis will be reviewed 
by a Roche Internal Monitoring Committee (IMC) with the primary objective of assessing 
the safety and efficacy of the CFs for starting treatment with SC Mircera.  This will be 
assessed using Hb (the pharmacodynamic marker), changes in dose, and assessment 
of the PK data to compare to the available pediatric PK data under IV dosing.  The 
variability of Hb will also be assessed at this time, with regard to protocol assumptions, 
and the sample size will be revised if necessary.
An individual’s Hb response will be based on the mean Hb during the evaluation period 
(Weeks 1721) and is defined as a mean Hb change from baseline within 1g/dL.  The 
90% CI for the average Hb change from baseline will be calculated. 
Interim PK and PK/PD analyses will be conducted, as follows:

External validation of the existing PK and PK/PD models against preliminary 
Study NH19708 data to highlight any deviation from the current knowledge of 
Mircera PK and pharmacodynamic properties; the bioavailability in pediatric patients 
will be carefully regarded. 

A Bayesian feedback approach will also be used on Mircera serum 
concentration-time data to get a first assessment of the individual PK parameters in 
pediatric patients receiving Mircera subcutaneously, especially bioavailability.
The full details of the interim analysis and any decision criteria will be specified in 
separate IMC documents. 
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.


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PRO and ClinRO data will be collected on paper questionnaires.  The data from the 
questionnaires will be entered into the EDC system by site staff. 
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments 
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/ EC review.  The study site must also 
allow inspection by applicable health authorities.


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7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms and child assent forms (if applicable), laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.


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8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form if applicable) will be provided to each 
site.  If applicable, it will be provided in a certified translation of the local language.  The 
Sponsor or its designee must review and approve any proposed deviations from the 
Sponsor's sample Informed Consent Forms or any alternate consent forms proposed by 
the site (collectively, the "Consent Forms") before IRB/EC submission.  The final 
IRB/ECapproved Consent Forms must be provided to the Sponsor for health authority 
submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 


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health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).


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Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 35 sites globally will participate to enroll approximately 40 patients.  
Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.


Mircera—F. Hoffmann-La Roche Ltd
68/Protocol NH19708, Version 4
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Mircera—F. Hoffmann-La Roche Ltd
69/Protocol NH19708, Version 4
10.
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Brandt JR, Avner ED, Hickman RO, et al. Safety and efficacy of erythropoietin in children 
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Burke JR. Low-dose subcutaneous recombinant erythropoietin in children with chronic 
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Cano F, Alarcon C, Azocar M, et al. Continuous EPO receptor activator therapy of 
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patients. J Lab Clin Med 1979;93:44958.
Chanu P, Gieschke R, Charoin JE, et al. Population pharmacokinetic/pharmacodynamic 
model for C.E.R.A. in both ESA-naïve and ESA-treated CKD patients with renal 
anemia. J Clin Pharmacol 2010;50:50720.
Chavers BM, Herzog CA. The spectrum of cardiovascular disease in children with 
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Legistlation-EudraLex Volume 10 Clinical trials guidelines [resource on the 
Internet]. 2008 [cited 14 April 2018]. Available 
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10/ethical_considerations_en.pdf.
Eckardt KU, Casadevall N. Pure red-cell aplasia due to anti-erythropoietin antibodies. 
Nephrol Dial Transplant 2003;18:8659.
Fischbach M, Wühl E, Meyer Reigner SC, et al. Efficacy and long-term safety of 
C.E.R.A. maintenance in pediatric hemodialysis patients with anemia of CKD. 
Clin J Am Soc Nephrol 2018;13:8190.
Gagnadoux MF, Loirat C, Berthélémé JP, et al. Treatment of anemia in hemodialyzed 
children using recombinant human erythropoietin (Eprex). Results of a French 
multicenter clinical trial. Nephrologie 1994;15:20711.
Geary DF, Keating LE, Vigneux A, et al. Darbepoetin alfa (AranespTM) in children with 
chronic renal failure.  Kidney Int 2005;68:175965.
Gerson A, Hwang W, Fiorenza J, et al. Anemia and healthrelated quality of life in 
adolescents with chronic kidney disease. Am J Kidney Dis 2004;44:101723.


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Greenbaum LA, Pan CG, Caley C, et al. Intravenous iron dextran and erythropoietin use 
in pediatric hemodialysis patients. Pediatr Nephrol 2000;14:90811.
Jarsch M, Brandt M, Lanzendörfer M, et al. Comparative erythropoietin receptor binding 
kinetics of C.E.R.A. and epoetin-beta determined by surface plasmon resonance
and competition binding assay. Pharmacology 2008;81:639.
[KDIGO] Kidney Disease: Improving Global Outcomes Anemia Work Group. KDIGO 
clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl 
2012;2:279335.
Klang B, Bjorvell H, Clyne N. Quality of life in predialytic uremic patients. Qual Life Res 
1996;5:10916.
Koshy SM, Geary DF. Anemia in children with chronic kidney disease. Pediatr Nephrol 
2008;23:20919.
Locatelli F, Aljama P, Barany P, et al. European Best Practice Guidelines Working 
Group. Revised European best practice guidelines for the management of 
anaemia in patients with chronic renal failure. Nephrol Dial Transplant 
2004;19(Suppl 2):ii147.
Locatelli F, Reigner B. C.E.R.A.: pharmacodynamics, pharmacokinetics and efficacy in 
patients with chronic kidney disease. Expert Opin Investig Drugs 2007;16:164961.
Ma JZ, Ebben J, Xia H, et al. Hematocrit level and associated mortality in hemodialysis 
patients. J Am Soc Nephrol 1999;10:61019.
McClellan W, Aronoff SL, Bolton WK, et al. The prevalence of anemia in patients with 
chronic kidney disease. Curr Med Res Opin 2004;20:150110.
MIRCERA(methoxy polyethylene glycol-epoetin beta) Prescribing Information, F. 
Hoffmann-La Roche Ltd.  2007 [updated April 2016; cited 29 June 2017]. Available 
from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125164s070lbl.pdf.
MIRCERA(methoxy polyethylene glycol-epoetin beta) Summary of Product 
Characteristics, F. Hoffmann-La Roche Ltd. 20 July 2007 [updated September 
2016; cited 29 June 2017]. Available from:  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000739/WC500033672.pdf.
Mitsnefes MM, Daniels SR, Schwartz SM, et al. Severe left ventricular hypertrophy in 
pediatric dialysis: prevalence and predictors. Pediatr Nephrol 2000;14:898902.
Morgan HE, Gautam M, Geary DF. Maintenance intravenous iron therapy in pediatric 
hemodialysis patients. Pediatr Nephrol 2001;16:77983.


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[KDOQI] National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical 
Practice Recommendations for 2006 Updates: Hemodialysis Adequacy, Peritoneal 
Dialysis Adequacy and Vascular Access. Am J Kidney Dis 48;(Guideline 6):S1-
S322, 2006 (suppl 1).
[NAPRTCS] North American Pediatric Renal Transplant Cooperative Study. 2014
Annual Report [resource on the Internet; cited 10 July 2017]. Available from:  
https://web.emmes.com/study/ped/annlrept/annualrept2014.pdf 
Pattaragarn A, Warady BA, Sabath RJ. Exercise capacity in pediatric patients with 
endstage renal disease. Perit Dial Int 2004;24:27480.
Pickett JL, Theberge DC, Brown WS, et al. Normalizing hematocrit in dialysis patients 
improves brain function. Am J Kidney Dis 1999;33:112230.
Schaefer F, Hoppe B, Jungraithmayr T, et al. Safety and usage of darbepoetin alfa in 
children with chronic kidney disease: prospective registry study. Pediatr Nephrol 
2016;31:44353.
Schmitt CP, Nau B, Brummer C, et al. Increased injection pain with darbepoetin-alpha 
compared to epoetin-beta in paediatric dialysis patients. Nephrol Dial Transplant 
2006;21:35204. 
Seeherunvong W, Rubio L, Abitbol CL, et al. Identification of poor responders to 
erythropoietin among children undergoing hemodialysis. J Pediatr 2001;138:7104.
Sieniawska M, Roszkowska-Blaim M. Recombinant human erythropoietin dosage in 
children undergoing hemodialysis and continuous ambulatory peritoneal dialysis. 
Pediatr Nephrol 1997;11:62830.
Sietsema KE, Hiatt WR, Esler A, et al. Clinical and demographic predictors of exercise 
capacity in end-stage renal disease. Am J Kidney Dis 2002;39:7685.
[USRDS] United States Renal Data System. 2016 Annual Data Report, Chapter 8: 
ESRD among children, adolescents, and young adults [resource on the Internet; 
cited 10 July 2017]. Available from:  https://www.usrds.org/2016/view/v2_08.aspx
Van Damme-Lombaerts R, Broyer M, Businger J, et al. A study of recombinant human 
erythropoietin in the treatment of anaemia of chronic renal failure in children on 
haemodialysis. Pediatr Nephrol 1994;8:33842.
Warady BA, Arar MY, Lerner G, et al. Darbepoetin alfa for the treatment of anemia in 
pediatric patients with chronic kidney disease. Pediatr Nephrol 2006;21:114452.
Warady BA, Barcia JP, Benador NM, et al. QW or Q2W Darbepoetin Alfa in Pediatric 
Subjects with Chronic Kidney Disease J Am Soc Nephrol 2015;26 (abstract 
edition):238A.
Warady BA, Ho M. Morbidity and mortality in children with anemia at initiation of dialysis. 
Pediatr Nephrol 2003;18:105562.


Mircera—F. Hoffmann-La Roche Ltd
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Wedekin M, Ehrich JH, Pape L. Effective treatment of anemia in pediatric kidney 
transplant recipients with methoxy polyethylene glycol-epoetin beta. Pediatr 
Transplant 2011;15:32933.
Xia H, Ebben J, Ma JZ, et al. Hematocrit levels and hospitalization risks in hemodialysis 
patients. J Am Soc Nephrol 1999;10:130916.


Mircera—F. Hoffmann-La Roche Ltd
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Appendix 1
Schedule of Activities Core Period (Week 3 to Week 21)
Study Period
Screening Period
~ 3 weeks a
Dose Titration Period
16 weeks
Evaluation Period
4 weeks
Visit Number
1
2
3
4
5
6
7
8
9
10
Name of the Visit Day 
(start of Week ...) b Week 3 a Week 1 a Week 1 c
Week 3
Week 5
Week 9
Week 13
Week 17
Week 19
Week 21
Follow-Up Visit d
Informed consent
x
Medical history e
x
Physical examination f
x
x
Pregnancy test g
x
Vital signs, weight h
x
x
x
x
x
x
x
x
Height 
x
x
Hematology i
x
x
x
x
x
x
x
x
x
x
Serum creatinine j
x
x
x
Iron parameters k
x
x
x
x
x
Kt/V for patients on PD
x
x
Kt/V or URR for 
patients on HD
x
x
x
x
x
x
x
Safety laboratory l
x
x
x
Anti-EPO and 
anti-Mircera antibody m
x
x
x
Injection pain 
questionnaire n
(x) o
(x) o
x
x
Concomitant therapy p
Recorded throughout screening, dose titration and evaluation periods


Appendix 1
Schedule of Activities Core Period (Week 3 to Week 21) (cont.)
Mircera—F. Hoffmann-La Roche Ltd
74/Protocol NH19708, Version 4
Study Period
Screening Period
~ 3 weeks a
Dose Titration Period
16 weeks
Evaluation Period
4 weeks
Visit Number
1
2
3
4
5
6
7
8
9
10
Name of the Visit Day 
(start of Week ...) b Week 3 a Week 1 a Week 1 c
Week 3
Week 5
Week 9
Week 13
Week 17
Week 19
Week 21
Follow-Up Visit d
Adverse events q
Recorded throughout the dose titration and evaluation periods
ESA administration
x r
Mircera administration
x c
x c
x c
x c
x c
Iron supplementation
As needed to maintain iron stores
PK sampling s
x
x
x
x
x
CKDchronic kidney disease; eCRFelectronic Case Report Form; eGFRestimated glomerular filtration rate; EPO erythropoietin; 
ESAerythropoietin-stimulating agent; Hbhemoglobin; HDhemodialysis; PDperitoneal dialysis; PKpharmacokinetic; TSAT transferrin 
saturation; URRurea reduction ratio.
a Visits 1 and 2 should be 2 weeks apart (3 days). The ESA dosing interval needs to be taken into account when planning Visits 1, 2, and 3, 
i.e., the number of days between Visits 2 and 3 should be based on the dosing interval of the ESA drug, which may result in a screening 
period of up to a maximum of 4 weeks.
b Visit window 3 days.  All study visits should be scheduled based on the date of the first Mircera dose at Visit 3 (Week 1). For patients under 
HD or patients converting to HD, the study visits should occur on the day of the mid-week dialysis.
c Mircera is administered every 4 weeks during dose titration and evaluation periods.
d Follow-up visit assessments should be performed before resuming epoetin alfa, epoetin beta, or darbepoetin alfa dose.  
e Medical history includes demographics, other diseases, etiology of CKD, details of dialysis, previous treatments including ESA treatments, and 
iron supplementation.
f
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems.  Any abnormality identified should be recorded on the corresponding page of the eCRF.
g Serum pregnancy test should be performed in post-pubertal female patients of childbearing potential. If a pregnancy is suspected, the serum 
pregnancy test must be repeated during the course of the study.


Appendix 1
Schedule of Activities Core Period (Week 3 to Week 21) (cont.)
Mircera—F. Hoffmann-La Roche Ltd
75/Protocol NH19708, Version 4
h Systolic and diastolic blood pressure and pulse rate will be recorded while the patient is if possible in a seated position, and they will be 
measured before blood sampling. The blood pressure should be measured at least twice and the average of these measurements should be 
recorded.  An appropriate-sized cuff should be used.  Blood pressure should be determined before and after the dialysis session for patients with 
HD.  Body weight will also be recorded (after dialysis for patients on HD).
i
Includes Hb, RBC, and absolute reticulocyte count.  Samples should always be obtained on the same day of the week, if possible, prior to 
injection of Mircera and, for patients on HD, before dialysis.  
j
Serum creatinine should be measured only for patients not on dialysis.  eGFR will be calculated using the Bedside Schwartz formula 
(see Appendix 3).
k Includes serum ferritin, serum iron and TSAT. TSAT will be calculated as described in Appendix 3 with either serum transferrin or total iron-
binding capacity.  The percentage of hypochromic red blood cells may be determined instead of TSAT.
l
Includes leukocytes plus differential, AST, ALT, serum albumin, ALP, C-reactive protein, potassium, phosphorus, calcium, and platelets.
m Anti-EPO and anti-Mircera antibody samples should be collected prior to study drug administration.
n Injection pain will be assessed by the patient, parent/guardian, and nurse/site staff member as appropriate.  Children under the age of 4 will not 
be asked to rate their own pain.  As much as possible, the same nurse/site staff member should rate pain at every visit.  The assessments will 
take place approximately 5 minutes after study drug injection.  Assessment of ESA injection pain during the screening period will be assessed in 
all patients who receive an ESA injection during either or both of the screening visits.
o Parentheses indicate that the assessment is optional.  The assessment at the screening visit is only necessary if ESA drug has been injected on 
that day.  Therefore, not all patients will assess injection pain.
p All concomitant therapy administered within 3 months before screening or during the screening or treatment periods should be reported.
q Prior to initiation of study drug, report only serious adverse events caused by a protocol-mandated intervention.
r
Treatment with ESAs should continue during the screening period at the previous dosing interval.  Note that depending on the dosing 
interval, ESA treatment may or may not be administered the same day as the screening period visit.
s At Visit 3 (Week 1), Visit 6 (Week 9), and Visit 8 (Week 17), samples should be drawn before the Mircera dose.  At the patient’s convenience, a 
sixth PK sample between 24 hours and 5 days after any one Mircera dose administration should also be collected. A minimum of one PK 
sample after treatment initiation is requested in patients younger than 2 years old; the sample on Week 1 can be omitted in these patients.  The 
exact time of PK blood sampling must be recorded on the lab requisition form and the exact time of the preceding Mircera administration must be 
recorded on the appropriate page in the eCRF. 


Mircera—F. Hoffmann-La Roche Ltd
76/Protocol NH19708, Version 4
Appendix 2
Schedule of Activities for Optional Safety Extension Period (Week 21 to Week 45)
Study Period
Safety Extension Period
24 Weeks
Visit Number
10
11
12
13
14
15
16
Name of the Visit Day 
(start of Week ...) a
Week 21 b
Week 25
Week 29
Week 33
Week 37
Week 41
Week 45
Final Safety Extension
Visit c
Informed consent
x
Physical examination d
x
x
Vital signs, weight e
x
x
x
x
x
x
x
Height
x
x
Hematology f
x
x
x
x
x
x
x
Serum creatinine g
x
x
Iron parameters h
x
x
x
x
Kt/V for patients on PD
x
x
Kt/V or URR for patients on HD
x
x
x
x
x
x
x
Safety laboratory i
x
x
x
Anti-EPO and anti-Mircera 
antibody j
x
x
Concomitant therapy
Recorded throughout the safety extension period
Adverse events
Recorded throughout the safety extension period
Mircera administration
x
x
x
x
x
x
Iron supplementation
As needed to maintain adequate iron stores


Appendix 2
Schedule of Activities for Optional Safety Extension Period (Week 21 to Week 45) (Cont.)
Mircera—F. Hoffmann-La Roche Ltd
77/Protocol NH19708, Version 4
eCRFelectronic Case Report Form; EPO erythropoietin; HDhemodialysis; PD peritoneal dialysis; URRurea reduction ratio.
a Visit window 3 days.
b Visit 10, Week 21 corresponds to the follow-up visit of the core study period (see Appendix 1).
c Final assessments should be performed before resuming epoetin alfa, epoetin beta, or darbepoetin alfa dose.
d Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems. Any abnormality identified should be recorded on the corresponding page 
of the eCRF.
e Every 4 weeks, systolic and diastolic blood pressure and pulse rate will be recorded while the patient is if possible in a seated 
position, and they will be measured before blood sampling.  The blood pressure should be measured at least twice and the 
average of these measurements should be recorded. An appropriate-sized cuff should be used.  Blood pressure should be 
determined before and after the dialysis session for patients on HD.  Body weight will also be recorded (after dialysis for patients
on HD).
f
Includes Hb, RBC, and absolute reticulocyte count.  Samples should always be taken on the same day of the week, if possible,
prior to the injection of Mircera and, for patients on HD, before dialysis.  
g Serum creatinine should be measured only for patients not on dialysis.  eGFR will be calculated using the Bedside Schwartz 
formula (see Appendix 3).
h Includes serum ferritin, serum iron and TSAT.  TSAT will be calculated as described in Appendix 3 with either serum transferrin or 
total iron-binding capacity.  The percentage of hypochromic red blood cells may be determined instead of TSAT.
i
Includes leukocytes plus differential, AST, ALT, serum albumin, ALP, C-reactive protein, potassium, phosphorus, calcium, and 
platelets. 
j
Anti-EPO and anti-Mircera antibody samples should be collected prior to study drug administration.


Mircera—F. Hoffmann-La Roche Ltd
78/Protocol NH19708, Version 4
Appendix 3
Formula Guidelines for Calculation of Dialysis Adequacy,
Transferrin Saturation, and eGFR
HEMODIALYSIS AND PERITONEAL DIALYSIS ADEQUACY
For assessing adequacy of hemodialysis and peritoneal dialysis, Kt/V or urea reduction 
ratio should be determined according to routine procedures established at each center.
TRANSFERRIN SATURATION
Transferrin saturation (TSAT) should be calculated using one of the following formulas1:
The conversion factors for iron and transferrin from SI units to conventional units are as 
follows:
Iron:
Transferrin:
ESTIMATED GLOMERULAR FILTRATION RATE CALCULATION
Estimated glomerular filtration rate determined by the Bedside Schwartz formula 2
Scr in Conventional Units:
eGFR
0.413 h
Scr
eGFR estimated glomerular filtration rate (mL/min/1.73 
m2); hheight (cm); Scr serum creatinine (mg/dL).
                                           
1 Wick M, Pinggera W, Lehmann P. Iron metabolism, anemias diagnosis and therapy. 4th ed.
Springer-Verlag Wien: New York, 2000:1601.
2 Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with 
CKD. J Am Soc Nephrol 2009;20:629–37.
[mg/dL]
in 
 transferr
Serum
70.9
 x 
[µg/dL]
iron 
Serum
[%]
TSAT

[µg/dL]
capacity 
binding
iron 
Total
100
 x 
[µg/dL]
iron 
Serum
  
[%]
TSAT

μg/dL
μmol/L
5.59
x 




mg/dL
μmol/L
7.96
x 






Appendix 3
Formulae Guidelines for Calculation of Dialysis Adequacy,
Transferrin Saturation, and eGFR (cont.)
Mircera—F. Hoffmann-La Roche Ltd
79/Protocol NH19708, Version 4
Scr in SI Units: 
eGFR
36.2 h
Scr
eGFRestimated glomerular filtration rate (mL/min/1.73 m2); 
hheight (cm); Scr serum creatinine (mol/L).
Measured creatinine should be in steady state. This formula may be most accurate in 
the range of 15 to 75 mL/min per 1.73 m2. 
This formula applies to enzymatic serum creatinine measurements calibrated to 
reference measurements by isotope dilution mass spectroscopy (IDMS), but not to 
alkaline picrate ("Jaffe") methods, even those traceable to IDMS. 


Mircera—F. Hoffmann-La Roche Ltd
80/Protocol NH19708, Version 4
Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents
Educational Program for Mircera
(methoxy polyethylene glycol-epoetin beta)
Physician’s Guide
Diagnosing and reporting of adverse drug reactions associated with 
Mircera
Anti-erythropoietin antibodymediated pure red cell aplasia associated 
with erythropoietin-stimulating agent
Contents
1.
Mirceraand anti-erythropoietin antibodymediated pure red cell aplasia 
(AEAB-mediated PRCA)
2.
What are the objectives of this educational program? 
3.
Loss of effect of ESA treatment
3.1
If an ESA loses its effect after having been effective in a patient, what 
should I do?
3.2
What are the most frequent causes?
4. 
What happens in AEAB-mediated PRCA?
4.1
Findings in blood and bone marrow
4.2
Timing of onset
4.3
Discontinuation of ESAs
5.
Diagnosis of PRCA
5.1
Hemoglobin decrease
5.2
Antibody testing
5.3
Bone marrow examination
6.
Follow-up after PRCA diagnosis
7.
Adverse drug reaction reporting
8.
Questionnaire
9.
How to obtain further information


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
81/Protocol NH19708, Version 4
10. Supporting information
10.1 Need and clinical importance of adverse drug reaction reporting
10.2 Important facts about EAB-mediated PRCA and ESAs
10.3 Testing approaches
10.4 Literature
1.
MIRCERA AND ANTI-ERYTHROPOIETIN ANTIBODYMEDIATED PURE 
RED CELL APLASIA (AEAB-MEDIATED PRCA)
Mircera is an erythropoietin-stimulating agent (ESA).
A very rare side effect of ESAs is anti-erythropoietin antibodymediated pure red cell 
aplasia (AEAB-mediated PRCA).
This side effect is an important identified risk in the E.U. risk management plan for 
Mircera.
2.
WHAT ARE THE OBJECTIVES OF THIS EDUCATIONAL PROGRAM?
The objectives of this booklet and the educational program are as follows:

To increase early awareness and knowledge of AEAB-mediated PRCA associated 
with ESAs

To encourage doctors to report adverse drug reactions to Mircera, especially 
AEAB-mediated PRCA

To improve understanding of the importance of collecting detailed information on 
AEAB-mediated PRCA with use of a questionnaire completed by the physician

To inform about Roche’s offer for free antibody testing after having received a report 
of a suspected case of AEAB-mediated PRCA.  This includes where loss of effect of 
unknown cause is associated with Mircera. 
Full details on the risks of potential PRCA can be found in the following section of 
Mircera Physician’s Prescribing Information (Summary of Product Characteristics): 
“Special warnings and special precautions for use” relating to important facts about 
ESAs, Mircera, and AEAB-mediated PRCA.


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
82/Protocol NH19708, Version 4
3.
LOSS OF EFFECT OF ESA TREATMENT
3.1.IF AN ESA LOSES ITS EFFECT AFTER HAVING BEEN EFFECTIVE IN A 
PATIENT, WHAT SHOULD I DO?
Investigate the main possible causes:

Hemolysis

Malnutrition

Iron deficiency

Aluminum toxicity

Chronic blood loss

Inadequate dialysis

Inflammatory disorders

Multiple myeloma, myelofibrosis

Other malignancies

Hyperparathyroidism or osteitis fibrosa

Vitamin deficiencies such as folate or vitamin B12 

Hemoglobinopathies such as alpha- and beta-thalassemias or sickle cell anemia

Adverse effects of concomitant drugs such as cytotoxic and immunosuppressive 
agents and angiotensin-converting enzyme  inhibitors
If none of these conditions are diagnosed, anemia should be fully investigated (see 
Section 5 of the protocol). 
3.2.WHAT ARE THE MOST FREQUENT CAUSES?
For acquired PRCA, the following are the most frequent causes:

Lymphoproliferative disorders

Infections such as parvovirus B19

Systemic autoimmune disease such as systemic lupus, rheumatoid arthritis

Drugs such as azathioprine, isoniazid, phenytoin

Thymoma (in approximately 5% of cases)

Idiopathic (in approximately 50% of cases)


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
83/Protocol NH19708, Version 4
4.
WHAT HAPPENS IN AEAB-MEDIATED PRCA?
Epoetin permits terminal maturation of erythroid precursor cells and thus treats anemia 
due to chronic kidney disease.  AEAB-mediated PRCA is an acquired immune disease 
in which erythropoiesis is inhibited by erythropoietin-specific neutralizing antibodies.
4.1.FINDINGS IN BLOOD AND BONE MARROW
The current diagnostic criteria for PRCA have been defined as follows:

Decrease in hemoglobin of approximately 0.1 g/dL/day

Reticulocyte count below 10 or 20109/L

No major changes in white cell count, platelet count, or differential leukocyte count

Normal cellularity of bone marrow, 1% erythroblasts (occasionally up to 5% 
proerythroblasts or basophilic erythroblasts), normal myeloid cells, and 
megakaryocytes
4.2.TIMING OF ONSET
The shortest and longest intervals of onset of PRCA after the start of treatment were 
reported within 2 months and 90 months, respectively.
4.3 DISCONTINUATION OF ESAS
There is consensus that ESAs should be discontinued in any patient with confirmed 
AEAB-mediated PRCA.  The physician should do the following:

Investigate for the presence of anti-erythropoietin antibodies

Perform a bone marrow examination
Patients must not be switched to another recombinant ESA because of cross-reactivity 
of antibodies with endogenous and all recombinant ESAs molecules.
5.
DIAGNOSIS OF PRCA
5.1.HEMOGLOBIN DECREASE
European Best Practice Guidelines suggest to strongly suspect PRCA if a patient treated 
with an ESA:

Has a sudden, rapid decrease in hemoglobin (Hb) concentration of approximately 
0.51 g/dL/week despite ongoing ESA treatment; or

Requires transfusions of 12 units of RBCs per week to maintain the Hb level


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
84/Protocol NH19708, Version 4
In these cases, a complete blood count with blood film examination and reticulocyte 
count should be performed.  A reticulocyte count below 10 or 20 109/L strongly 
suggests a PRCA. 
5.2.ANTIBODY TESTING
Upon request from a physician, Roche will offer testing or re-testing of serum samples in 
a reference laboratory.  This is a free-of-charge service for cases of suspected or 
confirmed AEAB-mediated PRCA or unexplained loss of effect (as documented in an 
adverse drug reaction [ADR] report and the questionnaire).
Sampling instructions will be sent to the physician (see Section 9 How to Obtain Further 
Information).
5.3.BONE MARROW EXAMINATION
A bone marrow examination should be performed in the case of a rapid and sustained 
decrease in the reticulocyte count.
PRCA is characterized by the following: 

Normal cellularity

1% erythroblasts

Occasionally erythroblasts up to 5% with evidence of a red cell precursor maturation 
block

Normal myeloid and megakaryocytic lineages
Bone marrow findings help to distinguish PRCA from aplastic anemia and 
myelodysplastic syndrome.  If no bone marrow examination is possible, a suspected 
diagnosis could suffice, but the level of confidence of the diagnosis may be lower.
6.
FOLLOW-UP AFTER PRCA DIAGNOSIS
The physician should check reticulocyte count regularly during a follow-up.  This is the 
best laboratory marker of RBC production.  The reticulocyte count indicates bone 
marrow activity with regard to daily RBC production.  A decrease in hemoglobin level will 
be preceded by a change in the rate of RBC production.  An unchanged reticulocyte 
count suggests that treatment is effective.
Any decrease in reticulocyte count should be investigated.  As one of the proposed 
diagnostic criteria for AEAB-mediated PRCA, an absolute reticulocyte count below 
10 or 20 109/L was suggested.


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
85/Protocol NH19708, Version 4
7.
ADVERSE DRUG REACTION REPORTING 
We need to know as much as possible about suspected case reports of AEAB-mediated 
PRCA potentially associated with Mircera treatment. 
An adverse drug reaction report should be considered when there are:

Confirmed report of AEAB-mediated PRCA, such as positive AEAB findings or bone 
marrow examination showing PRCA

Suspected AEAB-mediated PRCA with insufficient or inconclusive results.  This 
includes a follow-up on updated investigational results and updated results of 
continued monitoring of these patients.

Reports of unexplained loss of effect, especially:

After exclusion of alternative causes of PRCA (see Section 3 Loss of Effect of ESA 
Treatment)

If a patient previously had a stable hemoglobin concentration after having had 
established the Mircera dose (i.e., not during titration).  Loss of effect could be 
reflected by findings such as “refractory anemia,” massive dose increase of the 
already established dose of Mircera, or a decrease in drug effect.
Suspected AEAB-mediated PRCA or the unexplained loss of therapeutic effect should 
be investigated through anti-erythropoietin antibody testing and hematological 
consultation.
8.
QUESTIONNAIRE
After receiving an adverse drug reaction report for AEAB-mediated PRCA or loss of 
effect, Roche will send the reporting physician a guided questionnaire, 
“Erythropoietin Stimulating Agents (ESAs) questionnaire on adverse event of 
anti-erythropoietin-mediated pure red cell aplasia, inadequate response to ESA 
treatment, anemia refractory to ESA treatment and unexplained loss of effect of ESA 
treatment.”
The questionnaire will be updated with available information. 
If appropriate, these collected data will support communication of a substantial 
changefor example, via a label update.


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
86/Protocol NH19708, Version 4
The questionnaire will collect data such as the following:

Diagnostic results to confirm the diagnosis or clinical suspicion

Relevant comorbidities or concomitant drugs

Alternative conditions to explain a sudden decrease in hemoglobin

Exposure to epoetin brands with regard to the onset of first signs or symptoms 
suggestive of AEAB-mediated PRCA 
This guided questionnaire is used only when adverse drug reaction reports are received 
for the use of Mircera outside of a clinical study.  In clinical studies, the study protocol 
will provide guidance on how to follow up a report of potential AEAB-mediated PRCA or 
loss of effect.
9.
HOW TO OBTAIN FURTHER INFORMATION
For further information on adverse drug reaction reporting, including the 
questionnaire:
Please address the local Roche affiliate 
For further information on antibody sampling and shipment:
Please address the local Roche affiliate 
For further information on Mircera including literature:
Please address the local Roche affiliate 
10. SUPPORTING INFORMATION
10.1.
NEED AND CLINICAL IMPORTANCE OF ADVERSE DRUG 
REACTION REPORTING
The aim of pharmacovigilance is the detection, assessment, and prevention of adverse 
reactions.  A critical number of case reports is needed for a signal.  As detection of rare 
adverse effects is increased and accelerated, the more physicians contribute to 
spontaneous reporting of adverse reactions (Meyboom et al. 1999).  According to Waller 
and Evans (2003), spontaneous adverse reaction reporting could be defined as an 
approach to collate individual case reports of clinical suspicion of an adverse drug 
reaction with the main aim of detecting unknown serious potential drug toxicity.  The 
primary role of spontaneous reporting from postmarketing experience is signal 
generation for type “A” effects (dose-related pharmacological effects of the drug) and 


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
87/Protocol NH19708, Version 4
type “B” effects (e.g., allergic or idiosyncratic reactions, AEAB-mediated PRCA) 
(Meyboom et al. 1999).
ADR reporting for a drug newly introduced to the market is not only for identification and 
quantification of unexpected adverse drug reactions but also for the identification of 
subgroups of patients at particular riskfor example, related to comorbidities, age, sex, 
and dose.  After introduction of a drug to the market, safety is continuously monitored to 
ensure that the benefit/risk assessment remains acceptable and to communicate 
appropriate information to health professionals (Stephens 2004).  Spontaneous ADR 
reporting is understood as a cornerstone of pharmacovigilance (Waller and Evans 2003).
10.2.
IMPORTANT FACTS ABOUT AEAB-MEDIATED PRCA AND ESAS
All exogenous proteins could be potentially immunogenic.  With therapeutic proteins, the 
reported incidence of antibody formation varies considerably depending on, for example, 
genetic background of the patient, the type of disease, type of protein, the route of 
administration, dose frequency, and duration of treatment.  In addition, manufacturing, 
handling, and storage might introduce contaminants or alter the three-dimensional 
structure of the protein via oxidation or aggregate formation (Schellekens 2002).
During the first 10 years (19881998) of epoetin treatment, three reports of 
AEAB-mediated PRCA were published, referring to treatment in several million patients 
(Bergrem et al. 1993; Peces et al. 1996; Prabhakar and Muhlfelder 1997).  Since 1998, 
there has been a sudden upsurge of reports of AEAB-mediated PRCA in patients with 
chronic kidney disease.  The majority of these were reported in patients treated 
subcutaneously with the human serum albumin-free epoetin alfa formulation marketed 
outside the United States (Eprex), with a peak in reports in 2001 and 2002 
(Rossert et al. 2004).
10.3.
TESTING APPROACHES
Two testing approaches were used during the development program of Mircera, and will 
be applied for investigations for future postmarketing experience.  The first test is a 
bridging ELISA test, the method for quantification of anti-erythropoietin (anti-EPO) 
antibodies and of anti-methoxy polyethylene glycol-epoetin beta (anti-Mircera) antibodies.  
The second type of testing is a neutralizing antibody assay, a functional assay based on 
the use of a standard in vitro assay to detect EPO or Mircera activity.  This assay 
measures the EPO or Mircerastimulated proliferation of an EPO receptorexpressing 
cell line in the presence and absence of patient serum.  The presence of neutralizing 
anti-EPO or anti-Mircera antibodies reduces or suppresses cell proliferation.  This assay 
can be optionally applied to samples with discrepancies between antibody titer 


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
88/Protocol NH19708, Version 4
determined by antibody enzyme-linked immunosorbent assay (ELISA) and clinical 
diagnosis.  Since the antibody ELISAs has a several-fold higher sensitivity compared 
with the neutralizing antibody assay, the neutralizing antibody assay is not expected to 
provide additional clinically relevant information for samples with low antibody titers or 
confirmed PRCA.
10.4.
LITERATURE
Practical and basic guidance on patient evaluation
The list below shows the relevant publications that are grouped according to the 
practical and basic guidance on patient evaluation.  The detailed aspects of the topic are 
summarized for each publication:

Which patients should be evaluated and when the work-up should begin, 
investigations for appropriate work-up of anemia in CKD, and diagnosis of 
renal anemia:  Revised European best practice guidelines on anaemia 
management (Section I:  anaemia evaluation). Nephrol Dial Transplant 
2004;19(Suppl 2):ii25.

Failure to reach or maintain target hemoglobin, criteria to suspect 
anti-erythropoietin antibody-mediated pure red cell aplasia (AEAB-mediated 
PRCA), and criteria to confirm AEAB-mediated PRCA:  Revised European best 
practice guidelines on anaemia management (Section IV:  failure to respond to 
treatment). Nephrol Dial Transplant 2004;19(Suppl 2):ii326.

Recommendations for diagnostic approach including discussions on 
potential findings:  Casadevall N, Cournoyer D, Marsh J, et al. Recommendations 
on haematological criteria for the diagnosis of epoetin-induced pure red cell aplasia. 
Eur J Haematol 2004;73:38996.
Further readings

Description of worldwide collection of reports of AEAB-mediated PRCA 
emphasizing the need of spontaneous reporting by physicians in order to 
document a change in the occurrence rate:  Bennett CL, Luminari S, Nissenson 
AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med 2004; 
351:14038.

Information on treatment and long-term follow-up of 191 patients with 
AEAB-mediated PRCA:  Bennett CL, Cournoyer D, Carson KR, et al. Long-term 
outcome of individuals with pure red cell aplasia and anti-erythropoietin antibodies in 
patients treated with recombinant epoetin: a follow-up report from the Research on 
Adverse Drug Events and Reports (RADAR) Project. Blood 2005;106:33437.


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
89/Protocol NH19708, Version 4

Clinical characterization of 13 patients with AEAB-mediated PRCA:  Casadevall 
N, Nataf J, Viron B, et al. Pure red-cell aplasia and antierythropoietin antibodies in 
patients treated with recombinant erythropoietin. N Engl J Med 2002;346: 46975.

Diagnosis and causes of AEAB-mediated PRCA:  Eckardt K-U, Casadevall N. 
Pure red-cell aplasia due to anti-erythropoietin antibodies. Nephrol Dial Transplant 
2003;18:8659.

Diagnosis, assays, epidemiology, and risk factors:  Rossert J, Casadevall N, 
Eckardt K-U. Anti-erythropoietin antibodies and pure red cell aplasia. J Am Soc 
Nephrol 2004;15:398406.

Consequences of antibody formation:  Schellekens H. Factors influencing the 
immunogenicity of therapeutic proteins. Nephrol Dial Transplant 
2005;20(Suppl 6):vi39.

Effects of antibodies on endogenous protein production, clinical effects of 
antibodies, and factors influencing immunogenicity:  Schellekens H. 
Immunogenicity of therapeutic proteins: clinical implications and future prospects. 
Clin Ther 2002;24:172040.


Appendix 4
Educational Program for Anti-Erythropoietin AntibodyMediated 
Pure Red Cell Aplasia Associated with 
Erythropoietin-Stimulating Agents (cont.)
Mircera—F. Hoffmann-La Roche Ltd
90/Protocol NH19708, Version 4
REFERENCES 
Bergrem H, Danielson BG, Eckardt K-U, et al. A case of antierythropoietin antibodies 
following recombinant human erythropoietin treatment. In: Bauer C, Koch KM, 
Scigalla P, et al. editors. Erythropoietin: molecular physiology and clinical 
applications. New York: Marcel Dekker, 1993:26573.
Meyboom RH, Egberts AC, Gribnau, FW, et al. Pharmacovigilance in perspective. Drug 
Saf 1999;21:42947.
Peces R, de la Torre M, Alcázar R, et al. Antibodies against recombinant human 
erythropoietin in a patient with erythropoietin-resistant anemia. N Engl J Med 
1996;335:5234.
Prabhakar SS, Muhlfelder T. Antibodies to recombinant human erythropoietin causing 
pure red cell aplasia. Clin Nephrol 1997;47:3315.
Rossert J, Casadevall N, Eckardt K-U. Anti-erythropoietin antibodies and pure red cell 
aplasia. J Am Soc Nephrol 2004;15:398406.
Schellekens H. Immunogenicity of therapeutic proteins: clinical implications and future 
prospects. Clin Ther 2002;24:172040.
Stephens M. Introduction. In: Talbot J, Waller P, editors. Stephen’s detection of new 
adverse drug reactions. Chichester: Wiley, 2004:12.
Waller PC, Evans SJ. A model for the future conduct of pharmacovigilance. 
Pharmacoepidemiol Drug Saf 2003;12:1729.


Mircera—F. Hoffmann-La Roche Ltd
91/Protocol NH19708, Version 4
Appendix 5
Blood Pressure Measurements in Children
The preferred method of blood pressure measurement is auscultation. Oscillometric 
devices are convenient and minimize observer error, but they do not provide measures 
that are identical to auscultation. The blood pressure in children should be measured 
with a standard clinical sphygmomanometer, using a stethoscope placed over the 
brachial artery pulse, proximal and medial to the cubital fossa, and below the bottom 
edge of the cuff (i.e., about 2 cm above the cubital fossa). The use of the bell of the 
stethoscope may allow softer Korotkoff sounds to be heard better. The use of an 
appropriately sized cuff may preclude the placement of the stethoscope in this precise 
location, but there is little evidence that significant inaccuracy is introduced, either if the 
head of the stethoscope is slightly out of position or if there is contact between the cuff 
and the stethoscope. 
Preparation of the child for standard measurement can affect the blood pressure level 
just as much as technique. Ideally, the child whose blood pressure is to be measured 
should have avoided stimulant drugs or foods, have been sitting quietly for 5 minutes, 
and seated with his or her back supported, feet on the floor and right arm supported, 
cubital fossa at heart level. The right arm is preferred in repeated measures of blood 
pressure for consistency and comparison to standard tables and because of the 
possibility of coarctation of the aorta, which might lead to false (low) readings in the left 
arm.
Correct measurement of blood pressure in children requires use of a cuff that is 
appropriate to the size of the child’s upper right arm. The equipment necessary to 
measure blood pressure in children, ages 3 through adolescence, includes child cuffs of 
different sizes and must also include a standard adult cuff, a large adult cuff, and a thigh 
cuff. The latter two cuffs may be needed for use in adolescents.
Two advantages of automatic devices are their ease of use and the minimization of 
observer bias or digit preference. Use of the automated devices is preferred for blood 
pressure measurement in newborns and young infants, in whom auscultation is difficult. 
The blood pressure should be measured at least twice and the average of these 
measurements should be recorded.
Hypertension is defined as average SBP or DBP that is greater than or equal to the 95th 
percentile for sex, age, and height on at least three separate occasions. Reference 
tables including 95th percentiles by sex, age and height have been included in 
Appendix 6.
Source:  Falkner B, Daniels SR, Flynn JT, et al. The fourth report on the diagnosis, evaluation, 
and treatment of high blood pressure in children and adolescents. Pediatrics. 
2004;114(2 III):555-76.








Mircera—F. Hoffmann-La Roche Ltd
95/Protocol NH19708, Version 4
Appendix 7
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events
HEMATOLOGY
Item
Grade 1 Toxicity
Grade 2 Toxicity
Grade 3 Toxicity
Grade 4 Toxicity
Hemoglobin
9.510.5 g/dL
8.09.4 g/dL
6.57.9 g/dL
6.5 g/dL
Absolute neutrophil count
10001500/mm3
750999/mm3
500749/mm3
500/mm3
Platelets
7500099999/mm3
5000074999/mm3
2000049999/mm3
20000/mm3
Prothrombin time (PT)
1.011.25ULN
1.261.5ULN
1.513.0ULN
3ULN
Activated partial thromboplastin
(APPT)
1.011.66ULN
1.672.33ULN
2.343ULN
3ULN
Fibrinogen
0.750.99LLN
0.500.74LLN
0.25 - 0.49LLN
0.25 x LLN
Fibrin split product
2040 mcg/mL
4150 mcg/mL
5160 mcg/mL
60 mcg/mL
Methemoglobin
5%9.9%
10.0%14.9%
15.0%19.9%
20%
LIVER ENZYMES
AST (SGOT)
1.252.5ULN
2.65ULN
5.110ULN
10ULN
ALT (SGPT)
1.252.5ULN
2.65ULN
5.110ULN
10ULN
GGT
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Alkaline phosphatase
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Amylase
1.11.5ULN
1.62.0ULN
2.15.0ULN
5.0ULN


Appendix 7
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Mircera—F. Hoffmann-La Roche Ltd
96/Protocol NH19708, Version 4
CHEMISTRIES
Hyponatremia
130135 mEq/L
123129 mEq/L
116122 mEq/L
< 116 or mental status 
changes or seizures
Hypernatremia
146150 mEq/L
151157 mEq/L
158165 mEq/L
> 165 mEq/L or mental status
changes or seizures
Hypokalemia
3.03.4 mEq/L
2.52.9 mEq/L
2.02.4 mEq/L or intensive
replacement Rx required or
hospitalization required.
2.0 mEq/L
or paresis or ileus or life-
threatening arrhythmia
Hyperkalemia
5.66.0 mEq/L
6.16.5 mEq/L
6.67.0 mEq/L
7.0 mEq/L
or life-threatening arrhythmia
Hypoglycemia
5564 mg/dL
4054 mg/dL
3039 mg/dL
30 mg/dL or mental status
changes or coma
Hyperglycemia (note if fasting)
116160 mg/dL
161250 mg/dL
251500 mg/dL
500 mg/dL or ketoacidosis
or seizures
Hypocalcemia (corrected for 
albumin)
8.47.8 mg/dL
7.77.0 mg/dL
6.96.1 mg/dL
6.1 mg/dL or life-threatening
arrhythmia or tetany
Hypercalcemia (correct for 
albumin)
10.611.5 mg/dL
11.612.5 mg/dL
12.613.5 mg/dL
13.5 mg/dL life-threatening
arrhythmia
Hypomagnesemia
1.41.2 mEq/L
1.10.9 mEq/L
0.80.6 mEq/L
0.6 mEq/L or 
life-threatening arrhythmia
Hypophosphatemia
2.02.4 mg/dL
1.51.9 mg/dL or
replacement Rx required
1.01.4 mg/dL intensive Rx 
or hospitalization required
1.0 mg/dL or life-threatening
arrhythmia


Appendix 7
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Mircera—F. Hoffmann-La Roche Ltd
97/Protocol NH19708, Version 4
CHEMISTRIES continued
Hyperbilirubinemia
1.11.5ULN
1.62.5ULN
2.65ULN
5ULN
BUN
1.252.5ULN
2.65ULN
5.110ULN
10ULN
Creatinine
1.11.5ULN
1.63.0ULN
3.16ULN
6ULN or required dialysis
URINALYSIS
Proteinuria
1or 0.3% or 3g/L
or 200 mg1 g loss/day
23or 0.31.0% or
310 g/L
12 g loss/day
4or 1.0% or 10 g/L
23.5 g loss/day
nephrotic syndrome or 3.5 g
loss/day
Hematuria
microscopic only
gross, no clots
gross clots
obstructive or required 
transfusion
CARDIAC DYSFUNCTION
Cardiac Rhythm
asymptomatic, transient
signs, no Rx required
recurrent/persistent; no Rx 
required
requires treatment
Hypertension
transient increase 20 mm;
no Rx required
recurrent, chronic, 20 mm,
Rx required
requires acute Rx; no
hospitalization required
requires hospitalization
Hypotension
transient orthostatic
hypotension, no Rx
symptoms correctable with 
oral fluids Rx
requires IV fluids; no
hospitalization required
requires hospitalization
Pericarditis
minimal effusion
mild/moderate
asymptomatic effusion, no
Rx required
symptomatic effusion; pain; 
EKG changes
tamponade;
pericardiocentesis or surgery
required
Hemorrhage, Blood Loss
microscopic/occult
mild, no transfusion
gross blood loss;
12 units transfused
massive blood loss;
3 units transfused


Appendix 7
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Mircera—F. Hoffmann-La Roche Ltd
98/Protocol NH19708, Version 4
RESPIRATORY
Cough
transient; no Rx
treatment-associated cough
local Rx
uncontrolled
Bronchospasm, Acute
transient; no Rx
80%70% FEV1
(or peak flow)
requires Rx normalizes with
bronchodilator; FEV1
50%70%
(or peak Flow)
no normalization with
bronchodilator;
FEV1 25%50%
(or peak flow retractions)
cyanosis:  FEV1
25%
(or peak flow) or intubated
GASTROINTESTINAL
Stomatitis
mild discomfort; no limits 
on activity
some limits on
eating/drinking
eating/talking very limited
requires IV fluids
Nausea
mild discomfort; maintains 
reasonable intake
moderate discomfort; intake 
decreased significantly; 
some activity limited
severe discomfort; no
significant intake; activities 
limited
minimal fluid intake
Vomiting
transient emesis
occasional/moderate
vomiting
orthostatic hypotension or 
IV fluids required
hypotensive shock or 
hospitalization required for IV 
fluid therapy
Constipation
mild
moderate
severe
distensions w/vomiting
Diarrhea
transient 34 loose
stools/day
57 loose stools/day
orthostatic hypotension or
7 loose stools/day or
required IV fluids
hypotensive shock or 
hospitalization for IV fluid 
therapy required


Appendix 7
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Mircera—F. Hoffmann-La Roche Ltd
99/Protocol NH19708, Version 4
NEURO AND NEUROMUSCULAR
Neuro-cerebellar
slight incoordination
dysdiadochokinesis
intention tremor, dysmetria, 
slurred speech; nystagmus
locomotor ataxia
incapacitated
Mood
mild anxiety or depression
moderate anxiety or
depression and therapy 
required
severe anxiety or
depression or mania;
needs assistance
acute psychosis;
incapacitated, requires
hospitalization
Neuro control (ADLactivities 
of daily living)
mild difficulty
concentrating; no Rx; mild
confusion/agitation; ADL 
unaffected
moderate
confusion/agitation some 
limitation of ADL; minimal 
Rx
severe confusion/agitation
needs assistance for ADL;
therapy required
toxic psychosis;
hospitalization
Muscle strength
subjective weakness
no objective 
symptoms/signs
mild objective
signs/symptoms no 
decrease in function
objective weakness
function limited
paralysis
OTHER PARAMETERS
Fever:  oral, 12 hours
37.7C 38.5C or
100.0F101.5F
38.6C39.5C or
101.6F102.9F
39.6C40.5C or
103F105F
40C or
105F
Headache
mild, no Rx therapy
transient, moderate; Rx
required
severe; responds to initial 
narcotic therapy
intractable; required repeated 
narcotic therapy
Fatigue
no decrease in ADL
normal activity decreased 
25%50%
normal activity decreased
50% can’t work
unable to care for self
Allergic Reaction
pruritus without rash
localized urticaria
generalized urticaria;
angioedema
anaphylaxis


Appendix 7
WHO Toxicity Grading Scale for Determining the Severity of Adverse Events (cont.)
Mircera—F. Hoffmann-La Roche Ltd
100/Protocol NH19708, Version 4
OTHER PARAMETERS continued
Local Reaction
tenderness or erythema
induration 10 cm or
phlebitis or inflammation
induration 10 cm or
ulceration
necrosis
Mucocutaneous
erythema; pruritus
diffuse, maculopapular rash, 
dry desquamation
vesiculation, moist
desquamation, or
ulceration
exfoliative dermatitis, mucous
membrane involvement or
erythema, multiforme or
suspected Stevens-Johnson 
or necrosis requiring surgery
NOTE:  For coding purposes, the following toxicity grades may be used interchangeably: 1mild; 2moderate; 3severe; 4life threatening.

SAP_001.pdf: 
 
Official Title: An Open-Label, Single-Arm, Multicenter Study to Ascertain the 
Optimal Starting Dose of Mircera® Given Subcutaneously for the 
Maintenance Treatment of Anemia in Pediatric Patients With 
Chronic Kidney Disease on Dialysis or not yet on Dialysis 
NCT Number: NCT03552393 
Document Date: SAP Version 1: 04-March-2021 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
STATISTICAL ANALYSIS PLAN
TITLE:
AN OPEN-LABEL, SINGLE-ARM, MULTICENTER STUDY TO 
ASCERTAIN THE OPTIMAL STARTING DOSE OF 
MIRCERA® GIVEN SUBCUTANEOUSLY FOR THE 
MAINTENANCE TREATMENT OF ANEMIA IN PEDIATRIC 
PATIENTS WITH CHRONIC KIDNEY DISEASE ON DIALYSIS 
OR NOT YET ON DIALYSIS
PROTOCOL NUMBER:
NH19708
STUDY DRUG:
Mircera (RO0503821)
VERSION NUMBER:
1
IND NUMBER:
10158
EUDRACT NUMBER:
2016-004779-39
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
See electronic date stamp below {XX Month Year}
DATE(S) AMENDED:
See electronic date stamp below
Date and Time(UTC)        Reason for Signing                              Name
04-Mar-2021 03:05:47
25-Feb-2021 11:22:08
24-Feb-2021 18:17:37
Company Signatory
Company Signatory
Company Signatory


Mircera—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NH19708 (Skipper) 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
2.1 
Protocol Synopsis .................................................................... 5 
2.2 
Outcome Measures ................................................................. 5 
2.2.1 
Primary Efficacy Endpoints ...................................................... 5 
2.2.2 
Secondary Efficacy Endpoints ................................................. 5 
2.2.3 
Exploratory Endpoints.............................................................. 6 
2.2.4 
Pharmacokinetic and Pharmacodynamic 
Endpoints… ............................................................................. 6 
2.2.5 
Safety Endpoints ..................................................................... 6 
2.3 
Determination of Sample Size ................................................. 6 
2.4 
Analysis Timing ....................................................................... 7 
3. 
STUDY CONDUCT ....................................................................................... 7 
3.1 
Randomization ......................................................................... 7 
3.2 
Data Monitoring ....................................................................... 7 
4. 
STATISTICAL METHODS ............................................................................ 8 
4.1 
Analysis Populations................................................................ 8 
4.1.1 
Intent to Treat (ITT) Population ................................................ 8 
4.1.2 
Per Protocol Population ........................................................... 8 
4.1.3 
Safety Population .................................................................... 8 
4.2 
Analysis of Study Conduct ....................................................... 8 
4.3 
Efficacy Analysis ...................................................................... 9 
4.3.1 
Primary Efficacy Endpoint ........................................................ 9 
4.3.2 
Secondary Efficacy Endpoints ............................................... 10 
4.3.2.1 
Number of patients within stable range of Hb ........................ 10 
4.3.2.2 
Change in Mircera dose over time ......................................... 10 
4.3.2.3 
Average Hb and Change from Baseline ................................ 10 
4.3.2.4 
Patients with Dose adjustments ............................................. 10 
4.3.3 
Exploratory Efficacy Endpoints .............................................. 11 
4.3.4 
Sensitivity Analyses ............................................................... 11 
4.3.5 
Subgroup Analyses ............................................................... 11 


Mircera—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NH19708 (Skipper) 
4.4 
Safety Analyses ..................................................................... 11 
4.4.1 
Exposure of Study Medication ............................................... 12 
4.4.2 
Adverse Events ..................................................................... 12 
4.4.3 
Laboratory Data ..................................................................... 13 
4.4.4 
Vital Signs .............................................................................. 13 
4.4.5 
Deaths ................................................................................... 15 
4.4.6 
Patient Narratives .................................................................. 15 
4.5 
Missing Data .......................................................................... 15 
4.6 
Interim Analyses .................................................................... 15 
4.7 
Optional Safety Extension ..................................................... 16 
5.
REFERENCES ........................................................................................... 17 
LIST OF APPENDICES 
Appendix 1 
  Protocol Synopsis....................................................................... 18 
Appendix 2 
 Schedule of Assessments .......................................................... 23 


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
1.
BACKGROUND
The NH19708 study is a pediatric study in patients aged 3 months to 17 years. It is an 
open-label, single-arm, multi-center study of Mircera administered once every 4 weeks 
subcutaneously (SC) for the maintenance treatment of anemia in pediatric patients with 
Chronic Kidney Disease (CKD). This study is the first use of Mircera in children under 6 
years of age, and addresses the questions about SC administration of Mircera, its use in 
patients on PD or not yet on dialysis, and confirmation of the results of the modeling and 
simulation studies.
The main objective of the study is to ascertain the starting dose for the SC administration 
of Mircera for the maintenance treatment of anemia in pediatric patients with CKD on 
dialysis or not yet on dialysis when switching from stable SC maintenance treatment with 
epoetin [epoetin alfa or epoetin beta or biosimilar] or darbepoetin alfa.
This analysis plan covers the proposed methods for the final analysis following the 
database lock at the end of the study.
2.
STUDY DESIGN
Patients will be screened for eligibility during a screening period of approximately three 
weeks. During this period, patients will continue to receive epoetin [epoetin alfa or 
epoetin beta or biosimilar] or darbepoetin alfa at the same weekly dose, route (SC), and 
interval as before screening. Provided that all eligibility criteria are met, including those 
for hemoglobin (Hb) levels and iron status, the patients will start Mircera administered 
subcutaneously.
At least 40 pediatric patients 3 months-17 years of age will be enrolled. Approximately 
10-15 of these patients will be < 12 years old, with a goal to include as many patients < 5 
years old as possible (with a minimum of 3 patients). Approximately 10-15 patients, 
irrespective of age, will not be on dialysis.
The core study will last for 23 weeks and consists of three periods: screening (3 weeks), 
dose titration (16 weeks), and evaluation (4 weeks).
Patients completing the 20 weeks of treatment with Hb within ± 1 g/dL of their baseline 
Hb and within the target range of 10-12 g/dL, will be eligible to enter an optional 24-week 
safety extension period. Those patients not eligible or not consenting to enter the long-
term safety extension should be treated according to clinical practice. All patients must 
complete the Week 21 visit (Visit 10), regardless of whether they continue in the safety 
extension period. Visit 10 will serve as the final visit of the core study and the first visit of 
the safety extension period for patients eligible and willing to continue in the study.
Once 12 patients have completed 20 weeks of treatment (dose titration and evaluation 
periods), an interim analysis to assess the pharmacokinetics, efficacy, and safety of 
Mircera has taken place as described in Section 6.9 of the study protocol.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
OUTCOME MEASURES
2.2.1
Primary Efficacy Endpoints
The primary efficacy endpoint in this study is the change in Hb concentration (g/dL) 
between the baseline and evaluation periods.
This is first calculated on a per-patient basis, using an Area Under the Curve (AUC) 
approach to calculate an individual’s average for both the baseline and evaluation 
periods and taking the difference.
The baseline period is defined as all assessments between the day of first study dose 
and the previous 35 days. If during the baseline period Hb measurements H0,…,Hn are 
taken at timepoints t0,…,tn, a time adjusted average baseline Hb value will be calculated 
by the formula below. This is referred to as the time adjusted average Hb value, as the 
time at which the Hb values are measured is taken into account.
 =
1
2(	
 −	) ( + )


(	 −	)
The Hb value on the day of the first dose is included in the baseline calculation as this 
assessment will be performed before the first dose is given.
The average Hb value for each individual during the evaluation period (all assessments 
between Visit 8 (Week 17) and Visit 10 (Week 21) inclusive) will be calculated using the 
same method as for baseline. Subtracting the baseline value from the evaluation period 
value gives the change in Hb concentration (g/dL) between the baseline and evaluation 
period. 
For patients with no recorded Hb during the evaluation period, the primary endpoint will 
be missing. Values missing in between non-missing assessments will not be replaced.
To correct for any increase in Hb caused by RBC transfusions, the Hb values measured 
within 3 weeks after an RBC transfusion will be deleted.
2.2.2
Secondary Efficacy Endpoints
1. The number of patients with an average Hb concentration during the evaluation 
period within ± 1 g/dL of their baseline Hb
2. The number of patients with an average Hb concentration above, within, or below 
the range of 10-12 g/dL


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
3. The change in Mircera dose over time, including the change between the starting 
dose and the evaluation period
The classification of each patient for endpoints 1 and 2 will be based on their average 
Hb for the baseline and evaluation periods as calculated for the primary endpoint.
2.2.3
Exploratory Endpoints
Assessment of injection pain using a VAS scale 5 minutes following ESA administration
will be done by the patient if 4 years or older, the parent/guardian and the nurse/site 
staff. The assessments will take place during the screening period for all patients who 
received an ESA injection during either or both of the visits, and at Week 1 (Visit 3) and 
Week 9 (Visit 6). Injection pain data will be plotted by visit for each patient and analyzed 
in an exploratory manner. Mean injection pain scores will be plotted for all patients per 
assessor category and per visit.
2.2.4
Pharmacokinetic and Pharmacodynamic Endpoints
Serum concentrations of Mircera and Hb will be used to evaluate the pharmacokinetics 
and pharmacodynamics using non-linear mixed effect modeling. The evaluation of the 
pharmacokinetic and pharmacodynamic objectives is outside the scope of this statistical 
analysis plan. The general outline of the analysis is given in the protocol synopsis.
2.2.5
Safety Endpoints

Occurrence and severity of adverse events

Change from baseline in targeted vital signs

Change from baseline in targeted clinical laboratory test results
Change in vital signs and laboratory parameters will be summarized separately- from 
baseline to evaluation period and from baseline to the end of study duration (including 
optional extension period) respectively.
Adverse events will be summarized separately for the core period and the entire study 
duration (including the optional extension period).
2.3
DETERMINATION OF SAMPLE SIZE
This is an exploratory study without a powered statistical group comparison. Therefore, 
no formal sample size estimation will be performed; however, the calculations below 
indicate the approximate precision that could be achieved.
Assuming a 30% withdrawal rate (based on the withdrawal rate for the NH19707 study), 
of the 40 patients evaluable for ITT and safety analysis, more than 26 patients will have 
data for the evaluation period. Twenty-six patients will be sufficient to provide 


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
approximately 90% power that the 90% CI for the Hb change from baseline to the 
evaluation period is between -1 and +1 g/dL, provided the standard deviation is smaller 
than 1.5 and the optimum dose conversion is able to maintain the Hb at the baseline 
level. This means that we assume there will be no change in the Hb levels from baseline 
to the evaluation period.
Approximately 10-15 of the patients will be < 12 years old, with the objective to include 
as many patients < 5 years old (minimum 3 patients) as possible. Approximately 10-15 
patients, irrespective of their age, will not be on dialysis. Available HD patients receiving 
their ESA subcutaneously are eligible for enrollment. No more than 10 patients on HD 
should be enrolled.
2.4
ANALYSIS TIMING
Two analyses of this study have been planned: 

Interim Analysis – An interim analysis was performed to assess efficacy, safety, 
and pharmacokinetics after 12 patients completed 20 weeks of treatment. The 
analysis was reviewed by a Roche Internal Monitoring Committee (IMC) with the 
primary objective of assessing the safety and efficacy of the CFs for starting 
treatment with SC Mircera. For more details of the related statistical analysis, 
please refer to the separate Statistical Analysis Plan for the Interim Analysis. The 
IMC met on 12 Sep 2019 and based on the review of the data and the meeting 
discussion, it recommended to continue the study unchanged. The IMC 
recommendation has been documented and filed in the trial master file.

Final Analysis – The final analysis will be performed at the end of study. The end 
of this study is defined as the date when the last patient, last visit (LPLV) occurs. 
LPLV is expected to occur approximately 44 weeks after the last patient is
enrolled if the patient participates to the safety extension.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Patients will be enrolled to receive Mircera once every 4 weeks, and no randomization
will be performed. An interactive voice or Web-based response system (IxRS) will be
used to track the enrollment and to monitor the disposition of patients with respect to the
different subgroups (age group and dialysis type).
3.2
DATA MONITORING
The IMC reviewed the general safety and efficacy of Mircera in this patient population as 
well as PK data on 12 September 2019, after 12 subjects completed the core study 
period (20 weeks of treatment). The IMC consisted of representative(s) from Clinical 
Science, Drug Safety, Clinical Pharmacology and Biostatistics. The main purpose of the 
IMC was to assess if the conversion factor from the previous ESA dose to give the 
starting dose of Mircera SC is appropriate to maintain stable hemoglobin (Hb). The SMT 


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
was recommended to plan and prepare for this interim analysis. The SMT Statistician 
and the Statistical Programming Analyst performed the interim analyses. Based on the 
review of the data and the meeting discussion, the IMC recommended to continue the 
study unchanged. The Development Review Committee (DRC) chair, on behalf of the 
study team, accepted the IMC recommendations. For detailed description of the role and 
process of the IMC, please refer to the IMC Agreement. 
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Intent to Treat (ITT) Population
The Intent to Treat (ITT) population consists of all patients enrolled in the study.
4.1.2
Per Protocol Population
The Per-Protocol (PP) population is defined as all patients included in the safety 
population and who have no major protocol deviations as defined below.
1. Patients with less than 3 Hb values during the evaluation period.
2. Patients who miss any application of study medication at week 13 or week 17.
3. Patients with an overdose of Mircera at week 17 captured as a protocol deviation
4. Patient with wrong Mircera starting dose
5. Patients who do not fulfill the inclusion criteria for:

hemoglobin 

iron levels

stable dose and dosing interval of SC treatment with epoetin alfa, epoetin 
beta or biosimilars, or darbepoetin alfa 
6. Patients who fulfill any of the exclusion criteria: 

Hemolytic anemia

Use of prohibited therapy
4.1.3
Safety Population
The safety analysis population consists of all patients who received at least one dose
of study drug regardless of whether they withdrew prematurely or not.
4.2
ANALYSIS OF STUDY CONDUCT
The summary of patient disposition will give a breakdown of the number and percentage 
of patients who: enrolled; started, discontinued (with reasons for discontinuation) and 
completed the core study and the safety extension period.
Premature withdrawals will be listed and summarized by age category and dialysis 
category. 
Patients completing 20 weeks of treatment (having returned for an assessment at study 
week 21) as defined in the protocol as a key cut-point will also be summarized.
Enrollment and major protocol deviations will be listed and evaluated for their potential 
effects on the interpretation of study results. Protocol deviations related to covid-19 will 


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
be tagged appropriately in the Protocol Deviation Management System (PDMS) and 
listed separately.
The distribution of patients based on the key strata of age at enrollment (<5, 5-11, ≥12), 
dialysis status (no dialysis, PD or HD) and previous ESA treatment (epoetin [epoetin alfa 
or epoetin beta or biosimilar] or darbepoetin alfa) will be summarized and compared by 
those who completed more than 20 weeks against those who did not.
4.3
EFFICACY ANALYSIS
The primary efficacy endpoint is the change in Hb concentration (g/dL) between the 
baseline and the evaluation period for each patient. The analysis population for the 
primary and secondary efficacy analyses will be the ITT population consisting of all 
enrolled patients.
4.3.1
Primary Efficacy Endpoint
Hb concentration values (g/dL) over time and change in Hb from baseline to evaluation 
period will be presented in summary tables and graphically. The estimates will be 
summarized descriptively using means, standard deviation and percentiles. 
The individual change from baseline will be reported using summary statistics (including
mean, standard deviation and 90% CI of mean change). No formal statistical testing will
be performed. Additional analysis will be performed by age category (<5, 5-11, ≥12 
years), dialysis type (not yet on dialysis, PD, HD) and previous ESA (epoetin [epoetin 
alfa or epoetin beta or biosimilar] or darbepoetin alfa), if numbers allow.
The 90% confidence interval (CI) for the average per-patient Hb change from baseline to 
the evaluation period (weeks 17-21) will be calculated. If the lower limit of the CI is ≥-1 
g/dL, the upper limit ≤1 g/dL and the number of dose increases and decreases are 
approximately balanced across the patients the conversion factor from prior ESA 
treatment for the first Mircera dose will be considered appropriate.
The Hb change from baseline is calculated on a per-patient basis, using an Area Under
the Curve (AUC) approach to calculate an individual’s average for both the baseline and 
evaluation periods and taking the difference. This per-patient change is then averaged 
over all patients and the confidence interval calculated.
The baseline period is defined as all assessments between the day of first study dose
and the previous 35 days. If during the baseline period Hb measurements H0,…,Hn are
taken at timepoints t0,…,tn, a time adjusted average baseline Hb value will be calculated
by


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
The value on the day of the first dose is included in the baseline calculation, as this
assessment will be performed before the first dose is given.
The average Hb value for each individual during the evaluation period will be calculated
using the same method as for the baseline period. The evaluation period is defined as
all assessments between Visit 8 (Week 17) and Visit 10 (Week 21) inclusive.
Subtracting the baseline period value from the evaluation period value gives the change
in Hb concentration (g/dL) between the baseline and evaluation period.
For patients with no recorded Hb during the evaluation period, the primary endpoint will
be missing. Values missing in between non-missing assessments will not be replaced or 
imputed. To correct for any increase in Hb caused by RBC transfusions, the Hb values 
measured within 3 weeks after an RBC transfusion will be deleted.
4.3.2
Secondary Efficacy Endpoints
4.3.2.1
Number of patients within stable range of Hb
The number of patients with an average Hb concentration during the evaluation period
within ± 1 g/dL of their baseline Hb or above, within, or below the range of 10-12 g/dL
and those who fulfill both criteria will be summarized. The classification of each patient 
will be based on their average Hb for the baseline and evaluation periods as calculated 
for the primary endpoint.
4.3.2.2
Change in Mircera dose over time
The change in Mircera dose over time, including the change between the starting dose
and the evaluation period, will be analyzed descriptively, overall and by age-group. The 
ratio of starting dose (Week 1) to the dose at the evaluation period (Week 17) will be 
summarized by using mean, median, minimum and maximum.
A dose change is defined as a change in the administered dose strength compared to 
the preceding dose. The number of patients with dose increases, dose decreases and 
both increases and decreases will be tabulated.
4.3.2.3
Average Hb and Change from Baseline
Average Hb values will also be summarized by Hb levels: < 10 g/dL, between 10 and 12 
g/dL, and > 12 g/dL. The number and percentage of patients within each Hb level will be 
presented. The Hb level at evaluation period, at baseline and the change from baseline 
to evaluation period will be listed for all the patients.
4.3.2.4
Patients with Dose adjustments
Patients with dose adjustments during the core study period will be summarized 
descriptively, overall and by age-group.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
4.3.3
Exploratory Efficacy Endpoints
The patient if 4 years or older, the parent/guardian, and the nurse/site staff member who
gives the injection will assess injection pain using a VAS scale 5 minutes following ESA
administration, as appropriate. The assessments will take place during the screening
period for all patients who received an ESA injection during either or both of the visits,
and at Week 1 (Visit 3) and Week 9 (Visit 6). Injection pain data will be plotted by visit
for each patient and separately for patient reported, nurse reported, and parent reported 
assessments. Descriptive summary statistics for the pain score assessed by nurse/ site 
staff, patient and parent respectively will be presented by visit. A plot of mean pain 
scores per assessor category per visit will be produced.
4.3.4
Sensitivity Analyses
Sensitivity analysis may be carried out for the primary efficacy endpoint based on the 
number of patients who do not respond to increasing doses of Mircera over the study 
duration. Sensitivity analysis for data exploration may also be done for the primary 
efficacy endpoint if a large volume of data is missing.
4.3.5
Subgroup Analyses
The main subgroups used for analysis in this pediatric study will be the age groups 
(based on age at study start) used for stratification: 
1. Age groups: 

< 5 years

5-11 years

≥ 12 years 
Additionally, the other stratification factor that may be used for subgroup analyses: 
2. Previous ESA treatment 

epoetin alfa or epoetin beta or biosimilar

darbepoetin alfa 
3. Dialysis type at study start

Not yet on dialysis

PD

HD
Analyses of the primary endpoint & the dose over time will be repeated by these 
subgroups.
4.4
SAFETY ANALYSES
Safety data for the whole study including the safety extension period will be presented.
The safety analysis population will consist of all patients who received at least one dose
of study drug regardless of whether they withdrew prematurely or not. The safety 
parameters will include vital signs, adverse events and the safety laboratory parameters 
including iron.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
4.4.1
Exposure of Study Medication
Exposure to study drug will be summarized, overall and by visit. The treatment duration
(in weeks) and number of doses will be summarized using descriptive statistics such as 
mean, median, minimum and maximum. The average dose (ug), average dose per kg of 
body weight and average dose per body surface area (BSA) will be summarized 
descriptively, both overall as well as by visit (using weight at that visit as reference). 
4.4.2
Adverse Events
All AEs recorded in the CRF will be listed and classified by System Organ Class (SOC) 
and Preferred Term (PT). Events will be coded using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA). Adverse event severity will be graded 
according to the WHO Toxicity Grading Scale for determining the severity of adverse 
events (refer to Appendix 7 of the study protocol for details). AEs that occurred during 
the treatment period: from the first treatment dose until 28 days after last dose or until 
the final visit (whichever is latest) will be summarized. Standard safety analyses for all 
AEs, related AEs, serious AEs, fatal AEs and AEs leading to study drug modification or 
discontinuation or withdrawal from study will be performed in terms of frequency tables 
by event and patient.
All adverse events of special interest (AESI) will be presented. AESI include but are not 
limited to the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST 
in combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7 of study protocol)

Suspected transmission of an infectious agent by the study drug, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is
considered an infectious agent. A transmission of an infectious agent may be
suspected from clinical symptoms or laboratory findings that indicate an infection in a 
patient exposed to a medicinal product. This term applies only when a contamination 
of the study drug is suspected.
Adverse events related to covid-19 will be identified using the special covid-19 SMQ 
containing a narrow basket of preferred terms (PTs) to provide a more targeted list of 
events related to the SARS-CoV-2 virus. Only events occurring in the pandemic 
timeframe (1 Dec 2019 onwards) will be included in this list. A listing of such adverse 
events associated with covid-19 will be provided. For those patients with confirmed 
covid-19 infection or positive PCR test (9 preferred terms from the above SMQ) any 
other AEs occurring within <=7 days before and <=30 days after start date of the AE
will also be considered as covid-19 associated events.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
4.4.3
Laboratory Data
For all safety laboratory parameters (including iron parameters), the change in average 
lab parameter values, from baseline to evaluation period will be summarized using 
descriptive statistics (mean, standard deviation, minimum, maximum and quartiles). For 
all safety laboratory parameters, the baseline is defined as last value before the first 
study drug administration. For the iron and selected hematology parameters 
(reticulocytes, red blood cells count, serum ferritin, serum iron, and Transferrin 
Saturation (TSAT)), baseline is defined using all the assessments between day -35 and 
the day of first study dose (day 1 pre-dose). For these parameters, baseline value is 
calculated using the time adjusted approach described in Section 4.3.1.
For safety labs, the assessment corresponding to Week 21 will be used as evaluation 
assessment. For Iron parameters (serum iron, serum ferritin, TSAT), the average of 
assessments done in evaluation period (i.e. all assessments between Week 17 and 
Week 21) will be used as evaluation assessment. For hematology labs (Hb, 
reticulocytes, RBC), the average value for each individual during the evaluation period 
will be calculated using the same method (time adjusted average) as for the baseline 
period.
Sites have the possibility to enter one of two alternative parameters: TSAT or 
hypochromic RBCs; transferrin or total iron binding capacity (TIBC). The same 
parameter should be recorded for a patient all the way through the study. For all 
patients, transferrin saturation will be recalculated as the ratio (%) of serum iron to 
serum transferrin (where available) or serum iron and TIBC if transferrin is not available
using the formulae given below. Summaries will be based on the calculated values. 
Listings will contain both the calculated TSAT values and those provided on the CRF 
where available.
Selected safety laboratory parameters (AST, ALP, ALT, leucocytes, serum albumin, c-
reactive protein, potassium, phosphorus, calcium, platelets) will be assessed for 
clinically significant abnormalities as well as shifts from baseline to worst post-baseline 
values.
4.4.4
Vital Signs
Vital signs (systolic and diastolic blood pressure and pulse rate) will be summarized 
descriptively at baseline and each pre-defined time point per protocol using summary 
statistics such as mean, std. dev., minimum, maximum and quartiles. To summarize the 


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
data from this pediatric population, normalized Z- scores will be used to assess if the 
population values are above or below age, sex and development stage-specific norms.
For patients on hemodialysis, pre and post hemodialysis assessments of vital signs will 
be summarized descriptively.
Normalized Z-scores 
Normalized Z-scores will be calculated for height, weight and blood pressure. These 
standardize the data relevant to a reference population using ranges based on age and 
sex (and additionally for blood pressure, height). This standardization makes results 
comparable across ages and allows meaningful calculation of summary statistics. A Z-
score of 0 indicates that a patient’s value is average for their sex and age (and 
development). In the standard normal distribution 68%, 95% and 99% of values fall 
within a Z-score of ±1, ±2 and ±3 respectively. Values outside of ±2 are therefore often 
considered as low/high, as in the reference population only 5% of comparable children 
have values this extreme. Percentiles corresponding to the Z-scores can also be used 
for summaries. Z-scores of -1.89, -1.65, -1.28, -0.68, 0, 0.68, 1.28, 1.65, and 1.89 
correspond to the 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97th percentiles 
respectively.
Height and Weight 
In this short study growth and development over time will not be assessed, but 
normalized scores will be used to summarize the population. The reference to be used is 
the US CDC (Centers for Disease Control and Prevention) Growth Charts. 
The method for calculating a standardized score is referred to as the ‘LMS method’ [1], 
which utilizes Box-Cox transformations to normalize the data. The Z-score for a given X 
(the height or weight value of interest), can be calculated as:
Where: L is the skewness parameter, M the median and S the generalized coefficient of 
variation. The L, M, S parameters are sex & age (in months) specific and can be 
obtained from the CDC website.
Blood Pressure 
Normalized scores for blood pressure are calculated using the methodology described in 
“The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure 
in Children and Adolescents” [2]. Blood pressure standards are based on a child’s sex, 
age and height. 
An expected blood pressure value for a child of age y with a height Z-score Zht 
(computed with the CDC method above) is calculated using the following equation.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
The α,β,γ parameter values are given in the reference document, with different values 
for systolic and diastolic blood pressure for males and females. A normalized Z-score is 
then calculated by taking the observed value minus this expected value and dividing by 
a sex and systolic/diastolic specific standard deviation. Reference to the standard 
normal distribution gives the corresponding percentiles for these Z-scores. 
Pediatric patients can be classified as hypertensive (above the 95th percentile on 3 or 
more occasions), or pre-hypertensive (above the 90th percentile) based on these 
percentiles.
4.4.5
Deaths
Details of any deaths will be presented in the form of an individual patient listing, patient 
narratives as well as a frequency table by cause of death.
4.4.6
Patient Narratives
All patients with Confirmed/Suspected COVID-19 serious adverse events will be
included as patient narratives. Additional listings of medical history, demographic and 
baseline characteristics in patients with confirmed/ suspected covid-19 may be provided 
to support the narratives.
4.5
MISSING DATA
For patients with no recorded Hb during the evaluation period, the primary endpoint will 
be missing. Values missing in between non-missing assessments will not be replaced. 
To correct for any increase in Hb caused by RBC transfusions, the Hb values measured 
within 3 weeks after an RBC transfusion will be deleted.
4.6
INTERIM ANALYSES
Once 12 patients have completed 20 weeks of treatment, an interim analysis to assess 
efficacy, safety, and pharmacokinetics was performed. The analysis was reviewed by a 
Roche Internal Monitoring Committee (IMC) with the primary objective of assessing the 
safety and efficacy of the CFs for starting treatment with SC Mircera. This was assessed 
using Hb (the pharmacodynamic marker), changes in dose, and assessment of the PK 
data to compare to the available pediatric PK data under IV dosing. The variability of Hb 
was also assessed at this time, with regards to protocol assumptions. 
An individual’s Hb response was based on the mean Hb during the evaluation period 
(Weeks 17-21) and is defined as a mean Hb change from baseline within ±1g/dL. The 
90% CI for the average Hb change from baseline was calculated. 
The full details of the interim analysis and any decision criteria have been specified in
separate IMC documents. The statistical analysis has been detailed in a separate 
Interim analysis SAP.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
4.7
OPTIONAL SAFETY EXTENSION
In the majority of cases efficacy endpoints are defined based on data from the core 
study period only; additional outputs containing related data from the safety extension 
period will be produced.
The following analysis of key data from the optional safety extension period will be
performed: 
1. Patient disposition: patients entering, ongoing, withdrawing (with reason) and 
completing the extension period 
2. Summary of Hb over time 
3. Change in vital signs
4. Change in laboratory parameters
5. Listing of blood transfusions 
6. Adverse events 
a. Number of deaths, all AEs, SAEs
b. Listing of AEs
c.
Summary of AEs 
Generally, for outputs displaying summaries over time (e.g. laboratory parameters, vital 
signs) all time points for the complete trial will be displayed in a single output (core and 
extension periods combined), so no special distinction between periods is required. 
For Adverse Events in most cases, for each summary classification, 3 outputs will be 
produced based on different time periods – core study, extension study and the 
complete study. 
Note: to have the option to participate in the safety extension period patients were 
required to have stable Hb levels (within ± 1 g/dL of their baseline Hb and within the 
target range of 10-12 g/dL).


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
5.
REFERENCES
1. Centers for Disease Control and Prevention, National Center for Health 
Statistics. CDC growth charts: United States. http://www.cdc.gov/growthcharts/. 
May 30, 2000.
2. “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents”
https://www.nhlbi.nih.gov/sites/default/files/media/docs/hbp_ped.pdf


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
Appendix 1
PROTOCOL SYNOPSIS
TITLE:
AN OPEN-LABEL, SINGLE-ARM, MULTICENTER STUDY TO 
ASCERTAIN THE OPTIMAL STARTING DOSE OF MIRCERA®
GIVEN SUBCUTANEOUSLY FOR THE MAINTENANCE
TREATMENT OF ANEMIA IN PEDIATRIC PATIENTS WITH 
CHRONIC KIDNEY DISEASE ON DIALYSIS OR NOT YET ON 
DIALYSIS
PROTOCOL NUMBER:
NH19708
VERSION NUMBER:
4
EUDRACT NUMBER:
2016-004779-39
IND NUMBER:
10158
TEST PRODUCT:
Mircera(RO0503821)
PHASE:
Phase II
INDICATION:
Chronic renal anemia
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will ascertain the starting dose of Mirceragiven subcutaneously for the maintenance 
treatment of anemia in pediatric patients with chronic kidney disease (CKD) on dialysis or not 
yet on dialysis when switching from stable subcutaneous (SC) maintenance treatment with 
epoetin alfa, epoetin beta, or darbepoetin alfa.  Specific objectives and corresponding endpoints 
for the study are outlined below.
Table 1 Objectives and Corresponding Endpoints
Efficacy Objective
Corresponding Endpoints
To ascertain the starting dose of 
Mircera given subcutaneously in 
pediatric patients with CKD on dialysis 
or not yet on dialysis when switching 
from stable SC maintenance treatment 
with epoetin alfa, epoetin beta, or 
darbepoetin alfa 
Primary endpoint:
Change in Hb concentration (g/dL) between the 
baseline and the evaluation period for each patient
Secondary endpoints:
Number of patients with an average Hb concentration 
during the evaluation period within 1 g/dL of their 
baseline Hb or above, within or below the range of 
1012 g/dL
Change in Mircera dose over time, including the 
change between the starting dose and the evaluation 
period
Safety Objective
Corresponding Endpoints
To assess the safety and tolerability of 
multiple doses of Mircera given 
subcutaneously in pediatric patients
Occurrence and severity of adverse events
Change from baseline in targeted vital signs


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
Change from baseline in targeted clinical laboratory 
test results
Pharmacokinetic and 
Pharmacodynamic Objective
Corresponding Endpoints
To evaluate the pharmacokinetics and 
the pharmacodynamics of Mircera in 
patients on dialysis or not yet on 
dialysis who receive the study 
medication by the SC route of 
administration
Serum concentrations of Mircera and Hb will be used 
to evaluate the pharmacokinetics and the 
pharmacodynamics of Mircera through PK and PK/PD 
models. 
CKDchronic kidney disease; Hbhemoglobin; PDperitoneal dialysis; PKpharmacokinetic; 
PK/PDpharmacokinetic/pharmacodynamic.
Study Design
Description of Study
This study is an open-label, single-arm, multicenter study to ascertain the optimal starting dose 
of Mircera given subcutaneously for the maintenance treatment of anemia in pediatric patients 
with CKD on dialysis or not yet on dialysis.
Following written informed consent from a parent or legal guardian and, if appropriate, assent 
from the child, the patient will be screened for eligibility during a screening period of 
approximately 3 weeks.  During this period, patients will continue to receive epoetin alfa, 
epoetin beta, or darbepoetin alfa at the same weekly dose, route (SC), and interval as before 
screening.  The total weekly doses 4 weeks before the first Mircera administration should not 
change 25% (increase or decrease).  Provided that all eligibility criteria are met, including 
those for hemoglobin (Hb) levels and iron status, the patients will start Mircera administered 
subcutaneously. 
At least 40 pediatric patients 3 months17 years of age will be enrolled.  Approximately 1015 
of these patients will be 12 years old, with a goal to include as many patients 5 years old as 
possible (with a minimum of 3 patients).  Approximately 1015 patients, irrespective of age, will 
not be on dialysis.  
Available hemodialysis (HD) patients receiving their erythropoiesis-stimulating agent (ESA) 
subcutaneously are eligible for enrollment.  No more than 10 patients on HD should be enrolled.
Mircera will be administered subcutaneously once every 4 weeks for the duration of the study.  
Dose adjustments may be performed every 4 weeks according to dose adjustment rules.
The core study will last for 23 weeks and consists of three periods:  screening (3 weeks), dose 
titration (16 weeks), and evaluation (4 weeks). 
Patients completing the 20 weeks of treatment with Hb within 1 g/dL of their baseline Hb and 
within the target range of 1012 g/dL, will be eligible to enter an optional 24-week safety 
extension period.  Those patients not eligible or not consenting to enter the long-term safety 
extension should be treated according to clinical practice.  All patients must complete the 
Week 21 visit (Visit 10), regardless of whether they continue in the safety extension period.  
Visit 10 will serve as the final visit of the core study and the first visit of the safety extension 
period for patients eligible and willing to continue in the study.
Once 12 patients have completed 20 weeks of treatment (dose titration and evaluation periods), 
an interim analysis to assess the pharmacokinetics, efficacy, and safety of Mircera will be 
performed.
Number of Patients
Approximately 40 pediatric patients (3 months17 years of age), who are evaluable for 
intent-to-treat (ITT) and safety analyses, who have clinically stable chronic renal anemia on 
dialysis or not yet on dialysis, and who are receiving maintenance SC treatment with an ESA, 
will be enrolled in this study.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent from parent/legal guardian and willingness of parent/legal 
guardian to abide by the requirements of the study  

Written informed consent or assent from child where appropriate  
If required by national legislation, patients 18 years of age at screening who are 
legally considered to be adults according to national legislation must consent in their 
own right. 

Pediatric patients 3 months17 years of age with clinically stable chronic renal anemia

CKD with estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m2 (determined by 
the Bedside Schwartz formula) or dialysis treatment for at least 8 weeks before the first 
dose of Mircera

For patients on peritoneal dialysis (PD):  a weekly Kt/V 1.8

For patients on HD:  adequate HD, urea reduction ratio (URR) 65% or Kt/V 1.2 for 
patients on HD three times per week.  
Patients with fewer than or more than three HD sessions per week should have a 
weekly Kt/V 3.6.

Baseline Hb concentration 10.012.0 g/dL determined from the mean of two Hb values 
measured at Visit 1 (Week 3) and Visit 2 (Week 1)

Stable SC maintenance treatment with epoetin alfa, epoetin beta, or darbepoetin alfa with 
the same dosing interval for at least 6 weeks before the first dose of Mircera

Stable dose of epoetin alfa, epoetin beta, or darbepoetin alfa treatment with no weekly dose 
change 25% (increase or decrease) for at least 4 weeks before the first dose of Mircera

Adequate iron status defined as ferritin 100 ng/mL or transferrin saturation (TSAT) 20% 
(or percentage of hypochromic red cells 10%); mean of two values measured during 
screening

For post-pubertal female patients of childbearing potential:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or to use acceptable contraceptive methods during 
the study and for 90 days after the final dose of Mircera
A female patient is considered to be of childbearing potential if she is postmenarcheal.
The following are acceptable contraceptive methods:  hormonal contraceptives; 
hormone-releasing intrauterine devices; copper intrauterine devices; male or female 
condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.

The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Overt gastrointestinal bleeding within 8 weeks before screening or during the screening 
period

RBC transfusions within 8 weeks before screening or during the screening period

Hemoglobinopathies (e.g., homozygous sickle-cell disease, thalassemia of all types)

Hemolytic anemia

Active malignant disease

PD subjects with an episode of peritonitis within the past 30 days prior to screening and/or 
during the screening period 

Uncontrolled or symptomatic inflammatory disease (e.g., systemic lupus erythematosus)


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)

Uncontrolled hypertension as assessed by the investigator

Epileptic seizures within 3 months prior to screening and during the screening period

Administration of any investigational drug within 4 weeks prior to screening or planned 
during the study

Kidney transplant with use of immunosuppressive therapies known to exacerbate anemia

Severe hyperparathyroidism (intact parathyroid hormone [PTH] 1000 pg/mL or whole 
PTH 500 pg/mL) or biopsy-proven bone marrow fibrosis

Known hypersensitivity to recombinant human erythropoietin (EPO), polyethylene glycol, or 
any constituent of the study drug formulation

Anti-EPO antibody (AEAB)-mediated pure red cell aplasia (PRCA) or history of 
AEAB-mediated PRCA or positive AEAB test result in the absence of PRCA

High likelihood of early withdrawal or interruption of the study (e.g., planned living donor 
kidney transplant within 5 months of study start)

Planned elective surgery during the entire study period

Females who are pregnant or breastfeeding or who intend to become pregnant during the 
study or within 90 days after the final dose of Mircera
Note:  Patients of childbearing potential must have a negative serum pregnancy test 
result within 21 days prior to initiation of study drug.
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs.  
LPLV is expected to occur approximately 44 weeks after the last patient is enrolled.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 41 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is Mircera.
Mircera will be administered subcutaneously once every 4 weeks for the duration of the study.  
Dose adjustments may be performed every 4 weeks according to dose adjustment rules.
The starting dose will be based on conversion factors (CFs) obtained from the dose-finding 
study (Study NH19707).  The initial dose of Mircera will be one of nine starting doses 
corresponding to the prefilled syringe strengths based on the total weekly ESA dose during the 
screening period.
Statistical Methods
Primary Analysis
The primary endpoint will be the change in Hb concentration (g/dL) between the baseline and 
the evaluation period for each patient.  
This is calculated on a per-patient basis, using an area under the curve approach to calculate 
an individual’s average for both the baseline and evaluation periods and taking the difference. 
The baseline period is defined as all assessments between the day of first study dose and the 
previous 35 days. If during the baseline period Hb measurements H0,…,Hn are taken at 
timepoints t0,…,tn, a time adjusted average baseline Hb value will be calculated by 



1
1
0)
(2
1







i
i
i
i
i
n
t
t
H
H
t
t
y
The value on the day of the first dose is included in the baseline calculation, as this assessment 
will be performed before the first dose is given. 


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
The average Hb value for each individual during the evaluation period will be calculated using 
the same method as for the baseline period.  The evaluation period is defined as all 
assessments between Visit 8 (Week 17) and Visit 10 (Week 21) inclusive.  Subtracting the 
baseline period value from the evaluation period value gives the change in Hb concentration 
(g/dL) between the baseline and evaluation period.
For patients with no recorded Hb during the evaluation period, the primary endpoint will be 
missing.  Values missing in between non-missing assessments will not be replaced, as these 
will be interpolated by the trapezoidal rule.  To correct for any increase in Hb caused by RBC 
transfusions, the Hb values measured within 3 weeks after an RBC transfusion will be deleted.
The individual change from baseline will be reported using summary statistics (including mean, 
standard deviation, and 90% CI of mean change).  No formal statistical testing will be 
performed.  Additional analysis will be performed by age category (5, 511, 12 years), 
dialysis type (not yet on dialysis, PD, HD) and previous ESA (epoetin alfa, epoetin beta, and 
darbepoetin alfa), if numbers allow.
Determination of Sample Size  
This is an exploratory study without a powered statistical group comparison.  Therefore, no 
formal sample size estimation will be performed; however, the calculations below indicate the 
approximate precision that could be achieved.  
Assuming a 30% withdrawal rate (based on the withdrawal rate for the NH19707 study), of the 
40 patients evaluable for ITT and safety analysis, more than 26 patients will have data for the 
evaluation period.  Twenty-six patients will be sufficient to provide approximately 90% power 
that the 90% CI for the Hb change from baseline to the evaluation period is between 1 and 
1 g/dL, provided the standard deviation is smaller than 1.5 and the optimum dose conversion is 
able to maintain the Hb at the baseline level.
Approximately 1015 of the patients will be 12 years old, with the objective to include as many 
patients 5 years old (minimum 3 patients) as possible.  Approximately 1015 patients, 
irrespective of their age, will not be on dialysis.  Available HD patients receiving their ESA 
subcutaneously are eligible for enrollment.  No more than 10 patients on HD should be enrolled.
To achieve the recruitment of the intended number of patients and in case of excessive dropout 
rate, additional patients may be enrolled to replace patients not treated for a minimum duration 
of 18 weeks.
Interim Analyses
Once 12 patients have completed 20 weeks of treatment, an interim analysis to assess efficacy, 
safety, and pharmacokinetics will be performed.  The analysis will be reviewed by a Roche 
Internal Monitoring Committee (IMC) with the primary objective of assessing the safety and 
efficacy of the CFs for starting treatment with SC Mircera.  This will be assessed using Hb (the 
pharmacodynamic marker), changes in dose, and assessment of the pharmacokinetic (PK) data 
to compare to the available pediatric PK data under IV dosing.  The variability of Hb will also be 
assessed at this time, with regard to protocol assumptions, and the sample size will be revised if 
necessary. 
An individual’s Hb response will be based on the mean Hb during the evaluation period 
(Weeks 1721) and is defined as a mean Hb change from baseline within 1g/dL.  The 90% CI 
for the average Hb change from baseline will be calculated.  
Interim PK and pharmacokinetic/pharmacodynamic (PK/PD) analyses will be conducted, as 
follows:

External validation of the existing PK and PK/PD models against preliminary 
Study NH19708 data to highlight any deviation from the current knowledge of Mircera PK 
and pharmacodynamic properties; the bioavailability in pediatric patients will be carefully 
regarded. 

A Bayesian feedback approach will also be used on Mircera serum concentration-time data 
to get a first assessment of the individual PK parameters in pediatric patients receiving 
Mircera subcutaneously, especially bioavailability.
The full details of the interim analysis, and any decision criteria, will be specified in separate 
IMC documents.


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
Appendix 2
Schedule of Assessments
Study Period
Screening 
Period
~ 3 weeks a
Dose Titration Period
16 weeks
Evaluation Period
4 weeks
Visit Number
1
2
3
4
5
6
7
8
9
10
Name of the 
Visit Day 
(start of 
Week ...) b
Week 
3 a
Week 
1 a
Week 
1 c
Week 
3
Week 
5
Week 
9
Week 
13
Week 
17
Week 
19
Week 21
Follow-Up 
Visit d
Informed 
consent
x
Medical history 
e
x
Physical 
examination f
x
x
Pregnancy test 
g
x
Vital signs, 
weight h
x
x
x
x
x
x
x
x
Height 
x
x
Hematology i
x
x
x
x
x
x
x
x
x
x
Serum 
creatinine j
x
x
x
Iron 
parameters k
x
x
x
x
x
Kt/V for 
patients on PD
x
x
Kt/V or URR 
for patients on 
HD
x
x
x
x
x
x
x
Safety 
laboratory l
x
x
x
Anti-EPO and 
anti-Mircera 
antibody m
x
x
x
Injection pain 
questionnaire n
(x) o
(x) o
x
x
Concomitant 
therapy p
Recorded throughout screening, dose titration and evaluation periods


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
Study Period
Screening 
Period
~ 3 weeks a
Dose Titration Period
16 weeks
Evaluation Period
4 weeks
Visit Number
1
2
3
4
5
6
7
8
9
10
Name of the 
Visit Day 
(start of 
Week ...) b
Week 
3 a
Week 
1 a
Week 
1 c
Week 
3
Week 
5
Week 
9
Week 
13
Week 
17
Week 
19
Week 21
Follow-Up 
Visit d
Adverse events 
q
Recorded throughout the dose titration and evaluation periods
ESA 
administration
x r
Mircera 
administration
x c
x c
x c
x c
x c
Iron 
supplementation
As needed to maintain iron stores
PK sampling s
x
x
x
x
x
CKDchronic kidney disease; eCRFelectronic Case Report Form; eGFRestimated 
glomerular filtration rate; EPO erythropoietin; ESAerythropoietin-stimulating agent; 
Hbhemoglobin; HDhemodialysis; PDperitoneal dialysis; PKpharmacokinetic; 
TSATtransferrin saturation; URRurea reduction ratio.
a Visits 1 and 2 should be 2 weeks apart (3 days). The ESA dosing interval needs to be 
taken into account when planning Visits 1, 2, and 3, i.e., the number of days between Visits 
2 and 3 should be based on the dosing interval of the ESA drug, which may result in a 
screening period of up to a maximum of 4 weeks.
b Visit window 3 days.  All study visits should be scheduled based on the date of the first 
Mircera dose at Visit 3 (Week 1).  For patients under HD or patients converting to HD, the 
study visits should occur on the day of the mid-week dialysis.
c Mircera is administered every 4 weeks during dose titration and evaluation periods.
d Follow-up visit assessments should be performed before resuming epoetin alfa, epoetin beta, 
or darbepoetin alfa dose.  
e Medical history includes demographics, other diseases, etiology of CKD, details of dialysis, 
previous treatments including ESA treatments, and iron supplementation.
f
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic 
systems.  Any abnormality identified should be recorded on the corresponding page of the 
eCRF.
g Serum pregnancy test should be performed in post-pubertal female patients of childbearing 
potential.  If a pregnancy is suspected, the serum pregnancy test must be repeated during the 
course of the study.
h Systolic and diastolic blood pressure and pulse rate will be recorded while the patient is if 
possible in a seated position, and they will be measured before blood sampling.  The blood 
pressure should be measured at least twice and the average of these measurements should 
be recorded.  An appropriate-sized cuff should be used.  Blood pressure should be 
determined before and after the dialysis session for patients with HD.  Body weight will also 
be recorded (after dialysis for patients on HD).
i
Includes Hb, RBC, and absolute reticulocyte count.  Samples should always be obtained on 
the same day of the week, if possible, prior to injection of Mircera and, for patients on HD, 
before dialysis.  


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
j
Serum creatinine should be measured only for patients not on dialysis.  eGFR will be 
calculated using the Bedside Schwartz formula (see Appendix 3 of protocol).
k Includes serum ferritin, serum iron and TSAT.  TSAT will be calculated as described in 
Appendix 3 of protocol with either serum transferrin or total iron-binding capacity.  The 
percentage of hypochromic red blood cells may be determined instead of TSAT.
l
Includes leukocytes plus differential, AST, ALT, serum albumin, ALP, C-reactive protein, 
potassium, phosphorus, calcium, and platelets.
m Anti-EPO and anti-Mircera antibody samples should be collected prior to study drug 
administration.
n Injection pain will be assessed by the patient, parent/guardian, and nurse/site staff member 
as appropriate.  Children under the age of 4 will not be asked to rate their own pain.  As much 
as possible, the same nurse/site staff member should rate pain at every visit.  The 
assessments will take place approximately 5 minutes after study drug injection.  Assessment 
of ESA injection pain during the screening period will be assessed in all patients who receive 
an ESA injection during either or both of the screening visits.
o Parentheses indicate that the assessment is optional.  The assessment at the screening visit 
is only necessary if ESA drug has been injected on that day.  Therefore, not all patients will 
assess injection pain.
p All concomitant therapy administered within 3 months before screening or during the 
screening or treatment periods should be reported.
q Prior to initiation of study drug, report only serious adverse events caused by a protocol-
mandated intervention.
r
Treatment with ESAs should continue during the screening period at the previous dosing 
interval.  Note that depending on the dosing interval, ESA treatment may or may not be 
administered the same day as the screening period visit.
s At Visit 3 (Week 1), Visit 6 (Week 9), and Visit 8 (Week 17), samples should be drawn before 
the Mircera dose.  At the patient’s convenience, a sixth PK sample between 24 hours and 5 
days after any one Mircera dose administration should also be collected.  A minimum of one 
PK sample after treatment initiation is requested in patients younger than 2 years old; the 
sample on Week 1 can be omitted in these patients.  The exact time of PK blood sampling 
must be recorded on the lab requisition form and the exact time of the preceding Mircera 
administration must be recorded on the appropriate page in the eCRF. 


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
Study Period
Safety Extension Period
24 Weeks
Visit Number
10
11
12
13
14
15
16
Name of the Visit Day 
(start of Week ...) a
Week 21 b
Week 25
Week 29
Week 33
Week 37
Week 41
Week 45 
Final Safety Extension 
Visit c
Informed consent
x
Physical examination d
x
x
Vital signs, weight e
x
x
x
x
x
x
x
Height
x
x
Hematology f
x
x
x
x
x
x
x
Serum creatinine g
x
x
Iron parameters h
x
x
x
x
Kt/V for patients on PD
x
x
Kt/V or URR for patients on HD
x
x
x
x
x
x
x
Safety laboratory i
x
x
x
Anti-EPO and anti-Mircera 
antibody j
x
x
Concomitant therapy
Recorded throughout the safety extension period
Adverse events
Recorded throughout the safety extension period
Mircera administration
x
x
x
x
x
x
Iron supplementation
As needed to maintain adequate iron stores


Mircera—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan NH19708 (Skipper)
eCRFelectronic Case Report Form; EPO erythropoietin; HDhemodialysis; PD peritoneal dialysis; URRurea reduction ratio.
a Visit window 3 days.
b Visit 10, Week 21 corresponds to the follow-up visit of the core study period (see Appendix 1 of protocol).
c Final assessments should be performed before resuming epoetin alfa, epoetin beta, or darbepoetin alfa dose.
d Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurologic systems. Any abnormality identified should be recorded on the corresponding page 
of the eCRF.
e Every 4 weeks, systolic and diastolic blood pressure and pulse rate will be recorded while the patient is if possible in a seated 
position, and they will be measured before blood sampling.  The blood pressure should be measured at least twice and the 
average of these measurements should be recorded.  An appropriate-sized cuff should be used.  Blood pressure should be 
determined before and after the dialysis session for patients on HD.  Body weight will also be recorded (after dialysis for patients 
on HD).
f
Includes Hb, RBC, and absolute reticulocyte count.  Samples should always be taken on the same day of the week, if possible,
prior to the injection of Mircera and, for patients on HD, before dialysis.  
g Serum creatinine should be measured only for patients not on dialysis.  eGFR will be calculated using the Bedside Schwartz 
formula (see Appendix 3 of protocol).
h Includes serum ferritin, serum iron and TSAT.  TSAT will be calculated as described in Appendix 3 of protocol with either serum 
transferrin or total iron-binding capacity.  The percentage of hypochromic red blood cells may be determined instead of TSAT.
i
Includes leukocytes plus differential, AST, ALT, serum albumin, ALP, C-reactive protein, potassium, phosphorus, calcium, and 
platelets. 
j
Anti-EPO and anti-Mircera antibody samples should be collected prior to study drug administration.