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Study Title: A Prospective Registry Study Observing the Safety and Patterns of Use of Darbepoetin Alfa in EU Paediatric Chronic Kidney Disease Patients Receiving or Not Receiving Dialysis

Product: Darbepoetin alfa

Indication: Anaemia in paediatric subjects with chronic kidney disease (CKD) receiving or not receiving dialysis

Brief Description: Prospective multi-centre, multi-national EU observational registry study of 321 paediatric subjects with CKD (on dialysis and not on dialysis) and CKD-related anaemia who were treated with darbepoetin alfa and followed for a maximum period of 2 years.

Study Sponsor: Amgen Inc., One Amgen Center DriveThousand Oaks, CA USA

Study No.: 20070211

Study Phase: Phase IV

Study Initiation Date: 26 February 2008 (first subject enrolled)

Interim Reports First annual report Second annual report Third annual report Fourth annual report

24 March 200917 March 201026 March 201126 March 2012

Study Completion Date: 15 February 2013 (last subject completed follow-up)

Principal Investigator(s): This study was conducted at 37 centres in 13 countries across Europe. Centres and principal investigators are listedin Appendix 3.

Contact Person: Jerome RossertTel: 805-447-1947FAX: 805-375-3389

Good Clinical / Pharmacoepidemiology Practice:

This study was conducted in accordance with applicable International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), Volume 10 of The Rules Governing Medicinal Products in the European Union - Guidelines on Pharmacovigilance for Medicinal Products for Human Use, and applicable country regulations. Essential documents will be retained in accordance with the guidelines.

Report Date: 12 July 2013

Product or Therapeutic Area:

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Darbepoetin alfaObservational Research Study Report: 20070211

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BODY OF REPORTName of Sponsor: Amgen Inc.,

One Amgen Center DriveThousand Oaks, CA USA

Product: Darbepoetin alfa

Indication: Anaemia in paediatric subjects with chronic kidney disease (CKD) receiving or not receiving dialysis

Title of Study: A Prospective Registry Study Observing the Safety and Patterns of Use of Darbepoetin Alfa in EU Paediatric Chronic Kidney Disease Patients Receiving or Not Receiving Dialysis

Investigator(s) and Study Center(s): This study was conducted at 37 study centres in 13 countries (Austria [3], Czech Republic [1], Finland [1], France [5], Germany [6], Hungary [2], Italy [6], Poland [3], Portugal [2], Slovakia [3], Spain [2], Sweden [2] and UK [1]) across Europe. Centres and principal investigators are listed in Appendix 3.

Publication(s): None

Study Period: 26 February 2008 (first subject enrolled) to 15 February 2013 (last subject completed follow-up)

Development Phase: Phase IV

Introduction and Objectives: Currently, darbepoetin alfa is indicated for the treatment of anaemia in adult and paediatric patients with CKD receiving or not receiving dialysis. However, while the results of Amgen Studies 980212 (An open-label randomized crossover study to determine the pharmacokinetics of novel erythropoiesis stimulating protein (NESP) in paediatric patients with chronic renal failure [CRF] or endstage renal disease [ESRD]) and 20000100 (An open-label, randomized, non-inferiority study of novel erythropoiesis stimulating protein (NESP) and recombinant human erythropoietin (rHuEPO) for the treatment of anemia in paediatric subjects with chronic renal insufficiency (CRI) or end-stage renal disease (ESRD) receiving dialysis) supported the treatment of anaemia with darbepoetin alfa in paediatric patients with CKD, there is limited information regarding the long-term safety of darbepoetin alfa in children.

Study 20070211 was a prospective multi-centre, multi-national European Union (EU)observational registry study designed to provide long-term safety data on darbepoetin alfa for the treatment for anaemia in paediatric subjects with CKD receiving and not receiving dialysis, including a minimum of 30 subjects younger than 6 years of age at the time of enrolment. This post-authorisation safety study (PASS) was developed in response to an EU regulatory request. The registry was entirely observational in nature, with no additional diagnostic or monitoring procedures applied to participating subjects. Subjects were observed for up to 2 years or until renal transplantation, permanent cessation of darbepoetin alfa treatment, enrolment into an interventional study, or withdrawal of informed consent.

The primary objective of the study was to assess the long-term safety of darbepoetin alfa therapy in paediatric subjects with CKD receiving or not receiving dialysis, as determined by the evaluation of incidence rates of serious adverse drug reactions (SADRs), serious adverse events (SAEs), and events of medical interest (EMIs, predefined for this study as thromboembolic or cardiovascular events, seizures, severe hypertension, pure red


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cell aplasia [PRCA], and hypersensitivity reactions). The secondary objective was to assess the usage pattern of darbepoetin alfa in this paediatric patient population, haemoglobin and selected related laboratory values over time, and non-serious adverse drug reactions (ADRs).

Study Hypothesis: This registry study was not designed to test a hypothesis, but rather to describe the safety profile of darbepoetin alfa in paediatric CKD patients.

Study Design/MethodologyThis study evaluated paediatric subjects with CKD on or not on dialysis who receiveddarbepoetin alfa for the treatment of anaemia. The study enrolled for 3 years, with each subject followed for up to 2 years or until renal transplantation, permanent cessation of darbepoetin alfa treatment, enrolment into an interventional study, withdrawal of informed consent, or death.

Diagnosis and Main Criteria for Eligibility:Main criteria for inclusion in the study included the following:

! 16 years of age or under! diagnosed with CKD (estimated glomerular filtration rate [eGFR]

< 60 mL/min/1.73m2 [Schwartz equation] for ≥ 3 months if not on dialysis, or receiving dialysis)

! diagnosed with anaemia attributed to CKD! treated with darbepoetin alfa! no active malignancy or current chemotherapy or radiation therapy

It was anticipated that approximately 240 to 300 subjects would enroll in this study during the 3-year enrolment period, including a minimum of 30 subjects under the age of 6 years at enrolment. It was also anticipated that approximately half the subjects enrolled would end study participation during the 2 year follow-up period as a result of receiving a renal transplant.

As an observational registry, there were no defined study procedures and data were collected only if available from routine clinical practice. Data were collected at study entry, and then at 3-month intervals; the information was obtained at subjects’ routine medical visits as per normal care. Baseline data collection included demographics, body weight and height, medical history (including primary cause of CKD and age at diagnosis, renal transplantations, and blood transfusions), dialysis status, modality and start date (if applicable), blood pressure, laboratory values (serum creatinine, haemoglobin, transferring saturation [TSAT], ferritin, c-reactive protein [CRP], parathyroid hormone [PTH]), history of erythropoiesis-stimulating agent (ESA) use prior to/at enrolment and current darbepoetin alfa use. During the treatment period, data regarding body weight and height, blood pressure, current dialysis status, kidney transplantation, darbepoetin alfa (or other ESA) usage, blood transfusions, laboratory values (haemoglobin, PTH), ADRs, SADRs, SAEs, EMIs, and hospitalizations werecollected.

For this study, an ADR was defined as an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a pre-existing medical condition that the investigator considered to be associated with the use of darbepoetin alfa. All serious and non-serious ADRs were recorded. An adverse event (AE) was defined for this studyas any untoward medical occurrence (sign, symptom, or diagnosis) or worsening of a pre-existing condition in a clinical investigation subject occurring from the time that the subject signed informed consent through the end of study, whether or not considered to


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have a causal relationship with darbepoetin alfa. Only AEs meeting serious criteria (eg, SAEs) were recorded. All EMIs (predefined for this study as thromboembolic or cardiovascular events, seizures, severe hypertension [at the investigator’s discretion andaccompanied by recorded blood pressure], PRCA, and hypersensitivity reactions) were collected.

Study Endpoints/Outcomes: The primary endpoints for this study were the occurrence of SADRs, SAEs, and EMIs.

Secondary endpoints included the dose of darbepoetin alfa over time, haemoglobin over time as well as selected laboratory values that may be related to haemoglobin over time, and non-serious adverse drug reactions.

Statistical Methods: All analyses were descriptive in nature. Continuous variables were summarized using n, mean, standard deviation, standard error, median, minimum, and maximum (and geometric mean, 25th and 75th percentiles and associated 95% confidence intervals [CI]if required). Categorical variables were summarized using frequency and percent. All summaries were based on the full analysis set (FAS) that included all subjects who received at least 1 dose of darbepoetin alfa during the study.

To address the study primary objectives, subject incidence rates of SADRs, SAEs, and EMIs were summarised using the actuarial life-table method with associated 95% CIs (Collett, 2003). Cumulative subject incidence rates at Month 22-24 were reported. Summaries of SADRs, SAEs, and EMIs were also presented as exposure-adjusted incidence event rates and exposure-adjusted event rates per 100 person-years of exposure with associated 95% CIs. Subgroup analyses were also performed for age (< 1 year, 1 to < 6 years, 6 to < 12 years, and ≥ 12 years of age) and baseline dialysis status (on dialysis, not on dialysis).

To address the secondary endpoints, the cumulative dose and cumulative weight-adjusted dose of darbepoetin alfa were summarized descriptively by monthly intervals. Haemoglobin was summarized descriptively at baseline and in 3-monthly intervals, as well as the number and percentage of subjects and time spent in haemoglobin categories (< 9 g/dL, < 10 g/dL, 10 to12 g/dL, > 12 g/dL, > 13 g/dL, and > 14 g/dL). Parathyroid hormone concentrations (pmol/L) and percent change from baseline PTH were summarised descriptively at baseline and by 3-monthly intervals. The incidence of non-serious ADRs was tabulated by system organ class, higher level group term and preferred term. Subgroup analyses of secondary endpoints were also performed for age and baseline dialysis status. Additional analyses were conducted to descriptively summarize vital signs, selected concomitant medications, transfusions, and hospitalisations.

Owing to the observational nature of this study, it was anticipated that there would be missing data. All data was utilized as collected and confirmed within the CRF with the exception of start dates of AEs and dialysis, the start and end dates for darbepoetin alfa dose records, transplant dates, and graft removal dates. Imputation rules for these variables are provided in the statistical analysis plan (SAP).

A complete description of the statistical methods is provided in the SAP (Appendix 2).


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Summary of Results: Enrolment and Disposition of Subjects: A total of 376 subjects were screened and 321 subjects were enrolled from 37 centres in 13 European countries (Table 14-1.1). Of those enrolled, 319 subjects were included in the FAS population; 2 subjects never received darbepoetin alfa and were excluded from the FAS population. One hundred forty-five (45.2%) subjects in the FAS completed the 2-year follow-up period(Table 14-1.2). The most common reason for discontinuation from the study was kidney transplant (121 [37.7%] subjects) (Table 14-1.3), which was one of the protocol-specified criteria for study discontinuation.

At study entry, 25 (7.8%) subjects had eligibility deviations of unmet inclusion criteria and 1 (0.3%) subject met an exclusion criterion (Table 14-1.5). The most frequent eligibility deviation was not receiving darbepoetin alfa treatment at entry (21 [6.5%] subjects).

Subject Characteristics: The mean (standard deviation [SD]) age of subjects at baseline was 9.1 (5.0) years (range: <1 to 16). The majority of subjects were male (177 [55.5%]) and White or Caucasian (274 [85.9%]) (Table 14-2.1.1). At baseline, the mean (SD) haemoglobin concentration was 11.1 (1.6) g/dL, serum ferritin was 230.2 (296.1) μg/L, TSAT was 28.3 (14.9) %, and CRP was 5.2 (13.6) mg/L (Table 14-2.2.1). Sixty-six (20.7%) subjects had received a kidney transplant prior tostudy entry (Table 14-2.3.1) and 57 (17.9%) had received ≥ 1 blood transfusion within 1 year prior to study entry (Table 14-2.6.1).

In the age subgroups, there were 13 (4.1%) subjects under 1 year of age, 83 (26.0%) subjects 1-< 6 years of age, 90 (28.2%) subjects 6-<12 years of age, and 133 (41.7%) subjects ≥12 years of age. Subjects < 1 year of age had lower eGFR, CRP concentrations, and systolic and diastolic blood pressure at baseline relative to subjects in older subgroups (Table 14-2.2.2). Peritoneal dialysis was more common in the 3 younger age groups, whereas haemodialysis was more common in the older age group (≥ 12 years) (Table 14-2.3.2).

At study entry, 158 (49.5%) subjects were receiving dialysis (haemodialysis, 74 subjects; peritoneal dialysis, 84 subjects) (Table 14-2.3.1). The median duration of dialysis prior to enrolment was 9.65 months (range < 1 to 190 months). One hundred and sixty (50.2%) subjects were not on dialysis at study entry, with a mean (SD) baseline eGFR of 37.31 (23.11) mL/min/1.73m2. More subjects receiving dialysis had a baseline history of blood transfusions, seizures, severe hypertension, and thromboembolic events thansubjects not receiving dialysis (Table 14-2.2.3 and Table 14-2.3.3).

At enrolment, 299 (93.7%) subjects were being treated with darbepoetin alfa, with a mean dose of 75.72 ∀g/month (Table 14-2.7.1 and Table 14-4.1.1). In violation of the protocol’s inclusion criteria, 21 (6.5%) subjects were not receiving darbepoetin alfa use at enrolment (Table 14-1.5); 1 of the 21 subjects was discontinued from the study on the same day as enrolment. Of the remaining 20 (6.3%) subjects who first received darbepoetin alfa after enrolment, 2 (0.6%) did not record any ESA use (ESA naive) in the 12 months prior to enrolment, while ESA use in the prior 12 months was unknown for the remaining 18 (5.6%) subjects (Table 14-2.2.1). These 20 subjects were all included in the FAS.


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Safety Results:Analysis of Primary EndpointsSerious Adverse Drug Reactions (SADR)For the purposes of this registry, an adverse drug reaction (ADR) was defined as an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a pre-existing medical condition that the investigator considered to be associated with the use of darbepoetin alfa; serious adverse drug reaction (SADRs) were ADRs that met the criteria for a serious event.

Four (1.3%) subjects experienced 9 SADRs during the study (2 subjects in the 6 to < 12 years of age subgroup and 2 subjects in the ≥ 12 years of age subgroup[Table 14-3.1.2]). No SADRs were reported for subjects < 1 year, or 1 to < 6 years of age. Three subjects receiving dialysis experienced SADRs and 1 non-dialysis subject experienced an SADR (Table 14-3.1.3).

Complete narratives are provided in Appendix 6 and summaries of these cases are provided below:

! Subject 211103015, a 14 year old female with a history of hypertension and chronic renal insufficiency due to membranoproliferative glomerulonephritis that was not on dialysis and had been treated with alternative medication for approximately 2 years, was hospitalised due to deterioration of her condition. The subject had no history of ESA use. Darbepoetin alfa therapy was initiated in the hospital and the subject was subsequently discharged. Approximately 22 days after initiation of darbepoetin alfa, the subject experienced SADRs of hemolysis, hemolytic anemia and thrombocytopenia. The subject was hospitalised with no treatment performed for the events. The patient was not seen by a hematologist. The investigator reported that there was no history of blood dyscrasias or concomitant viral or bacterial infections leading up to the event. According to the physician, PRCA could be excluded. Darbepoetin alfa treatment was discontinued approximately 1 week later. Thrombocytopenia resolved approximately 85 days after diagnosis, at which time darbepoetin alfa treatment was resumed. Hemolytic anemia resolved approximately 175 days after diagnosis while receiving darbepoetin alfa therapy. The investigator reported that there was a reasonable possibility that the events of hemolytic anemia and thrombocytopenia were related to investigational product as the events resolved after stopping the investigational product and other unspecified medications.

! Subject 211103008, a 15 year old female was hospitalised for suspected haemolytic uremic syndrome (HUS)(IgM positive for E. Coli 0157) following several days of moderate diarrhoea, recurrent fainting, and vomiting. It was noted that her brother and father had experienced post-streptococcal glomerulonephritis in their respective childhoods and that the family used raw milk directly bought from a farm. Darbepoetin alfa therapy was initiated during the hospitalization. Approximately 2 days after initial exposure to darbepoetin alfa, the subject developed an SADR of partial blindness with retinal bleeding and macular oedema. Chronically elevated blood pressure, decreased liver function, decreased platelet count, and increased lactate dehydrogenase werenoted at this time, but these measures subsequently improved. Darbepoetin alfa was permanently discontinued 3 days after initiation. Partial blindness resolved approximately 16 days after diagnosis. The investigator reported that the event


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of partial blindness may have been caused by darbepoetin alfa, or by the underlying HUS.

! Subject 211143011, an 11 year old male with a history of treatment resistant nephrotic syndrome, chronic renal failure, ESRD treated with haemodialysis then peritoneal dialysis, and seizure, experienced 3 episodes of priaprism starting approximately 15 months after initiation of darbepoetin alfa administration. In the first episode, the subject experienced a severe episode of priapism 1 week after the most recent darbepoetin alfa injection, which required puncture of the sinus cavernosus as an outpatient procedure. Approximately 14 days later, the subject once again developed priapism after receiving dialysis and darbepoetin alfa the same day. This event was moderate and treated with local anesthesia. The dose of darbepoetin alfa was decreased. Seven days later, the subject developed a third episode of severe priapism and underwent another puncture of sinus cavernosus. This event was considered medically significant. Each event of priapism resolved on the same day that it occurred. Darbepoetin alfa administration continued. The investigator stated that there was a reasonable possibility that priapism was related to darbepoetin alfa.

! Subject 211164004, a 10 year old male with a history of chronic renal failureunder dialysis, concomitantly receiving ramipril and amlodipine, experienced SADRs of thrombosis of the forearm arteriovenous (AV) fistula and thromboembolism. The subject had been receiving darbepoetin alfa therapy for approximately two and a half months prior to the event, with a decrease in dose approximately 1 month prior to the event. The subject had no previous episodes of thromboembolism, no other embolism at the time of the AV fistula thrombosis, nor did the subject experience previous complications with the AV fistula in the forearm. The investigator reported the event will never be resolved because the fistula was closed. The investigator reported that the subject did not receive medication for the event and a new fistula was created. Darbepoetin alfa therapy was temporarily discontinued and resumed 26 days after the event, with no reappearance of symptoms. The investigator reported that there was a reasonable possibility that arteriovenous fistula thromboembolism was related to darbepoetin alfa. Ramipril and amlodipine were considered to be co-suspect drugs.

Serious Adverse Events (SAE)A total of 434 SAEs were reported by 162 subjects during the study, with an exposure-adjusted event rate of 101.8 per 100 subject-years of exposure to darbepoetin alfa (Table 1 and Table 14-3.6.1). The most common SAEs reported by preferred term were peritonitis (32 [10.1%] subjects, all of whom were on peritoneal dialysis at the time of the adverse event), gastroenteritis (19 [6.0%] subjects), and hypertension (13 [4.1%]subjects) (Table 1 and Table 14-3.3.8).


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The number and exposure-adjusted event rate of SAEs by age subgroup and baseline dialysis status provided in Table 1, including the most frequently reported preferred terms per subgroup. Overall exposure adjusted event rates (per 100 person-years) for SAEs were higher for subjects in the younger 2 age groups (< 1 year and 1- < 6 years) compared with those in the older groups (6- <12 years and ≥ 12 years). This difference,at least in part, reflects epidemiological differences known to exist between these age groups, such as higher rates of infectious events in younger children (‘infections and infestations’ exposure adjusted event rates: < 1 year, 64.77 [95% CI: 31.06, 119.12];1- < 6 years, 59.63 [45.92, 76.14]; 6- <12 years, 26.67 [18.47, 37.27]; and ≥ 12 years,31.83 [24.04, 41.33]) (Table 14-3.6.2 to Table 14-3.6.5). For events that are related to the underlying disease state and treatment, such as hypertension, exposure adjusted event rates were similar between age groups (hypertension: < 1 year, 6.48 [0.16, 36.09]; 1- < 6 years, 10.25 [5.12, 18.34]; 6- <12 years, 3.14 [0.85, 8.03]; and ≥ 12 years,3.98 [1.60, 8.20]. Higher overall exposure adjusted event rates were also observed insubjects receiving dialysis at baseline compared with those not receiving dialysis at baseline.

Table 1. Serious Adverse Events(Full Analysis Set and Subgroups)

Subgroup CategorySubgroup

Overall Serious Adverse Event rateMost common preferred term

Number of subjects reporting

eventn (%)

Number of

events reported

Exposure AdjustedEvent Rate

per 100 Person-years(95% CI)

Serious Adverse Events – All subjects 162 (50.8) 434 101.83 (92.47, 111.87)Peritonitis 32 (10.0) 44 10.32 (7.50, 13.86)Gastroenteritis 19 (6.0) 22 5.16 (3.23, 7.82)Hypertension 13 (4.1) 23 5.40 (3.42, 8.10)

Age subgroup< 1 year of age

Overall Serious Adverse Event 7 (53.8) 23 148.98 (94.44, 223.54)Gastroenteritis 2 (15.4) 2 12.95 (1.57, 46.80)Catheter Site Infection 2 (15.4) 2 12.95 (1.57, 46.80)

1 to < 6 years of age

Overall Serious Adverse Event 51 (61.4) 164 152.79 (130.30, 178.05)

Peritonitis 13 (15.7) 18 16.77 (9.94, 26.50)Gastroenteritis 8 (9.6) 9 8.39 (3.83, 15.92)Hypertension 6 (7.2) 11 10.25 (5.12, 18.34)

6 to < 12 years of ageOverall Serious Adverse Event 39 (43.3) 88 69.03 (55.36, 85.04)

Peritonitis 10 (11.1) 14 10.98 (6.00, 18.43)Hypertension 4 (4.4) 4 3.14 (0.85, 8.03)Convulsion 4 (4.4) 6 4.71 (1.73, 10.24)

Page 1 of 2CI = confidence intervalSource: Table 14-3.3.8 to Table 14-3.3.10, and Table 14-3.6.1 to Table 14-3.6.7


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Table 1. Serious Adverse Events(Full Analysis Set and Subgroups)


Overall Serious Adverse Event rateMost common preferred term


eventn (%)

Number of

events reported



Age subgroup (continued)≥ 12 years of age

Overall Serious Adverse Event 65 (48.9) 159 90.37 (76.87, 105.56)Peritonitis 8 (6.0) 10 5.68 (2.73, 10.45)Gastroenteritis 7 (5.3) 9 5.12 (2.34, 9.71)Pyelonephritis 5 (3.8) 6 3.41 (1.25, 7.42)Hypertensive Crisis 5 (3.8) 6 3.41 (1.25, 7.42)

Baseline dialysis status subgroupDialysis at baseline

Overall Serious Adverse Event 85 (53.8) 252 140.32 (123.53, 158.76)

Peritonitis 25 (15.8) 36 20.05 (14.04, 27.75)Hypertension 11 (7.0) 19 10.58 (6.37, 16.52)Gastroenteritis 8 (5.1) 8 4.45 (1.92, 8.78)

Not on dialysis at baselineOverall Serious Adverse Event 77 (48.1) 182 73.80 (63.47, 85.33)

Gastroenteritis 11 (6.9) 14 5.68 (3.10, 9.52)Peritonitis 7 (4.4) 8 3.24 (1.40, 6.39)Renal Failure Chronic 6 (3.8) 6 2.43 (0.89, 5.30)Urinary Tract Infection 6 (3.8) 7 2.84 (1.14, 5.85)

Page 2 of 2CI = confidence intervalSource: Table 14-3.3.8 to Table 14-3.3.10, and Table 14-3.6.1 to Table 14-3.6.7

Fatal Serious Adverse Events

Six (1.9%) subjects had a fatal event,1 none of which were considered to be related to darbepoetin alfa by the investigator. Three of the fatal events (pulmonary oedema, severe hypertension, gastrointestinal necrosis) were reported in the < 1 year age subgroup, and one event was reported in each of the other age subgroups (mitochondrial disease, 1 to < 6 year group; sepsis, 6-< 12 year group; pulmonary oedema, ≥ 12 year group). Four subjects experiencing a fatal event were receiving dialysis; two were not receiving dialysis.

1 Note: In the second interim analysis dated 17 March 2010 and submitted to BfArM on 19 April 2010,

Subject 211212005 was reported to have had a fatal SAE on 07 November 2009. However, this subject had discontinued the study after receiving a kidney transplant on 22 April 2009. Since this fatal SAE has been confirmed as occurring after the end of study, it is not discussed in this study report.


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Complete narratives are provided in Appendix 6 and summaries of these cases are provided below:

! Subject 211151023, an 11-month old female with a history of congenital idiopathic steroid-resistant nephrotic syndrome with diffuse mesangial sclerosis on the kidney leading to endstage renal disease, undeveloped upper airway anatomical structures and respiratory difficulties, anemia, thrombocytosis, difficulties in dialysis via the central venous catheter, peritonitis, subglottic laryngitis, extreme metabolic acidosis, hypoalbuminemia, hypoproteinemia, proteinuria, oliguria, increased blood pressure, and low levels of immunoglobulin G with high CD4/CD8 ratio, experienced a fatal SAE of pulmonary oedema approximately 35 days after initiation of darbepoetin alfa treatment. The subject experienced diarrhea, vomiting and a marked decrease in urine output, then worsening dyspnea referring to severe pulmonary edema with Cheynes Stokes breathing. On hospital admission, the subject was put on a respirator. She had good blood pressure but presented symptoms of significant peripheral circulatory failure with pale and marbled skin and cyanotic lips, left-sided heart failure, moderate edema, and hypothermia. She also had bloody and foamy discharge coming out from her tracheal tube, pulmonary hemorrhage and diffusely mixed rales over the lungs. Lab tests showed lactic acidosis, moderate hyperkalemia, hypocalcemia and a chest x-ray revealed significant congestion in the pulmonary circulation. Despite multiple treatments, supportive measures, and resuscitation, the subject experienced a fatal SAE of pulmonary oedema. The possible causes of death in addition to the underlying disease were fluid retention with electrolyte abnormalities resulting from a viral infection, secondary left-sided heart failure and pulmonary edema which were further deteriorated by multi-organ failure following multiple reanimations. The investigator considered chronic renal failure and onset of oliguria as risk factors for the event. The investigator reported that there was not a reasonable possibility that fatal pulmonary oedema was related to darbepoetin alfa therapy.

! Subject 211211002, a 7 year old female with a history of autosomal recessive polycystic kidney disease (ARPKD) not on dialysis, cholangitis, and mild hypertension experienced a fatal SAE of sepsis approximately 8 months after initiation of darbepoetin alfa therapy. The subject died from sepsis one day after event onset. No further information was provided as the subject died in ahospital not associated with the study. The source of sepsis was not identified. The investigator reported that there was not a reasonable possibility that fatal sepsis was related to darbepoetin therapy.

! Subject 211212008, a 6 month old female with a history of ARPKD with hepatic fibrosis, end-stage renal disease under dialysis, and hypertension, experienced an SAE/EMI of severe hypertension, that led to cardiomyopathy, subsequent cardiac arrest, and death approximately 3 months after initiation of darbepoetin alfa therapy. The subject was hospitalized for worsening shortness of breath thought to be due to pneumonia. After some initial improvement with treatment, she developed pulmonary edema and cardiogenic shock which required intubation and therapy with vasopressors and intravenous inotropic agents. Her echocardiogram showed left ventricular hypertrophy and outlet obstruction with a gradient of 50 mm of Hg. Given her poor prognosis and hepatic and renal failure, the family decided on comfort care only. The cause of death was reported as "arrest cardiac by cardiomyopathy due to severe hypertension associated with ESRD in the context of (autosomal recessive polycystic kidney disease)


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ARPKD." The investigator reported there was not a reasonable possibility that the fatal hypertension was related to darbepoetin alfa treatment.

! Subject 211221001, a 15 year old male with a history of chronic renal failure due to nephronophthisis under peritoneal dialysis, Joubert's syndrome with autism and delayed psychomotor development, and failed renal transplantation received darbepoetin alfa treatment on study for approximately nine and a half months. The subject then discontinued darbepoetin alfa treatment. Approximately 2 weeks after discontinuation of darbepoetin alfa therapy, the subject developed difficulty breathing and fatigue, and was hospitalised. It was reported that peritoneal dialysis had worked well initially; however, the adequacy of peritoneal dialysis had been progressively worsening with time. His physicians agreed that the subject would not be approved for re-transplantation and that hemodialysis was not a suitable alternative. The family agreed on palliative care and peritoneal dialysis was withdrawn. The subject experienced a fatal SAE of pulmonary edema 2 days later. Autopsy was not performed. The investigator reported there was not a reasonable possibility that the pulmonary edema may have been caused by darbepoetin alfa treatment.

! Subject 211151012, a 5 year old male with a history of bilateral renal hypoplasia, chronic renal failure not on dialysis at study entry, and repeated airway infectionswas hospitalised twice, once for hypokalemia and possible seizure and then again for seizure. The seizures were attributed to intermittent fever. Subsequent magnetic resonance imaging and spectroscopy of the brain indicated mitochondrial disease, this diagnostic being also supported by so-called ragged blue filaments in a muscle biopsy. Approximately 9 days after the diagnosis of mitochondrial disease, darbepoetin alfa therapy was initiated. Over the next several weeks, the mitochondrial disease worsened; the subject experienced a fatal SAE of mitochondrial disease approximately 4 weeks after initiating darbepoetin alfa therapy. His last dose of darbepoetin alfa was 9 days before his death. The investigator reported there was not a reasonable possibility that the fatal mitochondrial disease was related to darbepoetin alfa treatment.

! Subject 211146017, a 15 month old male with a history of autosomal recessive polycystic kidney disease and bilateral nephrectomy on peritoneal dialysis, seizures, gastroenteritis, and repeated peritonitis, the subject developed immediately life threatening ileum necrosis approximately 10 months after initiating darbepoetin alfa therapy. Fifteen days later, the subject experienced a fatal SAE/EMI of gastrointestinal necrosis. Further information was not provided. The investigator reported that there was a not reasonable possibility that the fatal gastrointestinal necrosis was related to darbepoetin alfa.


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Events of Medical Interest (EMI)The EMIs predefined for this study were thromboembolic or cardiovascular events, seizures, severe hypertension, PRCA, and hypersensitivity reactions. Events of medical interest that were considered serious by the investigator were considered as both an EMI and an SAE; EMIs that were considered related to darbepoetin alfa were considered as both an EMI and an ADR; EMIs that were considered both related and serious were reported in the summaries of events of interest, SAEs, ADRs, and SADRs; and non-serious, non-related events of medical interest were reported only as EMIs.

The EMIs reported for this study are provided in Table 2. The most common EMIs were severe hypertension and seizures. No events of PRCA were reported.

EMIs by age subgroup and baseline dialysis status are also provided in Table 2. This table includes all EMIs reported per subgroup. Subjects in the 2 youngest age subgroups (< 1 year and 1-< 6 years) had higher point estimates for overall exposure adjusted event rates (per 100 person-years) than subjects in the 2 older groups (6 - < 12 years and ≥ 12 years), however the confidence intervals for all of the age subgroups overlapped. Subjects receiving dialysis at baseline had higher overall exposure adjusted event rates relative to those not receiving dialysis at baseline, including higher rates for severe hypertension and seizures.

Table 2. Events of Medical Interest(Full Analysis Set and Subgroups)


Number of subjectsreporting event

Number of eventsreported

Exposure AdjustedEvent Rateper 100 Person-years(95% CI)

All subjectsEvents of Medical Interest – Overall 39 82 19.24 (15.30, 23.88)

Severe Hypertension 21 34 7.98 (5.52, 11.15)Seizures 14 24 5.63 (3.61, 8.38)Thromboembolic/cardiovascular events

12 21 4.93 (3.05, 7.53)

Hypersensitivity reactions 3 3 0.70 (0.15, 2.06)PRCA - - -

Age Subgroup< 1 year of age

Events of Medical Interest-Overall 2 5 32.39 (10.52, 75.58)Severe Hypertension 1 1 6.48 (0.16, 36.09)Seizures 1 4 25.91 (7.06, 66.34)Thromboembolic/cardiovascular events

- - -

Hypersensitivity reactions - - -PRCA - - -

Page 1 of 2CI = confidence interval; PRCA = pure red cell aplasia.

Events of medical interest defined for this study were thromboembolic or cardiovascular events, seizures, severe hypertension, PRCA, and hypersensitivity reactions.

Source: Table 14-3.7.1 to Table 14-3.7.7


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Table 2. Events of Medical Interest(Full Analysis Set and Subgroups)



event

Number of events

reported



Age Subgroup (cont.)1 to < 6 years of age


4 9 8.39 (3.83, 15.92)


6 to < 12 years of ageEvents of Medical Interest-Overall 13 20 15.69 (9.58, 24.23)


5 8 6.28 (2.71, 12.36)

Hypersensitivity reactions - - -PRCA - - -

≥ 12 years of ageEvents of Medical Interest-Overall 12 25 14.21 (9.20, 20.97)


3 4 2.27 (0.62, 5.82)


Baseline dialysis statusDialysis at baseline


8 14 7.80 (4.26, 13.08)


Not on dialysis at baselineEvents of Medical Interest-Overall 11 23 9.33 (5.91, 13.99)


4 7 2.84 (1.14, 5.85)


Page 2 of 2CI = confidence interval; PRCA = pure red cell aplasia.

Events of medical interest defined for this study were thromboembolic or cardiovascular events, seizures, severe hypertension, PRCA, and hypersensitivity reactions.

Source: Table 14-3.7.1 to Table 14-3.7.7


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Analysis of Secondary EndpointsNon-serious Adverse Drug Reactions (ADRs)Four (1.3%) subjects reported non-serious ADRs (Table 14�3.8.1), all for injection site pain.

! Subject 211137001, a 12 year old male, experienced injection site painapproximately 29 months after initiating darbepoetin alfa therapy; darbepoetin alfa treatment and study participation were discontinued on the same day.

! Subject 211191021, a 6 year old female, experienced injection site painapproximately 1 month after initiating darbepoetin alfa therapy; darbepoetin alfa treatment and study participation were discontinued on the same day.

! Subject 211111016, a 1 year old male, provided non-verbal cues that suggested a worsening of pain during administration of darbepoetin alfa approximately 7 months after initiating darbepoetin alfa therapy; darbepoetin alfa treatment and study participation were discontinued on the same day.

! Subject 211191008, a 10 year old female, experienced pain during administration of darbepoetin alfa approximately 2 months after initiating darbepoetin alfa therapy; darbepoetin alfa treatment and study participation were discontinued on the same day.

Injection site pain is a known ADR associated with the use of darbepoetin alfa and identified in the darbepoetin alfa core data sheet (CDS).


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Haemoglobin Concentration Over TimeAt baseline, the mean haemoglobin concentration was 11.1 g/dL. Mean haemoglobinconcentrations remained consistent throughout the duration of the study, ranging between 11.3 and 11.5 g/dL (Table 1��.1.1 and Figure 14-5.1.1).

Mean haemoglobin concentrations also remained constant when assessed by age subgroup (Figure 1 and Table 14-5.1.2).

Mean haemoglobin levels ranged between 10.9 g/dL and 11.5 g/dL for subjects receiving dialysis at baseline and between 11.2 g/dL and 11.7 g/dL for subjects not receiving dialysis at baseline (Table 14-5.1.3).

Figure 1. Mean (95% CI) Haemoglobin Level by 3-Monthly Intervals and Baseline Age Group

(Full Analysis Set)


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Table 3 summarises the proportion of subjects with at least 1 haemoglobin value< 9 g/dL, < 10 g/dL, 10 to ≤ 12 g/dL, > 12 g/dL, > 13 g/dL and > 14 g/dL at any time during the study and the cumulative time spent in each category. The majority (95.0%) of subjects had at least 1 haemoglobin value between 10 and 12 g/dL (inclusive) at some time during the study. The haemoglobin category with the highest cumulative time spent was the ≥ 10.0 to ≤ 12 g/dL category (37.92 weeks).

Table 3. Proportion of Subjects and Cumulative Time Spent Within EachHaemoglobin Category

(Full Analysis Set)

Haemoglobin category

Number of subjects with ≥ 1 Hbin Hb categorya

n (%)

Cumulative time spent inHb categoryb

mean (SE) weeks

< 9.0 g/dL 118 (37.0) 10.18 (1.27)

< 10.0 g/dL 210 (65.8) 17.36 (1.31)

≥ 10.0 - ≤ 12 g/dL 303 (95.0) 37.92 (1.52)

> 12 g/dL 248 (77.7) 27.43 (1.44)

> 13 g/dL 174 (54.5) 14.78 (1.10)

> 14 g/dL 82 (25.7) 8.27 (0.84)Page 1 of 1

Hb = haemoglobin; SE = standard error.a A subject is counted as having a specific Hb value for a timepoint if they have recorded at least one Hb

result within the timepoint. A subject is included in the denominator (Number of Subjects) if they have recorded any Hb results within the timepoint.

b Hb values are assumed to be stable between 2 consecutive assessments. For each change in category, the duration of previous category = start date of next category - start date of previous category, where the start date is the date of Hb value triggering the change of the category.

Source: Table 14-5.2.1.1, Table 14-5.2.2.1, Table 14-5.2.3.1, Table 14-5.2.4.1, Table 14-5.2.5.1,Table 14-5.2.6.1 and Table 14-5.3.1


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Darbepoetin Alfa Dose Over TimeAt baseline, the overall weight adjusted geometric mean darbepoetin alfa dose was 1.99 μg/kg/month (95% CI: 1.82, 2.18), with 2.89 μg/kg/month (2.43, 3.43) for the IV dose and 1.75 μg/kg/month (1.58, 1.93) for the subcutaneous (SC) dose(Table 14-4.2.1). The overall and SC darbepoetin alfa doses remained relatively consistent over the study period (1.44 μg/kg/month [1.22, 1.69] and 1.30 μg/kg/month [1.08, 1.57] at month 24, respectively) (Figure 2), whereas the IV dose decreased slightly over time (1.92 μg/kg/month [1.46, 2.53]).

Figure 2. Geometric Mean (95% CI) Weight Adjusted Darbepoetin Alfa Dose by Monthly Interval and Route of Administration

(Full Analysis Set)

Weight adjusted geometric mean monthly darbepoetin alfa doses remained consistent across the study for all age subgroups (Figure 3; Table 14-4.2.2 to Table 14-4.2.5), with slightly higher doses observed for the youngest 2 age groups (< 1 year and 1 - < 6 year).

For the baseline dialysis status subgroup, weight adjusted geometric mean monthly doses remained consistent over the study period, with the exception of a slight decrease in IV doses for subjects on dialysis at baseline (Figure 14-4.2.6 and Figure 14-4.2.7;Table 14-4.2.6 and Table 14-4.2.7). Weight adjusted geometric mean monthly doses were higher for subjects receiving dialysis at baseline compared with subjects not on dialysis at baseline.


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Figure 3. Geometric Mean (95% CI) Weight Adjusted Darbepoetin Alfa Dose by Monthly Interval and Baseline Age Subgroup

(Full Analysis Set)

Parathyroid hormone (PTH) over timePTH concentrations over time in 3-month intervals are summarised in Table 14-6.1.1. At baseline, the mean PTH concentration was 34.88 ρmol/ L (95% CI: 27.27, 42.49); the mean PTH concentration remained consistent over the study period.

Additional AnalysesBlood pressure

Systolic and diastolic blood pressure measures are summarised by 3-monthly intervals (Table 14-7.1.1 and Table 14-7.2.1). Over the study period, the median systolic blood pressure varied between 111 to 116 mmHg and the median diastolic blood pressure varied between 65 and 70 mmHg. The range of median systolic blood pressure was 87.5 to 111.5 mg Hg for the < 1 year group, 103.0 to 107.0 mg Hg for the 1- < 6 year group, 106.0 to 115.0 mg Hg for the 6- < 12 year group, and 118.5 to 123.0 mg Hg for the ≥ 12 year group (Table 14-7.1.2). The range of median diastolic blood pressure was 51.0 to 66.0 mg Hg for the < 1 year group, 62.0 to 67.5 mg Hg for the 1- < 6 year group, 65.0 to 70.5 mg Hg for the 6- < 12 year group, and 69.0 to 73.0 mg Hg for the ≥ 12 year group (Table 14-7.2.2).

Concomitant Medications

Among the selected concomitant medications, the most common medication classes were iron preparations (229 [71.8%] subjects), vitamin D and analogues(182 [57.1%] subjects) and agents acting on rennin angiotensin system(178 [55.8%] subjects) (Table 14-8.2.1).

Blood transfusions

The number of subjects receiving blood transfusions and the number of days on transfusion for all subjects and by subgroup are provided in Table 4. Across all groups,


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the majority of transfusions were of red blood cells (RBC). A greater percentage of subjects in the youngest 2 age subgroups received RBC transfusions relative to the older subgroups. A greater number of subjects who were on dialysis at baseline received RBC transfusions than subjects not on dialysis at baseline.

Table 4. Blood Transfusions by Blood Product Type(Full Analysis Set and Subgroups)

TransfusionRBC Plasma Platelets

n (%)

Days with tranfusion

s n (%)

Days with tranfusion

s n (%)Days with

tranfusionsAll subjects 48 (15.0) 115 3 (0.9) 13 2 (0.6) 2

Age subgroup< 1 year of age 3 (23.1) 4 0 (0.0) 0 0 (0.0) 01 to < 6 years of age 20 (24.1) 54 1 (1.2) 1 1 (1.2) 16 to < 12 years of age

12 (13.3) 31 2 (2.2) 12 1 (1.1) 1

≥ 12 years of age 13 (9.8) 26 0 (0.0) 0 0 (0.0) 0

Baseline dialysis status subgroupDialysis 32 (20.3) 67 3 (1.9) 13 2 (1.3) 2Not on dialysis 16 (10.0) 48 0 (0.0) 0 0 (0.0) 0

Page 1 of 1RBC = red blood cell.n is number of subjects receiving transfusion.

Percentages based on N.Source: Table 14-9.1.1, Table 14-9.1.2, and Table 14-9.1.3


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Hospitalisations

A total of 218 (68.3%) subjects were hospitalised during the study (Table 5), with a median duration per hospitalization of 16 days (interquartile range of 6 and 35 days). A greater percentage of subjects in the youngest 2 age subgroups were hospitalised with longer durations relative to subjects in the older subgroups. Hospitalisations were similar between the baseline dialysis status subgroups.

Table 5. Hospitalisations by Subgroup(Full Analysis Set and Subgroups)

Number of subjects

hospitalisedn (%)

Number of hospitalisations

during studyn

Cumulative duration(days) of

hospitalisationmedian (Q1, Q3)

All subjects 218 (68.3) 698 16.0 (6.0, 35.0)

Age subgroup< 1 year of age 11 (84.6) 32 23.0 (19.0, 61.0)1 to < 6 years of age 62 (74.7) 205 19.0 (8.0, 40.0)6 to < 12 years of age 54 (60.0) 184 13.0 (7.0, 37.0)≥ 12 years of age 91 (68.4) 277 15.0 (6.0, 28.0)

Baseline dialysis status subgroupDialysis 112 (70.9) 365 17.0 (7.0, 40.0)Not on dialysis 106 (66.3) 333 15.0 (5.0, 26.0)

Page 1 of 1RBC = red blood cell.n is number of subjects receiving transfusion.

Percentages based on N within each group.Source: Table 14-10.1.1, Table 14-10.1.2, and Table 14-10.1.3

Bias/Limitations:This study was designed as an observational registry study. Factors with the potential to bias the results of this study included:

! Missing values! Withdrawals! Concurrent use of other ESAs! Distribution of the interim analyses results

As this was an observational study, data were utilised as collected, with the exception of the start dates of adverse events, the start and end dates for darbepoetin alfa dose records, dialysis start dates, transplant dates, and graft removed dates. For these exceptions, imputation rules (provided in the SAP) were implemented to minimize the impact of missing data.

It was anticipated that approximately half the subjects enrolled would withdraw from study participation during the 2 year follow-up period as a result of receiving a renal transplant, as paediatric ESRD patients typically have a more rapid transition to renal transplantation than adult ESRD patients. A slightly lower percentage (37.7%) of subjects withdrew due to receiving a renal transplant than originally anticipated. The


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exposure-adjusted analyses for adverse events were conducted to account for early withdrawals.

The use of concomitant ESAs was not restricted in this study. Data regarding concomitant ESA use were collected and summarised.

Although interim analyses were conducted to summarize data for annual reporting, study conduct was not likely altered as data were not disseminated beyond submission to the EMA.

Conclusions:

! This prospective multi-centre, multi-national EU observational registry study was conducted to obtain long-term safety data on darbepoetin alfa for the treatment ofanaemia in paediatric subjects with CKD receiving and not receiving dialysis.

! A total of 319 subjects enrolled while receiving darbepoetin alfa therapy, including 13 subjects under 1 year of age, 83 subjects 1-< 6 years of age, 90 subjects 6-<12 years of age, and 133 subjects ≥12 years of age. At study entry, 158 (49.5%) subjects were receiving dialysis.

! For the primary endpoints (occurrence of SADRs, SAEs, and EMIs), the following were reported:

o SADRs: Among the 9 SADRs reported by 4 subjects in this study, the events of hemolysis, hemolytic anemia, thrombocytopenia, partial blindness, and priapism are not listed as adverse reactions in the current darbepoetin alfa CDS. The case that included hemolysis, hemolytic anemia, and thrombocytopenia is complicated by a limited diagnostic work-up, lack of consultation by a hematologist, simultaneous discontinuation of darbepoetin alfa and ‘other unspecified medications’, and a negative rechallenge with darbepoetin alfa. In the event of blindness, the patient experienced HUS, which is known to be associated with blindness, and this diagnosis occurred prior to initiation of darbepoetin alfa therapy. In the case of priapism, the subject had a medical history of nephrotic syndrome which is known to be associated with priapism. Each of these cases was confounded by insufficient information or the subject’s underlying condition. These events do not, therefore, change the safety profile of darbepoetin alfa. The event of thrombosis and thromboembolism areconsistent with the current CDS, where they are listed as ADRs.

o SAEs: 434 events were reported by 162 subjects, of which the most common were peritonitis (all in subjects receiving peritoneal dialysis), gastroenteritis, and hypertension. With the exclusion of the SADRs discussed above, all other SAEs were reported by the investigator as not related to darbepoetin alfa treatment.� Fatal SAEs: None of the 6 fatal events were considered related to

darbepoetin alfa by the investigator. Among these events, sepsis, gastrointestinal necrosis, pulmonary oedema, and mitochondrial disease are not listed as adverse reactions in the current darbepoetin alfa CDS. For the cases of sepsis and gastrointestinal necrosis, the information provided is too limited for a meaningful assessment of the cause of these events. One case of pulmonary oedema was complicated by underlying renal disease, fluid retention with electrolyte abnormalities resulting


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from a viral infection, and multi-organ failure. The second case of pulmonary oedema was complicated by the subject’s underlying disease, withdrawal of peritoneal dialysis, and discontinuation of darbepoetin alfa therapy approximately 2 weeks prior to the event. The event of severe hypertension, although listed as an ADR in the current CDS, was complicated by the subject’s underlying condition, including a history of hypertension. Based on the assessment of these events, there is no change in the safety profile of darbepoetin alfa.

o EMIs: The EMIs predefined for this study are comprised of ADRs previously identified for darbepoetin alfa. Eighty-two events were reported by 39 subjects, of which the most common were severe hypertension and seizures. As the EMIs predefined for this study are comprised of ADRs previously identified for darbepoetin alfa, the occurrence of these events is consistent with the safety profile of darbepoetin alfa.

! Although the primary endpoint events include adverse events not currently listed in the CDS, the cases were confounded by the lack of sufficient information or the subjects’ underlying conditions and the evidence provided by these cases does not suggest a causal association with darbepoetin alfa. These findings indicate that the safety profile for darbepoetin alfa in this paediatric population was consistent with the known safety profile for darbepoetin alfa; no new safety signals were identified.

! Mean haemoglobin concentrations and mean weight-adjusted darbepoetin doses remained relatively constant over the study period for the entire study population and within all age subgroups.

! In conclusion, this analysis did not identify any safety issues not already reflected in the CDS, and the pharmacodynamics of darbepoetin alfa appears stable in this population when estimated by haemoglobin concentrations and weight-adjusted darbepoetin alfa dose over time.

Reference ListCollett, D. (2003) Modelling Survival Data in Medical Research, 2nd ed., Chapman & Hall/CRC, USA, pp.17-19.


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csr published - original - aranesp - synopsis... · of darbepoetin alfa in eu paediatric chronic...

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