Anemia, Renal Insufficiency, Chronic
Conditions
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.
Interventions
DRUGMircera
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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 17 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric participants 3 months to 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 participants on peritoneal dialysis (PD): a weekly Kt/V≥ 1.8 * For participants on hemodialysis (HD): adequate HD, urea reduction ratio (URR) \> 65% or Kt/V \> 1.2 for participants on HD three times per week. Participants 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.
Exclusion criteria
* 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) * 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 * Severe hyperparathyroidism (intact parathyroid hormone \[PTH\]≥ 1000 pg/mL or whole PTH≥ 500 pg/mL) or biopsy-proven bone marrow fibrosis * Kidney transplant with use of immunosuppressive therapies known to exacerbate anemia * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin (Hb) Concentration Between the Baseline and the Evaluation Period for Each Patient | Baseline up to Week 21 | The Hb change from baseline was calculated on a per-participant basis using an individual's average for both the baseline and evaluation periods and taking the difference. The baseline period was defined as the time between the day of first study dose and the previous 35 days. The evaluation period was defined as the period between Week 17 and Week 21, inclusive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Hb Values and Change From Baseline | Baseline, Weeks 3, 5, 9, 13, 17, 19, 21, 25, 29, 33, 37, 41, 45 | The mean Hb concentration over time and the mean change in Hb from baseline over time are presented. |
| Change in Mircera Dose Over Time | Week 1 to Week 17 | A dose change was defined as a change in the administered dose strength compared to the preceding dose. |
| Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL | Week 17 up to Week 21 | Number of participants with an average Hb concentration during the evaluation period within ± 1 g/dL of their baseline Hb is reported as well as the number of participants with an average Hb concentration above, within or below the range of 10-12 g/dL. The evaluation period was defined as the period between Week 17 and Week 21 inclusive. |
| Number of Participants With Adverse Events by Severity as Assessed by Highest World Health Organization (WHO) Toxicity Grade | Baseline up to Week 45 | An adverse event is 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 existing disease (a worsening in the character, frequency, or severity of a known condition), recurrence of an intermittent medical condition or any deterioration in a laboratory value or other clinical test. |
| Bioavailability (F) of Mircera in Pediatric Participants Based on Population PK Model | Pre-dose at Week 1, 9, 17; Post-dose at Week 3, Week 19 and additional sample taken between 24 hours and 5 days at participant's convenience | Bioavailability (F) is defined as the percentage of the administered drug, that reaches the systemic circulation. A population PK model was developed for Mircera that adequately describes pediatric data: a 1-compartment model with first order absorption and elimination processes. The bioavailability (F) was estimated using all the data points listed under time frame using the population PK model. |
| Ratio of Mircera Starting Dose (Week 1) to the Dose at Week 17 | Week 1, Week 17 | The ratio of Mircera dose was calculated as the median (min-max) ratio of starting dose (Week 1) to the dose at Week 17. Participants who withdrew before Week 17 or who were not administered a Mircera dose at Week 17 visit due to the applicable dose adjustment rules were excluded from the ratio computation. |
Countries
France, Hungary, Italy, Lithuania, Poland, Spain, United States
Participant flow
Recruitment details
The core study was 23 weeks and consisted of three periods: screening (3 weeks), dose titration (16 weeks) and evaluation (4 weeks). Participants completing the 20 weeks of treatment with hemoglobin (Hb) within +/- 1g/dL of their baseline and within the target range of 10-12 g/dL were eligible to enter an optional 24-week safety extension period.
Pre-assignment details
A total of 40 pediatric participants (ages 3 months to 17 years) with a diagnosis of anemia due to chronic kidney disease (CKD) who may or may not have been on dialysis at the time of study start were switched from stable subcutaneous (SC) maintenance treatment with epoetin alfa/beta or darbepoetin to methoxy polyethylene glycol-epoetin beta (Mircera).
Participants by arm
| Arm | Count |
|---|---|
| Mircera Mircera was administered subcutaneously once every 4 weeks. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Core Period | Kidney Transplant | 1 |
| Core Period | Prohibited Medication | 1 |
| Safety Extension Period | Kidney Transplant | 4 |
Baseline characteristics
| Characteristic | Mircera |
|---|---|
| Age, Continuous | 10.32 years STANDARD_DEVIATION 5.69 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 40 |
| other Total, other adverse events | 28 / 40 |
| serious Total, serious adverse events | 13 / 40 |
Outcome results
Primary
Change in Hemoglobin (Hb) Concentration Between the Baseline and the Evaluation Period for Each Patient
The Hb change from baseline was calculated on a per-participant basis using an individual's average for both the baseline and evaluation periods and taking the difference. The baseline period was defined as the time between the day of first study dose and the previous 35 days. The evaluation period was defined as the period between Week 17 and Week 21, inclusive.
Time frame: Baseline up to Week 21
Population: ITT population included all participants enrolled in the study. Number analyzed is the number of participants with Hb concentration assessment at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Change in Hemoglobin (Hb) Concentration Between the Baseline and the Evaluation Period for Each Patient | Baseline | 11.05 grams/deciliter (g/dL) | Standard Deviation 0.51 |
| Mircera | Change in Hemoglobin (Hb) Concentration Between the Baseline and the Evaluation Period for Each Patient | Change at Evaluation Period | 0.48 grams/deciliter (g/dL) | Standard Deviation 1.03 |
Secondary
Bioavailability (F) of Mircera in Pediatric Participants Based on Population PK Model
Bioavailability (F) is defined as the percentage of the administered drug, that reaches the systemic circulation. A population PK model was developed for Mircera that adequately describes pediatric data: a 1-compartment model with first order absorption and elimination processes. The bioavailability (F) was estimated using all the data points listed under time frame using the population PK model.
Time frame: Pre-dose at Week 1, 9, 17; Post-dose at Week 3, Week 19 and additional sample taken between 24 hours and 5 days at participant's convenience
Population: PK population included all participants enrolled in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mircera | Bioavailability (F) of Mircera in Pediatric Participants Based on Population PK Model | 67 percentage |
Secondary
Change in Mircera Dose Over Time
A dose change was defined as a change in the administered dose strength compared to the preceding dose.
Time frame: Week 1 to Week 17
Population: Safety population included all participants who received at least one dose of study drug regardless of whether they withdrew prematurely or not. Number analyzed signifies number of participants evaluable at specified time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Mircera | Change in Mircera Dose Over Time | Week 1 | 75.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Change at Week 5 | 0.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Week 9 | 50.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Week 5 | 75.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Change at Week 9 | 0.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Week 13 | 50.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Change at Week 13 | -25.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Week 17 | 50.00 micrograms (µg) |
| Mircera | Change in Mircera Dose Over Time | Change at Week 17 | -20.00 micrograms (µg) |
Secondary
Mean Hb Values and Change From Baseline
The mean Hb concentration over time and the mean change in Hb from baseline over time are presented.
Time frame: Baseline, Weeks 3, 5, 9, 13, 17, 19, 21, 25, 29, 33, 37, 41, 45
Population: ITT population included all participants enrolled in the study. Number analyzed signifies number of participants evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mircera | Mean Hb Values and Change From Baseline | Week 17 | 11.46 g/dL | Standard Deviation 1.33 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 17 | 0.42 g/dL | Standard Deviation 1.39 |
| Mircera | Mean Hb Values and Change From Baseline | Week 37 | 11.04 g/dL | Standard Deviation 0.77 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 37 | -0.03 g/dL | Standard Deviation 0.9 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 45 | -0.35 g/dL | Standard Deviation 1.13 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 33 | 0.02 g/dL | Standard Deviation 1.24 |
| Mircera | Mean Hb Values and Change From Baseline | Baseline | 11.02 g/dL | Standard Deviation 0.53 |
| Mircera | Mean Hb Values and Change From Baseline | Week 3 | 11.69 g/dL | Standard Deviation 0.97 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 3 | 0.67 g/dL | Standard Deviation 0.74 |
| Mircera | Mean Hb Values and Change From Baseline | Week 5 | 11.21 g/dL | Standard Deviation 1.02 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 5 | 0.19 g/dL | Standard Deviation 0.94 |
| Mircera | Mean Hb Values and Change From Baseline | Week 9 | 11.68 g/dL | Standard Deviation 1.42 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 9 | 0.64 g/dL | Standard Deviation 1.21 |
| Mircera | Mean Hb Values and Change From Baseline | Week 13 | 11.56 g/dL | Standard Deviation 1.17 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 13 | 0.51 g/dL | Standard Deviation 1.1 |
| Mircera | Mean Hb Values and Change From Baseline | Week 19 | 11.81 g/dL | Standard Deviation 1.11 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 19 | 0.77 g/dL | Standard Deviation 1.14 |
| Mircera | Mean Hb Values and Change From Baseline | Week 21 | 11.10 g/dL | Standard Deviation 0.91 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 21 | 0.05 g/dL | Standard Deviation 0.99 |
| Mircera | Mean Hb Values and Change From Baseline | Week 25 | 11.29 g/dL | Standard Deviation 1.04 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 25 | 0.21 g/dL | Standard Deviation 1.12 |
| Mircera | Mean Hb Values and Change From Baseline | Week 29 | 11.22 g/dL | Standard Deviation 1.18 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 29 | 0.15 g/dL | Standard Deviation 1.11 |
| Mircera | Mean Hb Values and Change From Baseline | Week 33 | 11.09 g/dL | Standard Deviation 1.11 |
| Mircera | Mean Hb Values and Change From Baseline | Week 41 | 10.83 g/dL | Standard Deviation 0.83 |
| Mircera | Mean Hb Values and Change From Baseline | Change at Week 41 | -0.22 g/dL | Standard Deviation 1.03 |
| Mircera | Mean Hb Values and Change From Baseline | Week 45 | 10.68 g/dL | Standard Deviation 1.02 |
Secondary
Number of Participants With Adverse Events by Severity as Assessed by Highest World Health Organization (WHO) Toxicity Grade
An adverse event is 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 existing disease (a worsening in the character, frequency, or severity of a known condition), recurrence of an intermittent medical condition or any deterioration in a laboratory value or other clinical test.
Time frame: Baseline up to Week 45
Population: Safety population included all participants who received at least one dose of study drug regardless of whether they withdrew prematurely or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mircera | Number of Participants With Adverse Events by Severity as Assessed by Highest World Health Organization (WHO) Toxicity Grade | Grade 1-2 | 25 participants |
| Mircera | Number of Participants With Adverse Events by Severity as Assessed by Highest World Health Organization (WHO) Toxicity Grade | Grade 3-4 | 8 participants |
Secondary
Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL
Number of participants with an average Hb concentration during the evaluation period within ± 1 g/dL of their baseline Hb is reported as well as the number of participants with an average Hb concentration above, within or below the range of 10-12 g/dL. The evaluation period was defined as the period between Week 17 and Week 21 inclusive.
Time frame: Week 17 up to Week 21
Population: ITT population included all participants enrolled in the study. Hb values within 21 days after blood transfusion(s) were excluded from analysis. Number analyzed is the number of participants with Hb concentration assessment at specified time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mircera | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL | Hb Above 1 g/dL of Baseline | 15 participants |
| Mircera | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL | Hb Maintained Within ± 1 g/dL of Baseline | 19 participants |
| Mircera | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL | Hb Below 1 g/dL of Baseline | 4 participants |
| Mircera | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL | Hb Above 12 g/dL | 12 participants |
| Mircera | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL | Hb Maintained Within 10-12 g/dL | 24 participants |
| Mircera | Number of Participants With an Average Hb Concentration During the Evaluation Period Within ± 1 g/dL of Their Baseline Hb and Above, Within or Below the Range of 10-12 g/dL | Hb Below 10 g/dL | 2 participants |
Secondary
Ratio of Mircera Starting Dose (Week 1) to the Dose at Week 17
The ratio of Mircera dose was calculated as the median (min-max) ratio of starting dose (Week 1) to the dose at Week 17. Participants who withdrew before Week 17 or who were not administered a Mircera dose at Week 17 visit due to the applicable dose adjustment rules were excluded from the ratio computation.
Time frame: Week 1, Week 17
Population: Participants who received a dose of study drug on Week 1 and Week 17 were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Mircera | Ratio of Mircera Starting Dose (Week 1) to the Dose at Week 17 | 1.44 ratio |